Ace844

This can make a big difference in treatability, as Dialysis pt's are notoriously difficult to get large bore or even small bore patent Iv lines in. Was this your point? No line, no fluid, etc...? ALso another follow up questin for ya. Does your systemt allow you to access the shunt? If not, did the pt still have the dialysis cath in when they hemmorraged? ACE844

Here's a great review article on this for all who are interetsed. HTH, ACE844 (Noninvasive Pco2 Monitoring for Respiratory Depression in the Nonintubated Patient By Nancy G. Murphy @ MD, and Neal L. Benowitz, MD) Arterial blood gas measurement of CO2 remains the gold standard for measuring the adequacy of ventilation, most commonly in the context of general anesthesia or critical illness in intubated (mechanically ventilated) patients. However, in these patients, as well as in nonintubated patients undergoing sedation, noninvasive measurements of CO2 have gained considerable importance in the last several years. The increasing frequency of procedural sedation, outpatient surgical and other painful procedures, and advanced pre hospital care, as well as the recognition that invasive monitoring has limitations, all have made noninvasive monitoring an important potential consideration in medical care. This is particularly true in the pediatric population, in which noninvasive monitoring is much less traumatic than more invasive monitoring procedures, such as arterial blood gas measurement. This paper will describe the physiology of CO2, the available techniques for monitoring CO2, the interpretation of CO2 values, and the clinical settings in which this type of monitoring is currently being used. The main focus of this review will be on monitoring of nonintubated patients with therapeutic or iatrogenic drug-induced respiratory depression. Procedural sedation and analgesia is the prime example of this clinical scenario. Potent, rapidly acting IV medications are administered to patients requiring brief, painful procedures, such as fracture reductions, electrical cardioversion, incision and drainage of abscesses, or reduction of joint dislocations. These medications are given in successive boluses to achieve both analgesia and sedation, with the goal of maintaining protective airway reflexes and respiratory drive. Titrating these pharmacologic agents can be challenging. Noninvasive monitoring can provide continuous, dynamic information to alert the clinician to subclinical respiratory depression. Although respiratory depression from self-administered pharmacologic agents, including drugs of abuse, is beyond the scope of this review, many of the same general principles covered should also apply to CO2 monitoring in that context. Physiology The CO2 levels as measured clinically are a reflection of the balance between metabolism, circulation, and ventilation. Cellular metabolism results in CO2 production, which can be substantially increased during marked motor activity (seizures, shivering) or with fever. CO2 production diminishes during general anesthesia or hypothermia.1 Changes in circulation can affect the partial pressure of CO2, or Pco2. The alveolar CO2 may markedly diminish in the context of decreased systemic blood flow, such as in cardiac arrest, even when alveolar ventilation is maintained. This is the result of concomitantly reduced pulmonary blood flow, thus leading to a lower amount of CO2 that is delivered to the lungs and exhaled air. Pulmonary embolism is another cause of reduced pulmonary blood flow that may also lead to a lower alveolar Pco2, or Paco2. The poorly perfused but ventilated areas of the lung result in an increase in the arterial-to-alveolar (Paco2 -Paco2 ) gradient, which is normally about 5 mm Hg.2 With respect to ventilation, alveolar gas exchange can usually compensate for changes in CO2 production. In most clinical settings, CO2 production remains relatively constant, such that Paco2 is mainly a function of alveolar ventilation.1 In the context of drug-induced respiratory depression, as may be encountered in procedural sedation, alveolar ventilation is reduced by either a reduced respiratory rate, reduced tidal volume, or both. Thus, the Pco2 measurements will increase, indicating inadequate alveolar gas exchange. Noninvasive Monitoring Techniques Noninvasive CO2 monitoring provides continuous, dynamic information about the adequacy of ventilation in patients. Arterial blood gas measurements are invasive and, although very accurate, provide only intermittent information about alveolar gas exchange, even if an indwelling arterial line allows relatively frequent assessment. There are currently two main techniques for noninvasive Pco2 monitoring in the clinical setting: end-tidal and transcutaneous methods. End-tidal CO2 (ETCO2) is a reflection of mixed alveolar CO2 and can be assessed by either chemical reactions (colorimetry) or measurement of CO2 molecules. This latter technique provides both a waveform and an actual Pco2 value, whereas colorimetry provides a single indication of the presence or absence of CO2 in exhaled air through a change in pH, and thus a change in the color of the test paper.2 The test paper turns blue or purple if the exhaled air contains <0.5% CO2 , and yellow if there is >2 to 4% CO2 in the exhaled air. For values between 0.5% and 2 to 4%, the colors are dependent on the manufacturer and should be verified prior to interpretation. Colorimetric indicators are small devices that attach to the endotracheal tube and are removed and discarded after use. Colorimetry is most useful in the confirmation of endotracheal tube placement in the prehospital setting, and for intermittent verifications of the proper positioning of the endotracheal tube.3 Measurement of CO2 molecules can be done by infrared spectroscopy, mass spectrometry, Raman gas analysis, or photoacoustic spectrography. Infrared spectroscopy is the most commonly used method. The Paco2 should be measured within the endotracheal tube in intubated patients, either by mainstream (directly in the endotracheal tube) or sidestream (air drawn through tubing to an analyzer) analysis. In nonintubated patients, the measurement should take place near the nares or mouth. This is accomplished via an oral/nasal cannula, with or without a port for oxygen administration.1 The waveform generated by this method can provide important information on ventilatory patterns. The most common display mode on the monitor is Pco2 vs time. The respiratory cycle is defined in four phases, as shown in Figure 1. Phase I is exhaled CO2 from the large airways, when Pco2 is zero. Phase II is the transition between large airway and alveolar gas. Phase III, the alveolar plateau, is normally flat and the end of this phase corresponds to ETCO2. Phase IV is inspiration, when once again the Pco2 decreases to baseline. If the waveform is absent (flat line), this could indicate apnea, airway obstruction, or a problem with the monitor or ventilator connections. -------------------------------------------------------------------------------- Figure 1. Top, the respiratory cycle as displayed on a capnogram. The ETCO2 is measured at the end of phase III. Bottom, apnea as displayed on a capnogram, in which case CO2 is equal to zero. -------------------------------------------------------------------------------- Good correlation between ETCO2 values and arterial values has been documented in several studies in the context of pediatric seizures, general anesthesia, and ICU monitoring.4-9 Other studies involving patient populations with pulmonary disease or other significant medical conditions, however, have found a lack of correlation between these two methods.10,11 If there is a significant ventilation/ perfusion mismatch, or a decrease in pulmonary blood flow, ETCO2 measurements will be much lower than arterial Pco2 (underestimated the extent of hypercapnia) because of a lower amount of CO2 reaching the alveoli. In general, patients undergoing procedural sedation do not tend to have significant pulmonary disease, and thus ETCO2 measurements should be reliable for monitoring purposes. Transcutaneous CO2 (TcCO2) monitors measure tissue CO2 through a skin electrode by means of the electrochemical Stow-Severinghaus method of analysis. The electrode is heated to about 42 to 44 °C to cause local vasodilation and arterialization of the tissue. The electrode may be attached to the abdomen or, as in newer models, to the earlobe. Once the electrode is applied, the monitor requires approximately 10 to 15 min for calibration. To avoid thermal injury, the site of the electrode must be changed every 4 to 12 hours, depending on the model. Because the CO2 measurements are taken through the skin, they may be affected by edema, scarring, hypoperfusion, and use of vasopressors,5 although using an earlobe sensor may minimize these issues. TcCO2 monitoring has been studied in adult and pediatric patients under general anesthesia, in nonintubated adults, and in pediatric and newborn patients in the ICU.12-14 The studies on this method of noninvasive monitoring have demonstrated excellent correlation between TcCO2 and arterial Pco2, with a higher accuracy than ETCO2. Direct comparison of end-tidal vs transcutaneous CO2 monitoring reveals advantages and disadvantages for both methods, depending on the clinical situation (Table 1). As previously mentioned, ETCO2 is a reflection of mixed alveolar gas and can become inaccurate if there is a ventilation/perfusion mismatch caused by abnormal pulmonary function. In addition, dramatically reduced systemic blood flow, as seen in cardiac arrest or systemic shock, can cause a significant decrease in ETCO2 and a widening of the ETCO2 -Paco2 gradient.15,16 In contrast, TcCO2 maintains its accuracy in the presence of pulmonary pathology, but can also be affected by hypoperfusion, abnormal skin conditions, and use of vasopressor agents. In addition, there is a lag time between changes in ventilation and reflection of these changes by TcCO2 of 1 min to several minutes,13 making ETCO2 more useful if sudden changes in ventilation are expected. Thus, there is no suitable substitute for ETCO2 monitoring in the setting of apnea, confirmation of endotracheal tube placement, or a disconnection of the ventilator to the patient, as the change in ETCO2 is reflected rapidly and is represented visually by a major change in the waveform.2 Another potential disadvantage of TcCO2 is the time needed to calibrate and equilibrate the monitor, the more regular maintenance required (changing the electrode membrane, replacing the calibration gas canister), and the potential for cutaneous thermal injury. However, when ETCO2 monitoring is not feasible, TcCO2 can play a crucial role. For example, measuring ETCO2 during bronchoscopy, thoracoscopy, or noninvasive positive pressure ventilation is difficult.12,13 In addition, TcCO2 monitoring in newborns is more convenient, more accurate, and better tolerated than ETCO2. When the accuracy of Pco2 measurements is of critical importance —such as in monitoring diabetic ketoacidosis or in head-injured patients with increased intracranial pressure—TcCO2 may also prove to be advantageous.7,17,18 In the setting of procedural sedation, only ETCO2 has been studied and therefore a direct comparison of the two methods cannot be made. -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- Procedural Sedation and Noninvasive Pco2 Monitoring Brief, painful procedures in the emergency department and ICU are commonly performed and require rapidly acting, potent sedatives and analgesics. Most of the medications used have the potential to cause respiratory depression. In particular, IV administration of propofol, opioids, methohexital, benzodiazepines (in combination with other medications), ketamine, and etomidate may result in subclinical or overt respiratory depression, as detected by hypercapnia, absent waveform, or hypoxia.19-24 Respiratory depression in this setting is defined as a change from baseline CO2 of >10 mm Hg, ETCO2 >50 mm Hg, or oxygen desaturation of <90% for at least 1 min. Capnography is superior to pulse oximetry in detecting subclinical respiratory depression, especially if supplemental oxygen is administered. As a result, capnography might alert the physician to hold off on further doses of sedatives, or to provide airway interventions as needed.25 The methods for performing procedural sedation have evolved considerably in the last decade, with development of specific protocols to ensure patient safety. The rate of adverse events during procedural sedation is relatively low in the hands of skilled, experienced health-care providers following an established protocol. Nonetheless, such complications do occur, including respiratory depression, hypotension, vomiting, laryngospasm, and rarely, pulmonary aspiration.26 Moroever, an ever-expanding variety of sedative agents also introduces opportunities for medical misadventure. Capnography provides additional information beyond that provided by standard cardiorespiratory monitoring that could further decrease the rate of adverse events. Interpretation of Pco2 Measurements Arterial Pco2 values are normally in the range of 35 to 45 mm Hg. ETCO2 tends to underestimate the Paco2 by 3 to 5 mm Hg, whereas TcCO2 tends to overestimate Paco2 by 2 to 4 mm Hg. There is no known interference between carbon monoxide and infrared spectroscopic measurement of ETCO2 , as is the case with pulse oximetry.27 An important concept is the arterial-to-alveolar gradient, which can change in certain disease states. This gradient has been well described and is normally about 5 mm Hg. The gradient has been used not only to describe the accuracy of ETCO2 compared with arterial blood gas measurements under normal conditions, but also to diagnose and monitor the treatment of pulmonary embolism.28 Hypercapnia is the major concern during procedural sedation in the nonintubated patient for all of the reasons stated previously. ETCO2 is inversely proportional to minute ventilation. When medications that depress respiratory drive are administered, respiratory rate and tidal volume may decrease, resulting in alveolar hypoventilation and an increase in the ETCO2. According to standard procedural sedation monitoring protocols, respiratory depression is defined as a change in ETCO2 from baseline of >10 mm Hg, any reading of >50 mm Hg, or apnea, as reflected by the absence of a waveform. As was noted previously, hypocapnia can occur during hypothermic states, under general anesthesia, in states of decreased pulmonary blood flow (pulmonary embolism), and in shock states (ie, cardiac arrest). In this context, ETCO2 has been used as a predictor of outcome in cardiac arrest and response to cardiopulmonary resuscitation (CPR). It has been shown that patients undergoing CPR for cardiac arrest have a poorer prognosis when the ETCO2 does not increase from <10 mm Hg compared with patients whose ETCO2 values increase closer to normal during CPR.15,16 In addition, ETCO2 has been shown to reflect the response to thrombolytic therapy in severe pulmonary embolism by increasing closer to normal values as pulmonary blood flow improves.27 Noninvasive CO2 monitoring of diabetic ketoacidosis has recently been investigated as well. Hypocapnia exists in this setting as a result of hyperventilation in response to a primary metabolic acidosis, and capnography has been shown to correlate well with serum bicarbonate values. Noninvasive CO2 monitoring in this setting may limit the need for frequent measurement of acid-base status and can also provide continuous, rather than intermittent, monitoring of the acid-base status.17,18 Conclusion Noninvasive CO2 measurement is evolving and is likely to become an integral technique for respiratory monitoring in the nonintubated patient undergoing procedural sedation. Understanding the limitations as well as the advantages of this technique will ensure appropriate interpretation of the CO2 values clinically. In addition, both end-tidal and transcutaneous CO2 monitoring can provide noninvasive and continuous clinical information for patients with metabolic, pulmonary, and circulatory disease. -------------------------------------------------------------------------------- References Moon RE, Camporesi EM. Respiratory monitoring. In: RD Miller, ed. Miller’s anesthesia. 6th ed. Philadelphia, PA: Elsevier/Churchill Livingstone, 2005; 1437–1481 Ahrens T, Sona C. Capnography application in acute and critical care. AACN Clin Issues 2003; 14:123–132 Bhende MS, LaCovey DC. End-tidal carbon dioxide monitoring in the prehospital setting. Prehosp Emerg Care 2001; 5:208–213 Reid CW, Martineau RJ, Miller DR, et al. A comparison of transcutaneous, end-tidal and arterial measurements of carbon dioxide during general anesthesia. Can J Anesth 1992; 39:31–36 Berkenbosch JW, Lam J, Burd RS, et al. Noninvasive monitoring of carbon dioxide during mechanical ventilation in older children: end-tidal versus transcutaneous techniques. Anesth Analg 2001; 92:1427–1431 Phan CQ, Tremper KK, Lee SE, et al. Noninvasive monitoring of carbon dioxide: a comparison of the partial pressure of transcutaneous and end-tidal carbon dioxide with the partial pressure of arterial carbon dioxide. J Clin Monit 1987; 3:149–154 McBride DS Jr, Johnson JO, Tobias JD. Noninvasive carbon dioxide monitoring during neurosurgical procedures in adults: end-tidal versus transcutaneous techniques. South Med J 2002; 95:870–874 Nosovitch MA, Johnson JO, Tobias JD. Noninvasive intraoperative monitoring of carbon dioxide in children: endtidal versus transcutaneous techniques. Paediatr Anaesth 2002; 12:48–52 Abramo TJ, Wiebe RA, Scott S, et al. Noninvasive capnometry monitoring for respiratory status during pediatric seizures. Crit Care Med 1997; 25:1242–1246 Prause G, Hetz H, Lauda P, et al. A comparison of the end-tidal CO2 documented by capnometry and the arterial Pco2 in emergency patients. Resuscitation 1997; 35:145–148 Sanders MH, Kern NB, Costantino JP, et al. Accuracy of end-tidal and transcutaneous Pco2 monitoring during sleep. Chest 1994; 106:472–483 Chhajed PN, Kaegi B, Rajasekaran R, et al. Detection of hypoventilation during thoracoscopy. Chest 2005; 127:585–588 Janssens JP, Howarth-Frey C, Chevrolet JC, et al. Transcutaneous Pco2 to monitor noninvasive mechanical ventilation in adults. Chest 1998; 113:768–773 Bernet-Buettiker V, Frey B, Hug MI, et al. Evaluation of a new combined transcutaneous measurement of Pco2/pulse oximetry oxygen saturation ear sensor in newborn patients. Pediatrics 2005; 115:e64–e68 Grmec S, Lah K, Tusek-Bunc K. Difference in end-tidal CO2 between asphyxia cardiac arrest and ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest in the prehospital setting. Crit Care 2003; 7:R139–R144 Grmec S, Klemen P. Does the end-tidal carbon dioxide (ETCO2) concentration have prognostic value during out-of-hospital cardiac arrest? J Emerg Med 2001; 8:263–269 Garcia E, Abramo TJ, Okada P, et al. Capnometry for noninvasive continuous monitoring of metabolic status in pediatric diabetic ketoacidosis. Crit Care Med 2003; 31:2539–2543 McBride ME, Berkenbosch JW, Tobias JD. Transcutaneous carbon dioxide monitoring during diabetic ketoacidosis in children and adolescents. Paediatr Anaesth 2004; 14:167–171 Miner JR, Heegaard W, Plummer D. End-tidal carbon dioxide monitoring during procedural sedation. Acad Emerg Med 2002; 9:275–280 Tobias JD. End-tidal carbon dioxide monitoring during sedation with a combination of midazolam and ketamine for children undergoing painful, invasive procedures. Pediatr Emerg Care 1999; 15:173–175 Hart LS, Berns SD, Houck CS, et al. The value of end-tidal CO2 monitoring when comparing three methods of conscious sedation for children undergoing painful procedures in the emergency department. Pediatr Emerg Care 1997; 13:189–193 Vinson DR, Bradbury DR. Etomidate for procedural sedation in emergency medicine. Ann Emerg Med 2002; 39:592–598 Miner JR, Martel ML, Meyer M, et al. Procedural sedation of critically ill patients in the emergency department. Acad Emerg Med 2005; 12:124–128 Bassett KE, Anderson JL, Pribble CG, et al. Propofol for procedural sedation in children in the emergency department. Ann Emerg Med 2003; 42:773–782 Yildizdas D, Yapicioglu H, Yilmaz HL. The value of capnography during procedural sedation or sedation/analgesia in pediatric minor procedures. Pediatr Emerg Care 2004; 20:162–165 Roback MG, Bajaj L, Wathen JE, et al. Preprocedural fasting and adverse events in procedural sedation and analgesia in a pediatric emergency department: are they related? Ann Emerg Med 2004; 44:454–459 Petroianu G, Maleck W, Bergler W, et al. Carbon monoxide and nonquantitative carbon dioxide detection. Prehospital Disaster Med 1996; 11:276–279 Wiegand UKH, Kurowski V, Giannitsis E, et al. Effectiveness of end-tidal carbon dioxide tension for monitoring of thrombolytic therapy in acute pulmonary embolism. Crit Care Med 2000; 28:3588–3592

I already mentioned most of my management, but I also have another question for you. Because this is a new graft does the pt still have a triple lumen central line in place, if so where, and is it patent? ACE844

(American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 171-177 @ (2006) © 2006 American Thoracic Society doi: 10.1164/rccm.200509-1507OC -------------------------------------------------------------------------------- Original Article Noninvasive Ventilation Improves Preoxygenation before Intubation of Hypoxic Patients Christophe Baillard, Jean-Philippe Fosse, Mustapha Sebbane, Gérald Chanques, Francçois Vincent, Patricia Courouble, Yves Cohen, Jean-Jacques Eledjam, Frédéric Adnet and Samir Jaber Department of Anesthesiology and Intensive Care, and SAMU 93, Avicenne Hospital, Paris 13 University–AP-HP, Bobigny; Intensive Care Unit, Department of Anesthesiology, DAR B University Hospital of Montpellier, and Saint Eloi Hospital, Montpellier University, Montpellier, France Correspondence and requests for reprints should be addressed to Dr. Samir Jaber, M.D., Ph.D., Intensive Care Unit, Department of Anesthesiology, DAR B CHU de Montpellier, Hôpital Saint Eloi, 80 avenue Augustin Fliche, 34295 Montpellier Cedex 5, France. E-mail: s-jaber@chu-montpellier.fr) Rationale: Critically ill patients are predisposed to oxyhemoglobin desaturation during intubation. Objectives: To find out whether noninvasive ventilation (NIV), as a preoxygenation method, is more effective at reducing arterial oxyhemoglobin desaturation than usual preoxygenation during orotracheal intubation in hypoxemic, critically ill patients. Methods: Prospective randomized study performed in two surgical/medical intensive care units (ICUs). Preoxygenation was performed, before a rapid sequence intubation, for a 3-min period using a nonrebreather bag-valve mask (control group) or pressure support ventilation delivered by an ICU ventilator through a face mask (NIV group) according to the randomization. Measurements and Main Results: The control (n = 26) and NIV (n = 27) groups were similar in terms of age, disease severity, diagnosis at admission, and pulse oxymetry values (SpO2) before preoxygenation. At the end of preoxygenation, SpO2 was higher in the NIV group as compared with the control group (98 ± 2 vs. 93 ± 6%, p < 0.001). During the intubation procedure, the lower SpO2 values were observed in the control group (81 ± 15 vs. 93 ± 8%, p < 0.001). Twelve (46%) patients in the control group and two (7%) in the NIV group had an SpO2 below 80% (p < 0.01). Five minutes after intubation, SpO2 values were still better in the NIV group as compared with the control group (98 ± 2 vs. 94 ± 6%, p < 0.01). Regurgitations (n = 3; 6%) and new infiltrates on post-procedure chest X ray (n = 4; 8%) were observed with no significant difference between groups. Conclusion: For the intubation of hypoxemic patients, preoxygenation using NIV is more effective at reducing arterial oxyhemoglobin desaturation than the usual method. Key Words: continuous positive airway pressure • intubation • preoxygenation In the intensive care unit (ICU), respiratory failure is a common problem. Airway management in critically ill patients usually requires orotracheal intubation. Complications associated with this procedure are more frequently encountered in this setting than in scheduled surgery in the operating room (1, 2). Approximately 10 to 30% of rapid sequence intubations are associated with transient oxyhemoglobin desaturation (SpO2 < 90%) (3–5). Moreover, profound oxyhemoglobin desaturation (SpO2 < 70%) is encountered in 2% of such procedures (4) and these desaturations have been shown to increase mortality in specific populations (5, 6). Usual preoxygenation ( 3 min of normal tidal volume ventilation with bag and mask with 100% O2) is recommended and effective in delaying arterial desaturation during the apnea related to endotracheal intubation (ETI) procedures (7, 8). Under optimal circumstances and in healthy patients, preoxygenation, by maximizing denitrogenation, prevents arterial desaturation during ETI and reduces the need for subsequent oxygen support. However, emergency intubation in critically ill patients occurs in quite different circumstances. During apnea, the time course of oxyhemoglobin desaturation to below 85% is only 23 s in a typical critically ill postoperative patient, whereas it is 502 s in a healthy adult (9). Also, Adnet and colleagues (1) have shown that, in emergency conditions, both the difficulty and the time necessary to complete intubation are increased as compared with a scheduled procedure. More recently, it has been shown that usual preoxygenation appeared marginally effective in critically ill patients (10). As a result, there is a need to optimize the technique of preoxygenation to prolong the safe duration of apnea during the intubation procedure in critically ill patients. Within the ICU, noninvasive ventilation (NIV) is widely used because it can reduce the need for intubation in selected populations (11–14). About 30 to 40% of patients are under NIV when the medical decision to initiate invasive ventilation is made (14–18). It has been shown that continuous positive airway pressure (CPAP) is effective in increasing the efficiency of gas exchange and in reducing the decrease in oxyhemoglobin saturation during fiberoptic bronchoscopy in hypoxemic patients (19). Some authors (8, 15, 20) have suggested the potential benefit of positive-pressure ventilation by CPAP for preoxygenating patients before intubation. To date, no study has evaluated using NIV in the pressure support mode (PSV) with positive end-expiratory pressure (PEEP) as a preoxygenation method in critically ill patients. Therefore, our aim was to ascertain whether NIV, as a preoxygenation method, is more effective at reducing arterial oxyhemoglobin desaturation than usual preoxygenation in hypoxemic, critically ill patients requiring tracheal intubation for invasive ventilation in the ICU. Some of the results of these studies have been previously reported in the form of abstracts (21, 22). METHODS TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES The study design was approved by the local ethics committee (Comité de Protection des Personnes dans la Recherche Biomédicale), and informed consent was obtained from the patient or from the patient's next of kin or legal representative. Because of the emergency conditions, delayed consent from patients or family was authorized. The investigators generated a random-number table on a computer, used the table to prepare envelopes for random patient allocation, and enrolled the patients. The envelopes were opaque, sealed, and numbered to ensure concealment and sequential use. Study Population Adults patients were recruited in two medicosurgical ICUs of two French university hospitals and considered eligible if they met two criteria: (1) acute respiratory failure requiring intubation and (2) hypoxemia, defined by a PaO2 less than 100 mm Hg under a high FIO2 mask driven by 10 L/min oxygen. Encephalopathy or coma, cardiac resucitation, and hyperkaliemia (> 5.5 mEq/L) were the exclusion criteria. Intubation was performed after failure of either oxygen supplementation alone or noninvasive respiratory support. A patient who received an ineffective trial of NIV before enrollment into the study was removed from NIV and then again placed on face-mask oxygen before preoxygenation was again attempted. Study Design and Measurements The design of the study is shown in Figure 1 and is very similar to that used by Maitre and colleagues (19). During the inclusion period (at least 10 min and maximum 30 min), the patients wore a high FIO2 mask, driven by 10 to 15 L/min oxygen, and were randomly assigned to a control or NIV group. Preoxygenation was then performed for a 3-min period before standardized rapid-sequence intubation. For the control group, preoxygenation was performed using a nonrebreather bag-valve mask driven by 15 L/min oxygen. Patients were allowed to breath spontaneously with occasional assistance (usual preoxygenation method). For the NIV group, PSV was delivered by an ICU ventilator (Evita IV ventilator; Dräger, Lübeck, Germany; or Servo 300; Siemens, Solna, Sweden) through a face mask (Airvie; Péters, Bobigny, France) adjusted to obtain an expired tidal volume of 7 to 10 ml/kg. The FIO2 was 100% and we used a PEEP level of 5 cm H2O. View larger version (19K): [in this window] [in a new window] Figure 1. Design of the study. During the inclusion period, the patients were randomized to a control or noninvasive ventilation (NIV) group. Clinical parameters were recorded and arterial blood gases (ABG 1) were sampled just (1–2 min) before preoxygenation. Preoxygenation was performed for a 3-min period. A second ABG measurement was performed (ABG 2), then the anesthetic drugs were administered and the trachea was intubated immediately after 60 s. After oral intubation, the patient was mechanically ventilated with usual settings and a third and fourth ABG measurement were performed (ABG 3 and ABG 4) at 5 and 30 min, respectively, after the intubation procedure. PEEP = positive end-expiratory pressure; RR = respiratory rate; TV = tidal volume. Standardized rapid-sequence intubation was performed by a senior physician (etomidate, 0.3 mg/kg; succinylcholine, 1 mg/kg; laryngoscopy with a Macintosh size 3 or 4 blade, and cricoid pressure to secure the airway). After oral intubation, the patient was mechanically ventilated, with a tidal volume of 8 to 10 ml/kg, a respiratory rate of 20 breaths/min, a PEEP of 5 cm H2O, and an FIO2 of 100%. Pulse oxymetry (SpO2) was continuously monitored throughout the procedure (Oxypleth 520A; Novametrix, Wallingford, CT). Arterial blood gases were sampled just before (1–2 min) and after preoxygenation and 5 and 30 min after intubation, and analyzed using an ABL 520 analyzer (Radiometer, Copenhagen, Denmark). The intubation conditions were reported using the intubation difficulty scale (1). Adverse events were defined as regurgitation (presence of gastric content seen during laryngoscopy), new infiltrate on post-ETI procedure chest X ray, and SpO2 less than 80% during the intubation procedure. Endpoints and Statistical Analysis The primary endpoint was the mean drop in SpO2 during ETI. We used data from the study performed by our group (15). In this study, in the hypoxemic patients, SpO2 during ETI was 82 ± 12%. We calculated that at least 25 patients would be required in each group to allow the detection of a 5% difference in the mean SpO2 during ETI, assuming an risk of 0.05 and a risk of 0.8. The secondary endpoints were PaO2 at 5 and 30 min after ETI. Nonparametric data were analyzed using Mann-Whitney U tests. For nominal data, we used 2 analysis or Fisher's exact test, as appropriate. Data are expressed as median values (with the interquartile range) or as means ± SD. All statistics were performed using SAS version 6.12 (SAS Institute, Cary, NC). p values of less than 0.05 were considered statistically significant. RESULTS TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES Characteristics of the Population before Preoxygenation Between October 2004 and February 2005, 78 patients needed orotracheal intubation (Figure 2). Twenty-one patients were intubated for reasons other than acute respiratory failure (e.g., neurologic causes, cardiac arrest). Consequently, 57 consecutive patients who fulfilled the study inclusion criteria were enrolled (none refused to participate). Four patients were not included for the analysis because of lack of exhaustive data (two patients in each group). Thus, 26 and 27 patients were evaluated in the control and NIV groups, respectively (Avicenne: control, n = 12; NIV, n = 12; Montpellier: control, n = 14; NIV, n = 15). The baseline characteristics of the two groups were similar in term of age, disease severity, organ failures, and diagnosis on admission (Table 1). Arterial blood gases and oxygen supply also did not differ between the two groups. Before inclusion, 15 and 16 patients in the control and NIV groups, respectively, had received at least one ineffective trial of NIV for first-line treatment of acute respiratory failure. There were no differences in patient characteristics between the Avicenne hospital (n = 24) and the Montpellier hospital (n = 29; data not shown). View larger version (16K): [in this window] [in a new window] Figure 2. Between October 2004 and February 2005, 78 patients needed orotracheal intubation. Twenty-one patients were intubated for reasons other than acute respiratory failure. Consequently, 57 consecutive patients who fulfilled the study inclusion criteria were enrolled. Four patients were not included for the analysis because of the lack of exhaustive data (two patients in each group). Thus, 26 and 27 patients were evaluated in the control and NIV groups, respectively. IDS = Intubation Difficulty Scale. View this table: [in this window] [in a new window] TABLE 1. CHARACTERISTICS OF STUDY PATIENTS BEFORE PREOXYGENATION Pulse Oxymetry and Arterial Blood Gas Monitoring Changes in mean SpO2 values during the entire procedure are shown in Figure 3. After preoxygenation, SpO2 increased in the control group from 90 ± 5% to 93 ± 6%, and in NIV group from 89 ± 6% to 98 ± 2% (p < 0.05). Preoxygenation did not improve SpO2 in six patients receiving the usual method, whereas SpO2 increased in all patients in the NIV group (p = 0.03). At the end of preoxygenation, SpO2 was statistically higher in the NIV group as compared with the control group (p < 0.05). During intubation, the difference between the two groups was more pronounced for minimal SpO2 values (93 ± 8% vs. 81 ± 15%, p < 0.001; Figure 3). Twelve patients in the control group and two in the NIV group had an SpO2 below 80% during ETI (p < 0.01; Figure 4). The minimal SpO2 values observed during ETI correlated with the SpO2 values obtained at the end of preoxygenation (p < 0.001; Figure 5). The difference in SpO2 values persisted 5 min after ETI (98 ± 2% vs. 94 ± 6%, p < 0.01). Thirty minutes after ETI, SpO2 was still higher in the NIV group but did not reach statistical significance (98 ± 3% vs. 97 ± 3%, p = 0.09). View larger version (8K): [in this window] [in a new window] Figure 3. Variation in mean SpO2 during preoxygenation and intubation (endotracheal intubation [ETI]). SpO2 is shown for the five steps of the study: (1) Before preoxygenation (i.e., baseline), when the patients are breathing with a mean of 13 L/min of O2 supply; (2) after 3 min of preoxygenation with either NIV or the usual method © according to the randomization (i.e., before ETI); (3) the minimal value during ETI; (4) 5 min after ETI; and (5) 30 min after ETI. Solid line: control © group; dotted line: NIV group. *p < 0.05, **p<0.01, comparison between the two groups at the same point. View larger version (7K): [in this window] [in a new window] Figure 4. Minimal SpO2 values recorded during ETI. Thick lines represent the lowest mean SpO2 values recorded in each group of patients. NIV (n = 27) and control (n = 26). View larger version (12K): [in this window] [in a new window] Figure 5. Correlation between the minimum SpO2 values during ETI and SpO2 values obtained at the end of preoxygenation (n = 53, r2 = 0.46; p < 0.001). Changes in mean PaO2 values are shown in Table 2. After preoxygenation, the increase in PaO2 was not significant in the control group (68 [60–79] vs. 97 [66–163] mm Hg, p = 0.08), whereas PaO2 increased significantly in the NIV group (60 [57–89] vs. 203 [116–276] mm Hg, p < 0.001). At the end of preoxygenation, PaO2 was statistically higher in the NIV group as compared with the control group (p = 0.01), and this difference persisted at 5 and 30 min after ETI (124 [70–183] vs. 160 [123–299] mm Hg, p = 0.03, and 137 [82–180] vs. 151 [144–247] mm Hg, respectively; p = 0.01). View this table: [in this window] [in a new window] TABLE 2. BLOOD GASES VALUES AFTER PREOXYGENATION, 5 AND 30 MINUTES AFTER ENDOTRACHEAL INTUBATION Preoxygenation and ETI Procedure Description The description of preoxygenation and ETI procedures is shown in Table 3. The mean level of PSV was 12 ± 2 cm H2O in the NIV group. Eight patients (31%) in the control group and one (4%) in the NIV group were unable to maintain SpO2 of more than 92% during the preoxygenation procedure (p = 0.02). In 12 patients (23%), two or three ETI attempts were needed, and the intervention of another skilled operator was required in six patients (11%), with no difference between groups (Table 3). Intubation difficulty scale results are shown in Table 3. Slight to major difficulties were observed in eight (31%) and nine patients (33%) in the control and NIV groups, respectively (p = 0.8). View this table: [in this window] [in a new window] TABLE 3. PREOXYGENATION AND ENDOTRACHEAL INTUBATION PROCEDURE DESCRIPTION ETI-related Complications and Outcome The incidence of ETI-related complications and outcome is reported in Table 4. Twelve patients (46%) in the control group and two (7%) in the NIV group had an SpO2 below 80% during ETI (p < 0.01; Figure 4). Regurgitation occurred in three patients (6%) and a new infiltrate on post-procedure chest X ray in four patients (7%), with no significant difference between groups (Table 4). Duration of mechanical ventilation, ICU length of stay, and ICU mortality were not different between groups. View this table: [in this window] [in a new window] TABLE 4. ENDOTRACHEAL INTUBATION–RELATED COMPLICATIONS AND OUTCOME DISCUSSION TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES The present study proposes for the first time preoxygenation using the NIV technique. The results have shown that this approach is safe and more effective in providing oxygenation and preventing arterial oxyhemoglobin desaturation than the usual method of preoxygenation during ETI in critically ill patients. We found that, despite similar baseline characteristics and oxygenation, NIV was more effective than the usual method in reducing the decrease in SpO2 and allowed enhancement of PaO2 up to 30 min after ETI. Preoxygenation in Critically Ill Patients Preoxygenation before intubation increases the maximum amount of time that a patient can tolerate the related apnea. In critically ill patients with oxygen transport limitations (2, 8, 19) and suspected time-consuming airway management, maximal preoxygenation is strongly indicated (2, 8, 20). In addition, when invasive ventilation is initiated to manage acute respiratory failure, the underlying lung disease (i.e., limited alveolar volume and enhanced shunt fraction) limits per se the efficiency of preoxygenation. As a result, hemoglobin desaturation is a well-known complication in this population (2, 4, 8, 20, 23, 24). In our study, the incidence of oxyhemoglobin desaturation below 80% was observed in 14 among 53 studied patients (Figure 4). In contrast with the NIV group, preoxygenation was ineffective in improving SpO2 in 6 of 26 patients receiving the usual method. This study confirms that preoxygenation does not always protect critically ill patients against hemoglobin desaturation during intubation. NIV Technique NIV has been proposed for several applications in the ICU, such as for avoiding endotracheal intubation and facilitation of weaning and extubation. To our knowledge, the use of NIV in the preoxygenation procedure has never been described. There is no delay that would limit the use of NIV for the purpose of preoxygenation because the need for ventilator equipment is usually anticipated in hypoxemic patients. Interruption of preoxygenation with NIV due to intolerance of the technique was not required in this study. These results argue against a limitation of NIV, used as a preoxygenation method, in this population of patients. Critically ill patients are usually considered to have a full stomach. Positive-pressure ventilation may increase gastric air content and hence may promote pulmonary aspiration during an ETI procedure. The risk exists with an insufflation pressure of greater than 20 cm H2O, which can be easily obtained using manual ventilation (25, 26). In our present study, NIV was used in a pressure-limited mode, which allowed for precise control of the insufflation pressure (PSV + PEEP levels). None of the NIV group of patients received an insufflation pressure of more than 20 cm H2O. In addition, pulmonary aspiration of gastric contents during ETI is frequently encountered in this clinical setting (2). In our study, regurgitation was observed in three patients and new infiltrate was present on the chest radiograph obtained after intubation in four patients. NIV did not increase regurgitation or new infiltrates. NIV effect on oxygenation and outcome. In acute respiratory failure, similarly to invasive ventilation, NIV improves oxygenation by delivering high oxygen concentration, by unloading respiratory muscle, by recruiting alveoli, and by increasing lung volumes (10). Few data are available regarding the time necessary to improve oxygenation. In the study of Rasanen and colleagues (27) and in others (28, 29), CPAP rapidly (10 min) improved oxygenation in patients with cardiogenic pulmonary edema. In the present study, 3 min of NIV significantly increased PaO2 and SpO2 as compared with usual preoxygenation. This clinical study did not allow for monitoring end-tidal oxygen concentration (FEO2). Nevertheless, we postulate that the significant improvement in oxygenation observed after 3 min of preoxygenation using NIV was mainly attributable to the high delivered oxygen concentration and to the recruitment of collapsed alveoli. Thus, in hypoxemic patients in a supine position, NIV probably increased FRC by recruiting collapsed alveoli, thereby allowing for an increase in the reserves of oxygen held within the body. This hypothesis is supported by the fact that only two patients in the NIV group had an SpO2 lower than 80% during ETI compared with 12 patients in the control group (Figure 4). The beneficial effect on PaO2 was still observed 30 min after ETI in patients who received NIV during preoxygenation. One explanation could be the residual effect of NIV in recruiting alveoli and increasing lung volume before ETI (30). The design of this study did not allow us to determine whether the minimal alteration on SpO2 and gas exchange in the patients in the NIV group improves outcome. Further studies are needed to clarify the potential benefits of NIV as a preoxygenation method on morbidity/mortality. Monitoring Preoxygenation In this study, SpO2 values obtained after preoxygenation were correlated with the minimal SpO2 value during the ETI procedure. However, a high SpO2 value (i.e., above 98%) before ETI did not predict safe airway management (Figure 5). This implies that SpO2, as a preoxygenation monitoring, is required but is not totally sufficient to ensure adequate oxygenation during subsequent ETI. During preoxygenation, arterial hemoglobin saturation increases without relationship to total body oxygen stores (31). The limitations of pulse oxymetry monitoring in this setting have been reported previously (9, 31, 32). Study limitations. Because our study could not be blinded, we chose instead to minimize bias by distancing the investigators from making clinical decisions about the included patients. However, there were unavoidable circumstances in which study investigators were part of the primary clinician teams caring for study participants. Although characteristics were similar between the subgroup of patients receiving (n = 31) and not receiving (n = 22) at least one NIV trial before the inclusion period, this may have influenced the results. Also, the number of patients is small and the results are limited to the spectrum of causes of acute respiratory failure presented in this study. The study presents a novel approach to preoxygenation that has not been previously reported. However, it is uncertain that this approach will improve clinical outcomes, and additional studies are warranted to determine its role, technique for application, and impact on important clinical outcomes. Conclusions In critically ill patients, NIV applied during 3 min before ETI ensured better SpO2 and PaO2 values during tracheal intubation as compared with the usual preoxygenation method. In contrast to NIV, usual preoxygenation was unable to improve SpO2 in all the patients. Further studies are needed to confirm the benefits of NIV use for preoxygenation in selected patients as a new indication of NIV. FOOTNOTES Originally Published in Press as DOI: 10.1164/rccm.200509-1507OC on April 20, 2006 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form September 27, 2005; accepted in final form April 19, 2006 REFERENCES TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES Adnet F, Borron S, Racine S, Clemessy J, Fournier J, Plaisance P, Lapandry C. The Intubation Difficulty Scale (IDS): proposal and evaluation of a new score characterizing the complexity of endotracheal intubation. Anesthesiology 1997;87:1290–1297.[CrossRef][Medline] Schwartz DE, Matthay MA, Cohen NH. Death and other complications of emergency airway management in critically ill adults. Anesthesiology 1995;82:367–376.[CrossRef][Medline] Cantineau JP, Tazarourte K, Merckx P, Martin L, Reynaud P, Berson C, Bertrand C, Aussavy F, Lepresle E, Pentier C, et al. Tracheal intubation in prehospital resuscitation: importance of rapid-sequence induction anesthesia. Ann Fr Anesth Reanim 1997;16:878–884.[Medline] Mort T. Emergency tracheal intubation: complications associated with repeated laryngoscopic attempts. Anesth Analg 2004;99:607–613.[Abstract/Free Full Text] Davis D, Dunford J, Poste J, Ochs M, Holbrook T, Fortlage D, Size M, Kennedy F, Hoyt D. 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Noninvasive ventilation: state of the art. Am J Respir Crit Care Med 2001;163:540–577.[Free Full Text] Auriant I, Jallot A, Hervé P, Cerrina J, Le Roy Ladurie F, Lamet Fournier J, Lescot B, Parquin F. Noninvasive ventilation reduces mortality in acute respiratory failure following lung resection. Am J Respir Crit Care Med 2001;164:1231–1235.[Abstract/Free Full Text] Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A, Simonneau G, Benito S, Gasparetto A, Lemaire F, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995;333:817–822.[Abstract/Free Full Text] Carlucci A, Richard J-C, Wysocki M, Lepage E, Brochard L. Noninvasive versus conventional mechanical ventilation: an epidemiological survey. Am J Respir Crit Care Med 2001;163:874–880.[Abstract/Free Full Text] Jaber S, Amraoui J, Lefrant J, Arich C, Cohendy R, Landreau L, Calvet X, Capdevila X, Mahata A, Eledjam J. Clinical practice and risk factors for immediate complications of endotracheal intubation in intensive care unit: a prospective multicenter study. Crit Care Med (In press) Esteban A, Frutos-Vivar F, Ferguson N, Arabi Y, Apezteguía C, González M, Epstein S, Hill N, Nava S, Soares M, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 2004;350:2452–2460.[Abstract/Free Full Text] Antonelli M, Conti G, Moro ML, Esquinas A, Gonzalez-Diaz G, Confalonieri M, Pelaia P, Principi T, Gregoretti C, Beltrame F, et al. Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study. Intensive Care Med 2001;27:1718–1728.[CrossRef][Medline] Chanques G, Jaber S, Delay J, Lefrant J, Perrigault P, Eledjam J. Phoning study about postoperative practice and application of non-invasive ventilation. Ann Fr Anesth Reanim 2003;22:879–885.[CrossRef][Medline] Maitre B, Jaber S, Maggiore S, Bergot E, Richard J, Bakhtiari H, Housset B, Boussignac G, Brochard L. Continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic patients: a randomized double-blind study using a new device. Am J Respir Crit Care Med 2000;162:1063–1067.[Abstract/Free Full Text] Reynolds S, Heffner J. Airway management of the critically ill patient: rapid-sequence intubation. Chest 2005;127:1397–1412.[Abstract/Free Full Text] Baillard C, Fosse JP, Sebbane M, Chanques G, Vincent F, Courouble P, Cohen Y, Eledjam JJ, Adnet F, Jaber S. La ventilation non invasive (VNI) améliore les conditions de pré oxygénation précédant l'intubation pour insuffisance respiratoire aiguë (IRA) en réanimation: etude randomisée contrôlée. Réan Urg 2006;15(Suppl 1):SO40. Baillard C, Fosse JP, Sebbane M, Chanques G, Vincent F, Eledjam JJ, Adnet F, Jaber S. La ventilation non invasive (VNI) améliore les conditions d'intubation pour insuffisance respiratoire aiguë (IRA) en reanimation: etude randomisée contrôlée. Ann Fr Anesth Réanim 2005;24:R091. Auriant I, Reignier J, Pibarot M, Bachat S, Tenaillon A, Raphael J. Critical incidents related to invasive mechanical ventilation in the ICU: preliminary descriptive study. Intensive Care Med 2002;28:452–458.[CrossRef][Medline] Le Tacon S, Wolter P, Rusterholtz T, Harlay M, Gayol S, Sauder P, Jaeger A. Complications of difficult tracheal intubations in a critical care unit. Ann Fr Anesth Reanim 2000;19:719–724.[Medline] Vyas H, Milner A, Hopkin I. Face mask resuscitation: does it lead to gastric distension? Arch Dis Child 1983;58:373–375.[Abstract] Ho-Tai L, Devitt J, Noel A, O'Donnell M. Gas leak and gastric insufflation during controlled ventilation: face mask versus laryngeal mask airway. Can J Anaesth 1998;45:206–211.[Abstract/Free Full Text] Rasanen J, Heikkila J, Downs J, Nikki P, Vaisanen I, Viitanen A. Continuous positive airway pressure by face mask in acute cardiogenic pulmonary edema. Am J Cardiol 1985;55:296–300.[CrossRef][Medline] Delclaux C, L'Her E, Alberti C, Mancebo J, Abroug F, Conti G, Guerin C, Schortgen F, Lefort Y, Antonelli M, et al. Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial. JAMA 2000;284:2352–2360.[Abstract/Free Full Text] Masip J, Betbesé A, Páez J, Vecilla F, Cañizares R, Padró J, Paz M, de Otero J, Ballús J. Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema: a randomised trial. Lancet 2000;356:2126–2132.[CrossRef][Medline] Rusca M, Proietti S, Schnyder P, Frascarolo P, Hedenstierna G, Spahn DR, Magnusson L. Prevention of atelectasis formation during induction of general anesthesia. Anesth Analg 2003;97:1835–1839.[Abstract/Free Full Text] Campbell I, Beatty P. Monitoring preoxygenation. Br J Anaesth 1994;72:3–4.[Free Full Text] Keogh B. When pulse oximetry monitoring of the critically ill is not enough. Anesth Analg 2002;94:96–99.

