Recent progress in advanced cardiac life support

FOCUSED REVIEW: CARDIAC MANAGEMENT

Recent Progress in Advanced Cardiac Life Support David J. Dries, MSE,

MD 1

1. Regions Hospital, University of Minnesota, St. Paul, Minn. Address for correspondence and reprints: David J. Dries, MSE, MD, Regions Hospital, University of Minnesota, 640 Jackson St., St. Paul, MN 55101-2595 Copyright © 2000 by Air Medical Journal Associates 1067-991X/2000/$8.00 + 0 Reprint no. 74/1/106436

Abstract

The revised guidelines for advanced cardiac life support (ACLS) from the American Heart Association are anticipated in the fall of 20001 Although dramatic changes in the approach to adult basic and ACLS are not anticipated, several controversies and new drugs on the horizon may radically change our approach to emergent cardiac resuscitation. This article features some of the evolving thinking on the emergent treatment of the adult with ventricular fibrillationor ventriculartachycardia, the critical rhythms seen in most cases of acute cardiac distress. Approaches to airway therapy drug administration and new agents also are described.

Overview

Adult cardiopulmonary resuscitation (CPR) is an area in which cardiac arrhythmias are compounded by hypoxemia and neuroendocrine derangement. Despite a variety of advances in CPR techniques, public education, and emerg e n c y cardiac care, s u d d e n cardiac death in the "field" from life-threatening a r r h y t h m i a s affects approximately 125,000 people in the United States each year.: The primary electrical conduction disturbance seen in the prehospital cardiac arrest patient is either ventricular tachycardia or ventricutar fibrillation. Despite initiation of ACLS measures i/l the field, only one in three prehospital cardiac arrest victims will reach the hospital alive, and only 3% to 13% of these patients will survive to be discharged from the hospital. ~ Early defibrillation remains the cru38

cial intervention for successfully resuscitaring ventricular tachycardia or ventricular fibrillation. Defibrillation has diminishing value if return to spontaneous circulation fails to occur after the first or second electrical countershock. Resuscitation measures introduced after the first three defibrillation attempts are unlikely to produce return to spontaneous circulation. However, administering antiarrhythmic agents before the third or fourth electrical countershocks may improve the outcome of patients with refractory ventricular tachycardia or ventricular fibrillation. M u c h r e c e n t attention has been directed toward the role of antiarrhythmic agents in acute resuscitation of patients with cardiac arrest as a result of ventricular fibrillation) Interventions

Defibrillation In adults, the most common primary arrhythmia at the onset of cardiac arrest

is ventricular fibrillation or pulseless ventricular tachycardia. 4 The overwhelming majority of eventual survivors come from this group. 5'6 If definitive therapy for these arrhythmias--defibrillation--can be implemented promptly, a perfusing cardiac rhythm may be restored, leading to long-term survival. The only intervention that has been shown to improve long-term survival unequivocally is basic life support (BLS) with defibrillation. Ventricular fibrillation is a readily treatable rhythm, but the chances of successful defibrillation decline with the passage of each minute after onset. AmpliApril-June 2000

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tude and waveform of ventricular fibrillation deteriorate rapidly, reflecting the depletion of myocardial energy stores. The rate of decline in success with defibrillation depends in part on the provision and adequacy of BIN. At best, BIN will maintain cardiac output at one-third to onequarter its previous level. As a result, the priority is to minimize any delay between the onset of cardiac arrest and the administration of defibrillating shocks. TM A variety of defibrillating devices have been developed recently. Most transthoracic defibrillation devices use a damped sinusoidal waveform pattern. Other techniques, including biphasic waveforms or sequentially overlapping shocks, may produce a rapidly shifting electrical vector during a multipulse shock and reduce the energy requirements for successful defibrillation. 9'1°Automated defibrillators that can deliver a current-based shock appropriate to the measured transthoracic impedance also are available and under evaluation. These devices may increase the efficacy of individual shocks while reducing myocardial injury in patients with unusually high or low transthoracic impedance) 1 The use of a group of three shocks will be retained in the coming revisions of adult cardiac life support algorithms. The European Resuscitation Council (ERC) recommends that initial sequence energies be 200 J, 200 J, and 360 j.7 This sequence is consistent with use of biphasic defibrillators in European resuscitation. Whether the American Heart Association (AHA) will follow suit and retain a second defibrillation shock at 200 J remains unclear, but the retention of monophasic defibrillation waveforms in the United States makes continued use of stairstep increases in defibrillation energy likely. Subsequent shocks, if required, should have energies of 360 J. If coordinated rhythm has occurred for a limited interval, no scientific basis exists for deciding whether to revert to 200 J or continue at 360 J with cardiac shocks. Although some evidence indicates that myocardial injury is greater with increasing energy utilization, comparative success rates are unavailable for defibrillation attempts for recurrent ventricular fibrillation or pulseless ventricular tachycardia after an interval of a coorAir Medical Journal

