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Part 3 SYSTOLIC DYSFUNCTION Systolic vs. Diastolic Dysfunction As many as 40 percent of patients with clinical heart failure have diastolic dysfunction with normal systolic function.32 In addition, many patients with systolic dysfunction have elements of diastolic dysfunction. With systolic dysfunction, the pumping ability of the ventricle is impaired. With diastolic dysfunction, ventricular filling is defective.Ventricular diastolic function depends on the pressure-to-volume relationship in the left ventricle. Decreased compliance of the left ventricular wall leads to a higher pressure for a given diastolic volume. The end result is impaired ventricular filling, inappropriately elevated left atrial and pulmonary venous pressure, and decreased ability to increase stoke volume. These dysfunctions lead to the clinical syndrome of heart failure. Findings suggestive of diastolic dysfunction on the two-dimensional echocardiogram are left ventricular hypertrophy, a dilated left atrium, a normal or nearly normal ejection fraction and reversal of the normal pattern of flow velocity (measured by Doppler flow studies) across the mitral valve (Figures 3 and 4). Systolic Dysfunction Disorders that cause systolic dysfunction may impair the entire heart or one area of the heart. As a result, the heart does not contract normally. Coronary artery disease is a common cause of systolic dysfunction. It can impair large areas of heart muscle because it reduces the flow of oxygen-rich blood to the heart muscle, which needs oxygen for normal contraction. Blockage of a coronary artery can cause a heart attack, which destroys an area of heart muscle. As a result, that area can no longer contract normally. Myocarditis (inflammation of heart muscle) caused by a bacterial, viral, or other infection can damage all or part of the heart muscle, impairing its pumping ability. Heart valve disorders—narrowing (stenosis) of a valve, which hinders blood flow through the heart, or leakage of blood backward (regurgitation) through a valve—can cause heart failure. Both stenosis and regurgitation of a valve can severely stress the heart, so that over time, the heart enlarges and cannot pump adequately. An abnormal connection (septal defects (see Birth Defects: Atrial and Ventricular Septal Defects and Septal Defect: A Hole in the Heart's Wall ) between the heart chambers can allow blood to recirculate within the heart, increasing the workload of the heart, and thus can cause heart failure. Disorders that affect the heart's electrical conduction system, producing changes in heart rhythms, (especially if heartbeats are fast or irregular), can cause heart failure. When the heart beats abnormally, it cannot pump blood adequately. Some lung disorders, such as pulmonary hypertension (see Pulmonary Hypertension), may alter or damage blood vessels in the lungs. As a result, the heart has to work harder to pump blood into the arteries that supply the lungs (pulmonary arteries). Pulmonary hypertension may lead to cor pulmonale (see Cor Pulmonale: A Disorder Stemming From Pulmonary Hypertension ). In this disorder, the right ventricle, which pumps blood to the lungs, becomes enlarged, eventually resulting in right-sided heart failure. Sudden, usually complete blockage of a pulmonary artery by several small blood clots or one very large clot (pulmonary embolism) also makes pumping blood into the pulmonary arteries difficult. A very large clot can be immediately life threatening. The increased effort required to pump blood into the blocked pulmonary arteries can cause the right side of the heart to enlarge and may cause the walls of the right ventricle to thicken, resulting in right-sided heart failure. Disorders that indirectly affect the heart's pumping ability include a deficiency of red blood cells or hemoglobin (anemia), an overactive thyroid gland (hyperthyroidism), an underactive thyroid gland (hypothyroidism), and kidney failure. Red blood cells contain hemoglobin, which enables them to carry oxygen from the lungs and deliver it to body tissues. Anemia reduces the amount of oxygen the blood carries, so that the heart must work harder to provide the same amount of oxygen to tissues. (Anemia has many causes, including chronic bleeding due to a stomach ulcer). An overactive thyroid gland overstimulates the heart, so that it pumps too rapidly and does not empty normally during each heartbeat. When the thyroid gland is underactive, levels of thyroid hormones are low. As a result, all muscles, including the heart, become weak because muscles depend on thyroid hormones to function normally. Kidney failure strains the heart because the kidneys cannot remove excess fluid from the bloodstream, so the heart has to pump more blood. Eventually, the heart cannot keep up, and heart failure develops. Causes of systolic heart failure Systolic heart failure can result from numerous and diverse causes (table 2). Identifying the cause is important, since appropriate treatment may reverse the process (eg, revascularization for ischemic heart disease and therapy for certain systemic disorders, such as thyroid replacement for hypothyroidism). If the underlying disorder is not treated promptly, left ventricular dysfunction is likely to be permanent. Table 2. Causes of systolic heart failure Coronary artery diseaseHypertensionMetabolic disorderThyroid diseaseVitamin deficiencyDiabetes mellitusInfectionToxin exposureCobaltChemotherapeutic agentsAlcoholCocaineInfiltrative diseaseCardiac amyloidosisHemochromatosisOtherNeuromuscular diseaseCollagen vascular diseaseValvular heart diseasePeripartum cardiomyopathyHigh-output heart failure Arteriovenous fistula Severe anemia Paget's diseaseIdiopathicChronic viral myocardial infection?Autoimmune mechanisms?Genetic factors? Coronary artery disease Ischemic coronary artery disease, with or without myocardial infarction, is the most common cause of CHF. Systolic heart failure may be a transient condition occurring around the time of acute infarction or an ongoing problem resulting from loss of myocardial tissue (3). Patients with ischemic heart disease may show improved ventricular function after revascularization, especially those with myocardial hibernation (left ventricular segments that are still viable, even though the segments may be chronically underperfused and hypocontractile). Revascularization of these segments may decrease the likelihood of CHF and improve survival (4,5). Hypertension Long-standing hypertension, particularly when it is poorly controlled, may lead to CHF. Both systolic and diastolic blood pressure play an important role (6). The incidence of CHF is higher in patients with electrocardiographic (ECG) criteria indicative of left ventricular hypertrophy, especially when repolarization abnormalities are present. ST- and T-wave changes may indicate subendocardial ischemia, which contributes further to cardiac dysfunction (1). Metabolic disorders Thyroid abnormalities can be responsible for CHF, especially in elderly patients. Thyroid hormone is a direct cardiac stimulant and can increase contractility and systolic performance. In hypothyroidism, lack of circulating thyroxine (T4) causes down-regulation of myocardial beta-adrenergic receptors and may modify the contractile process, leading to CHF. Patients with a structurally normal heart usually can tolerate excess thyroid hormone without experiencing compromised cardiac function. However, when underlying heart disease is present, hyperthyroidism may precipitate systolic heart failure; angina is often an early symptom. Arrhythmias, particularly atrial fibrilation and other supraventricular tachycardias, may worsen already-compromised cardiac function. Symptoms and signs of systolic dysfunction usually improve with treatment of thyroid disease. Other metabolic disorders that may lead to development of CHF include vitamin deficiencies (eg, thiamine, ascorbic acid), endocrine abnormalities (eg, acromegaly, diabetes mellitus, pheochromocytoma), and rare disorders (eg, porphyria). Infectious diseases Infection can be an important cause of dilated cardiomyopathy and may present as acute myocarditis, which may or may not improve with treatment. CHF symptoms usually do not present until several weeks after the initial infection, suggesting a possible immunologic mechanism for development of systolic dysfunction. The most common viral cause of myocarditis is coxsackievirus B, but at least two dozen others, including hepatitis viruses, adenovirus, arbovirus, cytomegalovirus, echovirus, influenza virus, and HIV, are also possibilities. Bacterial myocarditis (distinct from rheumatic carditis) is very uncommon. Rarely, it complicates the clinical course in patients with fulminant disease secondary to infection with brucella, clostridium, salmonella, toxigenic strains of Corynebacterium diphtheriae, Legionella pneumophila, meningococcus, and streptococcus. Lyme disease can cause myocarditis that may lead to transient left ventricular dysfunction or heart block. In Central and South America, infection with the protozoa Trypanosoma cruzi (the causative agent in Chagas' disease) may result in acute myocarditis with development of biventricular heart failure many years later. Toxin exposure Exposure to several toxic substances, including cobalt and such chemotherapeutic agents as doxorubicin hydrochloride (Adriamycin, Rubex), may cause dilated cardiomyopathy. Long-term alcohol use is a leading cause of CHF, and cocaine abuse may also contribute to development of systolic dysfunction. Infiltrative disease Some diseases, such as cardiac amyloidosis and hemochromatosis, can progress to severe systolic dysfunction. Other causes Neuromuscular disease, collagen vascular disease, valvular heart disease, peripartum cardiomyopathy, and high-output heart failure (eg, from arteriovenous fistulas, severe anemia, Paget's disease) also may result in CHF. Finally, in many patients, dilated cardiomyopathy has no clear cause. Possible explanations have included chronic viral myocardial infection, autoimmune mechanisms, and genetic factors that directly contribute to development of the disease (7). Heart Failure Society Of America: Guidelines for Management of Patients with Heart Failure Caused by Left Ventricular Systolic Dysfunction-Pharmacological Approaches Treatment of Diastolic or Systolic Dysfunction *--Diuretics are best used to treat acute congestive heart failure and as adjunctive therapy for hypertension.†--Note that the likelihood of angioedema and renal insufficiency is increased with ACE inhibitors and angiotensin-receptor blockers. Watch for late-breaking results from clinical trials on the efficacy of angiotensin-receptor blockers alone and in combination with ACE inhibitors compared with ACE inhibitors alone.‡--The addition of milrinone is preferred in patients already receiving a beta blocker. FIGURE 5. Suggested algorithm for the treatment of diastolic or systolic dysfunction. (ACE = angiotensin-converting enzyme; NYHA = New York Heart Association; IV = intravenous.) Differentiating between systolic and diastolic dysfunction is essential because their long-term treatments are different33 (Table 434 and Figure 5). The treatments of choice in patients with systolic dysfunction are ACE inhibitors, digoxin, diuretics and beta blockers. In patients with diastolic dysfunction, the cornerstones of treatment depend on the underlying cause. Beta blockers and calcium channel blockers are frequently used when diastolic dysfunction is secondary to ischemia or hypertension. The history, physical examination, ECG and chest radiographs provide some clues that can be helpful in differentiating systolic and diastolic dysfunction. For example, predominantly systolic dysfunction is suggested by a history of myocardial infarction and younger patient age, a displaced point of maximal impulse and an S3 gallop on the physical examination, the presence of Q waves on the ECG and the finding of cardiomegaly on the chest radiograph. In contrast, diastolic dysfunction is suggested by a history of hypertension and older patient age, a sustained point of maximal impulse and an S4 gallop on the physical examination, left ventricular hypertrophy on the ECG and a normal-sized heart on the chest radiograph.36 However, the findings can overlap considerably, and echocardiography of the heart is usually necessary. I. Treatment of Acute CHF Secondary to Systolic Dysfunction A. Precipitators of acute pulmonary edema (in a previously compensated patient). Poor compliance with medical or diet therapy, increased metabolic demands (infection, especially pneumonia, pregnancy, anemia, hyperthyroidism), progression of underlying heart disease, arrhythmias (e.g., tachycardia), drug effect (beta-blockers, calcium-channel blockers, other negative inotropes), silent MI, pulmonary embolism. B. Diagnosis. The diagnosis of pulmonary edema is usually made initially by physical exam and confirmed by CXR. Treatment may have to be started before one obtains a detailed history, etc. However, once the patient is stable, a careful work-up should be undertaken to determine underlying causes and precipitating factors. 1. History. Past history of cardiac and pulmonary disease or hypertension. History of shortness of breath, orthopnea, dyspnea on exertion, faintness, chest pain. Recent weight gain, edema. Recent infection, exposure to toxic inhalants, smoke, possible aspiration. Current medication regimen, compliance with diet and medications. However, PND and orthopnea are not specific for CHF. 2. Physical exam. Tachypnea, tachycardia, often BP is elevated. If patient has fever, suspect concurrent infection, which may increase metabolic demand and lead to CHF. Cyanosis, diaphoresis, retractions, use of accessory muscles of respiration, wheezing ("cardiac asthma"), and rales on lung auscultation. Cough may be productive of pink, frothy sputum. Listen for S3 gallop or murmurs. Peripheral edema and positive hepatojugular reflux are suggestive of CHF, and bruits may be a clue to underlying vascular disease. C. Diagnostic tests. 1. Lab tests. Electrolytes, BUN, creatinine, cardiac enzymes, serum protein and albumin, urinalysis, differential CBC count, and ABG. 2. CXR. Initially will show interstitial edema as well as thickening and loss of definition of the shadows of pulmonary vasculature. Fluid in septal planes and interlobular fissures cause the characteristic appearance of Kerley A and B lines. Eventually, pleural effusions and perihilar alveolar edema may develop in the classic "butterfly" pattern. CXR findings may lag behind the clinical presentation by up to 12 hours and may take 4 days to clear after clinical improvement in the patient. 3. EKG. Evaluate for evidence of MI and arrhythmia. The sudden onset of atrial fibrillation or PSVT may cause acute decompensation in previously stable chronic CHF. LVH may signal underlying aortic stenosis, hypertension, or cardiomyopathy. 4. Echocardiography. Not imperative acutely. In work-up for underlying cause, it is useful to evaluate for valvular disease, valvular vegetations, wall-motion abnormalities, LV function, and cardiomyopathy. D. Treatment 1. Oxygen. By nasal cannula or mask. May require endotracheal intubation if unable to adequately oxygenate despite use of 100% oxygen by non-rebreather mask. Mask continuous positive airway pressure (CPAP) has been shown to reduce the need for intubation and is an excellent alternative. 2. Other general measures. Elevate head of bed 30 degrees. May need Swan-Ganz catheter for hemodynamic monitoring if the patient becomes hypotensive. However, Swan-Ganz catheters may have an adverse effect on mortality and should be used only after careful consideration. If indicated, place a Foley catheter for fluid management. 3. Medications. a. Vasodilators are considered the first drug of choice in acute CHF and act by preload and afterload thereby decreasing LV work. May also reverse myocardial ischemia. IV nitroglycerin is commonly used, especially if there is concern that ischemia is an underlying or precipitating factor. Start at 10 to 20 mg/min and increase by increments of 10 to 20 mg/min Q5 min until the desired effect is achieved. Sublingual nitroglycerin 0.4 mg repeated Q5 min PRN can also be used acutely as can topical nitrates. However, topical nitrates may not be effective acutely with a maximal effect at 120 minutes. Nitroprusside is an alternative (start at 0.5 mg/kg/ min and increase by 0.5 mg/kg/min Q5 min). Most patients respond to less than 10 mg/kg/min but titrate to effect. Nitroprusside is more likely to cause hypotension than is IV nitroglycerin. A fluid bolus may help to reverse nitrate-induced hypotension but should be used judiciously in those with CHF. b. Furosemide and other diuretics. If the patient has never been treated with furosemide may start with 20 mg IV and observe response. Titrate dose upward until adequate diuresis is established. If the patient is receiving furosemide over a long-term give 1 to 2 times the usual daily dose by slow (over 1 to 2 minutes) IV bolus. Larger doses (up to 1 g) may be needed in those patients receiving large doses or with a history of renal disease. Alternatively, a furosemide drip can be established for higher doses. Give 20% of the dose as a bolus (that is, 200 mg) and infuse the rest over 8 hours. This has a greater efficacy than a single, large bolus does. Up to 2 g has been safely administered in this fashion. Ethacrynic acid 25 to 100 mg IV may be needed if the patient does not respond to furosemide. Bumetanide (0.5 to 1.0 mg IV) may also be used. Adding metolazone (5 to 20 mg) or chlorothiazide 500 mg IV to furosemide may generate additional diuresis. Some authors would consider phlebotomy if diuretics are ineffective and patient has a high HCT, but this is a high risk procedure. c. Morphine acts as a venodilator and decreases anxiety. Start with 1 to 2 mg IV. Tritiate carefully in COPD and CHF, since narcotics can decrease respiratory drive. d. ACE inhibitors can be used acutely in the management of CHF but are more common as chronic therapy. Captopril 12.5 to 25 mg SL or IV at 0.16 mg/min increased by 0.08 mg/min every 5 minutes until it has the desired effect. This is safe and effective and should can be used in patients unresponsive to oxygen, nitrates and diuretics. e. Dobutamine (2.5 to 15 mg/kg/min) or dopamine (2 to 20 mg/kg/ min) may be needed for pressure support or as a positive inotrope. These drugs are effective immediately; however, al- though dopamine increases renal perfusion, it may not increase GFR. f. Digoxin. Check ECG, serum potassium, BUN, and creatinine first before loading with digoxin. After digoxin loading, it may be difficult to distinguish ischemic changes on ECG from digoxin effect. Inquire about previous use of digoxin and any adverse reactions. Determine if patient has any history of renal, pulmonary, liver, or thyroid disease. Be aware of other medications that the patient takes that might affect digoxin levels such as amiodarone, flecainide, quinidine, and verapamil. Decrease digoxin dose if the patient has renal disease. The aim is to achieve serum levels of 1.0 to 1.5 ng/ml. 4. Surgery may be indicated under rare conditions such as valvular heart disease or rupture of ventricular septum after an MI. In severe LV failure, an intra-aortic balloon pump may be beneficial as a temporizing measure. II. Outpatient Treatment of CHF Secondary to Systolic Dysfunction A. Nonpharmacologic therapy. Avoid excessive physical stress, reduce dietary salt, consider compressive stockings if needed to reduce risk of DVT (consider SQ heparin if inpatient), and weight loss if obese. Work on walking and endurance training. B. Pharmacologic therapy. 1. Drugs that have been shown to reduce mortality in CHF: ACE inhibitors, beta-blockers (e.g., metoprolol), spironolactone and the combination of hydralazine + isosorbide dinitrate. 2. Diuretics. Loop diuretics are usually recommended (e.g., furosemide). Some patients develop resistance to loop diuretics after chronic usage. A single dose of metolazone (5 to 20 mg QD) will often result in significant diuresis in such patients. Patients with heart failure who are receiving diuretics should have potassium and magnesium levels monitored. Supplementation should be provided if necessary, since hypokalemia and hypomagnesemia are risk factors for the development of arrhythmias. The use of spironolactone at low dose (25 mg QD) has recently been shown to reduce morbidity in patients even if already treated with a standard therapy, including loop diuretics (RALES trial). 3. ACE inhibitors. These agents function primarily as afterload reducers and have been shown to reduce morbidity (CHF progression, MI, need for hospitalization) and mortality. ACE inhibitors also improve hemodynamics and increase exercise tolerance in heart failure. Up to now only captopril, enalapril, lisinopril, and ramipril have been shown to be efficacious in large controlled clinical trials however, it is likely a class specific effect. Begin therapy at low doses such as enalapril 2.5 mg PO BID and titrate to 10 mg PO BID gradually. Observe the patient for hypotension or persistent cough. Monitor electrolytes and renal function because ACE inhibitors can cause elevation of serum potassium and can cause a reversible decrease in renal function in some patients. Patients at high risk for adverse effects from ACE inhibitors include those with connective tissue diseases, preexisting renal insufficiency, or bilateral renal artery stenosis. Contraindications to their use include a history of hypersensitivity to ACE inhibitors, serum potassium greater than 5.5 mEq/L (consider evaluation for hypoaldosteronism or Addison’s disease), or a previous episode of angioedema during their use. Relative contraindications include renal failure and hypotension. However, ACE inhibitors actually protect renal function in those with chronic renal failure (see Chapter 8 for details). In the latter two patient groups, ACE inhibitor therapy should be initiated at half the usual starting dose and titrated to desired effect. 4. Beta-blockers. The use of beta-blockers in patients with CHF caused by systolic dysfunction is now the standard of care. The initiation and titration of these medications should be undertaken with care. The studied agents that are recommended are carvedilol and metoprolol (specifically Toprol-XL). These agents appear to confer myocardial protection by inhibiting a variety of damaging neurohumoral effects activated by CHF. 5. Angiotensin-receptor blockers (ARBs) function by afterload reduction and have been shown to have an equivalent effect to ACE inhibitors. The limitations of ACE inhibitors (cough, angioedema) are not prevalent with these agents; however, their effects on renal function are still under investigation. They should not supplant ACE inhibitors but can be substituted for them for patients who are intolerant of ACE-I. The results of studies investigating the combined use of ARBs with ACE inhibitors are not yet known. 6. Other vasodilators. ACE-I therapy increases survival in heart failure more than the combination hydralazine and isosorbide therapy. However, in patients unable to tolerate ACE inhibitors or an ARB, a combination of hydralazine and isosorbide dinitrate may be used. 7. Digoxin is shown to improve symptoms in severe heart failure and in cases where atrial fibrillation is a complication of CHF. However, digoxin has no effect on mortality because of a proarrhythmic effect and should be considered a measure for symptom control only. Rapid digitalization is not necessary in patients with chronic CHF. The half-life of digoxin is 11/2 to 2 days in patients with normal renal function. The usual starting dose is 0.25 mg/day. Decrease the dose in small or elderly patients and in those receiving other drugs (such as quinidine, amiodarone, and verapamil) that raise digoxin levels. Decrease the dose in patients with impaired renal function. Monitor levels, especially after dose adjustments or after changes in other medications that may affect digoxin levels (such as quinidine, verapamil, and oral azole antifungals). Avoid digoxin in patients with idiopathic hypertrophic subaortic stenosis (IHSS) and those with diastolic dysfunction. Watch potassium levels closely; hypokalemia renders the heart more sensitive to digoxin and will predispose to digoxin toxicity. 8. Intermittent intravenous inotrope infusions. Dobutamine is the parenteral inotropic agent of choice in severe, chronic CHF. Onset of action is immediate and stops quickly when the infusion is discontinued. It should not be used in patients with IHSS except in consultation with a cardiologist. May cause tachycardia, angina, and ventricular arrhythmias. Alternatively, Milrinone may be used to both improve contractile functions and cause some degree of vasodilation. May cause ventricular arrhythmias. Effect of these modalities on mortality is not yet known. 9. Calcium-channel blockers. Some calcium-channel blockers, especially verapamil and diltiazem, are relatively potent negative inotropic agents and should generally be avoided in patients with poor LV function. In patients with CHF and hypertension, amlodipine (a second-generation dihydropyridine calcium-channel blocker with no negative inotropic effect) has been shown to be efficacious. 10. Antithrombotic therapy. Patients with a previous history of embolism or A fib are at high risk for thromboembolic complications and should be considered for warfarin therapy unless a contraindication exists. Titrate the dose to an INR of 2.0 to 3.0 (prothrombin time not more than 1.5 times normal) to avoid increased risk of bleeding complications. If warfarin cannot be used, consider aspirin for the antiplatelet effect (80 to 300 mg/day). 11. Ventricular Assist Devices (VADs). These devices have been shown to improve morbidity and survival in selected patients waiting to undergo transplantation. The decision to implant such a device should be made only after careful evaluation by a surgeon trained in their insertion. Follow-up care involves close collaboration with transplant facility. VADs are being studied as stand-alone therapy for patients not considered candidates for transplantation. III. Follow-up. Once the acute episode of pulmonary edema is under control, a careful search for the underlying cause must be undertaken. Further work-up might include echocardiography to evaluate valve function and chamber size, radionuclide studies to evaluate LV and RV ejection fraction and wall motion, and cardiac catheterization. IV (IHSS) most commonly presents in young adults before the third decade. A. Etiology and Examination. Caused by a thickened septum impinging on anterior mitral leaflet and creating a dynamic obstruction in the left ventricular outflow tract. It is an autosomal dominant mutation, 50% penetrance, male/female equal occurrence. Signs are commonly dyspnea, angina, syncope, and fatigue. Examination is notable for a laterally displaced apical impulse, rapid rise and biphasic carotid pulse, variably split S2 and loud S4, harsh crescendo-decrescendo murmur at the lower left sternal border and apex. The murmur classically increases and lengthens with Valsalva, decreases with handgrip. B. Management and Treatment Aimed at reducing ventricular rate, allowing increased ventricular volume and outflow tract dimensions. Most commonly beta-blockers or calcium channel blockers. Do not use digitalis preparations. Avoiding strenuous physical activity, especially competitive sports. Some recommend AV sequential pacing. Surgical therapy may be helpful in selected cases, with left ventricular myomectomy or heart transplantation for cases with severe left ventricular failure. TABLE 4Clues for Differentiating Between Systolic and Diastolic Dysfunction in Patients with Heart Failure Clues from the evaluation Systolic dysfunction Diastolic dysfunction History Hypertension XX XXX Coronary artery disease* XXX X Diabetes mellitus XXX XX Valvular heart disease* XXX -- Physical examination Third heard sound (S3) gallop* XXX X Fourth heart sound (S4) gallop* X XXX Rales XX XX Jugular venous distention XX X Edema XX X Displaced point of maximal impulse* XX -- Mitral regurgitation* XXX X Chest radiograph Cardiomegaly* XXX X Pulmonary congestion XXX XXX Electrocardiogram Q wave XX X Left ventricular hypertrophy* X XXX Echocardiogram Decreased ejection fraction* XXX -- Dilated left ventricle* XX -- Left ventricle hypertrophy* X XXX X = suggestive; the number of Xs reflects the relative weight; -- = not suggestive.