Resuscitation, 24 (1992) 263-272
Elsevier Scientific Publishers Ireland Ltd.
Catecholamines during cardiopulmonary resuscitation for cardiac arrest S.P. Woodhouse, D. Lewis-Driver and H. Eller Department of Cardiology and Department of Emergency Medicine. Princess Alexandra Hospital, Brisbane (Australia)
(Received July 2801, 1992; Accepted August 24th, 1992) Serum catecholamines were measured during continued prolonged cardiopulmonary resuscitation and after 10 mg increments of intravenous epinephrine. This was part of an ongoing trial of 10 mg epinephrine versus placebo. Eight patients were in the placebo arm and seven in the epinephrine arm and the rhythms were two ventricular fibrillation, nine asystole and four electromechanical dissociation. Data were analysed by time from onset of the cardiac arrest and samples were analysed for levels of DHPG (dihyand DGPAC droxyphenylglycol) nor-epinephrine, epinephrine, DGPA (dihydroxyphenylalanine) (dihydroxyphenyl acetic acid). There was a significant (P < 0.001) difference between arterial and venous samples of epinephrine but not the other catechohunines. High levels of catecholamines were maintained in all time phases except for norepinephrine where significant (P < 0.0003) reduction occurred progressively after 20 min. Non-steady state kinetics were suggested between epinephrine and norepinephrine and DHPG and nor-epinephrine for the first 20 min. Very large increases in epinephrine were achieved with administered 10 mg epinephrine and this resulted in high DHPG levels supporting the experimental belief that exogenously administered epinephrine induces myocardial release of norepinephrine. This data supports the known effects of CPR on catecholamine release. It provides data on the other neurotransmitter hormones and supports the relationships shown in other animal and human data. It is suggested that supplementation with epinephrine during CPR may be unnecessary and the levels reached may be deleterious. Nor-adrenaline supplementation may be necessary after prolonged CPR. Key worok: cardio-ptdmonary
resuscitation (CPR); catecholamines; epinephrine; nor-epinephrine
The stress of acute life threatening illness results in release of catecholamines (epinephrine, nor-epinephrine and dopamine) in an attempt to maintain the body homeostasis1-3. The models for examining this response are haemorrhagic shock, and acute hypoglycaemia as these together with cardiac arrest stimulate near maximum secretion of epinephrine and an explosive increase in plasma catecholamines4-“. The sustained excess in catecholamines may be a contributing factor in the genesis of ventricular dysrhythmias 7P12.The major source of the early released epinephrine and nor-epinephrine seems to be the adrenal medulla6>‘3. The cardiac Correspondence to: S.P. Woodhouse, Department of Cardiology Medicine, Princess Alexandra Hospital, Brisbane, Australia.
0300-9572/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
arrest increase in sympathetic activity may be a reflex to stimulation of cardiac receptors in the low-perfusion myocardium14 and nor-epinephrine may be released directly into the circulation from ischaemic myocardium15. There is however a difference in timing and epinephrine levels in haemorrhagic shock rise rapidly to a plateau in 5-60 min whereas nor-epinephrine concentrations steadily increase6yi3. Although intravascular depletion seems the most likely stimulus for epinephrine secretion, glucocorticoids and arterial pH may also play an important role in catecholamine synthesis and release in these acute states16. Release of nor-epinephrine from sympathetic nerves is subject to negative feedback mechanisms but no mechanism is available to limit release of epinephrine from the adrenal medulla. The magnitude of epinephrine release in cardiac arrest is not found even in large catecholamine secreting tumours which suggests that maximum release of the adrenal stores requires intact release mechanisms and some sort of amplification loop. These are likely to be provided by at least two feedback circuits. Firstly, epinephrine stimulation of the renin angiotensin system with angiotensin II facilitation of release from both the adrenal medulla and the sympathetic nerves. Secondly, epinephrine stimulation of B2 receptors of the pituitary causing corticotrophin release which in turn stimulates the adrenal medulla and cortex4. The relationship between DHPG (dihyroxyphenylglycol) and nor-epinephrine allows estimation of the component of DHPG derived from recapture of norepinephrine ‘* . A recent review has examined the source, fate and functions of the catecholamine neurotransmitters present in the circulation”. Epinephrine given intravenously or transbronchially will rapidly raise plasma levels above those present in cardiac arrest. Exogenous adrenaline may activate prejunctional betaadrenoreceptors in the atria17. The therapeutic use of epinephrine has potential for serious cardiac, renal and cerebral side effects and is generally now reserved for use in cardiac arrest. This use is dependent on the conversion of fine ventricular fibrillation resistant to electrical defibrillation to coarse ventricular fibrillation which can be electrically converted20-24. In asystole, administration