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dinated rhythm for 200 J versus 360 J. Either strategy may be acceptable. Finally, guidelines for optimal lead placement to facilitate effective delivery of defibrillation shocks have been developedf

Airway While recognizing that tracheal intubation remains the optimal procedure for airway control, recent ERC guidelines acknowledge that, in the setting of adult ACLS, orotracheal intubation may be difficult and sometimes hazardous. The laryngeal mask airway offers an alternative to tracheal intubation, and although it does not guarantee absolutely against aspiration, the incidence is low in series reported to date. The pharyngotracheal lumen airway and the esophageal/tracheal Combitube may be alternatives, but they require more training and have specific use problemsJTM Lung characteristics change during cardiac arrest and CPR with increased dead space and reduced compliance with the development of pulmonary edema. The primary objective in cardiac resuscitation is oxygenation. Oxygen should be supplied at a concentration of 1.0.7'15Carbon dioxide production and delivery to the lungs is limited during the initial period of cardiac arrest. Tidal volumes should be adequate, however, to facilitate carbon dioxide elimination and prevent the potential development of hypercarbic acidosis after the administration of carbon dioxide-producing buffers, such as sodium bicarbonate.

Drug Delivery Venous administration remains the optimal method of drug delivery during CPR. Central venous catheters rapidly deliver agents to the central circulation. If a central catheter is not present, the risks associated with this technique (which themselves can be life-threatening) mean that the decision for peripheral versus central cannulation will depend on the skill of the operator, the nature of the surrounding events, and available equipment. Central venous cannulation, if attempted, must not delay defibrillation attempts, CPR, or airway stability. If peripheral venous cannulation and drug delivery are carried out, a flush of 20 mL of 0.9% saline is recom-

mended to expedite entry of drugs into the circulation. 7 Keats, garsan, and coworkers 16'17 demonstrated that peak drug concentrations and biologic effects of epinephrine and lidocaine were greater after administration directly into the central circulation. Studies on drug administration during CPR show little difference among peripheral intravenous, intrapulmonary, or intracardiac administration. 18Supradiaphragmatic central venous drug administration is preferred to other central routes with closed chest compression,as It is important to reemphasize the value of bolus injections of 20 mL of saline to enhance the circulation time and peak levels of drugs administered into the peripheral circulation during cardiac arrest. As reviewed by Gonzales, the drug administration route does not appear to affect overall bioavailability during closed chest compression. Gonzales suggests that this indication likely is a result of impaired biotransformation and delayed renal elimination of drugs in cardiac arrest) 9'2° Epinephrine, atropine, lidocaine, naloxone, bretylium, propranolol, and isoproterenol may be given endotracheally during resuscitation if intravenous access cannot rapidly be securedY 2 Animal studies suggest that endotracheal administration of epinephrine affects heart rate and blood pressure similarly to intravenous epinephrine. Endotracheal administration of epinephrine in humans produces a lower and slightly delayed peak plasma concentration but more sustained physiological response. Gonzales suggests this response may be caused by epinephrine trapped in the lungs because of local vasoconstriction. Pharmacokinefic data regarding administration of atropine through the lung are scarce? It is important to dilute drugs to ensure optimal pharmacologic response when the endotracheal route is usedY Sterile water and normal saline have been evaluated as diluents in this setting. A study of the effects of endotracheal sterile water and normal saline on arterial blood gases in dogs found that endotracheal administration of normal saline produces fewer detrimental effects on the arterial blood gas than sterile water. 39

