Epinephrine in cardiac arrest: a critical review.

COLLECTIVE REVIEW epinephrine, cardiac arrest

Epinephrine in Cardiac Arrest: A Critical Review [Paradis NA, Koscove EM: Epinephrine in cardiac arrest: A critical review. Ann Emerg Med November 1990;19:i288-1301.]

INTRODUCTION Despite extensive research and standardization of therapy, the prognosis for patients with cardiac arrest remains poor, and the action of therapeutic agents is poorly understood. Epinephrine hydrochloride (USP) has been a major part of therapy for cardiac arrest during most of this century and is a mainstay of widely disseminated guidelines (Advanced Cardiac Life Support, ACLS). ~ While epinephrine's biochemistry and pharmacology during spontaneous circulation have been studied extensively, 2 5 its effects specifically during cardiac arrest have received less attention. Recent investigations have shed light on epinephrine's mechanism of action and appropriate dosage during CPR, 6 12 making review of this subject worthwhile.

HISTORY Epinephrine's first use in cardiac arrest has frequently been ascribed to a 1906 work by Crile and Dolley, in which they demonstrated that, compared with artificial ventilation and cardiac massage alone, the infusion of epinephrine greatly increased the proportion of dogs that could be resuscitated successfully.l.~ However, this work was antedated by Crile's 1903 and 1904 reports on successful resuscitation of animals "apparently dead" for up to 15 minutes, using "artificial respiration, rhythmic pressure upon the heart, and the infusion of adrenalin. ''14 16 Of interest is his mention of the successful temporary resuscitation of two human beings using these three techniques. ~7 Several European researchers had earlier described epinephrine's cardiovascular effects and use in resuscitation. In 1894-95, Szymonowicz and Cybulski; along with Oliver and Schafer, reported the effects of adrenal gland extracts.18-2° The latter authors described the vasoconstrictive effects, subsequently reporting successful use in reviving asystotic isolated animal hearts. In 1896, Gottlieb used adrenal extract and thoracic compressions to resuscitate an asystolic rabbit. 2t In this report, he proposed its use for cardiac arrest in human beings. In 1899, Abel named the active principal epinephrine. 22 Takamine purified this substance and coined the term adrenalin in 1901.2:5 About this time Lewandowsky and Langley noted the similarities between sympathetic nerve stimulation and the effect of adrenal gland compounds. ~4,2s Further work led to the synthesis of epinephrine in 1905. 26 In the following decades it was increasingly used as a pressorY

Norman A Paradis, MD* New York, New York Eric M Koscove, MDr Los Angeles, California From the Department of Emergency Medical Services, Bellevue Hospital Center, New York University Medical Center;* and the Department of Emergency Medicine, Los Angeles County-University of Southern California Medical Center, Los Angeles. t Received for publication March 13, 1989. Revisions received December 11, 1989, and June 13, 1990. Accepted for publication June 12, 1990. Dr Paradis is supported by a grant from the Aaron Diamond Foundation. Address for reprints: Norman A Paradis, MD, Department of Emergency Medical Services, Bellevue Hospital Center, First Avenue and 27th Street, New York, New York 10016.

ADRENERGIC PHYSIOLOGY A brief synopsis of adrencrgie physiology and pharmacology during spontaneous circulation will assist in understanding epinephrine's mechanism of action in cardiac arrest. Extensive treatment of these subjects can be found elsewhere.2-4, zs More than 40 years after the isolation of epinephrine, Ahlquist studied the physiological effects of sympathomimetic amines on different tissues. 29 He ranked the order of potency of these amines and noted that there were two different sequences. In the first sequence, the agents had excitatory actions in the following descending order: epinephrine, nor ~

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EPINEPHRINE Paradis & Koscove

epinephrine, isoproterenol. These were termed ~ effects. The agents in the second sequence caused mostly inhibitory actions in the following descending order: isoproterenol, epinephrine, norepinephrine. These inhibitory effects (including paradoxically, stimulation of the heart) were designated p effects. It was proposed that drugs bind to specific cell surface receptors, and the receptor binding properties of a drug determine its individual pharmacological effects. In the case of adrenergic drug;, it was suggested that there are two types of receptors: and f~. Stimulation of ~ receptors caused certain physiological effects, while s t i m u l a t i o n of p-receptors caused other, or opposite, effects. For instance, c~-receptor s t i m u l a t i o n caused v a s o c o n s t r i c t i o n , w h i l e p stimulation caused vasodilatation. A r n o l d and Lands divided the p-receptors into two separate subtypes, ~-1 and p-2. ,3° Stimulation of p-l-receptors increased the force of myocardial contraction. Beta-2 stimulation resulted in relaxation of vascular and bronchial smooth muscle. Similar to Ahlquist's earlier work, Arnold and Lands developed a rank order of drug effect. At the ~-l-receptots, the comparative potencies were isoproterenol > epinephrine ~> norepinephrine. At the p-2-receptors, the relative order was isoprotereno] /> epinephrine > norepinephrine. Once p h a r m a c o l o g i c a l l y active agents such as catecholamines bind to specific cell membrane receptors at their target organs, a number of post-receptor events occur that ultimately produce physiological effects. For e x a m p l e , b'inding can cause changes in the intracellular concentration of cyclic AMP, 31 phosphatidylinositol, or free calcium.32, ,33 Effects mediated through different receptor-secondary messenger systems cause the physiologidal changes seen after drug administration. 4 A brief overview of adrenergic receptors and the effects of their stimulation is shown (Table). In the past decade, the technique of radiolabeled ligand binding has expanded our understanding of drug/receptor systems. While a complete discussion of this research is beyond our present scope, a brief summary will assist in the subsequent discussion. 34 In these studies, drugs or compounds are labeled with radioac100/1289

tive substances and then allowed to bind to preparations containing receptors. Such preparations are usually derived from homogenized cells or tissues, but sometimes such larger preparations as isolated blood vessels or whole organs are used. The ability of a drug to compete with a radiolabeled ligand for a receptor is measured. Various parameters of the drug and receptor are assessed: binding affinity, stereospecificity, and reversibility, as well as the effects of agonists and antagonists. Results of these studies have generally conformed to the known physiological potencies of adrenergic agents. For example, the rank order of p-agonist p o t e n c i e s described above is the same as their order of binding affinity to B-receptors i n vitro. Therefore, the receptors bound in these preparations are probably equivalent to the physiologic adrenergic receptors. Adrenergic receptors have been found in m a n y tissues, including such divergent types as platelets, vasc u l a r s m o o t h m u s c l e , and t h e brain. 35 Central nervous system and peripheral vascular adrenergic receptors, however, may be different. Because of the importance of peripheral vascular adrenergic stimulation to resuscitation (see Mechanism of Action), we will limit our discussion primarily to the physiology of peripheral receptors. Langer proposed that R receptors had two distinct subtypes, ~-1 and o~-2.36 Alpha-l-receptors were located postsynaptically and were excitatory, while c¢-2-receptors were presynaptic and inhibitory. This simple system was later modified when it became apparent that c~-2 may be both presynaptic and postsynaptic.37 Both a-1 and c~-2 postsynaptic receptors mediate vasoconstriction. 38 Binding studies have characterized the ~-1 and R-2 effects of different adrenergic agents. These studies reveal a c o n t i n u u m of s p e c i f i c i t y from drugs that selectively stimulated c~-i receptors, such as phenylephrine and methoxamine, to those that selectively stimulated c~-2-receptors, such as clonidine. 39 Epinephrine and norepinephrine are relatively nonselective and stimulate c~-i and R-2-receptors with roughly similar potency. 39 Epinephrine, in addition to its a effects, also stimulates p-1 and p-2-receptors. 4o Radiolabeled ligand binding Annals of Emergency Medicine

studies have revealed the existence of processes that may modulate adrenergic response during pathological states. These include an increase in the number of receptors (up-regulation), a decrease in the number of receptors (down-regulation), 41 and an uncoupling of the receptor from its second messenger (uncoupling). 4~ 43 M o s t of the studies on r e c e p t o r changes in the cardiovascular system have been done on myocardial receptors during spontaneous circulation, and their applicability to peripheral vascular receptors during cardiac arrest is unknown. In some laboratory preparations, myocardial ~-1 receptor number has been found to increase in ischemia. 44 After one hour of ischemia, animal hearts were found to have increases in ~ receptor number accompanied by uncoupling of the adenyl cyclase system.43, 45 Others, however, have reported just the opposite. 46 The importance of these phenomena, should they occur in the periphery during cardiac arrest, lies in the potential to choose the optimal drug and its dosage based on matching its properties to the actual receptor environment. However, crucial in the application of these results to cardiac arrest is the time course of these changes. This has not been as well studied. With the exception of a general un o coupling of receptors from their secondary messengers, these processes, especially up- and down-regulation, probably take considerably longer to occur than typical times from cardiac arrest to resuscitation. 4z Therefore, the clinical relevance of these processes during human cardiac arrest is unknown.

