Pre-hospital Hypotension!@ traumatic hemmhor management.....

[Ace844]

Ace,

I think that there are few out there that really understand the disease well enough to comment on your article. Not that they are dumb or stupid, but that EMS has taught cookbook medicine when it comes to trauma and not really explained it too the masses. I know that any one can understand, God knows i learned it, its just a matter of the teachers and lecturers or our industry getting educated on it and taking it back to there students and co workers and teaching them. I know for a fact that if it wasn't for my time and Vanderbilt I would still be saying "well its what our protocols say to do".

I agree and understand, and this is partially why I posted the info which I did. I guess I just find it sad that theose of us who want to learn and practice medicine in an educated fashion are such a small part of the EMS census....:idea: :!:

out here,

Ace844

[Ace844]

Hi All,

here's an interetsing journal article relative to the discussion...::

Prolonged Low-Volume Resuscitation with HBOC-201 in a Large-Animal Survival Model of Controlled Hemorrhage.

Journal of Trauma-Injury Infection & Critical Care. 59(2):273-283, August 2005.

Fitzpatrick, Colleen M. MD; Biggs, Kristen L. MD; Atkins, B Zane MD; Quance-Fitch, Fonzie J. DVM; Dixon, Patricia S.; Savage, Stephanie A. MD; Jenkins, Donald H. MD; Kerby, Jeffrey D. MD, PhD

Abstract:

Background: Military guidelines call for two 500-mL boluses of Hextend for resuscitation in far-forward environments. This study compared a hemoglobin-based oxygen carrier (HBOC-201; Hemopure) to Hextend when used to treat hemorrhagic shock in situations of delayed definitive care military operations.

Methods: Yorkshire swine (55-65 kg) were hemorrhaged to a mean arterial blood pressure (MAP) of 30 mmHg. Hypotension was maintained for 45 minutes followed by resuscitation with either Hextend (HEX) (n = 8) or HBOC-201 (HBOC) (n = 8). Over 8 hours, animals received up to 1,000 mL of either fluid in an effort to sustain an MAP of 60 mmHg. At the end of 8 hours, HEX animals received 2 L of lactated Ringer's solution followed by shed blood. HBOC animals received 4 L of lactated Ringer's solution only. Animals were killed and necropsied on postprocedure day 5. Hemodynamic data were collected during shock and resuscitation. Complete blood counts, amylase, lactate, coagulation studies, and renal and liver function were measured throughout the experiment.

Results: Equivalent volumes were hemorrhaged from each group (HBOC, 44.3 +/- 2.2 mL/kg; HEX, 47.4 +/- 3.0 mL/kg). The HBOC group achieved the goal MAP (HBOC, 60.0 +/- 2.3 mmHg; HEX, 46.4 +/- 2.3 mmHg; p < 0.01) and required less volume during the initial 8 hours (HBOC, 12.4 +/- 1.4 mL/kg; HEX, 17.3 +/- 0.3 mL/kg; p < 0.01). The HBOC group had lower SvO2 (HBOC, 46.3 +/- 2.4%; HEX, 50.7 +/- 2.5%; p = 0.12) and cardiac output (HBOC, 5.8 +/- 0.4 L/min; HEX, 7.2 +/- 0.6 L/min; p = 0.05), but higher systemic vascular resistance (HBOC, 821.4 +/- 110.7 dynes [middle dot] s [middle dot] cm-5; HEX, 489.6 +/- 40.6 dynes [middle dot] s [middle dot] cm-5; p = 0.01). Base excess, pH, lactate, and urine output did not differ between groups. HEX group survival was 50% (four of eight) versus 88% for the HBOC group (seven of eight). All animals survived the initial 8 hours. Animals surviving 5 days displayed no clinical or laboratory evidence of organ dysfunction in either group.

Conclusion: HBOC-201 more effectively restored and maintained perfusion pressures with lower volumes, and allowed for improved survival. These data suggest that hemoglobin-based oxygen carriers are superior to the current standard of care for resuscitation in far-forward military operations.

[ffemt819]

just be careful in chest trauma. If you have a injury to the heart or you believe you might have an injury to the heart keep the fluid going cause if you cause a lack of cardiac perfusion they will be dead.

[fireresque51]

Now if we can just get the FDA to approve it for Pre-Hospital use.

[fireresque51]

just be careful in chest trauma. If you have a injury to the heart or you believe you might have an injury to the heart keep the fluid going cause if you cause a lack of cardiac perfusion they will be dead.

The jice thing about hemopure is the fact it has 300 time greater affinity to oxygen than human hemoglobin so a little can go a long way in coranary profussion, but good pont.

[Ace844]

Ace,

I think that there are few out there that really understand the disease well enough to comment on your article. Not that they are dumb or stupid, but that EMS has taught cookbook medicine when it comes to trauma and not really explained it too the masses. I know that any one can understand, God knows i learned it, its just a matter of the teachers and lecturers or our industry getting educated on it and taking it back to there students and co workers and teaching them. I know for a fact that if it wasn't for my time and Vanderbilt I would still be saying "well its what our protocols say to do".

Also, it should be noted that in my original post I covered the phys and principles of this D/O, and management, so that those who don't know can learn about it....

Ace844

[Ace844]

just be careful in chest trauma. If you have a injury to the heart or you believe you might have an injury to the heart keep the fluid going cause if you cause a lack of cardiac perfusion they will be dead.

Read my original post..it covers this...

Ace844

[Ace844]

hello Everyone,

Here's some more data on this subject...

Hope this Helps,

ACE844

(Timing of Fluid Resuscitation Shapes the Hemodynamic Response to Uncontrolled Hemorrhage: Analysis Using Dynamic Modeling.

Original Articles

Journal of Trauma-Injury Infection & Critical Care. 60(6):1221-1227 @ June 2006.

Hirshberg, Asher MD; Hoyt, David B. MD; Mattox, Kenneth L. MD

Abstract:

Background: Timing of fluid resuscitation with respect to intrinsic hemostasis is an unexplored aspect of uncontrolled hemorrhage, because most animal models do not allow direct monitoring of blood loss. The aim of this study was to define how timing of crystalloid administration affects the bleeding patient's hemodynamic response to fluids, using a computer model of blood volume changes during uncontrolled hemorrhage.)

Methods: A multi-compartment lumped-parameter deterministic model of intravascular volume changes in a bleeding adult patient was developed and implemented. The model incorporates empirical mathematical descriptions of intrinsic hemostasis and rebleeding.

Results: The predicted hemodynamic response to uncontrolled hemorrhage closely corresponds to that seen in animal studies. A 2-L crystalloid bolus given during ongoing hemorrhage increases blood loss by 4 to 29%, an effect that is inversely related to the initial bleeding rate. A similar bolus given after intrinsic hemostasis may trigger rebleeding if given when the hemostatic clot is mechanically vulnerable. This period of clot vulnerability (ranging from 0-34 minutes) changes with both the initial bleeding rate and the rate of fluid administration.

Conclusions: The timing of crystalloid administration with respect to intrinsic hemostasis shapes the bleeding patient's hemodynamic response. An early bolus delays hemostasis and increases blood loss, while a late bolus may trigger rebleeding. These observations provide valuable insight into the hemodynamic response to fluid resuscitation.

(Trauma Associated Severe Hemorrhage (TASH)-Score: Probability of Mass Transfusion as Surrogate for Life Threatening Hemorrhage after Multiple Trauma.

Original Articles

Journal of Trauma-Injury Infection & Critical Care. 60(6):1228-1237 @ June 2006.

Yucel, Nedim MD; Lefering, Rolf PhD; Maegele, Marc MD; Vorweg, Matthias MD; Tjardes, Thorsten MD; Ruchholtz, Steffen MD; Neugebauer, Edmund A. M. PhD; Wappler, Frank MD; Bouillon, Bertil MD; Rixen, Dieter MD; the "Polytrauma Study Group of the German Trauma Society)

Abstract:

Background: To develop a simple scoring system that allows an early and reliable estimation for the probability of mass transfusion (MT) as a surrogate for life threatening hemorrhage following multiple trauma.

Methods: Potential clinical and laboratory variables documented in the Trauma Registry of the German Trauma Society (DGU) (1993-2003; n = 17,200) were subjected to univariate and multivariate logistic regression analysis to predict the probability for MT.