Here's a great How to Article which if you are interested in doing research may help you get started... Hope This Helps, ACE844

It wasn't an attack but a reference to the NUMEROUS discussions we have had here about EMS treatment, efficacy, and definative care, etc... As a long time member here you have had the ability and even soemtimes participated in these, hence my comment. :roll: That was what the comment was referencing. I cannot control how you choose to interpret this, but I can further clarify and explain as I have just done...Lastly, this is a basic 'tenet' of medicine, something that should not be new to all but the most newest of 'rookies' and even then this should have been soemthing covered in their program. (BY that I mean that Dialysis pt's are by their nature unstable and sick pts, like I mentioned in my post) Out Here, ACE844

(Journal of Emergency Medicine Volume 31 @ Issue 1 , July 2006, Pages 65-68 doi:10.1016/j.jemermed.2005.08.012 Copyright © 2006 Elsevier Inc. All rights reserved. Selected topic: Toxicology Vasopressin treatment for cyclic antidepressant overdose James David Barry MD⁎, , David W. Durkovich DO† and Saralyn R. Williams MD‡ †Department of Emergency Medicine, Naval Medical Center, San Diego (NMCSD), San Diego, California ‡Department of Emergency Medicine, University of California, San Diego (UCSD), San Diego, California ⁎Department of Emergency Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas Received 1 June 2004; revised 14 April 2005; accepted 4 August 2005. Available online 22 June 2006) Abstract Due to neurotransmitter reuptake inhibition, peripheral alpha receptor blocking effects, and sodium channel blockade, severe cyclic antidepressant poisoning may lead to intractable hypotension. We report a case of severe amitriptyline toxicity, with hypotension unresponsive to direct alpha receptor agonists after pH manipulation, but improved with intravenous vasopressin. Vasopressin use in the setting of cyclic antidepressant toxicity has not been previously reported. Vasopressin may be a beneficial agent in the treatment of recalcitrant hypotension associated with poisoning or overdose. The anecdotal nature of this report must be emphasized and the use of vasopressin requires further research to define efficacy, dose, and potential side effects. Introduction Intractable hypotension may occur in the setting of many poisonings and overdoses. Direct acting alpha agonists may not consistently improve hypotension in the setting of severe poisonings. We report the beneficial use of intravenous (i.v.) vasopressin in a case of severe amitriptyline poisoning with hypotension unresponsive to direct α-receptor agonists and pH manipulation. To our knowledge, the use of vasopressin in the setting of cyclic antidepressant toxicity has not been previously reported. The mechanisms of vasopressin’s vasoconstrictive properties and its clinical uses are discussed. Case report A 56-year-old man was found unresponsive by paramedics, near an empty bottle of amitriptyline. Initial blood pressure was palpated at 80 mm Hg with a wide complex rhythm on the monitor. Therapy initiated by the paramedics included orotracheal intubation without sedation, one liter normal saline i.v. bolus, and 70 mEq sodium bicarbonate i.v. bolus. Enroute to the hospital the patient developed generalized tonic-clonic convulsions and received 5 mg of i.v. midazolam. In the Emergency Department (ED), the vital signs were a pulse of 105 beats/min, blood pressure of 48/23 mm Hg, respiratory rate of 20 breaths/min with bag-valve ventilation, and temperature of 36.3°C (97.4°F). Pulse oximetry revealed a saturation of 97% on the 100% FIO2 via the bag-valve ventilation. Review of his past medical history revealed that he was positive for the human immunodeficiency virus (HIV) and he had a history of alcoholism. Other medications found in a separate room included clonazepam, vicodin, trazodone, and buproprion. Physical examination revealed no response to painful stimuli, recurrent episodes of seizure activity, and was remarkable for 3-mm pupils that were unresponsive to light. Corneal reflexes were absent. An electrocardiogram (EKG) demonstrated a junctional rhythm with QRS and QTc intervals of 156 and 552 ms, respectively, and a pronounced R wave in lead aVR. Resuscitation in the ED included a total of 3 L of normal saline, 400 mEq (8 ampules) of i.v. sodium bicarbonate, 10 mg lorazepam i.v., and a norepinephrine infusion. Multiple attempts at placement of a nasogastric tube were unsuccessful, so gastric decontamination was postponed. Initial laboratory values revealed: sodium 143 mmol/L, potassium 3.6 mmol/L, chloride 108 mmol/L, bicarbonate 29 mmol/L, blood urea nitrogen 10 mg/dL, creatinine 1.2 mg/dL, glucose 76 mg/dL, aspartate aminotransferase 65 U/L, alkaline phosphatase 64 U/L, total bilirubin 0.4 mg/dL, creatinine phosphokinase103 U/L, magnesium 1.5 mg/dL, calcium 6.2 mg/dL, white blood cell count 4.9 K/cmm, hematocrit 36.8%, platelets 154 K/UL, plasma alcohol 125 mg/dL, salicylate < 1.0 mg/dL, acetaminophen 3.1 ug/mL. A urine immunoassay drug screen was positive for benzodiazepines as a class, opiates as a class, cyclic antidepressants as a class, and tetrahydrocannabinol. In the intensive care unit (ICU), hypotension persisted despite titration of norepinephrine to 20 μg/min (Figure 1). The patient’s blood pressure improved only transiently during convulsive activity. Bicarbonate therapy (infusion and boluses) was continued, but further alkalinization was limited by a serum pH of 7.64. A lidocaine infusion titrated to 3 mg/min resulted in no change in clinical status. Because a nasogastric tube could not be placed while the patient was in the ED, an esophagogastroduodenoscopy (EGD) was performed and revealed a Billroth II anastomosis with erythema of the gastric remnant. Fifty grams of activated charcoal were administered during the EGD procedure, 4 ½ h after presentation. (9K) Figure 1. MAP vs. vasopressin. Convulsions continued despite 48 mg of i.v. lorazepam and 5 mg of i.v. midazolam over 6 h. Severe persistent hypotension limited the administration of phenobarbital. A vasopressin infusion was started 5 h after arrival at 0.04 U/min and shortly thereafter i.v. phenobarbital was administered to control convulsions (total dose 2 g). The convulsions ceased and blood pressure improved over the next 3 h, allowing the norepinephrine infusion to be decreased. The initial hospital course was complicated by multiple episodes of wide complex tachycardia requiring cardioversion. Convulsions did not recur after phenobarbital loading and all vasopressor agents were weaned off by 35 h. The patient’s neurologic status gradually improved over the next 4 days. He was transferred from the ICU on hospital Day 5. He was discharged to the psychiatry service with no obvious neurologic sequelae on hospital Day 7. Discussion This case exemplifies the challenges in treating a severe cyclic antidepressant poisoning associated with wide complex dysrhythmias, recalcitrant hypotension, and persistent convulsions. In this patient, alkalemia (serum pH 7.64) limited further use of bicarbonate therapy. Hypertonic saline was considered, but not utilized because serum sodium was above 145 mEq/L after aggressive alkalinization. Lidocaine infusion failed to control dysrhythmias. Convulsions continued despite aggressive benzodiazepine therapy and barbiturate administration was limited by hypotension. Neuromuscular paralysis was considered, however, continuous electroencephalogram monitoring was not available. Hypotension was unresponsive to alkalinization, sodium loading, and high dose norepinephrine infusion. Glucagon was not considered. The etiology of the patient’s hypocalcemia was unclear, but serum alkalosis and ethanol ingestion are likely to have contributed. Vasopressin infusion was temporally related to an improvement in blood pressure and allowed completion of phenobarbital loading. In this way, the initiation of vasopressin coincided with the beginning of the patient’s stabilization. Vasopressin (AVP) is an endogenous hormone released from the posterior pituitary when water deprivation or other factors lead to increased plasma osmolality, hypovolemia, or hypotension (1). Vasopressin receptors are widely distributed throughout the body and mediate the vascular and other non-renal actions of this hormone. Unlike V2 receptors that stimulate adenylate cyclase in the renal collecting duct system, V1 receptors work through a G-protein with actions strikingly similar to those of α1-adrenergic receptors. The binding of AVP to the V1 receptor leads to Gq-protein mediated activation of membrane-bound phospholipases (2). The activation of these phospholipases leads to a number of cellular events, resulting in increased intracellular calcium concentrations (1 and 3). In the smooth muscle cells of blood vessels, increased intracellular concentrations of calcium are the stimulus for vasoconstriction. In addition to stimulating vasoconstriction, AVP also inhibits vasodilatory mechanisms that contribute to hypotension and vascular hyporeactivity (2, 4, 5, 6 and 7). Traditional inotropic agents and vasopressors (epinephrine, norepinephrine, dopamine, etc.) have diminished action in the setting of vasodilatory shock states (3, 4, 5, 6, 8, 9, 10, 11 and 12). Low-dose AVP infusions have resulted in significant increases in arterial blood pressure in these life-threatening hypotensive situations (2, 5, 6, 9, 11, 12 and 13). The dramatic response to AVP in these settings may be due to a relative AVP deficiency as suggested by documented low plasma concentrations (4, 6, 9, 11 and 14). Vasopressin also potentiates the vasoconstrictor effects of traditional inotropic agents such as norepinephrine (4, 5, 10 and 15). Although AVP has gained praise in the critical care setting for the treatment of severe hypotension, there is little data regarding its use in the poisoned patient. Clinical studies utilizing vasopressin for intractable hypotension have been relatively small and focused only on physiologic end points (2, 5, 11, 12, 14, 16, 17 and 18). Extensive study of its efficacy, side effects, and dose response has not been performed. Although small studies have found no detrimental effects on end-organ perfusion and function (2, 5, 12, 13, 14, 16 and 17), AVP administration carries the theoretical risks of deleterious end-organ vasoconstriction (2, 4 and 18), decreased myocardial contractility (5, 10, 11 and 17), and microcirculatory occlusion by AVP-induced platelet aggregation (4 and 19). The most advantageous dose of AVP is unclear at this time. Although most authors advocate “low dose” AVP infusions, the definition of “low dose” is variable, ranging from 0.01U/min to 0.1U/min (10, 11, 15, 16, 17 and 18). Some have hinted that doses > 0.04U/min may be associated with increased adverse events (4 and 15). Our case illustrates the use of vasopressin in the setting of severe intractable hypotension due to amitriptyline toxicity. Its use was temporally related to improvement in the patient’s blood pressure and may have played a role in the ultimate positive outcome in this case. Although amitriptyline poisoning was not confirmed with serum levels, the patient later admitted to an ingestion of an entire bottle of amitriptyline (actual number of pills unknown) and unknown quantities of alcohol in a suicide attempt. The history is consistent with the clinical course observed. Other vasoactive co-ingestants or medication effects (most notably propylene glycol from large doses of lorazepam administered) may have made less important contributions to his intractable hypotension. In addition to cyclic antidepressants, his urine drug screen was also positive for benzodiazepines and opiates consistent with his outpatient medications. Although the patient denied co-ingestants, ingestion of other medications or treatment medications could have contributed to the clinical presentation of intractable hypotension and convulsions. The institution of the vasopressin may have corresponded with the routine evolution of improvement seen in many patients with cyclic antidepressant poisoning. Vasopressin is a novel vasopressor agent that may be beneficial in the treatment of intractable hypotension in the poisoning patient. The anecdotal nature of this report must be emphasized and the administration of vasopressin requires further investigation to determine efficacy, proper dose, and potential side effects. References 1 E.K. Jackson, Vasopressin and other agents affecting the renal conservation of water. In: J.G. Hardman and L.E. Limbird, Editors, Goodman & Gillman’s the pharmacological basis of therapeutics (10th edn.), McGraw-Hill, New York (2000), pp. 789–808. 2 M.W. Dunser, J.A. Mayr and H. Ulmer et al., The effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock a retrospective analysis, Anesth Analg 93 (2001), pp. 7–13. Abstract-MEDLINE 3 R.A. Hessler, Cardiovascular principles. In: L.R. Goldfrank, N.E. Flomenbaum, N.A. Lewin, M.A. Howland, R.S. Hoffman and L.S. Nelson, Editors, Goldfrank’s toxicologic emergencies (7th edn.), Appleton & Lange, Stamford, CT (2002), pp. 315–334. 4 C.L. Holmes, B.M. Patel and J.A. Russel et al., Physiology of vasopressin relevant to management of septic shock, Chest 120 (2001), pp. 989–1002. Abstract-Elsevier BIOBASE | Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef 5 D.L. Morales, D. Gregg and D.N. Helman et al., Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock, Ann Thorac Surg 69 (2000), pp. 102–106. SummaryPlus | Full Text + Links | PDF (161 K) 6 D. Morales, J. Madigan and S. Cullinane, Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock, Circulation 100 (1999), pp. 226–229. Abstract-Elsevier BIOBASE | Abstract-EMBASE | Abstract-MEDLINE 7 D.W. Landry and J.A. Oliver, The pathogenesis of vasodilatory shock, N Engl J Med 345 (2001), pp. 588–595. Abstract-EMBASE | Abstract-Elsevier BIOBASE | Abstract-MEDLINE | Full Text via CrossRef 8 International Consensus on Science. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care, Circulation 102 (2000) (Suppl I), pp. I130–I131. 9 D.W. Landry, H.R. Levin and E.M. Gallant, Vasopressin deficiency contributes to the vasodilation of septic shock, Circulation 95 (1997), pp. 1122–1125. Abstract-MEDLINE 10 J.A. Gold, S. Cullinane and J. Chen et al., Vasopressin as an alternative to norepinephrine in the treatment of milrinone-induced hypotension, Crit Care Med 28 (2000), pp. 249–252. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef 11 M. Argenziano, A.F. Choudhri and M.C. Oz, A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement, Circulation 96 (1997) (Suppl II), pp. II286–II290. Abstract-EMBASE 12 E.B. Rosenzweig, T.J. Starc and J.M. Chen et al., Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery, Circulation 100 (1999) (Suppl II), pp. II182–II186. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE 13 M. Argenziano, J.M. Chen and S. Cullinane et al., Arginine vasopressin in the management of vasodilatory hypotension after cardiac transplantation, J Heart Lung Transplant 18 (1999), pp. 814–817. SummaryPlus | Full Text + Links | PDF (114 K) 14 J.M. Chen, S. Cullinane and T.B. Spanier et al., Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors, Circulation 100 (1999) (Suppl II), pp. II244–II246. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE 15 C.L. Holmes, K.R. Walley and D.R. Chittock et al., The effects of vasopressin on hemodynamics and renal function in severe septic shock a case series, Intensive Care Med 27 (2001), pp. 1416–1421. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef 16 B.M. Patel, D.R. Chittock and J.A. Russell et al., Beneficial effects of short-term vasopressin infusion during severe septic shock, Anesthesiology 96 (2002), pp. 576–582. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef 17 J. Gold, S. Cullinane and J. Chen et al., Vasopressin in the treatment of milrinone-induced hypotension in severe heart failure, Am J Cardiol 85 (2000), pp. 506–508. SummaryPlus | Full Text + Links | PDF (86 K) 18 I. Tsuneyoshi, H. Yamada and K. Yasuyuki et al., Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock, Crit Care Med 29 (2001), pp. 487–493. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef 19 R.J. Gazmuri and S.A. Shakeri, Low dose vasopressin for reversing vasodilation during septic shock, Crit Care Med 29 (2001), pp. 673–675. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef

(Journal of Emergency Medicine Volume 31 @ Issue 1 , July 2006, Pages 1-5 doi:10.1016/j.jemermed.2005.08.007 Copyright © 2006 Elsevier Inc. All rights reserved. Original contribution How well do paramedics predict admission to the hospital? A prospective study Saul D. Levine MD⁎, , Christopher B. Colwell MD⁎, Peter T. Pons MD⁎, Craig Gravitz EMT-P, RN†, Jason S. Haukoos MD, MS⁎ and Kevin E. McVaney MD⁎ †Paramedic Division, Denver Health Medical Center, Denver, Colorado ⁎Department of Emergency Medicine, Denver Health Medical Center, Denver, Colorado Received 2 July 2004; revised 4 April 2005; accepted 1 August 2005. Available online 22 June 2006.) Abstract A study was designed to determine whether paramedics accurately predict which patients will require admission to the hospital, and in those requiring admission, whether they will need a ward bed or intensive care unit (ICU) monitoring. This prospective, cross-sectional study of consecutive Emergency Medical Service (EMS) transport patients was conducted at an urban city hospital. Paramedics were asked to predict if the patient they were transporting would require admission to the hospital, and if so, whether that patient would be admitted to a ward bed or require an ICU bed. Predictions were compared to actual patient disposition. During the study period, 1349 patients were transported to our hospital. Questionnaires were submitted in 985 cases (73%) and complete data were available for 952 (97%) of these patients. Paramedics predicted 202 (22%) patients would be admitted to the hospital, of whom 124 (61%) would go the ward and 78 (39%) would require intensive care. The actual overall admission rate was 21%, although the sensitivity of predicting any admission was 62% with a positive prediction value (PPV) of 59%. Further, the paramedics were able to predict admission to intensive care with a sensitivity of 68% and PPV of 50%. It is concluded that paramedics have very limited ability to predict whether transported patients require admission and the level of required care. In our EMS system, the prehospital diversion policies should not be based solely on paramedic determination. Introduction The nationwide problem of Emergency Department (ED) and hospital overcrowding has brought the practice of ambulance diversion to the forefront. Diversion has grown increasingly complex and many hospitals now have numerous different categories of diversion, such as ED, intensive care unit (ICU), trauma, obstetric, pediatric ICU, ward, and psychiatric diversions. In order for a particular type of diversion category to be effectively acted upon, an implied assumption is made that when a hospital declares a diversion, the prehospital caregiver is able to accurately triage patients and predict the need for admission and level of care. Several studies have evaluated the role of prehospital providers in Emergency Medical Services (EMS) systems and the ability of paramedics to determine clinical diagnosis and prognosis (1). Some investigators have found EMS providers to be accurate in their ability to triage patients, whereas others have found accuracy rates to be unacceptable (2, 3, 4, 5, 6, 7, 8 and 9). A number of publications have raised the question of whether paramedics can safely predict if a patient needs transport at all (4, 10 and 11). If field personnel are able to accurately predict which patients will require admission, and particularly the need for intensive care, specific EMS diversion categories may be possible. The purpose of this study was to determine whether paramedics can accurately determine which patients will require admission to the hospital, and in those who are admitted, whether they will require admission to a ward bed or an ICU. Methods Denver Health Medical Center (DHMC) is an urban county hospital and level I trauma center that accepts both medical and trauma EMS transports. The annual ED census at DHMC is approximately 55,000. The overall admission rate from the ED is approximately 18% and, of those, approximately 25% are admitted to the operating room (OR) or ICU. The Denver Health and Hospital Authority is the agency contracted to provide 911 emergency medical service to the City and County of Denver using a two-tier system in which fire serves as the first basic life support tier and paramedics serve as the second advanced life support tier. The Denver Health Paramedic Division serves a population of approximately 550,000 based upon year 2000 census data with 136 paramedics, covering a geographical area of approximately 150 square miles. Paramedic Division ambulances respond to approximately 65,000 requests for emergency medical assistance annually and transport approximately 45,000 patients to Denver area hospitals. At the time of the study, Denver Health employed only Emergency Medical Technician (EMT) paramedics and not EMT basics. The average duration of paramedic experience at the time of the study was 7.4 years, with a range of 0.3 to 28 years. A prospective, cross-sectional study was performed that surveyed paramedics treating all EMS patients transported to DHMC from June 18 to July 18, 2001. All patients transported to DHMC were included in the study. Patients transported to other hospitals were excluded. The paramedic attending to the patient on each transport was asked to complete a standardized form upon arrival at the hospital. The forms were collected and stored in a locked data collection box in the ED. Data collected included the EMS trip number, a field diagnosis, and whether or not the paramedic believed the patient would be admitted. If the paramedic did predict admission, the further distinction of “ward” or “ICU” admission or “other” was made. Ward admission was defined as those patients admitted to any inpatient service including medicine, surgery, neurosurgery, orthopedics, obstetrics/gynecology, or psychiatry, and ICU admission was defined as those patients admitted to the medical, surgical, or coronary intensive care unit. Patients who were thought to require a bed with telemetry monitoring, but not intensive care unit monitoring, were classified as ward admissions. The category “other” included the morgue, the psychiatric emergency area, the obstetric screening room, or leaving against medical advice (AMA). For the purposes of the study, admission was defined as actual transfer to an in-hospital bed, not just the decision by the physician that the patient should be admitted. Data from the study form were entered into a Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, WA) for analysis. Sensitivities, specificities, positive predictive values (PPVs) and negative predictive values (NPVs) with 95% confidence intervals (CIs) were calculated using Stata Version 8 (Stata Corporation, College Station, TX). The study was approved by our Institutional Review Board and a waiver of informed consent was granted. Results According to computer-assisted dispatch records, 1349 patients were transported to DHMC during the 1-month study period. This accounted for 55% of all EMS transports performed in the City and County of Denver by the Paramedic Division during the same time period. Research forms were completed on 985 patients (73%) and complete data were available for 952 (97%) of these. Of the 952 patients, 533 (56%) were men and 847 (89%) were over the age of 17 years. Twenty patients (2%) who were triaged immediately upon arrival from the ED to the psychiatric emergency care area, the obstetric screening room, or were dead on arrival and sent to the morgue were excluded, leaving a total of 932 patients included in the final analysis. Paramedics predicted 202 (22%; 95% CI: 19%–25%) patients would require admission and 730 (78%; 95% CI: 76%–81%) would be discharged from the ED. Of the 202 patients expected to be admitted, 124 (61%) were felt to be candidates for admission to a ward bed and 78 (39%) were felt to require an ICU bed (Table 1). Table 1. Paramedic Predictions of Patient Disposition from the ED vs. the Actual Patient Disposition Actual disposition from ED (n) ICU admission Ward admission Discharge from ED Total Paramedic predictions of patient disposition from ED ICU admission 39 24 15 78 Ward admission 8 49 67 124 Discharge from ED 10 65 655 730 Total 57 138 737 932 ED = Emergency Department. Of 78 patients predicted to go to the ICU, 63 (81%; 95% CI: 70%–89%) were admitted to the hospital. However, only 39 (50%; 95% CI: 38%–62%) were actually admitted to the ICU, whereas 24 (31%; 95% CI: 21%–42%) went to a ward bed, and 15 (19%; 95% CI: 11%–31%) were discharged home. Of the 124 patients paramedics believed would be admitted to a ward bed, 67 (54%; 95% CI: 45%–63%) were discharged and 8 (7%; 95% CI: 3%–12%) were admitted to the ICU. Of the 730 patients paramedics felt would be discharged, 75 (10%; 95% CI: 8%–13%) were admitted, of whom 10 (13%; 95% CI: 7%–23%) were admitted to the ICU. The sensitivity, specificity, PPV, and NPV of the paramedics’ triage decisions for patient admission to the hospital (all admissions), ICU, and ward compared with actual outcomes are shown in Table 2, Table 3 and Table 4. Similarly, the sensitivity, specificity, PPV, and NPV of the paramedics’ triage decisions for patient admission to the hospital (all admissions) based upon the nature of the emergency (medical vs. trauma) are shown in Table 5 (29 patients were not included due to incomplete data needed to categorize the nature of their emergency). Analysis of the medical vs. trauma admission data was post hoc and not part of the original study design. Table 2. Paramedic Predictions for Admission to the Hospital (ICU plus Ward) vs. Actual Admission to the Hospital Actual disposition % (95% CI) Admission Discharge Total Sens. 62% (54–68) Paramedic predictions of disposition Admission 120 82 202 Spec. 89% (86–91) Discharge 75 655 730 PPV 59% (52–66) Total 195 737 932 NPV 90% (87–92) CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value. Table 3. Paramedic Predictions for Admission to the Intensive Care Unit vs. Actual Admission to the ICU Actual disposition % (95% CI) ICU admission Non-ICU admission Total Sens. 68% (55–80) Paramedic predictions of disposition ICU admission 39 39 78 Spec. 96% (94–97) Non-ICU admission 18 836 854 PPV 50% (39–62) Total 57 875 932 NPV 98% (97–99) CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value. Table 4. Paramedic Predictions for Admission to the Ward (Compared to All Other Outcomes: ICU Admission and Discharge from the ED) vs. Actual Admission to the Ward Actual disposition % (95% CI) Requires ward admission All other dispositions⁎ Total Sens. 36% (28–44) Paramedic predictions of disposition Requires ward admission 49 75 124 Spec. 91% (88–93) All other dispositions⁎ 89 719 808 PPV 40% (31–49) Total 138 794 932 NPV 89% (87–91) CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value. ⁎ Admit to ICU or discharge from ED. Table 5. Paramedic Predictions for Admission to the Hospital (ICU and Ward) vs. Actual Admission Stratified by Nature of the Admission (Medical or Trauma)⁎ Actual disposition % (95% CI) Requires admission† Discharge Total Medical Sens. 53% (43–62) Paramedic predictions of disposition Requires admission† 60 40 100 Spec. 86% (81–89) Discharge 54 236 290 PPV 60% (50–70) Total 114 276 390 NPV 81% (76–86) Trauma Sens. 71% (60–80) Paramedic predictions of disposition Requires admission† 61 41 102 Spec. 91% (88–93) Discharge 25 406 431 PPV 60% (50–69) Total 86 447 533 NPV 94% (92–96) CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value. ⁎ Twenty-nine patients were not included as there were insufficient data to categorize the nature of their emergency. † Admit to ICU or ward bed. Discussion The problem of ED overcrowding is well documented (12, 13, 14 and 15). One result of overcrowding is for hospitals to declare a diversion status in an effort to direct patients being transported by ambulance to other hospitals. This places a greater burden on EMS crews to determine which patients are appropriate for particular or specific hospitals. Some categories of hospital diversion appear straight forward (ED divert) whereas others are less well defined (ICU, ward, psychiatry, CT, etc.). Diversions also have been shown to increase transit times and distances traveled (8). Novel approaches to hospital diversion could be implemented if prehospital caregivers were capable of accurately categorizing patients in terms of level of needed care. Studying prehospital triage decisions has been problematic, however, due to patient variability and the lack of objective triage protocols. Richards and Ferrall demonstrated certain patient characteristics and chief complaints associated with increased admission rates, which potentially make hospital admission somewhat more predictable (4). These researchers attempted to evaluate paramedics in terms of their “gut feeling.” Our study also asked paramedics to subjectively triage patients. Hauswald found paramedics are unable to determine which patients do not need transport (10). Similar studies have also demonstrated a poor agreement between predicted triage and actual disposition or diagnosis (6, 7, 9 and 16). Other research, however, demonstrates excellent paramedic diagnostic accuracy by chief complaint or organ system (2 and 3). The paramedics in our study were asked to predict whether or not patients they were transporting to the ED required admission to the hospital and, if so, the level of required care at the hospital. This study demonstrates that paramedics have a modest ability to predict the need for admission to an ICU and limited ability to determine the need for admission to a non-ICU bed. Of note, the paramedics were somewhat better able to predict these bed needs for trauma patients when compared with non-trauma patients. Only half of the patients in our study with a paramedic anticipated ICU requirement ended up actually admitted to the intensive care unit. In addition, there were 10 patients the paramedic thought would be discharged home who were ultimately admitted to the ICU. There are several limitations to our study. Selection bias may have resulted because 27% of EMS transports to the hospital did not have a data collection form completed and because we did not capture EMS transports to other receiving hospitals. The decision to admit a patient is based upon numerous historical and clinical factors that are not routinely available to paramedics. In addition, the decision to admit is not one that paramedics routinely participate in or have formal training about, thus limiting their ability to make accurate predictions. Variable paramedic experience, particularly history of working in an ED, may have affected their ability to make an accurate admission prediction. Further bias, in the form of incorporation bias, may have resulted if paramedics discussed the cases with physicians, nurses or technicians in the ED, as well as their direct observation of continued care before the admission prediction card was submitted. We used the Emergency Physician’s decision (in conjunction with consultants in some cases) as the criterion standard to which the paramedic prediction was compared. Discrepancies in the patient’s disposition between different physicians or consultants may have also biased the results. Conclusion Based on our investigation, paramedics have limited ability to predict whether transported patients need admission to the hospital and, more specifically, whether they require intensive care or ward admission. This has important implications about the limitations of diversion strategies that rely on paramedic prediction, and whether prehospital diversion policies should be based on paramedic determination. Further work to develop, assess and utilize hospital diversion guidelines and categories as well as the ability of prehospital providers to accurately implement those categories is needed (17). References 1 K.W. Neely, M.E.R. Drake and J.C. Moorhead et al., Multiple options and unique pathways a new direction for EMS?, Ann Emerg Med 30 (1997), pp. 797–799. SummaryPlus | Full Text + Links | PDF (303 K) 2 J.J. Schaider, J.C. Riccio and R.J. Rydman et al., Paramedic diagnostic accuracy for patients complaining of chest pain or shortness of breath, Prehospital Disaster Med 10 (1995), pp. 245–250. Abstract-MEDLINE 3 R. Sahni, J.J. Meneqazzi and V.N. Mosesso Jr, Paramedic evaluation of clinical indicators of cervical spine injury, Prehosp Emerg Care 1 (1997), pp. 16–18. Abstract-MEDLINE 4 J.R. Richards and S.J. Ferrall, Triage ability of emergency medical services providers and patient disposition a prospective study, Prehospital Disaster Med 14 (1999), pp. 174–179. Abstract-MEDLINE 5 K. Qazi, J.A. Kempf and N.C. Christopher et al., Paramedic judgment of the need of trauma team activation for pediatric patients, Acad Emerg Med 5 (1998), pp. 1002–1007. Abstract-MEDLINE | Abstract-EMBASE 6 J.P. Santoro, P. Smith and T.J. Mader et al., Accuracy of field diagnosis by paramedics [abstract], Acad Emerg Med 5 (1998), p. 390. 7 S.M. Sasser, M. Brokaw and T.H. Blackwell, Paramedic vs. emergency physician decisions regarding the need for emergency department evaluation [abstract], Acad Emerg Med 5 (1998), p. 391. 8 K.W. Neely, R.L. Norton and G.P. Young, The effect of hospital resource unavailability and ambulance diversions on the EMS system, Prehospital Disaster Med 9 (1994), pp. 172–176. 9 J.E. Pointer, M.A. Levitt and J.C. Young et al., Can paramedics using guidelines accurately triage patients?, Ann Emerg Med 38 (2001), pp. 268–277. Abstract | PDF (99 K) 10 M. Hauswald, Can paramedics safely decide which patients do not need ambulance transport or emergency department care?, Prehosp Emerg Care 6 (2002), pp. 383–386. Abstract 11 S. Silvestri, S.G. Rothrock and D. Kennedy et al., Can paramedics accurately identify patients who do not require emergency department care?, Prehosp Emerg Care 6 (2002), pp. 387–390. Abstract 12 G.M. O’Brien, M.D. Stein and S. Zierler et al., Use of the ED as a regular source of care associated factors beyond lack of health care insurance, Ann Emerg Med 30 (1997), pp. 286–291. 13 R.A. Hayward, A.M. Bernard and H.E. Freeman et al., Regular source of ambulatory care and access to health services, Am J Public Health 81 (1991), pp. 434–438. Abstract-EMBASE | Abstract-MEDLINE 14 K. Grumbach, D. Keane and A. Bindman, Primary care and public emergency department overcrowding, Am J Public Health 83 (1993), pp. 372–378. Abstract-EMBASE | Abstract-MEDLINE 15 R.A. Lowe, G.P. Young and B. Reinke et al., Indigent health care in emergency medicine an academic perspective, Ann Emerg Med 20 (1991), pp. 790–794. Abstract 16 W.G. Baxt, C.C. Berry and M.D. Epperson et al., The failure of prehospital prediction rules to classify trauma patients accurately, Ann Emerg Med 18 (1989), pp. 1–8. Abstract 17 J.P. Campbell, V.A. Maxey and W.A. Watson, Hawthorne effect implications for prehospital research, Ann Intern Med 26 (1995), pp. 590–594. SummaryPlus | Full Text + Links | PDF (508 K) Original Contributions is coordinated by John Marx, md, of Carolinas Medical Center, Charlotte, North Carolina Reprint Address: Saul D. Levine, md, Department of Emergency Medicine, University of California, San Diego, 200 W. Arbor Drive, Box 8676, San Diego, CA 92103-8676

