Use of naloxone during cardiac arrest and CPR: Potential adjunct for postcountershock electrical-mechanical dissociation

ORIGINAL CONTRIBUTION resuscitation, cardiac, experimental, naloxone

Use of Naloxone During Cardiac Arrest and CPR: Potential Adjunct for Postcountershock Electrical.Mechanical Dissociation Naloxone has been shown to increase arterial pressure in hemorrhagic and septic shock. To determine if naloxone has salutary effects during cardiac arrest with conventional closed-chest~ cardiopulmonary resuscitation (CPR), ten dogs were studied during 20 mindtes of ventricular fibrillation (VF) and CPR and during a 30-minute postcountershock period. Central aortic (Ao) and right atrial (RA) systolic and end-diastolic (EDP) pressures, instantaneous Ao-RA pressure difference (coronary perfusion pressure), and electromagnetic Ao flow were measured. Ao and RA samples were analyzed during a control period and at five-minute intervals during CPR for PO 2, PCO 2, and pH. During VE a piston-cylinder device was used to perform anteroposterior sternal depressions and positive pressure ventilations (100% 02) at standard rates and ratios. After 15 minutes of CPR, animals were randomized and given either naloxone (5 mg/kg) or epinephrine (1 mg). Defibrillation was attempted five minutes later using 1 J/kg and then, if necessary, 2, 4, 8, 12, and 16 J/kg until VF was terminated or the m a x i m u m energy dose was reached. If VF persisted or if countershock resulted in asystole or a nonperfusing rhythm (electrical-mechanical dissociation [EMD]), the alternate drug (naloxone or epinephrine) was then given. Measured systolic pressures, coronary perfusion pressures, aortic flow, and blood gases were not significantly different during the control period or at five, ten, and 15 minutes of VF and CPR between animal groups prior to drug administration. When compared to hemodynamic values measured at 15 minutes, naloxone had no significant effect on pressures or aortic flow measured five minutes after administration. Epinephrine significantly increased 20-minute values (P < .05) when compared to those at I5 minutes: Ao, 110 +_ 26 m m Fig vs 69 +_ 17; AoEDP, 50 +_ 19 vs 21 +_ 5; RA, 116 +_ 19 vs 95 +- 16; coronary perfr2sion pressure, 49 + 29 vs 16 +- 11. No animal that initially received naloxone prior to countershock was defibrillated despite use of the maximal energy dose; following epinephrine, countershock produced a perfusing rhythm in four of five animals. In contrast, countershock resulted in EMD in four of five of these animals that initially received epinephrine. Naloxone was then given, and all four developed a perfusing rhythm. We conclude that naloxone has no hemodynamic effect during CPR and does not facilitate defibrillation, and that naloxone m a y be of benefit in the management of EMD following countershock. [Rothstein RJ, Niemann JT, Rennie CJ, Suddath WO, Rosborough JP: Use of naloxone during cardiac arrest and CPR: Potential adjunct for postcountershock electrical-mechanical dissociation. Ann Emerg Med March 1985;14:198-203.]

Robert J Rothstein, MD* James T Niemann, MD* Charles J Rennie, III, MD* William O Suddath, MD* Torrance, California John P Rosborough, PhD1Houston, Texas From the UCLA School of Medicine, the Department of Emergency Medicine, and the William Newman Resuscitation Research Laboratory, Harbor-UCLA Medical Center, Torrance, California;* and the Department of Physiology, Baylor College of Medicine, Houston, Texas.t Received for publication June 7, 1984. Revision received September 11, 1984. Accepted for publication December 6, 1984. Presented in part at the University Association for Emergency Medicine Annual Meeting in Louisville, Kentucky, May 1984. This project was supported in part by a Biomedical Research Support Grant (RR05541) from the National Institutes of Health, Bethesda, Maryland; and a General Laboratory Support Grant from the Physio-Control Corporation, Redmond, Washington. Address for reprints: Robert J Rothstein, MD, Department of Emergency Medicine, Box 21, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509.