Results: Clinical and laboratory variables available from data sets were screened for their association with mass transfusion. MT was defined by transfusion requirement of >=10 units of packed red blood cells from emergency room (ER) to intensive care unit admission. Seven independent variables were identified to be significantly correlated with an increased probability for MT: systolic blood pressure (<100 mm Hg = 4 pts, <120 mm Hg = 1 pt), hemoglobin (<7 g/dL = 8 pts, <9 g/dL = 6 pts, <10 g/dL = 4 pts, <11 g/dL = 3 pts, and <12 g/dL = 2 pts), intra-abdominal fluid (3 pts), complex long bone and/or pelvic fractures (AIS 3/4 = 3 pts and AIS 5 = 6 pts), heart rate (>120 = 2 pts), base excess (<-10 mmol/L = 4 pts, <-6 mmol/L = 3 pts, and <-2 mmol/L = 1 pt), and gender (male = 1 pt). These variables were incorporated into a risk score, the Trauma Associated Severe Hemorrhage Score (TASH-Score, 0-28 points). Performance of the score was tested with respect to discrimination, precision, and calibration. Increasing TASH-Score points were associated with an increasing probability for MT.

Conclusion: The TASH-Score is an easy-to-use scoring system that reliably predicts the probability for MT after multiple trauma. Taken as a surrogate for life threatening bleeding calculation may focus attention on relevant variables indicative for risk and impact strategies to stop bleeding and stabilize coagulation in acute trauma care.

http://www.cinahl.com/cexpress/hta/summ/summ823.pdf

http://www.guideline.gov/summary/summary.a...37&nbr=4811

http://www.nice.org.uk/page.aspx?o=apprais...progress.trauma

Hope this helps,

ACE844

[Ace844]

(Influence of negative expiratory pressure ventilation on

hemodynamic variables during severe hemorrhagic shock

Anette C. Krismer @ MD; Volker Wenzel, MD; Karl H. Lindner, MD; Achim von Goedecke, MD;

Martin Junger, BS; Karl H. Stadlbauer, MD; Alfred Königsrainer, MD; Hans-U. Strohmenger, MD;

Martin Sawires, MD; Beate Jahn, MSc; Christoph Hörmann, MD)

This project was approved by the Austrian Federal Animal Investigational Committee, and the animals were managed in accordance with the American Physiologic Society, institutional guidelines, and the position of the American Heart Association on Research From the Department of Anesthesiology and Critical Care Medicine (ACK, VW, KHL, AG, MJ, KHS, HUS, MS, CH), the Department of Surgery (AK), and the Department of Medical Statistics, Informatics and Health Economics (BJ), Innsbruck Medical University, Innsbruck, Austria. Supported, in part, by the Austrian National Bank grants 9513 and 11448, Vienna, Austria, and the Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Austria. The authors have not disclosed any potential conflicts of interest. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000229886.98002.2B

Objective: Outcome after trauma with severe hemorrhagic shock is still dismal. Since the majority of blood is present in the venous vessels, it might be beneficial to perform venous recruiting via the airway during severe hemorrhagic shock. Therefore, the purpose of our study was to evaluate the effects of negative expiratory pressure ventilation on mean arterial blood pressure, cardiac output, and short-term survival during severe hemorrhagic shock. Design: Prospective study in 21 laboratory animals. Setting: University hospital research laboratory.

Subjects: Tyrolean domestic pigs.

Interventions: After induction of controlled hemorrhagic shock (blood loss _45 mL/kg), 21 pigs were randomly ventilated with

either zero end-expiratory pressure (0 PEEP; n _ 7), 5 cm H2O positive end-expiratory pressure (5 PEEP; n _ 7), or negative

expiratory pressure ventilation (up to _30 cm H2O at the endotracheal tube during expiration; n _ 7). Measurements and Main Results: Mean (_SD) arterial blood pressure was significantly higher in the negative expiratory pressure ventilation swine when compared with the 0 PEEP (38 _ 5 vs. 27 _3 mm Hg; p _ .001) and the 5 PEEP animals (38 _ 5 vs. 20 _ 6 mm Hg; p < .001) after 5 mins of the experiment. Cardiac output was significantly higher in the negative expiratory pressure ventilation

swine when compared with the 0 PEEP (3.1 _ .4 vs. 1.9 _ .9 L/min;p _ .001) and 5 PEEP animals (3.1 _ .4 vs. 1.2 _ .8 L/min; p < .001) after 5 mins of the experiment. All seven negative expiratory pressure ventilation animals, but only three of seven 0 PEEP animals (p _.022), survived the 120-min study period, whereas all seven of seven 5 PEEP animals were dead within 35 mins (p < .001). Limitations include that blood loss was controlled and that the small sample size

limits the evaluation of survival outcome. Conclusions: When compared with pigs ventilated with either

0 PEEP or 5 PEEP, negative expiratory pressure ventilation during severe hemorrhagic shock improved mean arterial blood pressure and cardiac output. (Crit Care Med 2006; 34:2175–2181)

Crit Care Med 2006 Vol. 34, No. 8 2175

Management of trauma patients in severe hemorrhagic shock is a challenging aspect of trauma care. Although there is an ongoing discussion regarding beneficial vs. adverse effects of fluid resuscitation during uncontrolled hemorrhagic shock, new approaches such as vasopressin to manage severe bleeding are entering the debate as well (1–4). However, both drugs and fluid resuscitation need to be administered intravenously to be effective. Unfortunately, especially in those patients who need therapy the most since blood pressure is collapsing, obtaining rapid intravenous access may be very difficult. A strategy to improve cardiocirculatory function even before an intravenous access can be obtained could be extremely beneficial in these patients. Since the majority of blood is present in the venous vessel system, it may be helpful to perform venous recruiting when managing a patient in severe hemorrhagic shock, until a venous access can be obtained. Previous studies described positive effects of an inspiratory impedance threshold valve during cardiopulmonary resuscitation and hemorrhagic shock (5– 8) in regard to optimizing right and left atrial filling and, therefore, cardiac output and mean arterial blood pressure. Although the venous recruiting concept of the inspiratory threshold valve is intriguing, it can only be used during cardiopulmonary resuscitation or spontaneous ventilation; however, extrapolating this concept to mechanical ventilation would be desirable. In that case, endotracheal intubation could be used to achieve a secured airway, oxygenation, and additionally venous recruiting with negative expiratory pressure. The purpose of this study was therefore to assess the effects of negative expiratory pressure ventilation with positive pressure ventilation with zero cm H2O PEEP (0 PEEP) and with positive pressure ventilation with 5 cm H2O PEEP (5 PEEP), respectively. The tested primary study outcome was the improvement of mean arterial blood pressure, and secondary study outcomes were cardiac output and short-term survival.

MATERIALS AND METHODS

Animal care and use were performed by qualified individuals, supervised by veterinarians, and all facilities and transportation comply with current legal requirements and guidelines. Anesthesia was used in all surgical interventions, all unnecessary suffering was avoided, and research would have been terminated if unnecessary pain or fear resulted. Our animal facilities meet the standards of the American Association for Accreditation of Laboratory Animal Care.

Surgical Preparations and Measurements.

This study was performed on 21 healthy, 12- to 16-wk-old swine weighing 35–45 kg. The animals were fasted overnight but had free access to water. The pigs were premedicated with azaperone (4 mg/kg intramuscularly,neuroleptic agent, Janssen, Vienna, Austria)and atropine (0.01 mg/kg intramuscularly) 1hr before surgery. Anesthesia was induced with a single bolus dose of ketamine (20mg/kg intramuscularly), propofol (1–2 mg/kgintravenously), and piritramid (30 mg intravenously,

opioid with_4–8 hrs half time, Janssen,Vienna, Austria) given via an ear vein. The animals were placed in a supine position, and their trachea was intubated during spontaneous ventilation. After intubation, pigs were ventilated with a prototype volume-controlled ventilator (CAREvent, O-Two-Systems, Mississauga, ON,Canada) with 35% oxygen at 12 breaths/min and

with a tidal volume adjusted to maintain normocapnia;furthermore, a PEEP of 5 cm H2O was applied during preparation and hemorrhage. The ventilator is a pneumatically powered, time-cycled, square-wave generator. The negative pressure was generated using an oxygenpowered Venturi vacuum generator. The Venturi vacuum generator was turned on at the

end of the inspiratory phase, remained on for the full duration of the expiratory phase, and was turned off at the commencement of the next inspiratory phase (Fig. 1). Respiratory variables were measured and analyzed using a

pulmonary monitor (CP-100, Bicore Monitoring System, Irvine, CA) attached to a variable orifice pneumotachograph (Varflex, Allied Health Products, Riverside, CA) and an esophageal balloon catheter (Smart Cath, Allied Health Products, Riverside, CA). The esophageal balloon catheter was 2 mm (7-Fr) in diameter, 70 cm long, and constructed from medical-grade polyurethane.