M E C H A N I S M OF A C T I O N Adrenergic agonists have various proportions of c~- and p-receptor activity. As a result, these agents have differing effects on such physiologic parameters as inotropy, chronotropy, preload, and afterload. 2 Administration of exogenous epinephrine during intact circulation results in dose-dependent augmentation of all these myocardial parameters as well as increased ectopy. 4s,49 However, concepts such as inotropy have limited meaning in the arrested heart. Beta-1 s t i m u l a t i o n obviously c a n n o t increase the force of contraction, although it may still affect cellular metabolism. Application of results ob19:11 November 1990

TABLE. Sympathomimetic amine-induced responses of effector organs subserved by ~, ~-1, and ~-2 adrenoceptors

Subserved by the Adrenonoceptor Effector Organ Response Vascular smooth muscle Vasoconstriction Liver Glycogenoiysis

Intestial smooth muscle

Relaxation

Subserved by the ~-1 Adrenoceptor EffectorO r g a n Response Heart

Augmented pacemaker Augmented contractility

Vascular smooth muscle coronary Relaxation intestine Relaxation Adipose tissue (white) Lipolysis Lipogenesis

Subserved by the ~-2 Adrenoceptor Effector O r g a n Response Vascular smooth muscle Vasodilatation Tracheal and bronchial smooth muscle Relaxation Skeletal muscle

Potassium uptake

rained during spontaneous circulation to the state of cardiac arrest is a common methodological error. D u r i n g the 1960s, Redding and Pearson did extensive w o r k on the p a t h o p h y s i o l o g y and t r e a t m e n t of cardiac arrest, s°-s6 (Unless otherwise noted, all work discussed here has been performed in dog models.) Their studies laid the foundation for many current recommendations. However, like m a n y subsequent studies, some of their animal models did not accurately m i m i c clinical scenarios, and their results were inappropriately applied to human resuscitation without the confirmation of prospective clinical trials. Like Crile before them, they noted that external chest compression had limited value unless adrenergic drugs were administered. In both asphyxial-electromechanical dissociation (EMD) and ventricular fibrillation models they established that adrenergic agonists increased the likelihood of return of spontaneous circulation.53,s4, s6 T h e s e b e n e f i t s were greatest w h e n the drug was given early in the resuscitation. 54 A l t h o u g h m o s t of their studies w e r e p e r f o r m e d in an a s p h y x i a l model, and their early efforts often l a c k e d s t a t i s t i c a l analysis, t h e i r c o n t r i b u t i o n c a n n o t be underestimated, s7 They concluded that concerns over epinephrine's dysrhythmogenic properties were unwarr a n t e d w i t h t h e a v a i l a b i l i t y of electrical defibrillation and demonstrated that what were then considered very high doses of epinephrine were beneficial. In retrospect, it may have been overly enthusiastic, but 19:11 November 1990

p r e m a t u r e a p p l i c a t i o n of Redding and Pearson's data that has led to certain current controversies in human therapy (see Dosage). Redding and Pearson observed that effective drugs shared the c o m m o n pharmacological property of causing peripheral vascular constriction. 54 The almost pure c~-l-agonist methoxamine was the most effective, resuscitating 12 of 12 animals with all surviving at least two hours. Use of epinephrine resulted in return of circulation in all animals, but two of 13 died shortly after resuscitation. The p u r e ~-agonist i s o p r o t e r e n o l was worse than no drug at all, with only one of 11 dogs achieving return of circulation compared with three of ten in the placebo group. Methoxamine has a relatively long halfqife. But because they did not study long-term survival, they were unable to evaluate the prolonged organ hypoperfusion that might have occurred after its use. Pearson and Redding also observed that effective drugs raised the aortic pressure during the relaxation phase of CPR. Otto and associates have confirmed the effectiveness of epinephrine in increasing the likelihood of return of spontaneous circulation in an ischemic model of ventricular fibrillation, s8 Because the majority of cardiac arrests in h u m a n beings are associated with myocardial ischemia and dysrhythmia, this latter model m o r e a c c u r a t e l y m i m i c s clinical pathophysiology. The arrest time in Otto et al's study, however, was only three m i n u t e s and their dosage of e p i n e p h r i n e was larger on a perAnnals of EmergencyMedicine

Contraction Glycogenolysis Hypokalemia

weight basis than that used clinically. Controlled h u m a n trials demonstrating epinephrine's efficacy compared with placebo in cardiac arrest are conspicuously lacking and would be ethically difficult to perform as they would require withholding therapy presently regarded as effective. This is a c o m m o n situation in the field of resuscitation. Because of the difficulties associated w i t h h u m a n research, therapies have been widely applied without clear demonstration of efficacy. Research on the receptor activity responsible for improved o u t c o m e has given insight into the mechan i s m of a c t i o n of the a d r e n e r g i c agents during cardiac arrest. Pearson and Redding's work indicated the imp o r t a n c e of the p e r i p h e r a l vasoconstriction k n o w n to result from c~-receptor s t i m u l a t i o n . O t t o and Yakaitis d e m o n s t r a t e d the importance of ~-adrenergic s t i m u l a t i o n using blocking agents in an asphyxial a s y s t o l e - E M D model. 59 Dogs pretreated with the n-blocker phenoxybenzamine anff resuscitated with isop r o t e r e n o l , a pure f~-agonist, did poorly (27% return of spontaneous circulation) c o m p a r e d w i t h those treated with epinephrine alone (100% return of spontaneous circulation). Dogs pretreated with F-blockers followed by resuscitation with phenylephrine, a pure c~ agent, did as well as those treated with epinephrine alone. In later work, they reported t h a t none of eight n-blocked animals subsequently treated with epinephrine achieved return of spontaneous cir1290/101


culation, compared with seven of eight control animals.~O A l t h o u g h they concluded that epinephrine's ~-adrenergic properties have no effect on outcome, this may have resulted from insensitivity in the study itself. It has not yet been determined if p-mediated increases in myocardial oxygen c o n s u m p t i o n are clinically detrimental in cardiac arrest. Return of spontaneous circulation has been suggested to be a function of maximizing the ratio of oxygen availability to, metabolic demand w i t h i n the m y o c a r d i u m . ~o Blood flows in the range of 15 to 20 mL/ m i n x 100 g have been estimated as necessary to meet the metabolic requirements of the fibrillating heart after short arrest times, and flows of this magnitude have been found to correlate with return of spontaneous circulation.a, 61 In an animal model without the use of adrenergic drugs, Ditchey and associates found that coronary blood flow during CPR was limited 62 and occurred primarily during the relaxation phase when the aortic-to-right atrial pressure difference was greatest. The relaxation phase aortic-to-right atrial pressure gradient has come to be accepted as the coronary perfusion pressure during CPR. 63,64 Pearson and Redding had observed a positive relationship between aortic diastolic pressure during CPR and the probability of return of spontaneous circulation.S4, 56 Indeed, this had been suggested 60 years earlier by Crile and Dolley. 1.3 Work in animals has demonstrated that increasing the coronary perfusion pressure results in an increase of coronary blood flow. 62,64-66 The correlation coefficient between perfusion pressure and myocardial blood flow may be as high as 0.84. 8 Higher coronary perfusion pressure has also been shown to be predictive of return of s p o n t a n e o u s circulation during CPR in h u m a n beings. 67 In this study, a m i n i m u m gradient of 15 m m Hg was necessary before return of s p o n t a n e o u s circulation occurred. Animal models have shown that in the absence of pressors, external chest compression provides coronary perfusion pressures and myocardial blood flows that probably are below those required for successful resuscitation.S,6S 70 In an extensive series of experiments, Michael and associates studied the relationship between epi102/1291