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(Journal of Emergency Medicine Volume 31 @ Issue 2 , August 2006, Pages 157-163 doi:10.1016/j.jemermed.2005.09.012 Copyright © 2006 Elsevier Inc. All rights reserved. Clinical communication Alcohol-related seizures Niels K. Rathlev MD⁎, , Andrew S. Ulrich MD⁎, Norman Delanty FRCPI† and Gail D’Onofrio MD, MS‡ †Department of Neurology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland ‡Section of Emergency Medicine, Yale University School of Medicine, New Haven, Connecticut ⁎Department of Emergency Medicine, Boston Medical Center and Boston, University School of Medicine, Boston, Massachusetts Received 17 April 2004; revised 29 April 2005; accepted 8 September 2005. Available online 20 July 2006) Abstract Alcohol-related seizures are defined as adult-onset seizures that occur in the setting of chronic alcohol dependence. Alcohol withdrawal is the cause of seizures in a subgroup of these patients; however, concurrent risk factors including pre-existing epilepsy, structural brain lesions, and the use of illicit drugs contribute to the development of seizures in many patients. New onset or a new pattern of alcohol-related seizures, e.g., focal seizures or status epilepticus, should prompt a thorough diagnostic evaluation. This is not indicated if patients have previously completed a comprehensive evaluation and the pattern of current seizures is consistent with past events. Treatment is initially directed at aggressively terminating current seizure activity. This should be followed by prevention of recurrent alcohol-related seizures and progression to status epilepticus during the ensuing 6-h high-risk period. Our purpose is to present recommendations for the diagnostic evaluation, treatment and disposition of these patients based on the current literature. Introduction Alcohol-related seizures represent a diverse spectrum of disease that presents in adults with chronic alcohol dependence. In more than 50% of cases they occur as a result of concurrent risk factors such as pre-existing epilepsy, structural brain lesions related to stroke or trauma, and the use of illicit drugs. Alcohol withdrawal seizures are caused by sudden abstinence and should be considered a diagnosis of exclusion once other risk factors have been considered and ruled out. The development of alcohol-related seizures is a major predictor of adverse health outcomes as the mortality rate of these patients is approximately fourfold that of the population at large. This is primarily due to complications of chronic alcoholism and delirium tremens rather than a direct result of seizures or status epilepticus (1). Based on the current literature, we present recommendations for the diagnostic evaluation, treatment and disposition of patients with alcohol-related seizures that present to the Emergency Department (ED). Clinical features Alcohol-related seizures are typically brief, generalized tonic-clonic seizures that occur 6 to 48 h after the last drink. Multiple seizures occur in approximately 60% of patients without treatment and the interval between the first and the last seizure is typically less than 6 h. Alcohol-related seizures frequently present in the absence of other signs of alcohol withdrawal and sympathomimetic stimulation such as tachycardia, fever and hypertension (2). They also occur in chronically alcohol-dependent patients with high blood alcohol concentrations that exceed the legal limit of intoxication. In some cases these levels would be highly intoxicating to non-dependent patients (3). This scenario is thought to be caused by a significant decline in the blood alcohol concentration from a customarily even higher level. Status epilepticus is an uncommon presentation of alcohol-related seizures accounting for less than 4% of cases (4). Conversely, alcohol withdrawal is responsible for 11% to 20% of all cases of status epilepticus; fortunately, seizures related to alcohol are generally associated with a favorable prognosis compared with other causes of status epilepticus (5). Focal brain lesions such as traumatic brain injury, stroke and intracranial mass lesions frequently cause partial rather than generalized seizures. Partial seizures recently have been reported to account for up to 51% of seizures in alcohol-dependent patients. The presence of both status epilepticus and partial seizures should prompt a careful evaluation for structural brain lesions and epilepsy (1). Diagnosis Approximately one-third of patients who are hospitalized for acute seizures report a recent history of heavy alcohol use (6). In spite of this, alcohol dependence is underestimated as a cause of generalized tonic-clonic seizures in adults, even when patients are evaluated by experienced clinicians. Twenty percent of patients who initially present with seizures of “unknown” etiology are retrospectively reclassified and diagnosed with alcohol-related seizures after evaluation of future convulsive episodes (7). Therefore, all patients presenting with seizures should be screened using a structured questionnaire for alcohol dependence when possible. The CAGE questionnaire is valuable as a practical instrument for identifying alcohol dependence in the ED setting, however, the role of this questionnaire in specifically diagnosing alcohol-related seizures has not been studied (8 and 9). Reliable serum markers for alcohol-related seizures have yet to be discovered. Significantly higher mean levels of plasma homocysteine and lower levels of folate have been found in alcohol-dependent patients who develop new-onset seizures compared with individuals without seizures (10). Larger and methodologically sound studies must confirm these results before plasma homocysteine and folate levels can be adopted as clinical predictors of seizures in alcohol dependent patients. Risk factors Alcohol withdrawal is an important risk factor in the genesis of alcohol-related seizures in a subgroup of patients, although its clinical relevance has been questioned by some investigators (11). Additional risk factors appear to lower the seizure threshold sufficiently to precipitate convulsive episodes in more than 50% of alcohol-dependent patients (12). Several authors have studied the prevalence of these risk factors that include: 1) idiopathic generalized epilepsy, 2) traumatic brain injury, stroke and intracranial mass lesions, 3) illicit drug use, and rarely, 4) alcohol-associated metabolic disorders (3, 12 and 13). The results of the most recent of these studies are listed in Table 1 (3). Table 1. Concurrent Risk Factors in 130 Patients with Alcohol-Related Seizures Etiology # Patients % of Total Alcohol withdrawal 55 42% Traumatic brain injury 36 28% Intracranial hemorrhage or contusion, depressed skull fracture, penetrating brain injury, > 30 min of unconsciousness or amnesia Idiopathic generalized epilepsy 22 17% Cerebrovascular accident 8 6% Non-traumatic intracranial lesions 5 4% Tumors, infection, gliosis Toxic/metabolic conditions 4 3% Cocaine abuse 2 Hypoglycemia (< 60 mg %) 1 Hypocalcemia (< 6.0 mEq/L) 1 Reprinted from Academic Emergency Medicine, 9(8); Etiology and Weekly Occurrence of Alcohol-Related Seizures, 824-828. Copyright 2002, with permission from Society of Academic Emergency Medicine. Alcohol Withdrawal The diagnosis of alcohol withdrawal seizures is made only after exclusion of other potential risk factors. They are categorized as acute symptomatic or situation-related seizures and occur in individuals who do not have epilepsy. Clinical and experimental observations suggest that partial or complete abstinence in chronically alcohol-dependent patients is a major prerequisite for seizures caused by alcohol withdrawal. Rathlev et al. and Hillbom separately reported an increased seizure frequency on Sundays and Mondays, 33% and 49.6%, respectively, following restricted access to alcohol on weekends (3 and 13). In contrast, Ng and associates concluded that seizures are the result of a direct toxic effect of rising levels of alcohol rather than withdrawal. Their conclusion must be viewed with skepticism because 84% of new-onset seizures in their series occurred during the “conventionally defined” withdrawal period, which is 6 to 48 h after the last drink (11). Idiopathic Generalized Epilepsy Idiopathic generalized epilepsy occurs on a genetic basis in otherwise normal individuals. Estimates are that the prevalence of epilepsy among alcoholics is at least three times that of the general population (14). Conversely, studies have correlated alcohol dependence with poor seizure control in patients with epilepsy (15). Several mechanisms have been suggested to explain this correlation, including a “stimulant” effect of alcohol, a withdrawal phenomenon, and decreased absorption and enhanced metabolism of antiepileptic drugs through hepatic enzyme induction. Altered sleep patterns and non-compliance with anticonvulsants may also contribute to poor seizure control. The pattern of epileptiform activity on electroencephalography has not been observed to differ between alcohol-dependent patients and controls in patients with epilepsy. Structural Central Nervous System Lesions Traumatic brain injury is associated with an increased risk of post-traumatic seizures depending on the severity of injury. Annegers et al. found that brain contusion associated with subdural hematoma is the strongest risk factor for post-traumatic seizures followed by skull fracture, age ≥ 65 years, and finally, loss of consciousness or amnesia for more than 1 day (16). Chronically alcohol-dependent individuals have an increased incidence of head trauma and susceptibility to brain injury as a result of falls, motor vehicle-related accidents, and assault (17). The incidence of cortical brain contusions is increased more than sixfold in patients with alcohol dependence compared to individuals without this affliction (18). Several studies indicate that alcohol-dependent patients are predisposed to cerebrovascular lesions such as intracerebral and subarachnoid hemorrhage due to coagulopathy. Moreover, heavy consumption of alcohol and binge drinking increase both systolic and diastolic blood pressure; the resulting hypertension and alcohol-induced vasospasm are significant contributors to lacunar stroke and cerebral hemorrhage (19, 20, 21 and 22). Atrial fibrillation related to withdrawal and alcohol-induced cardiomyopathy are also potent risk factors for thromboembolic stroke. The incidence of structural brain abnormalities in alcohol-dependent individuals with seizures far exceeds the rate in non-drinkers with epilepsy (23). A forensic autopsy study with neuropathology examination found structural brain lesions in 13 of 19 (68%) alcohol-dependent patients with recurrent seizures (18). Lesions potentially responsible for seizures included old cortical contusions in 11 (58%) cases and old cerebral infarcts in 2 (10%). The results suggest that structural brain lesions are underrepresented as a cause of seizures in clinical series that have studied the etiology of alcohol-related seizures (3 and 13). These series have reported an incidence of 36% to 40% of structural brain abnormalities related to trauma, stroke and non-traumatic mass lesions. Toxic-Metabolic Disorders Several Emergency Medicine studies note that patients with alcohol-related seizures rarely present with severe toxic-metabolic abnormalities that trigger the presenting seizure. Hypoglycemia is the most frequently encountered metabolic cause of seizures in general, however, it is found in less than 1% of adults who present to the ED with alcohol-related seizures (24 and 25). Alcohol substantially depletes liver glycogen, and chronically alcohol-dependent patients typically maintain poor nutritional support. Hyperventilation frequently accompanies alcohol withdrawal and the resultant respiratory alkalosis may produce hyperexcitability of the central nervous system and reduce the seizure threshold. Decreasing levels of magnesium and calcium during withdrawal also have been implicated as possible precipitants of seizures, however, measurably low serum levels of these cations are rarely found in the clinical setting (24 and 25). Illicit use of cocaine, heroin, phencyclidine or amphetamines is a potential cause of seizures (26 and 27). Intoxication with stimulant drugs has been documented as an increasingly frequent cause of seizures although still accounting for only 0.0025% of all seizure admissions (28). Another study described current cocaine use by 2 of 75 patients with concurrent risk factors other than alcohol withdrawal (3). Seizures also can be precipitated by withdrawal from a variety of drugs such as benzodiazepines, barbiturates and narcotics. Evaluation Laboratory Testing Patients presenting with new-onset alcohol-related seizures or a new pattern such as partial seizures or status epilepticus should undergo a thorough evaluation for concurrent risk factors. Although the recommendation is not supported by prospective evidence, it is likely that unsuspected risk factors will be discovered in many patients. The most important laboratory test is a serum glucose level based on the presented evidence. Rapid assessment of serum glucose is indicated initially in all patients with an altered mental status who present after a new-onset or recurrent alcohol-related seizure. However, it is unlikely to be low in patients with a normal mental status after a seizure, in part, because of hyperadrenergic stimulation. The results of blood, urine or saliva toxicology screens are important if illicit drug use or overdose is considered. Blood levels should be obtained if the patient is currently taking anti-epileptic drugs. There is no current evidence to support further laboratory testing in these patients, assuming that they do not present with additional acute medical problems and rapidly return to baseline mental status. Assuming that the pattern of the presenting seizures is consistent with past events, repetition of the recommended work-up is not required if patients have been previously diagnosed with alcohol-related seizures after a comprehensive evaluation. Computed Tomography Computed tomography (CT) scan of the brain should be performed on all alcohol-dependent patients with a new-onset or partial seizure, status epilepticus, a prolonged postictal state, or significant head trauma as previously described (16, 29 and 30). Fortunately, life-threatening structural lesions are very unlikely in the absence of these features. The presence of focal deficits on physical examination is not sensitive for intracranial lesions in patients with alcohol-related seizures. Earnest et al. obtained CT scans in 259 patients with a first generalized alcohol-related seizure without evidence of traumatic brain injury or severe toxic-metabolic disorder (31). Sixteen patients (6.2%) had clinically significant intracranial lesions including chronic subdural hematoma (4), subdural hygroma (4), vascular malformation (2), neurocycsticercosis (2), cerebral aneurysm (1), possible tumor (1), skull fracture with subarachnoid hemorrhage (1), and cerebral infarct (1). Clinical management was altered as a result of the study in 10 (3.9%) cases. The history and physical examination did not correlate with CT scan findings. Feussner et al. evaluated the usefulness of CT scan in 151 patients with a history of alcohol-related seizures and found that 15% revealed focal structural lesions including 11 with old strokes, 7 with subdural hematomas, 2 with hygromas, and 2 with intracranial hemorrhages. Of the 6 patients who required operative intervention, only 5 demonstrated focal deficits on physical examination. Abnormal CT scans were found in 30% of patients with focal deficits compared to 6% of patients with a non-focal neurological examination (32). Magnetic Resonance Imaging Magnetic resonance imaging (MRI) of the brain is the imaging method of choice in the assessment of seizures, however, the value of this modality in patients with alcohol-related seizures has not been determined (33). It is preferable to computed tomography because of superior soft tissue contrast and multi-planar imaging capability leading to a greater sensitivity and accuracy in diagnosing small mass lesions such as tumors and cerebrovascular lesions (34). It appears reasonable to reserve MRI for patients with negative CT scan who may be at higher risk for structural abnormalities because of status epilepticus or partial seizures. Electroencephalography Electroencephalography (EEG) in waking and sleeping states is used to support the diagnosis and classification of epilepsy in patients in whom the clinical history indicates a significant probability of epileptic seizures. Indications for EEG in patients with suspected alcohol-related seizures have not been established to date. Current recommendations are similar to the indications for MRI, i.e., partial seizures or status epilepticus. The EEG examination ideally should be performed 48 h or more after the initial seizure. Obtaining an EEG immediately after a seizure may yield misleading results and the study is therefore rarely indicated in the Emergency Department (35). A routine EEG is most likely normal in patients with alcohol-related seizures without epilepsy, but may demonstrate mild non-specific slowing and attenuation of the background amplitude (36, 37 and 38). Treatment Alcohol typically accounts for 50% of the caloric intake of alcohol-dependent individuals and therefore displaces normal nutrients such as folate, thiamine and other vitamins. In order to prevent Wernicke-Korsakoff syndrome, thiamine should be administered intramuscularly, intravenously, or orally to all patients undergoing treatment for alcohol withdrawal. Although thiamine has no effect in preventing seizures or delirium tremens, Wernicke’s encephalopathy may present subtly and elude careful evaluation by clinicians (18 and 39). Folate and multivitamins also should be administered to patients because they should be assumed to be clinically malnourished. Benzodiazepines There is significant evidence to suggest that benzodiazepines are effective in preventing both initial and recurrent seizures in alcohol-dependent individuals (40). They offer excellent anti-convulsant activity with minimal respiratory and cardiac depression. They exhibit cross-tolerance with alcohol, act at the GABA receptor site in place of alcohol, and reduce the signs and symptoms of the alcohol withdrawal syndrome. Benzodiazepines should be given not only for the treatment of active convulsions, but also for short-term prophylaxis within the 6- to 12-h window in which patients are at high risk for recurrent alcohol-related seizures. This is particularly true for patients who are at high risk because of a prior history of epilepsy, alcohol-related seizures, or multiple previous detoxifications (41). High doses of benzodiazepines equivalent to 60 mg of diazepam—administered orally in divided doses—is associated with a lower rate of seizures in the ED compared with lower doses (42). All benzodiazepines appear to be equally efficacious in reducing the signs and symptoms of withdrawal. However, longer-acting agents such as chlordiazepoxide and diazepam may be more effective than shorter-acting drugs in preventing seizures. Longer-acting agents can, however, pose a risk of increased sedation in the elderly and in patients with advanced liver disease. Oxazepam and lorazepam are preferable in these cases because they do not undergo hepatic oxidation and have fewer active metabolites (43 and 44). Marx and colleagues randomized 831 patients admitted to a detoxification unit from the ED (45). Patients receiving chlorazepate developed significantly fewer seizures (0.7%) than patients receiving phenytoin (3.0%) or placebo (6.2%) during a 96-h observation period. Lorazepam appears to be an ideal agent for the treatment of patients with alcohol-related seizures and should be given within the 6- to 12-h period when recurrent seizures typically occur. It has minimal depressant effects on respirations and the circulation and has a shorter half-life than diazepam with no active metabolites. It controls seizures longer than diazepam (12 to 24 h vs. 15 to 30 min, respectively) due to favorable pharmacokinetics (5). Therapeutic central nervous system concentrations persist for a significantly longer period of time because lorazepam is less lipid-soluble than diazepam; it is therefore redistributed into fatty tissues at a slower rate. Lorazepam has the additional advantage that it can be administered intramuscularly with good effect if intravenous access is not available. A prospective, randomized, controlled trial by D’Onofrio demonstrated lorazepam to be an extremely effective agent for the prevention of recurrent seizures in patients who present following an initial alcohol-related seizure (25). Among patients receiving lorazepam, 3% had a second seizure during a 6-h observation period, compared with 24% in the placebo group (p < 0.0001). Lorazepam should therefore be administered routinely upon presentation to the ED, unless contraindicated because of heavy sedation due to intoxication, head injury etc. Anti-epileptic Drugs In limited series, anti-epileptic drugs appear to be effective in preventing primary alcohol withdrawal seizures but do not confer additional benefit when combined with longer-acting benzodiazepines such as chlordiazepoxide or diazepam (40). Large, prospective trials demonstrating the efficacy and safety of antiepileptic drugs in alcohol-dependent patients have not been performed. Anti-epileptic drugs have not been shown to be effective and safe in preventing recurrent alcohol withdrawal seizures. Alldredge et al. and Rathlev et al. independently demonstrated a lack of efficacy of phenytoin compared with placebo in these patients (24 and 46). A randomized, controlled study from Finland also failed to demonstrate effectiveness of carbamazepine and valproic acid in this setting (47). The efficacy of the newer generation anticonvulsant drugs, e.g., gabapentin, lamotrigine and topiramate, has not been studied in controlled trials although they appear to be safe in this setting (48). Patients with chronic alcohol dependence and epilepsy are often non-compliant with their drug regimen and are therefore at increased risk for further seizures. Hillbom and Hjelm-Jager reported that the sudden withdrawal of phenytoin may actually increase the frequency of seizures (49). The risks and benefits of anticonvulsant therapy must therefore be carefully considered in chronically non-compliant patients. Prescribing expensive medications with questionable efficacy and possible risks for chronically non-compliant patients is not warranted. Conversely, patients with a known structural brain lesion or an electroencephalogram indicating an epileptogenic abnormality should be placed on long-term anti-convulsant therapy (50 and 51). Disposition Discharge to a detoxification center is dependent on recovery of patients to baseline mental status and their ability to safely ambulate (52). Most patients with alcohol-related seizures that have been treated with appropriate doses of lorazepam, and in whom concurrent risk factors have been ruled out by history, physical examination and diagnostic testing, can be safely discharged after a 3-h period of observation (25). Patients are unlikely to develop further seizures if recurrent events do not develop within a 3-h window after initial benzodiazepine administration. The focus of patient management should be on promoting primary prevention by encouraging patients to seek help in a structured detoxification program. The patient should be referred to a detoxification unit, and receive treatment with longer acting benzodiazepines to prevent further sequelae of alcohol withdrawal including recurrent seizures. The occurrence of a new-onset seizure should be viewed as a major adverse consequence of alcohol dependence, and presents an opportunity for the physician to assess the patient’s readiness for change and to successfully link them to a treatment center (53, 54 and 55). References 1 G. Brathen, E. Brodtkorb, G. Helde, T. Sand and G. Bovim, The diversity of seizures related to alcohol use. A study of consecutive patients, Eur J Neurol 6 (1999), pp. 697–703. Abstract-EMBASE | Abstract-Elsevier BIOBASE 2 N.K. Rathlev, A.S. Ulrich, S.S. Fish and G. D’Onofrio, Clinical characteristics as predictors of recurrent alcohol-related seizures, Acad Emerg Med 7 (2000), pp. 886–891. Abstract-EMBASE | Abstract-MEDLINE 3 N.K. Rathlev, A. Ulrich, T. Shieh, M. Callum, E. Bernstein and G. D’Onofrio, Etiology and weekly occurrence of alcohol-related seizures, Acad Emerg Med 9 (2002), pp. 824–828. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef 4 M. Victor and C. 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Kornhuber, Plasma homocysteine is a predictor of alcohol withdrawal seizures, Neuroreport 11 (2000), pp. 2749–2752. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE 11 S.K.C. Ng, W.A. Hauser, J.C.M. Brust and M. Susser, Alcohol withdrawal and consumption in new-onset seizures, N Engl J Med 319 (1988), pp. 666–673. Abstract-MEDLINE | Abstract-EMBASE 12 M.P. Earnest, Etiologies of acute alcohol-related seizures. In: R.J. Porter, R.H. Mattson, J.A. Cramer and I. Diamond, Editors, Alcohol and seizures basic mechanisms and clinical concepts, FA Davis Company, Philadelphia, PA (1990), pp. 197–205. 13 M.E. Hillbom, Occurrence of cerebral seizures provoked by alcohol abuse, Epilepsia 21 (1980), pp. 459–466. Abstract-EMBASE | Abstract-MEDLINE 14 A.W. Chan, Alcoholism and epilepsy, Epilepsia 26 (1985), pp. 323–333. Abstract-MEDLINE | Abstract-EMBASE 15 R.H. Mattson, M.L. Fay, J.K. Sturman, J.A. Cramer, J.D. Wallace and E.M. Mattson, The effect of various patterns of alcohol use on seizures in patients with epilepsy. In: R.J. Porter, R.H. Mattson, J.A. Cramer and I. Diamond, Editors, Alcohol and seizures basic mechanisms and clinical concepts, FA Davis Company, Philadelphia, PA (1990), pp. 233–240. 16 J.F. Annegers, A. Hauser, S.P. Coan and W. Rocca, A population-based study of seizures after traumatic brain injuries, N Engl J Med 338 (1998), pp. 20–24. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef 17 P. Davidson, J. Koziol-McLain, L. Harrison, D. Timken and S.R. Lowenstein, Intoxicated ED patients a 5-year follow-up of morbidity and mortality, Ann Emerg Med 30 (1997), pp. 593–597. SummaryPlus | Full Text + Links | PDF (470 K) 18 K. Skullerud, S.N. Andersen and J. Lundevall, Cerebral lesions and causes of death in male alcoholics a forensic autopsy study, Int J Legal Med 104 (1991), pp. 209–213. Abstract-MEDLINE | Abstract-EMBASE 19 K. Seppa and P. Sillanaukee, Binge drinking and ambulatory blood pressure, Hypertension 33 (1999), pp. 79–82. Abstract-MEDLINE | Abstract-EMBASE 20 A.L. Klatsky, M.A. Armstrong, S. Sidney and G.D. Friedman, Alcohol drinking and the risk of hemorrhagic stroke, Am J Cardiol 88 (2001), pp. 703–706. SummaryPlus | Full Text + Links | PDF (81 K) 21 G. Mazzaglia, A.R. Britton, D.R. Altman and L. Chenet, Exploring the relationship between alcohol consumption and non-fatal and fatal stroke a systematic review, Addiction 96 (2001), pp. 1743–1756. Abstract-MEDLINE | Abstract-EMBASE 22 J.S. Gill, M.J. Shipley and S.A. Tsementzis et al., Alcohol consumption—a risk factor for hemorrhagic and non-hemorrhagic stroke, Am J Med 90 (1991), pp. 489–497. Abstract 23 W.A. Hauser and L.T. Kurland, The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967, Epilepsia 16 (1975), pp. 1–66. Abstract-MEDLINE | Abstract-EMBASE 24 N.K. Rathlev, G. D’Onofrio and S.S. 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Lewis, Determining the need for admission in patients with new-onset seizures, Ann Emerg Med 24 (1994), pp. 1108–1114. Abstract-EMBASE | Abstract-MEDLINE 30 T.R. Brown and G.L. Homes, Epilepsy, N Engl J Med 344 (2001), pp. 1145–1151. 31 M.P. Earnest, H. Feldman, J.A. Marx, B.S. Harris, M. Biletch and L.P. Sullivan, Intracranial lesions shown by CT scans in 259 cases of first alcohol-related seizures, Neurology 38 (1988), pp. 1561–1565. Abstract-EMBASE | Abstract-MEDLINE 32 J.R. Feussner, E.W. Linfors, C.L. Blessing and C.F. Starmer, Computed tomography brain scanning in alcohol withdrawal seizures. Value of the neurologic examination, Ann Intern Med 94 (1981), pp. 519–522. Abstract-EMBASE | Abstract-MEDLINE 33 L. Tanenbaum, B.P. Grayer and R.E. Anderson et al., Epilepsy American College of Radiology. ACR appropriateness criteria, Radiology 215 (2000), pp. 459–470. Abstract-MEDLINE 34 Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of epilepsy in adults. A national clinical guideline (SIGN publication no. 70). Edinburgh, UK: Scottish Intercollegiate Guidelines Network (SIGN); 2003. 35 J.S. Huff, D.L. Morris and R.U. Kothari et al., Emergency department management of patients with seizures a multicenter study, Acad Emerg Med 8 (2001), pp. 622–628. Abstract-MEDLINE | Abstract-EMBASE 36 T. Sand, G. Brathen, R. Michler, E. Brodtkorb, G. Helde and G. Bovim, Clinical utility of EEG in alcohol-related seizures, Acta Neurol Scand 105 (2002), pp. 18–24. Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Abstract-EMBASE | Full Text via CrossRef 37 G.L. Krauss and E. Niedermeyer, Electroencephalogram and seizures in chronic alcoholism, Electroencephalogr Clin Neurophysiol 78 (1991), pp. 97–104. Abstract 38 E. Deisenhammer, D. Klingler and H. Tragner, Epileptic seizures in alcoholism and the diagnostic value EEG after sleep deprivation, Epilepsia 25 (1984), pp. 526–530. Abstract-EMBASE | Abstract-MEDLINE 39 S.C. Kaim, C.J. Klett and B. Rothfeld, Treatment of the acute withdrawal state a comparison of four drugs, Am J Psychiatry 125 (1969), pp. 1640–1646. Abstract-MEDLINE 40 M. Hillbom, I. Pieninkeroinen and M. Leone, Seizures in alcohol-dependent patients. Epidemiology, pathophysiology and management, CNS Drugs 17 (2003), pp. 1013–1030. Abstract-MEDLINE | Full Text via CrossRef 41 W.A. Morton, L.K. Laird, D.F. Crane, N. Partovi and L.H. Frye, A prediction model for identifying alcohol withdrawal seizures, Am J Drug Alcohol Abuse 20 (1994), pp. 75–86. Abstract-MEDLINE | Abstract-EMBASE 42 M. Kahan, B. Borgundvaag, D. Midmer, D. Borsoi, C. Edwards and N. Ladhani, Treatment varability and outcome differences in the emergency department management of alcohol withdrawal, Can J Emerg Med 7 (2005), pp. 87–92. Abstract-EMBASE 43 A. Hill and D. Williams, Hazards associated with the use of benzodiazepines in alcohol detoxification, J Substance Abuse Treat 10 (1993), pp. 449–451. Abstract 44 M. Mayo-Smith and D. Bernard, Late onset seizures in alcohol withdrawal, Alcohol Clin Exp Res 19 (1995), pp. 656–659. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef 45 J.A. Marx, J. Berner and D. Bar-Or et al., Prophylaxis of alcohol withdrawal seizures a prospective study (abstract), Ann Emerg Med 15 (1986), p. 637. 46 B. Alldredge, D. Lowenstein and R. Simon, Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures, Am J Med 87 (1989), pp. 645–648. Abstract 47 M. Hillbom, R. Tokola and V. Kuusela et al., Prevention of alcohol withdrawal seizures with carbamazepine and valproic acid, Alcohol 6 (1989), pp. 223–226. Abstract 48 A. Rustembegovic, E. Sofic and G. Kroyer, A pilot study of topiramate in the treatment of tonic-clonic seizures of alcohol withdrawal syndromes, Med Arh 56 (2002), pp. 211–212. Abstract-MEDLINE 49 Hillbom M, Hjelm-Jager M. Should alcohol withdrawal seizures be treated with antiepileptic drugs? Acta Neurol Scand 1984;15:69:39–42. 50 N.R. Temkin, S.S. Dikmen, A.J. Wilensky, J. Keihm, S. Chabal and H.R. Winn, A randomized double-blind study of phenytoin for the prevention of post-traumatic seizures, N Engl J Med 323 (1990), pp. 497–502. Abstract-MEDLINE | Abstract-EMBASE 51 W.A. Hauser, M. Ramirez-Lassepas and R. Rosenstein, Risk for seizures and epilepsy following cerebrovascular insults (abstract), Epilepsia 25 (1984), p. 666. 52 ACEP Clinical Policies Committee; Clinical Policies Subcommittee on Seizures, Clinical policy critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures, Ann Emerg Med 43 (2004), pp. 605–625. 53 E. Bernstein, J. Bernstein and S. Levenson, Project ASSERT an ED-based intervention to increase access to primary care, preventive services and the substance abuse treatment system, Ann Emerg Med 30 (1997), pp. 181–189. SummaryPlus | Full Text + Links | PDF (817 K) 54 G. D’Onofrio, E. Bernstein and S. Rollnick, Motivating patients for change a brief strategy for negotiation. In: E. Bernstein and J. Bernstein, Editors, Emergency medicine and the health of the public, Jones and Bartlett, Boston, MA (1996), pp. 51–62. 55 G. D’Onofrio, E. Bernstein and J. Bernstein et al., Patients with alcohol problems in the ED, Part 2 intervention and referral, Acad Emerg Med 5 (1998), pp. 1210–1217. Clinical Communications (Adults) is coordinated by Ron Walls, MD, of Brigham and Women’s Hospital and Harvard University Medical School, Boston, Massachusetts. Reprint Address: Niels K. Rathlev, MD, Department of Emergency Medicine, Boston Medical Center, One Boston Medical Center Place, Boston, MA 02118

Here's an interesting article on the systemic failure of healthcare institutions which I touch on in my post. [web:cb71c37497]http://www.liebertonline.com/doi/pdf/10.1089/bsp.2006.4.135[/web:cb71c37497] What do you all think now? Out Here, ACE844

There was no personal attack involved. Everyone here should know that even at 'their stable base-line' a dialysis pt is one of the most sick and complicated we can encounter as clinicians in medicine. Fact of the matter is just the dialysis treatment itself can soemtimes cause metabolic and physiologic problems. Now compund that with a 10-20% total volume Blood loss. This patient clearly needs ALS asessment and potentially interventions to treat co-comittant 'disorders' which are or could be occuring with this patient. The patient recieveing early beneficial care which is unavailable for the average basic to provide is what is important here. Furthermore there is so much rationale I could post loads of info about it. This patient warrants ALS, there is no question. If you need for me to post more info on dialysis and renal failure, and or point you in the direction of some sources to get you started I will be more than happy to. Furthermore, I would expect you as a long time member of this site to know better than to think this is about being X mins for a hospital and more about providing your patient with access to appropriate timely treatment as well as continuing care. Out here, ACE844

(Acad Emerg Med Volume 13 @ Number 4 365-371, published online before print March 10, 2006, doi: 10.1197/j.aem.2005.11.078 © 2006 Society for Academic Emergency Medicine This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Cited by other online articles Google Scholar Articles by Peacock, W. F. Articles by Emerman, C. E. PubMed PubMed Citation Articles by Peacock, W. F. Articles by Emerman, C. E. -------------------------------------------------------------------------------- CLINICAL INVESTIGATION Impact of Impedance Cardiography on Diagnosis and Therapy of Emergent Dyspnea: The ED-IMPACT Trial W. Frank Peacock, MD, Richard L. Summers, MD, Jody Vogel, MD and Charles E. Emerman, MD From the Department of Emergency Medicine, Cleveland Clinic (WFP), Cleveland, OH; Department of Emergency Medicine, University of Mississippi (RLS), Jackson, MS; Wayne State University (JV), Detroit, MI; and Department of Emergency Medicine, Case Western Reserve University (CEE), Cleveland, OH. Address for correspondence and reprints: W. Frank Peacock, MD, The Cleveland Clinic Foundation, Department of Emergency Medicine, Desk E-19, 9500 Euclid Avenue, Cleveland, OH 44195. Fax: 216-445-4552; e-mail: peacocw@ccf.org.) Background: Dyspnea is one of the most common emergency department (ED) symptoms, but early diagnosis and treatment are challenging because of multiple potential causes. Impedance cardiography (ICG) is a noninvasive method to measure hemodynamics that may assist in early ED decision making. Objectives: To determine the rate of change in working diagnosis and initial treatment plan by adding ICG data during the course of ED clinical evaluation of elder patients presenting with dyspnea. Methods: The authors studied a convenience sample of dyspneic patients 65 years and older who were presenting to the EDs of two urban academic centers. The attending emergency physician was initially blinded to the ICG data, which was collected by research staff not involved in patient care. At initial ED presentation, after history and physical but before central lab or radiograph data were returned, the attending ED physician completed a case report form documenting diagnosis and treatment plan. The physician then was shown the ICG data and the same information was again recorded. Pre- and post-ICG differences were analyzed. Results: Eighty-nine patients were enrolled, with a mean age of 74.8 ± 7.0 years; 52 (58%) were African American, 42 (47%) were male. Congestive heart failure and chronic obstructive pulmonary disease were the most common final diagnoses, occurring in 43 (48%), and 20 (22%), respectively. ICG data changed the working diagnosis in 12 (13%; 95% CI = 7% to 22%) and medications administered in 35 (39%; 95% CI = 29% to 50%). Conclusions: Impedance cardiography data result in significant changes in ED physician diagnosis and therapeutic plan during the evaluation of dyspneic patients 65 years and older. Key words: dyspnea; hemodynamics; impedance cardiography; bioimpedance; cardiac output; systemic vascular resistance; noninvasive INTRODUCTION TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION LIMITATIONS CONCLUSIONS REFERENCES Dyspnea is one of the most common emergency department (ED) symptoms in older patients.1 Various conditions, including heart failure, chronic obstructive pulmonary disease, pneumonia, pulmonary embolus, and acute coronary syndromes, may occur alone or in combination in a given patient, adding uncertainty to diagnosis and treatment. In patients with both cardiac and pulmonary disease, the initial assessment and therapy in the ED are challenging. Because cardiovascular disease, specifically decompensated heart failure (HF), is a relatively common cause of dyspnea in elders, an assessment of hemodynamics, including cardiac output, systemic vascular resistance, and fluid status, may provide important information and aid decision making beyond what is possible from history and physical examination alone. Unfortunately, hemodynamic parameters cannot be accurately determined by patient history or physical examination.2,3,4,5 Until recently, hemodynamic data could only be obtained by pulmonary artery catheterization. Because this invasive procedure is not practical in the ED, physicians typically are left to make diagnosis and treatment decisions without reliable information about a patient's hemodynamic status. Noninvasive hemodynamic monitoring by impedance cardiography (ICG) has been used in more than four million patients. Cardiac output (CO) by ICG has been shown to correlate well with CO obtained by invasive methods in hospitalized patient populations with correlation coefficients for CO by ICG and thermodilution ranging from 0.76 to 0.89.6,7,8,9,10 ICG also has been used as an alternative to invasive monitoring in the critical care setting.11 In the ED setting, ICG has been studied for the differential diagnosis of dyspnea12,13,14 and the identification of pulmonary edema15,16 and provides prognostic information about hospitalization costs and length of stay.17 ICG results are available within a few minutes, allowing more rapid patient evaluation than that afforded by radiographic or laboratory studies. Given the high rate of morbidity, mortality, and hospital readmissions for patients with dyspnea and acute decompensated HF, there is an urgent need to examine technologies that could lead to improvements in care in the ED. The present study examines an aspect of therapeutic efficacy18 as it relates to ICG and the acutely dyspneic emergency patient, and not simply the performance of ICG as a testing modality. Put into context, previous studies of commonly used ED tools, such as pulse oximetry19,20 and B-type natriuretic peptide (BNP) testing,21 suggest that a 5% to 11% rate of change in diagnosis, or 10% rate of change in therapy, is clinically relevant. The effect of ICG-derived hemodynamics on diagnosis and treatment of dyspnea in the ED is not yet known. The purpose of this study was to determine the rate of change in diagnosis and therapy resulting from the availability of ICG data during the initial evaluation of older ED patients presenting with dyspnea. METHODS TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION LIMITATIONS CONCLUSIONS REFERENCES Study Design This was a prospective study of dyspneic patients that was designed to determine the frequency of change in the ED physician's initial diagnosis and therapeutic plan after physician access to noninvasive ICG hemodynamic data. The study was approved by each hospital's institutional review board. All patients gave informed consent before enrollment in the study. Study Setting and Population The setting was two large urban academic EDs with experience in using noninvasive hemodynamic monitoring. A convenience sample was obtained from patients age 65 years or older who were presenting with a chief complaint of dyspnea or symptoms of HF, as determined by the ED physician. Because ICG is not currently recommended (per U.S. Food and Drug Administration guidelines) for the diagnosis of acute coronary syndromes, including acute myocardial infarction (MI), patients were excluded if electrocardiogram (ECG) or serum markers were positive for acute MI. Additional exclusions included the following: if ICG monitoring was not possible because of inability to place electrodes, if the patient's weight was greater than 341 pounds, or if the patient had an activated minute ventilation pacemaker (which uses an impedance signal). Also, although severe aortic regurgitation that could give a falsely elevated ICG CO is rare and generally evident on ED evaluation, we excluded those with aortic regurgitation by past history, and those with the typical diastolic murmur. Last, because the treatment and disposition actions for patients needing immediate intubation and mechanical ventilation are generally well defined from the emergency physician point of view, and because it was our intent to study the diagnostically most challenging patients, those requiring urgent intubation and mechanical ventilation upon presentation to the ED were excluded. Study Protocol Project coordinators screened candidates and an independent research nurse, not involved in the diagnosis or treatment of the patient, obtained hemodynamic data. Hemodynamic data were collected by using the BioZ ICG monitor (CardioDynamics, San Diego, CA), as has been described elsewhere.22 ICG data are obtained by the following technique: four dual sensors (each sensor consisting of two electrodes) are placed on the patient, as shown in Figure 1, on opposite sides of the neck at a level between the ears and shoulders and on either side of the chest in the mid-axillary line at the level of the xiphoid process. The outer electrodes in each sensor transmit a low-amplitude, high-frequency current (2.5 mA, 70 kHZ), and the inner electrodes detect thoracic voltage changes. Changes in voltage are used to calculate changes in impedance (Z). Baseline, static impedance is indicative of chest fluid volume, and dynamic impedance is affected by aortic blood volume and velocity. Beat-to-beat changes in thoracic impedance are processed to calculate blood flow per heartbeat (stroke volume) and per minute (cardiac output). By using standard equations, other hemodynamic parameters, such as systemic vascular resistance, are calculated. The reciprocal of baseline thoracic impedance can provide an index of intrathoracic fluid and is termed thoracic fluid content (TFC). TFC has been used to identify intravascular and extravascular fluid changes23,24 and to titrate diuretic therapy.25 View larger version (81K): [in this window] [in a new window] Figure 1. Front view of impedance cardiography method. Before study initiation, participating physicians received instruction regarding the interpretation of the hemodynamic values obtained by the ICG device. Attending physicians, all of whom were board-certified or board-eligible in emergency medicine, were given a description of ICG technology and hemodynamic parameters provided on the ICG report, including definitions and normal values for cardiac index (CI), resistance, thoracic fluid content, and measures reflecting left ventricular performance. This was performed at departmental grand rounds and at the monthly attending-physician staff meeting. Additional information was disseminated in hardcopy by mailing and was duplicated by e-mail. The pathophysiology of HF and hemodynamic findings most suggestive of dyspnea caused by decompensated HF (reduced CI, elevated systemic vascular resistance, and increased TFC) were described. The expected effects of various medications on hemodynamic parameters were discussed, including use of diuretics, vasodilators, and drugs affecting contractility. Additionally, physicians were provided personal reference cards for use at their discretion that detailed normative values for all ICG data. Copies of the data card were also kept fixed to the ICG device. These data were also shown at the time of ICG unblinding. For any given parameter, ICG data are presented as a bar indicating the normal human range. The average result and the currently measured data point then are indicated on this bar, such that variations from normal are readily apparent. All staff involved with patient care were blinded to the ICG data until after the initial history and physical examination by the attending physician. After the initial history and physical exam, but before initiation of therapy (other than supplemental oxygen), and before obtaining any central laboratory or radiographic data, the attending physician completed a case report form indicating his or her working diagnoses and short-term therapeutic plans. The physician was then immediately shown the ICG hemodynamic data and was asked to complete the case report form again, this time with consideration of the ICG data. All patient care then proceeded according to usual ED routine. Blood tests, including electrolytes, blood urea nitrogen (BUN), serum creatinine (Cr), and BNP levels, were obtained in the majority of cases. Although these data were not mandated as part of the protocol, they were used in most cases to determine final ED diagnosis. Measures The two primary endpoints were 1) the rates of change in working diagnosis and 2) medical therapy after the addition of ICG data to the physician's initial clinical assessment and therapeutic plan. In the cases in which the diagnosis changed on the basis of ICG data, a comparison to the final diagnosis was made to determine whether the pre- or post-ICG diagnosis was more consistent with the final ED diagnosis. The final ED primary diagnosis was defined as the principal diagnosis at the end of the ED visit after all diagnostic testing was completed and reviewed by the ED physician responsible for disposition. A change in therapy was defined as the addition or subtraction of a drug or procedure. Changing the dose of a previously ordered drug was not considered a therapeutic change. Adverse events were defined as cardiac arrest, intubation for respiratory failure, urgent cardioversion, or blood transfusion. Data Analysis The size of the study was prospectively determined on the basis of the number needed to detect a 5% rate of change in diagnosis or therapy. Given an alpha of 0.05 and a beta of 0.20, a sample size of 100 was needed to detect a statistically significant change. Data were analyzed by an independent statistician using SAS Software (Cary, NC). Demographic data are reported descriptively. Continuous variables are reported as mean ± standard deviation (SD). Rates of change were calculated by dividing the number of patients in whom diagnosis or therapeutic plan changed by the total number of patients and were reported as percentages. An analysis of variance was performed to assess for differences among vital signs and ICG parameters in the final diagnosis categories. RESULTS TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION LIMITATIONS CONCLUSIONS REFERENCES Eighty-nine patients, cared for by 31 ED staff physicians, were enrolled from December 2001 through July 2003 and are included in the analysis. No adverse event, defined as cardiac arrest, intubation, cardioversion, or blood transfusion, occurred during the course of the ED observation during this study. The patient characteristics and vital signs are summarized in Table 1. The mean (± SD) age of the subjects was 74.8 (± 7.0) years. Fifty-eight percent of the patients were African American, and 61% had a history of HF, including 13% with a history of both HF and chronic lung disease. The prevalence of chronic lung disease, including asthma, was 38%. The average respiratory rate was 22.2 (± 5.1) min–1 with systolic BP and heart rate of 145.5 (± 29.3) mm Hg and 84.6 (± 18.8) min–1, respectively. The hemodynamic values for the population as a whole are listed in Table 2. View this table: [in this window] [in a new window] TABLE 1. Patient Characteristics and Vital Signs View this table: [in this window] [in a new window] TABLE 2. Hemodynamic Values at Presentation Patients could be categorized by final primary diagnosis at the time of ED discharge or hospital admission into three major groups: 1) HF (n = 43); 2) chronic obstructive pulmonary disease (COPD; 20); and 3) "other" (26). The other group included other cardiovascular and lung conditions not included in the HF or COPD groups: atrial fibrillation (n = 4), bronchitis (4), hypertension (2), pneumonia (2), pulmonary hypertension (2), anemia (1), influenza (1), lung cancer (1), palpitations (1), upper respiratory infection (1), atypical chest pain (1), hypoxia (1), intra-abdominal abscess (1), non-cardiac shortness of breath (1), pulmonary fibrosis (1), vertigo (1), and dehydration (1). Chest radiographs and ECG results were recorded by the ED physician in 85 patients (96%). The various ECG and radiographic findings are summarized in Table 3. ECG findings were described as normal or nonspecific in the vast majority (82%), and the chest radiograph was normal or nondiagnostic in nearly half, with only 16% showing either HF or upper zone redistribution consistent with pulmonary venous congestion. View this table: [in this window] [in a new window] TABLE 3. Electrocardiographic and Chest Radiographic Findings Diagnosis Changes A summary of the rates of diagnosis and therapy change that resulted from ICG data are presented in Figure 2. ICG data changed the working diagnosis in 12 (13%; 95% CI = 7% to 22%). When diagnoses were categorized as either cardiac or noncardiac, the post-ICG diagnosis was the same as the final diagnosis in 8 of 12 patients in whom ICG resulted in a change (67%, 95% CI = 35% to 90%). Of the four patients in whom a change in diagnosis after ICG did not match the final ED diagnosis, one who was ultimately diagnosed with a cardiac cause of dyspnea had normal hemodynamic parameters, suggesting a pulmonary cause. In another patient, altered hemodynamic parameters suggested cardiac dyspnea that was later attributed to an exacerbation of COPD. One patient with lung cancer had hemodynamic findings consistent with diastolic HF. Finally, one patient who initially was thought to have pulmonary dyspnea had altered hemodynamic findings that were believed to be nondiagnostic by the evaluating physician; that patient was ultimately treated for fluid overload and discharged home. View larger version (7K): [in this window] [in a new window] Figure 2. Category rate of change from pre-ICG to post-ICG (mean values with 95% confidence intervals). Results Grouped by Final Diagnosis. A summary of the patient vital signs and hemodynamic characteristics grouped by final ED diagnosis is listed in Table 4. No diagnosis group had vital sign data that were significantly different from those of any other group (p = 0.1332). Of the hemodynamic parameters, cardiac index, systemic vascular resistance index, and thoracic fluid content had one diagnosis group that differed significantly from the other two (p < 0.02). HF patients had greater amounts of lung water, as reflected by a mean TFC (38.5 ± 12.3 kOhm–1) that was significantly higher than that of the other two diagnosis groups (30.0 ± 6.17 and 30.4 ± 5.6 for the COPD and other groups, respectively). Patients with COPD had higher CI (3.08 ± 0.57 vs. 2.39 ± 0.56 and 2.48 ± 0.65) and lower SVR (1,361 ± 407 vs. 1,772 ± 565 and 1,789 ± 638) than did patients in the HF or other groups, respectively. View this table: [in this window] [in a new window] TABLE 4. Initial Vital Signs and Selected Hemodynamic Parameters by Final Diagnosis Laboratory measurements, including electrolytes, BUN, Cr, WBC, Hgb, and BNP were analyzed by final diagnosis. Of the laboratory measurements, only BNP, measured in 72 patients, exhibited a statistically significant difference (p < 0.0001) among the three diagnosis groups. The HF group had a significantly higher mean BNP level (940 pg/mL) than did the other diagnosis groups (137 pg/mL, and 357 pg/mL for COPD and other groups, respectively). Treatment Changes Changes in planned medication orders, occurring after ICG information was revealed (and without other input to the treating physician), are shown in Table 5. Thirty-five patients (39%, 95% CI = 29% to 50%) had a total of 54 changes in the medication plan after initial assessment and review of ICG data. Use of diuretics most often was altered based on ICG findings, suggesting fluid overload or cardiac cause of dyspnea. When looking at medication changes by category of final diagnosis, there were 17 medication changes in the 43 patients with a final diagnosis of HF, 20 medication changes in the 20 patients with a final diagnosis of COPD, and 17 medication changes in the 26 patients in the other group. Twenty-three of 54 (43%) medication changes that resulted from the availability of hemodynamic information were changes in the use of diuretics or bronchodilators. View this table: [in this window] [in a new window] TABLE 5. Therapeutic Changes Post- vs. Pre-ICG Listed by Medication Class DISCUSSION TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION LIMITATIONS CONCLUSIONS REFERENCES In cases of elder dyspneic patients who may require urgent treatment, the ED physician must assess status, formulate a working diagnosis, and institute therapy, in many cases before all information is available. Hemodynamic information, which reflects the contribution of the cardiovascular system to the current presentation, may have an important impact on the process of care. Our results demonstrate that knowledge of ICG data leads to a change of working primary diagnosis in 13% of elder patients presenting with dyspnea to the ED. When changes in diagnosis were made, they were consistent with the final diagnosis at time of ED disposition in two-thirds of cases. In addition to changes in diagnosis, ED physicians made medication changes on the basis of ICG-derived hemodynamic information in 39% of cases. Finally, unlike vital signs, which were similar across the various diagnostic groups, hemodynamic data varied based on causes of dyspnea. These findings are consistent with the hypothesis that hemodynamic information is relevant and actionable in the ongoing evaluation and treatment of such patients. Patients presenting with dyspnea are commonly at risk for exacerbation of either cardiac or pulmonary disease. Those with acute HF typically have reduced cardiac output and elevated vascular resistance. Those with a pulmonary or other noncardiac cause of their dyspnea typically have normal cardiac output and hemodynamic parameters. Because the accuracy and reproducibility of ICG have been validated in a variety of patient populations and settings, it is not surprising that physicians used this information to help guide diagnosis and treatment in dyspneic patients. Our finding of different values of hemodynamic parameters among the diagnostic groups is consistent with this paradigm. The relatively high rate of change of diagnosis, when ICG-derived information was revealed to treating physicians, suggests acceptance of the technical and diagnostic accuracy efficacies of the test. Not only does the information result in altered diagnosis, but the noninvasive hemodynamic data provided by ICG was applied by the physicians to therapeutic decision making, an indication of therapeutic efficacy, as defined by Pearl.18 Thus, our results support the potential value of such information and support a practical role for this technology in the ED assessment of such patients. Recently, BNP testing has been shown to be a useful bedside tool to aid in diagnosis of patients presenting with shortness of breath.26 However, despite the availability of point-of-care laboratory testing, real-time diagnosis and treatment can be delayed. In fact, one large trial of cardiac markers found that even with point-of-care testing, the door-to-brain time (the time from ED arrival until cardiac marker results are available for the physician to act upon) exceeded one hour.27 ICG data are available within several minutes. And, unlike the hemodynamic information obtained by a pulmonary artery catheter, performance of ICG is noninvasive and can be readily accomplished in the ED without specialized training and at minimal risk to the patient. The magnitude of the changes in diagnosis and treatment resulting from ICG-derived hemodynamic data can be compared with that from other technologies that are currently the standard of care in most EDs. Historically, changes in therapy on the order of 5% to 11% appear to define utility of testing in the ED. In one study, Summers et al.19 reported that the ED physician assessment of patient severity of illness was changed by pulse oximetry in 3% of cases. Kosowky et al.,21 evaluating BNP testing in patients older than 40 years of age, found that BNP data changed the diagnosis in 10%, and treatment in 11%, of cases. These trials suggest that the rate of change that resulted from ICG use in the present study would be clinically significant in the ED environment. Moreover, ICG can be performed concurrently with existing diagnostic and therapeutic strategies, such that the information is incremental in the decision-making process. The changes in ED decision making from esophageal Doppler results, a more invasive and less common form of cardiac output measurement, have been studied elsewhere.28 Those investigators found a change in management decisions in 31% of cases. Our results show a greater change in therapy alone, perhaps because of the incremental information provided by systemic vascular resistance and thoracic fluid content parameters. Although most ED physicians would not subject a patient to esophageal monitoring to obtain hemodynamic measurements, it is likely that many would consider the collection of ICG data, which requires little more time or inconvenience than obtaining an electrocardiogram. We did not measure the time required to obtain ICG data; however, in routine use, these data can be obtained in about 3 to 5 minutes and require 30 to 60 seconds to interpret. Because ICG provides early and accurate data, there is a potential for significant clinical impact from its use. We did not specifically study the financial effects of ICG in this study or how it might have affected length of ED stay or hospital admission rate. However, at a procedural cost for each test of less than $20 and with the cost of a day in intensive care at more than $1,000, the provision of ICG would be cost-effective even if, for example, it reduced hospital length of stay by only one day for every 50 patients monitored. LIMITATIONS TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION LIMITATIONS CONCLUSIONS REFERENCES We acknowledge several limitations. This study evaluated the effect of ICG on working diagnosis and initial treatment plan before the results of chest radiograph, ECG, or BNP level. Thus, it is impossible to gauge the relative importance of the information obtained from ICG to that obtained by these other tests or to judge the additional contribution of ICG for cases in which the results of other tests were available before performing ICG. Although blood work and various ancillary testing such as chest radiography are part of the complete ED evaluation of such patients, the results are generally not available within the first few minutes of patient assessment. By design, this study evaluated ICG's effect on working diagnosis and therapy in a manner that would be consistent with clinical practice in the ED, where patients presenting with dyspnea might be evaluated with ICG either before or within minutes of the ED physician's initial assessment. Furthermore, as seen in our study, the findings of ECGs and chest radiographs are often normal or nonspecific and may not provide significant diagnostic certainty. Because ICG is not part of the diagnostic criteria for acute coronary syndromes, including acute MI, we did exclude patients with evidence of myocardial necrosis from analysis. Therefore, the role of ICG in providing possible clues in the evaluation of patients with dyspnea as a manifestation of MI cannot be assessed by the present study. Our study was also limited by the use of the final ED diagnosis as the criterion standard for diagnostic categorization. Although it is possible that this diagnosis was incorrect or incomplete in some patients, this represents the real-life diagnosis based on current evaluation strategies during the patient's ED visit. It is also possible that a physician had the right diagnosis and treatment plan before reviewing ICG results and that ICG data resulted in inappropriate therapies. A larger prospective outcome-based study will be required to determine the potential for this to occur. In our study, ICG data were available and likely contributed to the final ED diagnosis, thereby introducing possible bias. However, the goal of this study was not to assess technical accuracy of the technology, which has been evaluated in previous studies. In contrast, this study was designed to assess whether physicians would incorporate early hemodynamic information into the process of formulating an initial working diagnosis and treatment plan. In addition, the study design does not allow us to draw conclusions about the sensitivity or specificity of ICG criteria, or to compare diagnostic accuracy to other measures, such as BNP or chest radiography. The accuracy of the post-ICG diagnosis based on these hemodynamic criteria could only be verified by a more standardized diagnostic approach including cardiac imaging studies, blinded reviews of subsequent hospital records with adjudication of discordant diagnoses, and long-term follow-up, which were not within the scope of the current study. CONCLUSIONS TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION LIMITATIONS CONCLUSIONS REFERENCES Knowledge of ICG data early in the ED evaluation of patients older than 65 years of age presenting with dyspnea results in significant changes in diagnosis and treatment plan. Whether changes in diagnosis, diagnostic certainty, or therapy from ICG improve outcomes or are cost-effective will require a prospective, randomized clinical trial with longer periods of clinical follow-up. ACKNOWLEDGMENTS The authors thank Gerard Smits, PhD, for his statistical assistance. FOOTNOTES Supported by GE Medical Systems (Milwaukee, WI), which provided devices and disposables for this study, and by CardioDynamics (San Diego, CA), which provided a study grant for support of research assistants. In addition, CardioDynamics participated in the creation of the educational process for the participating physicians before study commencement. The sponsor had no role in data collection or statistical analyses, and the manuscript is the sole responsibility of the authors. W.F.P. and R.L.S. received honoraria in 2003 for speaking for CardioDynamics. Presented as a moderated poster at the American College of Emergency Physicians Research Forum, October 2003. REFERENCES TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION LIMITATIONS CONCLUSIONS REFERENCES McCraig LF, Burt CW. National hospital ambulatory medical care survey: 2001 emergency department summary. Report from Centers for Disease Control and Prevention, National Center for Health Statistics. Advance Data Vital Health Stat. 2003; 335:18. Eisenberg PR, Jaffe AS, Schuster DP. Clinical evaluation compared to pulmonary artery catheterization in the hemodynamic assessment of critically ill patients. Crit Care Med. 1984; 12:549–53.[Medline] Speroff T, Connors AF Jr, Dawson NV. Lens model analysis of hemodynamic status in the critically ill. Med Decis Making. 1989; 9:243–52.[Medline] Neath SX, Lazio L, Guss DA. Utility of impedance cardiography to improve physician estimation of hemodynamic parameters in the emergency department. Congest Heart Fail. 2005; 11:17–20.[Medline] Van De Water JM, Dalton ML, Parish DC, Vogel RL, Beatty JC, Adeniyi SO. Cardiopulmonary assessment: is improvement needed? World J Surg. 2005; 29(Suppl 1):S95–8.[CrossRef] Sageman WS, Riffenburgh RH, Spiess BD. Equivalence of bioimpedance and thermodilution in measuring cardiac index after cardiac surgery. J Cardiothorac Vasc Anesth. 2002; 16:8–14.[CrossRef][Medline] Drazner M, Thompson B, Rosenberg P, Yancy C. Comparison of impedance cardiography with invasive hemodynamic measurements in patients with heart failure secondary to ischemic or nonischemic cardiomyopathy. Am J Cardiol. 2002; 89:993–5.[CrossRef][Medline] Van De Water JM, Miller TW. Impedance cardiography: the next vital sign technology? Chest. 2003; 123:2028–33.[Abstract/Free Full Text] Yung GL, Fedullo PF, Kinninger K, Johnson FW, Channick RN. Comparison of impedance cardiography to direct Fick and thermodilution cardiac output determination in pulmonary arterial hypertension. Congest Heart Fail. 2004; 10(2 Suppl 2):7–10. Albert NM, Hail MD, Li J, Young JB. Equivalence of bioimpedance and thermodilution in measuring cardiac output in hospitalized patients with advanced, decompensated chronic heart failure. Am J Crit Care. 2004; 3:469–79. Silver M, Cianci P, Brennan S, Longeran-Thomas H, Ahmad F. Evaluation of impedance cardiography as an alternative to pulmonary artery catheterization in critically ill patients. Congest Heart Fail. 2004; 10(2 Suppl 2):17–21. Springfield C, Sebat F, Johnson D, Lengle S, Sebat C. Utility of impedance cardiography to determine cardiac vs. noncardiac cause of dyspnea in the emergency department. Congest Heart Fail. 2004; 10(2 Suppl 2):14–6. Han J, Lindsell C, Tsurov B, Storrow A. The clinical utility of impedance cardiography in diagnosing congestive heart failure in dyspneic emergency department patients [abstract]. Acad Emerg Med. 2002; 9:439–40.[Abstract/Free Full Text] Barcarse E, Kazanegra R, Chen A, Chiu A, Clopton P, Maisel A. Combination of B-type natriuretic peptide levels and non-invasive hemodynamic parameters in diagnosing congestive heart failure in the emergency department. Congest Heart Fail. 2004; 10:171–6.[Medline] Peacock WF, Albert NM, Kies P, White RD, Emerman CL. Bioimpedance monitoring: better than chest x-ray for predicting abnormal pulmonary fluid? Congest Heart Fail. 2000; 6(2):32–5. Newman RB, Pierre H, Scardo J. Thoracic fluid conductivity in peripartum women with pulmonary edema. Obstet Gynecol. 1999; 94:48–51.[Abstract/Free Full Text] Milzman D, Morrisey J, Pugh C, Napoli A, Gerace T, Fernandez E. Occult perfusion deficits in heart failure patients: identification through noninvasive central hemodynamic monitoring [abstract]. Crit Care Med. 1999; 27:A88. Pearl WS. A hierarchical outcomes approach to test assessment. Ann Emerg Med. 1999; 33:77–84.[Medline] Summers R, Anders R, Woodward L, Jenkins A, Galli R. Effect of routine pulse oximetry measurements on ED triage classification. J Emerg Med. 1999; 16:5–7.[CrossRef] Mower WR, Sachs C, Nicklin EL, Safa P, Baraff LJ. Effect of routine emergency department triage pulse oximetry screening on medical management. Chest. 1995; 108:1297–302.[Abstract/Free Full Text] Kosowsky JM, Weiner C, Morrissey JH. Impact of B-type natriuretic peptide testing on medical decision-making for older patients with dyspnea. Ann Emerg Med. 2003; 42:S11. Summers R, Schoemaker W, Peacock WF, Ander D, Coleman T. Bench to bedside series: impedance cardiography (ICG). Acad Emerg Med. 2003; 10:669–80.[Abstract/Free Full Text] Luepker R, Michael JR, Warbasse JR. Transthoracic electrical impedance: quantitative evaluation of a noninvasive measure of thoracic fluid volume. Am Heart J. 1973; 85:83–93.[CrossRef][Medline] Van de Water JM, Mount BE, Chandra KM, Mitchell BP, Woodruff TA, Dalton ML. TFC (thoracic fluid content): a new parameter for assessment of changes in chest fluid volume. Am Surg. 2005; 71:81–6.[Medline] Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension. 2002; 39:982–8.[Abstract/Free Full Text] Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002; 347:161–7.[Abstract/Free Full Text] Peacock WF, Roe MT, Chen AY, et al. Vein-to-brain time: an emergency department quality of care marker for non-ST-segment elevation acute coronary syndrome [abstract]. Acad Emerg Med. 2004; 11:569.[Abstract] Urrunaga J, Rivers E, Mullen M, et al. Hemodynamic assessment of the critically ill: the clinician versus esophageal Doppler monitoring (EDM) [abstract]. Acad Emerg Med. 2000; 7:587b.