*--Particularly helpful in distinguishing systolic from diastolic dysfunction in heart failure.Adapted with permission from Young JB. Assessment of heart failure. In: Braunwald E. Atlas of heart disease. Vol 4. Philadelphia: Current Medicine, 1995:7.1-7.2. Assessment of Left-Ventricular Function Physical Examination Coronary artery disease and hypertension are the leading causes of heart failure. A complete physical examination is the second component in the diagnosis of heart failure. The patient's general appearance should be assessed for evidence of resting dyspnea, cyanosis and cachexia. Blood Pressure and Heart Rate The patient's blood pressure and heart rate should be recorded. High, normal or low blood pressure may be present. The prognosis is worse for patients who present with a systolic blood pressure of less than 90 to 100 mm Hg when not receiving medication (angiotensin-converting enzyme [ACE] inhibitors, beta blockers or duretics).16 Tachycardia may be a sign of heart failure, especially in the decompensated state. The heart rate increases as one of the compensatory ways of maintaining adequate cardiac output. A decrease in the resting heart rate with medical therapy can be used as a surrogate marker for treatment efficacy. A weak, thready pulse and pulsus alternans are associated with decreased left ventricular function. The patient should also be monitored for evidence of periodic breathing (Cheyne-Stokes respiration). TABLE 3New York Heart Association Functional Classification of Congestive Heart Failure The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication. Jugular Venous Distention Jugular venous distention is assessed while the patient is supine with the upper body at a 45-degree angle from the horizontal plane. The top of the waveform of the internal jugular venous pulsation determines the height of the venous distention. An imaginary horizontal line (parallel to the floor) is then drawn from this level to above the sternal angle. A height of more than 4 to 5 cm from the sternal angle to this imaginary line is consistent with elevated venous pressure (Figure 1). FIGURE 1. Assessment of jugular venous distention. Elevated jugular venous pressure is a specific (90 percent) but not sensitive (30 percent) sign of elevated left ventricular filling. The reproducibility of the jugular venous distention assessment is low.17 Point of Maximal Impulse The point of maximal impulse of the left ventricle is usually located in the midclavicular line at the fifth intercostal space. With the patient in a sitting position, the physician uses fingertips to identify this point. Cardiomegaly usually displaces the cardiac impulse laterally and downward. At times, the point of maximal impulse may be difficult to locate and therefore loses sensitivity (66 percent). Yet the location of this point remains a specific indicator (96 percent) for evaluating the size of the heart.14 Third and Fourth Heart Sounds A double apical impulse can represent an auscultated third heart sound (S3). Just as with the displaced point of maximal impulse, a third heart sound is not sensitive (24 percent) for heart failure, but it is highly specific (99 percent).14 Patients with heart failure and left ventricular hypertrophy can also have a fourth heart sound (S4). The physician should be alert for murmurs, which can provide information about the cause of heart disease and also aid in the selection of therapy. Pulmonary Examination Physical examination of the lungs may reveal rales and pleural effusions. Despite the presence of pulmonary congestion, rales can be absent because of increased lymphatic drainage and compensatory changes in the perivascular structures that have occurred over time. Wheezing may be the sole manifestation of pulmonary congestion. Frequently, asthma is erroneously diagnosed in patients who actually have heart failure. Liver Size and Hepatojugular Reflux The key component of the abdominal examination is the evaluation of liver size. Hepatomegaly may occur because of right-sided heart failure and venous congestion. The hepatojugular reflux can be a useful test in patients with right-sided heart failure. This test should be performed while the patient is lying down with the upper body at a 45-degree angle from the horizontal plane. The patient keeps the mouth open and breathes normally to prevent Valsalva's maneuver, which can give a false-positive test. Moderate pressure is then applied over the middle of the abdomen for 30 to 60 seconds. Hepatojugular reflux occurs if the height of the neck veins increases by at least 3 cm and the increase is maintained throughout the compression period.18 Lower Extremity Edema Lower extremity edema, a common sign of heart failure, is usually detected when the extracellular volume exceeds 5 L. The edema may be accompanied by stasis dermatitis, an often chronic, usually eczematous condition characterized by edema, hyperpigmentation and, commonly, ulceration. Valsalva's Maneuver Valsalva's maneuver is rarely used in the evaluation of patients with heart failure. Yet this test is simple to perform and carries one of the best combinations of specificity (91 percent) and sensitivity (69 percent) for the detection of left ventricular systolic and diastolic dysfunction in patients with heart failure.19,20 Valsalva's maneuver is performed with the blood pressure cuff inflated 15 mm Hg over the systolic blood pressure. While the physician auscultates over the brachial artery, the patient is asked to perform a forced expiratory effort against a closed airway (the Valsalva's maneuver). A normal response would be an initial rise in systolic blood pressure at the onset of straining (phase I) with Korotkoff's sounds heard (Figure 2). While the maneuver is maintained (phase II), a decrease in the blood pressure occurs with loss of Korotkoff's sounds. Release of the maneuver (phase III) is followed by an overshoot of blood pressure and the reappearance of heart sounds (phase IV). Abnormal responses occurring in patients with heart failure are maintenance of beats throughout Valsalva's maneuver (square wave) or lack of reappearance of Korotkoff's sounds after release of the maneuver (absent overshoot). FIGURE 2. Arterial blood pressure response and Korotkoff's sounds during Valsalva's maneuver. (A) Sinusoidal response in normal patient. ( Absent overshoot in patient with heart failure. © Square wave response in patient with heart failure. The red lines indicate when Korotkoff's sounds are heard. (BP = blood pressure) Diagnostic Challenges Diagnosing heart failure in elderly patients may be particularly challenging because of the atypical presentations in this age group. Anorexia, generalized weakness and fatigue are often the predominant symptoms of heart failure in geriatric patients. Mental disturbances and anxiety are also common. When older persons become symptomatic on exertion, they decrease their level of activity to the point of becoming relatively asymptomatic. A cycle of symptoms on exertion and consequent decrease in activity frequently continues as the disease progresses, until the patient finally becomes symptomatic at rest (i.e., NYHA class IV). The physical findings in older patients with heart failure may be difficult to interpret accurately. Resting tachycardia is uncommon, and pulse contour abnormalities are difficult to assess secondary to peripheral arteriosclerotic changes. At times, auscultatory findings on the lung examination are atypical because of concomitant pulmonary disease.21 Patients with suspected heart failure should undergo echocardiography or radionuclide ventriculography to measure EF (if information about ventricular function is not available from previous tests). (Strength of Evidence = B.) Measurement of left-ventricular performance is a critical step in the evaluation and management of almost all patients with suspected or clinically evident heart failure. The combined use of history, physical examination, chest x-ray, and electrocardiography cannot be relied on to distinguish between the major etiologies of heart failure: left-ventricular systolic dysfunction (i.e., EF < 35-40 percent), left-ventricular diastolic dysfunction (i.e., heart failure occurring despite EF 40 percent), valvular heart failure disease, or a noncardiac etiology. A substantial proportion (up to 40 percent in some studies) of patients with signs and symptoms of heart failure have EF's greater than 50 percent. [26, 29, 30, 68, 69] These patients generally have valvular disease, intermittent ischemia, or ventricular diastolic dysfunction. If measurement of ventricular performance is not obtained in these patients, inappropriate treatments may be instituted (e.g., digoxin, which has not been shown to be effective in patients with normal ventricular systolic function). [69] Echocardiography or radionuclide ventriculography can substantially improve diagnostic accuracy in distinguishing between systolic and diastolic dysfunction. [27, 29, 30, 69- 75] Patients whose symptoms are fully accounted for by an underlying noncardiac condition (see above) or who have previously documented decreased ventricular performance (e.g., recent echocardiogram or contrast ventriculogram) do not require determination of EF. Although elderly patients with mild symptoms are often managed without measurement of ventricular performance, this practice is discouraged for the following reasons: · The elderly are the very individuals in whom it may be most difficult to make the diagnosis of heart failure and to determine whether failure is due to systolic or diastolic dysfunction. · Although mild diuretic therapy may cause little harm in patients with fluid retention of any etiology, use of other medications-such as ACE inhibitors, digoxin, or nitrates-has significant risks and no established benefit unless they are specifically indicated. These agents may even worsen the condition of patients with heart failure secondary to left-ventricular diastolic dysfunction. Both echocardiography and radionuclide ventriculography are appropriate measures for the evaluation of left-ventricular performance. Although EF measured by radionuclide ventriculography may have a higher correlation with cineangiography than that measured by echocardiography (r = 0.88 versus r = 0.78, respectively), [76] echocardiography has good reproducibility (r = 0.89) [77] and accuracy for measuring EF (r = 0.78-0.89). [76- 78] The use of quantitative techniques has been found to improve measurement of EF in some studies. [66, 78] However, Stamm et al. found that real-time estimation by the echocardiographer was more accurate than any of several algorithms tested. [77] In general, the panel considered echocardiography to be the preferred test because of its ability to assess valvular function and left-ventricular hypertrophy, but selection of a diagnostic test should depend on the capabilities of individual clinical centers. Between 8 and 18 percent of patients will have technically inadequate echocardiograms, in which case radionuclide ventriculography should be performed. [79- 81] Although there are no studies in the literature on the quality of echocardiography and radionuclide ventriculography in community practice, the panel perceives significant quality problems in the performance and interpretation of both tests. When referred to a specialist, patients should be encouraged to bring a video of the actual images of their echocardiogram with them, rather than a written report. In this way, the quality of the study can be determined directly. Advantages and disadvantages of echocardiography and radionuclide ventriculography are summarized in Table 4. It is important to note that although echocardiography or radionuclide ventriculography is essential for determining the presence and degree of left-ventricular dysfunction, these tests are less useful in determining the etiology of that dysfunction. Specifically, the presence or absence of regional wall motion abnormalities is of limited value in determining whether a patient's disease is due to coronary artery disease or to idiopathic dilated cardiomyopathy. [79, 80, 82, 83] For example, Diaz et al. found that 56 percent of patients with idiopathic dilated cardiomyopathy had regional wall motion abnormalities rather than global hypokinesis. [80] Conversely, 35 percent of patients with coronary artery disease had global hypokinesis without regional wall motion abnormalities. Similarly, right-ventricular dilatation is not helpful in distinguishing idiopathic dilated cardiomyopathy from ventricular dysfunction due to ischemia or prior MI. [80, 84] Thus, the findings from echocardiography or radionuclide ventriculography should not be used to determine the etiology of a patient's cardiomyopathy or the need for further evaluations of coronary artery disease, such as coronary artery angiography. Interpretation of Left-Ventricular Function Testing The majority of patients with heart failure have moderate-to-severe left-ventricular systolic dysfunction and EF's of <35-40 percent. This guideline is directed at the management of such patients. However, patients with symptoms of heart failure and EF's greater than 40 percent may still have heart failure due to left-ventricular diastolic dysfunction, valvular disease, or pericardial disease. The majority of these etiologies will be discernible with echocardiography. A full discussion of the diagnosis and treatment of these conditions is beyond the scope of this guideline, although a few comments on diastolic dysfunction are necessary because of its high prevalence Determination of Specific Etiologies for Left-Ventricular Systolic Dysfunction Once left-ventricular dysfunction is confirmed, the results of the history and physical examination should be reviewed to search for clues to potentially treatable causes of heart failure. Additional information should be sought as appropriate. Clinicians should follow up any positive findings with appropriate laboratory testing. Routine use of myocardial biopsy is not warranted. (Strength of Evidence = C.) The most common causes of left-ventricular systolic dysfunction are coronary artery disease, idiopathic dilated cardiomyopathy, hypertension, and alcohol abuse. The most common potentially reversible cause of heart failure is myocardial ischemia. Therefore, patients should be carefully questioned concerning a history of chest pain or recurring episodes of sudden pulmonary edema suggestive of ischemia. Evaluation of patients with angina is discussed subsequently in the section on revascularization. Alcoholism is important to detect and treat because alcohol may aggravate cardiac dysfunction. [91- 93] Where appropriate, patients should also be asked about cocaine use, and a urine test for cocaine may be helpful in selected patients. Specific treatable etiologies (e.g., sarcoidosis) should be considered when the constellation of systemic findings suggests a diagnosis. Patients with a history of liver disease, unexplained hepatomegaly, diabetes or other endocrine dysfunction, or bronze discoloration of the skin should be evaluated for hemochromatosis with a serum iron level, total iron binding capacity, and ferritin level. An exhaustive search for the etiology of heart failure in a patient without specific findings on history and physical examination is of little value Table 1--Cardiac Pump Function During and After Acute Hypertensive Pulmonary Edema * DHF Compared to SHF SHF (n = 20) DHF (n = 18) (n = 18) % Variables During After During After During After LVEDV, mL 131 138 85 94 LVESV, mL 78 83 36 37 LVSV, mL 53 55 49 57 -7 +3 HR, beats/min 87 77 79 66 -9 -15 LVEF, % 40 40 58 61 +43 +52 CO, L/min 4.6 4.3 3.9 3.8 -15 -12 * Derived from Gandhi et al. (1) Since their article included no HR or volume data for the SHF group, these data were computed via spreadshhet from the published DHF and combined DHF-SHF values. To achieve the best approximation of the original observations (available from the author), LVEF values were then calculated from the computed volumes, minor deviations anticipated due to precision/rounding error. LVES = LV end-systolic volume; LVSV = LV stroke volume; LVEDV = left ventricular end-diastolic volume. Table 2--LVEF: Meaningless in Terms of Cardiac Output Without the Coexisting LVEDV * Variables Normal SHF DHF-1 DHF-2 SDf LVEDV, mL 120 250 100 85 200 LVESV, mL 50 200 50 35 130 LVSV, mL 70 50 50 50 70 HR, beats/min 60 60 60 60 60 LVEF, % 60 20 50 60 35 CO, L/min 4.2 3.0 3.0 3.0 4.2 [DELTA]CO, from normal, % 0 -30 -30 -30 0 * Derived from Braunwald et al, (9) whose angiographic volume indexes are converted here to absolute volumes using nominal body surface area (1.73 [m.sup.2] and liberal rounding to facilitate interpretation (but in all cases <2%). DHF-1 = DHF due to mild-to-moderate DDf; DHF-2 = DHF due to severe DDf; SDf = systolic dysfunctions without HF; see Table 1 for expansion of abbreviates. Systolic Dysfunction Systolic dysfunction refers to impaired ventricular contraction. In chronic heart failure, this is most likely due to changes in the signal transduction mechanisms regulating cardiac excitation-contraction coupling. The loss of cardiac inotropy (i.e., decreased contractility) causes a downward shift in the Frank-Starling curve (Figure 1). This results in a decrease in stroke volume and a compensatory rise in preload (often measured as ventricular end-diastolic pressure or pulmonary capillary wedge pressure). The rise in preload is considered compensatory because it activates the Frank-Starling mechanism to help maintain stroke volume despite the loss of inotropy. If preload did not rise, the decline in stroke volume would be even greater for a given loss of inotropy. Depending upon the precipitating cause of the heart failure, there will be ventricular hypertrophy, dilation, or a combination of the two. The effects of a loss of intrinsic inotropy on stroke volume, and end-diastolic and end-systolic volumes, are best depicted using ventricular pressure-volume loops (Figure 2). Loss of intrinsic inotropy decreases the slope of the end-systolic pressure-volume relationship (ESPVR). This leads to an increase in end-systolic volume. There is also an increase in end-diastolic volume (compensatory increase in preload), but this increase is not as great as the increase in end-systolic volume. Therefore, the net effect is a decrease in stroke volume (shown as a decrease in the width of the pressure-volume loop). Because stroke volume decreases and end-diastolic volume increases, there is a substantial reduction in ejection fraction (EF). Stroke work is also decreased. The force-velocity relationship provides insight as to why a loss of contractility causes a reduction in stroke volume (Figure 3). Briefly, at any given preload and afterload, a loss of inotropy results in a decrease in the shortening velocity of cardiac fibers. Because there is only a finite period of time available for ejection, a reduced velocity of ejection results in less blood ejected per stroke. The residual volume of blood within the ventricle is increased (increased end-systolic volume) because less blood is ejected. The reason for preload rising as inotropy declines is that the increased end-systolic volume is added to the normal venous return filling the ventricle. For example, if end-systolic volume is normally 50 ml of blood and it is increased to 80 ml in failure, this extra residual volume is added to the incoming venous return leading to an increase in end-diastolic volume and pressure. An important and deleterious consequence of systolic dysfunction is the rise in end-diastolic pressure. If the left ventricle is involved, then left atrial and pulmonary venous pressures will also rise. This can lead to pulmonary congestion and edema. If the right ventricle is in systolic failure, the increase in end-diastolic pressure will be reflected back into the right atrium and systemic venous vasculature. This can lead to peripheral edema and ascites. Treatment for systolic dysfunction involves the use of inotropic drugs, afterload reducing drugs, venous dilators, and diuretics. Inotropic drugs include digitalis (commonly used in chronic heart failure) and drugs that stimulate the heart via beta-adrenoceptor activation or inhibition of cAMP-dependent phosphodiesterase (used in acute failure). Afterload reducing drugs (e.g., arterial vasodilators) augment ventricular ejection by increasing the velocity of fiber shortening (see force-velocity relationship). Venous dilators and diuretics are used to reduce ventricular preload and venous pressures (pulmonary and systemic) rather than augmenting systolic function directly. Excitation-Contraction Coupling Excitation-contraction coupling (ECC) is the process by which an action potential triggers a myocyte to contract. When a myocyte is depolarized by an action potential, calcium ions enter the cell during phase 2 of the action potential through L-type calcium channels located on the sarcolemma. This calcium triggers a subsequent release of calcium that is stored in the sarcoplasmic reticulum (SR) through calcium-release channels ("ryanodine receptors"). Calcium released by the SR increases the intracellular calcium concentration from about 10-7 to 10-5 M. The free calcium binds to troponin-C (TN-C) that is part of the regulatory complex attached to the thin filaments. When calcium binds to the TN-C, this induces a conformational change in the regulatory complex such that troponin-I (TN-I) exposes a site on the actin molecule that is able to bind to the myosin ATPase located on the myosin head. This binding results in ATP hydrolysis that supplies energy for a conformational change to occur in the actin-myosin complex. The result of these changes is a movement ("ratcheting") between the myosin heads and the actin, such that the actin and myosin filaments slide past each other thereby shortening the sarcomere length. Ratcheting cycles occur as long as the cytosolic calcium remains elevated. At the end of phase 2, calcium entry into the cell slows and calcium is sequestered by the SR by an ATP-dependent calcium pump (SERCA, sarco-endoplasmic reticulum calcium-ATPase), thus lowering the cytosolic calcium concentration and removing calcium from the TN-C. To a quantitatively smaller extent, cytosolic calcium is transported out of the cell by the sodium-calcium-exchange pump. The reduced intracellular calcium induces a conformational change in the troponin complex leading, once again, to TN-I inhibition of the actin binding site. At the end of the cycle, a new ATP binds to the myosin head, displacing the ADP, and the initial sarcomere length is restored. Mechanisms that enhance the concentration of cytosolic calcium increase the amount of ATP hydrolyzed and the force generated by the actin and myosin interactions, as well as the velocity of shortening. Physiologically, cytosolic calcium concentrations are influenced primarily by beta-adrenoceptor-coupled mechanisms. Beta-adrenergic stimulation, as occurs when sympathetic nerves are activated, increases cAMP which in turn activates protein kinase to increase in calcium entry into the cell through L-type calcium channels. Activation of the IP3 signal transduction pathway also can stimulate the release of calcium by the SR through IP3 receptors located on the SR. Furthermore, activation of the cAMP-dependent protein kinase phosphorylates a protein (phospholamban) on the SR that normally inhibits calcium uptake. This disinhibition of phospholamban leads to an increased rate of calcium uptake by the SR. Therefore, beta-adrenergic stimulation increases the force and shortening velocity of contraction (i.e., positive inotropy), and increases the rate of relaxation (i.e., positive lusitropy). Another potential regulatory mechanism for ECC involves altering the sensitivity of TN-C for calcium. There are investigational drugs that enhance TN-C calcium sensitivity and thereby exert a positive inotropic influence on the heart. One potential downside with these drugs, however, is that enhanced TN-C binding to calcium can reduce the rate of relaxation, thereby causing diastolic dysfunction. In systolic heart failure, ECC can be impaired at several different sites. First, there can be decreased influx of calcium into the cell through L-type calcium channels (resulting from impaired signal transduction), which decreases subsequent calcium release by the SR. There can also be a decrease in TN-C affinity for calcium, so that a given increase in calcium in the vicinity of the troponin complex has less of an activating effect on cardiac contraction. In some forms of diastolic heart failure, there is evidence that the function of the SR ATP-dependent calcium pump is impaired. This defect would retard the rate of calcium uptake by the SR and reduce the rate of relaxation, leading to diastolic dysfunction. Signal Transduction Mechanisms (G-Protein and IP3-Linked) There are several major signal transduction mechanisms found in cells of the cardiovascular system, the most important being the G-protein pathway, IP3 pathway, and the nitric oxide-cyclic GMP pathway. Described below are the G-protein and IP3 pathways found in the heart. Signal transduction mechanisms regulating vascular smooth muscle contraction and relaxation are found elsewhere. G-proteins are linked to adenylyl cyclase that dephosphorylates ATP to form cyclic AMP (cAMP). Gs activation (e.g., via b-adrenoceptors) increases cAMP, which activates a protein kinase that causes increased gCa++ by direct effects on calcium channels and enhanced release of Ca++ by the sarcoplasmic reticulum in the heart; these actions increase inotropy. Gs-protein activation also increases heart rate. Gi activation (e.g., via adenosine and muscarinic receptors) decreases cAMP and protein kinase activation, and causes increased gK+; activation of the Gi-protein pathway therefore enhances repolarization. Gi-protein activation therefore decreases heart rate and inotropy. The IP3 pathway is linked to activation of a1-adrenoceptors, angiotensin II (AII) receptors, and endothelin-1 (ET-1) receptors. Increased IP3 stimulates Ca++ release by the sarcoplasmic reticulum in the heart, thereby increasing inotropy. R, receptor; Gs and Gi, stimulatory and inhibitory G-proteins; AC, adenylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-triphosphate; DAG, diacylglycerol; PK, protein kinase; SR, sarcoplasmic reticulum; a and b , adrenoceptor agonist; M2, muscarinic receptor agonist; A1, adenosine receptor agonist; AII, angiotensin receptor agonist; ET-1, endothelin. Altered signal transduction mechanisms may be responsible for the loss of inotropy in heart failure. For example, desensitization of b1-adrenoceptors on the heart will decrease inotropic responses to sympathetic activation. Uncoupling of the b1-adrenoceptor and the Gs-protein would reduce the ability to activate adenylyl cyclase. If the ability of protein kinase A (PK-A) to phosphorylate L-type calcium channels is impaired, then calcium influx into the cell would be reduced, leading to a smaller release of calcium by the sarcoplasmic reticulum. Reduced calcium release would impair excitation-contraction coupling, thereby decreasing inotropy. Inotropy Changes in stroke volume can be accomplished by changes in ventricular inotropy (contractility). Changes in inotropy are unique to cardiac muscle. Skeletal muscle, for example, cannot alter its intrinsic inotropic state. Changes in inotropy result in changes in force generation, which are independent of preload (i.e., sarcomere length). This is clearly demonstrated by use of length-tension diagrams in which an increase in inotropy results in an increase in active tension at a given preload. Furthermore, inotropy is displayed in the force-velocity relationship as a change in Vmax; that is, a change in the maximal velocity of fiber shortening at zero afterload. The increased velocity of fiber shortening that occurs with increased inotropy increases the rate of ventricular pressure development. During the phase of isovolumetric contraction, an increase in inotropy is manifested as an increase in maximal dP/dt (i.e., rate of pressure change). Changes in inotropy alter the rate of force and pressure development by the ventricle, and therefore change the rate of ejection (i.e., ejection velocity). For example, an increase in inotropy shifts the Frank-Starling curve up and to the left (point A to C in Figure 1). This causes a reduction in end-systolic volume and an increase in stroke volume as shown in the pressure-volume loops depicted in Figure 2. The increased stroke volume also causes a secondary reduction in ventricular end-diastolic volume and pressure because there is less end-systolic volume to be added to the incoming venous return. It should be noted that the active pressure curve that defines the limits of the end-systolic pressure-volume relationship (ESPVR) is shifted to the left and becomes steeper when inotropy is increased. The ESPVR is sometimes used as an index of ventricular inotropic state. It is analogous to the shift that occurs in the active tension curve in the length-tension relationship whenever there is a change in inotropy. Changes in inotropy produce significant changes in ejection fraction (EF). Increasing inotropy leads to an increase in EF, while decreasing inotropy decreases EF. Therefore, EF is often used as a clinical index for evaluating the inotropic state of the heart. In heart failure, for example, there often is a decrease in inotropy that leads to a fall in stroke volume as well as an increase in preload, thereby decreasing EF. The increased preload, if it results in a left ventricular end-diastolic pressure greater than 20 mmHg, can lead to pulmonary congestion and edema. Treating a patient in heart failure with an inotropic drug (e.g., beta-adrenoceptor agonist or digoxin) will shift the depressed Frank-Starling curve up and to the left, thereby increasing stroke volume, decreasing preload, and increasing EF. Changes in inotropic state are particularly important during exercise. Increases in inotropic state help to maintain stroke volume at high heart rates. Increased heart rate alone decreases stroke volume because of reduced time for diastolic filling, which decreases end-diastolic volume. When the inotropic state increases at the same time, end-systolic volume decreases so that stroke volume can be maintained. Factors Regulating Inotropy The most important mechanism regulating inotropy is the autonomic nerves. Sympathetic nerves play a prominent role in ventricular and atrial inotropic regulation, while parasympathetic nerves (vagal efferents) have a significant negative inotropic effect in the atria but only a small effect in the ventricles. Under certain conditions, high levels of circulating epinephrine augment sympathetic adrenergic effects. In the human heart, an abrupt increase in afterload can cause a small increase in inotropy (Anrep effect) by a mechanism that is not fully understood. An increase in heart rate also stimulates inotropy (Bowditch effect; treppe; frequency-dependent inotropy). This latter phenomenon is probably due to an inability of the Na+/K+-ATPase to keep up with the sodium influx at higher heart rates, which leads to an accumulation of intracellular calcium via the sodium-calcium exchanger. Systolic failure that results from cardiomyopathy, ischemia, valve disease, arrhythmias, and other conditions is characterized by a loss of intrinsic inotropy. In addition to these physiological mechanisms, a variety of inotropic drugs are used clinically to simulate the heart, particularly in acute and chronic heart failure. These drugs include digoxin (inhibits sarcolemmal Na+/K+-ATPase), beta-adrenoceptor agonists (e.g., dopamine, dobutamine, epinephrine, isoproterenol), and phosphodiesterase inhibitors (e.g., milrinone). Mechanisms of Inotropy Most of the signal transduction pathways that stimulate inotropy ultimately involve Ca++, either by increasing Ca++ influx (via Ca++ channels) during the action potential (primarily during phase 2), by increasing the release of Ca++