INTRODUCTION Endorphins are endogenous opiatelike substances derived from pituitary betalipotropinA, 2 Several studies 3-6 have d o c u m e n t e d the release of endorphins in response to physiologic stresses and suggest that endorphins, because of their myocardial depressant properties, 7 m a y be involved in the common pathway of various shock states. 8-11 In published studies, changes in blood pressure appear to be largely the result of improved myocardial contractility and cardiac output, as changes in vascular tone have not been demonstrated consistentlyA2,13 Cardiac arrest can be viewed simplistically as the ultimate shock state. Cardiac arrest may follow acute hemorrhage or overwhelming endotoxemia, 14:3 March 1985

Annals of Emergency Medicine

198/17

USE OF NALOXONE Rothstein et al

TABLE 1. Hemodynamic values during sinus rhythm and during 20 minutes of resuscitation*

Minutes

Ao Systolic

Ao EDP

Ao Mean

Naloxone (N = 5)

0 (control) 5 10 15 20

98 64 60 76 74

-+ -+ -+ -+ -+

15 20 20 20 29

75 29 24 22 19

+ _+ -+ + +

15 7 10 11 11

83 44 36 36 39

Epinephrine ( a = 5)

0 (control) 5 10 15 20

117 61 62 69 110

-+ -+ -+ -+

17 10 16 17 26§

93 22 20 21 50

-+ 16 -+ 4 -+ 4 -+ 5 -+ 1911

101 36 35 38 75

+ + + + +

15 13 10 10 17

RA Systolic

RA EDP

RA Mean .2 8 11 14 14

Diastolic CPPt

61 57 70 78

-+ ---+ ---

15 24 25 29

7 6 5 6

-+ _+ -+ -+

7 7 7 6

4 29 25 29 34

-+ -+ + -+ -+

--- 16 --- 7 70 9 85 + 9 95 + 2111 116

-+ -+ -+ -+

24 19 16 19§

8 4 5 8

-+ _+ -+ _+

6 6 6 6

3 29 34 43 48

-+ 4 --- 11 15 -+ 6 17 + 12 16 -+ 11 49

19 16 16 12

Aortic Flow*

__ 10 -+ 8 -+ 8 _+ 7

726 + 287 95 -+ 40 76 + 50 56_+ 16 59 -+ 34

_+ 11 _+ 9 _+ 11 -+ 29§

678 93 87 77 46

-+ 212 -+ 25 _+ 54 _+ 42 -+ 46

*All values are mean -+ SD. tDiastolic CPP = peak diastolic aortic minus right atrial pressure difference. *Aortic flow = mL/minute; all other values = mm Hg. §P < .05. P < .02 (two-tailed, unpaired Student t test).

or it may be of neurogenic or primary cardiac origin. The purpose of this study was to investigate the hemodynamic effects of naloxone during prolonged ventricular fibrillation (VF) and cardiopulmonary resuscitation (CPR) in the canine model during fibrillation and following countershock.

METHODS Instrumentation Ten mongrel dogs of both sexes, weighing 21 to 28 kg and unselected for thoracic dimensions, were anesthetized with ketamine hydrochloride 10 mg/kg intramuscularly. They were then intubated with a standard cuffed 9-French endotracheal tube, and inhalation anesthesia was begun with methoxyflurane (Metafane®). Positive pressure ventilations with 100% 0 2 were given at a rate of 15 to 20 per minute at a tidal volume of 10 to 15 mL/kg. Lead II of the surface electrogram was obtained in each animal from silver-silver chloride pads applied to small areas of shaved skin on the right shoulder and left hind limb, and was monitored during instrumentation and the experimental protocol. Transducer-tipped catheters with 7French side-holes were inserted percutaneously into a femoral artery and vein, and the catheter tips were positioned in the proximal aorta and right atrium. Catheters were calibrated in 0.9% saline prior to intravascular in18/199