I apologize if I was wrong and misread the context of your post. For me I think this truely would be a very hard call to amke in the context of a written scenario because so much would depend on the H&P-P/E and observation. This pt would defenately get the full ALS work up, but as to whther I would progress to meds or lots of fluid for HYpotension and shock....That would depend on alot of the aforementioned factors and what i found during the course of my pt contact. Out Here, ACE844

( Annals of Emergency Medicine Volume 48 @ Issue 1 , July 2006, Pages 98-100 doi:10.1016/j.annemergmed.2006.03.003 Copyright © 2006 Published by Mosby, Inc. Evidence-based emergency medicine/systematic review abstract What Is the Preferred First-Line Therapy for Status Epilepticus? Eddy S. Lang MDCM, CCFP(EM), CSPQa, EBEM Commentator Contact and James E. Andruchow MScb, EBEM Commentator Contact aEmergency Department, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada bDepartments of Medicine and Dentistry, McGill University, Montreal, Quebec, Canada. Available online 27 April 2006.) [Ann Emerg Med. 2006;58:98-100.] Systematic review source This is a systematic review abstract, a regular feature of the Annals’ Evidence-Based Emergency Medicine (EBEM) series. Each features an abstract of a systematic review from the Cochrane Database of Systematic Reviews and a commentary by an emergency physician knowledgeable in the subject area. The source for this systematic review abstract is: Prasad K, Al-Roomi K, Krishnan PR, et al. Anticonvulsant therapy for status epilepticus. The Cochrane Database of Sytematic Reviews 2006, Issue 1. Art No.: CD 003723. DOI: 10.1002/14651858. CD003723. The Annals’ EBEM editors assisted in the preparation of the abstract of this Cochrane systematic review, as well as selection of the Evidence-Based Medicine Teaching Points. Objective The objective of this systematic review was to compare selected anticonvulsant therapies against each other or placebo for treatment of status epilepticus in terms of effectiveness and safety. Furthermore, the review attempted to identify reasons for disagreements in the literature about optimal anticonvulsant therapy, and to highlight areas for further research. Data sources The authors searched for randomized controlled trials from several electronic databases, including the Cochrane Epilepsy Group Specialized Register (July 2005), Cochrane Central Database of Controlled Trials (CENTRAL) (Issue 2, 2005), MEDLINE (1966 to August 2004), and EMBASE (1966 to January 2003). Study selection Studies were selected if they were randomized controlled trials using random or quasirandom treatment allocation and included patients with several stages of status epilepticus: premonitory (period during which seizures became increasingly frequent or severe but did not meet the definition of status epilepticus), early (the first 30 minutes of seizure activity), established (either more than 30 minutes of continuous seizure activity or 2 or more seizures without recovery of full consciousness between the seizures), or refractory (seizure activity uncontrolled for 1 to 2 hours despite first-line treatment). Selected studies compared anticonvulsant drugs against placebo or another anticonvulsant and examined the outcome of “treatment failure,” defined primarily as the noncessation of seizure activity. Data extraction and analysis Two reviewers independently selected published trials for inclusion and methodologic quality; disagreements were adjudicated by a third reviewer. Data on the number of participants with a given outcome in each treatment arm were independently extracted and verified by 2 reviewers. The authors initially proposed to study risk of treatment failure as the primary outcome and to conduct separate analyses for each of several stages of status epilepticus, including premonitory, early, established, and refractory status epilepticus; however, this was not possible owing to limitations of the data, and these groups were combined for analysis. Heterogeneity among trials was examined with the χ2 test, and where no heterogeneity was evident, trials were combined using a fixed-effects model to provide a summary estimate of effect. Main results Eleven studies with analyzable data containing 2,017 participants were included in the review. Five of the 11 trials studied patients with premonitory status, 1 each with established and refractory status, 2 with mixed status, and 2 with the stage poorly defined. Seven of these studies included only adult patients, 4 only children. Fourteen different therapeutic comparisons were made in these trials, but only 3 of these were replicated in multiple studies to permit meta-analysis. All comparisons of the intravenously administered benzodiazepines diazepam and lorazepam against placebo significantly favored the intervention arms. The comparisons of lorazepam intravenously versus phenytoin intravenously, lorazepam intravenously versus diazepam intravenously, and an examination of diazepam intrarectal gel efficacy are of particular interest and will be presented in detail. Lorazepam intravenously was superior to phenytoin intravenously in a single study with 198 participants, with lower risk for noncessation of seizures (relative risk [RR] 0.62; 95% confidence interval [CI] 0.45 to 0.86). According to 3 trials with 289 participants, lorazepam intravenously was more effective than diazepam intravenously for decreasing the risk of noncessation of seizures (RR 0.64; 95% CI 0.45 to 0.90) and continuation of status epilepticus requiring a different drug or general anesthesia (RR 0.63; 95% CI 0.45 to 0.88); however, lorazepam did not significantly reduce the requirement for ventilatory support (RR 0.73; 95% CI 0.36 to 1.49) or the number of adverse effects (risk difference [RD] −0.03; 95% CI −0.10 to 0.03). Furthermore, there was no statistically significant difference in deaths between the groups according to data available from 2 of the studies with 203 patients (RD 0.02; 95% CI −0.04 to 0.08). Diazepam intrarectal gel was superior to placebo gel according to 2 studies with a total of 165 participants, demonstrating lower risk for noncessation of seizures (RR 0.43; 95% CI 0.30 to 0.62). Conclusions The authors conclude that lorazepam is superior to either diazepam or phenytoin for cessation of seizures, and compared to diazepam carries a lower risk of continuation of status epilepticus requiring the use of a different drug or general anesthesia. Lorazepam and diazepam are both better than placebo for the same outcomes, and diazepam intrarectal gel is useful in premonitory status. Cochrane Systematic Review Author Contact Kameshwar Prasad, DM, MSc Neurosciences Center All India Institute of Medical Sciences New Delhi, India E-mail drkameshwarprasad@yahoo.co.in Commentary: Clinical implication Status epilepticus is defined as a period of continuous motor seizure activity lasting 30 minutes or more or 2 or more consecutive seizures without a return to full consciousness between the seizures. Overall, seizure disorders are common in the emergency department (ED); however, status epilepticus is an infrequently encountered condition. Its importance lies in the fact that it is a dangerous disease, with high morbidity and mortality. First-line therapy for status epilepticus is usually a benzodiazepine, many of which are commonly available in EDs, including diazepam (Valium), lorazepam (Ativan), and midazolam (Versed). Benzodiazepine administration should be followed by phenytoin whose long-acting anticonvulsant properties prevent recurrence and thus play an integral role in the management of status epilepticus. Finally, in patients without a known seizure disorder, search for the causative insult (eg, bleeding, trauma, other medications, infections) is necessary. Because of the rapidity with which severe injury or death can occur in status epilepticus, using optimal anticonvulsant therapy is essential to minimizing adverse outcomes such as cerebral injury, cardiac arrhythmias, aspiration, and rhabdomyolysis. Unfortunately, current emergency medicine textbooks and guidelines for treatment of status epilepticus either do not specify a preferred first-line agent 1 and 2 or present limited justification for their choice.3 This systematic review presents new evidence and highlights the need to update our resources with current evidence-based information. This Cochrane review collected the best available evidence on the use of a variety of interventions for the treatment of status epilepticus. Overall, the review covers the topic broadly; however, it fails to identify sufficiently similar comparisons to draw useful conclusions to many questions. The meta-analysis evidence presented in this review suggests that lorazepam is more effective than diazepam for first-line treatment of status epilepticus, perhaps in part because of its more favorable pharmacokinetics, including a longer redistribution half-life than diazepam.4 The longer duration of clinical efficacy also facilitates the transition to antiepileptic medications such as phenytoin for long-term seizure control. Better control of status epilepticus results in not only improved patient outcomes but also considerable savings to the health care system, with less costly and invasive treatment requirements, such as airway control and general anesthesia. Given that lorazepam is only marginally more expensive than diazepam, lorazepam should be the preferred first-line agent for status epilepticus in the ED. Because diazepam intrarectal gel is also effective in controlling premonitory status epilepticus, with relative ease of use but high cost, it may be most useful in the out-of-hospital setting. While the cessation of motor seizures is often used clinically to signify the termination of a status epilepticus episode, the absence of motor seizures does not preclude either nonconvulsive status epilepticus or subtle convulsive status epilepticus and concomitant ongoing cerebral injury. Thus, altered level of consciousness persisting after motor seizures have ceased should be treated with a high level of clinical suspicion in the ED and should be investigated further, ideally with emergency electroencephalogram.5 Take-home message Lorazepam provides better control over status epilepticus than does either diazepam or phenytoin. Both intravenous lorazepam and diazepam are effective in controlling status epilepticus; diazepam intrarectal gel also can be used in premonitory status. Standardization of seizure terminology and clinical research protocols is necessary to facilitate more detailed analyses of the therapeutic options for status epilepticus. EBEM Commentator Contact Eddy S. Lang, MDCM, CCFP(EM) CSPQ Emergency Department SMBD Jewish General Hospital Montreal, Quebec, Canada E-mail eddylang@videotron.ca EBEM teaching point Broad versus narrow scope in systematic reviews. Systematic reviews may address questions that are either broad or narrow.6 Broad-based reviews might examine whether any of a variety of therapeutic options are useful in achieving a certain outcome, as was done in this review examining the efficacy of various anticonvulsants in control of status epilepticus. In contrast, reviews with a narrow scope address a specific question, often directly examining the effect of a particular therapy on a well-defined outcome. Both approaches have advantages and disadvantages; whereas broad questions tend to be more easily generalizable to multiple settings and populations, they often prove more time consuming and expensive to answer. Furthermore, results may be difficult to synthesize and interpret, and validity may be compromised, particularly when the results of large numbers of heterogeneous studies are combined. Narrow questions may provide better-defined answers but tend not to be as generalizable. The choice of whether to use a narrow or broad-based approach in a systematic review should depend on the nature and complexity of the problem being addressed, the available evidence to synthesize, and the availability of resources to address it. References 1 In: J.A. Marx, R.S. Hockberger and R.M. Walls, Editors, Rosen’s Emergency Medicine Concepts and Clinical Practice (6th ed.), Mosby, St. Louis, MO (2005). 2 Working Group on Status Epilepticus, Treatment of convulsive status epilepticus recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus, JAMA 270 (1993), pp. 854–959. 3 In: J.E. Tintinalli, G.D. Kelen and J.S. Stapczynski, Editors, Emergency Medicine A Comprehensive Study Guide (6th ed.), McGraw-Hill, Medical Division, New York, NY (2004). 4 D.M. Treiman, Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus, Epilepsia 30 (1989), pp. S4–S10. Abstract-EMBASE 5 American College of Emergency Physicians Clinical Policies Committee and Clinical Policies Subcommittee on Seizures, Clinical policy critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures, Ann Emerg Med 43 (2004), pp. 605–625. 6 Higgins JPT, Green S, eds. Formulating the problem. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005], section 4. Available at: http://www.cochrane.org/resources/handbook/book.htm. Accessed May 31, 2005

(Annals of Emergency Medicine Volume 48 @ Issue 1 , July 2006, Pages 86-97 doi:10.1016/j.annemergmed.2005.11.024 Copyright © 2006 American College of Emergency Physicians Published by Mosby, Inc. Cardiology/evidence-based emergency medicine review Vasopressin or Epinephrine for Out-of-Hospital Cardiac Arrest Peter C. Wyer MDa, , , Phillips Perera MDa, Zhezhen Jin PhDb, Qi Zhou PhDd, Deborah J. Cook MDc, d, Stephen D. Walter PhDd and Gordon H. Guyatt MDc, d aEmergency Medicine Residency Program, New York Presbyterian Hospital, New York, NY bDepartment of Biostatistics, Columbia University, New York, NY cDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada. dDepartment of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. Received 13 January 2005; revised 1 June 2005, 30 August 2005, 1 November 2005; accepted 14 November 2005. Available online 10 February 2006.) Study objective The use of vasopressin in patients with cardiac arrest presenting with specific rhythms is controversial. We performed an evidence-based emergency medicine review of evidence comparing vasopressin to epinephrine in structured cardiac arrest protocols. Methods We searched MEDLINE, EMBASE, the Cochrane Library, and other databases for randomized trials or systematic reviews comparing vasopressin to epinephrine for adults with cardiac arrest and measuring survival to hospital discharge and neurologic function in survivors. We used standard criteria to appraise the quality of published trials and systematic reviews. We used the random effects model in supplementary analyses to summarize results and to test for significant differences across subgroups of patients presenting with different arrest rhythms. Results We found 3 high-quality well-reported randomized trials and 1 rigorous meta-analysis. The evidence does not confirm a consistent benefit of vasopressin over epinephrine in increasing survival or improving neurologic outcome in survivors. Subgroup analysis reveals a large difference in effect of vasopressin over epinephrine in cardiac arrest patients with asystole, compared to other arrest rhythms, coming from within-trial comparisons. The difference is not consistent across otherwise similar trials, is not statistically significant, may reflect the application of multiple unplanned subgroup analyses, and is not supported by a plausible biological hypothesis. Conclusion Evidence from randomized trials does not establish a benefit of vasopressin over epinephrine in increasing survival to discharge or improving neurologic outcomes in adult patients with nontraumatic cardiac arrest. Article Outline Clinical scenario Formulating the question Searching for and selecting the best evidence Examining the evidence Description of the trials Primary results of the trials Subgroup analysis Was the subgroup difference suggested by comparisons within rather than between studies? Was the magnitude of the subgroup difference large? Was the subgroup difference consistent across studies? Was the subgroup difference statistically significant? Applying the evidence Critically Appraised Topic (CAT): Does vasopressin in place of epinephrine improve survival to discharge without worsening neurological function in patients with out-of-hospital cardiac arrest? References Clinical scenario You are the medical and education director of a regional emergency medical system with basic and advanced life support capabilities. Publicity about a recent trial of vasopressin as an alternative to epinephrine for patients with cardiac arrest leads several members of your training committee to ask when your system is shifting to that alternative. They point out that the American Heart Association guidelines for cardiac resuscitation that you use as the basis for your own advanced life support protocols already list vasopressin as an option. Your paramedic ambulances do not stock vasopressin, nor do your training and recertification programs include it. You decide to examine the evidence favoring vasopressin over epinephrine before making a major revision in your protocols. The following evidence-based emergency medicine review1 seeks an answer to the question posed by this scenario. Formulating the question Hospital inpatients receiving cardiac resuscitation might have a prognostic advantage over patients outside of the hospital by virtue of earlier recognition and more rapid initiation of basic and advanced life support interventions. On the other hand, inpatients’ prognosis may be adversely affected by their concomitant acute conditions. The magnitude and direction of difference in effect of vasopressin on cardiac arrest outcomes between patients inside and outside of the hospital are unpredictable. We therefore included inpatient studies. We confined our review to survival to hospital discharge and good neurologic function, outcomes that we believe patients themselves most value. Patients and families might consider admission to an ICU with no increased chance of survival to discharge to constitute an undesirable consequence of a new resuscitation drug. For expediency, resuscitation trialists sometimes define “survival to admission” as their primary outcome measure.2 and 3 Unfortunately, an intervention’s impact on a surrogate outcome such as survival to hospital admission is no guarantee of patient-important benefit.4 and 5 Several studies suggest that survival to ICU admission is not a good surrogate for survival to hospital discharge.2, 3 and 6 We formulated our question as: In patients with cardiac arrest not attributable to trauma or environmental exposures, what is the impact on survival to hospital discharge and survivor neurologic function of vasopressin compared to epinephrine, administered at the first point in a cardiac arrest protocol at which epinephrine would routinely be given? Searching for and selecting the best evidence We searched for randomized trials and systematic reviews comparing vasopressin to epinephrine for adults in cardiac arrest. We searched MEDLINE from 1966 to July 2004 and EMBASE from 1980 to January 2004 with the OVID interface, using search terms “vasopressin,” “epinephrine,” “cardiac arrest,” and “heart arrest,” with no language restrictions. We limited our MEDLINE search, but not our other searches, to randomized trials or systematic reviews using epinephrine as the comparison intervention. We included randomized trials or systematic reviews of randomized trials, with no other exclusion criteria. Our search yielded 271 results. We also searched all databases of the Cochrane Library7 through 2004 issue 1, Emergency Medical Abstracts (available online at http://ccme.org) from 1977 through December 2004,8 and online resources including BestBETS (available online at http://www.bestbets.org), using the single search term “vasopressin.” These databases yielded a total of 1,036 results. We reviewed the bibliographies of eligible trials and systematic reviews and of selected non–systematic reviews and commentaries for citations of additional eligible articles. Finally, we searched the bibliography of the relevant sections of the 2000 update of the American Heart Association Advanced Cardiac Life Support guideline.9 We found 3 trials comparing vasopressin to epinephrine in patients with cardiac arrest, 2 out-of-hospital10 and 11 and 1 limited to inpatients.12 One published systematic review,13 1 protocol in the Cochrane Database of Systematic Reviews,14 and 1 “shortcut review,”15 as well as our bibliographical reference review, revealed no additional trials. We found no placebo-controlled trials or other human randomized trials involving vasopressin for patients with cardiac arrest. The systematic review by Biondi-Zoccai et al13 was limited in its reporting, was not restricted to clinical trials, and did not include the most recent and largest randomized trial by Wenzel et al.11 After the completion of our primary searches and after the initial submission of our review, a second, well-reported, systematic review appeared that used inclusion criteria identical to our own.16 Aung and Htay16 identified the same 3 trials identified by our searches, as well as 2 additional clinical trials.17 and 18 We will focus the rest of this review on the Aung and Htay16 meta-analysis, supplemented by elements of our own analysis that either differ from or go beyond that of Aung and Htay.16 Examining the evidence Aung and Htay16 restricted their review to randomized trials comparing vasopressin to epinephrine in patients with cardiac arrest and reporting patient-important outcomes. They independently selected studies for inclusion. Aung and Htay16 report a rigorous search of MEDLINE, EMBASE, the Cochrane Library, CINAHL, bibliographies of related articles, registries of conference proceedings, and unpublished trials. They found a statistical test for evidence of studies not identified by their search to be negative. In addition to the 5 trials mentioned previously,10, 11, 12, 17 and 18 Aung and Htay16 also report the existence of a trial in progress, the Cardiac Arrest Research Project being conducted by the University of Pittsburgh (available online at http://newsbureau.upmc.com/emergency/vasopressin04.htm). This trial compares vasopressin to placebo as an addition to standard therapy including epinephrine and will not be eligible for inclusion in our review. Description of the trials Table 1 summarizes the key features of the 5 randomized trials identified by Aung and Htay16 and included in their analysis. Of the 2 trials not identified in our own independent search, one was limited to 10 patients and was published in abstract form only,17 and the other was published in a Chinese journal.18 The inclusion of non-English studies and abstracts in systematic reviews is controversial.19 and 20 Exclusion of unpublished studies may lead to underestimation of treatment effect.19 and 21 On the other hand, inclusion of non-English and incompletely reported studies may have little impact on the results of most systematic reviews.22 and 23 Table 1. Summarizing the characteristics of 5 randomized trials comparing vasopressin to epinephrine in patients with cardiac arrest. Study Patients Interventions Comparisons Outcomes Wenzel et al,11 2004 1,186 European adult patients with out-of-hospital arrest, average age 66 years, 70% men. Excluded terminally ill patients, those successfully defibrillated without drugs or with trauma; 61% arrests attributed to cardiac causes; 40% ventricular fibrillation, 44% asystole; 78% arrests witnessed, average time from arrest to basic life support 7.9 min and to advanced life support 14.9–15.6 min 40 IU vasopressin intravenously either immediately or after 3 attempts at defibrillation Dose repeated in 3 minutes if no return of circulation 1 mg Of epinephrine intravenously after same protocol as for vasopressin Survival to hospital admission and to discharge, neurologic function by cerebral performance scale24 and 25 Stiell et al,12 2001 200 Adult patients with cardiac arrest in Canadian hospitals or emergency wards; 81% inpatients, 50% ward patients, 22% ICU. Average age 70 years, 64% men. Excluded terminally ill patients or those with trauma or exsanguination; 30% of arrests attributed to cardiac causes; 18% ventricular fibrillation, 31% asystole; 81% of arrests witnessed, average time from arrest to basic life support 1.4–1.9 min and to advanced life support 2.5–3.2 min 40 IU Vasopressin intravenously at the point in ACLS protocols that epinephrine first indicated. One dose only 1 mg epinephrine intravenously after same protocol as for vasopressin Survival to hospital discharge, neurologic function by cerebral performance scale 25 and the Mini-Mental State examination38 Lindner et al,10 1997 40 Adult European patients with out-of-hospital ventricular fibrillation arrest. Average age 65 years, 72% men. Excluded patients with trauma or terminal illness and patients who received epinephrine by endotracheal tube. Average time from arrest to basic life support 6.1–6.5 min, and to advanced life support 13.9–15.1 min 40 IU Vasopressin intravenously after shocks failed to restore rhythm. One dose only 1 mg Epinephrine intravenously once after shocks failed to restore rhythm Survival to admission and to hospital discharge, neurologic function by Glasgow Coma Scale score Lee et al, 200017 10 Patients in a large university teaching hospital. Other details ambiguous or not reported. 40 Units vasopressin given 0.1 unit/kg/min “as a bolus” Epinephrine, dose not stated Return of spontaneous circulation not otherwise described. Neurologic outcome not otherwise described. Li et al, 199918 83 Adult Chinese hospital inpatients. Average age 57 years, 67% men. “Average cardiac arrest time” 10 min, not otherwise characterized. Other population details not reported. 0.5 U/kg Vasopressin or 1.0 U/kg vasopressin administered every 10 min 1.0 mg Epinephrine or 5.0 mg epinephrine administered every 5 minutes Hospital discharge. No neurologic assessment reported. ACLS, Advanced cardiac life support. Two members of our own author team fluent in Chinese (QZ and ZJ) reviewed the full text of the study by Li et al.18 The reports by Lee17 and Li18 do not allow full assessment of their study populations, treatment protocols, or the susceptibility to bias, nor do they provide information about the distribution of presenting rhythms between their study groups. We are unclear about the relationship of the results reported by Lee et al17 to our own target outcomes. Aung and Htay16 report failed attempts to obtain more information from the authors of these 2 trials. We did not attempt to reproduce their inquiry. The inclusion of these studies in a pooled analysis might distort the estimates in ways that the parsimoniously reported data does not allow an investigator to anticipate or assess. The 3 fully reported trials encompass a broad range of settings and variability within potentially important parameters, such as time from arrest to initiation of advanced life support. For example, in contrast to the patients studied by Wenzel et al11 and Lindner et al,10 the patients studied by Stiell et al12 had concomitant acute problems warranting emergency department or hospital admission. Twenty-two percent were in the ICU at arrest.12 Aung and Htay16 did not perceive these factors to prohibit pooling of the results of their primary outcomes across the trials, nor do we perceive them to constitute a priori incompatibility of these studies. The 2 largest trials11 and 12 used a common measure of neurologic outcome, a previously published cerebral performance instrument characterized by clear and discrete gradations of functional recovery, ranging from death to full recovery.24 Other investigators have used this instrument in cardiac resuscitation research.25 A preliminary report by Nesbitt et al26 indicates that this instrument correlates well with a highly validated measure of health-related quality of life27 but may overestimate the extent of functional recovery in survivors.26 Aung and Htay16 performed independent assessment of the quality of the trials included in their review, with particular attention to concealment of randomization, blinding, completeness of follow-up, and outcome assessment.16 They found uniformly high quality in the 3 assessable trials using these criteria,10, 11 and 12 although the blinding of outcome assessment was not explicit in the study by Lindner et al.10 Aung and Htay16 report 80% agreement for their independent assessments (κ=.64). Table 2 summarizes our own assessment of the likelihood of bias within the 3 fully reported trials, using criteria similar to those used by Aung and Htay.16 and 28 The loss of 76 patients to complete follow-up (6% of patients randomized) in the Wenzel et al11 study is potentially problematic. If these patients and their outcomes were not randomly distributed between the treatment groups, the results of the trial might be substantially affected. Table 2. Summarizing the assessment for susceptibility to important bias of the 3 fully reported trials. Criterion Wenzel et al,11 2004 Stiell et al,12 2001 Lindner et al,10 1997 Randomization Multicenter randomized trial. Randomization blocked in groups of 10 and stratified by center Multicenter randomized trial. Random distribution of study drugs to crash carts in treatment centers. Stratified by center Single-center randomized trial. Computer-generated randomization of identical syringes Concealment Adequate Adequate Adequate Intention to treat Yes 74 (27%) Patients were excluded post hoc by means of blinded adjudicated revision of eligibility assessment; 50 were due to cardiac arrest before arrival in hospital. The others were due to protocol violations or ineligibility caused by clinical circumstances Yes Baseline comparisons 38% of patients receiving vasopressin presented with ventricular fibrillation versus 41% of patients receiving epinephrine 20% Of patients receiving vasopressin presented with ventricular fibrillation versus 16% of patients receiving epinephrine. Treatment times were somewhat longer in vasopressin group Well balanced within limits of small number of allocations Blinding Blinded with respect to patients, care providers, and data collectors, except for 5 patients whose protocols were broken after hospital admission. Reporting of blinding not explicit for assessors of neurologic outcome or data analysts Blinded with respect to patients, care providers, and data collectors. Reporting of blinding not explicit for assessors of neurologic outcome or data analysts Blinded with respect to patients, care providers. Reporting of blinding not explicit for data collectors, assessors of neurologic outcome, or data analysts Cointerventions Bystander CPR 19% vasopressin, 18% epinephrine. Time from BLS to ACLS interventions 7.0 min in vasopressin group, 7.7 min in epinephrine group. About 2% more of the vasopressin group received lytics, and 2% fewer received amiodarone and atropine compared to epinephrine group Time from arrest to study drug 3.2 min vasopressin, 2.5 min epinephrine. No consistent pattern of imbalance in reported drug therapies other than the study drugs Bystander CPR 20% vasopressin, 25% epinephrine. Time from arrest to study drug 15.1 min vasopressin, 13.9 min vasopressin. Distribution of other cointerventions not reported Complete follow-up 33 (2.8%) Patients could not be included in analysis because of missing study-drug codes. Additionally, 20 patients, equally divided, were lost to follow-up before hospital discharge, and another 23 patients who survived to discharge were lost to neurologic follow-up. Complete Complete CPR, Cardiopulmonary resuscitation; BLS, basic life support. Primary results of the trials Aung and Htay16 chose the random effects model to summarize data from the 5 trials they included.29 and 30 The random effects model usually leads to wider confidence intervals (CIs) around the pooled result than does the fixed effects model and may be considered “more conservative” for this reason.31 Aung and Htay16 used standard methods to assess for statistical heterogeneity between the results of the included studies. They used the I2 statistic to provide an estimate of the percentage of the variability between the results of studies being pooled that is due to true differences between the studies, as opposed to variability due to chance alone.32 and 33 When all 5 trials were included, Aung and Htay16 report a high degree of heterogeneity for the primary outcome of death before hospital discharge.16 The χ2 test for heterogeneity yielded a P value of .09, which is less than the commonly preferred cutoff of .1. I2 was 34%, suggesting a substantial portion of variability between the studies to be due to actual differences. In our own analysis, using odds ratios for the same outcome and including only the 3 fully reported trials, the P value for heterogeneity was .21, and the I2 value was 35%. Most of the heterogeneity is due to a trend in the direction of benefit of vasopressin in the study by Lindner et al,10 a trend not observed in the studies by Wenzel et al11 and Stiell et al.12 and 16 A review of the characteristics of the Lindner et al10 study, compared to the analogous characteristics of the studies by Wenzel et al11 and Stiell et al,12 (Table 1) fails to reveal consistent differences that would explain this difference in trend. Under the circumstances, pooling of these 3 studies, as elected by Aung and Htay,16 may reasonably provide a more generalizable result.34 Aung and Htay16 report a pooled relative risk of death before hospital discharge, vasopressin compared to epinephrine, across the 3 fully reported trials of 0.99 (95% CI 0.95 to 1.02). When the trials by Li et al18 and Lee et al17 were included, the relative risk was 0.96 (95% CI 0.87 to 1.05). Our own analysis also used the random effects model and preferred odds ratios to risk ratios because of important inconsistencies between the results when risk ratios were used. Such inconsistencies commonly occur when outcome rates are extremely high, as in cardiac arrest. Our pooled odds ratio for the outcome of predischarge mortality, vasopressin compared to epinephrine, was 0.91 (95% CI 0.52 to 1.57). In all analyses, the CI around the pooled effect included values favoring epinephrine. Aung and Htay16 analyzed the effect of vasopressin on death before hospital discharge or neurologic impairment. They grouped patients with only moderate disability together with those who died or were in a persistent vegetative states and included the study by Lee et al17 with those by Stiell et al12 and Wenzel et al.11 The Lee et al17 study contributed substantial heterogeneity to this analysis (I2 of 34%).16 Aung and Htay16 report a pooled relative risk of death or neurologic impairment, vasopressin compared to epinephrine, of 1.0 (95% CI 0.94 to 1.07). A disadvantage of the Aung and Htay16 approach to assessment of neurologic outcome is that a patient with some residual neurologic deficit but still able to engage in part-time employment is grouped with patients who die or survive with major functional or cognitive impairment. To correct for this disadvantage, including data from the 2 trials that used a common measure of outcome, we classified patients in the 2 worst neurologic outcome categories by the cerebral performance instrument 24 and 25 used by Stiell et al12 and Wenzel et al11 as “poor neurologic outcome.” Such patients may have some cognitive function but no independence in activities of daily living. A patient without poor neurologic function by these criteria is at least able to engage in part-time employment in a sheltered environment.25 We believe that this definition of the outcome is more likely to cohere with the values of patients and their families than is that used by Aung and Htay.16 Using this revised composite outcome of death or major disability, the pooled odds ratio, vasopressin compared to epinephrine, is 1.32, 95% CI 0.82 to 2.14 (Figure 1). We found no important trends with respect to other measures of cognitive function used by Stiell et al12 and Lindner et al.10 (38K) Figure 1. Forest plot of outcome of death or severe disability in the 2 trials using a common measure of neurologic outcome. For each trial, the small square corresponds to the observed odds ratio for predischarge mortality, and the horizontal line defines the 95% CI. An odds ratio of 1, identified by the vertical line, would reflect an identical effect of the 2 drugs. The lowest plot provides the pooled random effects odds ratio and CI. Poor neurologic outcome is defined as a score of 3 or greater on the cerebral performance score.25 Subgroup analysis Wenzel et al11 emphasized an apparent positive effect of vasopressin in decreasing hospital mortality among patients presenting with asystole when advanced life support interventions were initiated. Three trials report data on predischarge mortality in subgroups of patients defined by presenting rhythm at initiation of resuscitation.10, 11 and 12 Lindner et al’s10 small trial was confined to patients presenting with ventricular dysrhythmias. Wenzel et al11 also reported apparent benefit of initial vasopressin over initial epinephrine among patients receiving additional doses of epinephrine after the 2 doses of the study drug provided for in the protocol failed to result in return of spontaneous circulation. Such patients are not prospectively identifiable, nor has this effect been reported in other trials. Aung and Htay16 detected no statistically significant difference between subgroups defined by presenting rhythm. Their analysis does not, however, exhaust the issue raised by Wenzel et al11 and others. We conducted a systematic subgroup analysis using published validity criteria (Table 3).35 and 36 We confined our consideration of the effect of vasopressin in subgroups to the hypothesis that vasopressin is of benefit in patients with asystole but not in those with ventricular fibrillation. We present the criteria in suggested order of application. Table 3. Summary of appraisal of presenting rhythm subgroups in 3 randomized trials comparing vasopressin to epinephrine in patients with cardiac arrest based on criteria proposed for evaluation of subgroup analyses in randomized trials.35 and 36 The hypothesis of a selective benefit of vasopressin over epinephrine in patients resenting with asystole fails with respect to several criteria. Criterion Conclusion Was the subgroup difference suggested by comparisons within rather than between studies? Yes. The effect of vasopressin compared to epinephrine on predischarge mortality was reported for the asystole subgroup within 2 of the 3 trials. Was the magnitude of subgroup difference large? Yes. The pooled odds ratio of 0.43 for predischarge mortality for patients in asystole must be considered a large effect compared to the pooled odds ratio of 1.00 for patients in the ventricular fibrillation subgroup (Figure 3). Was the subgroup difference consistent across studies? No. Only 1 trial showed benefit in patients presenting with asystole. One trial showed a trend toward benefit in patients presenting with ventricular fibrillation, a trend that was not observed in the other 2 trials. Was the subgroup difference statistically significant? No. The effect of vasopressin compared to epinephrine on predischarge mortality in patients with asystole was not statistically different from that in patients with ventricular fibrillation. Did the trialists plan the subgroup analysis in advance? Unclear. The only study to report a subgroup effect did not report advance planning of the analysis. Were many subgroup analyses performed and selectively reported? Unclear in the Wenzel et al 11 trial. Stiell et al 12 considered many subgroups. Is the difference in effect in the subgroup supported by biological hypothesis? No. A biological hypothesis supporting a selective benefit of vasopressin in patients presenting in asystole or in another rhythm class has not been elaborated in either the trials or other sources reviewed in preparation for our analysis. Was the subgroup difference suggested by comparisons within rather than between studies? When investigators conduct independent trials on different subgroups of patients (eg, one trial includes only patients with asystole, another only patients with ventricular fibrillation), apparent differences in effect between the studies may originate from differences in the study populations other than that hypothesized (differences in comorbidity rather than differences in cardiac rhythm) or in aspects of study design (blinding of clinicians or outcome assessors) rather than from differences in response between the subgroups on whom the investigators focus (ventricular fibrillation versus asystole). The apparently greater benefit of vasopressin in patients with asystole reported by Wenzel et al11 is an example of a “within-study” comparison (both Wenzel et al11 and Stiell et al12 included patients with ventricular fibrillation and asystole), and this strengthens the hypothesis that the difference in effect may be real. Was the magnitude of the subgroup difference large? The larger the observed difference in effect between subgroups, the less likely it is to have arisen by chance alone. SDW and QZ performed an exact analysis using a logistic regression model to assess the magnitude and precision of subgroup effects. We believe this method to be more reliable in the setting at hand because exact models are generally preferable, and particularly so when, as here, the data are sparse. The pooled odds ratio for predischarge mortality of patients treated with vasopressin compared to those treated with epinephrine from our exact inference analysis was 0.43 for the asystole subgroups reported by Wenzel et al11 and Stiell et al,12 contrasting with 1.00 for the ventricular fibrillation subgroups of all 3 trials. This large difference supports the subgroup hypothesis. Was the subgroup difference consistent across studies? Wenzel et al11 observed a trend in the direction favoring vasopressin over epinephrine among patients presenting with asystole and a trend in the opposite direction among patients presenting with ventricular fibrillation (and with pulseless electrical activity). In the trial by Stiell et al,12 the trends in both asystole and ventricular fibrillation subgroups favored epinephrine. The Lindner et al10 study of patients with ventricular fibrillation observed a trend in favor of vasopressin. Hence, a consistent pattern of subgroup effects does not emerge from the trials to date. Was the subgroup difference statistically significant? Investigators and authors sometimes contrast a statistically significant difference between treatment and control in one subgroup (such as those with asystole) with the lack of statistical significance in another subgroup (such as those with other presenting rhythms). This, however, misses the important question, can the difference between the apparent effects in different subgroups (asystole versus ventricular fibrillation) be explained by chance?36 Aung and Htay16 applied a statistical test for heterogeneity to pooled results in each of the 3 rhythm subgroups. This approach is illustrated in simplified form in Figure 2. In both the Aung and Htay16 analysis and our own, the tests for significance yield P values well above .1 and low values of I2, indicating that the observed effect of vasopressin compared to epinephrine in patients with asystole is consistent with a hypothesis of a uniform underlying effect across all rhythm subgroups. This falls short of a direct test of the difference in comparative effect of vasopressin between asystole and other rhythm subgroups. Our own analysis illustrates such a direct test. (39K) Figure 2. Forest plot illustrating an indirect approach to testing for statistical significance of differences in subgroup effect. See legend to Figure 1 for the explanation of the plot. Subgroup data are pooled across the 2 studies that included patients with all 3 presenting rhythm subtypes. A statistical test for heterogeneity is applied. The P value of .51 indicates that the effect of vasopressin compared to epinephrine on mortality within these 3 subgroups is consistent with an underlying effect. The I2 value of 0 further suggests that all of the observed variation between the subgroups is attributable to chance. We started our exact analysis by considering the possibility of an interaction between presenting rhythm subgroup and treatment effect. When we found no significant interaction, we repeated the analysis without the interaction term and computed exact tests of the subgroup and treatment main effects. The method was applied to all 3 trials (Figure 3)10, 11 and 12 and—because this is restricted to within-study comparisons of ventricular fibrillation and asystole subgroups—to the studies by Wenzel et al11 and Stiell et al.12 (55K) Figure 3. Forest plot illustrating the pooled subgroup effects from the analysis. The analysis uses paired and unpaired data pertaining to the asystole and ventricular fibrillation subgroups from the trials by Wenzel et al,11 Stiell et al,12 and Lindner et al.10 See legend to Figure 1 for the explanation of the plot. Odds ratios for the effect on mortality of vasopressin compared to epinephrine are pooled within each subgroup. See text for further explanation. Figure 3 displays the results of our statistical analysis of the subgroup effect. The question we are asking is, can the difference in the odds ratios in the asystole group (0.43) and the ventricular fibrillation group (1.00) be explained by chance? The ratio of these 2 odds ratios is 0.43, and the 95% CI is 0.12 to 1.37. The CI includes 1 and indicates that the difference between the original odds ratios of 0.43 and 1.00 is compatible with chance, ie, it is not statistically significant (P=.18). The odds ratio for mortality for these 2 subgroups from the 3 trials is 0.87 (95% CI 0.58 to 1.29) favoring vasopressin. As a further control for study effect in the exact model, the ratio of odds ratios of effect on mortality of vasopressin in asystole compared to ventricular fibrillation subgroups in the strictly paired analysis is 0.38 (95% CI 0.11 to 1.22; P=.12), and the odds ratio for mortality in both subgroups combined is 0.95 (95% CI 0.62 to 1.44), both reflecting trends favoring vasopressin. In summary, when a direct test of statistical significance is applied, the trend toward a mortality benefit of vasopressin compared to epinephrine in patients with asystole is not significantly different from the comparative effect in patients with ventricular fibrillation. As summarized in Table 3, the remaining criteria for believability of the subgroup hypothesis about vasopressin compared to epinephrine in patients with asystole were not met. Applying the evidence Returning to our clinical scenario, as the director of emergency medical services and personnel in your region, you must consider a number of issues in deciding whether to upgrade the status of vasopressin in your protocols for patients in cardiac arrest. The recent trial of vasopressin compared to epinephrine received high publicity in the lay press. An editorial accompanying the Wenzel et al11 trial report in the New England Journal of Medicine called for unscheduled conventions of the American Heart Association and the American College of Cardiology to incorporate a recommendation of vasopressin for patients presenting in asystole.37 You consequently may be under some pressure to provide the perceived benefits of the new therapy to the region and may even be identified as the cause of any delay. Changing regional emergency medical services protocols, however, entails considerable effort and expense, whether or not unscheduled meetings and conferences are required. Your regional emergency medical services committee would have to approve the new protocol, and you would have to administer a training update to all relevant care providers. To justify this effort, you need convincing evidence that a patient-important benefit of vasopressin exists. We have summarized the data from a well-done meta-analysis and from the 3 fully reported randomized trials and have found no overall effect of vasopressin compared to epinephrine in reducing mortality before discharge. After systematically applying 7 published criteria for evaluation of subgroup analyses in randomized trials of effectiveness, we have concluded that the evidence of an important survival benefit of vasopressin over epinephrine for patients with asystole is not compelling. It also remains unclear whether vasopressin compared to epinephrine improves or worsens neurologic outcomes in survivors. Our review is subject to the limitations inherent in shortcut reviews.1 However, a well-done meta-analysis and our own independent analysis all suggest that you may reasonably decide not to change cardiac arrest protocols until new evidence becomes available. References 1 P.C. Wyer, B.H. Rowe and G.H. Guyatt et al., The clinician and the medical literature when can we take a shortcut?, Ann Emerg Med 36 (2000), pp. 149–155. Abstract | Abstract + References | PDF (38 K) 2 P. Dorian, D. Cass and B. Schwartz et al., Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation, N Engl J Med 346 (2002), pp. 884–890. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 3 P.J. Kudenchuk, L.A. Cobb and M.K. Copass et al., Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation, N Engl J Med 341 (1999), pp. 871–878. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 4 G. Guyatt, V. Montori and P.J. Devereaux et al., Patients at the center in our practice, and in our use of language, ACP J Club 140 (2004), pp. A11–A12. Abstract-MEDLINE 5 H. Bucher, G. Guyatt and D. Cook et al., Therapy and applying the results surrogate outcomes. In: G. Guyatt and D. Rennie, Editors, Users’ Guides to the Medical Literature A Manual for Evidence-Based Clinical Practice, American Medical Association, Chicago, IL (2002), pp. 393–413. 6 C. Vandycke and P. Martens, High dose versus standard dose epinephrine in cardiac arrest a meta-analysis, Resuscitation 45 (2000), pp. 161–166. Abstract 7 Wiley InterScience. The Cochrane library. Available at: http://www3.interscience.wiley.com/cgi-bin.../106568753/HOME. Accessed June 1, 2005. 8 The Center for Medical Education. Emergency medical abstracts. Available at: http://ccme.org. Accessed June 1, 2005. 9 American Heart Association, Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care, part 6 advanced cardiovascular life support, Circulation 102 (2000) (suppl), pp. I86–I166. 10 K.H. Lindner, B. Dirks and H.U. Strohmenger et al., Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation, Lancet 349 (1997), pp. 535–537. SummaryPlus | Full Text + Links | PDF (389 K) 11 V. Wenzel, A.C. Krismer and H.R. Arntz et al., A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation, N Engl J Med 350 (2004), pp. 105–113. Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 12 I.G. Stiell, P.C. Hebert and G.A. Wells et al., Vasopressin versus epinephrine for inhospital cardiac arrest a randomised controlled trial, Lancet 358 (2001), pp. 105–109. SummaryPlus | Full Text + Links | PDF (86 K) 13 G.G.L. Biondi-Zoccai, A. Abbate and Q. Parisi et al., Is vasopressin superior to adrenaline or placebo in the management of cardiac arrest? a meta-analysis, Resuscitation 59 (2003), pp. 221–224. Abstract 14 I. Jacobs and F. Finn, Adrenaline and Vasopressin for Cardiac Arrest (Protocol) The Cochrane Library, John Wiley & Sons, Chichester, UK (2004). 15 Hogg K. Vasopressin or adrenaline in cardiac resuscitation [bestBETs Web site]. Available at: http://www.bestbets.org/cgi-bin/bets.pl?record=00407. Accessed March 2, 2004. 16 K. Aung and T. Htay, Vasopressin for cardiac arrest, Arch Intern Med 165 (2005), pp. 17–24. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 17 C.C. Lee, Y.S. Jung and S.K. Yoon et al., Vasopressin administration in out-of-hospital cardiac arrest [abstract], Ann Emerg Med 36 (2000), p. S91. 18 P.J. Li, T.T. Chen and J.M. Zhang et al., Clinical study on administration of vasopressin during closed chest cardiopulmonary resuscitation, Chinese Crit Care Med 11 (1999), pp. 28–31. 19 S. Hopewell, S. McDonald and M. Clarke et al., Grey literature in meta-analyses of randomized trials of health care interventions, The Cochrane Database of Methodology Reviews (2002) Issue 4. 20 D.J. Cook, G.H. Guyatt and G. Ryan et al., Should unpublished data be included in meta-analyses?, JAMA 269 (1993), pp. 2749–2753. Abstract-MEDLINE | Abstract-EMBASE 21 L. McAuley, B. Pham and P. Tugwell et al., Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses?, Lancet 356 (2000), pp. 1228–1231. SummaryPlus | Full Text + Links | PDF (78 K) 22 P. Juni, F. Holenstein and J. Sterne et al., Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses?, Int J Epidemiol 31 (2002), pp. 115–123. Abstract-MEDLINE | Full Text via CrossRef 23 D. Fergusson, A. Laupacis and L.R. Salmi et al., What should be included in meta-analyses? an exploration of methodological issues using the ISPOT meta-analyses, Int J Technol Assess Health Care 16 (2000), pp. 1109–1119. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef 24 B. Jennett and M. Bond, Assessment of outcome after severe brain damage a practical scale, Lancet 1 (1973), pp. 480–484. 25 The Brain Resuscitation Clinical Trial II Study Group, A randomized clinical trial of calcium entry blocker administration to comatose survivors of cardiac arrest design, methods, and patient characteristics, Control Clin Trials 12 (1991), pp. 525–545. 26 L.P. Nesbitt, I.G. Stiell and D. Cousineau et al., Is the cerebral performance category score a valid measure of functional outcome after out-of-hospital cardiac arrest?, Acad Emerg Med 12 (2005), p. 71 [abstract]. 27 D. Feeny, K. Farris and I. Cote et al., A cohort study found the RAND-12 and Health Utilities Index Mark 3 demonstrated construct validity in high-risk primary care patients, J Clin Epidemiol 58 (2005), pp. 138–141. SummaryPlus | Full Text + Links | PDF (160 K) 28 G. Guyatt, D. Cook and P.J. Devereaux et al., Therapy. In: G. Guyatt and D. Rennie, Editors, Users’ Guides to the Medical Literature A Manual of Evidence-Based Clinical Practice, American Medical Association, Chicago, IL (2002), pp. 55–79. 29 J.L. Fleiss, The statistical basis of meta-analysis, Stat Methods Med Res 2 (1993), pp. 121–145. Abstract-MEDLINE 30 R. DerSimonian and N. Laird, Meta-analysis in clinical trials, Control Clin Trials 7 (1986), pp. 177–188. Abstract 31 V. Montori, G. Guyatt and A. Oxman et al., Summarizing the evidence fixed-effects and random-effects models. In: G. Guyatt and D. Rennie, Editors, Users’ Guides to the Medical Literature A Manual for Evidence-Based Clinical Practice, American Medical Association, Chicago, IL (2002), pp. 539–545. 32 J.P.T. Higgins and S.G. Thompson, Quantifying heterogeneity in a meta-analysis, Stat Med 21 (2002), pp. 1539–1558. Abstract-EMBASE | Abstract-Elsevier BIOBASE | Abstract-MEDLINE | Full Text via CrossRef 33 J.P.T. Higgins, S.G. Thompson and J.J. Deeks et al., Measuring inconsistency in meta-analyses, BMJ 327 (2003), pp. 557–560. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 34 V. Montori, R. Hatala and G. Guyatt, Summarizing the evidence evaluating differences in study results. In: G. Guyatt and D. Rennie, Editors, Users’ Guides to the Medical Literature A Manual for Evidence-Based Clinical Practice, American Medical Association, Chicago, IL (2002), pp. 547–552. 35 A.D. Oxman and G.H. Guyatt, A consumer’s guide to subgroup analyses, Ann Intern Med 116 (1992), pp. 78–84. Abstract-MEDLINE | Abstract-EMBASE 36 A. Oxman and G. Guyatt, Summarizing the evidence when to believe a subgroup analysis. In: G. Guyatt and D. Rennie, Editors, Users’ Guides to the Medical Literature A Manual for Evidence-Based Clinical Practice, American Medical Association, Chicago, IL (2002), pp. 553–565. 37 K.M. McIntyre, Vasopressin in asystolic cardiac arrest, N Engl J Med 350 (2004), pp. 179–181. Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 38 E.L. Teng and H.C. Chui, The modified Mini-Mental State (3MS) examination, J Clin Psychiatry 48 (1987), pp. 314–318. Abstract-MEDLINE Critically Appraised Topic (CAT): Does vasopressin in place of epinephrine improve survival to discharge without worsening neurological function in patients with out-of-hospital cardiac arrest? Question In patients with cardiac arrest not attributable to trauma or environmental exposures, what is the impact on survival to hospital discharge and survivor neurological function of vasopressin compared to epinephrine when administered at the first point in a cardiac arrest protocol at which epinephrine would routinely be given? Reviewed by Wyer PC, Perera P, Jin Z, Zhou Q, Cook DJ, Walter SD, Guyatt GH Date November 1, 2005 Expiration date November 1 2007 Clinical bottom line Vasopressin, administered to patients with out-of-hospital or in-hospital cardiac arrest, has no proven survival benefit compared to epinephrine when given at the same point in a structured resuscitation protocol, despite a possible increase in likelihood of hospital admission. A subgroup analysis of data from 3 randomized trials does not reveal a statistically significant benefit of vasopression in patients presenting with asystole or with other specific arrest rhythms. The trials suggest a possible trend towards worse neurological functional outcomes with vasopressin. Current evidence from randomized trials does not support vasopressin use in victims of cardiac arrest. A well done meta-analysis came to the same conclusion. Search Strategy The search for randomized trials enrolling adults with cardiac arrest included MEDLINE, EMBASE, the Cochrane Library from the dates of origin through July of 2004, and Emergency Medical Abstracts from 1977 to December 2004. The MEDLINE search was limited to trials comparing vasopressin to epinephrine. Authors of a recent well done meta-analysis conducted an exhaustive search including registries of conference proceedings and unpublished trials. Citations Primary: Meta-analysis Aung K, Htay T. Vasopressin for cardiac arrest. Arch Intern Med. 2005;165:17-24. Secondary: 3 fully reported trials 1. Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105-113. 2. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: A randomised controlled trial. Lancet. 2001;358:105-109. 3. Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet. 1997;349:535-537. Primary study characteristics Study population Adult patients in Canada, Europe and Asia with cardiac arrest in and out of hospital. One study limited to patients with ventricular arrest rhythms. Settings and populations poorly described in 2 Asian studies. Interventions 40 IU vasopressin or 1 mg epinephrine iv either immediately or after 3 attempts at defibrillation in patients with ventricular fibrillation. Dose repeated in 3 minutes if no return of pulse in the largest European study. Study protocol poorly described in 2 Asian studies. Outcome Measures Survival to hospital discharge in all studies. Neurological function by cerebral performance scale in survivors to discharge in 2 studies. Study Design Limited to randomized trials comparing vasopressin to epinephrine in human subjects. Critical appraisal The systematic review employed an exhaustive search strategy, included registries of unpublished trials and abstracts and otherwise controlled for publication and selection bias. Quality appraisal and data abstraction were performed independently by 2 reviewers with substantial agreement above chance. Heterogeneity was assessed and was substantial when the 2 Asian studies were included. High quality was observed in 3 fully reported trials and could not be assessed in 2 Asian studies. Results Primary and secondary outcomes All trials reporting outcome Fully reported trials only Pre-discharge mortality (Aung) RR+ .96 (.87, 1.05) RR+ .99 (.95, 1.02) Death or any disability (Aung) δ RR+ 1.00 (.94, 1.07) — Death or major disability δδ — OR+ 1.32 (.82, 2.14) + Relative risk (RR) or odds ratio(OR) and 95% confidence intervals vasopressin compared to epinephrine. ed to epinephrine. Values of RR or OR <1 favor vasopressin; values of RR or OR >1 favor epinephrine. δ By cerebral performance score or by estimate of outcome from incompletely reported study. δδ Data from trials of Wenzel and Stiell using the cerebral performance score. Patients in the lowest 2 categories were considered to have poor neurological outcome and were characterized as dependent on others for activities of daily living and with severe memory disturbance or in a vegetative state. Subgroup analyses Evidence supporting the hypothesis of selective benefit of vasopressin over epinephrine in cardiac arrest patients with asystole, compared to other arrest rhythms, includes a large difference in effect size coming from within-trial comparisons. The difference in effect of vasopressin in presenting rhythm subgroups, however, is not consistent across otherwise similar trials, is not statistically significant when appropriate analytical methods are applied, may reflect the application of multiple unplanned subgroup analyses and is not supported by a plausible biological hypothesis. Supervising editor: Brian H. Rowe, MD, MScFunding and support: The authors report this study did not receive any outside funding or support.Reprints not available from the authors. Address for correspondence: Peter C. Wyer, MD, Columbia University College of Physicians and Surgeons, Emergency Services, 446 Pelhamdale Avenue, Pelham Manor, NY 10803; 914-738-9368, fax 914-738-6537