TABLE 4 Clues for Differentiating Between Systolic and Diastolic Dysfunction in Patients with Heart Failure Clues from the evaluation Systolic dysfunction Diastolic dysfunction History Hypertension XX XXX Coronary artery disease* XXX X Diabetes mellitus XXX XX Valvular heart disease* XXX -- Physical examination Third heard sound (S3) gallop* XXX X Fourth heart sound (S4) gallop* X XXX Rales XX XX Jugular venous distention XX X Edema XX X Displaced point of maximal impulse* XX -- Mitral regurgitation* XXX X Chest radiograph Cardiomegaly* XXX X Pulmonary congestion XXX XXX Electrocardiogram Q wave XX X Left ventricular hypertrophy* X XXX Echocardiogram Decreased ejection fraction* XXX -- Dilated left ventricle* XX -- Left ventricle hypertrophy* X XXX X = suggestive; the number of Xs reflects the relative weight; -- = not suggestive.*--Particularly helpful in distinguishing systolic from diastolic dysfunction in heart failure.Adapted with permission from Young JB. Assessment of heart failure. In: Braunwald E. Atlas of heart disease. Vol 4. Philadelphia: Current Medicine, 1995:7.1-7.2. Treatment of Diastolic or Systolic Dysfunction *--Diuretics are best used to treat acute congestive heart failure and as adjunctive therapy for hypertension.†--Note that the likelihood of angioedema and renal insufficiency is increased with ACE inhibitors and angiotensin-receptor blockers. Watch for late-breaking results from clinical trials on the efficacy of angiotensin-receptor blockers alone and in combination with ACE inhibitors compared with ACE inhibitors alone.‡--The addition of milrinone is preferred in patients already receiving a beta blocker. Table 1--Cardiac Pump Function During and After Acute Hypertensive Pulmonary Edema * DHF Compared to SHF SHF (n = 20) DHF (n = 18) (n = 18) % Variables During After During After During After LVEDV, mL 131 138 85 94 LVESV, mL 78 83 36 37 LVSV, mL 53 55 49 57 -7 +3 HR, beats/min 87 77 79 66 -9 -15 LVEF, % 40 40 58 61 +43 +52 CO, L/min 4.6 4.3 3.9 3.8 -15 -12 * Derived from Gandhi et al. (1) Since their article included no HR or volume data for the SHF group, these data were computed via spreadshhet from the published DHF and combined DHF-SHF values. To achieve the best approximation of the original observations (available from the author), LVEF values were then calculated from the computed volumes, minor deviations anticipated due to precision/rounding error. LVES = LV end-systolic volume; LVSV = LV stroke volume; LVEDV = left ventricular end-diastolic volume. Table 2--LVEF: Meaningless in Terms of Cardiac Output Without the Coexisting LVEDV * Variables Normal SHF DHF-1 DHF-2 SDf LVEDV, mL 120 250 100 85 200 LVESV, mL 50 200 50 35 130 LVSV, mL 70 50 50 50 70 HR, beats/min 60 60 60 60 60 LVEF, % 60 20 50 60 35 CO, L/min 4.2 3.0 3.0 3.0 4.2 [DELTA]CO, from normal, % 0 -30 -30 -30 0 * Derived from Braunwald et al, (9) whose angiographic volume indexes are converted here to absolute volumes using nominal body surface area (1.73 [m.sup.2] and liberal rounding to facilitate interpretation (but in all cases <2%). DHF-1 = DHF due to mild-to-moderate DDf; DHF-2 = DHF due to severe DDf; SDf = systolic dysfunctions without HF; see Table 1 for expansion of abbreviates. *****>>>>NOTE:::: I was unable to post all of them as my "flow charts" wouldn't copy onto the board and i couln't figure out how to post them.....So is anyone knows how and is willing to share that I will Post the others... Also, you can PM me with your e-mail and I'll send it in MS word to you....>>>>>******* Hope this helps, Ace844