sertion. The right atrial catheter tip was positioned by advancing the catheter until a characteristic right ventricular pressure trace was recorded; the catheter was then withdrawn until typical right atrial pressure waves were seen. The position of the aortic catheter was confirmed and adjusted by palpation of the aorta after thoracotomy for flow probe insertion. A conventional 7-French bipolar pacing catheter was inserted percutaneously into a femoral vein and was advanced until the distal electrode was in contact with the right ventricular endocardium. Endocardial contact was confirmed when the characteristic intracardiac electrogram was recorded (large QRS complex with ST segment elevation - - "current of injury"). Each animal was then placed in the right lateral decubitus position, and a left thoracotomy was performed at the level of the fourth intercostal space. The proximal ascending aorta was dissected from the main pulmonary artery, and the adventitia was freed of fat. A 16-mm or 18-mm (internal diameter) calibrated perivascular flow probe was then placed around the ascending aorta just above the aortic valve. Probe size was chosen to produce a snug fit and an approximate 10% to 15% reduction in aortic diameter. Aortic flow was measured with a square-wave e l e c t r o m a g n e t i c flow meter. After hemostasis was assured, Annals of Emergency Medicine

the thoracotomy incision was closed tightly in layers, and air was evacuated from the thoracic cavity using a standard 28-French thoracostomy tube attached to suction. All animals then were placed in the supine position; control intravascular pressures and aortic flow were recorded; and blood samples were obtained from the central aorta and right atrium for analysis of 02 and CO 2 tensions and pH.

Experimental Protocols After control measurements were obtained, ventricular fibrillation (VF) was induced by alternating current s t i m u l a t i o n of the right ventricle using the bipolar catheter. VF was confirmed by surface electrocardiography and by the cessation of aortic pressure fluctuations. Zero aortic flow baseline was confirmed after induction of VF when the aortic pressure tracing had stabilized. After the zeroflow baseline was established, anteroposterior chest compressions and positive pressure artificial ventilation (CPR) were begun using a pneumatic piston-cylinder device powered by 100% O 2 at 60 to 80 psi. Chest compressions were administered at a rate of 60 compression-relaxation cycles per minute. Chest compression (systole) was maintained for 500 ms and was followed by a relaxation period (diastole) of equal duration. During VF and CPR, chest compression force was adjusted as necessary to produce an 14:3 March 1985

TABLE 2. Arterial and venous blood gas values during CPR* Minutes

PaO 2

PaCO 2

pHat

PvO 2

PvCO 2

pHv:~

0 5 10 15 20

435 333 341 362 337

--_ +-_ + -+ _+

178 142 150 96 56

32 15 11 12 13

-+ + +-+ _+

9 4 2 1 2

7.38 7.45 7.43 7.39 7.31

+ .07 ___ .13 + .13 + .04 + .08

44 19 18 19 15

+ + +-+ +-

6 4 6 4 6

43 44 43 45 53

+_ ___ + +_ _+

2 14 12 10 9

7.33 7.22 7.20 7.17 7.08

_+ + +_ _+ +

.03 .17 .04 .03 .05

Epinephrine

0

(N = 5)

5

508 377 420 412 364

-+ 42 + 123 ___ 77 _ 94 ___ 88

28 13 15 15 15

+ + _+ + _+

8 5 6 7 4

7.46 7.61 7.50 7.47 7.37

___ .06 -+ .14 + .07 + .09 + .12

46 22 20 16 18

-+ --+ +_ -+

7 4 6 4 4

35 38 36 41 49

+_ 7 _+ 13 _+ 6 +_ 17 _+ 21

7.40 7.34 7.30 7.24 7.18

+ _+ _+ + _+

.06 .07 .07 .11 .09

Naloxone (N = 5)