nephrine, standard and simultaneous ventilation-compression CPR, and organ blood flow,aT ° They demonstrated that myocardial and cerebral blood flow decrease d r a m a t i c a l l y with time during standard CPR. Administration of epinephrine reversed this decline, and a continuous infusion maintained increased blood flow for up to 50 minutes. Animals in which it was possible to maintain adequate aortic relaxation pressures with epinephrine also tended to have return of spontaneous circulation. Without the use of epinephrine, they observed that cerebral blood flow would decrease suddenly at the same time that there was a sudden increase in the aortic-to-carotid pressure gradient, suggestive of carotid arterial collapse. These investigators theorized that the beneficial effect of epinephrine resulted not only from peripheral vasoconstriction, but also from prevention of collapse of intrathoracic arteries during chest compression. These observations, along with the studies described above, suggest that the efficacy of adrenergic drugs in cardiac arrest occurs primarily from ~-adrenergic receptor-mediated increases in vasomotor tone. This results in elevation of aortic pressure and increased myocardial and cerebral blood flow. The a s s u m p t i o n that increased blood flow improves the myocardial oxygen supply-demand equilibrium with the effect of improving intracellular high-energy phosphates has not been clearly demonstrated. Ditchey found that epinephrine improved both perfusion pressure and endocardial blood flow but that this did not translate into increased myoCardial adenosine triphosphate (ATP) or decreased myocardial lactate. 71 This study is difficult to interpret for a number of reasons. Epinephrine administration was early after cardiac arrest, and the small sample size resulted in a low statistical power. The animals were alkalotic, a state that prevents oxygen release to the tissues. The model also required invasive prearrest sampling, and the biopsy times may have been too long. Any of these factors could depress cellular ATP. It would be of interest to see if these results can be confirmed by noninvasive in v i v o techniques such as phosphate magnetic resonance spectroscopy. 72 The coronary blood flows during standard Annals of Emergency Medicine

CPR may be so low that even statistically significant increases may not provide sufficient substrate for regeneration of high-energy phosphates. Interestingly, it is possible that the increases in aortic pressure after administration of epinephrine result in a decrease in cardiac output at the same time they increase vital organ blood flow through redistribution. This has recently been reported by Sanders and associates in an animal model 73 and may be a contributing mechanism to the drop in end-tidal carbon dioxide reported to occur after administration of epinephrine.69,z4, z5 This dissociation between cardiac output and blood flow to the heart and brain indicates a fundamental difference b e t w e e n the hemodynamics of spontaneous circulation and cardiac arrest. Because ~-adrenergic stimulation appears crucial to successful resuscitation, attention has been given to c~-receptor physiology in attempting to understand why certain drugs and dosages may be more effective than others. In some studies, vascular s-lreceptors have been found to be located i n t r a s y n a p t i c a l l y , and are therefore less accessible to stimulation by circulating catecholamines, z6 while ~-2-receptors have been found to be principally extrasynaptic. 76 Therefore, it would be expected that exogenous catecholamines are effective in cardiac arrest primarily because of their ~-2 stimulation. It has also been suggested that ~-2-receptots are more important than c~-i in cardiac arrest after the onset of ischemia.77, TM Down-regulation of ~-l-receptors has also been suggested to occur. 77 These events, however, have not been demonstrated in vascular tissue early in cardiac arrest. Redding and Pearson had reported that the pure R-1 agent methoxamine was "most effective," and some patients were resuscitated successfully with m e t h o x a m i n e after failure of epinephrine, s4 A study using a canine model of asphyxial arrest found that 0.18 mg/kg of the pure ~-i agent phenylephrine (weight interpolated) increased the aortic relaxation pressure during cardiac arrest, z9 However, a more thorough study in swine found no significant difference in cardiac outputs or aortic pressures after drug administration when comparing phenylephrine in doses of 1.0 and 10 mg/kg to 0.2 mg/kg of epinephrine, 19:11 November 1990

w h i c h is an R-I, ~ - 2 - a g o n i s t . 8o Studies of pure ~-2-agents are limited. One study of the pure ~-2-agonist UK 14,304-18 found no increase in aortic relaxation pressure or myocardial blood flow compared withCPR alone. 81 This m a y have occurred because the peripheral vasoconstriction was offset by a centrally mediated vasodepressor effect. Nevertheless, this result is not consistent w i t h the h y p o t h e s i s t h a t c~-2-adrenergic receptors are of primary importance in resuscitation from cardiac arrest.

DOSAGE The optimal dosage of epinephrine in cardiac arrest is not known.~l Inv e s t i g a t o r s w o r k i n g in a n i m a l models have used dosages greater, on a per-weight basis, than those currently recommended for human beings. Recent studies in animals and human beings have specifically evalu a t e d the effects of h i g h e r epinephrine doses and suggest that standard doses may be too low. During their early in~restigations, Redding and Pearson found that 1.0 mg of epinephrine was effective in dogs with average weights of approximately 10 kg. 5~ This is equal to 0.1 mg/kg. They also demonstrated that a total dose of 0.2 rng was not effective in dogs of unspecified weight, s2 The c u r r e n t ACLS r e c o m m e n d e d adult dose is 0.5 to 1 mg IV every five minutes, without variation for body weight. 1 In a 70-kg patient, this is equal to 0.007 to 0.014 mg/kg. It is unclear w h y this dose is considerably lower than the mg/kg dose in Redding and Pearson's study provided as a major reference in the ACLS guidelines. N o h u m a n d o s e - r e s p o n s e curves or v o l u m e s of distribution during arrest exist as a basis for this difference. It appears that the same 1-mg dose found effective in 10-kg dogs was applied unchanged to hum a n beings. Perhaps Pearson and Redding's anecdotal report that in human beings a l-rag dose was "satisfactory" provided uncited support for this. s6 Also of note is their comment that this 1-rng dose was used "with benefit in children down to 18 months of age. ''56 In such children, using a approximate weight of 12 kg, this would equal 0.083 mg/kg, at least six times their recommended adult dosage. It is important to remember the context in which this re19:11 November 1990

search was done. In the early 1960s m o s t p h y s i c i a n s ' experience with pressors such as epinephrine was in patients with spontaneous circulation. The doses being recommended by Pearson and Redding must have seemed quite large. As late as 1985, these researchers were being described as promoting "high-dose epinephrine therapy. ''57 Most studies of epinephrine in cardiac arrest have been conducted in animal models and have used dosages that were greater on a mg/kg basis than the standard human dose. Holmes showed that dosages in the range of 0.05 mg/kg increased blood flow to the heart and brain, but only to approximately l0 mL/kg × min. 83 This is less than the 15 to 20 mL/kg x rain estimated to be the minimum n e c e s s a r y to m e e t the m e t a b o l i c needs of the early fibrillating myocardiurn and found predictive of successful resuscitation.6~, s4 The clinical applicability of Holmes' model is questionable because each animal was subjected to multiple fibrillatory episodes, and CPR was started immediately after fibrillation. Otto and associates, using an ischemic ventricular fibrillation model, found that a dosage of 0.077 mg/kg increased the fraction of animals with successful defibrillation, s5 In their investigations, Michael and associates showed that a 0.034-mg/kg bolus followed by an infusion of 0.004 mg/kg x rain was clearly efficacious.8, 7o In an EMD model, Ralston and associates demonstrated a dose-response relationship between epinephrine and percent successful resuscitation. In this model, 0.01 mg/kg had a 40% resuscitation rate, while an approximately 90% success rate was obtained with 0.1 mg/kg. 86 Brown and associates examined the dose-response relationship between epinephrine and vital organ blood flow. 6,9 Their swine model of ventricular fibrillation incorporated a ten-minute arrest interval before initiation of CPR. The swine vascular system and chest anatomy may more closely resemble that of human beings than the canine, although it lacks the collaterals present in persons with coronary artery disease. This, along with the longer arrest time, makes this an excellent model of human cardiac arrest. They found that 0.2 mg/kg of epinephrine, approximately 15 times the standard Annals of Emergency Medicine

