cardiopulmonary bypass after cardiac arrest and prolonged closed-chest cpr in dogs

ORIGINAL CONTRIBUTION bypass, cardiopulmonary, canine CPR, bypass, canine

Cardiopulmonary Bypass After Cardiac Arrest and Prolonged Closed-Chest CPR in Dogs

We studied a clinically realistic field-to-hospital scenario in dogs with four- minute ventricular fibrillation (VF) cardiac arrest fol lowed by 30-minute standard external CPR basic life support (BLS). A t the end of this 34-minute insult, cardiopulmonary bypass (CPB) was used for early defibrillation and assisted circulation for one hour (n = 10). Recovery was compared with that of control dogs (n = 10) in which standard CPR with advanced life support (ALS) for another 30 minutes was used for restoration of spontaneous circulation (ROSC). Both groups had hemodilut ion and heparinization; controlled blood pressure, blood gases, ventilation, and other parameters for 20 hours; and intensive care to 72 hours. During CPR-BLS of 30 minutes in both groups signs of cerebral viability returned. CPB achieved ROSC more successfully (ten of ten vs five of ten CPR-ALS controls) (P < .02); and more rapidly, with less defibrillation energy (first countershock in eight of ten) and with less epinephrine (P < .01). CPB improved 72-hour survival (seven of ten vs three of ten controls) (P < .05). Between two and 24 hours, of those with ROSC, cardiac complications ki l led three of ten CPB dogs (after weaning), and two of five CPR-ALS dogs (NS). All seven CPB survivors to 72 hours were neurologically normal; of the three CPR-ALS survivors, one remained with severe neurologic deficit and two were neurologically normal (seven of ten CPB vs two of ten controls, P = .025). Starting CPR-BLS within four minutes of arrest can maintain cerebral viability CPB increases cardiovascular resuscitability and thereby survival wi thout neurologic deficit as compared to CPR-ALS. [Levine R, Gorayeb M, Safar P, A b r a m s o n N, Stezoski W, Kelsey S: Cardiopulmonary bypass after cardiac arrest and prolonged closed-chest CPR in dogs. Ann Emerg Med June 1987;16:620-627.]

INTRODUCTION After more than four minutes of cardiac arrest or more than 20 minutes of

basic life support (BLS) CPR cardiovascular and cerebral resuscitat ion success rates have been very low in human beings 1-3 and dogs. 4 8 This is because standard external CPR does not re l iably produce the perfusion pressures needed or the carotid, cerebral, and coronary blood flows required to restore and maintain viabili ty of brain and heart3, 8qo At tempts to improve standard external CPR have so far been impract ical or have failed to enhance prompt restoration of spontaneous circulation (ROSC) or improve neurologic outcome.l,4,7

Cardiopulmonary bypass (CPB) permits control over flow, pressure, oxygenation, temperature, and composi t ion of blood during reperfusion and prolonged assisted circulation. 11-2o The results of uncontrol led clinical trials of CPB for normothermic 17 and hypo the rmic 18 cardiac arrest, and for cardiogenic shock19, 2o and other purposes 2I appear promising. Emergency CPB can. be applied clinically wi thout thoracotomy, using a portable CPB apparatus, with venoarterial pumping by membrane oxygenator, using plasma sub- stitute priming and heparinization35,17

In 1982 we initiated a research program using CPB for prolonged cardiac arrest in dogs. 13q6 In the first study, I3 superiori ty of CPB over CPR-advanced life support (ALS) in reversing normothermic cardiac arrest of 20 minutes was demonstrated. In the second study,14 we could restart the heart after up to 90 minutes of ice water submersion. In the third study, is VF-cardiac arrest

Robert Levine, MD*t Marc Gorayeb, MD§ Peter Safar, MD* Norman Abramson, MD* William Stezoski* Sheryl Kelsey, PhD¢ Pittsburgh, Pennsylvania

From the Resuscitation Research Center,* the Departments of Anesthesiology and Critical Care Medicine,t and Epidemiology,4: and the Division of Emergency Medicine,§ University of Pittsburgh School of Medicine, and the Presbyterian-University Hospital, Pittsburgh, Pennsylvania.

Received for publication April 14, 1986. Revisions received August 9 and November 14, 1986. Accepted for publication December 31, 1986.

