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High-dose epinephrine improves outcome from pediatric cardiac arrest
ORIGINAL CONTRIBUTION cardiac arrest, pediatric; epinephrine
High.Dose Epinephrine Improves Outcome From Pediatric Cardiac Arrest Study objective: Animal studies suggest that the standard dose of epinephrine (SDE) for treatment of cardiac arrest in human beings m a y be too low. We compared the outcome after SDE with that after high-dose epinephrine (HDE) in children with refractory cardiac arrest. Design: Prospective intervention versus historic control groups. Type of participants: Two similar groups of 20 consecutive patients each (median ages, 2.5 and 3 years) with witnessed cardiac arrest who remained in arrest after at least two SDEs (0.01 mg/kg). Interventions: Treatment with an additional SDE versus HDE (0.2 rag~
kg).
Measurements and main results: The rates of return of spontaneous circulation and long-term survival were compared. Fourteen of the FIDE group (70%) had return of spontaneous circulation, whereas none of the SDE group did (P < .001). Eight children survived to discharge after HDE, and three were neurologically intact at follow-up. No significant toxicity from HDE was observed. Conclusion: HDE provided a higher return of spontaneous circulation rate and a better long-term outcome than SDE in our series of pediatric cardiac arrest. FIDE m a y warrant incorporation into standard resuscitation protocols at an early enough point to prevent irreversible brain injury. [Goetting MG, Paradis NA." High-dose epinephrine improves outcome from pediatric cardiac arrest. Ann Emerg Med January 1991;20:22-26.7
Mark G Goetting, MD*t Norman A Paradis, MDt Detroit, Michigan From the Departments of Pediatrics* and Emergency Medicine,t Henry Ford Hospital, Detroit, Michigan. Received for publication August 1, 1990. Revision received September 10, 1990. Accepted for publication September 17, 1990. This study was made possible by a grant from the Christopher C Tackett, Jr Memorial Research Fund. Address for reprints: Mark G Goetting, MD, Department of Pediatrics, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202.
INTRODUCTION Standard treatment for pediatric cardiac arrest often fails to induce the return of spontaneous circulation (ROSC), and neurologic morbidity is high among survivors. 1-6 The systemic hypoxia that causes or immediately results from cardiac standstill produces tissue acidosis and an oxygen debt in the heart and brain as well as other organs. Animal and human studies suggest the inadequacy of myocardial and cerebral blood flow to repay this debt with basic cardiac life support alone and thus prevent further hypoxic injury. 710 In addition, cardiac output and myocardial and cerebral perfusion diminish rapidly after the first few minutes of CPR.8,11 Therefore, it appears that the best brain-oriented treatment of cardiac arrest is prompt ROSC and that the greatest chance for ROSC is early during CPR. Epinephrine is the most effective drug therapy for cardiac arrest, m Its potent c,-adrenergic properties elevate vasomotor tone, thereby increasing the aortic-right atrial pressure gradient during the chest relaxation phase of CPR.8,13, ]4 This gradient, coronary perfusion pressure, correlates directly with myocardial blood flow in animal models and is a good predictor of ROSC in animals and human beings.iS In addition, epinephrine enhances cerebral perfusion by increasing aortic pressure, preventing carotid collapse at the thoracic inlet, and diverting cephalic blood flow from extracerebral structures.S,13 Recent animal studies reveal a dose-response relationship between epinephrine and coronary and brain blood flow that suggests that the current pediatric recommendation of 0.01 mg/kg may be less than optimal for the treatment of cardiac arrest. 14 Anecdotal experience in adults supports this. 16 We recently reported our preliminary findings of a beneficial effect of high-dose epinephrine (HDE) in pediatric cardiac arrest refractory to a
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H I G H - D O S E EPINEPHRINE Goe t t i ng & Paradis
standard dose (SDE). t7 The present report extends these observations to a larger group of patients and allows a better e s t i m a t e of efficacy for ROSC, patient outcome, and drug toxicity. MATERIALS
AND
METHODS
Twenty consecutive children treated for cardiac arrest who failed to have ROSC after at least two standard doses of IV epinephrine (0.01 mg/kg) five minutes apart were administered HDE (0.2 mg/kg) in a 1:10,000 dilution for infants and a 1:1,000 dilution for older patients. All patients had had witnessed arr e s t s with treatment initiated within seven minutes using advanced cardiac life support (ACLS) guidelines. 18 The IV line was flushed after each dose of medication to facilitate distribution of the drug. Atropine 0.01 mg/kg (minimum dose, 0.1 rag) was given for bradycardia and asystole with the first two SDEs. Sodium bicarbonate (1 mEq/kg) was administered once before the second SDE. Ventilation was with 100% oxygen through an endotracheal tube. All patients were monitored by continuous ECG. ROSC was defined as a supraventricular rhythm with either palpable pulses or a systolic arterial pressure of 60 m m Hg or more by invasire monitoring. Recorded for each patient were age, diagnosis, recent previous cardiac arrest, use of vasopressors at the onset of arrest, time delay to initiation of CPR and administration of the first epinephrine dose, presenting rhythm, and outcome. The records of the previous 20 consecutive children treated by the same author during a 12-month period for cardiac arrest who had received more than two SDEs, had witnessed arrests with ACLS within five minutes, and had received the same resuscitation protocol except for HDE were reviewed to establish a group of historic controls, t7 A two-sided, twosample t test was used to determine differences, with significance defined as P < .05. RESULTS
Patient characteristics and diagnoses are given (Tables 1 and 2). There were no significant differences between groups in age, percentage on vasopressors at the time of arrest, 46/23
TABLE 1. Characteristics of pediatric cardiac arrest patients:
Control versus intervention group
No. of patients Median age Previous CPR (%)
Control
HDE
20 3 yr (1 mo - 18 yr)
20 2,5 yr (2 mo - 16 yr)
30
40
Vasopressors (%) Time to CPR (mean _+ SD)
30 3.4 + 1.7 rain
40 3.4 _+ 1.6 min
Time to first dose of epinephrine (mean _+ SD)
4.7 _+ 2.3 min
4.9 +_ 2,4 rain
proportion who received previous CPR, time from arrest to initiation of CPR, or time from arrest to first dose of epinephrine (P ~> .28). Two of the control and none of the HDE groups had t a c h y a r r h y t h m i a s and were treated with lidocaine and defibrillation or cardioversion. All other patients had either bradycardia or asystole as the initial arrest rhythm. Seve n t e e n of the HDE group (85%) received the higher dose after only two SDEs, whereas the remaining three received three doses first. Fourteen of the HDE group (70%) had ROSC within five minutes of administering the high dose, whereas none of the control group regained spontaneous h e m o d y n a m i c s (P < .001). Of the six who failed to respond to HDE, four did not respond to an additional HDE five minutes later and two did not respond to repeated SDEs. All 14 of the survivors of cardiac arrest responded to HDE with sinus tachycardia for at least 15 minutes, and none developed life-threatening tachyarrhythmias. A period of mildto-moderate hypertension lasting less than 20 minutes occurred in eight but did not require treatment. Ten were placed on vasopressor IV drips after arrest. In all patients, ECGs within one day of ROSC showed no evidence of ischemic injury. Eight survived to discharge. Six regained their prearrest n e u r o l o g i c function, three of whom were developmentally normal six to.17 months after resuscitation, as judged by the parents and evaluation by a pediatric neurologist. The causes of arrest in these three were severe bilateral pulm o n a r y c o n t u s i o n s and acute hypoxia, h y p o v o l e m i a , and s e p t i c shock. Three others had severe preexisting cognitive disabilities but retained their prearrest developmental achievements, according to their parAnnals of Emergency Medicine
TABLE 2. Diagnoses of pediatric cardiac
arrest patients: Control versus intervention group
Diagnosis
Control HDE
Aspiration
4
3
Asphyxia Asthma
3 3
2 0
Sepsis Increased intracranial pressure
3 2
3 3
Smoke inhalation
1
1
Hypovolemia Multiple trauma
1 1
3 2
Pneumonia Poisoning
1 1
1 0
Sudden infant death syndrome
0
2
ents and pediatricians. The other two suffered serious global cortical damage, either from previous or the studied cardiac arrest. One of the eight who died after ROSC donated his kidneys. DISCUSSION In 1903, Crile demonstrated the effectiveness of epinephrine in the resuscitation of dogs from cardiac arr e s t . 19 Since then, epinephrine has become a major part of therapy for cardiac arrest, although the optimal dose for human beings is unknown. 12 Investigators working with animal models of cardiac arrest have used greater doses per weight than those currently recommended for huma~n 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 the 8DE may be too low. 12,14 During their early investigations, Redding and Pearson found that 1.0 mg epinephrine is effective in resuscitating dogs with average weights of approximately l0 kg, a dose of 0.1 20:1 January 1991
HIGH-DOSE EPINEPHRINE Goetting & Paradis
mg/kg. 2° The current recommended dose in children is 0.01 mg/kg, is It is unclear why this is considerably less than that used by Redding and Pearson, whose report is provided as a major reference in the ACLS guidelines. Of note is their comment that this 1-mg dose was used "with benefit in children down to eighteen months of age. ''21 Using an approximate weight of 12 kg, this equals 0.08 mg/kg, eight times the SDE. Most studies on the effect of epinephrine in cardiac arrest have been performed in animals. Using an ischemic ventricular fibrillation model, Yakaitis and associates found that a dose of 0.077 mg/kg increases the percentage of animals with successful defibrillation. ~ In an electromechanical dissociation model, one of greater relevance to pediatric arrest, Ralston and associates demonstrated a dose-response relationship between epinephrine and percentage with ROSC. In this model, administration of 0.01 mg/kg produced a 40% resuscitation rate, whereas 0.1 mg/kg resulted in resuscitation of approximately 90% of animals. 23 Brown and associates examined the dose-response relationship between epinephrine and vital organ blood flow.24,25 In their swine model, they f o u n d t h a t 0.2 m g / k g epinephrine produces cerebral blood flows that are severalfold higher than those produced with 0.02 mg/kg. In all areas of the sampled myocardium, blood flow with the higher close is greater than flow with the lower dose. As an example of the magnitude of the improved perfusion, the mean left ventricular endocardial blood flow increased from 2.5 to 176 mL/100 g x min. In all measured areas, the higher dose produced myocardial blood flow that was greater than the threshold of 20 mL/100 g x rain found to be necessary to meet the metabolic demands of the fibrillating heart. 26 Although no statistically significant difference was detected between 0.2 and 2 mg/kg, blood flow was less for most of the myocardium in the highest dose. This "leveling off" of the dose-response curve suggests that although the optimal dose is probably m u c h higher than that recommended, there may be a limit to the benefit of even higher doses. A beneficial effect from higher doses of epinephrine has been noted 20:1 January 1991
in human beings. Gonzalez and associates recently reported the vasopressor response to 1-, 3-, and 5-mg doses in adults with prehospital cardiac arrest. 27 They found that 5 mg increased chest relaxation-phase arterial pressure compared with the preepinephrine state, whereas 1- and 3-mg doses did not. In another study, c o r o n a r y p e r f u s i o n p r e s s u r e increased in human beings with prolonged arrest after 12 to 14 mg, whereas there was no change after 1 rag. 28 There is a report of two adults having ROSC after 5 or 6 mg epinephrine, respectively, when multiple SDEs failed. 16 The need for such large amounts o f exogenous epinephrine is unknown. It may be that adrenergic receptor downregulation or uncoupling occurs in cardiac arrest. 29-31 An additional factor underlying the need for larger doses may be the mechanism of action of the drug itself. Administration of approximately 14-fold more epinephrine to adults in cardiac arrest resulted in only a 2.6-fold increase in arterial plasma levels. 3~ This suggests either an enhanced metabolism or increased volume of distribution with greater doses. Cardiac arrest is the state of maximal biologic stress and is associated with the highest plasma levels of epinephrine and norepinephrine. Plasma epinephrine levels are approximately 0.03 ng/mL in normal resting human beings. 33 With cardiac arrest, these levels can increase several hundredfold w i t h o u t e x o g e n o u s epinephrine. 34 The r e l a t i v e i n c r e a s e in plasma levels after the SDE is not nearly as great as that from cardiac arrest alone. Wortsman and associates found the average plasma epinephrine level increased from 10 to 72 n g / m L a f t e r e x o g e n o u s epinephrine dosing in ICU patients suffering cardiac arrest. 33 Quinton and associates found an increase from 12 to 55 ng/mL in prehospital cardiac arrest patients. 35 Thus, taken in the context of the spontaneous increase in plasma epinephrine levels during cardiac arrest, the additional fivefold to sevenfold increase from 1 mg of exogenous epinephrine seems less impressive. Kern and associates recently studied the relationship between plasma catecholamines and outcome after eight and 12 minutes of cardiac arrest. 36 They found that the absolute Annals of Emergency Medicine
levels as well as the magnitude of increase in endogenous catecholamines after arrest did not predict which animals w o u l d be r e s u s c i t a t e d successfully. However, the increase in plasma levels after exogenous epinephrine was predictive of outcome. Animals with ROSC had a mean 53fold increase in levels, whereas those that remained in arrest had only a 23fold increase. If an increase in plasma epinephrine of 50-fold is necessary for resuscitation of animals, then the fivefold to sevenfold increase found in human beings after SDEs is probably inadequate. Most pediatric cardiac arrests are b r a d y a s y s t o l i c . The lower intramyocardial pressures in this condition may result in greater myocardial blood flow for a given coronary perfusion pressure than in ventricular fibrillation. Theoretically, this should result in greater clinical efficacy for a given dose of a pressor. For this reason, children may stand to benefit the most from HDE. Toxicity is a relative concern in the treatment of cardiac arrest. Very high levels of catecholamines can cause a characteristic pattern of myocardial injury called " c o n t r a c t i o n band necrosis. ''37 This lesion is seen not only after therapeutic and experimental exposure to pharmacologic doses, but also in pathologic states such as myocardial ischemia, pheochromocytoma, and sudden cardiac death. 3s In addition to myocardial damage, catecholamines may cause vascular injury. 39 Most reports of epinephrine toxicity have been from studies on hemodynamically intact animals and human beings. Whether these findings apply to the low-flow state of cardiac arrest is unknown. Delineation of toxicity in this setting is difficult; the outcomes tend to be poor, and contraction band necrosis m a y be present w i t h o u t exogenous epinephrine. The absence of ECG ischemic changes in our patients is reassuring but does not rul~ out myocardial injury. In a preliminary report comparing HDE with SDE in adults, incidence rates of arr h y t h m i a s and ECG changes, and peak creatine kinase levels did not differ. 4o Our study showed a dramatic improvement in the rate of ROSC after HDE in refractory pediatric cardiac arrest. The limitations of the study, specifically, the use of historic con24/47
HIGH-DOSE EPINEPHRINE Goetting & Paradis
trols and the unblinded administration of HDE, must be considered when interpreting the results. Nonetheless, the study strongly supports the superiority of HDE. The high rates of ROSC and long-term survival after three doses of epinephrine are unprecedented. Previous reports describe a total of 70 children who received two or three SDEs during cardiac arrest. 4-6 Fourteen percent were alive at 24 hours, and none survived to hospital discharge. In the study in which an ROSC rate was given, ten of 18 (56%) of those who failed to respond to a single epinephrine dose never regained spontaneous hemodynamics. 5 Our 70% ROSC rate and 40% long-term survival rate after three or four epinephrine doses contrast strikingly. After our favorable experience with HDE in adult clinical studies~8, 41 and anecdotally in adults and children,16,17 we question the ethics of using a prospective control group. What is the optimal epinephrine dose, and how HDE should be integrated into a pediatric resuscitation protocol are important questions. We chose the dose of 0.2 mg/kg based on animal studies and scant h u m a n data. 14,15,17,42 It is u n k n o w n what dose provides the maximum beneficial effect in human beings with the least risk of toxicity. However, our experience as well as that of others 42 suggests that this dose is effective and usually well tolerated. Brain injury is usually the limiting factor in a satisfactory recovery after R o s e . In adults, the duration of CPR, independent of the preceding time in arrest, strongly correlates with neurologic disability, 43 further implicating the ineffectiveness of CPR to adequately perfuse the brain. The time limits of cerebral viability during CPR in children are unknown but can be expected to demonstrate considerable individual variability, depending on the cause of arrest, body temperature, 44 age, 45 and effectiveness of chest compressions. However, it can be reasoned that after establishment of adequate ventilation and oxygenation and the institution of chest c o m p r e s s i o n s , efforts to promptly increase coronary perfusion pressure, the best p r e d i c t o r of ROSC, tS should take priority. After failure of two standard doses of epinephrine to satisfactorily increase perfusion pressure within five 48/25
minutes, as evidenced by continued cardiac arrest, it seems unlikely that repeating this dose will succeed. We would consider HDE at this point. To delay this intensive therapy may risk neurologic injury and even failure to induce ROSC. Although some patients have complete recovery from prolonged cardiac arrest when treated conventionally, this is exceptional, and the approach to resuscitation should provide the best opportunity for intact survival in all individuals in whom it is attempted. CONCLUSION Results from our study show the superiority of HDE over SDE in children with refractory cardiac arrest. The resuscitation rate was m u c h higher, and there was no evidence of significant toxicity. HDE allowed long-term survival in a substantial percentage of patients, some with full neurologic recovery. HDE should be considered in cardiac arrest early enough to prevent irreversible brain injury. REFERENCES 1. Friesen RM, Duncan P, Tweed WA, et al: Appraisal of pediatric cardiopulmonary resuscitation. Can Med J 1982;126:1055-1058. 2. Lewis JK, Minter MG, EsheIman SJ, et ah Outcome of pediatric resuscitation. Ann Emerg Med 1983;12: 297-299. 3. Torphy DE, Minter MG, Thompson BM: Cardiorespiratory arrest and resuscitation of children. A m J Dis Child 1984;138:1099-1102. 4. Nichols DG, Kettrick. RG, Swedlow DB, et al: Factors influencing outcome of cardiopulmonary resuscitation in children. Pediatr Emerg Care 1986;2:1-5. 5. Ginis J, Dickson D, Rieder M, et al: Results of inpatient pediatric resuscitation. Crit Care Med 1986;14: 469-471. 6. Zaritsky A, Nadkarni V, Getson P, et ah CPR in children. Ann Emerg Med i987;16:1107-1111. 7. Eleisher G, Sagy M, Swedlow DB, et al: Open- versus closed-chest cardiac compressions in a canine model of pediatric cardiopulmonary resuscitation. A m J Emerg Med 1985;3:305-310. 8. Schleien CL, Dean JM, Koehler Re, et al: Effect of epinephrine on cerebral and myocardial perfusion in an infant animal preparation of cardiopulmonary resuscitation. Circulation 1986;73:809-817. 9. Fleisher G, Delgado-Paredes C, H e y m a n S: Slow versus rapid closed-chest cardiac compression during eardiopulroonary resuscitation in puppies. Crit Care Med 1987;15:939-943. 10. Goetting MG, Preston G: Cerebral oxygen extraction during CPR in children (abstract). Ann Emerg Med 1988;17:436. 11. Berkowitz ID, Chantarojanasiri T, Koehler RC, et ah Blood flow during cardiopulmonary resuscitation with simultaneous compression and ventilation in infant pigs. Pediatr Res 1989;26:558-564. 12. Paradis NA, Koscove EM: Epinephrine in cardiac arrest: A critical review. Ann Emerg Med 1990;19:12881301. 13. Michael JR, Guerci AD, Koehler RC, et al: Mechanisms by which epinephrine augments cerebral and
Annals of Emergency Medicine
myocardial perfusion during cardiopulmonary resuscitation in dogs. Circulation 1984;69:822-835. 14. Brown CG, Werman HA: Adrenergic agonists during cardiopulmonary resuscitation. Resuscitation 1990;19: 1-16. 15. Paradis NA, Martin GB, Rivers EP, et al: Coronary perfusion pressure and the return of spontaneous circulation in human cardiopuImonary resuscitation, lAMA 1990;263:1106-1113. 16. Koscove EM, Paradis NA: Successful resuscitation from cardiac arrest using high-dose epinephrine therapy. JAMA 1988;259:3031-3032. 17. Goetring MG, Paradis NA: High dose epinephrine in refractory- pediatric cardiac arrest. Crit Care Med 1989;17:1258-1262. i8. Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). JAMA 1986;255:2841-3044. 19. Crile GW: Preliminary note on a method of resuscitation of apparently recently dead animals. Cleve Med J 1903;2:35. 20. Redding J8~ Pearson JW: Evaluation of drugs for cardiac resuscitation. Anaesthesia 1963;24:203-207. 21. Pearson JW, Redding JS: The role of epinephrine in cardiac resuscitation. Anesth Analg 1963;42:599-606. 22. Yakaitis RW, Otto CW, Blitt CD: Relative importance of alpha and beta adrenergic receptors during resuscitation. Crit Care Med 1979;7:293-296. 23. Ralston SH, Tacker WA, Showen L, et al: Endotracheal versus intravenous epinephrine during electromechanic dissociation with CPR in dogs. Ann Emerg Med 1985;14:1044-1048. 24. Brown CG, Werman HA, Davis EA, et al: Comparative effect of graded doses of epinephrine on regional brain blood flow during CPR in a swine model. Ann Emerg Med 1986;15:1138-1144. 25. Brown CG, Werman HA, Davis EA, et al: The effect of graded doses of epinephrine on regional myocardial blood flow during eardiopuImonary resuscitation in swine. Circulation 1987;75:491-497. 26. Neimann JT: Differences in cerebral and myocardial perfusion during closed-chest resuscitation. Ann Emerg Med 1984;13:849-853. 27. GonzaIes ER, Ornato JP, Garnett AR, et al: Dosedependent vasopressor response to epinephrine during CPR in h u m a n beings. A n n Emerg Med 1989;18: 920-926. 28. Paradis NA, Martin GB, Rivers EP, et ah High-dose epinephrine and coronary perfusion pressure during cardiac arrest in human beings (abstract). Ann Emerg Med 1989;18:478. 29. Bristow MR, Ginsburg R, Minobe W, et ah Decreased catecholamine sensitivity and beta-adrenergicreceptor density in failing human hearts. N Engi J Med 1982;307:205-211. 30. Lefkowitz RJ, Caron MG, Stiles GL: Mechanisms of membrane-receptor reguIation: Biochemical, physiological, and clinical insights derived from studies of the adrenergic receptors. N Engl J Med 1984;310: 1570-1579. 31. Vatner DE, Knight DR, Shen YT, et ah One hour of myocardial ischemia in conscious dogs increases betaadrenergic receptors, but decreases adenylate cyclase activity. J Mol Cell Cardiol 1988;310:1570-1579. 32. Paradis NA, Rivers EP, Martin GB, et ah The change in arterial epinephrine levels after standard a~xl high dose epinephrine during CPR in humans {abstract). Crit Care Med 1990;18:$221. 33. Wortsman J, Frank S, Cryer PE: Adrenomedullary response to m a x i m a l stress in humans. A m J Med 1984;77:779-784. 34. Little RA, Frayn KN, Randall PE, et ah Plasma catecholamines in patients with myocardial ischemia and in cardiac arrest. Q J Med 1985;54:133-140. 35. Quinton DN, O'Byme G, Aitkenhead AR: Comparison of endotracheal and peripheral intravenous adrenaline in cardiac arrest: Is the endotracheal route reliable? Lancet 1987;1:828-829.
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HIGH-DOSE EPINEPHRINE Goetting & Paradis
36. Kern KB, Elchisak MA, Sanders AB, et al: Plasma catecholamines and resuscitation from proIonged cardiac arrest, Crit Care Med 1989;17:78679I.
39. Haft JI: Cardiovascular injury induced by sympathetic catecholamines. Prog Cardiovasc Dis 1974;17: 73-86.
significantly improves resuscitation rates in human vict i m s of cardiac arrest (abstract). Ann Emerg Med 1990;19:490-491.
37. Todd GL, Baroldi G, Pieper GM, et al: Experimental catechoiamine-indnced myocardial necrosis: I. Morphology, quantification and regional distribution of the acute contraction band lesion. [ Moi Cell Cardio] i985;I7:317-338.
40. CalIaham M, Barton C, Kayser S: Potential adverse effects of high-close epinephrine in human survivors of cardiac arrest (abstract). A n n Emerg Med 1990;19: 479-480.
43. Abramson NS, Safar P, Detre KM: Nenrologic recovery after cardiac arrest: Effect of duration of ischemia. Crit Care Med 1985;13:930-931.
41. Paradis NA, Goetting MG, Rivers EP, et ah High dose epinephrine therapy and return of spontaneous circulation during human pseudo-electromechanical dissociation (abstract]. Ann Emerg Med 1990;19:491.
44. Orlowski JP: Drowning~ near-drowning, and ice-water submersion. Peddatr Clin North A m 1987;34:75-92.
38. Baroldi G, I~aIzi G, Mariane T: Sudden cardiac death: A postmortem study in 208 selected cases compared to 97 "controlled" subjects. A m Heart J 1979; 98:20-31.
42. Barton CW, Callaham M: High-dose epinephrine
45. Altman D1, Powers WJ, Perlman JM, et al: Cerebral blood flow requirement for brain viability in newborn is lower than in adults. Ann NeuroI 1988;24:218-226.
See related editorial, p 104.
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High.Dose Epinephrine Improves Outcome From Pediatric Cardiac Arrest Study objective: Animal studies suggest that the standard dose of epinephrine (SDE) for treatment of cardiac arrest in human beings m a y be too low. We compared the outcome after SDE with that after high-dose epinephrine (HDE) in children with refractory cardiac arrest. Design: Prospective intervention versus historic control groups. Type of participants: Two similar groups of 20 consecutive patients each (median ages, 2.5 and 3 years) with witnessed cardiac arrest who remained in arrest after at least two SDEs (0.01 mg/kg). Interventions: Treatment with an additional SDE versus HDE (0.2 rag~
kg).
Measurements and main results: The rates of return of spontaneous circulation and long-term survival were compared. Fourteen of the FIDE group (70%) had return of spontaneous circulation, whereas none of the SDE group did (P < .001). Eight children survived to discharge after HDE, and three were neurologically intact at follow-up. No significant toxicity from HDE was observed. Conclusion: HDE provided a higher return of spontaneous circulation rate and a better long-term outcome than SDE in our series of pediatric cardiac arrest. FIDE m a y warrant incorporation into standard resuscitation protocols at an early enough point to prevent irreversible brain injury. [Goetting MG, Paradis NA." High-dose epinephrine improves outcome from pediatric cardiac arrest. Ann Emerg Med January 1991;20:22-26.7
Mark G Goetting, MD*t Norman A Paradis, MDt Detroit, Michigan From the Departments of Pediatrics* and Emergency Medicine,t Henry Ford Hospital, Detroit, Michigan. Received for publication August 1, 1990. Revision received September 10, 1990. Accepted for publication September 17, 1990. This study was made possible by a grant from the Christopher C Tackett, Jr Memorial Research Fund. Address for reprints: Mark G Goetting, MD, Department of Pediatrics, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202.
INTRODUCTION Standard treatment for pediatric cardiac arrest often fails to induce the return of spontaneous circulation (ROSC), and neurologic morbidity is high among survivors. 1-6 The systemic hypoxia that causes or immediately results from cardiac standstill produces tissue acidosis and an oxygen debt in the heart and brain as well as other organs. Animal and human studies suggest the inadequacy of myocardial and cerebral blood flow to repay this debt with basic cardiac life support alone and thus prevent further hypoxic injury. 710 In addition, cardiac output and myocardial and cerebral perfusion diminish rapidly after the first few minutes of CPR.8,11 Therefore, it appears that the best brain-oriented treatment of cardiac arrest is prompt ROSC and that the greatest chance for ROSC is early during CPR. Epinephrine is the most effective drug therapy for cardiac arrest, m Its potent c,-adrenergic properties elevate vasomotor tone, thereby increasing the aortic-right atrial pressure gradient during the chest relaxation phase of CPR.8,13, ]4 This gradient, coronary perfusion pressure, correlates directly with myocardial blood flow in animal models and is a good predictor of ROSC in animals and human beings.iS In addition, epinephrine enhances cerebral perfusion by increasing aortic pressure, preventing carotid collapse at the thoracic inlet, and diverting cephalic blood flow from extracerebral structures.S,13 Recent animal studies reveal a dose-response relationship between epinephrine and coronary and brain blood flow that suggests that the current pediatric recommendation of 0.01 mg/kg may be less than optimal for the treatment of cardiac arrest. 14 Anecdotal experience in adults supports this. 16 We recently reported our preliminary findings of a beneficial effect of high-dose epinephrine (HDE) in pediatric cardiac arrest refractory to a
20:1 January 1991
Annals of Emergency Medicine
22/45
H I G H - D O S E EPINEPHRINE Goe t t i ng & Paradis
standard dose (SDE). t7 The present report extends these observations to a larger group of patients and allows a better e s t i m a t e of efficacy for ROSC, patient outcome, and drug toxicity. MATERIALS
AND
METHODS
Twenty consecutive children treated for cardiac arrest who failed to have ROSC after at least two standard doses of IV epinephrine (0.01 mg/kg) five minutes apart were administered HDE (0.2 mg/kg) in a 1:10,000 dilution for infants and a 1:1,000 dilution for older patients. All patients had had witnessed arr e s t s with treatment initiated within seven minutes using advanced cardiac life support (ACLS) guidelines. 18 The IV line was flushed after each dose of medication to facilitate distribution of the drug. Atropine 0.01 mg/kg (minimum dose, 0.1 rag) was given for bradycardia and asystole with the first two SDEs. Sodium bicarbonate (1 mEq/kg) was administered once before the second SDE. Ventilation was with 100% oxygen through an endotracheal tube. All patients were monitored by continuous ECG. ROSC was defined as a supraventricular rhythm with either palpable pulses or a systolic arterial pressure of 60 m m Hg or more by invasire monitoring. Recorded for each patient were age, diagnosis, recent previous cardiac arrest, use of vasopressors at the onset of arrest, time delay to initiation of CPR and administration of the first epinephrine dose, presenting rhythm, and outcome. The records of the previous 20 consecutive children treated by the same author during a 12-month period for cardiac arrest who had received more than two SDEs, had witnessed arrests with ACLS within five minutes, and had received the same resuscitation protocol except for HDE were reviewed to establish a group of historic controls, t7 A two-sided, twosample t test was used to determine differences, with significance defined as P < .05. RESULTS
Patient characteristics and diagnoses are given (Tables 1 and 2). There were no significant differences between groups in age, percentage on vasopressors at the time of arrest, 46/23
TABLE 1. Characteristics of pediatric cardiac arrest patients:
Control versus intervention group
No. of patients Median age Previous CPR (%)
Control
HDE
20 3 yr (1 mo - 18 yr)
20 2,5 yr (2 mo - 16 yr)
30
40
Vasopressors (%) Time to CPR (mean _+ SD)
30 3.4 + 1.7 rain
40 3.4 _+ 1.6 min
Time to first dose of epinephrine (mean _+ SD)
4.7 _+ 2.3 min
4.9 +_ 2,4 rain
proportion who received previous CPR, time from arrest to initiation of CPR, or time from arrest to first dose of epinephrine (P ~> .28). Two of the control and none of the HDE groups had t a c h y a r r h y t h m i a s and were treated with lidocaine and defibrillation or cardioversion. All other patients had either bradycardia or asystole as the initial arrest rhythm. Seve n t e e n of the HDE group (85%) received the higher dose after only two SDEs, whereas the remaining three received three doses first. Fourteen of the HDE group (70%) had ROSC within five minutes of administering the high dose, whereas none of the control group regained spontaneous h e m o d y n a m i c s (P < .001). Of the six who failed to respond to HDE, four did not respond to an additional HDE five minutes later and two did not respond to repeated SDEs. All 14 of the survivors of cardiac arrest responded to HDE with sinus tachycardia for at least 15 minutes, and none developed life-threatening tachyarrhythmias. A period of mildto-moderate hypertension lasting less than 20 minutes occurred in eight but did not require treatment. Ten were placed on vasopressor IV drips after arrest. In all patients, ECGs within one day of ROSC showed no evidence of ischemic injury. Eight survived to discharge. Six regained their prearrest n e u r o l o g i c function, three of whom were developmentally normal six to.17 months after resuscitation, as judged by the parents and evaluation by a pediatric neurologist. The causes of arrest in these three were severe bilateral pulm o n a r y c o n t u s i o n s and acute hypoxia, h y p o v o l e m i a , and s e p t i c shock. Three others had severe preexisting cognitive disabilities but retained their prearrest developmental achievements, according to their parAnnals of Emergency Medicine
TABLE 2. Diagnoses of pediatric cardiac
arrest patients: Control versus intervention group
Diagnosis
Control HDE
Aspiration
4
3
Asphyxia Asthma
3 3
2 0
Sepsis Increased intracranial pressure
3 2
3 3
Smoke inhalation
1
1
Hypovolemia Multiple trauma
1 1
3 2
Pneumonia Poisoning
1 1
1 0
Sudden infant death syndrome
0
2
ents and pediatricians. The other two suffered serious global cortical damage, either from previous or the studied cardiac arrest. One of the eight who died after ROSC donated his kidneys. DISCUSSION In 1903, Crile demonstrated the effectiveness of epinephrine in the resuscitation of dogs from cardiac arr e s t . 19 Since then, epinephrine has become a major part of therapy for cardiac arrest, although the optimal dose for human beings is unknown. 12 Investigators working with animal models of cardiac arrest have used greater doses per weight than those currently recommended for huma~n 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 the 8DE may be too low. 12,14 During their early investigations, Redding and Pearson found that 1.0 mg epinephrine is effective in resuscitating dogs with average weights of approximately l0 kg, a dose of 0.1 20:1 January 1991
HIGH-DOSE EPINEPHRINE Goetting & Paradis
mg/kg. 2° The current recommended dose in children is 0.01 mg/kg, is It is unclear why this is considerably less than that used by Redding and Pearson, whose report is provided as a major reference in the ACLS guidelines. Of note is their comment that this 1-mg dose was used "with benefit in children down to eighteen months of age. ''21 Using an approximate weight of 12 kg, this equals 0.08 mg/kg, eight times the SDE. Most studies on the effect of epinephrine in cardiac arrest have been performed in animals. Using an ischemic ventricular fibrillation model, Yakaitis and associates found that a dose of 0.077 mg/kg increases the percentage of animals with successful defibrillation. ~ In an electromechanical dissociation model, one of greater relevance to pediatric arrest, Ralston and associates demonstrated a dose-response relationship between epinephrine and percentage with ROSC. In this model, administration of 0.01 mg/kg produced a 40% resuscitation rate, whereas 0.1 mg/kg resulted in resuscitation of approximately 90% of animals. 23 Brown and associates examined the dose-response relationship between epinephrine and vital organ blood flow.24,25 In their swine model, they f o u n d t h a t 0.2 m g / k g epinephrine produces cerebral blood flows that are severalfold higher than those produced with 0.02 mg/kg. In all areas of the sampled myocardium, blood flow with the higher close is greater than flow with the lower dose. As an example of the magnitude of the improved perfusion, the mean left ventricular endocardial blood flow increased from 2.5 to 176 mL/100 g x min. In all measured areas, the higher dose produced myocardial blood flow that was greater than the threshold of 20 mL/100 g x rain found to be necessary to meet the metabolic demands of the fibrillating heart. 26 Although no statistically significant difference was detected between 0.2 and 2 mg/kg, blood flow was less for most of the myocardium in the highest dose. This "leveling off" of the dose-response curve suggests that although the optimal dose is probably m u c h higher than that recommended, there may be a limit to the benefit of even higher doses. A beneficial effect from higher doses of epinephrine has been noted 20:1 January 1991
in human beings. Gonzalez and associates recently reported the vasopressor response to 1-, 3-, and 5-mg doses in adults with prehospital cardiac arrest. 27 They found that 5 mg increased chest relaxation-phase arterial pressure compared with the preepinephrine state, whereas 1- and 3-mg doses did not. In another study, c o r o n a r y p e r f u s i o n p r e s s u r e increased in human beings with prolonged arrest after 12 to 14 mg, whereas there was no change after 1 rag. 28 There is a report of two adults having ROSC after 5 or 6 mg epinephrine, respectively, when multiple SDEs failed. 16 The need for such large amounts o f exogenous epinephrine is unknown. It may be that adrenergic receptor downregulation or uncoupling occurs in cardiac arrest. 29-31 An additional factor underlying the need for larger doses may be the mechanism of action of the drug itself. Administration of approximately 14-fold more epinephrine to adults in cardiac arrest resulted in only a 2.6-fold increase in arterial plasma levels. 3~ This suggests either an enhanced metabolism or increased volume of distribution with greater doses. Cardiac arrest is the state of maximal biologic stress and is associated with the highest plasma levels of epinephrine and norepinephrine. Plasma epinephrine levels are approximately 0.03 ng/mL in normal resting human beings. 33 With cardiac arrest, these levels can increase several hundredfold w i t h o u t e x o g e n o u s epinephrine. 34 The r e l a t i v e i n c r e a s e in plasma levels after the SDE is not nearly as great as that from cardiac arrest alone. Wortsman and associates found the average plasma epinephrine level increased from 10 to 72 n g / m L a f t e r e x o g e n o u s epinephrine dosing in ICU patients suffering cardiac arrest. 33 Quinton and associates found an increase from 12 to 55 ng/mL in prehospital cardiac arrest patients. 35 Thus, taken in the context of the spontaneous increase in plasma epinephrine levels during cardiac arrest, the additional fivefold to sevenfold increase from 1 mg of exogenous epinephrine seems less impressive. Kern and associates recently studied the relationship between plasma catecholamines and outcome after eight and 12 minutes of cardiac arrest. 36 They found that the absolute Annals of Emergency Medicine
levels as well as the magnitude of increase in endogenous catecholamines after arrest did not predict which animals w o u l d be r e s u s c i t a t e d successfully. However, the increase in plasma levels after exogenous epinephrine was predictive of outcome. Animals with ROSC had a mean 53fold increase in levels, whereas those that remained in arrest had only a 23fold increase. If an increase in plasma epinephrine of 50-fold is necessary for resuscitation of animals, then the fivefold to sevenfold increase found in human beings after SDEs is probably inadequate. Most pediatric cardiac arrests are b r a d y a s y s t o l i c . The lower intramyocardial pressures in this condition may result in greater myocardial blood flow for a given coronary perfusion pressure than in ventricular fibrillation. Theoretically, this should result in greater clinical efficacy for a given dose of a pressor. For this reason, children may stand to benefit the most from HDE. Toxicity is a relative concern in the treatment of cardiac arrest. Very high levels of catecholamines can cause a characteristic pattern of myocardial injury called " c o n t r a c t i o n band necrosis. ''37 This lesion is seen not only after therapeutic and experimental exposure to pharmacologic doses, but also in pathologic states such as myocardial ischemia, pheochromocytoma, and sudden cardiac death. 3s In addition to myocardial damage, catecholamines may cause vascular injury. 39 Most reports of epinephrine toxicity have been from studies on hemodynamically intact animals and human beings. Whether these findings apply to the low-flow state of cardiac arrest is unknown. Delineation of toxicity in this setting is difficult; the outcomes tend to be poor, and contraction band necrosis m a y be present w i t h o u t exogenous epinephrine. The absence of ECG ischemic changes in our patients is reassuring but does not rul~ out myocardial injury. In a preliminary report comparing HDE with SDE in adults, incidence rates of arr h y t h m i a s and ECG changes, and peak creatine kinase levels did not differ. 4o Our study showed a dramatic improvement in the rate of ROSC after HDE in refractory pediatric cardiac arrest. The limitations of the study, specifically, the use of historic con24/47
HIGH-DOSE EPINEPHRINE Goetting & Paradis
trols and the unblinded administration of HDE, must be considered when interpreting the results. Nonetheless, the study strongly supports the superiority of HDE. The high rates of ROSC and long-term survival after three doses of epinephrine are unprecedented. Previous reports describe a total of 70 children who received two or three SDEs during cardiac arrest. 4-6 Fourteen percent were alive at 24 hours, and none survived to hospital discharge. In the study in which an ROSC rate was given, ten of 18 (56%) of those who failed to respond to a single epinephrine dose never regained spontaneous hemodynamics. 5 Our 70% ROSC rate and 40% long-term survival rate after three or four epinephrine doses contrast strikingly. After our favorable experience with HDE in adult clinical studies~8, 41 and anecdotally in adults and children,16,17 we question the ethics of using a prospective control group. What is the optimal epinephrine dose, and how HDE should be integrated into a pediatric resuscitation protocol are important questions. We chose the dose of 0.2 mg/kg based on animal studies and scant h u m a n data. 14,15,17,42 It is u n k n o w n what dose provides the maximum beneficial effect in human beings with the least risk of toxicity. However, our experience as well as that of others 42 suggests that this dose is effective and usually well tolerated. Brain injury is usually the limiting factor in a satisfactory recovery after R o s e . In adults, the duration of CPR, independent of the preceding time in arrest, strongly correlates with neurologic disability, 43 further implicating the ineffectiveness of CPR to adequately perfuse the brain. The time limits of cerebral viability during CPR in children are unknown but can be expected to demonstrate considerable individual variability, depending on the cause of arrest, body temperature, 44 age, 45 and effectiveness of chest compressions. However, it can be reasoned that after establishment of adequate ventilation and oxygenation and the institution of chest c o m p r e s s i o n s , efforts to promptly increase coronary perfusion pressure, the best p r e d i c t o r of ROSC, tS should take priority. After failure of two standard doses of epinephrine to satisfactorily increase perfusion pressure within five 48/25
minutes, as evidenced by continued cardiac arrest, it seems unlikely that repeating this dose will succeed. We would consider HDE at this point. To delay this intensive therapy may risk neurologic injury and even failure to induce ROSC. Although some patients have complete recovery from prolonged cardiac arrest when treated conventionally, this is exceptional, and the approach to resuscitation should provide the best opportunity for intact survival in all individuals in whom it is attempted. CONCLUSION Results from our study show the superiority of HDE over SDE in children with refractory cardiac arrest. The resuscitation rate was m u c h higher, and there was no evidence of significant toxicity. HDE allowed long-term survival in a substantial percentage of patients, some with full neurologic recovery. HDE should be considered in cardiac arrest early enough to prevent irreversible brain injury. REFERENCES 1. Friesen RM, Duncan P, Tweed WA, et al: Appraisal of pediatric cardiopulmonary resuscitation. Can Med J 1982;126:1055-1058. 2. Lewis JK, Minter MG, EsheIman SJ, et ah Outcome of pediatric resuscitation. Ann Emerg Med 1983;12: 297-299. 3. Torphy DE, Minter MG, Thompson BM: Cardiorespiratory arrest and resuscitation of children. A m J Dis Child 1984;138:1099-1102. 4. Nichols DG, Kettrick. RG, Swedlow DB, et al: Factors influencing outcome of cardiopulmonary resuscitation in children. Pediatr Emerg Care 1986;2:1-5. 5. Ginis J, Dickson D, Rieder M, et al: Results of inpatient pediatric resuscitation. Crit Care Med 1986;14: 469-471. 6. Zaritsky A, Nadkarni V, Getson P, et ah CPR in children. Ann Emerg Med i987;16:1107-1111. 7. Eleisher G, Sagy M, Swedlow DB, et al: Open- versus closed-chest cardiac compressions in a canine model of pediatric cardiopulmonary resuscitation. A m J Emerg Med 1985;3:305-310. 8. Schleien CL, Dean JM, Koehler Re, et al: Effect of epinephrine on cerebral and myocardial perfusion in an infant animal preparation of cardiopulmonary resuscitation. Circulation 1986;73:809-817. 9. Fleisher G, Delgado-Paredes C, H e y m a n S: Slow versus rapid closed-chest cardiac compression during eardiopulroonary resuscitation in puppies. Crit Care Med 1987;15:939-943. 10. Goetting MG, Preston G: Cerebral oxygen extraction during CPR in children (abstract). Ann Emerg Med 1988;17:436. 11. Berkowitz ID, Chantarojanasiri T, Koehler RC, et ah Blood flow during cardiopulmonary resuscitation with simultaneous compression and ventilation in infant pigs. Pediatr Res 1989;26:558-564. 12. Paradis NA, Koscove EM: Epinephrine in cardiac arrest: A critical review. Ann Emerg Med 1990;19:12881301. 13. Michael JR, Guerci AD, Koehler RC, et al: Mechanisms by which epinephrine augments cerebral and
Annals of Emergency Medicine
myocardial perfusion during cardiopulmonary resuscitation in dogs. Circulation 1984;69:822-835. 14. Brown CG, Werman HA: Adrenergic agonists during cardiopulmonary resuscitation. Resuscitation 1990;19: 1-16. 15. Paradis NA, Martin GB, Rivers EP, et al: Coronary perfusion pressure and the return of spontaneous circulation in human cardiopuImonary resuscitation, lAMA 1990;263:1106-1113. 16. Koscove EM, Paradis NA: Successful resuscitation from cardiac arrest using high-dose epinephrine therapy. JAMA 1988;259:3031-3032. 17. Goetring MG, Paradis NA: High dose epinephrine in refractory- pediatric cardiac arrest. Crit Care Med 1989;17:1258-1262. i8. Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). JAMA 1986;255:2841-3044. 19. Crile GW: Preliminary note on a method of resuscitation of apparently recently dead animals. Cleve Med J 1903;2:35. 20. Redding J8~ Pearson JW: Evaluation of drugs for cardiac resuscitation. Anaesthesia 1963;24:203-207. 21. Pearson JW, Redding JS: The role of epinephrine in cardiac resuscitation. Anesth Analg 1963;42:599-606. 22. Yakaitis RW, Otto CW, Blitt CD: Relative importance of alpha and beta adrenergic receptors during resuscitation. Crit Care Med 1979;7:293-296. 23. Ralston SH, Tacker WA, Showen L, et al: Endotracheal versus intravenous epinephrine during electromechanic dissociation with CPR in dogs. Ann Emerg Med 1985;14:1044-1048. 24. Brown CG, Werman HA, Davis EA, et al: Comparative effect of graded doses of epinephrine on regional brain blood flow during CPR in a swine model. Ann Emerg Med 1986;15:1138-1144. 25. Brown CG, Werman HA, Davis EA, et al: The effect of graded doses of epinephrine on regional myocardial blood flow during eardiopuImonary resuscitation in swine. Circulation 1987;75:491-497. 26. Neimann JT: Differences in cerebral and myocardial perfusion during closed-chest resuscitation. Ann Emerg Med 1984;13:849-853. 27. GonzaIes ER, Ornato JP, Garnett AR, et al: Dosedependent vasopressor response to epinephrine during CPR in h u m a n beings. A n n Emerg Med 1989;18: 920-926. 28. Paradis NA, Martin GB, Rivers EP, et ah High-dose epinephrine and coronary perfusion pressure during cardiac arrest in human beings (abstract). Ann Emerg Med 1989;18:478. 29. Bristow MR, Ginsburg R, Minobe W, et ah Decreased catecholamine sensitivity and beta-adrenergicreceptor density in failing human hearts. N Engi J Med 1982;307:205-211. 30. Lefkowitz RJ, Caron MG, Stiles GL: Mechanisms of membrane-receptor reguIation: Biochemical, physiological, and clinical insights derived from studies of the adrenergic receptors. N Engl J Med 1984;310: 1570-1579. 31. Vatner DE, Knight DR, Shen YT, et ah One hour of myocardial ischemia in conscious dogs increases betaadrenergic receptors, but decreases adenylate cyclase activity. J Mol Cell Cardiol 1988;310:1570-1579. 32. Paradis NA, Rivers EP, Martin GB, et ah The change in arterial epinephrine levels after standard a~xl high dose epinephrine during CPR in humans {abstract). Crit Care Med 1990;18:$221. 33. Wortsman J, Frank S, Cryer PE: Adrenomedullary response to m a x i m a l stress in humans. A m J Med 1984;77:779-784. 34. Little RA, Frayn KN, Randall PE, et ah Plasma catecholamines in patients with myocardial ischemia and in cardiac arrest. Q J Med 1985;54:133-140. 35. Quinton DN, O'Byme G, Aitkenhead AR: Comparison of endotracheal and peripheral intravenous adrenaline in cardiac arrest: Is the endotracheal route reliable? Lancet 1987;1:828-829.
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HIGH-DOSE EPINEPHRINE Goetting & Paradis
36. Kern KB, Elchisak MA, Sanders AB, et al: Plasma catecholamines and resuscitation from proIonged cardiac arrest, Crit Care Med 1989;17:78679I.
39. Haft JI: Cardiovascular injury induced by sympathetic catecholamines. Prog Cardiovasc Dis 1974;17: 73-86.
significantly improves resuscitation rates in human vict i m s of cardiac arrest (abstract). Ann Emerg Med 1990;19:490-491.
37. Todd GL, Baroldi G, Pieper GM, et al: Experimental catechoiamine-indnced myocardial necrosis: I. Morphology, quantification and regional distribution of the acute contraction band lesion. [ Moi Cell Cardio] i985;I7:317-338.
40. CalIaham M, Barton C, Kayser S: Potential adverse effects of high-close epinephrine in human survivors of cardiac arrest (abstract). A n n Emerg Med 1990;19: 479-480.
43. Abramson NS, Safar P, Detre KM: Nenrologic recovery after cardiac arrest: Effect of duration of ischemia. Crit Care Med 1985;13:930-931.
41. Paradis NA, Goetting MG, Rivers EP, et ah High dose epinephrine therapy and return of spontaneous circulation during human pseudo-electromechanical dissociation (abstract]. Ann Emerg Med 1990;19:491.
44. Orlowski JP: Drowning~ near-drowning, and ice-water submersion. Peddatr Clin North A m 1987;34:75-92.
38. Baroldi G, I~aIzi G, Mariane T: Sudden cardiac death: A postmortem study in 208 selected cases compared to 97 "controlled" subjects. A m Heart J 1979; 98:20-31.
42. Barton CW, Callaham M: High-dose epinephrine
45. Altman D1, Powers WJ, Perlman JM, et al: Cerebral blood flow requirement for brain viability in newborn is lower than in adults. Ann NeuroI 1988;24:218-226.
See related editorial, p 104.
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