Interestingly, a subsequent clinical study produced a contradictory view.~'2~ Optimal doses of medication during endotracheal drug administration continue to be unclear. Epinephrine doses as high as 10 times the intravenous quantity are necessary to duplicate hemodynamic effects when this drug is given through the endotracheal tube. Current reviews continue to recommend an increase of 2.5 times the intravenous dose when a medication is given through the endotracheal tube? 6'27 As noted in a review by Gonzalez, proper drug administration technique is critical to optimize drug absorption when the endotracheal tube is used. Medication should be diluted into 20 mL of normal saline or sterile water to permit distribution over the largest possible surface area. Ideally, the diluted medication should be injected through a catheter or tube extending beyond the end of the endotracheal tube and should be followed by forceful lung inflations to enhance bioavallability. Temporary interruption of cardiac compressions during endotracheal administration may reduce reflux of instilled medications up the endotracheal tube? Various drug delivery routes have been studied infrequently during CPR in humans. When Kuhn and associates 28 evaluated the concentrations of indocyanine green in the arterial circulation after central venous administration, a peak was noted at 30 seconds, and recirculation time was 3 minutes in patients with refractory cardiac arrest. Time to peak dye concentration and recirculation was 90 seconds and greater than 4 minutes, respectively, after peripheral venous administration of indocyanine green. Another interesting study compared peripheral venous and endotracheal delivery of epinephrine in cardiac arrest victims. Plasma epinephrine concentration increased threefold after peripheral venous administration; peak levels were delayed more than 5 minutes after peripheral venous administration. No change in plasma epinephrine concentration was observed after endotracheal drug administration. Poor technique or pulmonary congestion may have compromised drug availability in this studyJ '29

40

Drug T h e r a p y

Epinephrine In animal studies, epinephrine improves myocardial and cerebral blood flow and resuscitation rates, and higher doses may be more effective than the standard dose of 1 mg. However, no clinical evidence suggests that epinephrine improves survival or neurologic recovery in humans regardless of whether standard or high doses are used. In fact, recent clinical trials report increased rates of spontaneous circulation with high dose epinephrine but no improvement in overall survival. 7'3°Reasons for these findings are unclear. Possible explanations include differences in underlying pathology between laboratory and out-of-hospital clinical settings and the possibility that high-dose epinephrine may be detrimental in the postresuscitation periodY 2 Despite the lack of consistent data supporting the use of epinephrine in adult cardiac resuscitation, this drug will maintain its position as a mainstay in resuscitation of ventricular fibrillation and pulseless ventricular tachycardia pending further randomized, prospective, placebo-controlled trials to better define the indications, dosage, and time interval between doses for epinephrinef For reasons discussed below, an intriguing possibility is the use of nonadrenergic vasopressors in cardiac resuscitation. At present, evidence with regard to other adrenergic and nonadrenergic agents is limited. Perhaps the most significant work questioning the efficacy of ACLS medication administration programs comes from the Ontario Trial of Active Compression-Decompression Cardiopulmonary Resuscitation?~In this study, the time of medication administration, confounding factors, and resuscitation outcomes were carefully recorded and evaluated. The objective of this analysis was to determine whether ACLS medications administered during inhospital cardiac arrest could be demonstrated to provide successful cardiac resuscitation. To carry out this objective, a secondary analysis was performed of all inhospital cardiac arrests entered into a multicenter, randomized, controlled clinical trial. In all, 1784 inhospital and prehospital patients experiencing cardiac ar-

rest were evaluated in the parent trial of active compression/decompression in BLSJ4 No improvement in survival with active compression/decompression BLS was found. Because all other resuscitation aspects followed the standard protocols recommended by the AHA, this secondary evaluation was deemed appropriate. Association of the administration of ACLS drugs--including epinephrine, atropine, bicarbonate, calcium, lidocaine, and bretylium--was compared with survival at 1 hour after resuscitation. A total of 773 patients underwent cardiac resuscitation; 269 (34.8%) survived for 1 hour. The use of epinephrine, atropine, bicarbonate, calcium, and lidocaine was associated with a decreased chance of successful resuscitation? 3 While controlling for significant patient factors (age, gender, previous cardiac or respiratory disease) and arrest factors (initial cardiac rhythm and cause of arrest), multivariate logistic regression demonstrated a significant association between unsuccessful resuscitation and these drugs. Drug effects did not improve when patients were grouped by initial cardiac rhythm. In conclusion, van Walraven and associates called for randomized clinical trials to determine whether other therapies may improve resuscitation from cardiac arrest compared with current ACLS drugs.