The inflated balloon was 0.9 cm in diameter and 10 cm long. The frequency response was 30 Hz. The esophageal balloon catheter was connected directly to the catheter port on the Bicore system. The Bicore system automatically

performs a vacuum leak test and fills the esophageal balloon with 0.8 mL of air. The pneumotachometer was connected directly to the proximal end of the airway tube. Airway pressure and flow were measured at the pneumotachometer.

The CO2 sampling port was sited above the flow transducer. The position of the esophageal balloon catheter was checked and

adjusted where necessary by observation of the cardiac artifact on the esophageal waveform, as recommended by the manufacturer. Anesthesia was maintained with propofol (6–8 mg/kg/hr intravenously) and a single injection of piritramid (15 mg intravenously). Lactated Ringer’s solution (10 mL/kg/hr intravenously) was administered in the preparation

phase, resulting in _500 mL of fluid replacement in all animals before initiation of the experimental protocol (9). A standard lead II electrocardiogram was used to monitor cardiac rhythm; depth of anesthesia was judged according to arterial blood pressure and heart rate. If cardiovascular variables during the preparation phase indicated a reduced depth of anesthesia,

additional propofol and piritramid were given. Body temperature was maintained at 38.5–39.5°C. A 7-Fr saline-filled catheter was advanced via femoral cutdown into the right atrium for measurement of right atrial pressure, and two catheters were advanced via bilateral femoral cutdown into the abdominal aorta for measurement of aortic blood pressure, withdrawal

of blood to induce hemorrhagic shock, and arterial blood samples. A 7.5-Fr pulmonary artery catheter was placed in the pulmonary artery via the internal jugular vein to measure cardiac output with the thermodilution technique. The intravascular catheters were attached to pressure transducers (1290A, Hewlett Packard, Boeblingen, Germany) that were aligned at the level of the right atrium. All pressure tracings were recorded with a data acquisition system (Dewetron port 2000, Graz, Austria; and Datalogger, custom-made software, Peter Hamm,departmental technician). Blood gases were measured with a blood gas analyzer (Chiron,Walpole, MA); end-tidal carbon dioxide was measured using an infrared absorption analyzer

(Multicap, Datex, Helsinki, Finland).

Experimental Protocol. After assessing baseline hemodynamic values and blood gases, propofol infusion was adjusted to 2 mg/kg/hr and infusion of lactated Ringer’s solution was stopped. Muscle paralysis was achieved with 0.2 mg/kg/hr pancuronium to prevent spontaneous or agonal breathing. Animals were ventilated with 100% oxygen and were bled _45

mL/kg (estimated 65% of their calculated blood volume) (10) via an arterial catheter over a period of 30 mins to simulate controlled hemorrhagic shock. Subsequently, 21 animals were randomized into three groups and then ventilated with either up to _30 cm H2O negative expiratory pressure ventilation (n _7), 0 cm H2O PEEP (n _ 7), or 5 cm H2O PEEP (n _ 7; investigators were blinded to the treatment protocol; Fig. 2) Besides the endexpiratory pressure level, no other variable was changed in the ventilator setting. One blinded researcher collected all blood gases and another blinded researcher measured cardiac output. Blood gases and cardiac output were measured every 10 mins during the first 60 mins. No fluids were administered during the

first 60 mins of the study period; after this time point, fluid resuscitation (25 mL/kg lactated Ringer’s and 25 mL/kg 3% gelatin solution, a colloid fluid used as a volume expander) was performed in all surviving pigs. After fluid resuscitation was started, blood gases and cardiac output were measured every 15 mins. From this point in time, animals were ventilated

with the same ventilator settings before randomization; no recruitment maneuver was performed. Animals were declared dead if mean arterial blood pressure fell below 10 mm Hg. At

Figure 1. Venturi powered vacuum generator for negative expiratory pressure ventilation.

2176 Crit Care Med 2006 Vol. 34, No. 8

the end of the 120-min study protocol, the surviving animals were killed with an overdose of fentanyl, propofol, and potassium chloride.

Statistical Analysis. Values are expressed as mean _ SD. Shapiro Wilks tests were used to test for normality distribution. Baseline data for hemodynamic variables and arterial blood gases were tested with one-way analysis of variance if Gaussian-distributed and with Kruskal-Wallis test if not Gaussian-distributed. Statistical investigation was performed only for baseline data before and after hemorrhage, cardiac output, mean arterial blood pressure, and short-term survival. We did not statistically analyze other variables in order to avoid overinterpretation of the data. To evaluate differences in mean arterial blood pressure and cardiac output between groups, analysis for repeated measurements was used. Because all animals in the 5 PEEP group died before the end of the intervention, differences between the negative expiratory pressure ventilation group and the 5 PEEP group were only tested until 10 mins after start of the intervention (otherwise until the end of the experimental phase). Survival rates were compared using Kaplan-Meier methods with log rank (Mantel Cox) comparison of cumulative survival by treatment groups. We considered p _ .05 to be statistically significant. No corrections were made for multiple comparisons. All statistical calculations were performed using SPSS, version 11.5, for Windows.

RESULTS

Before induction of hemorrhagic shock, there were no differences in study end points between groups (Tables 1, 2). After induction of hemorrhagic shock, mean arterial blood pressure, cardiac output, and mean right atrial pressure were considerably

decreased when compared with baseline values but were comparable between

Figure 2. Flowchart of the experiment. Hearts, measurement of hemodynamic variables; triangles,

measurement of airway pressures, tidal volumes, and flow rates with a pneumotachometer; teardrops,

sampling of blood gases; PEEP, positive end-expiratory pressure; NEP, negative expiratory pressure.

Table 1. Hemodynamic variables during the hemorrhage phase, the experimental phase, and fluid resuscitation

Variable

Hemorrhage Phase Experimental Phase Fluid Resuscitation

BL 1 BL 2 5 Mins 10 Mins 20 Mins 30 Mins 60 Mins 90 Mins 120 Mins

End-tidal CO2, mm Hg

NEP 36 _1 20_5 37_3 38 _3 39 _2 41_3 41_2 41_1 38_ 4

0 PEEP 37 _1 19_7 25_6 25 _5 24 _8 30_4 29_9 37_4 35_ 1

5 PEEP 36 _2 23_4 20_7 22 _7 21 _6 16_5 — — —

Heart rate, beats/min

NEP 88 _ 5 184 _ 46 217 _ 20 219 _ 19 227 _ 18 230 _ 20 235 _ 21 183 _ 36 187 _ 57

0 PEEP 82 _ 8 183 _ 26 200 _ 28 204 _ 33 198 _ 43 222 _ 19 187 _ 22 184 _ 65 153 _ 36

5 PEEP 90 _ 4 186 _ 36 181 _ 30 186 _ 25 177 _ 14 163 _4 — — —

Mean right atrial blood pressure, mm Hg

NEP 90 _ 4 186 _ 36 181 _ 30 186 _ 25 177 _ 14 163 _4 90_ 4 186 _ 36 181 _ 30

0 PEEP 8 _1 2_1 1_1 1_1 1_1 1_1 2_2 8_1 5_ 3

5 PEEP 7 _1 3_4 5_2 3_1 3_1 3_1 — — —

Mean pulmonary artery blood pressure, mm Hg

NEP 18 _1 10_1 5_5 6_1 7_2 7_1 7_2 18_2 19_ 3

0 PEEP 18 _2 11_2 11_2 11 _2 11 _2 13_1 12_1 20_2 18_ 1

5 PEEP 20 _3 10_2 10_2 12 _1 11 _0 10_2 — — —

Pulmonary artery occlusion pressure, mm Hg

NEP 8 _2 2_2 0_1 1_1 0_ 1 _1 _3 0_1 8_3 8_ 2

0 PEEP 8 _2 3_3 6_3 4_3 3_3 4_1 5_2 8_2 8_ 2

5 PEEP 9 _2 2_2 4_3 5_1 5_1 7_3 — — —

Cardiac output, L/min

NEP 3.7 _ 0.4 1.1 _ 0.4 3.1 _ 0.4a,b 3.2 _ 0.3a,b 3.2 _ 0.5b 3.5 _ 0.4b 4.0 _ 0.6b 6.0 _ 1.2 7.5 _ 1.4

0 PEEP 3.8 _ 0.5 1.1 _ 0.4 1.9 _ 0.9 2.0 _ 1.0 1.9 _ 0.7 2.5 _ 0.6 2.3 _ .8 6.2 _ 0.1 6.1 _ 1.2

5 PEEP 4.3 _ 0.9 1.0 _ 0.2 1.2 _ 0.8 0.9 _ 0.9 2.0 _ 0.3 0.4 — — —

BL 1, baseline 1, measurements before hemorrhage; BL 2, baseline 2, measurements after controlled hemorrhage (_45 mL/kg blood loss); NEP,

negative expiratory pressure ventilation; 0 PEEP, ventilation with 0 cm H2O positive end-expiratory pressure; 5 PEEP, ventilation with 5 cm H2O positive

end-expiratory pressure; —, not measured due to death of all animals.