dose, produced cerebral blood flows that were significantly higher than with 0.02 mg/kg, the latter of which is approximately 70% greater than the standard l-rag dose in human beings. In all areas of the myocardium sampled, blood flow after administration of 0.2 mg/kg was statistically greater than with 0.02 mg/kg. As an example of the magnitude of this improvement, left ventricular endocardial blood flow was 2.5 _+ 0.1 mL/ rnin × 100 g with 0.02 mg/kg and 176 -+ 103.5 mL/rnin x 100 g with 0.2 mg/kg. It is worth noting that the dose of 0.2 mg/kg was associated in all their measurements with blood flows greater than the 20 mL/min x 100 g estimated necessary to meet the needs of the fibrillating heart, as well as above the 16 mL/min x 100 g c o r r e l a t e d w i t h s u r v i v a l in one study.61, 84 Although no statistically s i g n i f i c a n t difference existed between 0.2 mg/kg and 2 mg/kg, blood flow was less for most of the myocardium with the higher dose. The "leveling off" of the dose-response curve suggests that, while the optimal dose is probably several times that currently recommended, there may be a limit to the benefit of even higher doses. It is unfortunate that these studies did not include a dosage comparable with that presently recommended for clinical use. A significant difference in vital organ blood flow between the standard and higher dosages would have been an important result. Almost all these experimental data are based on work in animals w i t h o u t c o r o n a r y artery disease. Caution must be used in applying these results to human beings with acute and/or chronic coronary artery obstruction. Gonzalez and associates recently reported the vasopressor response to 1-, 3-, and 5-mg doses in ten patients with prehospital cardiac arrest. 69 They found that doses of 5 mg significantly raised the diastolic blood pressure compared with preepinephrine levels, while 1- and 3-mg doses did not. The measurement of vascular pressures during human cardiac arrest is a difficult task, making these kind of data extremely valuable. Care must be exercised in the application of these results because the patients in this study had been in arrest for approximately one hour before measurements were taken. Ano t h e r s t u d y in h u m a n beings reported to have found an adverse ef1292/103


fect of "high-dose" epinephrine, s7 However, this study's "high dose" was the standard 1 rag, and it had multiple methodological flaws. 8a A preliminary report examining the effect of standard and high-dose epinephrine on the coronary perfusion pressure in human beings found significant increases after 12 to 14 mg of epinephrine but not after 1 mgY While Pearson and Redding recommended a 1-mg dose during human cardiac arrest, o t h e r authors, as long as 20 to 30 years ago, recommended doses up to 5 mg. 89 There is a report of successful resuscitation in adults using 5-mg and 6-mg doses, 9° and a small study in pediatric patients indicates that dosages of 0.2 mg/kg may result in better outcomes than standard dosages. 91 Another retrospective study compared patients who received a total epinephrine dose less than 5 mg with those whose total dose was more than 13 mg. 92 This study had a number of potential flaws, and, although a greater proportion of the patients receiving the higher dosage were admitted, the proportion surviving at four days was no different. Another recent study in patients with EMD had similar flaws and outcomes: there was a higher rate of return of spontaneous circulation but no difference in long-term survival, w h i c h was zero in both groups. 9a Results of some radiolabeled ligand binding studies indirectly support the contention that large doses of catecholamines may be required in cardiac arrest. As discussed above, some of these studies have found that in ischemic myocardium or the failing heart, adrenergic receptor down-regulation or uncoupling may occur. 41-4a If similar events occur in the peripheral vasculature, the result of either down-regulation or uncoupling would be to decrease the effect of catecholamines. Other investigators, however, have found just the opposite effects, 44,94 and it has not been demonstrated that either process occurs with sufficient rapidity after the onset of ischemia to be clinically important in human cardiac arrest. An additional factor underlying the need for larger dosages in cardiac arrest may be the mechanism of action of the drug itself. There is a preliminary report that administration of an approximately 14 times greater dos104/1293

age of epinephrine to patients in cardiac arrest resulted in only a 2.6-fold increase in arterial plasma level. 95 This suggests the intriguing possibility that as efficacious dosages of epinephrine increase organ perfusion, s the volume of distribution for the drug is also increased. This may be true of any pressor that raises intravascular pressure enough to open capillary beds and increase organ perfusion. Because the literature is incomplete, it is difficult to make specific r e c o m m e n d a t i o n s for epinephrine dosing during cardiac arrest. There is no scientific evidence that justifies the use of the p r e s e n t l y recommended 1-mg dose in adults. It is important to emphasize t h a t the original data of Pearson and Redding, rather than supporting the present dose, actually indicate a need for higher doses. In their research, a dose of 0.1 m g / k g was found effective, while a lower dose was not. s~,s2 In a typical adult, this dose would translate to a 7.0-rag bolus. The additional studies cited above provide experimental support for a dosage between 0.03 and 0.2 mg/kg. In a 70-kg patient this equals 2.1 to 14 mg. In retrospect, it is ironic that these higher doses may be close to those used by Crile and Dolley 80 years ago. 13 This cannot be said with certainty because the activity of their formulation (possibly a biological extract) is unknown. Because 0.03 to 0.2 mg/kg more closely reflects the amounts used in most research, it may be ina p p r o p r i a t e to call this t h e r a p y "high-dose epinephrine." Some have described the standard dose as "homeopathic. ''96 A l t h o u g h the studies described above are persuasive, alone they may not provide a basis for changing the standard of care. Unfortunately, outcome studies in either human beings and animals are notably absent, and it should be remembered that return of spontaneous circulation is not the same as neurologically intact longterm survival. Until studies with this end point are performed, the question of the optimal dosage must be considered open. These studies may be difficult to perform because any improvement in long-term survival may be small, and inadequate sample size could fail to detect it (type II error). 97 The field of resuscitation has sufAnnals of Emergency Medicine

fered under the m i s a p p l i c a t i o n or premature application of animal and anecdotal h u m a n data. These concerns, however, must be balanced against the almost uniformly fatal outcome of cardiac arrest that is unresponsive to initial measures. Use of higher doses of epinephrine soon after failure of an initial standard dose may be appropriate. However, higher doses should not be given so late that a successful cardiac resuscitation results after irreversible brain injury has occurred. P r e s e n t r e c o m m e n d a t i o n s treat cardiac arrest as a homogenous state, with the same 1-mg epinephrine dose being recommended for any pathophysiologic process resulting in ces~ sation of circulation in an adult. This may not be correct; EMD may not re~ quire the same dosage as asystole. It may be that different types of cardiac arrest not only need a different initial dose, but that the duration of arrest may have varying effects on the dose required.

PHARMACOLOGY Although the pharmacology of epinephrine has been studied extensively during spontaneous circulation,98, 99 this subject has received less attention in cardiac a r r e s t research. The available data, however, may support the need for larger epinephrine doses during arrest. Cardiac arrest is the state of maximal biologic stress, and it is associated with the highest plasma levels of both epinephrine and norepineph-. fine. m° Plasma epinephrine levels during s p o n t a n e o u s circulation in human beings are approximately 0.03 ng/mL in normal resting subjects. 1°° With cardiac arrest, these levels increase from ten to 100-fold even before administration of exogenous epinephrine.tin, mz These dramatic increases in catecholamines initially led some authors to believe that exogenous epinephrine would not raise the plasma concentration enough to be clinically significant. 1°1 This belief is not supported by the numerous studies described above, which have shown a significant increase in organ perfusion after administration of epinephrine. However, the relative increase in plasma levels after standard doses of exogenous epinephrine is not nearly as great as after cardiac arrest alone. Wortsman studied ICU patients suffering cardiac arrest and 19:11 November 1990