of intravenous or transbronchial epinephrine will often result in an intrinsic rhythm but there is no proof that it promotes successful defibrillation 4p5 . Newer animal models more closely approximating the human state will provide more meaningful data 23,24.The half life of parenterally administered epinephrine is measured in minutes due to rapid metabolism by cathechol-O-methyl transferase and mono amine oxidase. The need for epinephrine to maintain adequate cerebral and myocardial blood flow is said to require regular further administration during prolonged resuscitation*. Recent work has suggested a possible role of other agents 25727although nor-epinephrine seems the most promising28~37.There is a current trend towards proposals to use higher dosages of epinephrine9,25Y27938 and the epinephrine proposals have recently been extensively reviewed39. There is limited information available on catecholamine levels during prolonged human cardiac resuscitation and it is possible that adequate epinephrine levels are maintained during good CPR l6. We have previously suggested that administered epinephrine during CPR may have, at worst, a negative effect on outcome and, at best, no effect on outcome40. Recent animal data have suggested a role for ad-
ministration of nor-epinephrine to maintain cerebral and myocardial blood flow with no increase in abnormal rhythms or fibrillatory thresholds21. As part of an ongoing blinded study of high dose epinephrine (10 mg increments) versus placebo in cardiac resuscitation25*26 we have measured catecholamine levels in patients with cardiac arrest who are receiving adequate cardiopulmonary resuscitation. METHODS
Hospital Ethics Committee approval was obtained for this study. Patients for this phase of the trial were limited to those presenting in the Accident and Emergency Department between 0800 and 1700 h, weekdays. All must have been pulseless and non-breathing, having good CPR and with either ventricular fibrillation, asystole or electromechanical dissociation. The protocol for management is shown in Fig. 1. As soon as possible a catecholamine sample was taken from the femoral artery and suitable patients were entered into the trial. Trial material was randomised in blocks of ten and used sequentially. After two intravenous ampoules of material were used (10 mg epinephrine/placebo) the supervising doctor could use discretion in the additional use of standard 1 mg epinephrine. After establishment of resuscitation measures, a central line was placed and subsequent catecholamine samples were removed from this site. Catecholamine samples were taken prior to using IV treatment material and at least 4-5 min after infusion. Ten-millilitre samples were collected into cold heparanised tubes transferred on ice to the laboratory and centrifuged at 4°C as soon as possible after collection. Plasma was transferred to plain tubes and stored at -70°C until transfer for analysis (Baker Institute Melbourne, Australia). AlllEST CALL I 1 ““TT”Y UNKNOWN ORB HOSPITAL WASD)
I *HYmM KNOWN (ACE. CC”)
I O”ICK LOOK PADDLES
?ULS!JLESS. NON BUXTWING “I ASTTOLE. BYD
Fig. 1. Protocol for cardiac arrest and high dose epinephrine-placebo
266 Table I.
Study patients and cardiac rhythm during resuscitation.
EMD, electromechanical dissociation.
Samples were assayed by HPLC using methods previously described4. Inter-assay coefficients of variation obtained using the same quality control plasma (arterial plasma from normal human subjects) and determined from 16 consecutive assays were DHPG lO.l%, NE 11.2%, DOPA 6.3%, EPI 34.3%, and DOPAC 15.8%. Intraassay coefficients of variation from eight repeated determinations were DHPG 1.7%, NE 2.9%, DOPA 1.8%, EPI 6.7%, and DOPAC 5.5%. Standard statistical methods were used with one way analyses of variance, Student’s t-test, regression analysis and Pearson’s correlation coefficient. RESULTS
Fifteen patients were entered into this phase of the trial, eight in the placebo arm and seven into the epinephrine arm: there were no successful resuscitations in this group of study patients. Table 1 shows the rhythms on entry into the trial. For the analysis of catecholamines, the placebo group and the pre-trial baseline values of the epinephrine group were used. The data only became intelligible when they were placed in a time sequence based on the onset of the cardiac arrest and this is shown in Table II. There are highly significant reductions in the nor-epinephrine levels be-
Table II. Tie
2-20 N=8 (6A, 2V) 21-40 N= IO (6‘4,4v) 40-55 N= 10 (4A, 6V) P-value
time from onset of cardiac arrest (mean f SD.).
4146 i 1694
3925 f 1251
5194 f 3695
3767 f 1345
4402 f 3558
2570 *I537 NS
812* ?? 473 * < 0.00 003
4021 f 1532 NS
1784 ?? 1304 NS
4049 f 1479 NS
DHPG, dihydroxyphenylglycol; NOR-EPI, norepinephrine; EPI, epinephrine; DGPA, dihydroxyphenylalanine; DGPAC, dihydroxyphenyl acetic acid; A, arterial sample; V, venous sample.
261 Table III.
Arterial (N = 16) Venous (N= 12)
throughout periods (arterial and venous samples), mean f SD.
3902 f 1570
4123 f 1294
5278 f 3442*
5742 * 4029
2842 f 1526
1965 f 2184
3631 f 1346
1581 zt 1086*
4165 + 2611
DHPG, dihydroxyphenylglycol; NOR-EPI, nor-epinephrine; DOPA, dihydroxyphenylalanine; dihydroxyphenylacetic acid. ?? P= 0.0014.