Values are given as mean _ SD of the mean.

ap _ .001 for negative pressure ventilation vs. 5 PEEP; bp _ .001 for negative pressure ventilation vs. 0 PEEP; since all animals in the 5 PEEP group died before the end of the intervention, differences between the negative expiratory pressure ventilation group and the 5 PEEP group where only tested until 10 mins after start of the intervention. No statistical comparison was performed for all other variables in order to avoid overinterpretation of the data.

Crit Care Med 2006 Vol. 34, No. 8 2177

groups. Also, total blood loss was comparable between groups.

Main Results.

Mean arterial blood pressure was significantly higher in the negative expiratory pressure ventilation swine

when compared with the 0 PEEP (p _.001) and 5 PEEP animals (p _ .001). Cardiac output was significantly higher in negative

expiratory pressure ventilation swine when compared with the 0 PEEP (p _.001) and 5 PEEP animals (p _ .001; Table

1, Fig. 3), Seven of seven negative expiratory pressure ventilation animals, but only three of seven 0 PEEP swine, survived

the 120-min study period, whereas seven of seven 5 PEEP pigs were dead within 35 mins. There was a statistically significant difference in cumulative survival between the negative expiratory pressure ventilation swine vs. the 0 PEEP pigs (p _ .022) and between the negative expiratory pressure ventilation swine vs. the 5 PEEP pigs (p _ .001; Fig. 4).

Secondary Results. During the shock phase, ventilation with negative expiratory pressure resulted in decreased mean airway

pressure and increased delta esophageal pressure and delta airway pressure when compared with the 0 PEEP and 5 PEEP

animals. (Table 3). When compared with the 0 PEEP and 5 PEEP group, end-tidal carbon dioxide was notably higher during

the experiment, but arterial oxygen partial pressure was considerably lower in the negative expiratory pressure ventilation animals after 20 mins of the shock protocol. Representative tracings of mean arterial pressure and right atrial pressure tracings

are given in Figures 5 and 6.

DISCUSSION

In this model of severe hemorrhagic shock, negative expiratory pressure ventilation ensured survival of seven of seven pigs for 60 mins without administration of vasopressors or fluid resuscitation and subsequently allowed 60 mins of hemodynamic stabilization with fluid resuscitation. In contrast, only three of seven 0 PEEP animals survived the 120-min Table 2. Arterial blood gases during the hemorrhage phase, the experimental phase, and fluid resuscitation

Variable Hemorrhage Phase Experimental Phase Fluid Resuscitation

BL 1 BL 2 5 Mins 10 Mins 20 Mins 30 Mins 60 Mins 90 Mins 120 Mins

Arterial pH

NEP 7.50 _ 0.02 7.50 _ 0.06 7.40 _ 0.09 7.31 _ 0.06 7.31 _ 0.05 7.30 _ 0.02 7.32 _ 0.04 7.37 _ 0.05 7.44 _ 0.06

0 PEEP 7.51 _ 0.02 7.49 _ 0.07 7.41 _ 0.09 7.33 _ 0.08 7.33 _ 0.07 7.28 _ 0.06 7.27 _ 0.15 7.38 _ 0.12 7.45 _ 0.05

5 PEEP 7.50 _ 0.03 7.49 _ 0.05 7.40 _ 0.07 7.34 _ 0.05 7.32 _ 0.06 7.34 _ 0.03 — — —

Arterial PCO2, mm Hg

NEP 38 _2 34_3 34_5 43_5 43_3 45_2 45_4 41_2 38_ 4

0 PEEP 38 _1 33_4 30_6 34_5 33_8 42_2 43_5 39_5 38_ 1

5 PEEP 38 _2 34_3 32_4 33_3 34_6 29_ 1 — — —

Arterial PO2, mm Hg

NEP 144 _ 12 443 _ 55 384 _ 58 337 _ 64 283 _ 56 307 _ 32 326 _ 36 397 _ 81 417 _ 62

0 PEEP 151 _ 21 375 _ 57 352 _ 57 355 _ 84 381 _ 50 394 _ 65 353 _ 48 441 _ 50 415 _ 38

5 PEEP 178 _ 93 424 _ 85 393 _ 80 373 _ 62 436 _ 48 390 _ 67 — — —

Arterial base excess,

mmol/L

NEP 6 _2 4_ 4 _4 _ 4 _5 _ 3 _5 _ 3 _4 _ 2 _3 _ 2 _2 _2 1_ 3

0 PEEP 6 _2 2_ 3 _5 _ 4 _7 _ 4 _4 _ 9 _7 _ 4 _7 _ 6 _2 _5 1_ 3

5 PEEP 6 _2 2_ 3 _5 _ 3 _8 _ 3 _8 _ 1 _10 _ 1 — — —

Arterial lactate, mmol/L

NEP 1.8 _ 0.5 4.7 _ 1.2 8.8 _ 1.8 7.8 _ 1.6 7.6 _ 1.4 7.5 _ 1.6 6.5 _ 1.9 6.1 _ 2.1 4.6 _ 1.9

0 PEEP 1.8 _ 0.4 5.8 _ 1.2 10.0 _ 2.5 9.8 _ 2.0 10.2 _ 2.2 10.1 _ 3.0 9.3 _ 2.6 7.8 _ 2.5 5.7 _ 1.9

5 PEEP 1.8 _ 0.6 5.6 _ 1.6 10.0 _ 2.3 10.4 _ 3.2 11.4 _ 5.0 9.4 _ 4.6 — — —

BL 1, baseline 1, measurements before hemorrhage; BL 2, baseline 2, measurements after controlled hemorrhage (_45 mL/kg blood loss); NEP,

negative expiratory pressure ventilation; 0 PEEP, ventilation with 0 cm H2O positive end-expiratory pressure; 5 PEEP, ventilation with 5 cm H2O positive

end-expiratory pressure; —, not measured due to death of all animals.

Values are given as mean _ SD of the mean. No statistical comparison was performed in order to avoid overinterpretation of data.

Figure 3. Mean _ SD mean arterial blood pressure during ventilation with negative expiratory pressure

ventilation (NEP; triangles), 0 cmH2O positive end-expiratory pressure (0 PEEP; diamonds), and 5 cm

H2O PEEP (5 PEEP; squares). BL 1, baseline 1 before blood withdrawal; BL 2, baseline 2 after 45 mL/kg

blood loss. Note that the time line between BL 1 and BL 2 is not subject to scale. Fluid resuscitation

indicates infusion of 25 mL/kg lactated Ringer’s solution and 25 mL/kg 3% gelatin solution. *p _ .001

between negative expiratory pressure and 0 cm PEEP, respectively.

study period, and seven of seven 5 PEEP animals died within 35 mins. We withdrew _65% of the calculated

blood volume in order to simulate severe hemorrhagic shock. Our pigs had a mean arterial blood pressure of _20 mm Hg immediately before randomization, indicating a critically decreased brain perfusion. A patient in this condition is most likely unconscious and should be immediately intubated and ventilated at the accident site according to the Advanced Trauma Life Support guidelines (11). Our prototype ventilator producing positive pressure during inspiration, and negative pressure during expiration, thus mimicking a “normal” ventilation cycle with reversed pressure ratios, may thus combine the advantage of ensuring ventilation plus enhancing venous return and perfusion. We deliberately withheld vasopressors and fluid resuscitation for the first 60 mins of the experiment in order to investigate the effects of different ventilation strategies over a prolonged period of time. Fluid resuscitation was then started to simulate further shock management and to determine whether the shock state was reversible or refractory. Since spontaneous inspiration decreases intrathoracic pressure and induces decreases in right atrial blood pressure, venous return increases (12). Mechanical ventilation reverses this effect, since positive airway pressure and PEEP ventilation increase intrathoracic pressure, causing venous return to decrease (12). In contrast to current Advanced Trauma Life Support treatment concepts, this may be of considerable clinical importance during management of severe hemorrhagic shock. For example, in a porcine study simulating severe hemorrhagic shock, positive pressure ventilation with 5 or 10 PEEP significantly decreased cardiac output and mean arterial blood pressure, resulting in death within 5–30 mins (13). In contrast, an inspiratory threshold valve maintains and prolongs a vacuum created within the thorax during inspiration. This results in increased venous return and vital organ blood flow during cardiopulmonary resuscitation with an active compression decompression device and during controlled hemorrhagic shock (14, 15). Unfortunately, the innovative inspiratory threshold valve concept to recruit venous return cannot be applied after mechanical ventilation is initiated; thus, severely injured patients who usually require both airway and blood pressure management may be unable to benefit of this novel technique. By analogy, noninvasive negative pressure ventilation also influences the cardiovascular system. Cuirass negative

pressure ventilation significantly improved cardiac output in children after cardiac surgery (16, 17). It has been therefore discussed as adjunctive hemodynamic therapy in patients with a low cardiac output (18). As demonstrated in our animals, negative expiratory pressure ventilation decreased mean airway pressure, and subsequently mean right atrial blood pressure, as well as mean pulmonary artery blood pressure. Accordingly, cardiac output almost tripled in the negative expiratory pressure ventilation animals and was even comparable to prehemorrhage levels. This was accompanied by significantly higher end-tidal carbon

Figure 4. Kaplan-Meier survival curves in animals being ventilated with either negative expiratory

pressure ventilation (NEP), 0 positive end-expiratory pressure (PEEP), or 5 PEEP. Note that the

hemorrhage phase is not presented.