found peak plasma epinephrine levels of 10.3 -+ 2.9 ng/mL before exogenous epinephrine and 72 + 31 ng/ mL after drug a d m i n i s t r a t i o n , me In patients suffering out-of-hospital cardiac arrest, Q u i n t o n and a s s o c i a t e s found a rise from 12 _+ 8 ng/mL to 55 _ 13 n g / m L w i t h i n two m i n u t e s of r e c e i v i n g 1 m g of e p i n e p h r i n e . 1°3 If endogenous s e r u m epinephrine levels rise 100-fold in h u m a n cardiac arrest even before a d m i n i s t r a t i o n of exoge n o u s e p i n e p h r i n e , t h e n t h e five to s e v e n f o l d i n c r e a s e after a s t a n d a r d 1-mg dose m a y be inadequate. As disc u s s e d above, t h e r e l a t i o n s h i p bet w e e n e p i n e p h r i n e dosage and arterial p l a s m a level m a y n o t be linear, 9s w i t h increasing doses of the drug resulting in a p r o p o r t i o n a t e l y lesser increase in arterial plasma level. Kern and associates recently studied the relationship b e t w e e n p l a s m a c a t e c h o l a m i n e s and o u t c o m e after cardiac arrests of eight and 14 minutes.104 T h e y found that the absolute level, as w e l l as t h e m a g n i t u d e of the increase, in endogenous catec h o l a m i n e s after a r r e s t d i d n o t predict w h i c h a n i m a l s w o u l d be resuscitated successfully. However, the rise in p l a s m a levels w i t h a d m i n i s t r a t i o n of exogenous epinephrine was predict i v e of o u t c o m e . A n i m a l s w i t h return of spontaneous circulation had a m e a n increase in p l a s m a levels of 53fold w h i l e a n i m a l s that r e m a i n e d in a r r e s t h a d o n l y a 23-fold i n c r e a s e . The s t u d y is s o m e w h a t c o n f o u n d e d by t h e e p i n e p h r i n e b e i n g b o t h adm i n i s t e r e d and sampled in the right atrium, ' and there is a recent report that the correlation b e t w e e n venous and arterial levels is good only during the first few m i n u t e s after administration, ms but the results are intriguing. If a 50-fold increase in p l a s m a epinephrine is needed for successfu! o u t c o m e in a n i m a l s w i t h o u t coron a p / a r t e r y disease, the five to sevenfold increases found in h u m a n beings a f t e r a d m i n i s t r a t i o n of 1 m g a r e clearly inadequate. T h e l i m i t e d studies of the p l a s m a l e v e l s a n d p r e s s o r e f f e c t s of e p i nephrine during h u m a n cardiac arrest i n d i c a t e c o n t i n u e d m e t a b o l i s m of the drug.ag, 1°5 If this is the case, then the low-flow state of CPR m a y allow for considerable c a t a b o l i s m of intravenously administered epinephrine before it reaches the arterial side of the c i r c u l a t i o n , c o n t r i b u t i n g to the need for larger dosages. 19:11 November 1990

More i m p o r t a n t than the pharmac o k i n e t i c s of e p i n e p h r i n e ' s p l a s m a level is the t i m e course of its pressor effect. In the s t u d y by Gonzales, 6~) epinephrine's effect on pressure p e a k e d at two to three m i n u t e s after a d m i n i s t r a t i o n and was gone by five m i n u t e s , r e s u l t s t h a t are c o n s i s t e n t w i t h previous a n i m a l data. t ~ Because it m a y n o t be b e n e f i c i a l to a l l o w perfusion pressures to return to preepinephrine levels during cardiac arrest, these results may indicate t h a t the currently r e c o m m e n d e d fivem i n u t e dosing interval is too long. A c i d o s i s i m p a i r s the p r e s s o r response to epinephrine during spontaneous circulation, lo6 It has been suggested to act similarly during cardiac arrest,~o7 although no h u m a n Studies exist to s u b s t a n t i a t e this. A r e c e n t p r e l i m i n a r y r e p o r t f o u n d t h a t acidosis, even if it is severe, does not i m p a i r the pressor response after adm i n i s t r a t i o n of e p i n e p h r i n e d u r i n g c a r d i a c a r r e s t in h u m a n beings, tO~ Alkalosis, as might develop from exc e s s i v e b i c a r b o n a t e t h e r a p y or extreme hyperventilation, decreased the pressor response. This study had n u m e r o u s l i m i t a t i o n s , i n c l u d i n g its p a t i e n t p o p u l a t i o n , p a t i e n t s late in arrest w h o were refractory to standard therapy, so the results m u s t be confirmed earlier in arrest. However, t r e a t m e n t of acidosis for the purpose of increasing the effectiveness of epinephrine m a y not be indicated.

COMPARISON WITH OTHER AGENTS The basis of m u c h of the research into alternative drugs has been conc e r n t h a t s o m e of e p i n e p h r i n e ' s f3-mediated effects could be h a r m f u l in cardiac arrest.rag, 1~o This has been suggested by the d r a m a t i c a l l y worse o u t c o m e s w i t h pure f~-agonists such as isoproterenol. 54,1 ~1 In intact circulations, p-2-agonists cause vasodilation, w h i c h m a y be c o m p e n s a t e d for by inotropic and chronotropic stimulation. In cardiac arrest, these compensatory m e c h a n i s m s are not available, and p-2 s t i m u l a t i o n m a y theoretically cause decreased perfusion pressure. T h e r e has also been concern that this may exacerbate the loss of vascular tone that occurs after cardiac arrest. At very low doses (eg, 0.003 to 0.03 txg/kg), e p i n e p h r i n e s t i m u l a t e s ~3-receptors, c a u s i n g a d e c r e a s e in b l o o d p r e s s u r e d u r i n g spontaneous circulation; however, at Annals of Emergency Medicine

the higher dosages used during card i a c a r r e s t , its c~ effects p r e d o m i nate 112 1 1 3 Although the studies described above d e m o n s t r a t e that an a b s o l u t e decrease in perfusion pressure is not produced by epinephrine's p-2 stimulation, it is reasonable to ask if it is the adrenergic drug of choice in cardiac arrest. Because t h e benefits of these drugs appear to s t e m p r i m a r i l y from their c~ adrenergic activity, pure c~ a g e n t s w o u l d be e x p e c t e d to be equally effective. As p r e v i o u s l y described, Pearson and Redding found t h a t m e t h o x a m i n e and p h e n y l e p h rine, drugs w i t h a l m o s t s o l e l y ~-1 activity, a p p e a r e d to be m o r e effect i v e t h a n e p i n e p h r i n e in c e r t a i n models.5,~, ,~4 T h e y a l s o r e f e r r e d to s e v e r a l p a t i e n t s in w h o m u s c of m e t h o x a m i n e r e s u l t e d in r e t u r n of spontaneous circulation after m u l t i ple a t t e m p t s w i t h e p i n e p h r i n e had failed.,~:~ A recent prospective trial comparing 10 m g m e t h o x a m i n e a n d 1 m g e p i n e p h r i n e in r e s u s c i t a t i o n of hum a n beings in EMD failed to demons t r a t e a d i f f e r e n c e , ll4 T h i s s t u d y , however, d e m o n s t r a t e d s o m e of the c o m m o n f a i l i n g s o c c u r r i n g in research on cardiac arrest. The dosage of e p i n e p h r i n e in t h i s s t u d y w a s probably too low to be effective. It is also not clear t h a t these were equipressor doses during cardiac arrest; if t h e y were, the m e t h o x a m i n e dose was also too low. Lastly, even if one of these drugs was significantly better than the other for s o m e clinically relevant end point, the sample size in t h i s s t u d y was p r o b a b l y m u c h too s m a l l to p e r m i t d e m o n s t r a t i o n of t h i s d i f f e r e n c e (possible t y p e II error). 97 Another randomized study comp a r i n g e p i n e p h r i n e 0.5 m g w i t h m e t h o x a m i n e 5.0 mg in prehospital ventricular fibrillation found a higher rate of successful r e s u s c i t a t i o n , defined as arrival at the emergency dep a r t m e n t w i t h a pulse, and a trend t o w a r d g r e a t e r s u r v i v a l , w i t h epin e p h r i n e . 11-~ T h i s s t u d y is open to the same criticisms as the previous ones. Because the dose of epinephrine was probably " h o m e o p a t h i c , " the results m a y a c t u a l l y have reflected a d e l e t e r i o u s effect of m e t h o x a m i n e . W h i l e the o p t i m a l dose of m e t h o x a m i n e r e m a i n s unclear, several authors have expressed concern over its longer half-life, w i t h possible impair1294/105