Antiarrhythmic Agents Therapy for cardiac arrhythmias often involves administration of antiarrhythmic agents. The appropriate first-line antiarrhythmic agent during acute cardiac resuscitation remains controversial. Lidocaine has been effective for patients with acute myocardial infarction and electrical instability but has not improved survival during adult acute cardiac resuscitation? '33The use of lidocaine was evaluated in patients with prehospital refractory ventricular fibrillation who were randomly assigned to receive either conventional ACLS without lidocaine or conventional care with lidocaine. Lidocaine failed to improve survival to hospital admission or discharge. 35 Bretylinm may be beneficial for treating patients in cardiac arrest because it raises the threshold for ventricular fibrillation, but no published data show that April-June 2000 19:2 Air Medical Journal

bretylium is superior to placebo in the setting of cardiac arrest. 3 Furthermore, bretylium and lidocaine have little difference in terms of conversion to normal sinus rhythm or overall patient survival. Lidocaine sometimes is considered the agent of choice in patients with ventricular tachycardia or ventricular fibrillation because it is less likely to produce hypotension than bretylium during bolus administration. Ironically, a lack of available bretylium will reduce its utility in American hospitals more than current clinical outcome data. Increased emphasis on procainamide is anticipated for patients with monomorphic ventricular tachycardia, particularly before the pulse is lost. In the past, procainamide clearly has been shown to prolong the ventricle's refractory period and slow or terminate ventricular tachycardia. However, the use of lidocaine to treat ventricular tachycardia has been based mainly on its observed efficacy to prevent ventricular fibrillation during acute ischemia.3~'37Recent data from Gorgels and associates38 suggests that procainamide is more effective than lidocaine to terminate spontaneously occurring monomorphic ventricular tachycardia and should be the drug of choice over lidocaine and adenosine in wide complex tachycardia of uncertain etiology. Procainamide and lidocaine efficacy in terminating spontaneous monomorphic ventricular tachycardia was assessed by Gorgels and coworkers in a randomized parallel study. This work excluded patients with acute myocardial infarction and those with poor hemodynamic tolerance of ventricular tachycardia. Procainamide (10 mg/kg) was given intravenously with an injection speed of 100 mg/min, and lidocaine was administered at an intravenous dose of 1.5 mg/kg in 2 minutes. Patients were randornized to lidocaine or procainamide as initial therapy. Termination occurred in 80% of patients receiving procainamide as opposed to 21% of patients receiving lidocaine. In addition, procainamide stopped eight of 11 patients with ventrieular tachycardia, which did not respond to lidocaine. Because of recurrence of ventricnlar tachycardia, 16 patients could be studied repeatedly with drugs given in the reAir Medical Journal

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versed order. In all, lidocaine terminated six of 31 episodes of ventricular tachycardia and procainamide 38 of 48 episodes. In only four cases was the protocol stopped because of adverse drug effects. Comparison of QRS width and QT intervals before and after injection revealed significant lengthening of these values with procainamide administration compared with lidocaine. Nonetheless, procainamide appears to be superior to lidocaine in the patient with spontaneously occurring monomorphic ventricular tachycardia?8 Since its introduction as a clinical antiarrhythmic agent in 1951, procainamide has proved effective and safe against ventricular arrhythmias when administered intramuscularly and orally. ~9Clinical use of intravenous procainamide for urgent ventricular arrhythmias has been unpopular because of reports of hypotension, altered heart rate and ECG intervals, drug-induced arrhythmias, and fatalities. Intravenous infusion at rates faster than 100 mg/min have been associated with vascular collapse, and even lower infusion rates have been associated with signs warranting drug cessation. In an important report, Giardina, Heissenbuttel, and Bigge? ° describe an effective use of intravenous procainamide by injecting 100 mg every 5 minutes until a cardiac arrhythmia was abolished without observing significant untoward drug effects. These authors suggest that such an administration method for procainamide in the setting of urgent ventricular arrhythmias may achieve antiarrhythmic drug concentrations rapidly, safely, and predictably. Giardina and colleagues report on 20 patients receiving 100 mg of procainamide intravenously every 5 minutes until a cardiac arrhythmia was abolished, 1 gm of drug was given, or untoward drug effects appeared. Only one patient did not respond. In 17 individuals, the desired arrhythmia was abolished. Therapy in this group of patients was never interrupted because of a drug-induced hypotension, atrial ventricular or intraventricular conduction disturbance, or arrhythmia. A strong linear correlation was found between plasma procainamide concentration and cumulative dose. A second important study describing