(Annals of Emergency Medicine Volume 48 @ Issue 1 , July 2006, Pages 66-74 doi:10.1016/j.annemergmed.2005.12.022 Copyright © 2006 American College of Emergency Physicians Published by Mosby, Inc. Cardiology/original research Amino-Terminal Pro-Brain Natriuretic Peptide for the Diagnosis of Acute Heart Failure in Patients With Previous Obstructive Airway Disease Roderick H. Tung MDa, Carlos A. Camargo, Jr MDb, Dan Krauser MDa, Saif Anwaruddin MDa, Aaron Baggish MDa, Annabel Chen MDa and James L. Januzzi, Jr MDa, , aDepartment of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA bDepartment of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Received 12 July 2005; revised 13 September 2005, 18 November 2005; accepted 20 December 2005. Available online 17 February 2006. Refers to: Getting the Right Message: Avoiding Overly Optimistic Interpretations of the Scientific Literature, Annals of Emergency Medicine, Volume 48, Issue 1, July 2006, Pages 75-76 David L. Schriger, a, SummaryPlus | Full Text + Links | PDF (62 K) Referred to by: Getting the Right Message: Avoiding Overly Optimistic Interpretations of the Scientific Literature, Annals of Emergency Medicine, Volume 48, Issue 1, July 2006, Pages 75-76 David L. Schriger, a, SummaryPlus | Full Text + Links | PDF (62 K) ) Study objective We evaluate results from amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing with or without those of clinical judgment for the evaluation of dyspneic patients with previous chronic obstructive pulmonary disease or asthma. Methods As a secondary analysis of previously collected observational data from a convenience sample of 599 breathless patients, 216 patients with previous chronic obstructive pulmonary disease or asthma who presented to the emergency department were analyzed according to results of NT-proBNP, clinical impression, and their final diagnosis. Test performance of NT-proBNP in these patients with chronic obstructive pulmonary disease or asthma was examined for the group as a whole, as well as in patients with and without previous heart failure. NT-proBNP results were compared to clinician-estimated likelihood for heart failure using receiver operating curves and as a function of NT-proBNP plus clinical evaluation. The final diagnosis was determined by 2 independent cardiologists blinded to NT-proBNP using all available data from the 60-day follow-up period. Results Overall, 55 patients (25%) had acute heart failure; the median value of NT-proBNP was higher in these patients compared with those without acute heart failure (2,238 vs 178 pg/mL); use of cut points of 450 pg/mL for patients younger than 50 years and 900 pg/mL for patients 50 years or older yielded a sensitivity of 87% (95% confidence interval [CI] 72% to 93%) and a specificity of 84% (95% CI 76% to 88%). In patients without previous heart failure (n=164), median NT-proBNP levels were also higher in patients with heart failure of new onset compared with those with chronic obstructive pulmonary disease or asthma exacerbation (1561 versus 168 pg/mL). High clinical suspicion for acute heart failure (probability >80%) detected only 23% of patients with new-onset heart failure, whereas 82% of these patients had elevated NT-proBNP levels. In patients who had both previous acute heart failure and chronic obstructive pulmonary disease or asthma (n=52), median NT-proBNP levels were significantly higher in those with acute heart failure (4,435 pg/mL) than patients with chronic obstructive pulmonary disease or asthma exacerbation (536 pg/mL). In patients with acute-on-chronic heart failure, NT-proBNP levels were elevated in 91%, whereas clinical impression considered only 39% of cases as high likelihood for acute heart failure. Conclusion NT-proBNP may be a useful adjunct to standard clinical evaluation of dyspneic patients with previous obstructive airway disease. Article Outline Introduction Background Importance Goals of This Investigation Materials and methods Study Design and Setting Selection of Participants Methods of Measurement Primary Data Analysis Results Characteristics of Study Subjects Main Results Limitations Discussion References SEE EDITORIAL, P. 75. Editor’s Capsule Summary What is already known on this topic Biomarkers B-type natriuretic peptide and its amino-terminal fragment (NT-proBNP) can aid in the detection of patients with acute decompensated heart failure in the emergency department. What question this study addressed This retrospective subanalysis of 216 patients from the ProBNP Investigation of Dyspnea in the Emergency Department study examined the discriminative capacity of NT-proBNP in patients with a history of asthma or chronic obstructive pulmonary disease. What this study adds to our knowledge These data suggest that NT-proBNP provided additional information to the clinician in patients with previous asthma or chronic obstructive pulmonary disease and possible acute heart failure. Patients with new heart failure were more often correctly identified with the cardiac biomarker than with clinical suspicion alone. How this might change clinical practice Because this was a retrospective subgroup analysis that used cut points determined from the data, these findings require replication before we can be certain that this test has diagnostic utility. Introduction Background B-type natriuretic peptide (BNP) and its amino-terminal fragment (NT-proBNP) have been demonstrated to be useful for diagnosing and excluding acute heart failure in the emergency department (ED).1 and 2 These markers may hold particular promise in elucidating the cause of dyspnea in patients with previous obstructive airways disease (including chronic obstructive pulmonary disease, chronic obstructive pulmonary disease, or asthma). However, NT-proBNP and B-type natriuretic peptide levels may rise in patients with pulmonary hypertension complicating chronic obstructive pulmonary disease or asthma,3, 4, 5, 6, 7 and 8 and data for NT-proBNP testing in those patients with previous lung disease are lacking. We recently reported the primary results of the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study,2 indicating the value of NT-proBNP testing for the identification or exclusion of acute heart failure in dyspneic patients. Importance Evaluation of dyspneic patients in the ED is challenging, particularly when detection of acute congestive heart failure is attempted among patients with a history of chronic obstructive pulmonary disease or asthma. Exacerbations of both obstructive airways disease and heart failure often have common symptoms, and there is often significant overlap in the findings from physical examination, laboratory tests, and chest radiographs for these patients.9 Diagnostic accuracy is further challenged when a dyspneic patient has a dual history of heart failure and chronic obstructive pulmonary disease or asthma. This scenario often leads to unnecessary administration of diuretics in patients with exacerbation of obstructive airway disease, as well as inappropriate treatment of heart failure patients with systemic steroids or inhalants for obstructive airway disease, the latter class of medications being particularly undesirable, given their cardiostimulant effects.10 Misdiagnosis with inappropriate therapeutic interventions in this setting may be associated with increased morbidity and mortality.11 Last, underrecognition of structural heart disease in patients with chronic obstructive pulmonary disease or asthma might also be accompanied by underuse of therapies such as angiotensin converting enzyme (ACE) inhibitors and β-blockers in such patients. Goals of This Investigation For the purposes of this analysis, we explored the performance of NT-proBNP testing for patients with history of chronic obstructive pulmonary disease or asthma in the PRIDE study to determine the test characteristics of NT-proBNP in these patients and to examine the value of NT-proBNP testing relative to standard clinical assessment for the evaluation of dyspneic patients with previous chronic obstructive pulmonary disease or asthma. Materials and methods Study Design and Setting This is a secondary analysis of a single-center prospective cohort study. The Partners Institutional Review Board approved all study methods. The methods of the PRIDE study have been previously described.2 Briefly, 600 dyspneic patients were enrolled in a prospective study designed to examine the value of NT-proBNP testing compared to clinical judgment blinded to NT-proBNP results for the identification of acute heart failure. For the current substudy, all patients with a history of emphysema, chronic bronchitis, chronic obstructive pulmonary disease, or asthma were analyzed and examined as a function of the final diagnoses of acute heart failure, chronic obstructive pulmonary disease or asthma exacerbation, or other causes. The history of asthma or chronic obstructive pulmonary disease was ascertained by patient self-report and review of the medical record at the ED visit. Selection of Participants The PRIDE study population was drawn from consenting patients aged 21 years or older and who presented with complaints of dyspnea to the ED of the Massachusetts General Hospital (Boston, MA), an urban ED with more than 80,000 visits a year. Enrollment extended between March and September 2003; a convenience sample of patients was enrolled 12 hours a day, 7 days per week. Exclusion criteria for the study were severe renal insufficiency (serum creatinine level >2.5 mg/dL), dyspnea after chest trauma, dyspnea as a result of severe coronary ischemia that was identified as greater than 0.1 mV ST-segment elevation or ST-segment depression on a 12-lead ECG if performed at presentation, greater than 2-hour delay after urgent intravenous loop diuretic administration (above any baseline maintenance dose), and unblinded natriuretic peptide level measurement. Of patients screened and found to be eligible for the PRIDE study as a whole, more than 95% agreed to enrollment, reflective of the low-risk nature of this diagnostic study. After enrollment, a 60-day follow-up was performed on every patient. Patients and their physicians were interviewed, and medical records, including inpatient and outpatient data, were reviewed for all clinical information available since enrollment. At the 60-day follow-up, 1 patient requested withdrawal from the trial, leaving a study sample of 599 patients for the PRIDE study as a whole. Using all information available from the 60-day follow-up period, a clinical diagnosis (including acute heart failure or chronic obstructive pulmonary disease or asthma exacerbation) was assigned to each patient by 2 study physicians who were blinded to NT-proBNP results. In cases in which the diagnosis was unclear or in doubt, a third study cardiologist rendered an adjudicated diagnosis. In these 10% of cases in which the diagnosis was unclear or in doubt or when disagreement about the final diagnosis existed, an adjudicated diagnosis was rendered in accordance with Framingham Heart Study criteria for diagnosis of heart failure. After adjudication of diagnoses, blood (collected into ethylenediamine tetraacetic acid tubes, processed, and frozen) samples from each patient were analyzed for NT-proBNP, using a validated, commercially available immunoassay (Elecsys ProBNP, Roche Diagnostics, Indianapolis, IN), using established methodology. Briefly, 20 μL of sample were incubated with biotinylated polyclonal capture antibodies and polyclonal ruthenium-complexed detection antibodies, both directed against NT-proBNP. After incubation, the captured NT-proBNP, bound to streptavidin-coated paramagnetic microparticles, was quantified by electrochemiluminescence. This assay has been reported to have less than 0.001% cross-reactivity with bioactive B-type natriuretic peptide, and in the PRIDE study, this assay had an interrun coefficient of variation of less than 1.0%. As established in the main PRIDE study, the suggested NT-proBNP concentrations for identifying acute heart failure were greater than 450 pg/mL for patients younger than 50 years and greater than 900 pg/mL for patients 50 years or older, whereas 300 pg/mL was suggested as an optimal cut point for excluding heart failure.2 Methods of Measurement Clinical data and a blinded NT-proBNP level were obtained prospectively for each study participant by clinical research assistants and enrolling physicians and entered on standardized case report forms. All patients had complete medical histories taken and underwent physical examinations. All had CBC count and standard blood chemistry tests (including electrolytes and measures of renal function), but none had an unblinded natriuretic peptide test. A 12-lead ECG was obtained in all but 12 patients in the main study; all patients in this ancillary analysis had an ECG available. Of those in PRIDE, 573 (96%) patients had chest radiography performed at presentation; among those in this analysis, all 216 patients (100%) had a chest radiograph performed as part of their standard evaluation. At the end of standard clinical assessment in the ED but before hospital admission or ED discharge, the attending physician in the ED, who could not be involved in enrollment, was asked to provide a professional estimate for the likelihood of the presence of acute heart failure in each patient, on a scale ranging from 0% to 100% using all available diagnostic testing, including chest radiography, laboratory tests, and previous or present echocardiography. “High” probability of the presence of heart failure was predetermined to be greater than or equal to 80%. The results of clinical estimated likelihood of the presence of heart failure, as well as the ED clinical diagnosis, were recorded for future correlation with NT-proBNP values. Primary Data Analysis In this observational ancillary study of the PRIDE study population, the primary endpoint was the examination of the performance of NT-proBNP in patients with chronic obstructive pulmonary disease or asthma, with a comparison of NT-proBNP and clinician-estimated likelihood of heart failure for the diagnosis of acute heart failure in patients with previous obstructive airway disease. NT-proBNP results were compared to clinical judgment by comparing the area under the receiver operating characteristic curves (with 95% confidence intervals [CIs]). Receiver operating characteristic curves were also used to evaluate sensitivity and specificity of NT-proBNP at cut points suggested from the main PRIDE study. In addition, as previously described,2 a logistic model combining the elements of NT-proBNP and clinical judgment was then compared to each component. This cohort of patients with previous obstructive airway disease was then analyzed in 2 subgroups, patients with heart failure history and patients without heart failure history, to test whether NT-proBNP would enhance the diagnostic yield of new-onset heart failure in the former group and correctly discern the cause of dyspnea in the latter. Receiver operating characteristic analyses were performed using Analyze-It software (Leeds, UK), whereas other statistics were performed using SPSS software (SPSS, Inc., Chicago, Ill.). Results Characteristics of Study Subjects A study flow diagram in the format of Standards for Reporting Studies of Diagnostic Accuracy is shown in Figure 1. Of the original 599 dyspneic patients who completed follow-up in PRIDE, 216 (36%) patients had a history of chronic obstructive pulmonary disease or asthma. The baseline characteristics of all patients with previous obstructive airway disease are illustrated in Table 1. Fifty-two (24%) of these patients had a history of heart failure. Patients with a history of heart failure tended to be older and had a higher incidence of hypertension, coronary artery disease, and previous myocardial infarction. Overall, 25% of the 216 patients (n=55) were ultimately diagnosed by study physicians as having presented with acute heart failure, whereas 31% (n=68) of patients were diagnosed as having presented with acute exacerbation of chronic obstructive pulmonary disease or asthma, which is slightly less than the incidence of heart failure in the overall PRIDE study (35% of all patients). In all cases, diagnoses were made independent of NT-proBNP values. (45K) Figure 1. Flow diagram for the present study. HF, Heart failure; COPD, chronic obstructive pulmonary disease. Table 1. Baseline characteristics of 216 dyspneic patients with previous obstructive airway disease. Characteristic HF History (n=52) No HF History (n=164) Demographics Age (mean±SD) 69±11 59±16 Male 28 (54%) 69 (42%) White 44 (85%) 148 (90%) Symptoms (%) Paroxysmal nocturnal dyspnea 11 (21) 14 (9) Orthopnea 15 (29) 20 (12) Lower-extremity edema 18 (35) 18 (11) Chest pain 14 (27) 55 (34) Cough 19 (37) 97 (59) Fever 5 (10) 26 (16) Increased sputum production 2 (4) 35 (21) Change in sputum quality 4 (8) 19 (12) Medical history (%) Arrhythmia 17 (33) 18 (11) Hypertension 32 (62) 69 (42) Coronary artery disease 21 (40) 26 (16) Previous myocardial infarction 8 (15) 10 (6) Tobacco use (pack-year, mean) 58±38 53±34 Medications β-Blocker 26 (50) 35 (21) Loop diuretic 37 (71) 33 (20) Hydrochlorothiazide 7 (13) 10 (6) Digoxin 12 (23) 6 (4) ACE inhibitor 23 (44) 23 (14) Short-acting inhaled β-agonist 27 (52) 110 (67) Inhaled anticholinergic 19 (37) 57 (35) Long-acting inhaled β-agonist 15 (28) 50 (30) Inhaled steroid 15 (28) 62 (38) Systemic steroid 13 (25) 18 (11) Leukotriene modifier 3 (6) 24 (15) Physical signs (%) Jugular venous distention 8 (15) 6 (4) S3 Gallop 0 (0) 1 (0.1) S4 Gallop 3 (6) 0 (0) Lower-extremity edema 24 (46) 34 (21) Rales 24 (46) 33 (20) Wheezing 20 (38) 78 (48) Main Results Overall, median NT-proBNP values were higher among patients with a final diagnosis of acute heart failure (2,238 pg/mL; interquartile range 1154 to 7080) than in patients without acute heart failure (178 pg/mL; interquartile range 68 to 545; Figure 2) The area under the receiver operating characteristic curve using NT-proBNP to detect acute heart failure among patients with previous chronic obstructive pulmonary disease or asthma was 0.90 (95% CI 0.85 to 0.94; Figure 3), which compares favorably with the area under the receiver operating characteristic curve reported for the entire 599 patients as a whole of 0.94.2 When compared to the results of standard clinical assessment, NT-proBNP testing had greater area under the receiver operating characteristic compared to clinical estimation (with its area under the receiver operating characteristic curve of 0.83; 95% CI 0.76 to 0.89) for the diagnosis of acute heart failure among these 216 chronic obstructive pulmonary disease or asthma patients. The combination of NT-proBNP plus clinical judgment had a superior area under the receiver operating characteristic curve of 0.94 (95% CI 0.89 to 0.97) for evaluation of patients with previous obstructive airways disease. (33K) Figure 2. Median NT-proBNP levels of 216 dyspneic patients with previous obstructive airway disease, stratified by the presence or absence of acute congestive heart failure. Boxes refer to interquartile ranges, whereas whiskers refer to the fifth and 95th percentile of each group. Outliers are depicted as open circles, whereas extremes are depicted as stars. The cut points of 450 pg/mL (for ages <50 years, dashed line) or 900 pg/mL (for ages ≥50 years, solid line) are depicted. (44K) Figure 3. Receiver operating characteristic curves for all study patients with a history of obstructive airway disease. Clinical judgment had an area under the curve (AUC) of 0.83, whereas NT-proBNP had an AUC of 0.90; the combination of NT-proBNP plus clinical judgment had an AUC of 0.94. Among all patients in this subanalysis, using the suggested age-adjusted cut points reported in the main PRIDE manuscript,2 NT-proBNP was 87% sensitive (95% CI 72% to 93%) and 84% specific (95% CI 76% to 88%). The results for all test characteristics of NT-proBNP are seen in Table 2 and Table 3. Using a cut point of 300 pg/mL as a “rule-out” threshold yielded an overall negative predictive value of 97%, with a sensitivity of 94% (95% CI 84% to 99%), specificity of 61% (95% CI 53% to 68%), positive predictive value of 44%, positive likelihood ratio of 2.4, and negative likelihood ratio of 0.09. Table 2. Test characteristics of NT-proBNP for the diagnosis of heart failure in the overall study population (N=216), patients without previous heart failure (N=164), and patients with previous heart failure (subgroup 2, N=52).⁎ Category Sensitivity, % (95% CI) Specificity, % (95% CI) PPV, % NPV, % Accuracy, % Likelihood Ratio + Likelihood Ratio − All (n=216) 87 (72–93) 84 (76–88) 65 95 85 5.4 0.2 No previous heart failure (n=164) 82 (75–97) 90 (83–95) 53 97 88 7.5 0.2 Previous heart failure (n=52) 91 (76–98) 47 (24–71) 75 75 75 1.7 0.2 NPV, Negative predictive value; PPV, positive predictive value; +, positive; −, negative. ⁎ NT-proBNP was considered positive when >450 pg/mL for patients younger than 50 years and >900 pg/mL for those aged 50 years or older. Table 3. Specific performance of the NT-proBNP assay in subgroups studied. Category NT-proBNP Elevated NT-proBNP Not Elevated All (n=216) Acute HF 48 Of 55 7 Of 55 Not acute HF 26 Of 161 135 Of 161 No previous HF (n=164) Acute HF 18 Of 22 4 Of 22 Not acute HF 16 Of 142 126 Of 142 Previous HF (n=52) Acute HF 30 Of 33 3 Of 33 Not acute HF 10 Of 19 9 Of 19 There were 164 patients with a history of chronic obstructive pulmonary disease or asthma without previous heart failure. As depicted in Figure 4, the final diagnosis of acute heart failure accounted for 13% of the cases (n=22), and exacerbation of chronic obstructive pulmonary disease or asthma was the diagnosis in 35% (n=58) of the cases. Median NT-proBNP levels were significantly higher in patients with a diagnosis of acute heart failure (1,561 pg/mL; interquartile range 893 to 2,387 pg/mL) when compared to patients with chronic obstructive pulmonary disease or asthma exacerbation (168 pg/mL; 95% CI 64 to 411 pg/mL); 82% of patients with acute heart failure had an elevated NT pro-BNP level compared to 6% of patients with chronic obstructive pulmonary disease or asthma exacerbation. Of the remaining patients without acute heart failure or exacerbation of obstructive airways disease, the remaining diagnoses of note included pneumonia or bronchitis in 37% of patients, chest pain or acute coronary syndromes in 27% of patients, and atrial arrhythmias in 14% of patients. (42K) Figure 4. NT-proBNP results in 216 dyspneic patients with previous chronic obstructive pulmonary disease or asthma, categorized by the presence or absence of a history of heart failure and the final diagnosis assigned to the ED presentation. Final diagnoses were made independently of the NT-proBNP results. An elevated NT-proBNP was defined as an NT-proBNP >450 or 900 pg/mL for patients <50 years and ≥50 years, respectively. Among patients with previous chronic obstructive pulmonary disease or asthma but without previous heart failure, NT-proBNP had an area under the receiver operating characteristic curve of 0.88 (95% CI 0.82 to 0.95); at the cut points used, NT pro-BNP had a sensitivity of 82% (95% CI 75% to 97%), a specificity of 90% (95% CI 83% to 95%), and an accuracy of 88% for detecting acute heart failure in patients with previous obstructive pulmonary diseases but without a history of heart failure. The negative predictive value of 300 pg/mL in this subgroup was 98%, with 90% sensitivity (95% CI 68% to 99%) and 66% specificity (95% CI 58% to 74%) and a positive likelihood ratio of 2.6 and a negative likelihood ratio of 0.15. Clinical estimation of likelihood for acute heart failure had an area under the receiver operating characteristic curve of 0.86 (95% CI 0.76 to 0.95); however, in this subgroup of patients, only 16% of patients were given a “high” likelihood for acute heart failure. Accordingly, because of this low confidence of the clinicians to give a high clinical suspicion for heart failure in the ED, only 23% of the cases of new-onset heart failure would have been classified as high likelihood, and a large percentage of patients would have been classified falsely an having acute heart failure (36%). In 52 patients with a dual history of heart failure and chronic obstructive pulmonary disease or asthma, 64% (n=33) of patients had a final diagnosis of acute heart failure, whereas 19% (n=10) of patients had exacerbation of chronic obstructive pulmonary disease or asthma (Figure 4). Of the remaining 9 patients, 4 patients had pneumonia, 3 patients had chest pain or acute coronary syndrome, and 2 patients had atrial arrhythmias. The median NT-proBNP levels were significantly higher in chronic obstructive pulmonary disease or asthma patients with acute-on-chronic heart failure (4,435 pg/mL; 95% CI 1,681 to 8,884 pg/mL) compared to chronic obstructive pulmonary disease or asthma patients with exacerbation of chronic obstructive pulmonary disease or asthma (535 pg/mL; interquartile range 188 to 1,256 pg/mL). Of patients with acute-on-chronic heart failure, most (91%) had an elevated NT-proBNP level compared to 30% of patients with a final diagnosis of chronic obstructive pulmonary disease or asthma exacerbation. Among the patients with acute-on-chronic heart failure with superimposed chronic obstructive pulmonary disease or asthma, the area under the receiver operating characteristic curve of NT-proBNP for the detection of acute heart failure was 0.85 (95% CI 0.73 to 0.95); at the cut points used, NT-proBNP had a sensitivity of 91% (95% CI 76% to 98%), a specificity of 47% (95% CI 24% to 71%), and an accuracy of 75% for detecting acute-on-chronic heart failure in this subgroup of patients. Also, in this subgroup, the “rule-out” cut point of 300 pg/mL had a negative predictive value of 80%, sensitivity of 97% (95% CI 84% to 100%), specificity of 21% (95% CI 6% to 46%), positive likelihood ratio of 1.2, and negative likelihood ratio of 0.14. Clinical impression for detection of acute-on-chronic heart failure in these patients had an area under the receiver operating characteristic curve of 0.78 (95% CI 0.66 to 0.92); however, with great infrequency of strong clinical suspicion (only 2% of cases were given a probability of heart failure ≥80%), only 39% of the cases of acute-on-chronic heart failure were detected using this approach, with a majority of the difference actually being incorrectly diagnosed as chronic obstructive pulmonary disease or asthma exacerbation. Considering the combination of NT-proBNP plus clinical judgment, 100% of patients presenting with acute heart failure would have been identified. Limitations Our study has the potential limitations that pertain to all previous studies in this area, in which establishing a criterion standard for the diagnosis of heart failure is difficult. Although this verification bias is possible, we attempted to minimize this risk by rendering a final diagnosis based on all available data from presentation through a 60-day follow-up period, which is considerably longer than most other studies of this kind,1 and 13 allowing for clearer assessment of the medical status of patients in the study. However, because of lack of uniformity in the evaluation of dyspnea among patients admitted to the hospital, evaluation bias cannot be eliminated and is inherent in studies of this nature. Because exacerbation of heart failure in a patient with previous obstructive airway disease may actually trigger acute bronchospasm, the possibility exists that some patients may actually have had acute exacerbations of both diagnoses at enrollment. Study physicians in PRIDE were instructed to identify the diagnosis most likely to have triggered presentation to the ED. Thus, it is possible that the methods of 2 mutually exclusive diagnostic classifications of heart failure or chronic obstructive pulmonary disease or asthma led to underdiagnosis or misdiagnosis of both presentations. The PRIDE study occurred in a single center from a large urban teaching hospital, which may influence the generalizability of our results. However, the prevalence of heart failure in our patient population and the clinical characteristics of our patients are similar to those in other multicenter trials of B-type natriuretic peptide testing.1 and 14 Our analysis of patients with histories of obstructive airway disease has the limitations of most substudies. The small sample size compromises the statistical power to make conclusions. In addition, the cut points for NT-proBNP used were derived from the original data set, which inherently biases the data. Further studies to confirm the cut points established in PRIDE are ongoing. Ideally, all patients should have had objective evidence corroborating their diagnosis of chronic obstructive pulmonary disease or asthma, including peak flow measurements and pulmonary function testing. However, there is precedent in the published literature for this method based primarily on self-report and available data at enrollment.1 and 14 Considering that the combination of NT-proBNP plus clinical judgment was based on a logistic model, as described,2 and 15 it may have inherent weaknesses in terms of reproducibility in actual situations. Discussion Routine natriuretic peptide testing of dyspneic patients in the ED setting has been demonstrated to be a useful adjunct to clinical diagnosis and radiographic studies because NT-proBNP and B-type natriuretic peptide can distinguish heart failure from other causes of dyspnea with high sensitivity, specificity, and accuracy.1, 2, 15, 16 and 17 However, there are few studies that investigate the test characteristics of B-type natriuretic peptide in patients with a history of obstructive airway disease,7 and 14 and no study to date has directly evaluated NT-proBNP in such patients. Optimal diagnosis and treatment of this patient population is a particular challenge in the ED setting because the symptoms and signs of chronic obstructive pulmonary disease or asthma exacerbation may frequently be difficult to differentiate from those of acute heart failure, and when the 2 diagnoses coexist, treatment decisions become incrementally more complex.18, 19 and 20 We found that NT-proBNP testing was useful for identifying and excluding acute heart failure in patients with previous obstructive airway diseases, even in patients with a history of heart failure, a subgroup of patients not previously assessed in studies of natriuretic peptides. In addition, we demonstrate the potential value of NT-proBNP relative to clinical assessment, demonstrating the superiority of a combined strategy of NT-proBNP testing and clinical assessment, which improved the diagnostic accuracy of the latter approach. We suggest that NT-proBNP testing is useful for the evaluation of the dyspneic patient with previous obstructive airway disease because it more often correctly identifies the presence of acute heart failure in such patients and thus potentially would allow earlier application of optimal therapies for heart failure, including the correct administration of diuretics, ACE inhibitors, or β-blockers, while minimizing the unnecessary use of steroids and cardiotonic medications such as β-agonists. NT-proBNP testing would also be valuable for correctly excluding a diagnosis of heart failure, which would allow for the avoidance of unnecessary diuresis, as well as use of drugs such as β-blockers, which may be associated with risk for bronchospasm in patients with hyperreactive airway disease. Because a patient’s medical history may be a major factor influencing a physician’s assessment when such a patient presents with dyspnea, we considered the value of NT-proBNP testing for 2 important subgroups: patients with chronic obstructive pulmonary disease or asthma only and patients with an overlapping history of chronic obstructive pulmonary disease or asthma plus heart failure in order to determine whether NT-proBNP testing may increase the detection of new-onset heart failure in the former, as well as correctly identify the cause of dyspnea in the latter. In addition, we examined what the effect would be of adding NT-proBNP testing to standard clinical assessment in the ED. In the group with a history of chronic obstructive pulmonary disease or asthma without a history of heart failure, 77% of the cases of new-onset heart failure would have been missed if the diagnosis had been based solely on clinical judgment. Our data suggest that for every 100 dyspneic patients with previous obstructive airway disease but without known heart failure tested with NT-proBNP that up to 8 cases of previously unrecognized heart failure might be diagnosed. Our data confirm the prevalence of structural heart disease among dyspneic patients with obstructive airway disease, as suggested by Bayes-Genis and colleagues,12 who also demonstrated the value of NT-proBNP for the detection of “masked” heart failure in similar patients. For such patients with comorbid obstructive airway disease and heart failure, more frequent application of therapies such as ACE inhibitors or β-blockers might be expected to reduce the risk of mortality.20, 21, 22 and 23 Such changes in patient treatment could have important mortality benefits because β-blockers are particularly underused among patients with obstructive airway diseases because of concern about exacerbating underlying lung disease. In the group of patients with overlapping histories of heart failure and chronic obstructive pulmonary disease or asthma, 61% of cases of heart failure exacerbation would have been missed based on clinical judgment alone. Among these patients, NT-proBNP testing was exceptionally sensitive; the addition of NT-proBNP testing to clinical judgment would correctly identify 3.3 additional patients for every 10 patients tested. Of note, the specificity of elevated NT-proBNP levels was lower, likely because of ongoing B-type natriuretic peptide release in these patients with chronically elevated left ventricular end diastolic pressures at baseline. However, the NT-proBNP values in patients with acute heart failure in this group were considerably higher than those without acute-on-chronic heart failure (4,435 vs 535 pg/mL). In this situation, nonetheless, the specificity of NT-proBNP testing may be less helpful than the enhanced sensitivity for clinical decisionmaking. In summary, we demonstrate that routine NT-proBNP measurement adds significantly to clinical evaluation in the diagnosis of acute heart failure in patients with previous chronic obstructive pulmonary disease or asthma presenting to the ED with dyspnea, a frequently encountered population that can be a challenge to evaluate and treat. Improved diagnosis or exclusion of acute heart failure in this population may aid clinicians in correctly initiating and titrating medical therapies, avoid potentially incorrect therapeutic interventions, and thus potentially improve patient care. Larger, prospective studies of natriuretic peptide testing for the evaluation of patients with obstructive airways disease are now warranted to confirm the role natriuretic peptide tests play in the standard evaluation of this clinically challenging patient subgroup. References 1 A.S. Maisel, P. Krishnaswamy and R.M. Nowak et al., Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure, N Engl J Med 347 (2002), pp. 161–167. Abstract-EMBASE | Abstract-Elsevier BIOBASE | Abstract-MEDLINE | Full Text via CrossRef 2 J.L. Januzzi, C.A. Camargo and S. Anwaruddin et al., N-terminal ProBNP for urgent evaluation of shortness of breath the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study, Am J Cardiol 95 (2004), pp. 948–954. 3 M. Ten Wolde, I.I. Tulevski and J.W. Mulder et al., Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism, Circulation 29 (2003), p. 107 2082-2084. 4 P. Pruszczyk, M. Kostrubiec and A. Bochowicz et al., N-terminal pro-brain natriuretic peptide in patients with acute pulmonary embolism, Eur Respir J 22 (2003), pp. 649–653. Abstract-Elsevier BIOBASE | Abstract-MEDLINE 5 N. Nagaya, T. Nishikimi and M. Uematsu et al., Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension, J Cardiol 37 (2001), pp. 110–111. Abstract-MEDLINE 6 H.H. Leuchte, M. Holzapfel and R.A. Baumgartner et al., Clinical significance of brain natriuretic peptide in primary pulmonary hypertension, J Am Coll Cardiol 43 (2004), pp. 764–770. SummaryPlus | Full Text + Links | PDF (140 K) 7 L.K. Morrison, A. Harrison and P. Krishnaswamy et al., Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea, J Am Coll Cardiol 39 (2002), pp. 202–209. SummaryPlus | Full Text + Links | PDF (184 K) 8 M. Bando, Y. Ishii and Y. Sugiyama et al., Elevated plasma brain natriuretic peptide levels in chronic respiratory failure with cor pulmonale, Respir Med 93 (1999), pp. 507–514. SummaryPlus | Full Text + Links | PDF (795 K) 9 C. Mulrow, C. Lucey and L. Farnett, Discriminating causes of dyspnea through the clinical examination, J Gen Intern Med 8 (1993), pp. 383–392. Abstract-MEDLINE | Abstract-EMBASE 10 S.R. Salpeter, T.M. Ormiston and E.E. Salpeter, Cardiovascular effects of beta-agonists in patients with asthma and COPD a meta-analysis, Chest 125 (2004), pp. 2309–2321. Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Abstract-EMBASE | Full Text via CrossRef 11 R.C. Wuerz and S.A. Meador, Effects of prehospital medications on mortality and length of stay in congestive heart failure, Ann Emerg Med 21 (1992), pp. 669–674. Abstract 12 W.B. Kannel, R.B. S’Agostino and H. Silbershatz et al., Profile for establishing risk of heart failure, Arch Intern Med 159 (1999), pp. 1197–1204. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 13 A. Bayes-Genis, M. Santalo-Bel and E. Zapico-Muniz et al., N-terminal pro-brain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction, Eur J Heart Fail 6 (2004), pp. 301–308. Abstract 14 P.A. McCullough, J.E. Hollander and R.M. Nowak et al., Uncovering heart failure in patients with a history of pulmonary disease rationale for the early use of B-type natriuretic peptide in the emergency department, Acad Emerg Med 10 (2003), pp. 198–204. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef 15 P.A. McCullough, R.M. Nowak and J. McCord et al., B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure analysis from Breathing Not Properly (BNP) Multinational Study, Circulation 106 (2002), pp. 416–422. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef 16 J.G. Lainchbury, E. Campbell and C.M. Frampton et al., Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath, J Am Coll Cardiol 42 (2003), pp. 728–735. SummaryPlus | Full Text + Links | PDF (184 K) 17 P.A. McCullough, E.F. Philbin and J.A. Spertus et al., Confirmation of a heart failure epidemic findings from the Resource Utilization Among Congestive Heart Failure (REACH) study, J Am Coll Cardiol 39 (2002), pp. 60–69. SummaryPlus | Full Text + Links | PDF (215 K) 18 S.T. Weiss, Epidemiology and heterogeneity of asthma, Ann Allergy Asthma Immunol 87 (2001), pp. 5–8. Abstract-MEDLINE | Abstract-EMBASE 19 P.M. Yurchak, Cardiac problems in the pulmonary patient. In: A.P. Fishman, Editor, Pulmonary Diseases and Disorders (2nd ed.), McGraw-Hill, New York, NY (1988). 20 The SOLVD Investigators, Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure, N Engl J Med 325 (1991), pp. 293–302. 21 The CONSENSUS Trial Study Group, Effects of enalapril on mortality in severe congestive heart failure results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), N Engl J Med 316 (1987), pp. 1429–1435. 22 Merit-HF Study Group, Effect of metoprolol CR/XL in chronic heart failure Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-heart failure), Lancet 353 (1999), pp. 2001–2007. 23 M. Packer, M.R. Bristow and J. Cohn et al., The effect of carvedilol on morbidity and mortality in patients with chronic heart failure U.S. Carvedilol Heart Failure Study Group, N Engl J Med 334 (1996), pp. 1349–1355. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef Supervising editor: W. Brian Gibler, MD Author contributions: JJ conceived the study, designed the trial, and obtained research funding. JJ supervised the conduct of the trial and data collection and analysis. RT, CC, DK, SA, AB, and AC undertook recruitment of patients and managed the data. RT drafted the manuscript, and all authors contributed substantially to its revision. RT and JJ take responsibility for the paper as a whole. Funding and support: Supported by a grant from Roche Diagnostics, Indianapolis, IN. Address for reprints: James L. Januzzi, Jr, MD, Massachusetts General Hospital, Yawkey 5800, 55 Fruit Street, Boston, MA 02114; 617-726-3443, fax 617-643-1620