10 15 20

*All values are mean _+ SD. 02 and CO2 tensions are in mm Hg. ta = arterial (aortic). ~v = venous (right atrial). Differences were not significant (two-tailed, unpaired Student t test).

aortic systolic pressure greater than or equal to 40 m m Hg. Positive pressure ventilations with 100% 02 were given during every fifth diastole at a tidal volume of 15 mL/kg. After 15 minutes of CPR, the animals were r a n d o m i z e d to receive either naloxone (5 mg/kg) or epinephrine (1 mg) by right atrial injection. Five minutes after drug administration, standard defibrillator paddles were pressed firmly to the shaved skin of the right and left thorax using electrode paste to ensure electrical contact; defibrillation was a t t e m p t e d using a variable energy output defibrillator. The initial countershock was attempted at a dose of 1 J/kg. If VF persisted, the energy dose was increased progressively (2, 4, 8, 12, and 16 J/kg) at 30-second intervals until defibrillation (any rhythm other than VF) was achieved or the maximum energy dose was reached. If VF persisted or a nonperfusing spontaneous cardiac rhythm {electrical-mechanical dissociation [ E M D ] ) f o l l o w e d countershock, the alternate drug (naloxone or epinephrine} was injected into the right atrium; mechanical CPR was reinstituted; and, ff necessa~ a second sequence of countershocks at increasing energy doses was given. The importance of adrenergic receptor stimulation in cardiac arrest and defibrillation has been reported previously.14 Because epinephrine is recognized by the American Heart Association as standard therapy in this setting, t5 we chose not to use a "control" group without therapy; rather, we felt it appropriate to compare 14:3 March 1985

naloxone with the standard, accepted therapy, epinephrine.

Definitions In our study, successful cardiac resuscitation was defined as a spontaneous perfusing r h y t h m (arterial pressure pulses and aortic flow) maintained for 30 minutes after successful countershock. Successful countershock was defined as termination of VF, regardless of postcountershock rhythm. EMD was defined as electrocardiographic ventricular depolarization, at any rate, not associated with an arterial pulse pressure greater than or equal to 20 m m Hg or aortic flow.

Measurements Peak systolic, end-diastolic (ED), mean aortic (Ao), and r i g h t atrial (RA) pressures were recorded during the control period and at 5, 10, 15, and 20 minutes after induction of VE Twenty-minute values represent pressures prior to the first eountershock at 1 J/ kg. Pulsatile (phasic) and mean electromagnetic aortic flow (in mL/min) were measured simultaneously during sinus rhythm and at five-minute intervals following VF. An electronic subtraction circuit was used to record instantaneous coronary perfusion pressure (Ao minus RA pressure difference) during CPR systole and diastole; this pressure was displayed on a separate channel. The peak or maximum Ao-RA pressure difference during CPR diastole was measured at five-minute intervals after VF induction. Aortic (arterial) and venous (right atrial} blood samples were obtained Annals of Emergency Medicine

anaerobically during sinus r h y t h m and at five-minute intervals after VF onset. Samples were analyzed for 02 and CO 2 tension (ram Hg) and pH. Analysis was performed immediately after sampling, or the heparinized samples were placed in an ice bath and analyzed within 60 minutes of withdrawal. The arterial pH was maintained at greater than or equal to 7.25 during the experiment, using sodium bicarbonate if necessary.

Data Analysis All h e m o d y n a m i c and blood gas values are reported as the mean plus or minus one standard deviation. The unpaired Student t test (two-tailed} was used to test the null hypothesis that h e m o d y n a m i c and blood gas values during CPR did not differ between animals that received naloxone and those given epinephrine prior to the first countershock. The paired Student t test (two-tailed) was used to test the null hypothesis that naloxone and epinephrine had no effect on hem o d y n a m i c and blood gas values. £ischer's exact test was used to test the null hypothesis that the frequency of countershock success did not differ between animals that received naloxone and those that were given epinephrine. A value of P less than or equal to .05 was considered statistically significant. RESULTS H e m o d y n a m i c values measured during the control period (time = 0) and at five-minute intervals after induction of ventricular fibrillation are 200/19