ment of organ perfusion in the postresuscitation period.96, H6 There are no animal studies comparing these drugs in terms of long-term survival. These types of studies are difficult to perform but should have been done before human trials were undertaken. Phenylephrine, another ~-1 selective agent, has been considered as an alternative because of its shorter half-life. H o l m e s and a s s o c i a t e s found that while epinephrine significantly increased blood flow to the brain, phenylephrine did not. a3 Both epinephrine and phenylephrine, however, were given in a dosage of 0.05 mg/kg, which is not equipressor and is probably too low during cardiac arrest. 80 Brillman and associates were unable to demonstrate a difference in survival or neurologic outcome between epinephrine 1 mg and phenylephrine 10 mg after a three-minute arrest. 1~7 In a different study, they failed to demonstrate that phenylephrine, in a dose of 0.74 mg/kg, resulted in improved outcome when compared w i t h epinephrine 0.076 mg/kg. 118 Brown and associates found that regional cerebral blood flow during CPR in swine was greater with epinephrine 0.2 mg/kg than with phenylephrine 1 mg/kg, s° There was a trend toward greater cerebral blood flows with epinephrine than phenylephrine 10 mg/kg, but it did not reach statistical significance, possibly because of the small sample size. In a later study, however, this group found that the myocardial oxygen extraction ratio was better with epinephrine 0.2 mg/kg than phenylephrine 1 mg/kg. 12 Although 80% of the epinephrine-treated animals were defibrillated successfully, none of those that received phenylephrine were. It is not clear why phenylephrine 10 mg/kg, which appeared effective in an earlier study, was not included. In a study of human cardiac arrest, p h e n y l e p h r i n e 1 m g / k g and epinephrine 0.5 mg/kg were found comparable in terms of outcome and untoward effects, such as post-resuscitation hypertension. 119 Once again, these dosages were probably inappropriate, making the study's results less useful. As was alluded to earlier, methodological errors are the rule in h u m a n cardiac arrest research, not the exception. At this time, it would appear that pure c~-adrenergic drugs have not been clearly demonstrated 106/1295

to offer any improvement over epinephrine. However, a recent preliminary report of increased pulmonary shunt after epinephrine indicates potential benefits of pure c~ agents in patients with marginal arterial blood gases. 1ao Robinson and associates recently c o m p a r e d e p i n e p h r i n e w i t h norepinephrine, a drug with [~-2-effects ten to 40 times less than those of epinephrine. 77 In their swine ventricular fibrillation model with ten minutes of cardiac arrest, norepinephrine 0.12 mg/kg and 0.16 mg/kg had a significantly better myocardial oxygen extraction ratio compared with epinephrine 0.2 mg/kg. There was a trend t o w a r d greater m y o c a r d i a l blood flow and successful defibrillation with 0.16 mg/kg. Perfusion pressures, however, were not significantly different. Care must be used in applying these results. Although improvements in myocardial blood flow and rates of defibrillation to an organized rhythm indicate that norepinephrine m a y have significant benefits, these end points should not be confused with clinical outcome. At this time, the O-agonist properties of epinephrine have not been clearly demonstrated to be detrimental in an outcome study. Drugs such as norepinephrine need further research, especially in m o d e l s t h a t evaluate long-term survival and neurologic outcome, before they can be considered as substitutes for epinephrine in clinical practice.

VENTRICULAR FIBRILLATION Cardiac arrest is the clinically uniform presentation for what is actually a heterogenous group of pathophysiologic processes. The usefulness of particular drugs in relation to specific etiologies, such a ventricular fibrillation, has only been indirectly addressed, usually as a function of the animal model used. Epinephrine has been reported to increase the amplitude of the fibrillatory waveform.6O, 9° A l t h o u g h this was thought to increase the likelihood of s u c c e s s f u l defibrillation, s o m e a u t h o r s h a v e r e c e n t l y expressed concern that it may have deleterious effects. 11o These include higher coronary vascular resistance due to increased myocardial wall tension, increased myocardial oxygen demands, and redistribution of blood flow away from the endocardium. Annals of Emergency Medicine

These processes have been observed in an arrest model of cardiopulmonary bypass with dipyridamole-induced coronary vasodilation. 60 By its very nature, however, this model prevents epinephrine's augmentation of coronary blood flow, which has been d e m o n s t r a t e d in n u m e r o u s o t h e r studies.9, 61 Applying results generated by this model to human CPR is clearly invalid. In the same study, these investigators examined the effect of pressors during open-chest cardiac massage and found that epinephrine caused a large increase in c o r o n a r y blood flow, w h i c h was equally divided between the endocard i u m and e p i c a r d i u m . T h e y also n o t e d that e p i n e p h r i n e caused a greater increase in myocardial blood flow than methoxamine, but not to a statistically significant degree. In the study by Michael and associates, administration of epinephrine resulted in an augmentation of blood flow to all areas of the myocardium, including the endocardium, 8 and this has been confirmed by others. 62 Although endocardial blood flow is important in ischemic states of spontaneous circulation, the assumption that this is also true during arrest has not been demonstrated. Coronary perfusion pressures significantly below the intramyocardial pressures postulated to be present during ventricular fibrillation have been found to be predictive of successful resuscitation in animal models.67,68, t21 Successful resuscitation from ventricular fibrillation requires defibrillation followed by return of spontaneous circulation. Receptor stimulation that improves t h e rate of one of these processes may have an adverse effect on the other. Ruffy found that pure [~-adrenergic stimulation lowered the defibrillation threshold while ~ blockade increased it.122,123 If f~ stimulation is important for defibrillation while R stimulation is important for return of circulation, then epinephrine, which has both properties, may be more effective than pure agents in ventricular fibrillation. Although Pearson and Redding demonstrated in one study that dogs were more readily defibrillated after treatment with epinephrine, s3 they did n o t o b s e r v e t h i s in a d i f f e r e n t model. 56 In animal models with and without coronary occlusion, Otto and Yakaitis found that epinephrine did 19:11 November 1990

not affect the rate of, or the amount of energy required for, defibrillation.85, t24 However, its use was an important determinant of restoration of spontaneous circulation after defibrillation. One of these studies may have lacked statistical power to detect a difference because nearly all the control dogs were successfully defibrillated (type II error). It would appear that while defibrillation is necessary, it is not, by itself, sufficient for return of spontaneous circulation, and the l i k e l i h o o d of the latter is increased by treatment with adrenergic drugs. In a retrospective review of patients with ventricular fibrillation, Weaver and associates found that those patients with high amplitude (coarse) waveforms were no more likely to defibrillate, to any other rhythm, than those with low amplitude (fine)waveforms3 2s However, those with coarse fibrillation tended to defibrillate into supraventricular rhythms, while those with fine ventricular fibrillation more frequently converted to asystole. Survival rates strongly correlated with ventricular fibrillation amplitude, with hospital discharge six times more likely in patients w i t h coarse v e n t r i c u l a r fibrillation than fine. This study, along with animal studies and clinical experience, suggests that coarse ventricular fibrillation is seen earlier in cardiac arrest, while fine ventricular fibrillation is more common later in arrest3 26 When cardiopulmonary bypass is used for the treatment of cardiac arrest, there is a coarsening in the fibrillatory waveform when bypass is initiated3 27 The coarsening of ventricular fibrillation after administration of epinephrine may be a manifestation of increased myocardial perfusion. It is reasonable to conclude that epinephrine can improve outcome in cardiac arrest caused by ventricular fibrillation. Numerous animal studies indicate its positive effect on short-term outcome and important physiologic parameters, s,56,61 As discussed above, its major benefit may be increased myocardial blood flow secondary to c~-receptor stimulation. Theoretically, its f~-adrenergic properties could be deleterious. However, its c~-vasoconstrictive effects probably dominate its f~ effects, even in present clinical dosages (see Comparison With Other Agents). At this 19:11 November 1990

time, no o t h e r pressor has been shown to be more effective or safer, and epinephrine should still be considered the drug of choice for ventricular fibrillation unresponsive to electrical defibrillation.