This work was performed during Dr Levine's and Dr Gorayeb's RRC Research Fellowships 1984/1985. Presented at the American Heart Association CPR Standards Conference, Dallas, Texas, July 1985; and at the Annual Meeting of the American Academy of Cardiovascular Perfusion, Washington, DC, January 1986; the Annual Meeting of the University Association for Emergency Medicine in Portland, Oregon, May 1986; and the Society of Critical Care Medicine, Washington, DC, May 1986.

Supported in part by the Bard Cardiosurgery Division, CR Bard, Inc, the Asmund S Laerdal Foundation, and Pharmacia Laboratories.

Address for correspondence: Dr Peter Safar, Resuscitation Research Center, University of Pittsburgh, 3434 Fifth Avenue, Pittsburgh, Pennsylvania 15260.

16:6 June t987 Annals of Emergency Medicine 620/29

BYPASS & CPR Lev ine et al

FIGURE 1. Mean arterial pressure (MAP) during standard external CPR basic life support (BLS) of 30 minutes. No difference between group later treated with CPR-ALS vs group treated with CPB.

of 12Y2 minutes was reversed by CPB alone, without preceding CPR. CPB gave superior survival and 72-hour recovery compared with CPR-ALS controls. The implementa t ion of CPB without preceding CPR, however, is clinically unlikely.

We, therefore, conducted this clinically relevant fourth study 16 to simu- late a survivable no-flow insult (VF- cardiac arrest of four minutesl, followed by a clinically common low- flow CPR-BLS of 30 minutes duration (simulating CPR by bystanders and emergency medical technicians during transportation, and giving time for cannulation of femoral vessels in the emergency department). We compared cardiovascular resnscitability and 72- hour recovery after the 34-minute insult after treatment with CPB as compared to CPR-ALS controls.

METHODS Design and Preparation

This study was approved by the Animal Care Committee of our in- stitution. Twenty-eight unpremedi- cated, healthy coon hounds of both sexes (20 to 25 kg) were used. We had previously established the dog model of VF-cardiac arrest of four minutes and CPR BLS of 30 minutes. 7 Prepara- tion, N20/O 2 halothane anesthesia, pancuronium paralysis, ventilation, monitoring, baseline measurements, and pre-CPR and post-CPR control of variables were as described in another paper.iS The 28 dogs were assigned alternately (paired) to the CPR-ALS control group or the CPB group by an assistant who was unaware of the treatment to be used. All experiments were carried out within a period of three months by the same team. Blind treatment was not feasible.

In the CPB group, during CPR-BLS, the right external jugular vein and right femoral artery were cannulated by sterile cutdowns. The jugular-to- venae cavae CPB catheter was a 35- cm, mul t ip l e -ho led , 20-F, t e f lon catheter. The tip of the cannula was placed blindly near the right atrium. The arterial CPB cannula was a 5-cm stainless steel 14-F cannula.

The CPB apparatus used (Bard Car-

200

MAP torr

vF I , 4'

100

MAP During CPR

VF CPR-BLS

i

', i "

0 ~ 0 5 10 15 20

Time (min)

. j CPR :~----~ CPB = =

X+_S.D

25 30

/ / /

diosurgery Division, Billerica, Mas- sachusetts) consists of a pump controller width e lec t romagnet ic flow meter (Biomedicus, Eden Prairie, Min- nesota), a six-hour battery pack, a temperature controller, and a dispos- able circuit. The latter includes a Bio- medicus pump head, clamp, connec- tors, tubings, heat exchanger, and a Bard hollow-fiber membrane oxygenator (which also serves as a filter). The non-occlusive self-regulating cen- trifugal Biomedicus pump creates negative pressure on the venous return, which makes a reservoir unnec- essary. The bypass system has a priming volume of 700 mL, and a pumping capacity of up to 10 L/rain. Priming fluid consisted of dextran 40 (in iso- tonic saline) and lactated Ringers' solution (50:50). Heparin 1.5 mg/kg was added to the priming solution, and an additional heparin 1.5 mg/kg was in- jected through the venous cannula immediately before bypass (both groups were heparinized and hemodiluted). The oxygenator was flushed continu- ously with 100% O~, using a flow of 3 to 5 L/min, adjusted to control PaCO2 at 25 to 30 mm Hg and PaO~ > 300 mm Hg.

All CPB and monitoring lines were presoaked in heparin and periodically flushed with small amounts of dilute heparin in saline. Activated clotting time (ACT) was monitored intermit- tently and the heparin doses adjusted to maintain the ACT at > 400 s.