USE OF NALOXONE Rothstein et al

Fig. 1. Diastolic coronary perfusion pressure. Comparison of dogs given naloxone and those given epinephrine. Fig. 2. Aortic end-diastolic pressure. Comparison of dogs given naloxone and those given epinephrine. Statistical significance is between 15- and 20-minute values. shown (Table 1). Arterial (aortic) and venous (right atrial) blood gas values during sinus rhythm (time = 0) and at five-minute intervals after induction of ventricular fibrillation are shown (Table 2). C o n t r o l pressures, aortic flow, and values measured during the first 15 minutes of CPR were not significantly different between animals that subsequently received naloxone or epinephrine 15 minutes after VF induction (Table 1I. After 15 minutes of VF and conventional CPR, naloxone (5 mg/kg) was given to five animals, and epinephrine (i rag) was administered to five animals. Drug therapy was randomized, and medications were given by central venous injection. Naloxone had no significant effect on h e m o dynamic values when 15-minute meas u r e m e n t s (preinjection) were compared to 20-minute values (precountershock) (Table 1). Epinephrine, however, produced significant increases in systolic, end-diastolic (EDP) and mean Ao and diastolic coronary perfusion pressures (Figures 1 and 2). RA systolic pressure also increased, but end-diastolic RA pressure was not affected s i g n i f i c a n t l y by e p i n e p h r i n e . Epinephrine a d m i n i s t r a t i o n produced a significant decrease in m e a n aortic flow. This decrease was due largely to an increase in phasic retrograde aortic flow, presumably the result of greater coronary arterial flow during CPR diastole. Successful defibrillation was accomplished in none of the five animals that were given naloxone prior to the first countershock sequence, despite a m a x i m u m countershock dose of 16 J/ kg. Four of these five animals, however, were defibrillated successfully and met study criteria for successful cardiac resuscitation when 1 mg epinephrine was given after the first sequence of countershocks failed and the second sequence was begun. Four of the five animals that received epinephrine prior to the first countershock were defibrillated successfully. All four a n i m a l s d e m o n 20/201

70,.Ob

I>,E

I

• Naloxone • Epinephrine • P < .05

60-

m

50-

r-

2 2 rO

d) dD

o

o-

40-30--

tS~ d) 13_

L_ I ! 7-

20-10--

I

I

I

I

10

15

20

Minutes

120 -1

100 -

I Mean _+ SD

• Naloxone • Epinephrine • P < .05

CY) 7-

E F

v

80o3 o9 O_ rO

60-

¢D i

~3 rIII O

40-

O

20-

.t I

I

I

I

I

0

5

10

15

20

Minutes

2

strated EMD after countershock. Defibrillation outcome was significantly different b e t w e e n a n i m a l s t h a t received naloxone prior to countershock Annals of Emergency Medicine

and those given epinephrine (P = .02, n a l o x o n e vs epinephrine, Fischer's exact test). Five minutes after postcountershock EMD was confirmed in 14:3 March 1985