(The American Journal of Emergency Medicine Volume 24 @ Issue 3 , May 2006, Pages 343-346 doi:10.1016/j.ajem.2005.11.004 Copyright © 2006 Elsevier Inc. All rights reserved. Therapeutics Intranasal midazolam therapy for pediatric status epilepticus Timothy R. Wolfe MD, and Thomas C. Macfarlane MD Department of Emergency Medicine, Jordan Valley Hospital, West Jordan, UT 84088, USA Received 5 November 2005; accepted 7 November 2005. Available online 25 April 2006. ) Abstract Prolonged seizure activity in a child is a frightening experience for families as well as care providers. Because duration of seizure activity impacts morbidity and mortality, effective methods for seizure control should be instituted as soon as possible, preferably at home. Unfortunately, parenteral methods of medication delivery are not available to most caregivers and rectal diazepam, the most commonly used home therapy, is expensive and often ineffective. This brief review article examines recent research suggesting that there is a better way to treat pediatric seizures in situations where no intravenous access is immediately available. Intranasal midazolam, which delivers antiepileptic medication directly to the blood and cerebrospinal fluid via the nasal mucosa, is safe, inexpensive, easy to learn by parents and paramedics, and provides better seizure control than rectal diazepam. Article Outline 1. Introduction 2. Discussion References 1. Introduction The cumulative lifetime incidence of epilepsy is 3%, with half of these cases beginning in childhood [1]. Approximately 10% to 20% of childhood epilepsy is refractory to medications, resulting in frequent breakthrough seizure episodes [1]. Most of these seizures are brief and resolve without treatment. However, if they persist for more than 5 minutes, prompt intervention is recommended [2]. Early antiepileptic intervention in an actively seizing patient reduces seizure duration, decreasing both morbidity and mortality [3] and [4]. Because most episodes of prolonged seizure activity begin outside the hospital, parents and caretakers need simple, safe, and effective treatment options to ensure early intervention. Currently, diazepam and lorazepam are the most widely used medications for the emergent management of seizures in both adults and children [5], [6] and [7]. Diazepam must be given intravenously (IV) or rectally because absorption is slow and erratic if given via the intramuscular route [8] and [9]. Lorazepam may be administered via the IV, intramuscular, or transmucosal route [10] and [11]. Outside the hospital, where IV and intramuscular therapy may be difficult or impossible, transmucosal rectal diazepam has emerged as the primary treatment option for breakthrough seizures. Unfortunately, compared with the IV formulation, rectal diazepam has a slower onset of action and is less effective at controlling seizures [8], [12], [13], [14] and [15]. Rectal drug administration is also less socially acceptable than other routes, making medication compliance an issue [16], [17] and [18]. Finally, because of patent protection, the commercially available rectal diazepam product (Diastat-Xcel pharmaceuticals, San Diego, Calif) is considerably more expensive than generic formulations of other commonly used benzodiazepines, making affordability difficult for some families (see Table 1). Table 1. Average wholesale prices for benzodiazepines commonly used to treat seizures Medication Diastat Diazepam Midazolam Lorazepam Packaging 10 mg (twin pack—2 doses) 5 mg/mL (2-mL vial) 5 mg/mL (2-mL vial) 2 mg/mL (1-mL vial) AWP $117.43 per dose $2.53 $3.20 $6.43 AWP, average wholesale price. Transmucosal delivery of generic benzodiazepines via the nasal mucosa offers an attractive and cost-effective alternative in the out-of-hospital setting. Midazolam and lorazepam easily cross the nasal mucosa and the blood brain barrier, resulting in a rapid rise in both the plasma and the cerebrospinal fluid concentrations [11], [13] and [19]. Numerous studies now demonstrate the efficacy and safety of intranasal benzodiazepines for seizure treatment, both within the hospital, prehospital, extended care, and home settings [15], [16], [17], [18], [20], [21], [22], [23], [24] and [25]. The following discussion will review the concept of intranasal medication delivery and the literature that supports hospital and home-based management of seizures with intranasal benzodiazepines. 2. Discussion Transmucosal intranasal benzodiazepine delivery for the treatment of breakthrough seizures offers several advantages over transmucosal rectal delivery. First of all, intranasal benzodiazepine delivery is easily understood and mastered by the lay public and does not carry the social taboos associated with rectal drug delivery [16], [17], [18] and [25]. Secondly, the nasal mucosa provides a large (180 cm2), highly vascular absorptive surface sitting adjacent to the brain [26]. This vascular plexus and the adjacent olfactory mucosa provide direct routes for benzodiazepine absorption into the blood stream and the cerebral spinal fluid [27] and [28]. In fact, within a few minutes of delivery, serum levels of intranasal midazolam are comparable with injectable levels [13]. In contrast, rectal administration of benzodiazepines results in substantially lower blood levels than IV administration [8] and [12]. The result is higher blood levels, faster onset of action, and more effective seizure control with intranasal than with rectally administered benzodiazepines [8], [12], [13], [14] and [15]. However, to achieve optimal results using intranasal benzodiazepine delivery, it is important to use highly concentrated medications delivered as a thin layer over the mucosa. Too much medication will run out of the nose or down the back of the throat, rendering it ineffective. Therefore, volumes more than about 1/2 mL per nostril are not optimally absorbed [29]. Absorption can be further enhanced if half the medication is placed into each nostril, cutting the volume per nostril in half while doubling the surface area available for absorption. The method chosen to deliver the medication to the nasal mucosa is also important. Covering a large mucosal surface area with a thin layer of medication will result in better drug absorption than administration of large droplets to a small surface area [27]. Nasal medication bioavailability increases as the drug delivery system is changed from a drop form to a spray form to an atomized form [28] and [30]. Three randomized controlled trials and 1 prehospital observational trial exist, comparing rectal diazepam to either buccal (oral transmucosal) or intranasal midazolam [15], [24], [31] and [32]. Scott et al [32] conducted a randomized controlled trial comparing buccal midazolam to rectal diazepam in epileptic students in an extended care school. A school nurse administered medication to all students who suffered continuous seizures for more than 5-minutes. Patients with persistent seizures for an additional 10 minutes were treated at the on-call physician's discretion. Oral transmucosal midazolam was effective in 75% of cases (30 of 40 seizures), whereas rectal diazepam was effective in 59% (23/39) (P = non significant). There were no adverse cardiorespiratory effects in either group. Although these differences did not achieve statistical significance, the trend toward a better outcome along with the more socially acceptable delivery of oral transmucosal medication led the school to change its preferred treatment to the oral transmucosal route. Camfield et al [31] found similar efficacy in their randomized trail comparing these 2 routes and drew identical conclusions—oral transmucosal midazolam was preferred over rectal diazepam because of ease of use and social acceptability. The third randomized controlled trial, conducted by Fisgin et al, compared intranasal (rather than buccal) transmucosal midazolam to rectal diazepam [15]. In this study, midazolam aborted 20 (87%) of 23 seizures and rectal diazepam 13 (60%) of 22 seizures (P < .05). These results were statistically significant in favor of the intranasal route when compared with the rectal route. Again, as in previous studies, no clinically important adverse events were identified in the 2 groups. The final study was conducted in a prehospital ambulance setting [24]. In this study, the entire emergency medical system converted from rectal diazepam to intranasal midazolam for treatment of pediatric seizures. The authors compared effectiveness and complication data before and after the change. The rates of prehospital seizure control (100% vs 78%), need for need for emergent intubation (0% vs 33%), and need for hospital admission (40% vs 89%) were all substantially less in the intranasal midazolam group compared with the rectal diazepam group. All these authors conclude that transmucosal midazolam is more convenient, easier to use, just as safe, and is more socially acceptable than rectal diazepam. Furthermore, when given via the intranasal route, midazolam is more effective than rectal diazepam. The above evidence clearly suggests that intranasal midazolam is superior to rectal midazolam for seizure therapy in children. However, IV benzodiazepines are first-line therapy in most hospitals—how does intranasal midazolam compare to IV benzodiazepines? Two randomized controlled trials comparing intranasal midazolam to IV diazepam answer this question [22] and [23]. Lahat et al [22] compared intranasal midazolam to IV diazepam in children seizing 10 minutes or longer. Patients were randomized to receive diazepam, 0.3mg/kg IV, or midazolam 0.2 mg/kg intranasally. Nasal midazolam stopped 23 (88%) of 26, whereas 24 (92%) of 26 were controlled with IV diazepam (P = non significant). The mean time from patient arrival to seizure cessation was 6.1 minutes with midazolam and 8.0 minutes with diazepam. The authors conclude that intranasal midazolam was as safe and effective as IV diazepam, but the overall time to cessation of seizures after arrival at the hospital was faster with intranasal midazolam because of the time required to establish an IV line in the diazepam group. A similar study was conducted by Mahmoudian and Zadeh [23]. These authors compared the efficacy of intranasal midazolam (0.2 mg/kg) to IV diazepam (0.2 mg/kg) in 70 patients (ages 2 to 15 years) presenting to the emergency department with seizure activity. Both methods were equally effective, and no adverse effects occurred in either group. These authors conclude that nasal midazolam should be used not only in medical centers but also in general practitioners' offices as well as at home by families of seizure-prone children after appropriate instruction. Perhaps the greatest benefit of intranasal midazolam will be for the treatment of seizures in the prehospital, home or extended care setting. Wilson et al [17] sent intranasal midazolam home with families of children suffering epilepsy and found that 33 (83%) of 40 who used it found it effective and 83% (20/24) preferred using transmucosal midazolam to rectal diazepam. Harbord et al [18] reported experience using intranasal midazolam for home treatment of 54 seizures in 22 children. These authors found it to be 89% effective, with no evidence of respiratory compromise. Ninety percent of families found no difficulty with nasal medication administration. Of the 15 parents with previous rectal diazepam experience, 13 thought intranasal delivery was easier and 14 preferred it to the rectal route. Jeannet et al [25] used intranasal midazolam both on the medical wards and as home therapy. Their experience with 26 children suffering 125 seizures note a 98% effectiveness in less than 10 minutes, with no serious adverse effects. When compared with rectal diazepam, they report that the intranasal route was both easier to use and that postictal recovery was faster. Scheepers et al [16] report their experience with intranasal medication delivery in an extended care facility caring for adolescents and adults with severe epileptic disorders. Of 84 uses, they found this route to be effective in 79 (94%). In the 5 instances when it was not effective, 3 of the 5 doses were delivered intraorally rather than intranasally. All these reports confirm that intranasal midazolam is safe and effective for treating seizures in the hospital, prehospital, and outpatient settings. Compared with the current “standard” of rectal diazepam, intranasal midazolam is preferred because of its superior efficacy, ease of use, reduced postictal period, and more dignified route of administration. These findings all suggest that intranasal midazolam should replace rectal diazepam as the preferred method for treating prolonged seizures in patients without IV access in place. In conclusion, intranasal midazolam offers a simple, safe, and effective way to treat prolonged seizures. This therapy is proven to effectively terminate and control most acute seizures. It is as effective as IV diazepam and more effective than rectal diazepam. Parents, caregivers, paramedics, nurses, and physicians can easily learn intranasal midazolam delivery. It is as safe as traditional rectal and IV delivery methods, and it is more dignified than rectal diazepam. Emergency physicians who manage epileptic children should consider intranasal midazolam as viable method to control breakthrough seizures at home, in the prehospital setting, and in the emergency department. References [1] M.V. Johnston, Seizures in childhood. In: R.E. Behrman, Editor, Nelson textbook of pediatrics, W.B. Saunders, Philadelphia (2004), pp. 1994–2009. [2] D.H. Lowenstein, Status epilepticus: an overview of the clinical problem, Epilepsia 40 (1999) (Suppl 1), pp. S3–S8. Abstract-EMBASE | Abstract-Elsevier BIOBASE [3] B.K. Alldredge, A.M. Gelb and S.M. Isaacs et al., A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus, N Engl J Med 345 (2001), pp. 631–637. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef [4] S. Bassins, T.L. Smith and T.P. Bleck, Clinical review: status epilepticus, Crit Care 6 (2002), pp. 137–142. [5] R.J. DeLorenzo, W.A. Hauser and A.R. Towne et al., A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46 (1996), pp. 1029–1035. Abstract-EMBASE | Abstract-MEDLINE [6] D.L. Gilbert, P.S. Gartside and T.A. Glauser, Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis, J Child Neurol 14 (1999), pp. 602–609. Abstract-EMBASE | Abstract-MEDLINE [7] T. Pang and L.J. Hirsch, Treatment of convulsive and nonconvulsive status epilepticus, Curr Treatm Opt Neurol 7 (2005), pp. 247–259. Abstract-EMBASE [8] I. Magnussen, H.R. Oxlund, K.E. Alsbirk and E. Arnold, Absorption of diazepam in man following rectal and parenteral administration, Acta Pharmacol Toxicol (Copenh) 45 (1979), pp. 87–90. Abstract-EMBASE | Abstract-MEDLINE [9] O.R. Hung, J.B. Dyck, J. Varvel, S.L. Shafer and D.R. Stanski, Comparative absorption kinetics of intramuscular midazolam and diazepam, Can J Anaesth 43 (1996), pp. 450–455. Abstract-EMBASE | Abstract-MEDLINE [10] J.Y. Yager and S.S. Seshia, Sublingual lorazepam in childhood serial seizures, Am J Dis Child 142 (1988), pp. 931–932. Abstract-MEDLINE | Abstract-EMBASE [11] D.P. Wermeling, J.L. Miller, S.M. Archer, J.M. Manaligod and A.C. Rudy, Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration, J Clin Pharmacol 41 (2001), pp. 1225–1231. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef [12] S. Dhillon, J. Oxley and A. Richens, Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients, Br J Clin Pharmacol 13 (1982), pp. 427–432. Abstract-EMBASE | Abstract-MEDLINE [13] P.D. Knoester, D.M. Jonker and R.T. Van Der Hoeven et al., Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers, Br J Clin Pharmacol 53 (2002), pp. 501–507. Abstract-Elsevier BIOBASE | Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef [14] C. Remy, N. Jourdil, D. Villemain, P. Favel and P. Genton, Intrarectal diazepam in epileptic adults, Epilepsia 33 (1992), pp. 353–358. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef [15] T. Fisgin, Y. Gurer and T. Tezic et al., Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol 17 (2002), pp. 123–126. [16] M. Scheepers, B. Scheepers, M. Clarke, S. Comish and M. Ibitoye, Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy?, Seizure 9 (2000), pp. 417–422. Abstract | Abstract + References | PDF (939 K) [17] M.T. Wilson, S. Macleod and M.E. O'Regan, Nasal/buccal midazolam use in the community, Arch Dis Child 89 (2004), pp. 50–51. Abstract-MEDLINE | Full Text via CrossRef [18] M.G. Harbord, N.E. Kyrkou, M.R. Kyrkou, D. Kay and K.P. Coulthard, Use of intranasal midazolam to treat acute seizures in paediatric community settings, J Paediatr Child Health 40 (2004), pp. 556–558. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef [19] J.M. Malinovsky, C. Lejus and F. Servin et al., Plasma concentrations of midazolam after i.v., nasal or rectal administration in children, Br J Anaesth 70 (1993), pp. 617–620. Abstract-EMBASE | Abstract-MEDLINE [20] T. Fisgin, Y. Gurer and N. Senbil et al., Nasal midazolam effects on childhood acute seizures, J Child Neurol 15 (2000), pp. 833–835. [21] N.O. Kutlu, C. Yakinci, M. Dogrul and Y. Durmaz, Intranasal midazolam for prolonged convulsive seizures, Brain Dev 22 (2000), pp. 359–361. SummaryPlus | Full Text + Links | PDF (68 K) [22] E. Lahat, M. Goldman, J. Barr, T. Bistritzer and M. Berkovitch, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ 321 (2000), pp. 83–86. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef [23] T. Mahmoudian and M.M. Zadeh, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav 5 (2004), pp. 253–255. SummaryPlus | Full Text + Links | PDF (98 K) [24] M. Holsti, B.L. Sill, S.D. Firth, S.M. Joyce, F. Filloux and R.A. Furnival, Prehospital intranasal versed for pediatric seizures American Academy of Pediatrics National Meeting, San Francisco (2004) [Abstract presentation]. [25] P.Y. Jeannet, E. Roulet, M. Maeder-Ingvar, M. Gehri, A. Jutzi and T. Deonna, Home and hospital treatment of acute seizures in children with nasal midazolam, Eur J Paediatr Neurol 3 (1999), pp. 73–77. Abstract | PDF (430 K) [26] T.H. Stanley, Anesthesia for the 21st century, BUMC Proceedings 13 (2000), pp. 7–10. Abstract-MEDLINE [27] Y.W. Chien, K.S.E. Su and S.F. Chang, Chapter 1: anatomy and physiology of the nose. Nasal systemic drug delivery, Dekker, New York (1989), pp. 1–26. [28] R.J. Henry, N. Ruano, D. Casto and R.H. Wolf, A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration, Pediatr Dent 20 (1998), pp. 321–326. Abstract-MEDLINE [29] O. Dale, R. Hjortkjaer and E.D. Kharasch, Nasal administration of opioids for pain management in adults, Acta Anaesthesiol Scand 46 (2002), pp. 759–770. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef [30] N. Mygind and S. Vesterhauge, Aerosol distribution in the nose, Rhinology 16 (1978), pp. 79–88. Abstract-MEDLINE | Abstract-EMBASE [31] P.R. Camfield, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, J Pediatr 135 (1999), pp. 398–399. Abstract-MEDLINE [32] R.C. Scott, F.M. Besag and B.G. Neville, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet 353 (1999), pp. 623–626. SummaryPlus | Full Text + Links | PDF (101 K)

Here's a study on subject from a local Flt service and which another member {not sure 100%} may have been involved with... HTH, ACE844 (The American Journal of Emergency Medicine Volume 24 @ Issue 3 , May 2006, Pages 286-289 doi:10.1016/j.ajem.2005.11.021 Copyright © 2006 Elsevier Inc. All rights reserved. Original Contribution Efficacy of fentanyl analgesia for trauma in critical care transport Michael A. Frakes APRN, CCNS, CFRN, CCRN, EMTPa, b, , , Wendy R. Lord BSN, CCRN, EMTPa, Christine Kociszewski MPH, EMTPb and Suzanne K. Wedel MDb aLIFE STAR/Hartford Hospital, Hartford, CT 06102-5037, USA bBoston MedFlight, Boston, MA 01730, USA Received 20 October 2005; revised 27 November 2005; accepted 28 November 2005. Available online 25 April 2006.) Abstract Introduction Pain relief is one of the most important interventions for out-of-hospital patient care providers. This paper documents the need for and benefits from the administration of fentanyl to trauma patients during critical care transport. Methods We underwent a retrospective review of the transport charts of 100 trauma patients who received fentanyl analgesia during transport and who were able to use a numeric response scale to rate their pain from 0 to 10. Results Mean initial pain report was 7.6 ± 2.2 units, relieved to 3.7 ± 2.8 units by a mean total fentanyl dose of 1.6 ± 0.8 μg/kg (P < .001). Neither initial pain level nor pain relief differed between male and female patients, but did differ between patients originating at the site of injury and those transferred between hospitals. Fentanyl dose correlated poorly with the magnitude of pain relief (r = 0.22), but a dose greater than 2 μg/kg provided more relief than lower doses (5.1 ± 2.1 vs 3.6 ± 2.4, P < .02). Conclusion Fentanyl analgesia from these critical care transport teams provided significant pain relief to trauma patients. Pain reduction was greater for patients who received more than 2.0 μg/kg of fentanyl. Article Outline 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusion References 1. Introduction Pain relief is an important practice focus for healthcare systems [1], [2] and [3]. The Emergency Medical Services Outcomes Project, a 5-year National Highway Traffic Safety Administration project designed to develop a foundation and framework for out-of-hospital research, identified discomfort relief as one of the most relevant outcome parameters for out-of-hospital patient care. In fact, those authors suggested that analgesia might be the out-of-hospital intervention with the greatest patient effect [4]. The National Association of EMS Physicians has similarly articulated a position that pain relief must be a priority for every emergency medical services (EMS) system [5]. Nevertheless, trauma patients receive analgesia from out-of-hospital providers at rates between 1.8% and 84.1% [6], [7], [8], [9], [10], [11], [12] and [13]. Administration rates seem to be higher for patients transported by dedicated critical care transport teams than for those transported by ground EMS [11], [12] and [13]. A number of factors suggest that fentanyl may be the preferred agent for out-of-hospital analgesia administration. It reaches peak effect rapidly, probably allowing safer titration and decreasing the potential for oversedation. In addition, the absence of a histamine release after administration reduces the risks for hypotension and nausea [14]. Finally, fentanyl has a short effective period, reducing the possibility of masking changes in mental status or physical examination by the receiving hospital [14], [15], [16] and [17]. In addition to these clinical advantages, the literature indicates that fentanyl is clearly safe when used for in-transport analgesia by critical care providers. Several reports from such teams have demonstrated the absence of significant changes or complications in systolic blood pressure, oxygen saturation, Glasgow Coma Scale, and end-tidal carbon dioxide after single and multiple doses of fentanyl analgesia for trauma [11], [12], [13], [18], [19] and [20]. In this body of literature, there are little reported objective data on the benefit or effectiveness of fentanyl analgesia in an out-of-hospital transport setting. This paper analyzes patient self-reports of pain to evaluate the need for and outcomes from fentanyl administration by dedicated critical care transport teams during critical care transport. 2. Methods We undertook a retrospective review of consecutive transport charts from trauma patients who received fentanyl analgesia during transport by a specialty critical care transport team and who were able to use a Numeric Response Scale (NRS) to rate their pain. The literature on pain assessment tools describes patient self-report as the most reliable indicator of pain existence and intensity. One-dimensional pain scales such as the NRS or Adjective Rating Scale are recommended for emergency and out-of-hospital settings, and the NRS appears to be the tool most readily completed by diverse populations [21], [22] and [23]. The Emergency Medical Services Outcomes Project recommends the NRS for out-of-hospital pain outcomes research [4]. The minimum change required for clinical significance on an 11-point NRS anchored with 0 as pain-free and 10 as maximal pain is 1.3 units [24]. Data are reported from 100 patients, with 50 from each of 2 critical care transport programs operating in overlapping service areas in New England. Records were from consecutive transports in third quarter of 2004, with the omission of records that did not have both initial and final NRS pain documentation. A total of 132 consecutive records were reviewed to gather the 100 that had complete documentation. The programs have generally similar operational profiles and medical practice standards, and both are members of the North East Air Alliance, a confederation of critical care transport programs with a history of collaborative operations. One program is a multimodal transport entity with fixed-wing, rotor-wing, and ground assets. The practice standards and transport team members are the same for all transport modes. The second program provides strictly rotor wing transport. Each uses a critical care transport nurse partnered in one case with a paramedic and, in the other, with a respiratory therapist. Both programs administer fentanyl for analgesia to trauma patients under protocols that do not require on-line medical direction, and patient care at each program is subject to intensive retrospective quality improvement processes. The maximum protocol doses of fentanyl at the 2 programs are 5 and 2 μg/kg, with individual doses and administration frequencies at the discretion of the clinicians. Each program also carries morphine, but the practice standards clearly identify fentanyl as the preferred analgesic for trauma patients. Institutional review boards at each organization approved the project. Each chart was abstracted by one of the authors, all of whom have at least 5 years of specialty experience in the field. The data for initial pain report, final pain report, site of origin (scene vs hospital), patient sex, and fentanyl dose are all specifically recorded in the transport charts and that information was transferred without interpretation into the research database. Pain reports were patient self-reports obtained by the transport team at the beginning and end of their encounter with the patient. Descriptive statistics and frequencies are reported. Comparisons of means were performed with paired-sample and independent-sample t tests, as appropriate. When those means involved groups with statistically significantly different starting points, a 1-way analysis of variance was used to control for that covariation. The strength of the linear relationship between dose and response was evaluated with the Pearson correlation. The sample size provided 80% power to detect a difference of 1.3 units to a 2-sided .05 significance level [25]. 3. Results Pain documentation included an NRS report for initial and postintervention pain in 75.6% of patients. Accordingly, 132 records were reviewed to obtain the 100 needed for data analysis. There were 61 male and 39 female patients retrieved evenly from scene (50%) and hospital (50%) locations. The mean patient age was 36.92 ± 17.9 years (range, 6-82 years). Overall, the mean initial pain report was 7.6 ± 2.2 units on a 0- to 10-unit NRS. After a mean fentanyl dose of 1.6 ± 0.8 μg/kg, patients reported a mean pain of 3.7 ± 2.8 units on arrival at the receiving hospital. The pain change in transport was significant (P < .001). There was no difference in initial pain level or in pain relief between male and female patients. Initial pain level was higher for patients originating at scenes than for those originating at hospitals (8.1 ± 1.9 vs 7.0 ± 2.4, P < .02). However, the magnitude of pain relief was greater for interhospital patients than for scene patients, with a change of 4.5 ± 2.5 units for patients being transported between hospitals and 3.2 ± 2.1 for those transported from the site of injury (P < .01). The amount of fentanyl used for analgesia correlated poorly with the magnitude of pain relief (r = 0.22). Pain reduction was significantly greater for patients receiving a total fentanyl dose of more than 2 μg/kg than for those receiving less than that amount (5.1 ± 2.1 vs 3.6 ± 2.4 units, P < .02). That difference was not appreciated when patients were grouped by doses of 1.0 or 1.5 μg/kg. There were practice and outcome differences between the 2 programs. The mean initial pain report was higher at one program than at the other (7.8 ± 1.9 vs 7.4 ± 2.5 units, P < .02). However, the mean fentanyl dose was higher at the second program (1.9 ± 0.9 vs 1.2 ± 0.6 μg/kg, P < .01). Similarly, the covariate-controlled mean pain reduction was higher at the program administering a higher mean fentanyl dose: 4.6 ± 2.4 vs 3.2 ± 2.2 units (P < .01). The program with higher mean medication doses and pain reduction was the program whose protocols allow administration of a higher maximum fentanyl dose. 4. Discussion Pain reduction is a priority outcome for out-of-hospital providers. This project augments the existing literature about the safety of fentanyl analgesia during transport of trauma patients by demonstrating a clear need for and benefit from that analgesia in critical care transport from both scene and hospital sites. The reported pain reduction is statistically significant and is well above the described threshold for clinical significance. In addition, when common correlations between the Adjective Rating Scale and NRS are used, the reported pain decreased from “very severe” to “moderate” [3]. It is interesting that there is poor correlation between analgesic dose and analgesic effectiveness. Two possible explanations for this poor relationship include the individualized nature of pain and analgesia experiences and the relatively low dose of fentanyl provided. Drug response often follows an S-shaped curve [24]. The recommended initial analgesic doses for fentanyl are between 1.0 and 3.0 μg/kg, with much higher doses in some circumstances, so it may be that the 1.6 μg/kg mean dose provided to these patients is on the left tail of the “S,” below a dose where the correlation would be stronger [11] and [23]. That conjecture is supported by the greater pain reduction effect, seen by patients receiving doses greater than 2.0 μg/kg than by those receiving less than that amount, and by the increased overall analgesic effect that is demonstrated by the transport team providing a higher mean fentanyl dose. Although the analgesia dose should always be individualized and titrated to patient response, identification of a safe dose range that best precludes oligoanalgesia seems an important area for continued research. The high initial pain reports in patients being transported from hospitals were unexpected. With the known low rates of out-of-hospital analgesia administration, the high initial pain reports of scene patients are not unexpected. However, there have been comprehensive pain management guidelines and recommendations for hospitals since the early 1990s [2]. This series included 50 patients who had contact with a hospital emergency center, yet presented for transport with a mean pain of 7 on a 0 to 10 scale. This “very severe” pain confirms the conclusions of other papers indicating that pain management is still not optimized in hospital settings. Admittedly, patients requiring subsequent critical care transport from the sending hospital likely represent a higher acuity subgroup of patients seen by the referring emergency departments, but the current results are still consistent with previous reports of emergency department oligoanalgesia and delays to analgesia of up to 113 minutes [7], [13] and [26]. The reasons for this are unclear and would also be a useful area for ongoing investigation. Pain decrease was greater for patients transported from hospitals than for those transported from the site of injury. A likely explanation for this is that patients on interhospital transports are more likely to have vascular access, some measure of exposure and evaluation, and splints and dressings in place before the arrival of the transport team. Conceivably, this would allow the team a greater time for attention to other interventions. This is strictly conjecture, and there may be other factors. This represents yet another opportunity for additional investigation. The frequency of pain documentation by the critical care transport team identifies an important point. Documentation deficiencies are one of the factors cited as contributing to ineffective pain management [3]. Patient satisfaction and pain management outcomes are improved when there is reliable documentation of initial and subsequent pain assessments [27], [28], [29] and [30]. Although there was objective pain scale documentation for about 75% of the patients in this report, the omission of that data for nearly one quarter may represent a population at risk for oligoanalgesia. 5. Conclusion The studied dedicated critical care transport teams provided significant pain relief from fentanyl administration during the transport of trauma patients from both scene and hospital locations. There was a poor correlation between analgesic dose and analgesic effect, but there was a significantly greater amount of pain reduction for patients who received more than 2.0 μg/kg of fentanyl. There are numerous additional opportunities for research in this area, particularly in establishing the reasons for oligoanalgesia in trauma patients and in identifying optimal medication doses. References [1] Joint Commission on Accreditation of Healthcare Organizations, Current understanding of assessment, management, and treatments Retrieved March 1, 2004 fromhttp://www.jcaho.org/news+room/health+care+issues/pain_mono_npc.pdf.. [2] U.S. Department of Health and Human Services, Acute pain management: operative or medical procedures and trauma, US Public Health Service, Rockville (Md) (1992). 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Reed, Time to analgesia for patients with painful extremity injuries transported to the Emergency Department by ambulance, Prehosp Emerg Care 7 (2003), pp. 445–447. Abstract-MEDLINE [8] L. Fullerton-Gleason, C. Crandall and D.P. Sklar, Prehospital administration of morphine for isolated extremity injuries: a change in protocol reduces time to medication, Prehosp Emerg Care 6 (2002) (4), pp. 411–416. Abstract [9] L.J. White, J.D. Cooper, R.M. Chambers and R.E. Gradisek, Prehospital use of analgesia for suspected extremity fractures, Prehosp Emerg Care 4 (2000) (3), pp. 205–208. Abstract [10] E.T. Dickinson, F.W. Wurster, C.C. Mechem and I.M. Reyes, Prehospital utilization and effectiveness of morphine (abstract), Prehosp Emerg Care 8 (2004), p. 103. [11] S.H. Thomas, O. Rago, T. Harrison, P.D. Biddinger and S.K. Wedel, Fentanyl trauma analgesia use in air medical scene transports, J Emerg Med 29 (2005) (2), pp. 179–187. SummaryPlus | Full Text + Links | PDF (129 K) [12] P. DeVellis, S.H. Thomas, R.J. Vinci and S.K. Wedel, Prehospital fentanyl analgesia in air-transported pediatric trauma patients, Pediatr Emerg Care 14 (1998), pp. 321–323. Abstract-EMBASE | Abstract-MEDLINE [13] P. DeVellis, S.H. Thomas and S.K. Wedel, Prehospital and emergency department analgesia for air-transported patients with fractures, Prehosp Emerg Care 2 (1998), pp. 293–296. Abstract-MEDLINE [14] D. Braude and M. Richards, Appeal for fentanyl prehospital use, Prehosp Emerg Care 8 (2004) (4), pp. 441–442. Abstract [15] S.H. Thomas, W. Silen, F. Cheema, A. Reisner, S. Aman and G.N. Goldstein et al., Effects of morphine analgesia on diagnostic accuracy in emergency department patients with abdominal pain: a prospective, randomized trial, J Am Coll Surg 196 (2003), pp. 18–31. SummaryPlus | Full Text + Links | PDF (218 K) [16] S.H. Thomas and W. Silen, Effect on diagnostic efficiency of analgesia for undifferentiated abdominal pain, Br J Surg 90 (2003) (1), pp. 5–9. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef [17] M.S. Kim, R.T. Strait, T.T. Saio and H.M. Hennes, A randomized clinical trial of analgesia in children with acute abdominal pain, Acad Emerg Med 9 (2002) (4), pp. 281–287. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef [18] S.H. Thomas, W. Benevelli, D.F.M. Brown and S.K. Wedel, Safety of fentanyl for analgesia in adults undergoing air medical transport from trauma scenes, Air Med J 15 (1996) (2), pp. 57–59. [19] T.H. Harrison, W. Ahmed, S.H. Thomas and S.K. Wedel, Effect of fentanyl on end-tidal carbon dioxide in air-transported patients (abstract), Ann Emerg Med 36 (2000), p. 4. [20] A.A. Aronson, S.H. Thomas, T. Harrison, M. Saia and H. Bach, Use of end-tidal carbon dioxide monitoring to detect occult hypoventilation in patients receiving opioids in the pre-hospital and emergency department settings (abstract), Chest 126 (2004) (4), p. 907S. [21] B. Blettery, L. Ebrahim and D. Honnart, Pain scale in an emergency care unit, Reanim Urgences 5 (1996), pp. 691–697. Abstract [22] D.E. Fosnocht, C.R. Chapman, E.R. Swanson and G.W. Donaldson, Correlation of change in the visual analog scale with pain relief in the ED, Am J Emerg Med 23 (2005) (1), pp. 55–58. [23] A. Ricard-Hibon, C. Chollet and S. Saada, A quality control program for acute pain management in out-of-hospital critical care medicine, Ann Emerg Med 34 (1999), pp. 738–744. SummaryPlus | Full Text + Links | PDF (43 K) [24] K.H. Todd and J.P. Funk, The minimum clinically important difference in physician-assigned visual analog pain scores, Acad Emerg Med 3 (1996), pp. 142–146. Abstract-MEDLINE | Abstract-EMBASE [25] R.G. O'Brien and K.E. Muller, Applied analysis of variance in behavioral science, Dekker, New York (1993). [26] B.G. Katzung, Basic and clinical pharmacology, McGraw-Hill, New York (2001). [27] D.E. Fosnocht, E.R. Swanson and P. Bossart, Patient expectations for delivery of pain medication, Am J Emerg Med 19 (2001) (5), pp. 399–402. Abstract | PDF (33 K) [28] S.C. Eder, E.P. Sloan and K. Todd, Documentation of ED patient pain by nurses and physicians, Am J Emerg Med 21 (2003) (4), pp. 253–257. SummaryPlus | Full Text + Links | PDF (70 K) [29] S.H. Thomas and L.M. Andruszkiewicz, Ongoing visual analog score display improves emergency department pain care, J Emerg Med 26 (2004) (4), pp. 389–394. SummaryPlus | Full Text + Links | PDF (86 K) [30] I.E. Scott, Effectiveness of documented assessment of post-operative pain, Br J Nurs 3 (1994), pp. 494–501. Abstract-MEDLINE