procainamide administration, plasma concentration, and clinical effects comes from Koch-Weser and Klein, 41 who examined the relationship of procainamide dosage to plasma concentration among 186 patients. They noted wide variation in this group resulting from individual differences in completeness of absorption, distribution space, and elimination rate. They noted that plasma concentration correlated well with therapeutic and toxic effects. Effective antiarrhythmic concentration was noted to be 4 to 8 m g / L . Toxic manifestations of procainamide were rare with concentrations less than 12 m g / L but common with concentrations greater than 16 mg/L. The authors suggest that administering procainamide in a daily dose of 50 m g / k g produces therapeutic plasma concentrations. To prevent fluctuations of plasma level exceeding 50%, 3-hour dosing intervais may be required. Where intravenous infusion of procainamide was required, the authors noted that rates allowing adequate distribution of drug to occur (50 rag/rain) carried no special risk. In patients with ongoing cardiac or renal failure or when usual doses failed or toxic manifestations appeared, plasma levels were useful guides to dosage. Data from recent arrhythmia trials more clearly define the risks and benefits of anfiarrhythmic drug therapy and the value of these agents to prevent sudden cardiac death. Amiodarone has gained increased popularity in a variety of clinical settings because of its diverse antiarrhythmic activity. Amiodarone's efficacy and tolerability for treatment of recurrent and refractory ventricular tachycardia and ventricular fibrillation have been demonstrated in clinical trials and case reports. 4244The agent has not been shown to increase mortality in any population study to date. Meta-analysis of patients with heart failure or recent myocardial infarction show that amiodarone was associated with a 13% reduction in mortality. The drug was associated with a larger proportional reduction in antiarrhythmic sudden death but no reduction in deaths from other cardiovascular causes. 4~ Intravenous amiodarone is effective against a wide range of arrhythmias in several patient populations, in41

cluding victims of cardiac arrest. Kudenchuck 46 evaluated the efficacy of intravenous amiodarone in more than 500 patients experiencing out-of-hospital pulseless ventricular tachycardia or ventricular fibrillation refractory to three initial countershocks. After CPR was initiated and an airway and IV access w e r e established, patients received epinephrine (1 rag) and, immediately afterward, IV amiodarone (300 mg IV push) or placebo in random fashion. Conventional ACLS followed. The primary endpoint was survival to hospital admission. Secondary endpoints included number of shocks after study drug, treatment after study drug, time to first shock, and patient status at hospital discharge. Intravenous amiodarone improved survival to hospital admission by 26% compared with placebo. For those patients in whom normal sinus rhythm was restored but not maintained by electrical countershock, amiodarone improved survival to the hospital by 56%.The need for additional antiarrhythmic drugs and the time to first shock did not differ significantly between amiodarone and placebotreated patients. Survival to hospital discharge and neurologic recovery were not evaluated because of small sample size. Later review of study data demonstrated no difference in hospital discharge rates. This important study suggests that intravenous amiodarone is more effective than placebo at improving survival to hospital admission in patients with out-ofhospital cardiac arrest characterized by ventricular tachycardia or ventricular fibrillation. Use of amiodarone versus lidocaine is being studied in patients with prehospital refractory ventricular fibrillation. As before, projected endpoints in the study are restoration of spontaneous circulation and survival to the hospital. Use of amiodarone in the universal resuscitation algorithm as a Class IIa agent is anticipated as the ACLS guidelines are reviewed and revised. Figure i illustrates the treatment sequence for life-threatening arrhythmias. Horizons Amiodarone

Gonzalez discusses the unique place of amiodarone among antiarrhythmic drugs in a recent commentary using the 42