animals that initially received epinephrine, naloxone (5 mg/kg) was injected into the right atrium, and CPR was reinstituted. A spontaneous perfusing rhythm subsequently developed in all four animals; these animals met criteria for successful cardiac resuscitation. One animal that received epinephrine prior to t h e first c o u n t e r s h o c k s e q u e n c e c o u l d n o t be defibrillated with an energy dose of up to 16 J/kg, and it failed to respond to naloxone and further countershock attempts. The total energy dose given was 32 J/kg. Hemodynamic results for each dog were not statistically different between 20-minute values and during the 30-minute postcountershock period, with values measured every five minutes. DISCUSSION This study suggests that naloxone (Narcan ®) may play a role in improving survival from fibrillatory cardiac arrest in the canine model. Although our observations fail to s h o w t h a t naloxone improves countershock outcome or d e f i b r i l l a t i o n t h r e s h o l d , naloxone seems to improve arterial blood pressure and aortic flow when successful electrical defibrillation resuks in EMD. The exact role of the endorphin system in potentiating the detrimental effects of shock states and the means by which these effects are reversed by opiate antagonists are n o t well defined. Current evidence points to the involvement of c a t e c h o l a m i n e s and the a u t o n o m i c nervous system.16,17 Enkephalins stored with epinephrine in adrenal medulla and nerve terminals in sympathetic ganglia also may have a primary role as a neurotransmitter in the central and peripheral nervous system. 18 Endogenous opioids may be responsible for tonic inhibition of neurally mediated adrenal catecholamine release. 2° The effects of naloxone in shock states, that is, increased mean arterial pressure and increased m y o c a r d i a l contractility, are similar to those observed after epinephrine administration; however, these effects are not observed in normal patients or animals in the absence of shock or exogenous opiates.3,s, lo Similar effects are seen after administration of antiserum to beta-endorphin. 21 In our canine study, naloxone was ineffective in facilitating electrical de14:3 March 1985

fibrillation. Following epinephrine and c o u n t e r s h o c k , however, E M D occurred in five dogs, and four of five developed arterial pressures and aortic flows comparable to prearrest values after naloxone was given. In the group that initially received naloxone but was s u c c e s s f u l l y defibrillated o n l y after epinephrine, four of five had a supraventricular r h y t h m and normal perfusion parameters after countershock. In light of current knowledge, we postulate that the stress of cardiac arrest causes a release of endogenous opiates that are partially responsible for cardiac and peripheral vascular depression. Moreover, the response to epinephrine m a y be a t t e n u a t e d by these substances, and this effect can be reversed by naloxone. A n alternative hypothesis is t h a t t h e enkephalins are involved in parasympathetic neurotransmission and result in a profound suppression of this pathway, producing asystole or an idioventricular rhythm associated with ineffective cardiac contractions. This, in turn, can be reversed by naloxone. Other, as yet undetermined, mechanisms also may be important. The dose of naloxone used in this experiment was large for several reasons. Numerous case reports and experimental studies 9q2 have demonstrated that larger doses of naloxone, for example, 1 to 10 mg/kg, are effective in reversing the effects of shock and releasing catecholamines w h e n smaller doses fail. Our preliminary, unpublished experience suggests that doses up to 1 mg/kg failed to show any effect similar to what we observed with 5 mg/kg. The optimal dose in this setting has yet to be established.

EI Du Pont De Nemours and Company, and thank Victor J Nickolson, PhD, Glenolden Laboratory, Glenolden, Pennsylvania, for supplying the naloxone, and Jenny Keshishian for her secretarial support in manuscript preparation.

CONCLUSION Naloxone 5 mg/kg has salutary effects in converting EMD to a perfusing r h y t h m after a d m i n i s t r a t i o n of epinephrine and defibrillation in dogs. Naloxone alone did not facilitate defibrillation; in combination with epinephrine, however, it prevented EMD. The mechanism for this effect is unclear, but likely is mediated by catec h o l a m i n e r e l e a s e and i m p r o v e d responsiveness of the heart to catecholamines after naloxone administration. Further validation of these findings and elucidation of mechanisms is needed.

10. Reynolds DG, Gurll NJ, Vargish T, et ah Blockade of opiate receptors with naloxone improves survival and cardiac performance in canine endotoxic shock. Circ Shock 1980;7:39-48.