Insult While paralysis was maintained,

halothane and NsO were changed to 100% Os for one minute of intermit- tent posit ive pressure vent i la t ion (IPPV), which was followed by IPPV with air for four minutes, to minimize the effect of anesthesia in a standard- ized way. The mean arterial pressure (MAP) was allowed to rise. The heat- ing blanket was switched off and the IV infusion stopped. VF then was induced by an external transthoracic electric shock of 50 V AC of two seconds duration (repeated with higher voltage if necessary) and IPPV was dis- continued. Pulselessness occurred immediately and the EEG because iso- electric within l0 to 20 seconds.

After four minutes of VF-cardiac arrest (no flow), standard external CPR- BLS was begun using a Michigan In- struments Thumper ® (Grand Rapids, Michigan) with a max imum chest compression pressure of 100 lb, adjusted to produce if possible a systolic arterial pressure of 70 to 100 mm Hg. Anterior-posterior chest compressions were performed with the dog immo- bilized at a 10 ° right oblique angle, which we have found in previous experiments to give better MAP than mid-sternum compression. To ensure comparability of insult, we monitored MAP and pupillary reactivity during CPR-BLS in both groups.

Resuscitation and Intensive Care In the CPR-ALS control group, at

the end of VF-cardiac arrest of four minutes and CPR-BLS of 30 minutes (34 minutes total insult time), a standard protocol for ROSC was used until

30/621 Annals of Emergency Medicine 16:6 June 1987

Best Outcome (time of death post cardiac arrest)

Brain Death

Coma, Vegetative State

Severe Deficit Conscious

Moderate Deficit Conscious

Normal

Conscious Survivors

OPC

No ROSC in 30'

VF Cardiac Arrest 4 min + CPR BLS 30 min

Control CPR ALS

0 0 0 0 0

(24 h)

(4 h)

(72 h)

\

Cardiopulmonary Bypass

(4 h) (5 h) (5 h)

tit -/r ~

(all 72 h)

/ *For OPC 1: P < .05.

• (72 h) • (72 h)

2/10 (5) 7/10

2

success or for 30 minutes . 7 Briefly, we started with an external electric countershock of 100 J, which was repeated if necessary wi th in a few seconds. Epi- nephrine 0.05 mg/kg plus N a H C O 3 0.5 mEq/kg were given through a cen- tral vein 30 seconds af ter the f irst countershock. If unsuccessful , countershocks were repeated wi th 200 J at one minute, 300 J at two minutes, and 400 J every minute thereafter to five minutes, and then every five minutes two countershocks of 400 J to 30 minutes. Ep inephr ine was r e p e a t e d at three minutes and every five minutes thereafter to 30 minutes. During CPR- ALS, after the first empirical dose of NaHCO 3 {above), subsequen t doses were given to normalize arterial base deficit. Ventr icular t a chyca rd i a and fibrillation were treated wi th l idocaine 1 to 3 mg/kg in a d d i t i o n to countershocks.

In the CPB t rea tment group, at the end of CPR-BLS of 30 m i n u t e s (34 minutes total insul t time), CPB was initiated to achieve early ROSC and was continued to assist the circulation

for at least one hour wi th a m a x i m u m of four hours of supported circulation. The pre-placed femoral artery cannula and per iphera l ly engaged right external jugula r ve in ca the t e r were con- n e c t e d to the CPB appa ra tu s . T h e jugular ve in ca the t e r was advanced into the venae cavae immedia te ly pri- or to start of CPB. At one minu te of CPB, the first external electric countershock was given wi th 100 J; if unsuccessful i t was increased every 60 seconds by 50 J to a m a x i m u m of 400 J. Early defibril lation was used to let the left side of the heart vent itself by spontaneous beat ing to prevent pul- m o n a r y c o n g e s t i o n . 22 In t h e CPB group, the f irst dose of ep ineph r ine was smaller (0.025 mg/kg), to achieve the same hyper tension {without over- shoot) of about MAP 130 m m Hg for five to ten minu te s in both groups. The first dose of NaHCO 3 was larger {starting wi th 1.5 mEq/kg), to achieve the same normal izat ion of base deficit in the presence of di lut ion by the CPB priming volume.