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:ky: :iroc: :violent2: :munky2:

Hi All, I saw this and was curious what you thought and whether you had seen any evidence of this in your practice...YES, I know the study was done on Pigs!!!! :roll: Endothelial Dysfunction After Lactated Ringer's Solution Resuscitation for Hemorrhagic Shock. Journal of Trauma-Injury Infection & Critical Care. 59(2):284-290, August 2005. Savage, Stephanie A.; Fitzpatrick, Colleen M.; Kashyap, Vikram S. MD ++; Clouse, W Darrin; Kerby, Jeffrey D. MD, PhD Abstract: Background: Endothelial dysfunction is presumed to occur after hemorrhagic shock and resuscitation. This study uses a novel large-animal model to evaluate the effects of diverse resuscitation regimens on endothelial function. Methods: Twenty-seven adult domestic pigs (Sus scrofa) were used in this study. Control pigs (n = 3) underwent instrumentation alone. The remaining pigs experienced controlled hemorrhagic shock to a mean arterial blood pressure of 30 +/- 5 mm Hg for 45 minutes. Pigs were resuscitated to their baseline mean arterial blood pressure +/-5 mm Hg with either shed blood (SB; n = 8), lactated Ringers solution (40 mL/kg) followed by shed blood (LRSB; n = 8), or lactated Ringers solution alone (LR; n = 8). At baseline, 1 and 4 hours after resuscitation, acetylcholine (5, 10, and 15 [mu]g/min) was infused into the proximal iliac artery to measure endothelial dependent relaxation (EDR). Sodium nitroprusside was infused to determine endothelial independent relaxation at the end of the study to insure smooth muscle vasomotor integrity. External iliac artery luminal diameter was measured using motion-mode ultrasonography. Statistical analysis was performed using repeated-measures analysis of variance with Tukey's post-hoc analysis. Results: All pigs survived the experiment. Pigs required ninefold more resuscitation with LR (370.58 +/- 29 mL/kg) versus SB (41.45 +/- 3.5 mL/kg) or LRSB (76.4 +/- 1.1 mL/kg) (p < 0.05). EDR for LR pigs 1 hour after initiation of resuscitation (R1) was 70.4 +/- 14.4% compared with 94.2 +/- 13.4% for SB and 106.1 +/- 8.2% for LRSB (p < 0.05). At 4 hours after resuscitation (R4), systolic luminal diameters were larger in the SB (0.45 +/- 0.01 cm) and LRSB (0.51 +/- 0.02 cm) groups compared with LR (0.41 +/- 0.03 cm) (LRSB versus LR; p = 0.01). At R4, EDR for the LR group was 78.3 +/- 10.7% compared with SB (101.4 +/- 8.3%) and LRSB (106.4 +/- 7.4%) (p < 0.05). Infusion of sodium nitroprusside confirmed integrity of smooth muscle vasorelaxation. Analysis of serum nitric oxide levels revealed decreased values after resuscitation with LR (9.44 +/- 0.76 mol/L) compared with SB (26.3 +/- 7.8 mol/L) and LRSB (16.3 +/- 1.0 mol/L) (p = not significant). Conclusion: This is the first description of a large-animal model to evaluate EDR after hemorrhagic shock. Resuscitation with LR requires significantly larger volumes than SB or LRSB. LR resuscitation leads to endothelial dysfunction, as determined by decreased EDR, versus SB or LRSB. Resuscitation with blood products may preserve nitric oxide bioactivity when compared with crystalloid resuscitation in the setting of hemorrhagic shock. out here, 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.

Thank you

This was meant to be a "something for everyone" post and suit all levels. It is watered down "alittle". If there are things in there that you want to see more of... or learn about feel free to speak up... out here, Ace844