Vaughan-Williams classification as a conceptual framework for understanding the clinical electrophysiologic properties of antiarrhythmic agents and their useJ 7'4sClass I agents are sodium channel blockers that reduce the maximum rate of action potential depolarization and thereby slow conduction. Class I antiarrhythmic agents are divided further into subclasses based on the extent of sodium channel blockade and additional changes in ventricuiar repolarization. Class I agents are very effective in suppressing ventricular ectopic beats, but they all have been associated with proarrhythmic effects. Beta-adrenergic blockers (propranolol, metoprolol, and atenolol) are Class II agents that raise the threshold for ventricular fibrillation and may prevent its occurrence. Class II agents generally are well tolerated but depress left ventricular function, particularly at higher doses. Class III agents (amiodarone and sotalol) produce potassium channel blockade and subsequently increase the duration of action potential. Because Class III agents reduce ventricular automaticity but do not decrease intraventricular conduction velocity, they a r e rarely proarrhythmic. Calcium channel blockers are Class IV agents in the Vanghan-Williams classification system. Two of these agents, verapamil and diltiazem, influence atrioventricular nodal electrophysiology and may alter the electrophysiologic properties of calcium-dependent channels during i s c h e m i a . 47'48 Amiodarone reduces membrane excitability and facilitates termination of sustained ventricular tachycardia or ventricular fibrillation by prolonging the action potential duration and retarding the refractory period of the myocardial electrical conduction system. Unlike most other Class III drugs, amiodarone also prolongs repolarization time at higher heart rates. This increase in the action potential and refractoriness creates homogeneous conditions of repolarization throughout the heart and gives amiodarone its antifibrillatory properties. Unlike studies with other agents, animal work suggests that intravenous amiodarone reduces the energy requirements for successful defibrillation. 49'5°

~ii ~ ;:i :, ~,~

lib Medications (given in sequence) Lidocaine Bretylium Magnesium sulfate Procainamide Sodium bicarbonate

~KudenchukP, Cobb LA, Copass MK, et aL Am,~arone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrilla¢ioh, N Engl J Med I999;341:871-8.

',Modified from @onzatez ER, Kannewuff BS. prnato dR, Intravenous amiodarone for ven#icular arrh~hmias: overView and clinical use,

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Although primarily a Class III antiarrhythmic agent, amiodarone possesses eleetrophysiological characteristics of the other three Vaughan-Williams classes. Amiodarone blocks sodium channels at rapid pacing frequencies, similar to Class I agents, with reduced membrane depolarization and impulse conduction rates. Similar to Class II agents, amiodarone possesses noncompetitive antisympathetic action that indirectly affects the myocardium's electrophysiological characteristics. The chronotropic effect of amiodarone in nodal tissue is similar to that of Class IV Vaughan-Williams agents. Intravenous amiodarone prolongs infranodal conduction but has little effect on the sinus cycle length, intraventricular conduction, or infranodal conduction. "~ Among amiodarone's hemodynamic effects are coronary artery dilatation and increased coronary blood supply as a result of direct effects on smooth muscle and calcium channel and alpha-adrenergic blocking properties. Amiodarone also causes peripheral arterial vasodilation and decreases systemic vascular resistance. A beneficial hemodynamic impact has been noted in patients with impaired left ventricular function. ~1Importantly, and unlike many other antiarrhythmic agents, amiodarone does not demonstrate significant arrhythmogenesis. The overall incidence of adverse rhythm changes is less than 2%. Amiodarone has been used safely as an alternative agent in patients who have developed torsades de pointes previously with Class Ia agents. 52 Other manifestations of cardiovascular toxicity may include the overexpression of the drug's normal electrophysiological actions, including sinus bradycardia, conduction abnormalities in the A-V node, and heart block. Patients with pre-existing sinus node or conduction system abnormalities should be given amiodarone cautiously. Amioda-rone should not be given to patients with profound sinus bradycardia or second or third degree atrial ventricular block without the availability of external pacing. Amiodarone has a relatively mild negative inotropic effect, but it does not precipitate or exacerbate heart failure in most patients. Hypotension has been obAir Medical Journal