ELECTROMECHANICAL DISS O C I A T I O N Recent research on EMD has altered established conceptions of this state. Clinically it is often defined as the presence of an organized rhythm without a palpable pulse, with the assumption that no cardiac output is present. However, studies in human beings do not support this conception. Berryman found that EMD in h u m a n beings is frequently associated with arterial pressure fluctuations. 128 Bocka and associates demonstrated echocardiographically that myocardial wall and valve m o t i o n correlating with ECG complexes occurred in a majority of their patients during EMD. 129 Other recent work indicates that EMD of cardiac origin m a y be a h e t e r o g e n o u s c o n d i tion, 13°A31 and there is a preliminary report that a significant fraction of patients diagnosed clinically to be in EMD actually have aortic pulse pressures3 32 Overall, the outcome of patients in clinical EMD is poor, 133,134 but the lumping together of these different pathophysiologic entities may hide subsets with better prognoses, such as post-countershock EMD. 135 This heterogeneity, along with a paucity of animal data, makes therapeutic recommendations difficult. Evaluation of several differing adrenergic agents in EMD have been reported. In an animal model of postcountershock EMD, Niemann found that myocardial blood flow was decreased by i s o p r o t e r e n o l and increased by epinephrineA 36 Predictably, isoproterenol was ineffective in achieving return of spontaneous circulation, while epinephrine was uniformly successful. Care should be exercised in applying these results to other settings, as post-countershock EMD probably has a better prognosis. Earlier recommendations to use isoproterenol in EMD have recently been changed. As discussed above, a h u m a n trial comparing epinephrine and methoxamine in EMD found no difference in outcome but may have been flawed in its methodology314 In the absence of studies that better define the clinical subsets of EMD and Annals of Emergency Medicine

their optimal therapy, epinephrine remains the drug of choice for EMD. Once again, consideration must be given to the correct dose of epinephrine in EMD. The lower intram y o c a r d i a l pressure during EMD m a y result in greater myocardial blood flow for a given coronary perfusion pressure than seen during ventricular fibrillation. Theoretically, this may lower the pressor dosage needed, but this has not been studied. Studies using animal models of EMD have used higher dosages than those used clinically311 There is a preliminary report that administration of high-dose epinephrine to patients in EMD who had central aortic pulse pressures resulted in an increase in the fraction of patients with return of spontaneous circulation. 93 However, this was done after prolonged cardiac arrest and did not result in an improvement in ultimate o u t c o m e . W h e t h e r earlier use of higher doses would improve outcome has not been investigated in adults. Children tend to suffer bradyasystolic arrests, a subset of EMD, after respiratory arrest, and a recent pediatric s t u d y using 0.2 m g / k g epinephrine found an improved outcome including long-term survival when compared with historical controls. 91

ASYSTOLE Most studies on cardiac arrest have been done in ventricular fibrillation models, while work on asystole has been limited. This is probably because resuscitation from asystole is rare, making outcome studies difficult even in animals. There is no reason to conclude that epinephrine's augmentation of coronary perfusion during CPR, which may be secondary to extramyocardial processes, does not o c c u r during asystole. As in EMD, it is possible that an improvement in peffusion pressure would result in higher myocardial blood flows than during ventricular fibrillation because of the lower intramyocardial resistance. Whether this will result in improved outcome is not clear. Asystole may also have varying etiologies with differing prognoses. W h e n it results from r e s p i r a t o r y arrest, as is c o m m o n in children, its prognosis may not be so grim. Beta-adrenergic stimulation, particularly arousal of ventricular pacemakers, has been thought to be re1296/107


sponsible for restarting the asystolic heart.~37,138 The absence of a workable animal model of asystole will make it difficult to test this hypothesis. Presently, no other drug has been shown to be more effective than epinephrine in resuscitating patients from asystole, and, despite low success rates, 139,140 its continued use is reasonable.t Because the prognosis for adult patients in asystole is so poor, it is a diagnosis in which early use of higher epinephrine doses may be indicated. Because the resuscitation rates are extremely low, a prospective study of therapy for asystole would need to be quite large in order to yield a statistically significant outcome. It is probable that our treatment of this entity will continue to have only an empirical or theoretical basis in the near future. NEUROLOGIC OUTCOME Any therapy that adversely affects neurologic outcome will have limited usefulness in resuscitation. Early institution of at least some components of ACLS therapy appears to be capable of blunting or even preventing the neurologic injury associated with global ischemia. 133 Although unusual, survival and even normal neurologic outcomes have been reported after prolonged resuscitations. Pressors, especially epinephrine, are a major part of this therapy and have been the subject of a significant share of the research in this area. It is widely accepted that the degree of cerebral injury is primarily a function of the duration and extent of ischemia. Studies in animals have shown that epinephrine greatly increases cerebral blood flow during external CPR. 70 Michael and associates demonstrated that epinephrine was able not only to reverse the time-dependent deterioration in the cerebral perfusion pressure (carotid minus intracranial) but raised it above immediate post-arrest levels, s While this was not associated with a larger common carotid blood flow, a dramatic increase in cerebral flow occurred s e c o n d a r y to r e d i s t r i b u t i o n away from extracranial tissues. These results have been confirmed by Luce and associates. 6s Brown showed a dose-dependent improvement in cerebral blood flow with epinephrine and significantly greater flows with dosages above 0.02 m g / k g . 6 Extremely low blood flow may be more 108/1297

damaging to neurons than complete i s c h e m i a of e q u a l l e n g t h , t41 In Brown's model, cerebral blood flow after 0.02 mg/kg was so low that he e x p r e s s e d c o n c e r n t h a t t h i s amounted to only "trickle flow." Only a limited number of studies have c o m p a r e d e p i n e p h r i n e w i t h other agents using neurologic end points. In a study by Holmes and associates, epinephrine increased cerebral blood flow while phenylephrine not only failed to do so but did little better t h a n the pure [3 drug isoproterenol. 83 As discussed above, however, the dosage of phenylephfine may have been inadequate, and higher dosages have been reported to produce cerebral blood flows equival e n t to t h o s e of h i g h - d o s e epinephrine, so Other investigators were unable to demonstrate a difference in 24-hour survival or neurologic deficit score b e t w e e n higher dosages of phenylephrine and epinephrine. 117 This model, however, had only a three-minute arrest. Studies in animals with intact circulation have shown that [~-adrenergic stimulation results in dilation of cerebral microvasculature and increased regional blood flow. 142,143 Whether this same process can occur during cardiac arrest, a state in which the cerebral microvasculature can be assumed to be m a x i m a l l y dilated from i n c r e a s e d e x t r a c e l l u l a r potassium, adenosine, and protons, is not known. If it does occur, it may represent a potential benefit of epin e p h r i n e over pure R - a d r c n e r g i c drugs. A particularly intriguing finding was the recent observation that c a t e c h o l a m i n c s m a y m o d u l a t e ischemic brain damage through pathways other than increases in vascular pressure. ~44 At this time, the use of pressors appears important in maintaining cerebral perfusion and neurologic viability during normothermic cardiac arrest. Epinephrine remains the drug of choice for this purpose, but animal studies indicate that dosages higher than the standard 1 mg may be needed before its full benefit is obtained.

R O U T E OF A D M I N I S T R A T I O N The route of epinephrine administration during cardiac arrest has received limited attention. Although the intracardiac route was popular in the past, more recent guidelines have not recommended it because of cornAnnals of Emergency Medicine

plications such as coronary artery laceration or pneumothorax. 1 Redding and Pearson compared the effectiveness of different routes of administration3 45 In their study, resuscitation rates using intracardiac, central venous, and endotracheal routes were comparable. The IM route was less effective. Although anecdotal success using endotracheal administration has been reported, 146 recent research raises serious questions concerning the continued recommendation that the endotracheal dose remain 1 mg in adults. Ralston and associates, in an EMD model with only a two-minute arrest time, found that the median effective IV dose was 0.014 mg/kg, but endotracheally it was 0.13 mg/kg or nearly ten times as much. 86 Quinton and associates, using standard epinephrine doses delivered in the proximal endotracheal tube during cardiac arrest in h u m a n beings, were unable to demonstrate any increase in arterial epinephrine concentrations. ~03 IV a d m i n i s t r a t i o n resulted in more than a threefold rise. The reference cited in the ACLS guidelines states that, in the animal model used, the m a x i m u m plasma e p i n e p h r i n e c o n c e n t r a t i o n s measured after endotracheal administration "are approximately one-tenth of those achieved with an equal IV dosage. ''147 Yet these guidelines continue to recommend an endotracheal dosage of 1 mg. L If, as discussed in the Dosage section, the current recommended IV dose may be too low in cardiac arrest, then the same dose endotracheally is totally inadequate. M a n y of the a n e c d o t a l cases in which it appeared effective may actually have been profound shock, 128 an entity that may mimic EMD and appears to be treatable by endotracheally administered standard doses. 148 Studies in a clinically relevant animal model are needed to determine the optimal dose of epinephrine endotracheally. The limited data currently available indicate that the dosage may be as high as 2 mg/kg, but this is only conjecture, and dosages this high may have significant pulmonary toxicity. ~2° There have been no studies directly comparing the efficacy of central and peripheral IV administration of epinephrine during cardiac arrest. A n i m a l studies using tracer subs t a n c e s indicate that the central r o u t e m a y p r o v i d e f a s t e r de]iv19:11 November 1990