Hello Everyone, Here's the follow up post to the Teaching Points::: ANAPHYLAXIS/EPI post here. Epinephrine (INN) or adrenaline (BAN) is a hormone and a neurotransmitter of molecular weight 183.2. A neurotransmitter is a specific kind of hormone, released by neurons to regulate activity of target tissues (e.g. brain cells, epinephrine anaphylaxis muscle cells,...). The Latin roots ad-+renes and the Greek roots epi-+nephros both literally mean "on/to the kidney" (referring lidocaine and epinephrine finger to the adrenal gland, which secretes epinephrine). Epinephrine is sometimes shortened to epi in medical jargon. Chemically, epinephrine reaction tribulus and increase and epinephrine and dopamine epinephrine is a catecholamine hormone, a sympathomimetic monoamine derived from epinephrine for weight loss the amino acids phenylalanine and tyrosine. The chemical formula of epinephrine is C9H13NO3. Its structure is shown right. ATC code C01CA24 William Bates headaches from epinephrine reported in the adrenaline, epinephrine New York Medical Journal in May 1886, the discovery of a substance produced by the suprarenal epimedium and increase and epinephrine and dopamine gland. Epinephrine was isolated and identified in 1895 by Napoleon Cybulski, Polish livestock epinephrine physiologist. The discovery schizandra and increase and epinephrine and dopamine was repeated in 1897 by John Jacob Abel. Jokichi Takamine discovered the same hormone in 1901, without knowing about the previous discovery, and called it adrenaline. serotonin dopamine epinephrine urine It was first artificially synthesized in epinephrine norepinephrine 1904 by Friedrich Stolz. Actions in the body Epinephrine plays a central role standing orders for epinephrine in the short-term stress reaction—the physiological response to threatening or exciting conditions (see Fight-or-flight response). It is secreted by the adrenal medulla. dose of epinephrine in dogs epinephrine and norepinephrine When released into the bloodstream, epinephrine binds to multiple receptors and has numerous effects throughout the body. It increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gut while dilating arterioles in leg muscles. epinephrine It elevates the blood sugar level by increasing hydrolysis of glycogen to glucose in the liver, and at the same time begins the breakdown of lipids in fat cells. Epinephrine is used as a drug epinephrine and role in glucogeneolysis to promote peripheral vascular epinephrine drip resistance chemistry 2% lidocaine with epinephrine of epinephrine via alpha-stimulated vasoconstriction in cardiac arrest and other cardiac disrhythmias resulting in diminished epinephrine central retinal or absent cardiac output, such that blood is shunted to the body's core. This beneficial action comes with a significant negative consequence, increased cardiac irritability, which may lead to additional complications racemic epinephrine dosing immediately following an otherwise epinephrine dosage successful resuscitation. Alternatives to this treatment mepivicaine spinal and epinephrine amount duration with and without epinephrine include vasopressin, a powerful antidiuretic which also promotes peripheral vascular epinephrine norepinenphrine resistance leading to blood shunting via vasoconstriction, but without the attendant epinephrine pen increase new york state law for epinephrine epinephrine and milrinone pens to myocardial irritability. Epinephrine is also used epinephrine and role in glycogenolysis as a vasoconstrictor in anaphylaxis and sepsis, and as how many mcg/cc is epinephrine 1:200,000 a bronchodilator for asthma epinephrine injection if specific beta-2-adrenergic agonists equine epinephrine are unavailable or ineffective. Allergy patients undergoing immunotherapy can get an epinephrine calculation lidocaine 2% and epinephrine rinse before their allergen extract is administered. Adverse reactions to epinephrine include palpitations, tachycardia, anxiety, headache, tremor, hypertension, and acute pulmonary edema. A pheochromocytoma is a tumor of the abbott, epinephrine adrenal gland (or, rarely, what nerve releases epinephrine the ganglia of the sympathetic nervous system) which secretes excessive amounts of epinephrine caffine panic attack catecholamines, usually epinephrine. Pharmacology Epinephrine's actions are mediated through adrenergic epinephrine long term effects receptors (sometimes referred to as adrenoceptors). It binds effect of epinephrine to α1 receptors of liver cells, which activate inositol-phospholipid signaling pathway, signaling the phosphorylation of insulin, leading to reduced ability of insulin to bind to its receptors. Epinephrine also activates β-adrenergic receptors of the liver and muscle cells, which activates the adenylate cyclase signaling pathway, which will in turn increase glycogenolysis. Epinephrine (EpiPen, Adrenalin) -- DOC for shock, angioedema, airway obstruction, bronchospasm, and urticaria in severe anaphylactic reactions. Administered SC or IM, except for patients in extremis for whom it is administered IV. May be administered SL or via ET when no IV access available. Continuous infusion may be administered in cases of refractory shock. Adult Dose :: 0.3-0.5 mL 1:1000 soln SC or IM q15min 1 mL 1:10,000 soln (diluted in 10cc NS) IV; slow administration; repeat prn 0.3-0.5 mL 1:1000 soln SL q15min 1.0 mL 1:1000 soln ET in approximately 10 cc NS IV infusion: 0.1-1 mcg/kg/min Pediatric Dose 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln SC or IM q15min 0.01 mL/kg (minimum 0.1 mL) 1:10,000 soln IV prn 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln SL q15min 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln ET in approximately 1-3 cc NS IV infusion: 0.1-1.0 mcg/kg/min Contraindications May be administered in life-threatening anaphylactic reactions, even when the following relative contraindications are present: (1) coronary artery disease, (2) uncontrolled hypertension, (3) serious ventricular arrhythmias, and (4) second stage of labor Interactions Sympathomimetics cause additive effects; beta-blockers antagonize therapeutic effects of epinephrine; digitalis potentiates proarrhythmic effect of epinephrine; TCAs and MAOIs potentiate cardiovascular effects of epinephrine; phenothiazine causes a paradoxical decrease in BP - Usually safe but benefits must outweigh the risks. Precautions Adverse effects:: include cardiac ischemia or arrhythmias, fear, anxiety, tremor, and hypertension with subarachnoid hemorrhage; use with caution in elderly and in patients that have diabetes mellitus, hyperthyroidism, prostatic hypertrophy, hypertension, cardiovascular disease, and cerebrovascular insufficiency; rapid IV infusions also may cause death from cerebrovascular hemorrhage or cardiac arrhythmias Epinephrine versus epinephrine molecule adrenaline While epinephrine is the International Nonproprietary Name (INN) and United epinephrine clearance kidneys States Approved Name (USAN), it is more commonly known as adrenaline, which epinephrine for livestock is the British Approved Name (BAN). The basis for the name epinephrine in the United States was out of necessity because the name adrenalin was registered as a trademark by Parke, Davis & Co. In other countries where this trademark was not registered, the name adrenaline was adopted racemic epinephrine at the insistence of the British pharmacologist Henry Hallett Dale. Resistance to the adoption of epinephrine has even resulted in some dispute as to the validity epinephrine and standing order of the name (Aronson, 2000). EPINEPHRINE (ADRENALIN) Class: Sympathomimetic. Mechanism of Action Direct acting alpha and beta agonist Alpha: bronchial, cutaneous, renal and visceral arteriolar vasoconstriction. Beta 1: positive inotropic and chronotropic actions, increases automaticity. Beta 2: bronchial smooth muscle relaxation and dilation of skeletal vasculature Blocks histamine release. Indications Cardiac arrest, asystole, PEA, VF unresponsive to initial defib. Severe bronchospasm, asthma, bronchiolitis. Anaphylaxis, acute allergic reactions. Contraindications Hypertension, hypothermia, pulmonary edema, coronary insufficiency, hypovolemic shock. Adverse Reactions Hypertension, dysrhythmias, pulmonary edema, anxiety, psychomotor agitation, nausea, angina, headache, restlessness. Drug Interactions Potentiates other sympathomimetics. Deactivated by alkaline solutions. MAOIs may potentiate effects of epinephrine. How Supplied 1 mg / ml (1:1,000) ampules and 0.1 mg / ml (1:10,000) prefilled syringes. Auto-injectors: EPI-Pen: 0. 3 mg / ml EPI-Pen Jr.: 0.15mg/ml Dosage and Administration Adult Allergic reactions and asthma: 0.3 - 0.5 mg (0.3 - 0.5 ml 1:1000) SC Anaphylaxis: 0.3 - 0.5 mg (3- 5 ml 1:10,000) IV Cardiac: (asystole, PEA, VF) 1 mg IV push (1:10,000) every 3- 5 minutes Endotracheal: 2.0- 2.5 mg (1:1,000) every 3- 5 minutes in 10ml NS Pediatric Allergic reactions and asthma: 0.01 mg/kg (0.01 mL/kg 1:1000) SC to maximum of 0.5 mg. Cardiac: (asystole, PEA, VF) IV, IO: Standard initial dose: 0.01 mg/kg (1:10,000, 0.1mL/kg) ET: 0.1 mg/kg (1:1,000, 0.1mL/kg) Second and subsequent doses: 0.1 mg/kg (1:1000, 0.1mL/kg) Duration of Action Onset: Immediate. Peak Effects: Minutes. Duration: Several minutes. Special Considerations Pregnancy safety: category C. Syncope in asthmatic children. If given ET, may dilute in sterile NS (10 ml in adults). EPINEPHRINE RACEMIC (MICRONEFRIN, VAPONEFRIN) Class Sympathomimetic. Mechanism of Action Stimulates beta -2 receptors in lungs: bronchodilatation with relaxation of bronchial smooth muscles. Reduces airway resistance. Useful in treating laryngeal edema; Inhibits histamine release. Indications Bronchial asthma, prevention of bronchospasm. Croup: laryngotracheobronchitis. Laryngeal edema. Contraindications Hypertension, underlying cardiovascular disease, Epiglottitis. Adverse Reactions Tachycardia, dysrhythmias. Drug Interactions MAOIs may potentiate effects. Beta-blockers may blunt effects. How Supplied MDI: 0.16-0.25 mg/ spray. Solution: 7.5, 15, 30 ml in 1%, 2.25% solutions Dosage and Administration Adult: MDI: 2-3 inhalations, repeated every 5 minutes PRN. Solution: dilute 5 ml (1%) in 5.0 ml NS, administer over 15 minutes. Pediatric: Solution: Dilute 0.25 ml (0.1%) in 2.5 ml NS (if less than 20 kg); Dilute 0.5 ml in 2.5 ml NS (if 20-40 kg); Dilute 0.75 ml in 2.5 ml NS (if greater than 40 kg) Administer by aerosolization. Duration of Action Onset: within 5 minutes. Peak effect: 5- 15 minutes. Duration: 1-3 hours. Special Considerations May cause tachycardias and other dysrhythmias. Monitor Vital Signs. Excessive use may cause bronchospasm. Hope this helps, Ace844