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served in some individuals receiving amiodarone intravenously. In this association, hypotension depends more on the rate of drug administration than the total amount given. A decrease in the infusion rate usually is all that is required to reverse amiodarone-induced hypotension. Amiodarone has been used successfully in patients with cardiogenic shock or hypotension. 5~5~ Adverse consequences with acute administration of intravenous amiodarone have been reported. ~2Sinus arrest and impaired left ventricular function in small groups of patients are among the adverse consequences reported. Hypotension requiring pressor agents was noted along with the requirement for temporary pacing in small groups of indMduals treated for recurrent ventricular tachycardia. Reports of amiodarone toxicity also involve other organ systems. Although the mechanism of toxicity is multifactorial, most side effects occur after weeks or months of therapy. A relatively small percentage (10% to 15%) of patients on chronic treatment with amiodarone requires withdrawal because of serious or life-threatening toxicity. Adverse events rarely, if ever, are experienced with short-term use of intravenous amiodarone for treatment of life-threatening arrhythmias.

Glucose Controversy Five percent dextrose in water is a common vehicle for intravenous drug delivery during CPR.3Administering glucose during CPR is controversial because of the potentially detrimental effects of hyperglycemia on neuronal function during periods of ischemia. The glucose controversy began in 1977 when Myers 36 noted that animals treated with fluids containing dextrose before cardiac arrest suffered neurologic damage and death shortly after resuscitation. This study concluded that exogenous glucose administration during ischemia impaired neuronal function. The mechanism linking hyperglycemia to poor neurologic outcome may be related to the interaction between hyperglycemia and lactic acidosis. During periods of ischemia, a hyperglycemic milieu increases lactic acid production through anaerobic metabolism. The resultant

acidosis may worsen neuronal injury. D'Alecy~7studied the effect of 5% dextrose administration on neurologic outcome after cardiac arrest in dogs. Each animal first was given 500 mL of either lactated Ringers solution or 5% dextrose in lactated Ringers. Blood glucose measured just before cardiac arrest was 129 mg/dL and 335 mg/dL in the lactated Ringers and dextrose/lactated Ringers groups, respectively. After 8 minutes of fibrillatory arrest, all six lactated Ringerstreated dogs and five of six dextrose/lactated Ringers dogs were resuscitated successfully. Two hours after resuscitation and thereafter, dogs receiving the dextrose/lactated Ringers solution experienced significantly greater neurologic deficits. D'Alecy concluded that the addition of 5% dextrose significantly increased the morbidity and mortality associated with CPR. Other studies in animals suggest that the administration of glucose during cardiac arrest increases the requirements for inotropic support, worsens neurologic outcome, and increases the mortality rate? Data for the glucose controversy in humans are inconclusive. Evidence exists that clinical outcome after cerebral ischemia is worsened by hyperglycemia in humans. Patients with cerebral ischemia and previous hyperglycemia have greater neurologic deficits when compared with euglycemic patients experiencing stroke? In a study of 430 outof-hospital cardiac arrest victims, Longstreth and Inui58conducted a retrospective study comparing blood glucose and neurologic outcome. After controlling for confounding variables, these investigators observed that the blood glucose level on admission was significantly related to neurologic outcome in patients receiving glucose-containing fluids during out-of-hospital cardiac arrest. Furthermore, blood glucose rose as a function of prolonged resuscitation time. Longstreth suggests that hyperglycemia was more likely a marker for prolonged resuscitation, which in turn produces neurologic deficits, and that hyperglycemia ultimately may not affect neurologic outcomef'5~ The clinical significance of these studies is unclear. Hyperglycemia in patients 43

with poor neurologic outcome may reflect prolonged and difficult resuscitation rather than exogenous glucose administration. Martin 6° studied insulin and glucose concentrations in a canine model of closed-chest CPR, and this study suggests that cardiac arrest impairs glucose utilization as suggested by a decrease in insulin levels and subsequent hyperglycemia. Mean serum insulin values during CPR were significantly reduced compared with prearrest levels. Glucose-containing fluids are commonly used during CPR as a vehicle for drug delivery and as a bolus to treat possible hypoglycemia in an unconscious victim. Data are inconclusive regarding the effects of glucose levels on neurologic outcome after CPR. Animal studies suggest hyperglycemia worsens neurologic recovery after cerebral ischemia. Hyperglycemia, however, may be only a marker for prolonged resuscitation with subsequent impairment in insulin release. Low levels of insulin during CPR may compromise myocardial glucose utilization. Until additional information is available, supplemental administration of glucose optimally is reserved for the patient with documented hypoglycemia}