The authors acknowledge the support of Annals of Emergency Medicine

REFERENCES 1. Hughes J, Smith TW, Kosterlitz HW, et ah Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;258:577-579. 2. Goldstein A: Opioid peptides (endorphins) in pituitary and brain. Science 1976;193:1081. 3. Holaday JW: Cardiovascular consequences of endogenous opiate antagonism. Biochem Pharmacol 1983;32: 573-585. 4. Holaday JW, Ruvio BA, Sickel J: Morphine exacerbates the cardiovascular pathophysiology of endotoxic shock in rats. Circ Shock 1982;9:169-171. 5. Gahhos FN, Chiu RCJ, Hinchey EJ, et ah Endorphins in septic shock: Hemodynamic and endocrine effects of an opiate receptor antagonist and agonist. Arch Surg 1982;117:1053-1060. 6. Faden AI, Jacobs TP, Holaday JW: Endorphin-parasympathetic interaction in spinal shock. J Auton Nerv Syst 1980; 2:295-304. 7. Florez J, Midiavilla A: Respiratory and cardiovascular effects of metenkephalin applied to the ventral surface of the brainstem. Brain Res 1977;138:585-590. 8. Weissglas I: The role of endogenous opiates in shock: In vitro, in vivo experimental and clinical studies. Adv Shock Res 1983;10:87-94. 9. Holaday JW, Faden AI: Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock. Nature 1978;275:450-451.

11. Vargish T, Reynolds DG, Gurll NJ, et ah Naloxone reversal of hemorrhagic shock in dogs. Circ Shock 1980;7:31-38. 12. Gurll NJ, Vargish T, Reynolds DG, et al: Opiate receptors and endorphins in the pathophysiology of hemorrhagic shock. Surgery 1981;89:364-369. 13. Dashwood MR, Feldberg W: A pressor response to naloxone. Evidence for the release of endogenous opioid peptides. J Physiol [London] 1978;281:30-31. 14. Yakaitis RW, Otto CW, Blitt CD: Relative importance of alpha and beta adrenergic receptors during resuscitation. Grit 202/2t

USE OF NALOXONE Rothstein et al

Care M e d 1979;7:293-295.

15. Standards and guidelines for eardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). JAMA 1980~ 244(suppl):485. 16. Mannelli M, Maggi NI, De Feo ML, et al: Naloxone administration releases eatecholamines. N e w Engl J M e d 1983;308: 654-655.

17. Lang RE, Ganten D, Unger TH: Enkephalins in the heart (abstract). Circ (Suppl III) 1983;68:77. 18. Konishi S, Tsunoo A, Otsuka M: Enkephalins as neurotransmitter for presynaptic inhibition in sympathetic ganglia. Nature 1981;294:80-82. 19. Sander GE, Giles TD: Facilatory effect of methionine-enkephalin upon epinephrine-induced cardiovascular responses (ab-

stract). Circ (Suppl III) 1983;68:79. 20. Cochrane KL, Brosnihan KB, Ferraric CM: Do opioids modulate neurally medi. ated adrenal catecholamine release? (ab. stract} Circ (Suppl III) 1983;68:249. 21. Ramirez-Gonzalez MD, Tehakarov L Mosqueda Garcia R, et al: Beta-endorphir~ acting on the brainstem is involved in the antihypertensive action of clonidine and methyldopa in rats. Circ Res 1983;53: 150-153.

1985 ACEP Council Resolution Deadline The ACEP Council will meet September 7-8, 1985, in Las Vegas, Nevada. All proposed amendments to the Constitution and Bylaws of the American College of Emergency Physicians must be received by the Council Secretary no later than 90 days in advance of the annual meeting. For the 1985 meeting that date is

June 10. All other resolutions should be submitted to the Secretary no later than 45 days in advance of the meeting. This year that date is July 24. Address resolutions to: Colin C Rorrie, Jr, PhD, Secreta~ ACEP Council, PO Box 619911, Dallas, Texas 75261-9911. Advance submission of resolutions is preferable to floor resolutions because it permits chapter review and allows staff time to prepare analyses of fiscal impact and previous College action. 22/203

Annals of Emergency Medicine

14:3 March 1985