Table 3. Secondary results

NEP 0 PEEP 5 PEEP

Baseline 2

Expiratory tidal volume, mL 603 _ 44 661 _ 81 657 _ 92

Respiratory rate, per min 12 _0 12 _0 12 _ 0

Peak airway pressure, cm H2O 34 _2 33 _3 32 _ 4

Mean airway pressure, cm H2O 15 _0 14 _0 14 _ 1

Peak inspiratory flow rate, mL/sec 572 _ 59 626 _ 96 583 _ 70

_ PES, cm H2O 6 _4 9_2 8_ 3

_ PAW, cm H2O 28 _2 26 _3 25 _ 4

Experimental phase

Expiratory tidal volume, mL 617 _ 66 683 _ 65 684 _ 97

Respiratory rate, per min 12 _0 12 _0 12 _ 0

Peak airway pressure, cm H2O 29 _2 29 _3 35 _ 6

Mean airway pressure, cm H2O 0 _0 12 _1 15 _ 1

Peak inspiratory flow rate, mL/sec 581 _ 57 594 _ 83 563 _ 63

_ PES, cm H2O 24 _ 12 10 _2 8_ 2

_ PAW, cm H2O 58 _4 27 _3 26 _ 4

Fluid resuscitation

Expiratory tidal volume, mL 644 _ 61 700 _ 57 —

Respiratory rate, per min 12 _0 12 _0 —

Peak airway pressure, cm H2O 35 _4 31 _5 —

Mean airway pressure, cm H2O 16 _1 15 _1 —

Peak inspiratory flow rate, L/sec 594 _ 62 645 _ 36 —

_ PES, cm H2O 7 _3 9_2 —

_ PAW, cm H2O 28 _4 24 _5 —

NEP, negative expiratory pressure ventilation; 0 PEEP, ventilation with 0 cm H2O positive

end-expiratory pressure; 5 PEEP, ventilation with 5 cm H2O positive end-expiratory pressure; Baseline

2, measurements after controlled hemorrhage (45 mL/kg blood loss); _ PES, pressure change in the

esophagus due to ventilation; _ PAW, peak airway pressure minus the minimum airway pressure

during each breath; —, not measured due to death of all animals.

Values are given as mean _ SD of the mean. No statistical comparison was performed in order to

avoid overinterpretation of data.

dioxide levels when compared with the 0 and 5 PEEP animals, indicating a stabilization of hemodynamic status. Negative expiratory pressure ventilation resulted in a lower, but not hypoxic, arterial oxygen partial pressure when compared with the 0 and 5 PEEP animals. Although speculative, this may be due to formation of atelectasis and increased pulmonary shunting; however, arterial oxygen partial pressure improved after the ventilator settings were changed to preshock parameters. Furthermore, no recruitment maneuver was necessary. Fluid resuscitation showed that shock was reversible, and pH, lactate, and base excess improved in the 1-hr observation period both in the negative expiratory pressure ventilation and also in the remaining 0 PEEP animals. Taken together, negative expiratory pressure ventilation may be a strategy to immediately

improve cardiac output, which may be especially beneficial in trauma patients with collapsing blood pressure (19). Limitations include that we withheld fluid resuscitation. Second, the small sample size limits the evaluation of survival outcome. Blood loss was controlled; and the effect of negative expiratory pressure ventilation in uncontrolled bleeding needs to be determined. Also, intubation with no subsequent fluid resuscitation may be contradictory to the Advanced Trauma Life Support guidelines but was used because of the experimental design of the study. We used young and healthy animals with flexible ribcages; therefore, it may be possible that the observed effects may be less profound in the elderly with a more rigid chest wall. Furthermore, we cannot report about the degree of functional residual capacity reduction or the extent of atelectasis formation. Also, we did not perform a histologic examination of the lungs. Further, negative pressure ventilation is a very stressful intervention for the lung. We do not know what happens with pulmonary mediator function and whether possible changes

are fully reversible after return to positive pressure ventilation. Since we do not know if potentially detrimental effects,

such as a negative pulmonary pressure edema, could occur during normovolemia, a fourth group of normovolemic

animals ventilated with negative pressure might have been interesting. We do not know if this mode of ventilation could

trigger an acute respiratory distress syndrome.

CONCLUSIONS

When compared with pigs ventilated with either 0 PEEP or 5 PEEP, negative expiratory pressure ventilation during severe hemorrhagic shock improved mean arterial blood pressure and cardiac output.

ACKNOWLEDGMENTS

We are indebted to Kathrin Ebert and Kevin Bowden for technical assistance.

REFERENCES

1. Du GB, Slater H, Goldfarb IW: Influences of

different resuscitation regimens on acute

early weight gain in extensively burned patients.

Burns 1991; 17:147–150

2. Stadlbauer KH, Wagner-Berger HG, Raedler

C, et al: Vasopressin, but not fluid resuscitation,

enhances survival in a liver trauma

model with uncontrolled and otherwise lethal

hemorrhagic shock in pigs. Anesthesiology

2003; 98:699–704

3. Voelckel WG, Raedler C, Wenzel V, et al:

Arginine vasopressin, but not epinephrine,

improves survival in uncontrolled hemorrhagic

shock after liver trauma in pigs. Crit

Care Med 2003; 31:1160–1165

4. Krismer AC, Wenzel V, Voelckel WG, et al:

Employing vasopressin as an adjunct vasopressor

in uncontrolled traumatic hemorrhagic

shock. Three cases and a brief analysis

of the literature. Anaesthesist 2005; 54:

220–224

Figure 5. Representative aortic and right atrial blood pressure tracings after hemorrhage and during

negative expiratory pressure (NEP) ventilation during the experimental phase.

Figure 6. Representative aortic and right atrial blood pressure tracings during the experimental phase

with negative expiratory pressure ventilation (NEP), 0 positive end-expiratory pressure (PEEP), or 5

PEEP.

2180 Crit Care Med 2006 Vol. 34, No. 8

5. Lurie KG, Voelckel WG, Zielinski T, et al:

Improving standard cardiopulmonary resuscitation

with an inspiratory impedance

threshold valve in a porcine model of cardiac

arrest. Anesth Analg 2001; 93:649–655

6. Lurie KG, Zielinski T, McKnite S, et al: Use of

an inspiratory impedance valve improves

neurologically intact survival in a porcine

model of ventricular fibrillation. Circulation

2002; 105:124–129

7. Samniah N, Voelckel WG, Zielinski TM, et al:

Feasibility and effects of transcutaneous

phrenic nerve stimulation combined with an

inspiratory impedance threshold in a pig

model of hemorrhagic shock. Crit Care Med

2003; 31:1197–1202

8. Voelckel WG, von Goedecke A, Fries D, et al:

Treatment of hemorrhagic shock. New therapy

options. Anaesthesist 2004; 53:1151–1167

9. Wenzel V, Padosch SA, Voelckel WG, et al:

Survey of effects of anesthesia protocols on

hemodynamic variables in porcine cardiopulmonary

resuscitation laboratory models before

induction of cardiac arrest. Comp Med

2000; 50:644–648

10. Hannon JP, Bossone CA, Wade CE: Normal

physiological values for conscious pigs used

in biomedical research. LabAnimSci 1990;

40:293–298

11. PHTLS Basic and Advanced Prehospital

Trauma Life Support. St. Louis, MO, Mosby,

2003

12. Pinsky MR: Recent advances in the clinical

application of heart-lung interactions. Curr

Opin Crit Care 2002; 8:26–31

13. Krismer AC, Wenzel V, Lindner KH, et al:

Influence of positive end-expiratory pressure

ventilation on survival during severe hemorrhagic

shock. Ann Ermerg Med 2005; 46:

337–342

14. Sigurdsson G, Yannopoulos D, McKnite SH,

et al: Cardiorespiratory interactions and

blood flow generation during cardiac arrest

and other states of low blood flow. Curr Opin

Crit Care 2003; 9:183–188

15. Lurie KG, Zielinski TM, McKnite SH, et al:

Treatment of hypotension in pigs with an

inspiratory impedance threshold device: A

feasibility study. Crit Care Med 2004; 32:

1555–1562

16. Shekerdemian LS, Bush A, Shore DF, et al:

Cardiorespiratory responses to negative pressure

ventilation after tetralogy of Fallot repair:

A hemodynamic tool for patients with a

low-output state. J Am Coll Cardiol 1999;

33:549–555

17. Shekerdemian LS, Bush A, Shore DF, et al:

Cardiopulmonary interactions after Fontan

operations: Augmentation of cardiac output

using negative pressure ventilation. Circulation

1997; 96:3934–3942

18. Shekerdemian LS, Schulze-Neick I, Redington

AN, et al: Negative pressure ventilation as

haemodynamic rescue following surgery for

congenital heart disease. Intensive Care Med

2000; 26:93–96

19. Cera SM, Mostafa G, Sing RF, et al: Physiologic

predictors of survival in post-traumatic

arrest. Am Surg 2003; 69:140–144

Crit Care Med 2006 Vol. 34, No. 8 2181

[Ace844]

(Resuscitation With Normal Saline (NS) vs. Lactated Ringers (LR) Modulates Hypercoagulability and Leads to Increased Blood Loss in an Uncontrolled Hemorrhagic Shock Swine Model

[Original Articles)

Kiraly, Laszlo N. MD; Differding, Jerome A. MS; Enomoto, T Miko MD; Sawai, Rebecca S. MD; Muller, Patrick J. MS; Diggs, Brian PhD; Tieu, Brandon H. MD; Englehart, Michael S. MD; Underwood, Samantha MS; Wiesberg, Tracy T. MD; Schreiber, Martin A. MD

From the Oregon Health & Science University, Portland, Oregon.

Submitted for publication December 20, 2005.

Accepted for publication March 14, 2006.

This work was supported in its entirety by US Army Medical Research Acquisition Activity Award# W81XWH-04-1-0104.

Presented at the 19th Annual Meeting of the Eastern Association for the Surgery of Trauma, January 10–14, 2006, Orlando, Florida.

Corresponding Author: Martin A. Schreiber, MD, FACS, Associate Professor of Surgery, Director of Surgical Critical Care, Trauma/Critical Care Section, Oregon Health & Science University, 3181 SW Sam Jackson Road L223A, Portland, OR 97239; email: schreibm@ohsu.edu.]

Abstract

Background: Lactated ringers (LR) and normal saline (NS) are used interchangeably in many trauma centers. The purpose of this study was to compare the effects of LR and NS on coagulation in an uncontrolled hemorrhagic swine model. We hypothesized resuscitation with LR would produce hypercoagulability.

Methods: There were 20 anesthetized swine (35 ± 3 kg) that underwent central venous and arterial catheterization, celiotomy, and splenectomy. After splenectomy blinded study fluid equal to 3 mL per gram of splenic weight was administered. A grade V liver injury was made and animals bled without resuscitation for 30 minutes. Animals were resuscitated with the respective study fluid to, and maintained, at the preinjury MAP until study end. Prothrombin Time (PT), Partial Thromboplastin Time (PTT), and fibrinogen were collected at baseline (0') and study end (120'). Thrombelastography was performed at 0'and postinjury at 30', 60', 90', and 120'.

Results: There were no significant baseline group differences in R value, PT, PTT, and fibrinogen. There was no significant difference between baseline and 30 minutes R value with NS (p = 0.17). There was a significant R value reduction from baseline to 30 minutes with LR (p = 0.02). At 60 minutes, R value (p = 0.002) was shorter while alpha angle, maximum amplitude, and clotting index were higher (p < 0.05) in the LR versus the NS group. R value, PT, and PTT were significantly decreased at study end in the LR group compared with the NS group (p < 0.05). Overall blood loss was significantly higher in the NS versus LR group (p = 0.009).

Conclusions: This data indicates that resuscitation with LR leads to greater hypercoagulability and less blood loss than resuscitation with NS in uncontrolled hemorrhagic shock.

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The choice of intravenous fluid for the resuscitation of hemorrhagic shock has been a source of ongoing controversy for over a century. Normal saline (NS) and lactated Ringers (LR) are treated as equivalent resuscitation fluids in many trauma systems. Numerous studies have examined differences in outcomes and parameters in patients receiving a saline solution versus a balanced salt solution. In vitro and in vivo experiments suggest that crystalloid resuscitation may lead to a hypercoagulable state.1–4 The majority of these trials have associated LR with a hypercoagulable state. A recent trial compared Hetastarch in a balanced salt solution, LR, and hetastarch in normal saline in terms of coagulation during surgery.4 The normal saline based hetastarch treated patients were hypocoagulable compared with baseline while the LR treated patients were hypercoagulable. The in vivo experiments have mainly focused on elective surgery patients.1,3–5 In vitro studies usually use blood from healthy volunteers diluted with a set amount of fluid. A study in an intact large animal trauma model has not been previously performed. Given the significant morbidity and mortality of both coagulopathic hemorrhage and thromboembolic disease in trauma patients, further investigation is warranted to assess the impact of resuscitation fluids on the coagulation system.

Beyond the hypercoagulable state seen in the setting of LR resuscitation, the use of NS has been associated with a hyperchloremic acidosis that has the potential to affect coagulation. Waters et al. found that in patients undergoing abdominal aortic aneurysm repair, NS resuscitation resulted in the use of significantly more blood products.5 This suggests that NS may have a harmful effect on the coagulation system.

The purpose of this study was to compare coagulation parameters after uncontrolled hemorrhage and resuscitation in an animal model and to determine the etiology of the differences seen between LR and NS. This model is intended to represent the prehospital or battlefield scenario. In this setting, surgical control has not been established and the treatment choices are limited to fluid resuscitation. We hypothesized that, in a swine grade V liver injury model, animals resuscitated with LR would become hypercoagulable compared with animals resuscitated with NS. This model offers an excellent reproduction of the massive resuscitation efforts commonly seen in the modern trauma setting. Given the complex interplay of fluid shifts, inflammatory mediators, and coagulation factors this model may offer a more realistic scenario as compared with previous in vivo and in vitro dilution studies.

MATERIALS AND METHODS

This was a randomized controlled trial using twenty female Yorkshire crossbred pigs. The pigs underwent a 16-hour preoperative fast except for water ad libitum and were preanesthetized with an intramuscular injection of 8 mg/kg Telazol (Fort Dodge Animal Health, Fort Dodge, Ind.). They then underwent oro-tracheal intubation with a 7.0 mm or 7.5 mm endotracheal tube and were placed on mechanical ventilation. Respiratory rate was adjusted to keep pCO2 values between 40 to 50 mm Hg. Anesthesia was maintained using 2% isoflurane in 100% oxygen. An esophageal thermometer was inserted.

Animal temperature was controlled utilizing external warming devices. Once the swine were anesthetized, left cervical cut downs were performed and polyethylene catheters were inserted into the common carotid artery and external jugular vein. The arterial catheter was used for continuous blood pressure monitoring and blood sampling. Mean arterial pressure (MAP) and heart rate (HR) were continuously recorded and averaged every 10 seconds using a digital data collection system with a blood pressure analyzer (DigiMed, Louisville, Ky.). The venous line was used for administration of the resuscitation fluids.

The animals underwent a midline celiotomy, suprapubic Foley catheter placement, and splenectomy. Splenectomies are performed in swine hemorrhage models because of the spleen's distensibility and the resultant variation in amounts of sequestered blood. The spleen was weighed and, based on randomization, either LR or NS solution was infused to replace three times the spleen weight. The abdomen was than closed with towel clamps.

Following a 15-minute stabilization period, the abdomen was opened and residual peritoneal fluid was removed. Preweighed laparotomy pads were placed in both paracolic gutters and the pelvis to facilitate blood collection. A standardized grade V liver injury (injury to a central hepatic vein) was created with a specially designed clamp. The clamp was positioned in the middle of the liver, placing the right hepatic vein, the left hepatic vein, and the portal vein at risk for injury. This protocol is based upon our experience in previous studies of uncontrolled hemorrhagic shock using the grade V liver injury model.6 The time of injury was considered the start time of the two-hour study period. Following 30 minutes of uncontrolled hemorrhage, the initial blood loss, measured by wall suction and the preweighed laparotomy pads, was determined. The abdomen was then closed.