cry. 149-151 H u m a n studies have been

consistent with this but have had a n u m b e r of limitations. One showed a lower arterial c o n c e n t r a t i o n w i t h per i p h e r a l a d m i n i s t r a t i o n , 149 a n d another, w h i c h examined only two patients, showed a delay to peak concentration.151 T h i s delay, however, ranged from 10 to 33 seconds. Therefore, the small possible advantage of c e n t r a l v e n o u s delivery is probably o u t w e i g h e d by the typical delay in e s t a b l i s h i n g t h i s IV route. Because experimental evidence is not yet definitive, it seems reasonable to adm i n i s t e r epinephrine by whatever IV route first becomes available. If both routes are available, central administration can be given preference. The endotracheal route can be used if IV access is unavailable; however, large doses should be considered. TOXICITY C a t e c h o l a m i n e s at a b n o r m a l l y high c o n c e n t r a t i o n s cause a characteristic p a t t e r n of myocardial damage, the microscopic appearance of w h i c h has led to the term "contract i o n b a n d necrosis."lsz, 153 T h i s lesion is not only observed after therap e u t i c or e x p e r i m e n t a l exposure to p h a r m a c o l o g i c a l doses, b u t also in t h e s e t t i n g of p a t h o l o g i c a l s t a t e s such as m y o c a r d i a l ischemia, pheochromocytoma, and in most cases of cardiac sudden death. ~54 This injury m a y be o b s e r v e d after e x p o s u r e to c a t e c h o l a m i n e s o t h e r t h a n epin e p h r i n e . ~ss In addition to myocard i a l effects, c a t e c h o l a m i n e s m a y cause Vascular injury.153,156 A direct toxic m e c h a n i s m and n o t an alteration in h e m o d y n a m i c s is suggested by the observation that these lesions m a y be present after use of either isoproterenol or norepinephrine, despite their quite different effects on hemod y n a m i c s , t54 T r e a t m e n t w i t h a [3 blocker prior to onset of ventricular f i b r i l l a t i o n m a y p r e v e n t the injury,157 i n d i c a t i n g t h a t [3-receptor s t i m u l a t i o n m a y be c e n t r a l to the m e c h a n i s m of injury. Changes i n cyclic AMP, i n t r a c e l l u l a r calcium, or energy charge have been p o s t u l a t e d as the secondary mediators. 15s-16° P a t i e n t s i n s p o n t a n e o u s circulation accidentally given large doses of epinephrine immediately complain of chest or abdominal pain and show signs of excessive sympathetic stimu l a t i o n w i t h severe transient hypert e n s i o n , often f o l l o w e d by p u l m o 19:11 November 1990

n a r y e d e m a a n d hypotension.48, '6~ A n IV dose of 3 mg has been reported as fatal, w h i l e o t h e r p a t i e n t s have s u r v i v e d IV d o s e s as l a r g e as 30 r a g . 162,163 Most reports on epinephrine toxicity have been in hemod y n a m i c a l l y i n t a c t a n i m a l s or hum a n beings. Whether it is appropriate to apply these results to the low-flow state p r e s e n t d u r i n g cardiac arrest w i t h CPR is n o t clear. D e l i n e a t i o n of toxicity i n this s e t t i n g is difficult; the o u t c o m e s tend to be poor, and the contraction band lesion is often present after sudden death even witho u t e x p o s u r e to e x o g e n o u s epinephrine. D u r i n g i n t a c t c i r c u l a t i o n , epin e p h r i n e is cleared rapidly from the e x t r a c e l l u l a r space. 99 Studies indicate t h a t the effect of e p i n e p h r i n e d u r i n g c a r d i a c a r r e s t is also t r a n sient.11, 69 T h e t o x i c i t y of i n t r a venously administered epinephrine m a y be decreased during cardiac arrest by its catabolism during the prolonged v e n o u s phase present during low flow. Although this might lower concentrations at sites susceptible to c a t e c h o l a m i n e toxicity, it m a y also result in decreased efficacy (see Dosage). It is conceivable that the plasma levels of a drug that would be toxic during spontaneous circulation may be therapeutic during cardiac arrest. Hypothetical toxicity is meaningless if the alternative is death. If [3-adrenergic blockade prevents the contraction band lesion, 157 its use m a y ameliorate potential toxicity of high-dose e p i n e p h r i n e therapy. T h i s has n o t been studied. Epinephrine has been s h o w n to increase s h u n t i n g in the p u l m o n a r y circulation during spontaneous circulation, an effect that can be prevented by [3 blockade. 164 It has recently been d e m o n s t r a t e d in b o t h a n i m a l s and h u m a n beings during CPR that epinephrine dosages that raise coronary perfusion pressure result i n a drop in end-tidal carbon dioxide.T4,16s A conc o m i t a n t drop in arterial oxygen and increase in carbon dioxide has been reported, lzo These adverse effects on gas exchange do not appear to be of a large enough magnitude to be import a n t u n d e r m o s t clinical situations, b u t this m u s t be confirmed in hum a n beings. In patients with marginal blood gases, the effect may be significant, indicating a potential super i o r i t y of pure c~ agents. T h e r e is, however, a p r e l i m i n a r y report that Annals of Emergency Medicine

use of h i g h - d o s e e p i n e p h r i n e does not result in clinically significant toxicity, t66 However, this study appears not to have had b l i n d e d randomization, and there was considerable range in w h a t was considered high-dose epinephrine. CONCLUSION Medicine is at a time of reassessmerit in the area of resuscitation. Initial e n t h u s i a s m has given way to the realization that the t r e a t m e n t of cardiac arrest is often ineffective. Epinephrine, as well as other therapies, m u s t be subject to this re-examination. The most i m p o r t a n t end point is the fraction of p a t i e n t s w h o are discharged neurologically intact. During this reassessment, our efforts m u s t m a i n t a i n a strong, c l i n i c a l l y relevant focus..

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19:11 November 1990

Epinephrine in out-of-hospital cardiac arrest: A critical review.

High-dose epinephrine in pediatric cardiac arrest.

High-dose epinephrine in adult cardiac arrest.

Four case studies: high-dose epinephrine in cardiac arrest.

Epinephrine in Out-of-hospital Cardiac Arrest: Helpful or Harmful?

Epinephrine Administration and Pediatric In-Hospital Cardiac Arrest.

Epinephrine Administration and Pediatric In-Hospital Cardiac Arrest--Reply.

High-dose epinephrine improves outcome from pediatric cardiac arrest.

Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data.

A pharmacologic review of cardiac arrest.

Cardiac arrest: a case-based review.

Comparison of two doses of endotracheal epinephrine in a cardiac arrest model.

Effects of epinephrine administration in out-of-hospital cardiac arrest based on a propensity analysis.

Year in review 2012: Critical Care--Out-of-hospital cardiac arrest and trauma.

Vasopressin improves survival compared with epinephrine in a neonatal piglet model of asphyxial cardiac arrest.

Plasma catecholamine levels after intraosseous epinephrine administration in a cardiac arrest model.

Non-critical care telemetry and in-hospital cardiac arrest outcomes.

An evidence-based review of epinephrine administered via the intraosseous route in animal models of cardiac arrest.

CRITICAL CARE ECHO ROUNDS: Echo in cardiac arrest.

Does a resuscitation pharmacologic bundle of epinephrine, terlipressin, and corticosteroids improve outcome from asphyxial cardiac arrest?

Improved neurologic outcomes after cardiac arrest with combined administration of vasopressin, steroids, and epinephrine compared to epinephrine alone.

Comparison of standard versus high-dose epinephrine in the resuscitation of cardiac arrest in dogs.

Epinephrine, vasopressin and steroids for in-hospital cardiac arrest: the right cocktail therapy?

ACP Journal Club. Combined vasopressin, steroids, and epinephrine improved survival in in-hospital cardiac arrest.