Catecholamines after high dose (10 mg) epinephrine.
Total patients Mean time from drug to sample Sample origin (epinephrine) Arterial Venous
7 3.2 f 0.44 min (n = 7) (n = 6)
2.280 zt 1.8 &ml 1.350 f 2.2 &ml
Catecholamines after high dose (10 mg) epinephrine.
9041 zt 3678 3612 zt 1246
2125 ztl172 2051 zt 2050
4798 f 465 4267 ?? 1139
2.14 h1.8 1.63 zt2.2
DOPAC (Pgw 5308 zt2116
1 /Lg = 10s pg.
tween each time phase (P < 0.00003) but no significant differences between any of the other catecholamine levels. There are significant differences between arterial and venous epinephrine samples (Table III) in all time categories (P = 0.0014) but not for other catecholamines. After high dose (10 mg) adrenaline the serum epinephrine levels are shown in Table IV and there is no difference between arterial and venous samples. The combined venous and arterial samples based on time from initiating CPR is shown in Table V. Here the DHPG levels are much in excess of levels in the same time interval when there was no exogenous epinephrine. DOPAC levels were at times not measured because of the dilutions required with high epinephrine levels. The relationship between epinephrine and nor-epinephrine is shown in Figs 2 and
DURATION 14 1
Y = -.43X t 8.0 R = 0.6
Relationship between nor-epinephrine and epinephrine in the first 20 min of CPR, P = 0.16.
DURATION Y = .47X
R = 0.92
NOR-EPINEPHRINE w/ml Fig.
Relationship between epinephrine and nor-epinephrine 21-55 min after CPR, P < 1 x 10d6.
Y = 1.37x
R = 0.8
Relationship between DHPG and nor-epinephrine
in the first 20 min of CPR, P = 0.016.
3. In the 2-20-min period there is a negative relationship and a variability between cases as evidenced by the low P-value time phase. The relationship of norepinephrine to DHPG in Figs 4 and 5 indicates an increased DHPG relationship in the later time phases. There were no other significant relationships found between the measured catecholamines. DURATION
14Y = .5X + 2.3
R = 0.5
0 , 2
Relationship between DHPG and nor-epinephrine in the period 21-55 min after CPR, P = 0.03.
These data support the known acute large increase in catecholamines during cardiac arrest. It indicates that when good CPR is maintained, catecholamines continue to be released although there are significant reductions in nor-epinephrine after 20 min of CPR. This is in contradistinction to animal data which show equivalent changes in both epinephrine and nor-epinephrine which peak by 6-8 min and fall threefold after 14-15 min”. The peak values for the human catecholamines and the arrest models are similar. This supports the view that acute nor-epinephrine release from the adrenal gland occurs 5. The data in Fig. 2 however indicate that in the early phases there is a disproportionally increased epinephrine level to produce mismatch which becomes normalized, after 20 min, to that seen in other conditions associated with raised catecholamine levels. There is inter-subject variability in this early phase. These cannot be adequately explained but may well reflect the early non-steady state or delays in nor-epinephrine release. Measurement of plasma nor-epinephrine levels has been criticized on the grounds that the increase in sympathetic stimulation may not be reflected by the absolute level of nor-epinephrine. There is evidence that in acute conditions clearance of norepinephrine is reduced 42. If this is so, the fall in nor-epinephrine levels with time, shown in our data may well be an underestimate and organ nor-epinephrine levels may be very low. A reduction in cardiac muscle nor-epinephrine may precipitate or worsen ventricular fibrillationlO. Other catecholamine levels particularly epinephrine and DHPG, do not alter and this suggests that continued sympathetic activity is maintained during good CPR. The relationship of DHPG and nor-adrenaline suggests a non-steady state in the first 20 min of CPR which in 20-60 min achieves the steady state relationship of overflow nor-adrenaline kinetics previously described. These data cannot add anything to the discussion on the relative merits of epinephrine and nor-epinephrine to maintain myocardial and cerebral blood flow or the benefits of o-1 or (r-2 stimulation. It does however indicate that endogenous epinephrine levels are high and are maintained during good CPR whereas norepinephrine levels fall and may require supplementation. The extremely high epinephrine levels achieved with 10 mg supplements of epinephrine warrant careful controlled study on the immediate effects of this therapy and its influence on both the immediate and later outcomes of cardiac arrest. The increase in DHPG levels with high dose epinephrine suggests that this dose may induce presynaptic facilitation of nor-epinephrine release5. These data support a view that epinephrine levels sufficient to maintain cerebral and myocardial blood flow are present during good human CPR for up to 60 min. It will be necessary to perform nor-epinephrine turnover studies during CPR in order to assess the need for nor-epinephrine supplementation during prolonged CPR ACKNOWLEDGEMENTS
The authors are indebted to Dr Murray Esler for the catecholamine measurements and helpful advice on the manuscript. We would like to thank MS Tessa O’Leary for typing the manuscript.
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