We blindly randomized (using a random numbers table) the swine to receive either NS or LR resuscitation at 165 mL/min. This rate is approximately one half the rate delivered by the Level I rapid infuser as the animals were approximately one half the weight of an average human. Resuscitation fluid was administered to achieve and maintain the baseline MAP for 90 minutes postinjury.

Upon completion of the 2-hour study period, the abdomen was reopened and the secondary blood loss was determined by adding the volume of intra-abdominal blood to the weight of the intra-abdominal blood clots. After the completion of the study the animals were sacrificed by exsanguination. To ensure comparable injuries between the study groups, we removed the liver and identified the number of hepatic vessels injured.

Blood specimens were collected at baseline and every 30 minutes until completion of the 2-hour study. Blood assays included lactate level, arterial blood gases, chemistry panel and hematocrit. Coagulation studies included partial thromboplastin time (PTT), prothrombin time (PT), and fibrinogen.

A TEG analyzer (TEG) (Hemoscope Corporation, Niles, Ill.) was used as a test for overall coagulation. This test was performed immediately after blood was removed from the animal and kaolin activation was utilized. The TEG values were measured every 30 minutes. Thrombelastography has been documented to be a more sensitive measure of coagulation disorders as compared with standard coagulation measures.7 Previous studies have documented hypercoagulability in trauma patients using thrombelastography.8,9 Individual parameters of the thrombelastograms (Fig. 1) can detail the cause of coagulopathy. The R value or reaction time represents the time to onset of clot formation. Elongation of the R value signifies a deficiency in coagulation factors. The [alpha] angle represents the rapidity of fibrin buildup and cross-linking. This value is affected by fibrinogen function and to a lesser extent, platelets. The K time is a measure of the speed to reach a certain level of clot strength. K is shortened by increased fibrinogen function and, to a lesser extent, by platelet function, and is prolonged by anticoagulants that affect both. The maximum amplitude (MA) measures the strength of the clot and is affected primarily by platelets but also by fibrinogen. The Clotting Index (CI) is a composite score of coagulation taking into account all of the above values.

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[Email Jumpstart To Image] Fig. 1. Example of TEG tracing. R value or reaction time represents the time to onset of clot formation. The [alpha] value represents the rapidity of fibrin buildup and cross-linking. The K time is a measure of the speed to reach a certain level of clot strength. The MA value is maximum amplitude and measures the strength of the clot.

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This protocol was approved by the Institutional Animal Care and Use Committee at Oregon Health & Science University. This facility adheres to the National Institutes of Health guidelines for the use of laboratory animals.

An independent samples t test was used to compare the means of continuous variables between the two groups. Statistical significance was defined as a p value <0.05. Values within a group were compared using a post hoc analysis of the variance (ANOVA). These values were calculated using SPSS version 13.0 software (SPSS Inc., Chicago, Ill.) and graphs were produced using Microsoft Excel 2003 (Microsoft Inc., Redmond, Wash.).

RESULTS

Ten animals were randomized to each group. One animal in the NS group died just before completion of the 2 hour study period. All other animals survived. Table 1 shows the mean initial weight, blood pressure, temperature, vessels injured, blood loss and fluid replacement compared between groups. Despite the fact that the number of vessels injured and initial blood loss were similar between groups, the NS group had greater blood loss after resuscitation and required more than twice the volume of resuscitation fluid to achieve and maintain the baseline blood pressure during the 90 minute resuscitation study period.

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[Email Jumpstart To Image] Table 1 Baseline and Postinjury Values. Comparison Between NS and LR Groups of Physiologic Parameters

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The NS group was significantly more acidotic compared with the LR pigs after resuscitation. Figures 2 through 4 detail the trend of laboratory parameters. pH was significantly lower in the NS group 30 minutes after injury until the end of study. Interestingly, at this point of the study, the only difference in treatment between the two groups was the equivalent volumes of splenic replacement fluids. The bicarbonate value and base excess were significantly lower 60 minutes after injury and beyond. The LR group did show an elevation of lactate level compared with the NS group. The elevation of lactate in the LR group was not accompanied by acidosis and it probably reflects the load of Na lactate from the rapid infusion.

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[Email Jumpstart To Image] Fig. 2. pH values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval.

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[Email Jumpstart To Image] Fig. 3. HCO3- and Base Excess values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval.

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[Email Jumpstart To Image] Fig. 4. Lactate values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval.

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Selected laboratory values are displayed in Table 2. The two groups had equivalent hematocrit values at the start of the study. By the end of the study, the NS group had a lower hematocrit. The partial thromboplastin time (PTT) and prothrombin time (PT) were both significantly greater in the NS group compared with the LR group. Fibrinogen was decreased in both groups compared with baseline.

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[Email Jumpstart To Image] Table 2 Baseline and End Study Laboratories. Comparison Between NS and LR Groups of Hematologic Laboratory Parameters Drawn at Discrete Time Points

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Figures 5 through 8 show the R value, alpha angle, MA, and CI of the two groups. All the parameters showed significant changes during the course of the study. At 60 minutes after injury and beyond, the R value and the alpha angle were significantly different in the LR group as compared with the NS group. At 30 minutes after injury and beyond the MA and CI were significantly higher in the LR group. By the end of the study all of the values in the groups were significantly different from baseline with the exception of the alpha angle in the NS group. These results indicate relative hypercoagulability in both groups but significantly more so in the LR group.

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[Email Jumpstart To Image] Fig. 5. TEG R values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value (p< 0.05). The shaded area indicates normal ranges.

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[Email Jumpstart To Image] Fig. 6. TEG Alpha Angle values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value. (p< 0.05) The shaded area indicates normal ranges.

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[Email Jumpstart To Image] Fig. 7. TEG MA values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value. (p< 0.05) The shaded area indicates normal ranges.

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[Email Jumpstart To Image] Fig. 8. TEG CI values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value. (p< 0.05) The shaded area indicates normal ranges.

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DISCUSSION

This study evaluated multiple measures of coagulation in a swine model of uncontrolled hemorrhage. There were significant differences between animals that received LR and NS in nearly every marker of coagulation measured. It is important to note that the saline group did not develop a significant hypocoagulable state in terms of the measured parameters. The more significant changes reflected a hypercoagulable state in the LR animals. There were multiple physiologic and chemical differences between the two groups.

The NS group received a mean of 10.9 L of fluid compared with 5.2 L in the LR group. This indicates that the saline group may have had a relative coagulation disorder secondary to a dilutional coagulopathy. Theoretically, this should have the most notable effect on the R value as it involves contact activation and fibrin formation. However, a previous in vitro study measured the coagulation effects of LR and hetastarch solutions by simple dilution. In vitro dilution of blood with LR up to 75% resulted in no significant effect on R time.10

There was a significant difference in several TEG parameters at the 30 minute interval. At this point in the study, the only difference between the two groups was the type of splenic replacement fluid. The actual volume of fluids was equivalent. This suggests that the coagulation changes are at least partially explained by the chemical composition of LR versus NS.

The acid base status of the groups was another area of significant difference. At 30 minutes, the mean pH of the NS group was significantly lower than the LR group. This difference progressively increased throughout the course of the study. Our laboratory has previously shown that, in this model, resuscitation with NS results in a profound hyperchloremic acidosis.11 Chloride levels were not measured in this experiment. However, as described in Figure 4, lactate levels were not elevated in the NS group. The resultant acidosis likely accounts for the physiologic differences between groups. Acidosis decreases cardiac contractility, and decreases the effectiveness of circulating catecholamines. Subsequent trials in our laboratory that are not yet published have documented a profound vasodilation in NS resuscitated swine. It is likely that increased blood loss during resuscitation combined with systemic vasodilatation resulted in the high fluid requirements seen with the NS animals.

Acidosis has been implicated as a contributor to ongoing bleeding in trauma patients.12 The overall mechanism has not been completely elucidated. An in vitro study documented a decrease in FVIIa and FVIIa tissue factor complex.13 Acidosis has been associated with coagulation changes in vivo as well.14 A recent in vivo model examined the independent contribution of acidosis to coagulopathy. The findings suggested that the acidosis caused a decrease in thrombin generation rates reflected as a decrease in the alpha angle of the TEG. The LR group did have a significantly higher alpha value compared with the NS group at 60 minutes. However, at this time point, the NS value was not significantly different from its baseline value.