For those of you here who see a fair amount of OD's I thought you may find this interesting. + the NARCAN threads are all locked?!?!?!? HTH, ACE844 (The American Journal of Emergency Medicine Volume 24 @ Issue 4 , July 2006, Pages 515-516 doi:10.1016/j.ajem.2005.09.008 Copyright © 2006 Elsevier Inc. All rights reserved. Correspondence Caution with naloxone use in asthmatic patients Paul J. Allegretti DO, FACOEPa, Jeff S. Bzdusek DOa, and Jim Leonard DOa aEmergency Medicine Residency, Midwestern University, Chicago College of Osteopathic Medicine, Chicago, IL 60515, USA Available online 17 June 2006.) The city of Chicago has a high prevalence of asthma and is currently in the midst of a heroin abuse epidemic. Higher-purity heroin is readily available and can be easily inhaled. As a result, the emerging pattern in heroin administration is changing, with inhalation being the most commonly reported route of use. This has contributed to a growing perception that heroin is not as dangerous or addictive as it used to be. The population of suburban youth inhaling heroin (younger than 25 years) demonstrates the largest increase. As more are attracted to use it, the incidence of acute asthma triggered by inhaled heroin will increase [1]. Clinicians need to maintain a high level of suspicion that heroin is another trigger for asthma and screen patients appropriately. The association between heroin and asthma exacerbation has been well described in various case studies reported in the literature. A recent article in Chest described 5 patients with life-threatening asthma that occurred shortly after inhaling heroin. Each patient had history of asthma and received the standard therapy to treat asthma. Mechanical ventilation was required for the treatment for 4 patients for an average of 5 days [2]. This was atypical because asthmatic patients usually require only 24 to 48 hours on a ventilator before they recover. The pulmonary inflammation and bronchospasm are more difficult to treat than in an asthmatic patient who has not used heroin. These cases demonstrate a link between inhaled heroin and asthma exacerbation. Several other studies have been conducted to elucidate the mechanism of heroin-induced airway inflammation. Investigators have identified that postoperative patients receiving morphine or heroin had significantly elevated histamine levels [3]. The opioids act as an allergen and stimulate this histamine release from the degranulation of mast cells. Histamine causes the contraction of smooth muscle [4]. It also contributes to the inflammatory response by activating the release of cytokines and inflammatory mediators from neighboring leukocytes [5]. Consequently, the muscles surrounding the airways constrict, causing the dyspnea, wheezing, and chest tightness characteristic of an asthma exacerbation. These data suggest that airway inflammation due to heroin use is mediated by an immunological pathway. Although the symptoms of opioid use are reversed by naloxone, this antidote must be used cautiously. Naloxone competitively binds opioid receptors to inhibit the effects of heroin. Heroin-induced respiratory depression is the primary cause of most opioid-related deaths, and in cases of life threatening heroin toxicity, naloxone is indicated. Naloxone may be given by way of the endotracheal, sublingual, intramuscular, intravenous, nebulized, and subcutaneous routes. Of significant concern is the appearance of characteristic withdrawal symptoms including agitation, nausea, and vomiting after the administration of naloxone. In a recent study, withdrawal was precipitated by injecting naloxone to morphine-dependent mice. The subsequent histological analysis of brain tissue revealed elevated levels of mast cells. The authors concluded that naloxone-induced morphine withdrawal increases the concentration of mast cells in the thalamus [6]. This strongly suggests that opioid withdrawal would exacerbate asthma by increasing mast cell degranulation and histamine release. The increased circulation of histamine would cause the immunologically mediated bronchoconstriction and airway edema. These symptoms have a strong tendency to worsen asthma, especially in asthmatic patients who are already in exacerbation. The administration of naloxone is a potentially dangerous practice and does not treat the underlying bronchospasm or inflammation. The authors' concern comes with heroin-using asthmatic patients struggling with pulmonary inflammation and bronchospasm without signs of respiratory depression. Naloxone given to these patients may worsen asthma symptoms because acute withdrawal has a deleterious effect on asthma. Precipitation of acute withdrawal in these patients may lead to a worsening of asthma and, possibly, respiratory failure. We have witnessed asthmatic patients in exacerbation who, after having received naloxone, proceed rapidly into respiratory failure. The judicious use of naloxone is warranted in heroin users and should be limited only to patients with altered mental status along with a respiratory rate less than 12 [7]. Caution should be exercised when administering naloxone in heroin users that present in status asthmaticus without respiratory depression. References [1] K. Kane-Willis and Schmitz-Bechteler, A multiple indicator analysis of heroin use in the Chicago metropolitan area from 1995-2002, Institute for Metropolitan Affairs of Roosevelt University (2003). [2] J. Cygan, M. Trunsky and T. Corbridge, Inhaled heroin–induced status asthmaticus: five cases and a review of the literature, Chest 117 (2000), pp. 272–275. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef [3] A. Deonicke, J. Moss and W. Lorenz et al., Intravenous morphine and nalbuphine increase histamine and catecholamine release without accompanying hemodynamic changes, Clin Pharmacol Ther 58 (1995), pp. 81–88. [4] D. Schmidt, E. Ruehlmann and D. Branscheid et al., Passive sensitization of human airways increases responsiveness to leukotriene C4, Eur Res J 14 (1999), pp. 315–319. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef [5] G. Marone, F. Granata and G. Spadaro et al., Antiinflammatory effects of oxatomide, J Investig Allergol Clin Immunol 9 (1999), pp. 207–214. Abstract-EMBASE | Abstract-MEDLINE [6] O. Taiwo, K. Kovacs and L. Sperry et al., Naloxone-induced morphine withdrawal increases the number and

Here's soemthing to add to this subject "Fiznat," which dove tails nicely with your scenario.... This should make for some interesting discussion at your clinical site. HTH, ACE844 (The American Journal of Emergency Medicine Volume 24 @ Issue 4 , July 2006, Page 512 doi:10.1016/j.ajem.2005.12.001 Copyright © 2006 Elsevier Inc. All rights reserved. Correspondence Does aging influence quality of care for acute myocardial infarction in the prehospital setting? Elderly patients with acute myocardial infarction F.X. Duchateau MDa, , A. Ricard-Hibon MDa, M.L. Devaud MDa, A. Burnod MDa and J. Mantz MD, PhDa aDepartment of Anaesthesiology and Intensive Care, Beaujon University Hospital, 92110 Clichy, France Available online 17 June 2006.) The primary goal of prehospital management in acute myocardial infarction (AMI) is to reduce the delay of reperfusion therapy. Quality of care of AMI is known to be lower for elderly patients, particularly because of disparities in the access to acute reperfusion therapy and the lower proportion of patients receiving adjunctive treatments [1] and [2]. A recent trial showed that this nonoptimal therapy for patients aged 80 years and older is already present in the ED [3]. The aim of this study was to evaluate whether our quality of care in elderly people with AMI was altered or not during the prehospital setting. This prospective, observational study was conducted in our Emergency Medical Service department, covering an area of 290 172 inhabitants during a period of 3 years. The survey was part of the regional AMI registry, supported by the Regional Medical Board, which originates from the Ministry of Health. Mobile Intensive Care Units (MICU) are physician staffed (French EMS system SAMU), who provide on-scene diagnosis of AMI and initiate reperfusion therapies. Patients were enrolled by the physician of the MICU when diagnosis of AMI was established. Inclusion criteria for reperfusion strategy were the presence of a typical chest pain associated with ST elevation in 2 contiguous leads or a new left bundle branch blockade on the electrocardiogram. Reperfusion strategy consisted of prehospital thrombolysis or primary angioplasty. The following data were collected: demographic characteristics, reperfusion strategy, adjunctive treatment, and different time intervals. Results are reported as mean values ± SD and percentages. Statistical analysis was performed using an analysis of variance for quantitative data and a Yates-corrected χ2 test for qualitative data. A P value of less than .05 was considered the threshold for significance. Of the 149 patients included, 18 (12 %) were aged 80 years or older. All patients aged less than 80 years had reperfusion therapy, whereas this was the case in 72% (n = 13) of patients aged 80 or older (P < .001). There was no significant difference in the proportion of patients receiving aspirin (95% vs 94%) or intravenous analgesics (60% vs 39%) in the 2 groups. For patients undergoing primary angioplasty, time from arrival of MCIU to hospital admission (64 ± 19 vs 67 ± 14 minutes), time from arrival of MCIU to arterial puncture (96 ± 49 vs 98 ± 26 minutes), and time from arrival of MICU to balloon inflation (105 ± 26 vs 106 ± 22 minutes) were similar in both groups (young vs elderly, respectively). These results confirm and extend those of previous studies, which show that patients aged more than 80 years are proposed for reperfusion therapy less frequently than those aged less than 80 years. Possible explanations have been suggested: fear of increased risk of therapy-related side effects or therapeutic nihilism toward older patients [3]. Nevertheless, adjunctive therapies were not observed to be less used, and when a reperfusion therapy was decided, quick admission in catheter laboratory was not delayed. References [1] K. Barakat, P. Wilkinson and A. Deaner et al., How should age affect management of acute myocardial infarction?, Lancet 353 (1999), pp. 955–959. SummaryPlus | Full Text + Links | PDF (132 K) [2] S.S. Rathore, R.H. Mehta and Y. Wang et al., Effects of age on the quality of care provided to older patients with acute myocardial infarction, Am J Med 114 (2003), pp. 307–315. SummaryPlus | Full Text + Links | PDF (91 K) [3] D.J. Magid, F.A. Masoudi and D.R. Vinson et al., Older emergency department patients with acute myocardial infarction receive lower quality of care than younger patients, Ann Emerg Med 46 (2005), pp. 14–21. SummaryPlus | Full Text + Links | PDF (212 K)

(The American Journal of Emergency Medicine Volume 24 @ Issue 4 , July 2006, Pages 451-454 doi:10.1016/j.ajem.2005.10.010 Copyright © 2006 Elsevier Inc. All rights reserved. Brief Report The relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failure Oral presentation at the 73rd annual assembly of the Swiss Society of Internal Medicine (May 25-27, 2005) in Basel, Switzerland. Alain Rudiger MDa, , , Oliver A. Burckhardt MDb, Paul Harpes MSc, S. Andreas Müller MDd and Ferenc Follath MDb aBloomsbury Institute of Intensive Care Medicine, Wolfson Institute of Biomedical Research, University College London, WC1E 6BT London, UK bDepartment of Internal Medicine, University Hospital Zurich, 8091 Zurich, Switzerland cDepartment of Biostatistics, University Zurich, 8001 Zurich, Switzerland dDepartment of Cardiology, Triemlispital Zurich, 8065 Zurich, Switzerland Received 4 September 2005; revised 7 October 2005; accepted 9 October 2005. Available online 17 June 2006) 1. Introduction Acute heart failure (AHF) is a common but ill-defined clinical entity. Because of an aging population and improvement in survival rates after myocardial infarction, its prevalence is increasing [1] and [2]. In addition, the syndrome is associated with a high short- and long-term mortality [3], [4] and [5]. Recently, several effective but costly therapies have been developed [6] and [7]. The difficulty remains to choose the most adequate treatment for each single patient with AHF. Hence, risk stratification is essential and urgently needed for appropriate triage and therapeutic decision making. Lymphocytopenia is common in hospitalized patients [8]. A decrease of the relative lymphocyte count in percentages (%L) has been observed in different cardiovascular disease states. It has been interpreted as a marker of the physiological stress response, mediated by an increased release of endogenous catecholamines [9] or cortisol [10]. Importantly, a decrease in the %L has been demonstrated to be predictive for mortality in patients with chronic heart failure [11], [12] and [13]. In patients with AHF though, the prognostic value of low %L is unknown. The aim of this study was to assess if the %L is a risk factor for long-term mortality in patients with AHF. 2. Methods 2.1. Study population The present study is a subgroup analysis from a multicenter study, and the full results are published separately [5]. The study population included consecutive patients admitted to the medical intensive care unit, coronary care unit, and medical wards at the Department of Medicine of the University Hospital Zurich with a diagnosis of AHF. Diagnostic criteria for AHF were in accordance with the guidelines of the European Society of Cardiology [14] and included the following: 1. an underlying heart disease; 2. at least two symptoms and signs of AHF (dyspnea, orthopnea, rales, elevated jugular venous pressure) or cardiogenic shock; 3. a chest x-ray compatible with pulmonary congestion; 4. a new onset or rapid worsening of these clinical symptoms and signs within 7days. Cardiogenic shock was defined by the presence of an impaired end-organ perfusion and a systolic blood pressure lower than 90 mm Hg despite adequate treatment with fluids or the need of inotropes or vasopressors. Baseline characteristics as well as routine laboratory values were collected from the patient's charts. Each patient was enrolled only once even when he was readmitted during the observation period. All patients had a follow-up after 12 months. Information regarding death was obtained from hospital records or telephone interviews with the patient's physician or a family member. 2.2. Laboratory Blood samples for routine blood cell count analyses were taken on admission and in the mornings of the following days. Three milliliters of blood was collected in Vacutainer tubes (Plymouth, UK). All analyses were performed at the laboratory of the University Hospital Zurich. Complete blood cell counts were done with a commercial automated system (ADVIA 120 Hematology System, Bayer Diagnostics AG, Switzerland). This machine can analyze 120 blood samples per minute at only minor expenses. In addition, the analyzer can differentiate leukocytes by peroxidase staining, cytochemical light scatter, and light absorption measurements, without taking more time for the analysis. The %L was defined as (absolute number of lymphocytes / absolute number of leukocytes) × 100. The lower cutoff value for %L at our institution is 25. 2.3. Statistical analysis All laboratory data were collected from the patient's electronic records. Mean, SDs, or percentages were calculated for the overall sample and subgroups. Comparisons were made with the use of the t test, Fisher exact test, or the χ2 test, as appropriate. The %L on admission and the minimum %L during the first 3 days were taken for the analysis. Logarithms of %L and renal dysfunction measurements were approximately normally distributed, so logarithms were taken whenever these variables were considered. Survival analysis for one or several risk factors was performed with a Cox proportional hazards regression. The null hypothesis was rejected for a 2-sided P value of less than .05. Confidence intervals (CIs) are given for the 95% level. All analyses were performed with SPSS 12 for Windows. 3. Results 3.1. General The study population included 96 consecutive patients with AHF. Mean age was 71 (SD 13), and 58 (60%) were men. A de novo AHF (no previous history of heart failure) was present in 28 (29%) patients. The most frequent underlying cardiac diseases were coronary artery disease in 57 (59%) patients and valvular cardiopathy in 24 (25%) patients. A history existed for atrial fibrillation in 21 (22%) patients and for elevated blood pressure in 51 (53%) patients. Left ventricular ejection fraction (LVEF) was measured in 63 (66%) patients. Of them, 32 (51%) had an LVEF less than 35%, 10 (16%) between 35% and 50%, and 21 (33%) greater than 50%. Relative lymphocyte counts were available in 91 (95%), 55 (57%), and 58 (60%) patients on days 1, 2, and 3, respectively. Two patients had no %L measurement during the first 3 days. 3.2. Outcome The baseline characteristics of our population are summarized in Table 1; the %L values on admission for different subgroups are shown in Table 2. After 1 year, 35 (36%) patients had died. In 1-year survivors and 1-year nonsurvivors, the mean %L on admission were 16.3 (SD 8.9) and 11.2 (SD 7.9), respectively (P = .04 with a t test for logarithms). A %L less than 25% on admission had a sensitivity and specificity for death at 1 year of 0.91 and 0.21, respectively, with an area under the curve of 0.680 (CI, 0.563-0.796) and a P value of .005 in the receiver operating characteristic analysis. This resulted in positive and negative likelihood ratios of 1.15 and 0.43. The according positive and negative predictive values for death at 1 year were 0.39 and 0.80, respectively. When we calculated with the minimum %L of the first 3 days of hospitalization, the mean values were 15.5 (SD 8.6) and 9.7 (SD 6.6) in 1-year survivors and 1-year nonsurvivors, respectively (P < .001 in a t test for logarithms). Only 11 (11%) patients had exclusively normal %L during the first 3 days of hospitalization, and they all survived 1 year. The minimum %L during the first 3 days of hospitalization was a stronger prognostic marker for long-term mortality than the %L on admission alone, although the difference was not statistically significant. Table 1. Baseline characteristics on admission of patients with AHF grouped depending on their outcome at 1 year Survivors (n = 61) Nonsurvivors (n = 35) P Age (y), mean (SD)* 70 (13) 73 (13) NS Male sex, n (%)* 38 (62) 20 (57) NS History of heart failure, n (%)* 44 (72) 24 (69) NS Coronary artery disease, n (%)* 36 (59) 21 (60) NS Shock, n (%)* 3 (4.9) 5 (14) NS LVEF (%), mean (SD)¶ 42 (17) 30 (16) .011 Troponin T (μg/L) (norm <0.1), mean (SD)§ 0.2 (0.6) 2.2 (8.5) NS Creatinine clearance (mL/min), mean (SD)† 55 (26) 47 (24) NS C-reactive protein (mg/L), mean (SD)† 32 (47) 71 (98) .031 Hemoglobin (g/L), mean (SD)* 122 (22) 117 (20) NS Leukocytes/μL, mean (SD)‡ 9181 (3677) 10 522 (5316) NS Lymphocytes/μL, mean (SD)§ 1458 (1024) 1015 (820) .006 %L, mean (SD)§ 16.3 (8.9) 11.2 (7.9) .004 Creatinine clearance was estimated by a modified Cockcroft and Gault formula. Results were available in *96, †94, ‡93, §91, and ¶63 patients. P values were calculated with Fisher exact test and t tests (for logarithms in creatinine clearances, lymphocytes, and %L). Table 2. Patients with AHF divided by different criteria, with the corresponding relative lymphocyte counts (%L) on admission No. of patients (%) %L, mean (SD) Age (y) <65 29 (32) 16.4 (9.6) ≥65 62 (68) 13.6 (8.3) Sex Female 37 (41) 15.6 (10.2) Male 54 (59) 13.7 (7.7) Coronary artery disease No 36 (40) 13.1 (7.4) Yes 55 (60) 15.3 (9.6) Shock No 83 (91) 14.6 (8.6) Yes 8 (9) 13.3 (11.7) LVEF (%) ≥35 29 (48) 16.6 (9.0) <35 31 (52) 15.4 (8.8) Troponin (μg/L) <0.1 61 (69) 15.4 (8.8) ≥0.1 28 (31) 13.0 (8.7) Creatinine clearance (mL/min) ≥50 40 (45) 16.7 (8.4)* <50 49 (55) 13.0 (8.9)* Outcome at 1 y Survivors 58 (64) 16.3 (8.9)† Nonsurvivors 33 (36) 11.2 (7.9)† Creatinine clearance was estimated by a modified Cockcroft and Gault formula. The numbers (percentages) refer only to the patients who had a %L measured. Differences between %L were not significant within the grouping variables, except for renal dysfunction and outcome at 1 year (P values *.016 and †.004 in a t test for logarithms). In a Cox regression analysis, %L and LVEF were both significant risks factors (P = .029 for log[%L] with a hazard ratio per unit change of 0.42 [CI, 0.19-0.91] and P = .018 for LVEF with a hazard ratio per unit change of 0.96 [CI, 0.93-0.99]). They were thus independent risks factors because %L was still significant after correcting for the effect of LVEF and conversely. The presence of shock was not a significant risk factor after adjusting for LVEF (P = .13, hazard ratio 0.43 [CI, 0.14-1.3]). Age, sex, underlying coronary artery disease, and renal dysfunction were not significant in the Cox regression analysis or log-rank test. 4. Discussion The present study revealed that a low %L on hospital admission was significantly related to an increased long-term mortality in patients with AHF. A decreased %L remained an independent risk factor after adjusting for age, sex, renal dysfunction, LVEF, shock, and coronary artery disease. The test had a good sensitivity to predict long-term mortality in patients with AHF. However, clinicians must consider its low specificity and poor positive predictive value. Our results correspond to published studies showing that %L is reduced in patients with severe cardiovascular disturbances. For instance, lymphocytopenia was observed in patients with acute myocardial infarction [15] and [16], and a study from our institution demonstrated that mechanical complications after myocardial infarction could be reliably predicted by lymphocytopenia in combination with the C-reactive protein level [17]. The present study included patients with AHF, but was not restricted to patients with myocardial infarction. Within our population, %L did neither differ between patients with coronary artery disease and patients without nor between patients with an elevated (>0.1 μg/L) and patients with a normal troponin T level. Prior studies indicated a predictive value of the relative lymphocyte concentration in patients with chronic heart failure [11], [12] and [13]. Cooper et al [12] limited their study population to patients who had an LVEF 35% or less, whereas Acanfora et al [13] included only patients who were older than 65 years. In contrast, our population was restricted neither by age nor by LVEF. Nevertheless, a low %L remained an independent risk factor for increased mortality, and %L was similar not only in patients with a reduced LVEF of 35% or less and in patients with an LVEF greater than 35%, but also in patients 65 years or younger and older than 65 years. The precise underlying mechanisms for our results remain speculative. Lymphocytopenia may reflect neurohormonal activation in patients with AHF. Cortisol and catecholamines, which are both elevated in patients with heart failure [18], induce lymphocyte apoptosis [19] and [20], and catecholamines down-regulate lymphocyte proliferation and differentiation [9]. Homing of lymphocytes in the lymphoreticular structures has been proposed [21]. However, a histological study in critically ill patients showing extensive lymphocyte depletion in the white pulp of the spleen does not support this assumption [22]. In addition, a decrease in %L may reflect the severity of immunologic disturbances in AHF. Lymphocytopenia may be an anti-inflammatory response that accompanies severe illness [23]. Whether the decline in the %L only reflects the severity of both neurohormonal and immune system disturbances or whether lymphocytopenia truly contributes to mortality by favoring the development of nosocomial infections [24] awaits further investigations. A limitation of the present study is the small sample size, which obviates an adjustment for all potential confounders. Hence, larger studies are needed to test the hypothesis that the %L is a truly independent risk factor. Other limitations are the lack of routinely measured B-type natriuretic peptide levels and the restricted use of echocardiography. In conclusion, modern automated systems can count the %L fast and at only minor additional expenses. A low %L may reflect the severity of both neurohormonal and immune system disturbances. We demonstrate for the first time that a low %L in a single blood sample on hospital admission is a risk factor for long-term mortality in patients with AHF. Future prospective studies are needed to validate our results and to identify the prognostic value of different lymphocyte levels. Acknowledgments The authors thank Franco Salomon for his contribution to their understanding of the importance of the relative lymphocyte count. References [1] M.R. Cowie, D.A. Wood and A.J.S. Coats et al., Incidence and aetiology of heart failure, Eur Heart J 20 (1999), pp. 421–428. Abstract-MEDLINE | Abstract-EMBASE [2] J.P. Hellermann, S.J. Jacobsen and M.M. Redfield et al., Heart failure after myocardial infarction: clinical presentation and survival, Eur J Heart Fail 7 (2005), pp. 119–125. Abstract [3] J.M. Brophy, G. Deslauriers and B. Boucher et al., The hospital course and short term prognosis of patients presenting to the emergency room with decompensated congestive heart failure, Can J Cardiol 9 (1993), pp. 219–224. Abstract-MEDLINE | Abstract-EMBASE [4] J.M. Brophy, G. Deslauriers and J.L. Rouleau, Long term prognosis of patients presenting to the emergency room with decompensated congestive heart failure, Can J Cardiol 10 (1994), pp. 543–547. Abstract-MEDLINE | Abstract-EMBASE [5] A. Rudiger, V.-P. Harjola and A. Müller et al., Acute heart failure: clinical presentation, one-year mortality and prognostic factors, Eur J Heart Fail 7 (2005), pp. 662–670. Abstract [6] J.B. Young and and the Publication Committee for the VMAC Investigators, Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure, JAMA 287 (2002), pp. 1531–1540. Abstract-EMBASE | Abstract-Elsevier BIOBASE [7] F. Follath, J.G.F. Cleland and H. Just et al., Efficacy and safety of intravenous levosimendan compared to dobutamine in severe low-output heart failure (the LIDO-study): a randomised double-blind trial, Lancet 360 (2002), pp. 196–202. SummaryPlus | Full Text + Links | PDF (113 K) [8] D.H. Castelino, P. McNair and T.W.H. Kay, Lymphocytopenia in a hospital population—what does it signify?, Aust N Z J Med 27 (1997), pp. 170–174. Abstract-MEDLINE | Abstract-EMBASE [9] J. Bergquist, A. Tarkowski and A. Ewing et al., Catecholaminergic suppression of immunocompetent cells, Immunol Today 19 (1998), pp. 562–567. SummaryPlus | Full Text + Links | PDF (185 K) [10] D.H. Nelson, A.A. Sandberg and J.G. Palmer et al., Blood levels of 17-hydroxycorticosteroids following the administration of adrenal steroids and their relation to levels of circulating leukocytes, J Clin Invest 31 (1952), pp. 843–849. Abstract-MEDLINE [11] S.R. Ommen, D.O. Hodge and R.J. Rodeheffer et al., Predictive power of the relative lymphocyte concentration in patients with advanced heart failure, Circulation 97 (1998), pp. 19–22. Abstract-MEDLINE | Abstract-EMBASE [12] H.A. Cooper, D.V. Exner and M.A. Woclawiw et al., White blood cell count and mortality in patients with ischemic and nonischemic left ventricular systolic dysfunction (an analysis of the studies of left ventricular dysfunction), Am J Cardiol 84 (1999), pp. 252–257. SummaryPlus | Full Text + Links | PDF (122 K) [13] D. Acanfora, M. Gheorghiade and L. Trojano et al., Relative lymphocyte count: a prognostic indicator of mortality in elderly patients with congestive heart failure, Am Heart J 142 (2001), pp. 167–173. Abstract | PDF (106 K) [14] M.S. Nieminen, M. Böhm and M.R. Cowie et al., Executive summary of the guidelines on the diagnosis and treatment of acute heart failure. The Task Force on Acute Heart Failure of the European Society of Cardiology, Eur Heart J 26 (2005), pp. 384–416. Abstract-MEDLINE | Abstract-EMBASE [15] S.P. Thomson, R.J. Gibbons and P.A. Smars et al., Incremental value of the leukocyte differential and the rapid creatine kinase–MB isoenzyme for the early diagnosis of myocardial infarction, Ann Intern Med 122 (1995), pp. 335–341. Abstract-MEDLINE | Abstract-EMBASE [16] B. Annen, G. Mang and E. Schuiki et al., C-reactive protein and relative lymphocytopenia: early markers of myocardial infarction? (article in German), Schweiz Med Wochenschr 129 (1999), pp. 1931–1934. Abstract-MEDLINE | Abstract-EMBASE [17] A. Widmer, A.Z. Linka and C.H. Attenhofer Jost et al., Mechanical complications after myocardial infarction reliably predicted using C-reactive protein levels and lymphocytopenia, Cardiology 99 (2003), pp. 25–31. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef [18] C.K. Connolly and M.R. Wills, Plasma cortisol levels in heart failure, BMJ 2 (1967), pp. 25–27. [19] F.C. Mooren, D. Blöming and A. Lechtermann et al., Lymphocyte apoptosis after exhaustive and moderate exercise, J Appl Physiol 93 (2002), pp. 147–153. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE [20] D.P. Cioca, N. Watanabe and M. Isobe, Apoptosis of peripheral blood lymphocytes is induced by catecholamines, Jpn Heart J 41 (2000), pp. 385–398. Abstract-MEDLINE [21] J. Westermann and U. Bode, Distribution of activated T cells migrating through the body: a matter of life and death, Immunol Today 20 (1999), pp. 302–306. Abstract | PDF (199 K) [22] R.S. Hotchkiss, P.E. Swanson and B.D. Freeman et al., Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction, Crit Care Med 27 (1999), pp. 1230–1248. [23] R.C. Bone, Sir Isaac Newton, sepsis, SIRS, and CARS, Crit Care Med 24 (1996), pp. 1125–1128. Abstract-MEDLINE | Full Text via CrossRef [24] G. Rajan and J.W. Sleigh, Lymphocyte counts and the development of nosocomial sepsis, Intensive Care Med 23 (1997), p. 1187. Abstract-MEDLINE | Full Text via CrossRef SEE RELATED ARTICLE, P. 66 [Ann Emerg Med. 2006;48:75-76.] In this issue, Tung et al report their subanalysis of the 600-person PRIDE trial dataset focusing on the ability of amino-terminal pro-brain natriuretic peptide (NT-proBNP) to differentiate heart failure from other conditions in the 216 patients who arrived in the emergency department (ED) complaining of shortness of breath and had a history of chronic obstructive pulmonary disease or asthma.1 and 2 The authors do a good job of acknowledging their study’s limitations which include a potentially imprecise gold standard and the many forms of confounding that can occur in a retrospective subgroup analysis. Their paper is a straightforward account of what they did and they openly acknowledge its limitations. Their conclusion, however, that “NT-proBNP may [emphasis added] be a useful adjunct to standard clinical evaluation of dyspneic subjects with previous obstructive airway disease” is not particularly helpful to clinicians since any claim can logically follow the word “may.” To ensure they are getting a balanced interpretation, readers may find it helpful to substitute “may or may not” for “may” every time they encounter it in a declarative statement. By doing so a reader can avoid being seduced by “may” into believing that the claim is true. A more helpful and precise conclusion for this study would have been “In this single-site retrospective study, elevated NT-proBNP levels were strongly associated with a clinical diagnosis of heart failure in dyspneic patients who have a history of chronic obstructive pulmonary disease or asthma; it remains to be seen whether the use of this test will improve patient outcomes.” If my reservations about the article’s conclusion simply concerned semantic accuracy, then this issue would not be worthy of my time or yours. Unfortunately, overly broad or optimistic conclusions are routine in the medical literature and can have effects that echo long after an article’s publication.3 Such conclusions can be (and are) used by those with an interest in selling the product. It is a slippery slope from “this may be useful” to “since it correlates with diagnosis, it is useful.” Marketing directors are as skillful as Olympic bobsledders in negotiating that slide. Just as I was wondering whether I was being overly paranoid about all of this, a 12 page glossy monograph on NT-proBNP funded by the test’s manufacturer arrived in the mail.4 It appears scholarly, comes from a prestigious medical center, offers continuing medical education, and cites 53 references to further enhance its credibility. Unfortunately, none of the cited studies compare outcomes in patients who receive this test to those who don’t, so there is no evidence to show that NT-proBNP or BNP improve patient care. Despite this, the monograph contains such statements as: “NT-proBNP provides an important diagnostic and prognostic test for these heart failure patients” and “whether they [the NP tests] will be integrated into the diagnostic workup of this latter group of patients [those with acute coronary syndrome or pulmonary embolism] will be determined by future studies that will evaluate their use as a guide to therapy.” The former quote offers as fact a statement that is unsubstantiated. The latter subtly implies that NP tests are already integrated into routine clinical practice for non-acute coronary syndrome dyspneic patients, despite no evidence to support this claim. It is just a matter of time before the Tung et al article is cited in similar fashion for a similar purpose. Some may argue that I am being petty. They could argue that we don’t have outcome studies for many things we do in medicine, so why are they required here? In response, I argue that we ought to try to change that tradition, and I point to the many tests and treatments that have shown promise and theoretical appeal but ultimately were shown to provide no benefit. Invasive central venous with wedge pressure monitoring makes perfect sense: it allows us to tailor therapy to the patient’s intravascular volume and cardiac function. Despite the logic of this, when studied in randomized trials, there is no evidence that it improves outcomes and some concern that it harms patients.5, 6 and 7 Should we continually repeat history by introducing ever-more-expensive modalities into practice based on incomplete evidence only to discover years later that they offer no benefit to patients? I am concerned that the following sequence has become routine in the research and marketing of new medical tests and treatments. Step 1 – perform research that suggests but, due to study design limitations and lack of patient-centered outcomes, fails to establish the utility of a test or treatment. Step 2 – perform additional research showing how the modality performs in subgroups. Step 3 – In the medical and marketing literature about the research on subgroups, make reference to the original study in a way that implies that the original research proved that the modality was effective, thereby creating a hegemonic belief that the test or treatment works. It is sequences like this that have led the editors of prominent medical journals to state “Medical journals are an extension of the marketing arm of pharmaceutical companies” and “Journals have devolved into information laundering operations for the pharmaceutical industry.”8 and 9 The damage goes way beyond the introduction of ineffective modalities into medical care. Ethicists have compellingly argued that these actions harm individuals and society at large by raising the cost of health care thereby depriving the less affluent of care.10 So my message to Annals readers is that it is your responsibility to protect our patients by interpreting original research papers very carefully and in proper context. We live in an age in which business interests fund the research and the continuing medical education activities that disseminate their message.8, 9, 10, 11 and 12 Research has shown that such relationships often shape the recommendations that are made.13 Journal peer review is an imperfect process for controlling the objectivity of conclusions, and journals have no control over how articles are cited and used after publication.14 The Tung et al article demonstrates some important characteristics of a potentially useful test. It does not measure patient outcomes and sheds no light on whether this test has a clinical role. Perhaps subsequent studies will establish that it is truly useful in these patients, perhaps not. Meanwhile, we should improve the soundness of our medical practice and the health of our society by introducing a new test or treatment only when there is solid evidence that it produces cost-effective improvement in patient outcome in relevant populations. The author thanks Marshall T. Morgan, MD, for his insightful comments on the word “may.” References 1 J.L. Januzzi, C.A. Camargo and S. Anwaruddin et al., N-terminal ProBNP for urgent investigation of shortness of breath the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study, Am J Cardiol 95 (2005), pp. 948–954. SummaryPlus | Full Text + Links | PDF (201 K) 2 Tung et al., Amino-Terminal pro-brain natriuretic peptide for the diagnosis of acute heart failure in patients with previous obstructive airway disease, Ann Emerg Med 48 (2006), pp. 66–74. SummaryPlus | Full Text + Links | PDF (388 K) 3 D.L. Schriger, Suggestions for improving the reporting of clinical research the role of narrative, Ann Emerg Med 45 (2005), pp. 437–443. SummaryPlus | Full Text + Links | PDF (296 K) 4 S.P. Collins, Use of NT-proBNP in the Emergency Department Evaluation of Shortness of Breath Implications for Clinical Practice, EMCREG, Cincinnati, OH (2005) 6. 5 A.F. Connors, T.S. Speroff and N.V. Dawson et al., The effectiveness of right heart catheterization in the initial care of critically ill patients, JAMA 276 (1996), pp. 889–897. Abstract-MEDLINE | Abstract-Elsevier BIOBASE 6 S. Harvey, D.A. Harrison and M. Singer et al., PAC-Man study collaboration: assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial, Lancet 366 (2005), pp. 472–477. SummaryPlus | Full Text + Links | PDF (106 K) 7 C. Binanay, R.M. Califf and V. Hasselblad et al., ESCAPE Investigators and ESCAPE Study Coordinators: evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial, JAMA 294 (2005), pp. 1625–1633. Abstract-MEDLINE 8 R. Smith, Medical journals are an extension of the marketing arm of pharmaceutical companies, PLoS Med 2 (2005), p. e138. Full Text via CrossRef 9 R. Horton, The dawn of McScience, New York Rev Books51 (2004), pp. 7–9. 10 M. Angell, The Truth about Drug Companies How They Deceive Us and What to Do about It, Random House, New York, NY (2005). 11 J.P. Kassirer, On the Take How Medicine’s Complicity with Big Business Can Endanger Your Health, Oxford University Press, New York, NY (2004). 12 B. Djulbegovic, M. Lacevic and A. Cantor et al., The uncertainty principle and industry-sponsored research, Lancet 356 (2000), pp. 635–638. SummaryPlus | Full Text + Links | PDF (77 K) 13 Abramson J. Drug profits infect medical studies. Los Angeles Times. January 7, 2006;sect B17:13.