Hi Everyone, After having read the wide variety of responses and posts to the Epi-Pens: BLS Usage? thread that perhaps I could make a teaching post on the subject of ANAPHYLAXIS and the reasons we administer Epi to our patients.... This first post will cover the physiology and the follow up will cover Epi, etc.... So if this helps or you like it, SOUND OFF!!! :!: :study: :computer: :idea: Hope this helps, Ace844 ANAPHYLAXIS INTRODUCTION: Anaphylaxis in its broadest sense represents a spectrum of clinical events from sneezing to shock depending on end organ sensitivity. Anaphylaxis is characterized as an explosive event resulting from release of histamine and preformed mediators causing profound end organ dysfunction (cardiac, respiratory, GI, dermatologic, neurologic). Immediate hypersensitivity reactions to foreign proteins were first appreciated 4000 years ago, in descriptions of insect sting fatalities. Reactions to stinging insects still claim 50 lives annually. Subsequently, the use of horse serums, (tetanus, diphtheria) and penicillin focused attention on the overwhelming effect antigens in the right host could quickly elicit. These effects are varied and encompass clinical manifestations such as hypotension, cardiac arrhythmias, asthma, urticaria, angioedema, profuse diarrhea, nausea, vomiting and rhinitis. In l966 Drs. K. and T. Ishizaka identified the immunoglobulin in humans primarily responsible for these reactions, IgE. In the last 22 years, fascinating insights into the mechanism of this immunologic reaction, both in its "normal gate-keeper" function and its role in disease have been described. DEFINITIONS: IMMEDIATE HYPERSENSITIVITY: The result of re-exposure to an antigen capable of eliciting an IgE response in a susceptible individual producing a clinical reaction (flushing, urticaria, etc.), within seconds to minutes as a result of degranulation of mast cells/basophils. Non-immunologic stimuli can also provoke basophil/mast cell degranulation without prior exposure (radiocontrast media, morphine) producing a reaction mimicking an IgE immediate hypersensitivity response. ATOPY: Describes the genetic predisposition to produce increased amounts of IgE antibody against common environmental antigens. This tendency is manifest by 20% of the population and is apparent clinically as anaphylaxis, asthma, eczema, hayfever, urticaria and angioedema dependent upon end organ susceptibility. ALLERGY: The term allergy was originally coined in 1906 by von Pirquet meaning "changed reactivity of the host when meeting an agent on a second or subsequent occasion". Allergy has become synonymous with the type I hypersensitivity. LATE PHASE RESPONSE: Reoccurrence of clinical symptoms four to twelve hours after antigen exposure mediated by the basophil, histamine releasing factors (HRF), the eosinophil and platelet activating factor. I. MAJOR COMPONENTS OF TYPE I REACTIONS A. IgE 1. Is glycoprotein MW 190,000 which is heat labile. 2. Has a serum half life of 2-3 days. Regulated by T cell factors (IgE binding factors) GEF, GIF. 3. Binds to basophils and mast cell through a high affinity Fc receptor. 4. Basal level is controlled by host factors: sex, age, race, skin and mucosal permeability. 5. Is 95% bound to cells for 3-4 weeks. Low IgE level is transmitted as an autosomal dominant. 6. Alternate pathway activation of complement is triggered by IgE-immune complexes. Is found in greater amounts in allergic individuals, and is a heterogeneous population (IgE+) (IgE-). IgE+ represents the response to histamine releasing factors. The greater the number of IgE+ an individual has the greater chance for disease through late phase response. 7. Normal increase in IgE with parasitic infections where IgE dependent binding of macrophages and eosinophils to parasites has been documented to cause cytotoxic reactions. 8. Low affinity Fc receptors for IgE are found on T-cells, B-cells, monocytes, macrophages, eosinophils and platelets indicating a regulatory function. B. Mast cell 1. Has high affinity receptors for IgE (105 /mast cell). 2. Composed of two distinct populations: a. Connective tissue mast cell: Predominantly found in skin w/stains intensely with metachromatic dyes. Forms prostaglandin D2 as metabolite b. Mucosal mast cell: Found in lung and lamina propria of the gut. Leukotriene C4 is major metabolite. 3. Has rounded nucleus with metachromatic staining granules, up to 1,000. 4. Has heterogeneous granules related to age, and polyanion of granule, i.e., Heparin sulfate or Chondroitin sulfate. 5. Originates in bone marrow. 6. Increases host response to parasitic infections. C. Basophil 1. Is a polymorphonuclear leukocyte generated in the bone marrow. 2. Comprises 0.2% to 1% of nucleated cells in bone marrow and peripheral blood. 3. Has lobulated nucleus with large metachromatic granules. 4. Has high affinity receptors for IgE. 5. Generates leukotriene C4. 6. Promotes late phase response i.e., asthma, contact dermatitis through IgE+ and histamine releasing factors. 7. Produce from precursors in the blood and bone marrow under the influence of IL-3. D. Eosinophil 1. Plays a major role in allergic inflammation and disease. 2. Composes less than 3% of circulating population of peripheral leukocytes. 3. Has bilobed nucleus with refractile cytoplasmic granules staining bright red with login. 4. Originates in bone marrow under influence of granulocyte - macrophage colony stimulating factors and by T-lymphocyte factors, IL 3 and 5. 5. Responds to chemoattractant properties of C5a, PAF, LTB4. 6. Contains major basic protein (MBP), cationic protein and neurotoxin contribute to sloughing of airway epithelium and killing of parasites. 7. Is a major component of the late phase response. E. Histamine Releasing Factors (HRF) 1. Produced by platelets, macrophages, lymphocytes. 2. Have a MW 15-30K, shared by a "family" of molecules. 3. Causes mediator release in the late phase as the result of HRF- basophil interaction in individuals with increased IgE+. 4. Selectively causes release in atopics (IgE+). 5. May discriminate between "extrinsic" and "intrinsic" asthma and anaphylaxis. II. MECHANISM OF IMMEDIATE HYPERSENSITIVITY A. Antigen interacts with antigen specific cell-surface bound IgE. (dimer) on mast cells. B. Generates a signal through the cross-linking of Fce IgE receptors. C. Membrane lipid and adenine metabolism is initiated. D. Granule solubilization and release of preformed amines, proteins, peptides and proteoglycans from granules occurs. III. MEDIATORS OF IMMEDIATE HYPERSENSITIVITY A. Preformed Mediators 1. Histamine is primary preformed vasoactive mediator in basophils and mast cells. a. Acts on H1 to contact smooth muscles, increase vascular permeability, and generate prostaglandins. b. Acts on H2 to increase vascular permeability, gastric acid secretion, stimulate suppressor lymphocytes, decrease PMN enzyme release, chemotaxis mast cell and basophil histamine release. c. Acts on H3 receptors to inhibit neurotransmitter and histamine release. 2. ECF-A (mast cell) preformed attracts and deactivates eosinophils and increases eosinophils' complement receptors. 3. HMW-NCF (mast cell) attracts and deactivates neutrophils. 4. Tryptase in the mucosal mast cell is a preformed enzyme which cleaves C3. 5. Kallikrein similar to plasma kallikrein cleaves bradykinin from HMW Kininogenase and activated Hageman factor. B. Newly Formed Mediators 1. PAF is generated by mast cells, macrophages, neutrophils and eosinophils. a. Aggregates platelets. b. Releases platelet amines. c. Generates platelet thromboxane. d. Attracts eos, neutrophils. 2. Arachidonic acid metabolites, leukotrienes (C,D,E) are generated by mast cells and basophils. a. Constrict smooth muscle. b. Increase vascular permeability. c. Synergistic with histamine. d. Cause cardiac depression. e. Inhibit lymphocyte response to mitogen. 3. Leukotriene B4 (LTB4) is most potent chemotactic factor for neutrophils and eosinophils. 4. Prostaglandin D2 (mast cell) causes constriction on bronchial smooth muscle. 5. Adenosine inhibits platelet aggregation, is potent bronchoconstrictor and enhances mast cell release. C. Granule - Associated Mediators 1. Heparin sulfate is the major preformed proteoglycan which binds histamine, inhibits complement activation, acts as a anticoagulant, binds platelet factor 4 and tryptase. 2. Chondroitin 4 an 6 sulfate is preformed in the basophil to bind histamine IV. REGULATION OF MAST CELL DEGRANULATION A. Intracellular cyclic nucleotides modulate mediator release. 1. Increased cAMP depresses mediator release. 2. Increased cGMP enhances mediator release. 3. Ca2 ion stores, intra and extracellular, modify Ag mediated histamine release. B. Basophils and mast cells have additional surface receptors. 1. Beta receptors are present on mast cells and basophils which when stimulated increase cAMP. 2. Beta receptors may be abnormal or decreased in atopic disease. 3. Beta agonists (isoproterenol, epinephrine) increase cAMP. 4. Alpha adrenergic receptors present on smooth muscle cause vasoconstriction. 5. Cholinergic stimulation increases mucus secretion and smooth muscle constriction. 6. Alpha, beta and cholinergic receptor abnormalities predispose atopic individuals to end organ sensitivity. 7. Mast cells and basophils have for C3a, c5a anaphylatoxin generated by complement activation. C. Eosinophils and neutrophils modulate responses provoked by mast cells and basophils in the late phase response. V. CLINICAL MANIFESTATIONS OF ANAPHYLAXIS A. Reactions are due to release of preformed mediators (histamine) and generation of leukotrienes, PAF. Severe reactions are marked by massive swelling of respiratory tract, constriction of bronchial smooth muscle and massive vasodilatation through mediator effect on capillary permeability. 1. Fatalities result in 3% of cases. 2.Significant upper and lower respiratory obstruction represent cause of death 70% of cases. 3. Cardiac arrhythmias and dysfunctions represent 24% of fatal cases. 4. Risk factors for fatalities include: a. protracted course b. Beta blockers c. adrenal insufficiency B. Host factors relevant to development of anaphylaxis include: 1. Antigen dose and mode of administration 2. Genetic predisposition 3. Stress/Chronic disease 4. Nutritional Status C. Anaphylaxis may be uniphasic, biphasic or protracted. 1. Laryngeal edema occurs more frequently in protracted (57%) or biphasic (40%) cases. 2. With oral agents biphasic or prolonged reactions are more common than perceived previously. 3. Glucocorticoids do not reproducibly prevent biphasic or protracted anaphylaxis. 4. Patients with reactions need to be observed for greater than 12 hours especially if upper airway obstruction is involved. D. Mechanisms involve IgE (atopy), IgE (non atopic) and non IgE. 1. Drugs IgE (non atopic). a. Antibiotics - prototype is penicillin. Reactions rates are 0.7% to 8% (4-15 cases/10,000 courses of PCN) 20% of the population claim a history of PCN allergy. There is a 10% reaction rate with a negative history. Forty percent reaction rate with positive history. Skin testing is performed with the major determinant pencilloyl-poly-L-lysine (PrePen) and minor determinant (benzyl penicillin). Positive minor determinant skin test is associated with anaphylaxis. If skin tests are negative less than 3% chance of anaphylaxis. Desensitization is possible in a controlled environment. (cephalosporins, tetracyclines, nitrofurantoin, streptomycin, chloramphenicol, bacitracin, neomycin, amphotericin . Non IgE - vancomycin, polymyxins. 2. Foreign Proteins IgE (non atopic). a. Insulin b. PTH c. ACTH d. Asparaginase e. Chymopapain f. Penicillinase g. Seminal Plasma h. Antilymphocyte globulin i. Hymenoptera venom j. Fire ant venom Insect Stings cause 50 fatalities annually. Patients with systemic reactions can receive venom specific therapy (bee, wasp, yellow jacket, hornet and fire ant). Immunotherapy is maintained at 100 micrograms per antigen for 60 months. Specific IgE and IgG titers can then help predict continued need for therapy. 3. Therapeutic agents (IgE). a. allergic extracts b. muscle relaxants c. estradiol d. hydrocortisone e. methylprednisolone f. protamine g. ethylene oxide h. thiopental i. local anesthetics i. Reactions are usually secondary to bisulfites or epinephrine. To document safety of a particular agent provocative skin testing can be performed. ii. Chemically there are two groups Group I (benzoic acid ester) or Group II (amide). There is cross reactivity in Group I not in Group II. If a reaction with a Group I agent occurs (Novocaine) a Group II agent (carbocaine) can be selected. j. vaccines k. streptokinase 4. Foods (IgE atopic). Fatalities usually occur in victims with prior knowledge i.e., past anaphylaxis. Usually it is a meal away from home, with alcohol, denial, reliance on p.o. antihistamines and no Epi-Pen. a. milk b. egg white c. nuts d. citrus e. wheat f. soybean/legumes/peanuts g. seeds (sunflower, pumpkin) h. grains i. cottonseed j. fish k. shellfish l. bananas m. beets n. corn o. safflower p. chamomile tea 5. Therapeutic agents (Non IgE) Reactions are secondary to anaphylatoxin production. a. Radiocontrast media reactions occur in 20% of all procedures. Patients with prior reactions have a 17-35% change of subsequent reaction. Pretreatment with antihistamines 50mg IM l hr. before the procedure and Prednisone 50mg 13, 7 and 1 hr. before the procedure has provided effective protection in 93% of patients with prior reactions (Greenberger et.al.). Reaction is not related to iodine. Atopics allergic to shellfish have a slightly increased risk. Low osmolality contrast media has decreased reactions with increased patient comfort. b. Transfusion reaction c. Gamma globulin infusion 6. Modulators of Arachidonic acid metabolism. Reactions are secondary to increases in by products of lipooxygenase pathway. a. ASA b. Nonsteroidal anti-inflammatory agents c. Azo dyes d. Yellow dye #5 e. Benzoates 7. Bisulfites which are used as sanitizing agents for food containers and fermentations equipment. FDA allows in non-thiamine containing foods. Sprayed on fresh vegetables, shellfish, beer, and wine. Ingest 20-100 mg per restaurant meal. Also found in medications. Mechanism of action thought to be secondary to stimulation of afferent cholinergic reflex arc by sulfur dioxide causing massive cholinergic discharge. 8. Exercise-induced anaphylaxis characterized by cutaneous warmth, pruritus, urticaria and vascular collapse. More common in atopics. may be related to specific food ingestion prior to exercise. 9. Idiopathic anaphylaxis (73 pts. reported by Boxer et.al.) no clear reproducible triggers. a. Usually more common in atopic females (59%) b. Reactions are infrequent 1-6 x a year (mild) (52%) c. Reactions are frequent 48% requiring maintenance antihistamines (H1) and prednisone. Remission has required an average of 1 yr. of prednisone therapy. 10. Progesterone allergy females who are frequently atopic demonstrate sensitivity to medroxyprogesterone documented by skin testing. Treatment involves use of androgens or oophorectomy/hysterectomy. E. Treatment 1. Epinephrine 0.3 - 0.ml (1:1000) S.C. 2. If profound hypotension, use IV Epinephrine 2-3 ml (1:10,000), although increase incidence of arrhythmias. Repeat dose every 15-20 min. as necessary. 3. Supportive therapy with fluids, vasopressors as necessary. 4. Addition of H1 blockers, H2 blockers 5. Corticosteroids (2-4 mg/kg q 4-6 hrs.) are helpful in preventing the late phase response. 6. Glucagon 1mg bolus in patients on Beta blockers. F. Prevention of anaphylaxis and anaphylactic death 1. Thorough drug allergy history 2. Give drug orally rather than parenterally when possible 3. Patients to wait in office 30 minutes after drug administration 4. Check all drugs for proper labelling 5. Predisposed patients to carry warning identification 6. Predisposed patients taught self-injection of epinephrine 7. When antiserum essential, use human 8. Skin test and desensitize when appropriate Background: Anaphylaxis refers to a severe allergic reaction in which prominent dermal and systemic signs and symptoms manifest. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated. Treatment for both conditions is similar, and this article uses the term anaphylaxis to refer to both conditions unless otherwise specified. Pathophysiology: Rapid onset of increased secretion from mucous membranes, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability occur after exposure to an inciting substance. These effects are produced by the release of mediators, which include histamine, leukotriene C4, prostaglandin D2, and tryptase. In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific immunoglobulin E (IgE) attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds. In an anaphylactoid reaction, exposure to an inciting substance causes direct release of mediators, a process that is not mediated by IgE. Increased mucous secretion and increased bronchial smooth muscle tone, as well as airway edema, contribute to the respiratory symptoms observed in anaphylaxis. Cardiovascular effects result from decreased vascular tone and capillary leakage. Histamine release in skin causes urticarial skin lesions. The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), IV contrast materials, Hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated. Anaphylaxis also may be idiopathic. Frequency: In the US: The true incidence of anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. Some authors consider up to 15% of the US population "at risk" for anaphylaxis. The frequency of anaphylaxis is increasing and this has been attributed to the increased number of potential allergens to which people are exposed. Up to 500-1,000 fatal cases of anaphylaxis per year are estimated to occur in the US. Internationally: Reactions to insects and other venomous plants and animals are more prevalent in tropical areas because of the greater biodiversity in these areas. Mortality/Morbidity: Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions. Race: Well-described racial differences in the incidence or severity of anaphylaxis do not exist. Cultural and socioeconomic differences may influence exposure rates. Sex: No major differences have been reported in the incidence and prevalence of anaphylactic reactions between men and women. Age: Anaphylaxis occurs in all age groups. While prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Adults are exposed to more potential allergens than are pediatric patients. The elderly have the greatest risk of mortality from anaphylaxis due to the presence of preexisting disease. History: Anaphylactic reactions almost always involve the skin or mucous membranes. More than 90% of patients have some combination of urticaria, erythema, pruritus, or angioedema. The upper respiratory tract commonly is involved, with complaints of nasal congestion, sneezing, or coryza. Cough, hoarseness, or a sensation of tightness in the throat may presage significant airway obstruction.Eyes may itch and tearing may be noted. Conjunctival injection may occur. Dyspnea is present when patients have bronchospasm or upper airway edema. Hypoxia and hypotension may cause weakness, dizziness, or syncope. Chest pain may occur due to bronchospasm or myocardial ischemia (secondary to hypotension and hypoxia).GI symptoms of cramplike abdominal pain with nausea, vomiting, or diarrhea also occur but are less common, except in the case of food allergy.In a classic case of anaphylaxis, the patient or a bystander provides a history of possible exposures that may have caused the rapid onset of skin and other manifestations. This history often is partial; exposure may not be recalled, or it may not be considered significant by the patient or physician. For example, when queried about medications, a patient may not mention over-the-counter (OTC) products. The clinician may not realize that, while reactions are usually rapid in onset, they also may be delayed. Physical: General Physical examination of patients with anaphylaxis depends on affected organ systems and severity of attack. Vital signs may be normal or significantly disordered with tachypnea, tachycardia, and/or hypotension. Place emphasis on determining the patient's respiratory and cardiovascular status. Frank cardiovascular collapse or respiratory arrest may occur in severe cases. Anxiety is common unless hypotension or hypoxia causes obtundation. Shock may occur without prominent skin manifestations or history of exposure; therefore, anaphylaxis is part of the differential diagnosis for patients who present with shock and no obvious cause. General appearance and vital signs vary according to severity of attack and affected organ system(s). Patients commonly are restless due to severe pruritus from urticaria. Anxiety, tremor, and a sensation of cold may result from compensatory endogenous catecholamine release. Severe air hunger may occur when the respiratory tract is involved. If hypoperfusion or hypoxia occurs, the patient may exhibit a depressed level of consciousness or may be agitated and/or combative. Tachycardia usually is present, but bradycardia may occur in very severe reactions. Skin The classic skin manifestation is urticaria (ie, hives). Lesions are red and raised, and they sometimes have central blanching. Intense pruritus occurs with the lesions. Lesion borders usually are irregular and sizes vary markedly. Only a few small or large lesions may become confluent, forming giant urticaria. At times, the entire dermis is involved with diffuse erythema and edema. Hives can occur anywhere on the skin. In a local reaction, lesions occur near the site of a cutaneous exposure (eg, insect bite). The involved area is erythematous, edematous, and pruritic. If only local skin reaction (as opposed to generalized urticaria) is present, systemic manifestations (eg, respiratory distress) are less likely. Local reactions, even if severe, are not predictive of systemic anaphylaxis on re-exposure.Lesions typical of angioedema also may manifest in anaphylaxis. The lesions involve mucosal surfaces and deeper skin layers. Angioedema usually is nonpruritic and associated lesions are nonpitting. Lesions most often appear on the lips, palms, soles, and genitalia. Pulmonary Upper airway compromise may occur when the tongue or oropharynx is involved. When the upper airway is involved, stridor may be noted. The patient may have a hoarse or quiet voice and may lose speaking ability as the edema progresses. Complete airway obstruction is the most common cause of death in anaphylaxis. Wheezing is common when patients have lower airway compromise due to bronchospasm or mucosal edema. In angioedema, due to ACE inhibitors, marked edema of the tongue and lips may obstruct the airway. Cardiovascular Cardiovascular examination is normal in mild cases. In more severe cases, compensatory tachycardia occurs due to loss of vascular tone. Intravascular volume depletion may take place as a consequence of capillary leakage. These mechanisms also lead to development of hypotension. Relative bradycardia has been reported. Causes: A wide variety of substances can cause anaphylaxis. Anaphylaxis also may be idiopathic. In the classic form of anaphylaxis, a foreign protein is the inciting agent (eg, antigen). On initial exposure, the antigen elicits generation of an IgE antibody. The antibody residue binds to mast cells and basophils. On re-exposure, the antigen binds to the antibody, and the receptors are activated. Clinical manifestations result from release of immune response mediators such as histamine, leukotrienes, tryptase, and prostaglandins. The same mechanism occurs when a nonimmunogenic foreign substance binds as a so-called hapten to a native carrier protein, creating an immunogenic molecule. Factors influencing severity of a reaction include degree of host sensitivity and dose, route, and rate of administration of the offending agent. Parenteral exposures tend to result in faster and more severe reactions. Most severe reactions occur soon after exposure. The faster a reaction develops, the more severe it is likely to be. While most reactions occur within hours, symptoms may not occur for as long as 3-4 days after exposure. Drugs Penicillin and cephalosporin antibiotics are the most commonly reported medical agents in anaphylaxis. This prevalence is a function of the immunogenicity and overuse of these agents. Because of their molecular and immunologic similarity, cross-sensitivity may exist. Reports often assert that 10% of patients allergic to a penicillin antibiotic are allergic to cephalosporins. A recent report suggests that actual incidence of cross-reactivity is lower (perhaps 1%), with most reactions considered mild. A more recent review indicated that patients with a history of allergy to penicillin seem to have a higher risk (by a factor of about 3) of subsequent reaction to any drug and that the risk of an allergic reaction to cephalosporins in patients with a history of penicillin allergy may be up to 8 times as high as the risk in those with no history of penicillin allergy (ie, at least part of the observed cross reactivity may represent a general state of immune hyperresponsiveness, which represents true cross-reactivity). Reactions tend to be more severe and rapid in onset when the antibiotic is administered parenterally. Anaphylaxis may occur in a patient with no prior history of drug exposure. History of penicillin or cephalosporin allergy often is unreliable and is not predictive of future reactions. Up to 85% of patients reporting an allergic reaction to penicillin do not react on subsequent exposure. When a drug in either class is the drug of choice for a patient with a life-threatening emergency, a number of options exist. When the history is indefinite, the drug may be administered under close observation; however, when possible, obtain the patient's informed consent. Immediate alternate treatment measures should be available. Alternatively, when the history is more convincing, a desensitization or prophylactic pretreatment protocol may be instituted. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) commonly are implicated in allergic reactions and anaphylaxis. Bronchospasm is common in patients with reactive airway disease and nasal polyps. Cross-reactivity may occur between the various NSAIDs. Intravenous radiocontrast media IV administered by radiocontrast media causes an anaphylactoid reaction that is clinically identical to true anaphylaxis and is treated in the same way. The reaction is not related to prior exposure. Shellfish or "iodine allergy" is not a contraindication to use of IV contrast and does not mandate a pretreatment regimen. As with any "allergic" patient, give consideration to use of low molecular weight (LMW) contrast. The term iodine allergy is a misnomer. Iodine is an essential trace element present throughout the body. No one is allergic to iodine. Patients who report iodine allergy usually have had either a prior contrast reaction or a shellfish allergy. Manage these patients as indicated earlier.Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a reaction. Use of LMW contrast decreases incidence of reactions to approximately 0.5%. Personnel, medications, and equipment needed for treatment of allergic reactions always should be available when these agents are administered. Obtain consent before administration.Reactions to radiocontrast usually are mild (most commonly urticarial), with only rare fatalities reported. Risk of a fatal reaction has been estimated at 0.9 cases per 100,000 exposures. Mucosal exposure (eg, GI, genitourinary [GU]) to radiocontrast agents has not been reported to cause anaphylaxis; therefore, a history of prior reaction is not a contraindication to GI or GU use of these agents. Pretreatment with antihistamines or corticosteroids and use of LMW agents lead to lower rates of anaphylactoid reactions to IV contrast. Consider these measures for patients who have prior history of reaction, since rate of recurrence is estimated at 17-60%. Patients who are atopic and/or asthmatic also are at increased risk of reaction. In addition, allergic reaction is more difficult to treat in those taking beta-blockers. Hymenoptera stings Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. An uncertain but enormous number of exposures occur; accurate reaction rates are difficult to estimate. In the United States, Hymenoptera envenomations result in fewer than 100 deaths per year. Local reaction and urticaria without other manifestations of anaphylaxis are much more common than full-blown anaphylaxis. Generalized urticaria is a risk factor for subsequent anaphylaxis; but a local reaction, even if severe, is not a risk factor for anaphylaxis. Caution patients treated and released from the ED after an episode of anaphylaxis or generalized urticaria from Hymenoptera envenomation to avoid future exposure when possible. Consider referral to an allergist for desensitization, particularly when further exposure is likely. Additionally, consider prescribing a treatment kit with an epinephrine auto-injector and oral antihistamine. Both are effective measures in preventing or ameliorating future reactions. Allergies Food allergy is common. Symptoms usually are mild and limited to the GI tract, but full-blown anaphylaxis can occur. Fatalities are rare compared to number of exposures; however, the number of exposures is so high that foods may be the commonest cause of anaphylaxis. Anaphylaxis due to foods may be an underrecognized cause of sudden death and an unappreciated cause of diagnosed anaphylaxis. Commonly implicated foods include nuts (especially peanuts), legumes, fish and shellfish, milk, and eggs. Latex allergy is an increasingly recognized problem in medical settings, where use of gloves and other latex products is ubiquitous. Most reactions are cutaneous or involve the mucous membranes. Anaphylactic reactions occur and have been reported with seemingly benign procedures (eg, Foley catheter insertion, intraperitoneal exposure to gloves during surgery). DIFFERENTIALS :: Angioedema Anxiety Asthma Conversion Disorder Epiglottitis, Adult Foreign Bodies, Trachea Myocardial Infarction Pulmonary Embolism Toxicity, Scombroid Urticaria Other Problems to be Considered: Globus hystericus Hereditary angioedema Monosodium glutamate poisoning (ie, Chinese restaurant syndrome) WORKUP Lab Studies: The diagnosis of anaphylaxis is clinical and does not rely on laboratory testing. When typical symptoms are noted in association with a likely exposure, diagnosis is virtually certain. Ancillary testing may help assess severity of reaction, although this is primarily a clinical judgment. When unclear, ancillary testing may help establish the diagnosis. The only potentially useful test at the time of reaction is measurement of serum mast cell tryptase. Tryptase is released from mast cells in both anaphylactic and anaphylactoid reactions. Levels are usually raised in severe reactions. Mast cell tryptase is raised transiently with blood levels reaching a peak approximately an hour after reaction onset. Tryptase levels may aid in later diagnosis and treatment. Consider the test in cases for which diagnosis of anaphylaxis is uncertain. The utility of this test awaits full evaluation. Cardiac monitoring in patients with severe reactions and in those with underlying cardiovascular disease is important, particularly when adrenergic agonists are used in treatment. Pulse oximetry also is useful. Imaging Studies: Imaging studies are not generally useful in the diagnosis and management of anaphylaxis, although they may be used as diagnostic aids when diagnosis is unclear. Other Tests: Sensitivity testing Testing for sensitivity to penicillin antibiotics may be useful when a penicillin or cephalosporin antibiotic is the drug of choice for a serious infection in a patient who has a history of severe allergic reaction. Obtain informed consent, and ensure that resuscitative equipment is immediately available. Protocols for acute testing for allergy to penicillin or cephalosporin antibiotics involve administration of increasing IV doses of the chosen antibiotic, while observing the patient for pruritus, flushing, urticaria, dyspnea, hypotension, or other manifestations of anaphylaxis. If no manifestations are observed, a full dose of the antibiotic may be administered safely. A suggested protocol for IV testing begins with 0.001 mg of the chosen drug. At 10-min intervals, incrementally increase the dose (eg, 0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 g, 0.5 mg, 1 mg, 10 mg, 50 mg, 100 mg, full dose), while observing the patient. Many other protocols exist. In most circumstances, perform desensitization on an inpatient basis. If the necessary resources are available, desensitization may be performed in the ED. Procedures: Intravenous contrast reaction prevention Patients with a history of severe reactions to IV contrast material may require use of contrast in an urgent or emergency situation. Alternatives (eg, spiral CT scan for ureteral stone, Doppler ultrasound for deep venous thrombosis [DVT]) should be considered but are not always feasible. In these circumstances, a prophylactic regimen of corticosteroids and antihistamines may be used. The precise efficacy of these regimens is difficult to evaluate, but they generally are considered effective. One author states that the recurrence rate for patients with a previous reaction was reduced from 17-60% to 9% when conventional contrast material was used; the rate was reduced to less than 1% when low osmolality material was employed after a pretreatment regimen. The use of H2 blockers has not been shown to decrease the risk of reaction to IV contrast. One study suggests H2 blockers actually appear to increase the risk. A widely quoted protocol for prevention of reactions to IV contrast suggests the following: Use low osmolality contrast. Administer hydrocortisone (200 mg IV); wait 2 hours if clinically appropriate. Administer diphenhydramine (50 mg IM) immediately before the procedure. Desensitization regimens Desensitization regimens for penicillin and cephalosporin antibiotic allergy have been shown effective. Because these regimens are lengthy (approximately 6 h), they have limited applicability to the ED. When patients wait for long periods in the ED or in an observation unit, consider desensitization regimens. A typical desensitization regimen involves administering the antibiotic of choice in an initial dose of 0.01 mg. While observing the patient, double the dose every 10-15 minutes until a full dose has been administered. Desensitization regimens do not protect against non–IgE-mediated reactions that may be severe or even life threatening (eg, Stevens-Johnson syndrome). While theoretically attractive, premedication regimens have not been clinically shown to decrease incidence or severity of IgE-mediated allergic reactions to antibiotics. TREATMENT:: Prehospital Care: Prehospital patients with symptoms of severe anaphylaxis should first receive standard interventions. Interventions include high-flow oxygen, cardiac monitoring, and IV access. These measures are appropriate for an asymptomatic patient who has a history of serious reaction and has been re-exposed to the inciting agent. Additional treatment depends upon the condition of the patient and the severity of the reaction. Measures beyond basic life support (BLS) are not necessary for patients with purely local reactions. Immediately assess airway patency due to the potential for compromise secondary to edema or bronchospasm. Active airway intervention may be difficult due to laryngeal or oropharyngeal edema. In this circumstance, it may be preferable to defer intubation attempts, and instead ventilate with a bag/valve/mask apparatus while awaiting medications to take effect. In extreme circumstances, cricothyrotomy or catheter jet ventilation may be lifesaving. Inhaled beta-agonists are used to counteract bronchospasm and should be administered to patients who are wheezing. The IV line should be of large caliber due to the potential requirement for large-volume IV fluid resuscitation. Isotonic crystalloid solutions (ie, normal saline, Ringer lactate) are preferred. A keep vein open (KVO) rate is appropriate for patients with stable vital signs and only cutaneous manifestations. If hypotension or tachycardia is present, administer a fluid bolus of 20 mg/kg for children and 1 L for adults. Further fluid therapy depends on patient response. Large volumes may be required in the profoundly hypotensive patient. Administer epinephrine to patients with systemic manifestations of anaphylaxis. With mild cutaneous reactions, an antihistamine alone may be sufficient, thus the potential adverse effects of epinephrine can be avoided. Patients on beta-blocker medications may not respond to epinephrine. In these cases, glucagon may be useful. The Medication section describes dosage, routes of administration, and contraindications for medications discussed in this section. Antihistamines (eg, H1 blockers), such as diphenhydramine (Benadryl) are important and should be administered for all patients with anaphylaxis or generalized urticaria. Corticosteroids are used in anaphylaxis primarily to decrease the incidence and severity of delayed or biphasic reactions. Corticosteroids may not influence the acute course of the disease; therefore, they have a lower priority than epinephrine and antihistamines. Emergency Department Care: ED care begins with standard monitoring and treatment, including oxygen, cardiac monitoring, and a large-bore IV with isotonic crystalloid solution. Further intervention depends on severity of reaction and affected organ system(s). Rapidly assess airway patency in patients with systemic signs or symptoms. If required, intubation may be difficult to achieve because of upper airway or facial edema. Standard rapid sequence induction (RSI) techniques can be used but may cause loss of the airway in a patient whose airway anatomy is altered by edema. Epinephrine may rapidly reverse airway compromise, and bag/valve/mask ventilation may be effective in the interim when intubation is not possible. Surgical airway intervention using standard cricothyrotomy is an option when orotracheal intubation or bag/valve/mask ventilation is not effective. Wheezing or stridor indicates bronchospasm or mucosal edema. Treatment with epinephrine and inhaled beta-agonists is effective for these indications. Recommendations to treat refractory bronchospasm with corticosteroids have been made because of their effectiveness in reactive airway disease. As in asthma therapy, onset of action is delayed for several hours. Aminophylline also has been recommended for bronchospasm in anaphylaxis and may be more rapidly effective than corticosteroids. Hypotension in anaphylaxis usually is due to vasodilatation and capillary fluid leakage. Epinephrine is the primary pharmacologic treatment for these findings. H1-blocking antihistamines also may have a role in reversing hypotension. Some authors also recommend H2-blocking agents. Large volume fluid resuscitation with isotonic crystalloid often is needed to support the circulation in patients with cardiovascular manifestations of anaphylaxis. Refractory hypotension first should be treated with large volumes of crystalloid and repeated doses of epinephrine or a continuous epinephrine infusion. If this is not effective, other pressors with alpha-adrenergic activity, such as levarterenol (Levophed) or dopamine, may be considered. Cases of effective use of military antishock trousers (MAST) for refractory hypotension have been reported. Mediators of anaphylaxis are not considered to have direct myocardial toxicity. In patients with preexisting heart disease, ischemic myocardial dysfunction may occur due to hypotension and hypoxia. Epinephrine still may be necessary in patients with severe anaphylaxis, but remember the potential for exacerbating ischemia. If pulmonary congestion or evidence of cardiac ischemia is present, fluid resuscitation should be approached more cautiously. Patients taking beta-blockers may be resistant to the effects of epinephrine. Larger than usual doses may be needed. Glucagon may be effective in this circumstance, because it increases intracellular cyclic adenosine monophosphate (cAMP) levels by a mechanism that does not depend upon beta-receptors. Cutaneous effects of anaphylaxis are uncomfortable but not life threatening. Patients often respond promptly to epinephrine and H1 antihistamines. Some authors state that corticosteroids help prevent recurrence of symptoms (both cutaneous and systemic) that may occur 6-8 hours after successful treatment (so-called biphasic reaction). H2 blockers may have an added effect. GI symptoms in anaphylaxis respond to H1 antihistamines and epinephrine. Consultations: Acute manifestations of anaphylaxis usually respond to ED treatment. In refractory cases, consult with an allergist, cardiologist, pulmonologist, or other intensivist. Consultation with an allergist (when available) is appropriate when desensitization to an antibiotic is contemplated. When a patient at high risk for contrast reaction is under consideration for a contrast study, consultation with the radiologist regarding pretreatment and choice of contrast agent is appropriate. Refer patients who are treated and released from the ED after an episode of anaphylaxis or generalized urticaria to their primary care physician or to an allergist for follow-up. At that time, consideration can be given to skin testing and possible desensitization. MEDICATION Primary drug treatments for acute anaphylactic reactions are epinephrine and H1 antihistamines. These agents clearly are effective; do not delay or defer their use in favor of other treatments. Inhaled beta-agonists lack some of the adverse effects of epinephrine. Inhaled beta-agonists are useful for cases of bronchospasm, but they may not have additional effects when optimal doses of parenteral epinephrine are used. Corticosteroids mainly are effective in preventing biphasic (ie, delayed) reactions. Due to this delayed effect, corticosteroids are not first-line treatments. H2-blocking antihistamines theoretically are attractive agents, but evidence supporting their clinical effectiveness is less than for H1-blocking agents. Glucagon may be useful in treating refractory cardiovascular effects in patients taking beta-blockers. Drug Category: Parenteral adrenergic agents -- Reverse cardiovascular, cutaneous, GI, and pulmonary manifestations of anaphylaxis. Drug Name Epinephrine (EpiPen, Adrenalin) -- DOC for shock, angioedema, airway obstruction, bronchospasm, and urticaria in severe anaphylactic reactions. Administered SC or IM, except for patients in extremis for whom it is administered IV. May be administered SL or via ET when no IV access available. Continuous infusion may be administered in cases of refractory shock. Adult Dose 0.3-0.5 mL 1:1000 soln SC or IM q15min 1 mL 1:10,000 soln (diluted in 10cc NS) IV; slow administration; repeat prn 0.3-0.5 mL 1:1000 soln SL q15min 1.0 mL 1:1000 soln ET in approximately 10 cc NS IV infusion: 0.1-1 mcg/kg/min Pediatric Dose 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln SC or IM q15min 0.01 mL/kg (minimum 0.1 mL) 1:10,000 soln IV prn 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln SL q15min 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln ET in approximately 1-3 cc NS IV infusion: 0.1-1.0 mcg/kg/min Contraindications May be administered in life-threatening anaphylactic reactions, even when the following relative contraindications are present: (1) coronary artery disease, (2) uncontrolled hypertension, (3) serious ventricular arrhythmias, and (4) second stage of labor Interactions Sympathomimetics cause additive effects; beta-blockers antagonize therapeutic effects of epinephrine; digitalis potentiates proarrhythmic effect of epinephrine; TCAs and MAOIs potentiate cardiovascular effects of epinephrine; phenothiazine causes a paradoxical decrease in BP Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adverse effects include cardiac ischemia or arrhythmias, fear, anxiety, tremor, and hypertension with subarachnoid hemorrhage; use with caution in elderly and in patients that have diabetes mellitus, hyperthyroidism, prostatic hypertrophy, hypertension, cardiovascular disease, and cerebrovascular insufficiency; rapid IV infusions also may cause death from cerebrovascular hemorrhage or cardiac arrhythmias Drug Category: Inhaled beta-agonists -- Used to treat bronchospasm. Doses are identical to those used in the treatment of asthma. Drug Name Albuterol (Proventil, Ventolin) -- Numerous inhaled beta-agonists are used for treatment of bronchospasm; albuterol is the most commonly used preparation. Adult Dose 0.5 mL 0.5% soln in 2.5 cc NS nebulized q15min Pediatric Dose 0.03-0.05 mL/kg 0.5% soln in 2.5 cc of NS via nebulizer q15min Contraindications In a life-threatening anaphylactic reaction, albuterol may be administered even in the presence of (1) severe coronary insufficiency or (2) uncontrolled, severe hypertension Significant effects are much less likely than with parenteral sympathomimetics Interactions Sympathomimetics cause additive effects; beta-blockers antagonize therapeutic effects; digitalis potentiates proarrhythmic effects; TCAs and MAOIs potentiate cardiovascular effects; phenothiazine causes a paradoxical decrease in BP Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Inhaled beta-agonists are relatively well-tolerated; beta 2-agonists, such as albuterol, have relatively few cardiovascular adverse effects when compared with agents that also have beta 1-agonist activity or with parenteral sympathomimetics Drug Category: H1-receptor blockers (Antihistamines) -- Primarily effective against cutaneous effects of anaphylaxis. Also may help antagonize cardiac and respiratory effects; should be used routinely in most cases of anaphylaxis. IV administration is preferable when a rapid effect is desired. IM dosing also is effective but has a slower onset than IV and may cause local tissue irritation. PO doses must be larger than parenteral doses because of 50% first-pass metabolism in the liver. Most recommendations for use of antihistamines state that they should be continued for 2-3 days after treatment of the acute anaphylactic event. Drug Name Diphenhydramine (Benadryl) -- Many effective H1 blockers exist; diphenhydramine is effective and widely available. Adult Dose 25-50 mg IV/IM q4-6h 50 mg PO q4-6h Pediatric Dose 1-2 mg/kg IV/IM q4-6h 2 mg/kg PO q4-6h Contraindications Documented hypersensitivity, MAOIs Interactions Potentiates effect of CNS depressants; due to alcohol content, do not give syrup dosage form to patient taking medications that can cause disulfiramlike reactions Pregnancy C - Safety for use during pregnancy has not been established. Precautions May exacerbate angle closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction Drug Category: H2-receptor blockers (Antihistamines) -- H2 blockers are used commonly by clinicians in treatment of allergic reactions and urticaria. Evidence of additive effect with H1-blocker anaphylaxis exists, but they should not be considered first-line therapy.Drug Name Cimetidine (Tagamet) -- Many H2 blockers are available. Cimetidine is the prototype drug; other agents have much less evidence of effectiveness in anaphylaxis. Adult Dose 300 mg PO/IV/IM q6h Pediatric Dose 5-10 mg/kg PO/IV/IM q6h Contraindications Documented hypersensitivity Interactions Multiple drug interactions are related to inhibition of hepatic microsomal enzymes; cimetidine is known to increase blood concentration of (1) warfarin, (2) benzodiazepines, (3) lidocaine, (4) TCAs, (5) terfenadine, (6) phenytoin, and (7) theophylline Pregnancy C - Safety for use during pregnancy has not been established. Precautions Cimetidine carries relatively few serious adverse effects, particularly when only short-term acute use is considered; in the acute setting consider important adverse effects to include (1) headache and confusion and (2) cardiac arrhythmias and hypotension from rapid IV administration Drug Category: Corticosteroids -- These agents have a role in reversing bronchospasm and cutaneous effects of anaphylaxis. Corticosteroids have a delayed onset of action and do not reverse the cardiovascular effects of anaphylaxis. These agents should be used in severe reactions, but the use of epinephrine and H1 antihistamines has a higher priority. Some authors state that corticosteroids help prevent or ameliorate recurrent (biphasic) anaphylaxis, but the true incidence of this condition has not been determined, and recurrences are usually less severe than the initial attack. While corticosteroids usually are administered IV in patients with anaphylaxis for presumed rapidity of effect, PO and IV corticosteroids are equally efficacious in asthma therapy. When administered acutely, corticosteroids commonly are continued for 2-3 days. In asthma treatment, large parenteral doses customarily are administered acutely, followed by lower PO dosing for varying periods. Long-acting parenteral preparations may be administered as an alternative and have been shown effective in asthma therapy. Optimal dosage range for corticosteroids has not been established; thus, a range of dosages is provided based on published recommendations.Drug Name Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol) -- A multitude of corticosteroid preparations are available. Methylprednisolone is widely available in the ED because of other uses (ie, acute asthma, spinal cord injury). Supplied in both parenteral and oral formulations. Discussed here as typical drug of this class. Adult Dose 40-250 mg IV/IM q6h 2-60 mg PO qd Pediatric Dose 1-2 mg/kg IV/IM q6h 1 mg/kg PO qd Contraindications Other than a previous severe reaction to the drug, there are no absolute contraindications to the use of corticosteroids for treatment of severe anaphylaxis Interactions The most important interactions in the acute setting are (1) ulcerogenesis with NSAIDs, (2) increased weakness in patients who have MyG with anticholinesterases, and (3) possible viral dissemination with live virus vaccines Pregnancy C - Safety for use during pregnancy has not been established. Precautions Short-term use of corticosteroids, even in large doses, has minimal harmful effects; multiple adverse effects from chronic usage; benefits and risks should be considered in pregnant females; patients who are immunosuppressed and are receiving corticosteroids are at risk for dissemination or activation of certain infections Drug Category: Antidote, Hypoglycemia -- Glucagon appears to benefit by stimulating the release of endogenous catecholamines.Drug Name Glucagon -- Has inotropic, chronotropic, and vasoactive effects that are independent of beta-receptors. Glucagon also causes endogenous catecholamine release. Patients taking beta-blocking agents may be resistant to effects of epinephrine or other adrenergic agents used to treat the cardiovascular effects of anaphylaxis. Glucagon may be effective in these patients. Should be used in addition to epinephrine, not as a substitute. Reports of effectiveness of glucagon in anaphylaxis are anecdotal; therefore, it is difficult to specify a dose. Smaller doses are effective in elevating blood sugar in patients with hypoglycemia, but larger doses have been recommended in beta-blocker overdose. Given parenterally. IV route is preferable, if available. Adult Dose 1-10 mg IV/IM/SC; typically 1-2 mg q5min to effect Pediatric Dose Not established; adult dose is approximately equivalent to 0.02 mg/kg Contraindications Documented hypersensitivity Interactions Effects of anticoagulants may be enhanced by glucagon (although onset may be delayed); monitor PT activity and for signs of bleeding in patients receiving anticoagulants; adjust dose accordingly Pregnancy C - Safety for use during pregnancy has not been established. Precautions Monitor blood glucose levels in hypoglycemic patients until they are asymptomatic; glucagon is effective in treating hypoglycemia only if sufficient liver glycogen is present; since liver glycogen availability is necessary to treat hypoglycemic patients, glucagon has virtually no effects on patients in states of starvation, adrenal insufficiency, or chronic hypoglycemia Further Inpatient Care: Most patients with anaphylaxis may be treated successfully in the ED and then discharged. Treatment success operationally may be defined as complete resolution of symptoms followed by a short period of observation. The purpose of observation is to monitor for recurrence of symptoms (ie, biphasic anaphylaxis). Hospital admission is required for patients who (1) fail to respond fully, (2) have a recurrent reaction or a secondary complication (eg, myocardial ischemia), (3) experience a significant injury from syncope, or (4) need intubation. As with many other conditions, consider a lower admission threshold when patients are at age extremes or when they have significant comorbid illness. The presenting manifestation(s) of anaphylaxis dictate inpatient care. Essentially, this care consists of continuing the care initiated in the ED. Consider ICU admission for patients with persistent hypotension. The primary means of support are adrenergic agents (eg, epinephrine, dopamine) and fluid resuscitation. Persistent hypotension in the face of pressors and fluid resuscitation is an indication for invasive hemodynamic monitoring with evaluation of cardiac function and peripheral vascular resistance. Use of these parameters provides the basis for objective decisions regarding the use of fluids and pressors. Inpatient management of airway compromise consists of continuation of parenteral and inhaled adrenergic agents and corticosteroids that were initiated in the ED. Cutaneous manifestations of anaphylaxis are treated with repeated doses of antihistamines. Further Outpatient Care: Discharged patients who have been successfully treated for anaphylaxis usually should continue antihistamines for 2-5 days to prevent recurrence. When corticosteroids have been used as part of the initial treatment, common practice continues that treatment for a short period. In/Out Patient Meds: Inpatient medications are identical to those listed for ED care (see Medication). Outpatient medications Outpatient medications primarily consist of oral forms of the medications used in ED treatment. Adrenergic medications are not listed in this chapter, as it is assumed that patients who require these on an on-going basis will be admitted. Consider patients who experience severe reactions to bites, stings, food, or other possibly unavoidable causes, as candidates for an epinephrine auto-injector prescription. These injectors may be packaged as kits that also contain an oral antihistamine. The following regimens are used commonly by clinicians, though very little hard data concerning the natural history of anaphylaxis treated in the ED exists. In light of this, do not construe the following as an unqualified recommendation or as a standard of care. Evidence for efficacy of H2-blocker antihistamines is particularly sparse. The newer nonsedating antihistamines have not been studied in the context of treatment for anaphylaxis. H1-blocker antihistamines Diphenhydramine (Benadryl) - Adults: 25mg PO q6h for 2-5d; Children: 1mg/kg PO q6h for 2-5d Hydroxyzine (Atarax) - Adults: 25mg PO q8h for 2-5d; Children: 1mg/kg PO q8h for 2-5d Corticosteroids Prednisone - Adults: 20-80 mg PO qd for 2-5d; Children: 1-2 mg/kg PO qd for 2-5d Many other glucocorticoid preparations may be used. H2-blocker antihistamines Cimetidine - 300 mg PO qid for 2-5d; Children: Not recommended Epinephrine auto-injectors prefilled syringes: A number of forms are available. Instructions for self-administration are included. Ana-Kit (Bayer): This product is a syringe with 0.3 cc 1:1000 epinephrine solution packaged with four 2-mg chewable chlorpheniramine tablets. The syringe has 0.1 cc gradations, allowing the injection of smaller doses for pediatric patients. EpiPen and EpiPen Jr. Auto-Injector (Center): This product is an auto-injecting syringe containing 0.3 cc 1:1000 epinephrine solution (EpiPen) or 0.3 cc 1:2000 solution (EpiPen Jr). Transfer: Requirements for treating a patient with anaphylaxis are likely to exist in most hospitals within the United States and Canada; therefore, transfer of patients with anaphylaxis would be a very unusual occurrence in these locations. Deterrence/Prevention: Preventive therapy for anaphylaxis depends on identification of the inciting agent. When the agent has been identified, the key to prevention is avoidance. Certain prophylactic or preventative therapies may be employed when re-exposure cannot be avoided. When the inciting agent is not obviously known from the history, allergy testing may help identify it. When the allergen is a therapeutic agent for which subsequent usage is medically necessary, desensitization or pretreatment protocols may be employed. Desensitization therapy for reactions to Hymenoptera venom is partially effective in preventing or ameliorating subsequent severe reactions. At minimum, patients discharged from the ED after a severe reaction to Hymenoptera venom should be informed of the availability of this treatment. Referral to the patient's primary care source or directly to an allergist also may be appropriate. Complications: Complications from anaphylaxis are rare, and most patients completely recover.