Nonadrenergic Vasopressors Because of the dismal outcome for

most victims of cardiac arrest, the fundamental endocrinologic responses to cardiac arrest and CPR have been investigated. Lindner and coworkers 61'62reported that circulating endogenous vasopressin concentrations were high in patients with cardiac arrest undergoing CPR and that levels were significantly higher in patients who were successfully resuscitated than in nonresuscitated patients. These researchers suggested that endogenously released vasopressin may be a crucial factor enhancing the pressor response to endogenously released epinephrine, norepinephrine, angiotensin II, and endothelin. More recent work from Lindner and colleagues 63 in Ulm, Germany, in a pig model of ventricular fibrillation revealed that administering exogenous vasopressin during open-chest CPR significantly improved blood flow to vital organs. A subsequent study was performed to compare the effects of epinephrine 44

with those of vasopressin on vital organ blood flow during closed-chest CPR in a pig model of ventricular fibrillation. This study was a randomized comparison in which 28 pigs received standard doses of epinephrine therapy versus low, medium, and high dose vasopressin. 64 Ventricular myocardial blood flow, coronary systolic perfusion pressure, coronary diastolic perfusion pressure, and cerebral blood flow were significantly increased with increasing doses of vasopressin in comparison with standard (optimal) epinephrine therapy. In addition to higher perfusion pressure and improved vital organ blood flow, vasopressin's effects lasted longer than epinephrine's. For example, 5 minutes after epinephrine administration, left ventricular and total cerebral blood flow were only 29% and 22% greater than baseline, respectively. In contrast, 5 minutes after high dose vasopressin, left ventricular and total cerebral perfusion were 217% and 111% greater than baseline, respectively. Animals in this study were followed during a 1-hour postresuscitation phase during which no adverse side effects of vasopressin on cardiac index or gas exchange were observed.~ Lindner and colleagues 65 subsequently performed a series of clinical resuscitation efforts using vasopressin on patients with refractory cardiac arrest in the hospital setting. In a summary of these case reports, eight adults with inhospital cardiac arrest were described. After intravenous epinephrine administered according to AHA guidelines and defibrillation efforts had failed, patients in cardiac arrest who were undergoing CPR received 40 units of vasopressin intravenously, followed by defibrillation. After vasopressin administration, spontaneous circulation was promptly restored in all patients. Three of these individuals were discharged from the hospital with intact neurologic function; the other five lived between 30 minutes and 82 hours. Among the reasons proposed for vasopressin's beneficial effects were greater vasoconstrictive effect under hypoxia and acidosis conditions than epinephrine and longer lasting effects. In addition, vasopressin does not increase myocardial oxygen consumption and lactate production in

the arrested heart, unlike epinephrine. 6~ In their most recent study, Lindner and coworkers 66 carried out a randomized comparison of epinephrine and vasopressin in patients experiencing out-ofhospital ventricular fibrillation. Forty patients in ventricular fibrillation resistant to electrical defibrillation were prospectively and randomly assigned to receive epinephrine or vasopressin as primary drug therapy for cardiac arrest. The endpoints for this double-blind study were successful resuscitation (hospital admission), survival for 24 hours, survival to hospital discharge, and neurologic outcome. Thirty-five percent of patients in the epinephrine group and 70% of patients in the vasopressin group survived to hospital admission. At 24 hours, 20% of epinephrine-treated patients and 60% of vasopressin patients were alive. Three patients in the epinephrine group and eight of 20 patients in the vasopressin group survived to hospital discharge. Among survivors, neurologic outcomes were similar at hospital discharge. This preliminary study demonstrated that a significantly larger proportion of patients treated with vasopressin than those treated with epinephrine were resuscitated and survived for 24 hours. A multicenter evaluation of vasopressin seems appropriate based on this initial work, funded by a grant from the Laerdal Foundation in Norway. ~6 Vasopressin use is not without risk. It may impair profusion of collateral-dependent myocardium and exacerbate regional myocardial ischemia.~ Adverse effects of vasopressin in humans after resuscitation with respect to impaired vital organ function and splanchnic circulation are unknown. Clearly, this work does not warrant widespread use of vasopressin in patients with refractory cardiac arrest. However, further investigation of this agent in patients experiencing cardiac arrest is appropriate and underway.

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