Here ya go "GAmedic," here's a current study about your favorite med, ACTIVATED CHARCOAL... (The American Journal of Emergency Medicine Volume 24 @ Issue 4 , July 2006, Pages 440-443 doi:10.1016/j.ajem.2005.12.025 Copyright © 2006 Elsevier Inc. All rights reserved. Original Contribution Influence of activated charcoal on the pharmacokinetics and the clinical features of carbamazepine poisoning Nozha Brahmi MD, a, , Nadia Kouraichi MDa, Hafedh Thabet MDa and Mouldi Amamou MDa aIntensive Care Unit, Centre d'Assistance Médicale Urgente, 1008 Montfleury, Tunis-Tunisia Received 1 December 2005; revised 29 December 2005; accepted 30 December 2005. Available online 17 June 2006.) Abstract Carbamazepine (CBZ) poisoning has been associated with cases of severe toxicity and death. Multiple-dose activated charcoal was proposed to enhance the clearance of CBZ elimination, but there are no prospective controlled studies that demonstrated a change in clinical outcome after the use of multiple-dose activated charcoal. The aim of this study was to determine the CBZ elimination kinetics and the evolution of clinical features according to the dose of activated charcoal in acute poisoning patients. It is a prospective study for 6 months, from January to June 2004, including all pure acute CBZ-poisoned patients. Twelve patients were randomized to receive a multiple-dose activated charcoal (G1) or a simple dose of 1g/kg (G2). Their mean age was 27.6 ± 12.2 years; the Simplified Acute Physiology Score (SAPS II), 16.37 ± 8.46; and the Acute Physiology and Chronic Health Evaluation (APACHE II), 8 ± 3.96. They were 8 men and 4 women. The mean concentration of blood CBZ at hospital admission was of 29.42 ± 6.68 mg/L. Each group includes 6 patients. The peak value of blood CBZ was comparable in the 2 groups: 33 ± 3.46 mg/L (G1) vs 32.6 ± 5.63 (G2) (P = .5); the requirement of mechanical ventilation was similar also (3 in each group). The duration of both coma and mechanical ventilation was significantly decreased in the first group compared with the second: 20.33 ± 3.05 vs 29.33 ± 4.11 hours for coma (P = .02) and 24.1 ± 4.2 vs 36.4 ± 3.6 hours for mechanical ventilation (P = .001). The length of stay was also significantly decreased in the first group: 30.3 ± 3.4 vs 39.7 ± 7.3 hours in the second group (P = .000006). Concurrently, we have noted a significant constant reduction of the half-life of CBZ from serum in the first group: 12.56 ± 3.5 hours after multiple dose vs 27.88 ± 7.36 hours after a simple dose (P = .0004). This decrease was correlated to the dose of charcoal. In summary, we can conclude that multiple-dose activated charcoal is more efficient than simple-dose; it permits a constant decrease of the half-life of blood CBZ without any rebound effect and could improve the prognosis by reducing the duration of coma and the length of stay. Article Outline 1. Introduction 2. Materials and methods 2.1. Patients 2.2. Methods 2.3.Statistics 3. Results 4. Discussion References 1. Introduction Carbamazepine (CBZ) poisoning is associated with cases of severe toxicity and death [1]. The frequency of CBZ poisoning is increasing during these last years. It represents about 8.4% of all drug intoxications in our unit. The degree of toxicity depends on the dose and the quality of the substance. Pharmacokinetic studies have demonstrated a discrepancy between absorption of solid and suspension formulations. A substantial interindividual variability of the half-life of CBZ has also been reported. This variability may be explained by some factors such as age, sex, coingestion of others substances, and administration of charcoal [2], [3], [4] and [5]. The aim of this study was to determine the CBZ elimination kinetics according to the modality of activated charcoal administration in acute CBZ-poisoning patients. 2. Materials and methods 2.1. Patients We prospectively included all patients admitted for CBZ poisoning on a period of 6 months from January to June 2004 in a 16-bed intensive care and toxicological unit. The diagnosis of CBZ poisoning was based on a history of CBZ ingestion, clinical features of poisoning, and laboratory findings. The determination of CBZ blood level was performed using gas chromatography (therapeutic value ranges between 5 to 12 mg/L). Children and mixed poisoning were excluded. 2.2. Methods Once CBZ poisoning was retained, no gastric lavage was done, and patients were randomized in 2 groups. The first group (G1) received multiple doses of activated charcoal (50 g every 6 hours), administrated via a nasogastric tube until a return to a CBZ blood concentration less than 12 mg/L. The second group (G2) received a simple-dose charcoal of 1g/kg. Symptomatic treatment as the need of mechanical ventilation or supportive treatment was the same in the 2 groups. Carbamazepine blood level was measured successively at admission (CBZH0) every 3 hours until the peak then every 6 hours until annulation of CBZ blood level. The half-life of CBZ in blood was calculated using the following equation: CBZ t1/2 = (t2 − t1) × ln (2)/ln (CBZ t1/CBZ t2), where CBZ t1/2 is the half-life CBZ in blood, t2 − t1 denotes the times between the 2 CBZ measurements, and ln, the natural logarithm. The criteria for judgment were the duration of coma, mechanical ventilation, and the length of stay. This protocol was approved by the hospital ethics committee. 2.3. Statistics Statistical analysis was performed with SPSS 11.0 (SPSS Inc, Chicago, Ill). Continuous variables were expressed as means (±SD) and subgroups evaluated by the χ2 test; a 2-tailed test was used in the statistical analysis. A P value less than .05 was considered statistically significant. Correlations were determined using both Pearson and Spearman rank methods. 3. Results Twelve patients were included in the study for acute CBZ poisoning in a suicidal attempt. Their mean age was 27.6 ± 12.2 years; the SAPS II, 16.37 ± 8.46; and the APACHE II, 8 ± 3.96. They were 8 men and 4 women. The mean concentration of blood CBZ at hospital admission (CBZH0) was of 29.42 ± 6.68 mg/L. Six of them were comatous, requiring mechanical ventilation with a mean Glasgow Coma Scale of 8.28 ± 1.60. The analysis of the CBZ blood elimination showed that the concentration (y) in the blood at given time is expressed by the following equation: y = −10.56 ln (x) + 32.436, where y is in mg/L and x is in hours. Each group includes 6 patients. The peak value of blood CBZ was comparable in the 2 groups: 33 ± 3.46 mg/L (G1) vs 32.6 ± 5.63 (G2) (P = .5). The requirement of mechanical ventilation was similar also (3 in each group). The duration of both coma and mechanical ventilation was significantly decreased in the first group compared with the second: 20.33 ± 3.05 vs 29.33 ± 4.11 hours for coma (P = .02) and 24.1 ± 4.2 vs 36.4 ± 3.6 hours for mechanical ventilation (P = .001). The length of stay was significantly decreased also in the first group: 30.3 ± 3.4 vs 39.7 ± 7.3 hours in the second group (P = .000006). Concurrently, we have noted a significant reduction of the half-life of CBZ from serum in the first group: 12.56 ± 3.5 hours after a multiple dose vs 27.88 ± 7.36 hours after a single dose (P = .0004) (Table 1). We have noted also a constant decrease of the CBZ blood concentration without any rebound effect in the first group (Fig. 1). A linear correlation was also found between the half-time of blood CBZ (y) and the dose of charcoal (x) (r = −0.93; P = .01), expressed by the following equation: y = 35.279 − 0.1458x, where y is in hours and x is in grams (Fig. 2). Table1. Influence of charcoal administration modality on the elimination of CBZ serum Multiple dose (n = 6) Simple dose (n = 6) P SAPS II 24 ± 11 13 ± 7.8 NS APACHE II 10.33 ± 3.5 6.5 ± 3 NS Glasgow Coma Scale 10 ± 7.8 12.3 ± 8.5 NS CBZ concentration at admission (mg/L) 29.33 ± 5.03 31 ± 6.08 NS Peak value of blood CBZ (mg/L) 33 ± 3.46 32.6 ± 5.63 NS Total dose of charcoal (g) 166.6 ± 28.8 61.7 ± 6.8 .000002 Half-life of blood CBZ (h) 12.56 ± 3.5 27.88 ± 7.36 .0005 NS, non significant. (15K) Fig. 1. Kinetics of CBZ according to the dose of activated charcoal. (15K) Fig. 2. Relationship between the half-life of CBZ and the dose of charcoal. 4. Discussion Carbamazepine distribution and metabolism is complex. Carbamazepine is reasonably bioavailable and rapidly absorbed from the gastrointestinal tract. It is highly bound to plasma proteins (75%-80%) with a moderately large volume of distribution (Vd = 1.0-2.0 L/kg) [2], [3] and [4]. Because of these characteristics (prolonged elimination and a small volume of distribution), several modalities have been proposed to enhance drug clearance of CBZ using multiple doses of activated charcoal and hemoperfusion [4] and [6]. Multiple-dose activated charcoal has been recommended by the American Association of Poison Centres and Clinical Toxicologists and the European Association of Poison Centres and Clinical Toxicologists in a consensus position statement as useful in enhancing systemic clearance of CBZ in severe or life-threatening cases of poisoning. However, it should be noted that currently, there are no prospective controlled studies that demonstrated a change in clinical outcome after the use of multiple-dose activated charcoal in CBZ poisoning [4] and [7]. In our study, we try to demonstrate the influence of multiple-dose activated charcoal on elimination of CBZ and the clinical features. In fact, the biologic half-life of CBZ in humans shows substantial interindividual variability. It averages 35 hours after the administration of a simple dose and 20 hours after a multiple dose [3]. Multiple-dose activated charcoal is thought to produce its beneficial effect by interrupting the enteroenteric and, in some cases, the enterohepatic and the enterogastric circulation of drugs. In addition, any unabsorbed drug still present in the gut will be adsorbed to activated charcoal, thereby reducing drug absorption. It should be used if no contraindication exists [2], [4] and [7]. A few series have studied the impact of charcoal on the elimination of CBZ and demonstrated a significant decrease of the half-life in those who have received charcoal compared with supportive measures [4]. In 1987, Boldy et al [7] have demonstrated that the half-life of CBZ after a total dose of 203 ± 58 g of activated charcoal decreased to 8.6 ± 2.4 hours in 15 acute poisoned patients. Montoya-Cabrera et al [8] also found approximately the same results as those of Boldy et al with a decrease of the half-life to 9.5 ± 1.9 hours after multiple doses of charcoal (386 ± 72 g). The decrease of the half-life was remarkable if compared with the half-life with only supportive treatment, as it is the case in the studies of Hundt et al [9] and Vree et al [10], who evaluated the half-life of the blood CBZ at approximately 19 hours and in the study of Wason et al [11], at 23.3 hours. In our study, the dose-activated charcoal has been found to influence the duration of both coma and mechanical ventilation, and, consequently, the length of stay. The beneficial effect of charcoal may be explained by the decrease of the blood CBZ half-life, which was in correlation with the dose of activated charcoal. We have demonstrated also that the metabolic clearance of CBZ depends on the activated charcoal dose in favor of multiple dose, and that with a simple dose, we can observe a distribution of CBZ from tissue stores. This rebound phenomenon was reported with simple dose and hemoperfusion [1]. In fact, metabolic clearance has been reported to increase from 20 mL/kg per hour after a single dose to 55 mL/kg per hour after multiple-dose [1]. As a result, multiple-dose activated charcoal seems to be as efficient as hemoperfusion, which has been reported to reduce serum concentrations by 25% to 50% and the half-life to 6 to 8 hours, and could be proposed instead of hemoperfusion in severe patients with hemodynamic disturbance because charcoal hemoperfusion is an invasive method of CBZ purifying [1], [4], [12] and [13]. They are also interesting because they showed that a simple dose of charcoal (1g/kg) was less efficient than multiple dose and could be compared with supportive measures. The same result was reported by Winnicka et al [3] who do not demonstrate any in fluency of 30 to 70 g of charcoal on the half-life of CBZ. In summary, in spite of the little number of patients, we can conclude that multiple-dose activated charcoal is more efficient than simple dose; it permits a constant decrease of the half-life of blood CBZ without any rebound effect and could improve the prognosis by reducing the duration of coma and the length of stay. References [1] C. Low, S. Haqqie and R. Desai et al., Treatment of acute carbamazepine poisoning by hemoperfusion, Am J Emerg Med 14 (1996), pp. 540–541. SummaryPlus | Full Text + Links | PDF (214 K) [2] A. Perez and J.F. Wiley, Pediatric carbamazepine suspension overdose—clinical manifestations and toxicokinetics, Pediatr Emerg Care 21 (2005), pp. 252–254. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef [3] R. Winnicka, B. Lopacinski and W. Szymczak et al., Carbamazepine poisoning: elimination kinetics and quantitative relationship with carbamazepine 10,11-epoxide, J Toxicol Clin Toxicol 40 (2002), pp. 759–765. Abstract-EMBASE | Abstract-Elsevier BIOBASE | Abstract-MEDLINE | Full Text via CrossRef [4] AAMT and EAPCCT, Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning, J Toxicol Clin Toxicol 37 (1999), pp. 731–751. [5] L. Bertilsson and T. Tomson, Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update, Clin Pharmacokinet 11 (1986), pp. 177–198. Abstract-MEDLINE | Abstract-EMBASE [6] D. Askenazi, S. Goldstein and I.F. Chang et al., Management of a severe carbamazepine overdose using albumin-enhanced continuous venovenous hemodialysis, Pediatrics 113 (2004), pp. 406–409. Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Abstract-EMBASE | Full Text via CrossRef [7] D. Boldy, A. Heath and S. Ruddock et al., Activated charcoal for carbamazepine poisoning, Lancet 1 (1987), p. 1027. Abstract [8] M.A. Montoya-Cabrera, J.M. Sauceda-Garcia and P. Escalante-Galindo et al., Carbamazepine poisoning in adolescent suicide attempters. Effectiveness of multiple-dose activated charcoal in enhancing carbamazepine elimination, Arch Med Res 27 (1996), pp. 485–489. Abstract-MEDLINE | Abstract-EMBASE [9] H.K.L. Hundt, A.K. Aucamp and F.O. Müller, Pharmacokinetic aspects of carbamazepine and its two major metabolites in plasma during overdosage, Hum Toxicol 2 (1983), pp. 607–614. Abstract-EMBASE | Abstract-MEDLINE [10] T.B. Vree, T.J. Janssen and Y.A. Hekster et al., Clinical Pharmacokinetics of carbamazepine and its epoxy and hydroxy metabolites in humans after an overdose, Ther Drug Monit 8 (1986), pp. 297–304. Abstract-EMBASE | Abstract-MEDLINE [11] S. Wason, R.C. Baker and P. Carolan et al., Carbamazepine overdose—the effects of multiple dose activated charcoal, J Toxicol Clin Toxicol 30 (1992), pp. 39–48. Abstract-MEDLINE | Abstract-EMBASE [12] H. Spiller, Management of carbamazepine overdose, Pediatr Emerg Care 17 (2001), pp. 452–456. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef [13] A. Graudins, G. Peden and R.P. Dowsett, Massive overdose with controlled-release carbamazepine resulting in delayed peak serum concentrations and life-threatening toxicity, Emerg Med 14 (2002), pp. 89–94. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef

(The American Journal of Emergency Medicine Volume 24 @ Issue 4 , July 2006, Pages 435-439 doi:10.1016/j.ajem.2005.12.017 Copyright © 2006 Elsevier Inc. All rights reserved. Original Contribution β-Blocker use in elderly ED patients with acute myocardial infarction Presented at the New York Regional SAEM, New York City, NY, March 31, 2004 as a moderated poster presentation (awarded “Best Moderated Poster”); the Scientific Assembly of the Pennsylvania Chapter, American College of Emergency Physicians, April 21, 2004, Philadelphia, Pa, as a poster presentation (awarded “Best Poster Presentation”); the National Society for Academic Emergency Medicine Scientific Assembly, May 16-19, 2004, Orlando, Fla, as a poster presentation. David D. Vega MD, a, , Kendra L. Dolan MDa and Marc L. Pollack MD, PhDa aDepartment of Emergency Medicine, York Hospital, York, PA 17405, USA Received 6 October 2005; accepted 21 December 2005. Available online 17 June 2006.) Original Contribution β-Blocker use in elderly ED patients with acute myocardial infarction Presented at the New York Regional SAEM, New York City, NY, March 31, 2004 as a moderated poster presentation (awarded “Best Moderated Poster”); the Scientific Assembly of the Pennsylvania Chapter, American College of Emergency Physicians, April 21, 2004, Philadelphia, Pa, as a poster presentation (awarded “Best Poster Presentation”); the National Society for Academic Emergency Medicine Scientific Assembly, May 16-19, 2004, Orlando, Fla, as a poster presentation. David D. Vega MD, a, , Kendra L. Dolan MDa and Marc L. Pollack MD, PhDa aDepartment of Emergency Medicine, York Hospital, York, PA 17405, USA Received 6 October 2005; accepted 21 December 2005. Available online 17 June 2006. Abstract Background Despite the effectiveness of early β-blocker (BB) use in reducing mortality in acute myocardial infarction (AMI), they remain underutilized in the emergency department (ED) management of AMI. The elderly, with higher AMI mortality, and women, may be particularly vulnerable to underutilization of BB. Objective To determine the effect of age and gender on BB use in AMI in the ED. Methods A retrospective study of all ST-elevation AMI (STEMI) ED patients presenting to a community hospital ED from 2001 to 2003. Any contraindication to BB use (hypotension, bradycardia, AV block, active bronchospasm, and active congestive heart failure) was determined. Chi-square analysis was used to determine differences by gender and age. Results Three hundred eighty-five patients with STEMI were identified. Thirty-eight percent were women and 71% were over 60 years of age. Of the 270 (70%) who did not receive BB, 141 (52%) had contraindications to BB use. The total BB eligible group was 244 (63%). Of patients without contraindications to BB, 53% did not receive BB in the ED. By gender, 83 (54%) males and 46 (51%) females did not receive BB (P= .669). By age, 96 subjects (59%) over age 60 and 33 subjects (41%) under age 60 did not receive BB (P= .011). Conclusion Despite convincing evidence of effectiveness, BB remain underutilized in ED management of AMI, especially in the elderly. There does not appear to be a gender difference in BB use. Education programs should be directed towards emergency physicians regarding BB use in AMI, especially in elderly ED patients. Article Outline 1. Introduction 2. Methods 2.1. Study design 2.2. Study population and setting 2.3. Measurements 2.4. Data analysis 3. Results 4. Discussion 5. Limitations and future questions 6. Conclusions References 1. Introduction The American Heart Association (AHA)/American College of Cardiology lists β-blockers (BBs) as a class I recommendation for the treatment of acute myocardial infarction (AMI) in patients without contraindications [1]. As early as 1971, BBs were recognized to reduce infarct size in experimental animals [2]. The use of BB in the setting of AMI has repeatedly been shown to significantly reduce morbidity and mortality [3], [4] and [5]. β-Blockers lower heart rate, decrease myocardial contractility, and decrease peripheral vascular resistance, thereby reducing oxygen demand and workload. They also reduce infarct size and decrease the risk of wall rupture [6] and [7]. β-Blockers also help to prevent dysrhythmias including ventricular tachycardia and ventricular fibrillation [8], [9] and [10]. Despite their effectiveness, BBs remain underused in AMI [11] and [12]. The AHA/American College of Cardiology recommends BB within 12 hours of infarction [1]; however, there is strong evidence that earlier administration of BB, that is, in the ED, is associated with decreased morbidity and mortality [13], [14] and [15]. β-Blocker use in the setting of AMI has been shown to have the greatest decrease in mortality if given within 2 hours of symptom onset [14]. Nonetheless, many patients without contraindications with AMI are not given BB in the ED [11] and [16]. A small ED study and others indicate that females and elderly patients may not receive BB as frequently as males and younger patients, respectively [16], [17], [18] and [19]. The objective of our study was to determine the frequency that BB are given in the ED to patients with ST-elevation AMI (STEMI) and to determine if there is a significant difference in the treatment of females and the elderly. 2. Methods 2.1. Study design This is a retrospective study of all patients with STEMI in the ED from December 2001 through October 2003. Patients were identified by admission diagnosis of AMI and were included if they had both STEMI (at least 1 mm in 2 contiguous limb leads or 2 mm in 2 precordial leads) on electrocardiographic review and positive cardiac markers (troponin I or creatine kinase–MB) on chart review. Once subjects were identified, BB (metoprolol) use in the ED was determined via review of Pyxis (a hospital medication administration system) data on medication use in the ED. For those subjects that were not given BB, the presence of any contraindications to BB use (hypotension, bradycardia, AV block, active bronchospasm, and active congestive heart failure [CHF]) were identified. Institutional review board approval was obtained, and HIPAA regulations were followed. 2.2. Study population and setting The study was performed in the ED of a 63 000 visits per year community teaching hospital. Patients with AMI in the York Hospital catchment area are not diverted by emergency medical services to other institutions because York Hospital is capable of performing all invasive cardiac procedures including angiography, stent placement, and coronary artery bypass graph surgery. We identified patients with STEMI through a retrospective chart review. Patients were considered to have a contraindication to BB use if they had hypotension (systolic blood pressure <100), bradycardia (heart rate <60), second- or third-degree heart block, acute asthma, or chronic obstructive pulmonary disease (COPD) exacerbation, or acute CHF (Table 1). A history of asthma, COPD, or CHF alone was not considered a contraindication to BB use. Table 1. Contraindications to BB use Systolic blood pressure <100 mm Hg Heart rate <60 beats per minute Second- or third-degree atrioventricular block Acute exacerbation of asthma or COPD Acute CHF 2.3. Measurements Standardized data collection sheets were used. All personnel collecting data were familiar with inclusion and exclusion criteria and had the definitions of contraindications to BB use available as outlined on the data collection sheets. 2.4. Data analysis χ2 Analysis was performed on the data. 3. Results A total of 1395 charts of adult patients with an admitting diagnosis of AMI from 2001 through 2003 were reviewed. Of these 1395 patients, 402 had positive cardiac markers and ST-segment elevation on the initial electrocardiograph consistent with our inclusion criteria. Sixteen patients were excluded from final analysis secondary to incomplete Pyxis data, leaving 385 patients. These patients included 238 (63%) males and 147 (38%) females. Of all patients, 112 (29%) were younger than 60 years and 273 (71%) were 60 years or older. Table 2 presents the demographics of the 385 patients included in this study. Table 2. Patient characteristics Characteristic Total no. of patients N = 385 Age mean ± SD (range), y 68 ± 14 (33-99) <60 112 (29%) ≥60 273 (71%) Sex Female 147 (38%) Male 238 (62%) Of the 385 patients, as illustrated in Fig. 1, 141 (37%) had contraindications to BB as identified via chart review, leaving 244 (63%) patients eligible to receive BB in the ED. The exact nature of the BB contraindication in the 141 patients is listed in Table 3. Of those eligible for BB, there were 153 (63%) males, 91 (37%) females, 81 (33%) younger than 60 years, and 163 (67%) older than 60 years. (58K) Fig. 1. Enrollment procedure of patients with STEMI. Table 3. Nature of contraindications to BB use (n = 141) n % Bradycardia 77 54.6 Hypotension 53 37.6 Acute CHF 49 34.8 Third-degree AV block 7 5 Second-degree AV block 3 2.1 Acute COPD 3 2.1 Acute Asthma 0 0 Ninety-four (66.7%) had single contraindication and 47 (33.3%) had multiple contraindications. Of the 244 patients with STEMI who were eligible to receive BB, 129 (53%) did not receive BB while in the ED. By sex, 83 (54%) of 153 males vs 46 (51%) of 91 females were not treated with BB (P = .669). By age, 59% (n = 96) of patients 60 years and older did not receive BB, whereas 41% (n = 33) of patients younger than 60 years did not receive BB (P = .011). 4. Discussion β-Blockers are an integral part of the treatment of AMI and have been listed as a class I recommendation for the treatment of AMI by the AHA [1]. β-Blockers reduce morbidity and mortality by lowering heart rate and decreasing oxygen demand and myocardial workload, which all help to reduce infarct size and decrease the risk of wall rupture and prevent dysrhythmias including ventricular tachycardia and ventricular fibrillation [2], [3], [4], [5], [6], [7], [8], [9], [10] and [20]. The AHA recommends the use of BB within 12 hours of symptoms [1]. However, other studies have shown BB have their greatest effect if used within 2 hours of symptom onset [14] and [15]. Therefore, for optimal patient outcomes, the emergency physician is responsible for the decision to administer BB to patients with AMI. Despite these data, BBs are still underused in AMI; in fact, some small studies showed that females and the elderly may be undertreated in comparison to males and younger patients, respectively [11], [12], [16], [17], [18] and [19]. Recent data show only 28% of patients with AMI received BB in the ED at a university-affiliated teaching hospital vs 48.6% who received BB within 24 hours of AMI in a multicenter study across the United States [16] and [17]. In our study of a large community teaching ED (Fig. 1), 47% of eligible patients with STEMI received BB while in the ED, which further adds validity to studies showing that BB use is underused in the ED. Likewise, our data show that the elderly without BB contraindications also receive treatment far less than their younger counterparts, that is, 59% of those older than 60 years vs 41% of those younger than 60 years did not receive BB (P = .011). This supports data from a multicenter trial that showed 51% of the elderly without contraindications did not receive BB [17]. However, our data did not support the previous finding that females with AMI receive BB less frequently than males [16]. A larger study is needed to further clarify sex differences in BB administration. We have demonstrated that BBs continue to be underused in the ED overall and particularly in the elderly. Our next goal is to identify the underlying reasons for suboptimal BB administration in the ED. A previous retrospective chart review at a community hospital supported several reasons—ED physicians wanting to defer to cardiologists, cardiologists who overestimate the amount of time they are giving BB, and ED physicians who do not know the current contraindications to BB use [11]. Based on informal discussions with EP, we hypothesize that BBs are underused in the ED for several reasons: clinicians unfamiliar with evidence showing benefit of early BB use, clinicians unclear of exact contraindications to BB use (particularly regarding nonacute asthma, COPD, and CHF), concern for more frequent adverse outcomes in the elderly, and time constraints in the ED [21]. Further studies are needed to identify and rectify the causes so that patient care can be improved. We plan to institute educational measures to improve quality and standardized AMI order sheets and reevaluate BB use in the ED. 5. Limitations and future questions The study method of retrospective chart review has inherent flaws. The data may be skewed by inadequate documentation of contraindications to BB use by clinicians, which would not be detected on chart review. The data extracted from the Pyxis pertained to the use of BB. When medicine is withdrawn from the Pyxis, it is recorded electronically and we assume that this medicine was then given to the patient unless the electronic record indicates that the medicine was returned to the Pyxis. However, we did not have adequate documentation of medicines that were discarded by the nursing staff, and it is plausible that some medicines were withdrawn and not administered. This would have resulted in an even larger nonutilization of BB. Nonetheless, given the nature of the study, it is felt that the errors of incomplete documentation and Pyxis data accuracy are minimal and unavoidable. External validity could be questioned, as this was a single-center study in a community teaching hospital. However, our data are supported by other studies that have found underuse of BB in the ED [11], [16] and [17]. 6. Conclusions Our study shows that BBs are underused for STEMI in the ED. Although there was no significant difference in BB use by sex, elderly patients were significantly less likely to receive BB than younger patients in the ED. We postulate that there are many factors contributing to poor compliance: clinicians unfamiliar with evidence showing benefit of early BB use, clinicians unclear of exact contraindications to BB use (particularly regarding nonacute asthma, COPD, and CHF), concern for more frequent adverse outcomes in the elderly, and time constraints in the ED. Certainly, if patients are moved rapidly from the ED to either the catheterization laboratory or the cardiac care unit, BB can be administered in other settings than the ED. A formal survey of ED providers may prove useful in determining reasons why EM physicians are not using BB as often as they should. We plan to develop educational programs for ED clinicians aimed at increasing the use of BB in STEMI. In addition, a recent study has demonstrated that standing orders increase compliance with BB use in AMI [22]. References [1] T.J. Ryan, E.M. Antman, N.H. Brooks, R.M. Califf, L.D. Hillis and L.F. Hiratzka et al., ACC/AHA 1999 guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction), Circulation 100 (1999), pp. 1016–1030. Abstract-EMBASE | Abstract-Elsevier BIOBASE | Abstract-MEDLINE [2] P.R. Maroko, J.K. Kjekshus and B.E. Sobel et al., Factors influencing infarct size following experimental coronary artery occlusions, Circulation 43 (1971), pp. 67–82. Abstract-MEDLINE [3] β-Blocker Heart Attack Trial Research Group, A randomized trial of propanolol in patients with acute myocardial infarction. I. Mortality results, JAMA 247 (1982), pp. 1707–1714. 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Arnman et al., A double-blind trial of metoprolol in acute myocardial infarction. Effects on ventricular tachyarrhythmias, N Engl J Med 308 (1983), pp. 614–618. Abstract-EMBASE | Abstract-MEDLINE [9] S. Ahnve, L. Erhardt and T. Lundman et al., Effect of metoprolol on QTc intervals after acute myocardial infarction, Acta Med Scand 208 (1980) (3), pp. 223–228. Abstract-MEDLINE | Abstract-EMBASE [10] H. Evrengul, D. Dursunoglu and M. Kayikcioglu et al., Effects of a beta-blocker on ventricular late potentials in patients with acute anterior myocardial infarction receiving successful thrombolytic therapy, Jpn Heart J 45 (2004) (1), pp. 11–21. Abstract-MEDLINE | Full Text via CrossRef [11] M.M. O'Bryan and J.S. Banas, Intravenous beta-blockers in acute myocardial infarction: perceived versus actual use by cardiologists and emergency physicians, Am J Emerg Med 16 (1998), pp. 623–626. SummaryPlus | Full Text + Links | PDF (437 K) [12] W.J. French, Trends in acute myocardial infarction management. Use of the national registry of myocardial infarction in quality improvement, Am J Cardiol 85 (2000), pp. 5B–9B. [13] R.M. Gunnar, P.D.V. Bourdillon and D.W. Dixon et al., Guidelines for the early management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association task force on assessment of diagnostic and therapeutic cardiovascular procedures (Subcommittee to Develop Guidelines for the Early Management of Patients with Acute Myocardial Infarction), J Am Coll Cardiol 16 (1990), pp. 249–252. [14] The TIMI Study Group, Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) phase II trial, N Engl J Med 320 (1989), pp. 618–627. [15] S. Yusuf, Early intravenous beta blockade in acute myocardial infarction, Postgrad Med Spec No (1988), pp. 90–95. Abstract-MEDLINE [16] D. Pancu and D.C. Lee, Beta-blocker use in the emergency department in patients with acute myocardial infarction undergoing primary angioplasty, J Emerg Med 24 (2003), pp. 379–382. SummaryPlus | Full Text + Links | PDF (66 K) [17] H.M. Krumholz et al., Early β-blocker therapy for acute myocardial infarction in elderly patients, Ann Intern Med 131 (1999), pp. 648–654. Abstract-MEDLINE | Abstract-EMBASE [18] T.J. McLaughlin, S.B. Soumerai and D.J. Willison et al., Adherence to national guidelines for drug treatment of suspected acute myocardial infarction: evidence for under treatment in women and the elderly, Arch Intern Med 156 (1996) (7), pp. 799–805. Abstract-EMBASE | Abstract-MEDLINE [19] J.H. Gerwitz, R.J. Goldberg and Z. Chen et al., Beta-blocker therapy in acute myocardial infarction: evidence for underutilization in the elderly, Am J Med 93 (1992) (6), pp. 605–610. [20] K.E. Ellison and G. Gandhi, Optimising the use of beta-adrenoceptor antagonist in coronary artery disease, Drugs 65 (2005) (6), pp. 787–797. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef [21] J. Chen, M.J. Radford and Y. Wang et al., Effectiveness of beta-blocker therapy after acute myocardial infarction in elderly patients with chronic obstructive pulmonary disease or asthma, J Am Coll Cardiol 37 (2001) (7), pp. 1950–1956. SummaryPlus | Full Text + Links | PDF (183 K) [22] E.H. Bradley, J. Herrin, J.A. Mattera and E.S. Holmboe et al., Quality improvement efforts and hospital performance rates of beta-blocker prescription after acute myocardial infarction, Med Care 43 (2005) (3), pp. 282–292. Abstract-MEDLINE | Full Text via CrossRef

Hello Everyone, Here's an SVT related study which i thought you may all find interesting, and it relates somewhat to this topic. HTH, ACE844 (The American Journal of Emergency Medicine Volume 24 @ Issue 4 , July 2006, Pages 402-406 doi:10.1016/j.ajem.2005.12.004 Copyright © 2006 Elsevier Inc. All rights reserved. Original Contribution A new algorithm for the initial evaluation and management of supraventricular tachycardia H.C. Tyler Richmond MDa, Lee Taylor III MDa, Michael H. Monroe MDa and Laszlo Littmann MD, a, aDepartment of Internal Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA Received 9 September 2005; revised 28 November 2005; accepted 1 December 2005. Available online 17 June 2006.) Original Contribution A new algorithm for the initial evaluation and management of supraventricular tachycardia H.C. Tyler Richmond MDa, Lee Taylor III MDa, Michael H. Monroe MDa and Laszlo Littmann MD, a, aDepartment of Internal Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA Received 9 September 2005; revised 28 November 2005; accepted 1 December 2005. Available online 17 June 2006. Abstract Interpretations by physicians and those generated by electrocardiograph computer softwares have poor ability to recognize different types of supraventricular tachycardia (SVT). Therefore, we developed and tested a new SVT algorithm based on easily identifiable morphological characteristics and a simple dichotomous yes/no format regarding initial electrocardiographic manifestation and response pattern. The algorithm was then tested by medical house staff during the initial evaluation of 50 adult ED and cardiac intensive care unit patients suspected of having SVT. For a wide representation of SVTs, the new algorithm gave an overall diagnostic accuracy rate of 90%. Adenosine use was limited to 54% of the cases. No patient developed hemodynamic instability after algorithm-dictated interventions were carried out. Electrocardiograph computer-generated diagnoses correctly identified the specific type of SVT in 38% of the cases. This study shows the effectiveness of the proposed new algorithm in the rapid bedside evaluation and management of SVTs and confirms that computer-generated diagnoses are unreliable. Article Outline 1. Introduction 2. Methodology 3. Results 4. Discussion 4.1. Existing SVT algorithms 4.2. Construction of the new SVT algorithm 4.3. Clinical utility of the new algorithm 5. Limitations 6. Summary References 1. Introduction Recognizing, diagnosing, and properly treating supraventricular tachycardia (SVT) are common tasks that emergency medicine and other physicians face. Rapid diagnosis and appropriate management can help decrease the potential morbidity and mortality associated with this class of arrhythmias. Thus, recognition and management of SVT have remained an integral component of physician education in the form of Advanced Cardiac Life Support (ACLS) [1]. Despite this training, physicians still have a poor ability to properly diagnose SVT. Two studies suggested that medical house staff and attending physicians diagnose narrow complex tachycardias incorrectly in approximately 40% of cases [2] and [3]. Overuse of adenosine is common [4] and with certain forms of SVT may actually decrease diagnostic success [2] and [4]. In addition, physicians are often misled by the frequently incorrect computer-generated interpretations of SVTs [5]. Correct SVT recognition may be problematic because the current ACLS algorithm for SVT requires a positive identification of the type of SVT at the initiation of the algorithm and omits frequently misdiagnosed SVTs such as sinus tachycardia [1]. In response to these areas of concern, we developed a new algorithm based on the following principles: (1) initial categorization of the SVT according to its electrocardiographic (ECG) manifestation rather than a specific diagnosis; (2) inclusion of all relatively frequent forms of SVT; and (3) clear distinction between SVT and wide complex tachycardia of uncertain etiology. We used a dichotomous yes/no flow sheet format dependent on the initial ECG manifestation of the tachycardia and the subsequent response pattern to maneuvers that block the AV node. The use of adenosine was only permitted under specific, well-defined circumstances. Fig. 1 shows our new SVT algorithm with detailed instructions on the appropriate use of various AV nodal blocking agents incorporated in footnotes [6] and [7]. (51K) Fig. 1. New algorithm for the initial evaluation and management of SVT. This pilot study was designed as a prospective investigation to determine whether our algorithm could aid medical house staff in diagnosing and treating SVTs at the bedside. 2. Methodology During a 7-month period, a sample of 50 patients was collected from our university-associated community teaching hospital with its 114 000–visits-per-year ED and 20-bed cardiac intensive care unit. We educated emergency medicine, family practice, internal medicine, and physical medicine and rehabilitation residents on the patient entry criteria and use of the algorithm. Patients presenting with symptomatic tachycardia were entered into the study by medical house staff at their discretion. If a patient was suspected of having an SVT, an unused printed copy of the algorithm was obtained by each resident and reviewed. The initial ECGs were recorded using GE-Marquette ECG carts (Milwaukee, WI) fitted with the 12-SL interpretative software. The diagnosis of SVT was allowed only under the following specific circumstances: (1) rate > 100/min; (2) QRS duration ≤ 0.11 second; or (3) wide complex tachycardia (QRS duration ≥ 0.12 second) with a typical bundle-branch block morphology plus constant P-QRS relationship or a preexisting bundle-branch block or an intraventricular conduction disturbance with a perfectly identical QRS morphology plus a constant P-QRS relationship [8]. All other wide complex tachycardias were excluded to follow the appropriate ACLS guidelines for wide complex tachycardia of uncertain type or ventricular tachycardia [1]. Of note, the house staff were encouraged to exclude patients with obvious sinus tachycardia of an identifiable cause and those who had a known history of atrial fibrillation (AF) and who presented with an increased ventricular rate. Once a resident determined eligibility for the study, he or she followed the algorithm with all physiological, pharmacologic, and electrical interventions performed accordingly. Rhythm strips and/or further ECGs were encouraged and obtained at the discretion of each resident. Starting at the top, the algorithm (Fig. 1) first branches with the question of whether the rhythm is regular. For a rhythm determined to be regular, the next distinction is whether it is sinus tachycardia. Identifying characteristics of sinus tachycardia (slightly irregular rhythm; upright P waves in leads I, II, and aVF; short normal PR intervals; the presence of premature atrial complexes; and heart rate modification by autonomic maneuvers) are offered for review. If the tachycardia is determined to be sinus, the algorithm terminates with “identify and treat the cause.” A further attempt to immediately establish the mechanism of the remaining regular tachycardias is not required. Instead, instruction is given to apply physiological or pharmacologic maneuvers that are intended to result in AV nodal block. Choices to induce AV block are listed and repeated attempts to block down the AV node are encouraged. Only if AV block cannot be achieved by any means is D/C cardioversion offered. If AV block is achieved, then the next question is whether the tachycardia is terminated. If the tachycardia is terminated with AV block, then the general diagnosis of reentrant tachycardia (AV nodal reentry or AV macro-reentry) is made and the initial treatment has been accomplished. If, however, AV block does not result in termination of the tachycardia, then atrial flutter or ectopic atrial tachycardia is unmasked as the diagnosis and standard ACLS treatment options are presented for consideration. Going back to the original branch point, if analysis of the ECG reveals an irregular rhythm, then the operator should determine if group beatings are present. If they are present, then the most likely diagnosis is a variable blocking of either atrial flutter or ectopic atrial tachycardia and standard treatment options are given for consideration. If there is no group beating present (ie, the tachycardia is irregularly irregular), then one is asked to look for discrete P waves. The presence of distinct P waves or sinus beats suggests multifocal atrial tachycardia (MAT), whereas their absence confirms a diagnosis of AF. For both types of arrhythmias, generally accepted treatment options are provided. While following the said algorithm in evaluating and treating the patients, the house staff marked a decision-intervention line tracing their path on the printed form. On the back of the page, each resident made note of the following: (1) patient identification data; (2) clinical diagnosis; (3) tachycardia diagnosis after use of the algorithm; (4) general description of clinical course and events, including untoward effects of therapy and hemodynamic problems; (5) general comments, problems, or recommendations for the algorithm; and (6) patient disposition. We reviewed the data forms biweekly to ensure that the entries met the appropriate requirements. After 50 samples were collected, an electrophysiologist reviewed all ECGs and rhythm strips. His interpretations were used as the correct diagnoses. 3. Results A total of 24 medical house staff participated in the study. There were 25 cases entered in the cardiac intensive care unit, 23 in the ED, and 2 in hospital wards. In Table 1, the tachycardia diagnoses as determined by the house staff's use of the algorithm are compared with the electrophysiologist's interpretation of the ECGs and rhythm strips. A wide variety of SVTs were encountered, and, appropriately, no case of ventricular tachycardia was entered. The medical house staff diagnoses were correct in 45 of the 50 cases (90%; see Table 1). Adenosine was used on 27 occasions (54%). There was no instance of hemodynamic instability after the algorithm-dictated interventions were carried out, and resident comments on the algorithm were uniformly positive. Table 1. Supraventricular tachycardia diagnoses SVT diagnoses by house staff Total no. of diagnoses No. of correct diagnoses No. of incorrect diagnoses Correct diagnoses Sinus tachycardia 6 6 0 Reentrant SVT 20 19 1 Ectopic atrial tachycardia AF 13 11 2 Multifocal tachycardia for both cases Atrial flutter 7 5 2 AF for both cases MAT 3 3 0 Ectopic atrial tachycardia 1 1 0 Total 50 45 5 The ECG computer-generated diagnoses were correct in only 24 of the 50 cases (48%); of these, a specific diagnosis (ie, other than SVT) was given in only 19 (38%). In 2 cases, an undetermined rhythm was noted; in 1 case, a wide QRS tachycardia was reported. The computer interpretation was incorrect on 23 occasions (46%). Through the implementation of the algorithm, the house staff rejected all 23 incorrect diagnoses generated by the ECG computer. Of these, another incorrect diagnosis was reached on 2 occasions, whereas the correct diagnosis was reached on 21 occasions. 4. Discussion Our proposed and tested SVT algorithm provides an organized, stepwise process in the interpretation of SVTs and will likely improve medical decision making and patient management. 4.1. Existing SVT algorithms To our knowledge, this is the first prospective evaluation of the clinical utility of an SVT algorithm in the literature. Despite the enormous scale on which the current ACLS guidelines are being taught, we are not aware of any attempt to verify its efficacy or usefulness. Other SVT algorithms have been published, but they appear too cumbersome for general use and subsequently have not been tested for their didactic or clinical value [6], [9] and [10]. 4.2. Construction of the new SVT algorithm The new SVT algorithm was constructed to follow easily recognizable morphological characteristics and a physiologically based logical path. It first separates regular and irregular SVTs—a generally easy task but one that is sometimes aided by the use of calipers. Of the regular SVTs, sinus tachycardia is the most common. Positive identification of this rhythm through reminders of its typical manifestations is a required step to avoid the use of adenosine and to emphasize the fact that sinus tachycardia is rarely a primary arrhythmia. Residents were instructed to always consider atrial flutter with 2:1 block, especially in patients who have a regular tachycardia with rates between 130 and 160 beats/min. A second, hidden P wave can sometimes be found by halving of the apparent P-P interval. Maneuvers are then offered to block down the AV node. Many strategies to block the node are listed with encouragement to try other strategies if one proves unsuccessful. Instructions are given on the appropriate use of the various AV nodal blocking agents. If AV block results in tachycardia termination, then AV nodal conduction must be an integral part of the tachycardia circuit defining AV nodal or AV macro-reentrant tachycardia as the etiology. If AV nodal block did not result in tachycardia termination, then the site of the regular SVT must have been above the node; ie, atrial flutter or ectopic atrial tachycardia with constant blocking ratio was the diagnosis. Of the irregular tachycardias, the first distinction is between regular rhythms that appear irregular because of variable AV block and truly irregular ones. Group beatings are defined as episodes of regular SVT separated by pauses that almost always represent atrial tachycardia or atrial flutter with variable block. The irregularly irregular SVTs are most often AF. Multifocal atrial tachycardia, however, may also manifest as an irregularly irregular SVT and is frequently incorrectly diagnosed as AF both by computer interpretation software and by physicians. A search for distinct sinus beats is required to avoid this misdiagnosis and should prompt the physician to consider the diagnosis of MAT if found. In our SVT algorithm, some therapy occurs simultaneously with interpretation, but, overall, we did not focus on details of the acute treatment of various types of SVT. The reentrant paroxysmal SVTs were terminated as part of the evaluation process. A common treatment box was offered for atrial tachycardia/atrial flutter with constant blocking ratio (regular SVT), for atrial tachycardia/atrial flutter with variable blocking ratio (irregular SVT with group beating), and for AF (irregularly irregular SVT without distinct sinus beats). This treatment box included consideration of anticoagulation, rate control, and antiarrhythmic management, without specifying the various antiarrhythmic treatment choices. With both sinus tachycardia and MAT, physicians were encouraged to identify and treat the underlying cause of these typically secondary tachyarrhythmias. 4.3. Clinical utility of the new algorithm This pilot study, although not statistically evaluated, suggests that our proposed algorithm is effective in the rapid bedside diagnosis and management of SVT. It disallows consideration of wide complex tachycardia of uncertain etiology from the outset through a more rigorous definition of SVT. It requires no a priori diagnosis, only the ability to answer yes/no questions based on standard ECG observations. Imperative for any guideline, it follows a logical pattern that is conducive for quick comprehension and recall. Furthermore, the use of adenosine is potentially decreased by separating out rhythms (namely, sinus tachycardia, MAT, and AF) whose diagnosis could be hampered by its use [2] and [4]. For patients presenting with new-onset symptomatic SVT, the bedside diagnostic accuracy rate was 90% when used by a representative group of house staff. A wide variety of supraventricular tachyarrhythmias were entered and, of note, no primary ventricular rhythm was included. It is not known, however, how many attempts at inclusion were aborted secondary to a failure to meet the strict SVT definition. Sinus tachycardia was correctly diagnosed without the use of adenosine in all 6 cases, and 19 of 20 reentrant tachycardias were correctly identified and terminated with the appropriate use of AV nodal blocking maneuvers (mostly adenosine). Overall, the use of adenosine was not necessary to elucidate the correct diagnosis or to initiate treatment in almost half of the cases. Of the 5 incorrect diagnoses made by the house staff, 2 occurred secondary to the occasional difficulty in distinguishing between the presence of P waves and that of AF waves in irregular rhythms without group beatings. Two other incorrect diagnoses were the result of misreading the presence or absence of group beatings in rapid irregular rhythms. The last incorrect diagnosis occurred through inappropriate use of the algorithm where a clearly irregular rhythm with group beatings was considered to be a regular rhythm. None of these said patterns of mistakes warrants a change in the algorithm as one cannot account for all reader abilities in such a format. 5. Limitations Weaknesses of the study include the lack of electrophysiological study to verify final diagnoses, the small sample size, user discretion on entry, and the lack of a controlled design. It is also not known how the algorithm would have worked with attending physicians. Based on well-described ECG principles, we feel that electrophysiological study is not necessary to make the general diagnostic distinctions called for by the algorithm [6], [9], [10], [11] and [12]. The user discretion was to avoid an abundance of obvious rhythms (trivial sinus tachycardia, AF) that would falsely inflate the overall accuracy rate. Unfortunately, an effective controlled trial is difficult to design and to implement as teaching of the algorithm may induce bias. A future controlled design could best be approached with a follow-up sequential study where house staff would collect electrocardiograms demonstrating SVT based on their use of the current ACLS SVT guidelines, followed by the teaching and use of our proposed new algorithm to collect cases. Relative usefulness could then be determined by comparing the 2 accuracy rates. 6. Summary The proposed new algorithm appears to be effective in the rapid bedside evaluation and management of SVTs and may prove valuable in the setting of an ED. References [1] The American Heart Association in collaboration with the International Liaison Committee on Resuscitation (ILCOR), Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: an international consensus on science, Circulation 102 (2000) (Suppl), pp. I1–I384. [2] J.B. Conti, L. 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Aliot et al., ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias—executive summary: a report of the American College of Cardiology, American Heart Association Task Force on Practice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines, J Am Coll Cardiol 42 (2003), pp. 1493–1531. [7] L. Littmann, J.D. Anderson and M.H. Monroe, Adenosine and Aggrenox: a hazardous combination, Ann Intern Med 137 (2002), pp. e–76. [8] L. Littmann and M.M. McCall, Ventricular tachycardia may masquerade as supraventricular tachycardia in patients with pre-existing bundle branch block: a potential cause of misdiagnosis and inappropriate management, Ann Emerg Med 26 (1995), pp. 98–101. SummaryPlus | Full Text + Links | PDF (329 K) [9] F.W. Bär, P. Brugada and W.R.M. Dassen et al., Differential diagnosis of tachycardia with narrow QRS complex (shorter than 0.12 second), Am J Cardiol 54 (1984), pp. 555–560. Abstract [10] G.K. Jones, A practical approach to narrow complex tachycardia, Int Med (1996), pp. 81–94. [11] L. Littmann, J. Tenczer and T. Fenyvesi, Atrioventricular nodal reentrant paroxysmal supraventricular tachycardia, Arch Intern Med 144 (1984), pp. 129–131. Abstract-MEDLINE | Abstract-EMBASE [12] L.I. Ganz and P.L. Friedman, Supraventricular tachycardia, N Engl J Med 332 (1995), pp. 162–173. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef