ORIGINAL CONTRIBUTION cardiac arrest, return of spontaneous circulation; epinephrine, high-dose

High-Dose Epinephrine Improves the Return of Spontaneous Circulation Rates in Human Victims of Cardiac Arrest

Study objectives: To evaluate the return of spontaneous circulation (RSC) rates in human victims of cardiac arrest treated with standard doses of epinephrine (SDE) or high-dose epinephrine (HDE).

Design: Prospective case series. Setting: A university hospital emergency department during 1987

through I989. Participants: Forty-nine adult victims of nontraumatic cardiac arrest. Interventions: At the discretion of the treating physician, patients re-

ceived epinephrine in bolus doses ranging from 1 to 15 rag. HDE was de- fined as a dose of at least 0.2 mg/kg; smaller doses were defined as SDE. Patients were grouped as + RSC if they developed a sustained spontaneous palpable pulse or blood pressure and as - R S C ff they did not develop a pulse or blood pressure.

Measurements: Patients were grouped as + RSC if they developed a sus- tained spontaneous palpable pulse or blood pressure and as - RSC if they did not develop a pulse or blood pressure. Patients were also grouped by their presenting rhythm. Potent ial ly perfusing rhy thm was electro- mechanical dissociation or ventricular tachycardia. Nonperfusing rhythm was asystole or ventricular fibrillation. Rates were analyzed using the Fisher exact test and the two-tailed unpaired t test. HDE improved the rate of initial resuscitation (P = .008). The effect was greatest in patients with nonperfusing rhythms (P = .014) and disappeared when evaluating patients with potentially perfusing rhythms. No patient survived to hospi- tal discharge.

Conclusion: High-dose epinephrine improves initial resuscitation rates in human victims of cardiac arrest. Its greatest effect is in patients with a nonperfusing rhythm. [Barton C, Callaham M: High-dose epinephrine im- proves the return of spontaneous circulation rates in human victims of cardiac arrest. Ann Emerg Med July 1991;20:722-725.]

INTRODUCTION One of the most important factors determining successful resuscitation

of the victim of cardiac arrest is the coronary perfusion pressure or myo- cardial blood flow. 1 Recent studies have demonstrated that standard doses of epinephrine (SDEs) as recommended by advanced cardiac life support (ACLS) guidelines produce suboptimal myocardial blood flow and rates of resuscitation in animals, z High doses of epinephrine (HDEs) have been shown to improve coronary perfusion pressure, myocardial blood flow, ce- rebral blood flow, and rates of resuscitation in an animal model of pro- longed cardiac arrest. 3-6

Recently, several reports of successful resuscitations in human beings who received higher-than-standard doses of epinephrine have been pub- lished. 7-9 As a result of these investigations, there has been a trend toward use of higher doses of epinephrine in resuscitation of victims of cardiac arrest in our hospital. Therefore, we sought to determine if HDE resulted in improvement in return of spontaneous circulation rates compared with SDE in human victims of cardiac arrest treated in our ED.

MATERIALS AND METHODS All patients more than 18 years old in nontranmatic prehospital cardiac

Christopher Barton, MD Michael Callaham, MD San Francisco, California

From the Division of Emergency Medicine, Department of Medicine, University of California, San Francisco.

Received for publication July 16, 1990. Revisions received November 30, 1990, and February 11, 1991. Accepted for publication February 21, 1991.

Presented at the Society for Academic Emergency Medicine Annual Meeting in Minneapolis, Minnesota, May 1990.

Address for reprints: Christopher Barton, MD, University of California, San Francisco 94143-0208.

40/722 Annals of Emergency Medicine 20:7 July 1991

IGH-DOSE EPINEPHRINE arton & Ca l laham

crest transported to the emergency ~partment of our hospital were eli- ible for en t ry in to the study. Pa- ents had to be apneic, with no pal- able pulse or blood pressure; those ~suscitated in the field were ex- luded. The study was approved by he universi ty 's Commi t t ee on Hu- man Research. Prehospital basic life support (BLS)

nd ACLS were p rov ided by fire- Lghters and paramedics according to he 1985 American Heart Association uidelines. 1° On arrival at the ED, re- nscitation was directed by the most enior physician (resident or attend- ng). Pa t ien t s were i n t u b a t e d and ~and-ventilated according to ACLS ;uidelines. Chest compress ion con- i n u e d w i t h a p r o g r a m m a b l e Phumper® using the Card iopulmo- lary Resuscitator Model 1005 (Mich- gan I n s t r u m e n t s , G r a n d Rapids , vlichigan) de l iver ing 80 compres - ;ions per minu te wi th a 50% corn- )ression cycle.

At the d iscre t ion of the t rea t ing )hysician, patients received epineph- :ine in bolus doses ranging from 1 to L5 rag. HDE was arbitrarily defined is an epinephrine dose of at least 0.2 7ng/kg given as a single bolus. Any Jose of epinephrine less than 0.2 mg/ kg was defined as SDE. The prehospi- tal record was examined to deter- mine the bystander CPR rate, esti- mated down-time, prehospital treat- ment t ime, and total r e susc i t a t ion time.

Patients were grouped into those with a return of a spontaneous circu- lation (+RSC) and those who never regained c i r cu l a t i on ( - R S C ) . T he RSC was used because this is a nec- essary (although not sufficient) con- dition for survival. Circulat ion was defined as an ECG rhy thm producing a palpable pulse or a m e a s u r a b l e blood pressure by Doppler, palpation, or auscultation, with a m i n i m u m du- ra t ion of f ive m i n u t e s . Cases in which the presence or absence of a pulse was unc l ea r were excluded. E l e c t r o m e c h a n i c a l d i s s o c i a t i o n (EMD) was defined as the presence of organized ventricular rhy thm in the absence of a detectable pulse or blood pressure. 11

Patients were further grouped ac- cording to the type of e l ec t r i c a l rhythm on presentation at the ED. A potentially perfusing rhy thm was de- fined as ven t r icu la r t achycard ia or EMD. A nonper fus ing r h y t h m was

TABLE 1. Demographics of study group

No. of Age Sex Asystole VF EMD Group

SDE Down-time (rain) ED time (rain) Total time (min)

HOE

Down-time (min) ED time (rain) Total time (min) *Data not recorded on the prehospital record, There were no cases of ventricular tachycardia. Numbers in parenttreses indicale SO,

Patients (yr) Male Female

39 71 19 18

10 69 6 4

+RSC -RSC +RSC -RSC +RSC -RSC

3 23 1 4 2 6 3 (3) 6 (3) 7 (2) 4 (1) 3 (3)

24 (15) 25 (11) * 21 (9) 9 (6) 32 (20) 45 (21) 54 (15) * 53 (1) 46 (19) 53 (16)

1 2 3 0 2 2

• * 5(5) 10 (14) 5 (7) 20 18 25 (11) 29 (16) 30 (6) • * 75 (41) 47 (10) 45 (16)

defined as asystole or ventricular fi- brillation.

D a t a w e r e a n a l y z e d u s i n g t he Fisher exact test and the two-tailed unpaired t test.

RESULTS Forty-nine patients were enrolled

in the study. There were 25 men and 22 women with mean ages of 71 and 69 years, respectively. Demographics of the g roup are g iven (Table 1). Twelve pa t ien ts had a re turn of a pulse, whereas 37 patients never re- gained a palpable pulse or blood pres- sure (Table 2). In all cases, the deter- minat ion of the return of a pulse, or lack thereof, was unequivocal . The mean dose of epinephrine per bolus i n the SDE group was 2.07 mg (SD, 1.6 mg), and the mean dose of epi- n e p h r i n e for pa t i en t s in the HDE group was 14.9 mg (SD, 0.1 mg).

Only one patient received a dose of epinephr ine be tween 0.03 and 0.2 mg/kg. This patient received a bolus dose of 10 mg, was categorized as SDE according to our criteria, and did not have a return of pulse. Of the 10 pat ients receiving HDE, two in the + RSC group received more than one bolus of HDE (each patient received a total of 30 mg epinephrine), whereas five pa t ien ts w i th - R S C received more than one bolus dose (average total dose, 36 mg epinephrine).

The mean total dose of epineph- rine given during the entire resuscita- t ion a t t empt (including prehospital epinephrine) in the SDE group was 7.1 mg (SD, 5.6 rag); the HDE group received an average of 28.5 mg (SD, 17.6), a s ignif icant difference (P < .0001). To correct for differences in doses and lengths of resusci ta t ion , the total cumulat ive dose of epineph- rine divided by the total resuscita-

TABLE 2. Two x two contingency tables comparing number of patients

per group

Group + RSC - RSC Total P

All Patients SDE 6 33 39 .008

HOE 6 4 10

Patients With Nonperfusing Rhythms SDE 4 26 30 .014

HDE 4 2 5

Patients With Perfusing Rhythms SDE 2 7 9 ,45

HOE 2 3 5 P values were calculated using Fisher's exact test,'

TABLE 3. Comparison between groups of mean dose of epinephrine per unit time by two-tailed unpaired t test.

Mean Dose Group N (mg epinephrine/min) SD P

+RSC 12 0,82 0.91 .09

-RSC 32 0.44 0.51

HDE 10 1.44 0,86 .0001

SDE 34 : 0.28 0.21 Five cases excluded with unknown prehospilal limes.

TABLE 4. Bystander CPR rates

Group + CPR - CPR Total

SDE 3 33 36

HDE 3 7 10

+RSC 4 . 8 12

- RSC 2 32 34

Total 6 40 46 P values calculated using the Fisher exact test.

P value

,11

.03

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H I G H - D O S E E P I N E P H R I N E Ba r ton & C a l l a h a m

TABLE 5. Estimated down-times compared by t test

Down-Time Group N (rain) SD P

HDE 8 5.1 6.9 .99

SDE 25 5.1 2.9

+RSC 10 4.1 5.9 .35

- RSC 23 5.6 3.0

P

.97

91

95% Confidence

Intervals

-0 .7 - 10.9

3.9 - 6.3

- 0,2 - 8.4

4.3 - 6.9

TABLE 6. ED resuscitation times compared by t test

ED Time Group N (min) SO

HDE 10 23.4 11.4

SDE 34 24.8 13.1

+RSC 12 20.8 13.1

-RSC 32 25.9 12.3

P

.76 ,96

.23 ,87

95% Confidence

Intervals

15.2 31.6

20.3 - 29.4

12.4 - 29.1

21.5 30.4

TABLE 7. Total resuscitation times compared by t test

Total ED Group N Time (min) SD P

HDE 9 53.8 13.2 .84

SDE 26 55.4 22.1

+ RSC 12 58 28.9 .52

- RSC 23 53.4 14

P

.96

.94

95% Confidence

Intervals

43.6 - 63.9

46.4 - 64.3

39.7 - 76,4

47.3 - 59.4

tion time was compared in patients who had +RSC. P a t i e n t s w i t h + RSC had a mean total dose per unit of t ime of 0.8 rag/rain (SD, 0.9), whereas patients with - R S C had a mean dose of 0.4 rag/rain (SD, 0.5) (Table 3).

Sixty percent of the patients re- ce iv ing HDE o b t a i n e d a pulse , whereas only 15.4% of those in the SDE group did - a significant differ- ence with P = .008 (Table 2). When the patients Were grouped by the type of rhythm on presentation to the ED, HDE was significantly better than SDE with nonper fus ing rhythms, whereas there was no significant dif- ference in RSC rates in patients pre- senting with a. perfusing rhythm.

The presence or absence of by- stander CPR was recorded in 46 of the 49 cases. There was no signifi- cant difference in bystander CPR rates in the SDE and HDE groups. Pa- tients who had a return of pulse were actually more likely to not have had bystander CPR (Table 4). The esti- mated down-time, ED time, and total

t ime were examined (in cases in which these data were available) for significant differences between the SDE and HDE groups to determine if the HDE group received longer, and hence possibly more aggressive, re- suscitation efforts. There was no sig- nificant difference in any of these pa- rameters when the patients were grouped by epinephrine dose or by the return of a pulse (Tables 5-7).

The sample size was small, and thus the possibility of missing a sig- nificant difference between groups is large (type II error). The f3 value for each comparison is listed (Tables 5-7). When the groups were further subdivided by type of rhythm (EMD, ventricular fibrillation, and asystole), no significant differences were found.

Few other drugs were received by the study group; only four patients received other adrenergic drugs. One pat ient receiving HDE also had a concurrent dopamine drip at more than 20 txg/kg/min. Three patients receiving SDE received dopamine drips at more than 10 ~xg/kg/min. Of

these four, only the patient receiving HDE therapy had a return of pulse. Recalculating the contingency table while excluding the patient who re- ceived dopamine and had a +RSC changes the P value to .018. No pa- t ient received an an t i a r rhy thmic agent before the return of a pulse.

Five patients (all men; mean age, 61 years; SD, 8.8 years) were ex- cluded because the exact epinephrine dosage could not be determined from the record. Of the excluded cases, two patients had a +RSC and three never had return of a palpable pulse. None of the excluded cases was dis- charged from the ED.

All patients died of cardiac arrest; no patient survived to hospital dis- charge.

DISCUSSION Epinephrine doses of 0.5 to 1 mg

(7.5 to 15 ~xg/kg) given intravenously have been recommended for more than 30 years in the American Heart Association ACLS guidelines, lo yet no study has ever proved the efficacy of this dose. 12

Crile and Dolley were the first to report successful resusci ta t ion in dogs using epinephrine doses averag- ing 200 ~g/kg. 13 Redding and Pear- son, whose research served as the f o u n d a t i o n for the in i t ia l ACLS guidelines, reported success with doses of 75 to 150 txg/kg. 14 Recently, s tudies in animals have demon- strated that doses approximately ten- fold those currently recommended (200 ~g/kg) are needed to produce sufficient blood flow to the heart and the brain to al low resusci ta t ion , whereas the standard dose levels (20 txg/kg) recommended in ACLS guide- lines produce insufficient myocardial and cerebral blood flow for successful resus citation. 2, 5, 6,15,16

Many clinicians have begun to ap- ply these data to clinical practice, and recommendations to use higher doses Of epinephrine in resuscitation of victims of cardiac arrest have be- gun to appear in the literature.i;, 17 There have been several reports doc- ument ing successful resusci ta t ion using higher doses of epinephrine in victims of cardiac arrest.S,9,18

In our hospital, clinicians have been using HDE (15 mg in the aver- age adult) in place of the usual l-rag dose recommended by ACLS with in- creasing frequency for the past three years. We are aware of only one other

42/724 Annals of Emergency Medicine 20:7 July 1991

HIGH-DOSE EPINEPHRINE Barton & Callaham

report comparing the effect of HDE with SDE on RSC rates in human be- ings. i9 No study to date has com- pared RSC rates in patients with var- ious under lying cardiac r h y t h m s treated with SDE or HDE.

This study demonstrates signifi- cantly higher initial rates of RSC (re- turn of spontaneous pulse) in all groups of patients treated with HDE. The improved rates are presumably related to improvements in coronary perfusion pressure. 2° The difference in rates is most likely not due to dif- ferences in resuscitation efforts. Both groups received similar efforts as re- flected in equivalent down-times, ED times, total times, absence of other vasopressor agents, and an insignifi- cant difference in bystander CPR r a t e s ,

The improvement in RSC rates was most pronounced in patients with rhythms traditionally thought of as nonperfusing. This improve- ment disappeared when looking only at patients with the potentially per- fusing rhythm of EMD. There are several possible explanations for this finding. First, this observat ion is based on only 14 patients and there- fore suffers from a significant [3 error. Several reports have confirmed that a significant percentage Of patients in EMD actually have ventricular con- tractions, aortic blood flow, and aor- tic pulse pressures, zu23 The lack of improvement in RSC rates with HDE in our study may suggest that any ad- ditional improvement in coronary perfusion pressure, by any mecha- nism, would be fruitless. These pa- tients may have fixed obstructions in coronary vessels or irreversible myo- cardial damage that is not amenable to any augmentation in coronary per- fusion pressure.

That HDE had a significant effect in patients 'who had nonperfusing rhythms and presumably the least coronary perfusion pressure may sug- gest that these patients are the most likely to derive a benefit from a sig- nificant augmentat ion of coronary perfusion pressure.

There are several limitations in a study such as this. The data, al- though collected and assembled pro- spectively, were nonrandomized, un- blinded, and analyzed retrospec- tively. Important variables such as

dosing intervals, use of other pressor agents, and length of resuscitation were similar but not rigidly con- trolled. Despite these limitations, we believe that this study provides im- po r t an t ev idence sugges t ing im- proved RSC rates in human victims of cardiac arrest when HDE is used. The lack of improvement in survival may be a result of the delay in ad- ministration of the first dose of HDE. No patient received HDE before ar- rival at the ED. The average time from onset of cardiac arrest to ear- liest administration of HDE was 31 minutes (mean total resuscitation time minus ED resuscitation time in HDE group).

It is conceivable that administra- tion of HDE at the onset of the resus- citation, in the prehospital phase, may result .in greater rates of resus- citation and survival. A study of ini- tial resuscitation rates and survival to hospital discharge in human vic- tims of cardiac arrest in which SDE and HDE therapy are administered to a larger group of patients as first-line t h e r a p y in a doub le -b l ind , ran- domized trial is needed and remains to be investigated.

CONCLUSION HDE therapy improves return of

spontaneous circulation rates in hu- man victims of cardiac arrest. The ef- fect of HDE was most pronounced in patients presenting with asystole or ventricular fibrillation, rhythms tra- ditionally thought to be nonperfusing and possibly presenting with the lowest coronary perfusion pressures. The effect of HDE disappeared when only patients presenting in EMD were evaluated.

A study of human victims in car- diac arrest receiving either HDE or SDE as first-line therapy is necessary. Until such a study has been com- pleted, the use of HDE in resuscita- t ion of v ic t ims of cardiac arrest should be used at the discretion of the clinician and not be assumed to be the standard of care.

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