"Race," Duly noted, I agree that may be a factor...so what do you suggest...???? Also, why not post your vote/response and then that would at least or give others a general idea of where you stand... Also, is there a way to modify an existing poll while it's in progress?? I only ask as I don't have that kind of IT know how... out here, Ace844

Come on guys.....This post was viewed over 900+ X's and there was ONLY 19 VOTES!!!???? Let's increase the sample abit and see if in our own little group of "working" providers if we as a "group" actually feel whether this and other "professional advancement type topics" are worthy of our time and attention or not.....

Hello Everyone, An example may be one similar to this one here...:: Teaching Points::::CHF. Rid also has one up from awhile back and a few others as well...I will look for the links and post them as well.... out here, Ace844

Come on guys.....This post was viewed over 200+ X's and there was ONLY 9 VOTES!!!???? Let's increase the sample abit and see if in our own little group of "working" providers if we as a "group" actually feel whether this and other "professional advancement type topics" are worthy of our time and attention or not.....

Come on guys.....This post was viewed over 1,000 X's and there was ONLY 33 VOTES!!!???? :roll: :!: Let's increase the sample abit and see if in our own little group of "working" providers if we as a "group" actually resemble the #'s or not.....

"akroeze@ others," The reason I made this a seperate thread, albeit somewhat loosely related to others is for the following reasons. A.) In order to stop a thread discussing one area of complex and interrelated topics from being brought "off topic", hijacked, or otherwise easily locked... B.) To confirm some suspicions/opinions, and to try to create open productive discussion on this topic. C.) To try to stimulate discussion on a variety of topics, some related, others not so much.... D.) To try to bring about more group awareness as to "industry-peer opinions" on different areas of our profession. E.) As I had started another poll which is closely related to this, and I have no idea how to conduct 2 simultaneous polls in the same thread which are related....So thus another poll/discussion thread. I'm not sure about biased (i.e.: meaning your reference to the fact I may be prejudice against certain ideas..opinions??) as to what you were referring..?? Hope this helps, Ace844

Hi All, do you think there is a definative recognition of the fact that a large part of your profession causes you to improvise, think, and actually learn/know abit about medicine?!??! Or are you of the opinion that ..."Nah, EMS is just monkey see monkey do!!!" out here, Ace844

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

Welcome to EMTCITY!!

Hi All, I and a few others here have now and in the past posted soem "teaching posts". The response has been varied. So I decided to make a poll and see whether you all want more, have any interest,etc... or want to let it die..??? Out here, Ace844

Hi All, Here's a link with soem good clinical info./RX of CHF from here::: Chest pain and breathing difficulty hope this helps, Ace844

There was a thread either here or on the old board in which we covered this here..just do a search...Also, the fact that they gave a new building and alot of "donations" to AHA had alot to do with it...!! out here, Ace844

Hi All, In short every call, and situation is different and dictates different approaches, there is no hard and fast concrete "SOP' or "rule" which can dictate what cations you take on a scene..period.. out here, Ace844

Please check and read the following links, they will more than set you on the path of what you are looking for... Position Statement on the Use of Amiodarone in Refractory Pulseless VT/VF Amiodarone for Resuscitation after Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation Amiodarone vs. Lidocaine Amiodarone in Cardiac Arrest: Barely ALIVE and Kicking? Clinical Trials Amiodarone for Resuscitation after Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation N. Engl. J. Med, 1999; 341: 871-878 , OPTIONS FOR CARDIAC ARRHYTHMIAS:, Journal of Pre-hospital Emergency care…:: AMIODARONE AND RURAL EMERGENCY MEDICAL SERVICES CARDIAC ARREST PATIENTS: A COST ANALYSIS PREHOSPITAL MANAGEMENT OF CARDIAC ARREST: HOW USEFUL ARE VASOPRESSOR AND ANTIARRHYTHMIC DRUGS There are more, and i suggest that you also search the JCCM, etc.. journal sites, the links are posted on the boards here..just do a search. Hope this helps, Ace844

I agree and I kind of thought it was weird that after I posted this, there were little to few replies. Which I thought was interesting with all of the trauma "junkies/dogs" we have on the board here. I guess I was on abit of a teaching post kick for awhile. I'm still interested to hear from everyone on this topic and the others.... Thanks, Out here, Ace844