Given the large blood loss in both groups and the significantly higher volume of fluid given to the NS group, the more pronounced hypercoagulable state in the LR group may be affected by relative hemoconcentration. The difference in hematocrit between the LR and NS groups at 120 minutes was significant (p = 0.028). The difference in actual red blood cell concentration contributes to coagulation. Several studies have detailed red blood cell membrane effects on the coagulation cascade. Activation of factor IX by erythrocyte membranes may cause intrinsic coagulation.15

A third notable difference between the groups was the calcium level. Along with volume dilution, the nontrivial amount of calcium in LR most likely explains this difference. At study end, the LR group had a concentration of 1.34 versus 1.22 for the NS group. Calcium is an important cofactor in the coagulation cascade. Though this difference reached statistical significance, the actual clinical relevance of this decrease is unclear. A recent study investigated coagulopathy and hypocalcemia in humans.16 Using citrated blood from healthy volunteers, various concentrations of calcium were added and TEGs were performed. Coagulopathy was only notable at concentrations less than 0.56 mmol/L. Given the small absolute difference, calcium likely does not account for the coagulation changes seen.

The total measured blood loss was significantly higher in the NS group suggesting that the differences in coagulation seen were clinically relevant. There is limitation in this measurement as the total intra-abdominal fluid represents both blood and ascites. The NS group presumably had more ascites secondary to higher volumes of crystalloid administered.

The relative hypercoagulability seen in both animal groups is likely the result of significant tissue trauma. Following injury tissue factor is exposed, de-encrypted and released into the bloodstream. It then complexes with activated factor VII resulting in activation of factors IX and X.17 Additional mechanisms relate to an imbalance of procoagulant and anticoagulant factors. A study measuring extensive coagulation profiles in critically injured patients found a negative correlation of functional protein C with severity of injury.18 Further studies show a decrease in plasma antithrombin III in the setting of trauma.18,19 These mechanisms combined with post-traumatic inflammation lead to a hypercoagulable state that has been documented in trauma patients early after admission.8,9

We have previously shown, using TEG, that Grade V liver injury without resuscitation results in a hypercoagulable state that is not affected by resuscitation with LR.20 This suggests that the use of LR for resuscitation has minimal effects on the coagulation changes after trauma. Alternatively, NS appears to modulate the post-trauma hypercoagulability by a series of physiologic derangements including acidosis and increased volume requirements.

Our study did have limitations in that the volume of fluid given was variable. However, the fluid was given with set resuscitation endpoints. In this way the physiology guided the resuscitation. This algorithm helped recreate the setting of a clinical trauma resuscitation. Therefore, the difference in volume reflects a more realistic scenario.

CONCLUSION

In a swine model of uncontrolled hemorrhage, resuscitation with NS resulted in modulation of the hypercoagulable state seen after injury and LR resuscitation. This effect most likely relates to acidosis and may be contributed to by the increased volume of fluid given to NS animals. This study suggests that the choice of crystalloid resuscitation has significant effects on coagulation. Administration of LR during resuscitation appears to have no effect on the hypercoagulable state induced by trauma. This hypercoagulable state may reduce bleeding and be protective initially, but may lead to thromboembolic complications later in the course of trauma admission. Resuscitation with NS modulates hypercoagulability after trauma and results in increased fluid requirements. These changes are associated with increased blood loss after injury and uncontrolled hemorrhage.

REFERENCES

1. Bergmann H, Blauhut B, Brucke P, Necek S, Vinazzer H. Early influence of acute preoperative haemodilution with human albumin and ringer's lactate on coagulation. Anaesthesist. 1976;25:175–180. Bibliographic Links [Context Link]

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DISCUSSION

Dr. Stephen M. Cohn (San Antonio, Texas): In this investigation, the authors have expanded their work focusing on the effects of various resuscitation fluids upon changes in coagulation following trauma.

In this experiment, pigs were resuscitated to baseline blood pressure with either lactated ringer's or normal saline following 30 minutes of uncontrolled hemorrhage from a severe liver injury.

The animals receiving lactated ringer's developed a hypercoagulable state, noted by a reduction in PT, PTT, and TEG values. Swine infused with normal saline required much greater fluid volumes to achieve baseline vital signs and did not become hypercoagulable.

I have a few questions for the authors. Why did the authors choose to resuscitate animals to baseline parameters, rather than, say, a mean pressure of 60? Resuscitation to lower target blood pressure would more closely replicate the typical clinical scenario and might have impacted on outcome measures, such as the volume of fluid required, the degree of blood loss and the subsequent coagulopathy noted.

What is the impact of the type of anesthesia administered on this animal hemorrhage model? Have the authors tried other methods of anesthesia with similar results?

Who ran the TEG analysis? And how did hypothermia impact on the results? This is a very user-dependent test. In fact, that's, I think, one of the major reasons why we have not applied it clinically in the trauma scenario.

Why did the normal saline group receive twice the volume of resuscitative fluid? Were these animals actually more severely injured or more ill at baseline?

The volume of resuscitative fluid may have diluted out the effects of various coagulation factors as well as impacted on platelet aggregation.

How can we be assured that the impact of fluid volume was not the primary factor causing differences in coagulation between lactated ringer's and normal saline rather than the type of fluid itself?

Another interesting question for the authors is what changes in coagulation would you expect to see over time in a hemorrhage model like this one? It would appear that becoming hypercoagulable after injury would lead to a survival advantage. Do you have survival data?

We currently routinely use normal saline for the resuscitation of trauma patients in the setting of head injury. Do the authors think that normal saline is dangerous? Should we avoid this in clinical care?

Dr. L. N. Kiraly (Portland, Oregon): In response to your first question, why we resuscitated to a MAP of 60, our previous models have resuscitated to a baseline blood pressure. We were varying one element of this model.

However, the mean pressures of these animals were a MAP of 70, so we were not going to the point of extreme resuscitation. The pigs do have a variable baseline blood pressure. And we were trying to keep things consistent from that point.

Next, in terms of anesthesia, we actually have developed a model, which was completed this summer, of a total IV anesthesia regimen and compared it to the isoflurane regimen. Preliminary results indicate that the isoflurane Does have a vaso dilatory response and results in a lower blood pressure.

Next, who ran the TEGs? We had an overwhelming majority of the TEGs run by a skilled technician that has done hundreds of these TEGs.

In terms of hypothermia, these animals were actively externally re-warmed to keep their temperature within a range of 36 to 38 degrees, so hypothermia was not an issue in these patients. The TEG machine can account for that by setting a different temperature if so desired.

Next, why they required different volumes of fluid? We have done some subsequent analysis and found that the normal saline group does have a profound vasodilatory response, making it more difficult for them to be resuscitated to their baseline MAPs.

In terms of the question of why is this alone responsible for the coagulation differences, as I mentioned, previous in vitro studies haven't shown this from just a simple dilution of blood products with crystalloid fluid in terms of the TEG values that we found.

Furthermore, another point is just with acidosis alone, a previous swine model by another group showed TEG changes similar to ours. That leads me to believe that acidosis is more responsible rather than just simple volume.

The next question is, is this clinically relevant? Do we have survival data? We plan to expand our animal model to a survival model to really investigate how these animals will do in the days following a trauma like this. But the clinically relevant point to take from this study is the blood loss, which does seem to be increased in the normal saline group.

Finally, in terms of head injury, based on this study, we see the normal saline animals required much more resuscitation fluid. They had increased bleeding and were more acidotic and made it difficult to maintain blood pressure.

I think all these argue against using normal saline in the setting of head injuries based on this study.

We have alternatives such as the judicious use of hypertonic saline or diuretics. But I have not seen evidence saying that the LR would be harmful in the setting of a head trauma.

Dr. Michael F. Rotondo (Greenville, North Carolina): I have one question from the podium. Your acid base status, you sort of suggested that animals develop an acidosis, yet they were getting a lot of normal saline.

Is this a hyperchloremic acidosis, or do you have any lactate levels to suggest what ideology this acidosis is?

Dr. L. N. Kiraly: From this study, we didn't gather the chloride levels. We had a previous model that used normal saline and showed a similar acidosis, and it was clearly a hyperchloremic acidosis.

Dr. Ken Proctor (Miami, Florida): Did you control Pco2?

Dr. L. N. Kiraly: Pco2 was controlled within a range of 40 to 50, and we did that based on the ABGs we did every half hour.

Dr. Ken Proctor: So why, then, as the Ph was falling in the normal saline group, didn't you hyperventilate?

Dr. L. N. Kiraly: The method we used, we based our ventilatory maneuvers based on the Pco2, not the pH.