The bypass flow was maximized (up

FIGURE 2. Best overall performance categories (OPC) achieved during the 72-hour life support, after VF cardiac arrest of four m i n u t e s fo l lowed by CPR-BLS of 30 minutes in dogs. Each dot or star represents one dog. Hours of survival in parentheses. Dogs were killed at 72 hours. ROSC = restora- t ion of s p o n t a n e o u s c i rcu la t ion . *After ROSC, there was at 72 hours a significantly greater proportion of conscious (OPC 1, 2, 3) survivors in the CPB than the CPR-ALS control group (seven of ten vs two of ten controls).

to 4 L/min} unt i l defibrillation. After defibrillation, assisted circulation was continued for at least one hour, wi th CPB flows of at least 50 to 100 mL/kg/ min, adjusted to mainta in MAP at 100 m m Hg, wi th norepinephrine if necessary. During CPB, IPPV wi th 100% 02 was given at a rate of five inflations per m i n u t e to p r e ve n t a t e l e c t a s i s . After CPB of one hour, the dogs were weaned slowly to spontaneous circulation. Weaning cri teria were no need for norepinephrine to mainta in MAP at 100 m m Hg wi th decreasing CPB 'flows; normal arterial blood gas and pH values; and no life-threatening ar- rhythmias. When weaning was unsuccessful, CPB was cont inued for a max- i m u m of four hours (two of ten dogs required more than one hour of CPB}.

In b o t h groups, e p i n e p h r i n e was used to facilitate ROSC and to achieve a modera te hyper tens ion for five to ten minutes immedia te ly upon ROSC. The dogs were c o n s i d e r e d to have achieved ROSC in the CPR-ALS con- t rol group w h e n spon taneous M A P was at least 50 m m Hg, and in the CPB group when r educ t ion of CPB flow a l lowed r educ t i on of MAP to about 50 m m Hg wi th spontaneous systolic pressure waves appearing su- perimposed. Once an organized heart rhy thm was achieved, a t i t rated IV infusion of norepinephrine was used if needed to mainta in MAP at 100 _+ 20 m m Hg. Immedia te ly after ROSC in the CPR-ALS group, a fluid load of 3 mL/kg was given IV over 15 minutes. Fluid loading in the CPB group was used on ly if neces sa ry to m a i n t a i n venous return required to achieve pre- scribed flows.

In both groups, hepar in iza t ion a n d hemodi lu t ion were used. The control group received heparin 3 mg/kg IV at the end of the 3 0 - m i n u t e CPR-BLS and after ROSC, normovolemic hemo- d i l u t i on to a h e m a t o c r i t of 25% to

16:6 June 1987 Annals of Emergency Medicine 622/31

B Y P A S S & C P R

L e v i n e et al

TABLE 1A. Course in dogs after ventricular fibrillation cardiac arrest of four minutes followed by CPR basic life support of 30 minutes

(A) CPR-ALS Control Group insult V J

During CPR-BLS (AC) Time to (DC) Dog MAP Pupils for ROSC for No.* torr React VF < 30 min Defibrillation

1 50 + 50 3 min 200

2 55 + 385 No ROSC 400 (<30 min)

3 40 + 50 No ROSC 300 (<30 min)

4 55 + 50 1 min 100

5 60 - 50 10 min 425

Course After ROSC Epinephrine 24 h 48 h 72 h 72 h

mg Total 0-4 h 4-24 h ND ND ND OPC

1 IPPV, NE IPPV, stable SB 33 40 3

5 . 5 . . . . .

Outcome Survival

Survived 72 h

No ROSC

7 . . . . No ROSC

2 IPPV, NE IPPV, stable SB 0 0 1 Survived 72 h

2 IPPV, NE IPPV, unstable - - - - Died 24 h CS MAP, ECG, Died 24 h, CS

6 25 - 125 No ROSC 1350 6 . . . . No ROSC (<30 min)

7 70 + 225 3 min 200 4 IPPV, NE IPPV, unstable - - - - - - Died 4 h CS Died 4 h, CS

8 60 + 125 No ROSC 400 7 - - - - - - No ROSC (<30 rain)

9 45 + 205 No ROSC 300 6 - - - - - - No ROSC (<30 min)

10 60 + 50 3 min 100 1 IPPV, NE IPPV, stable SB 0 0 1 Survived 72 h

Mean 52 131 17.0 4.0 377 205 4.2

±SD _+13 +111 ±13.8 ±3.5 +361 +132 _+2.4

n 10 8/10 10 5/10 10 5/10 10 NE 5/5

Signifi- NSt NS NS :~ NS ~ NS :~ canoe

For abbreviations, see Table lB. *Experiments of dogs listed in Tables 1A and 1B were conducted in alternating sequence between groups, ie, with concurrent controls. In the tables the data are grouped according to treatment and within each treatment group in chronologic order.

tNot statistically significant difference. ::CPB vs CPR-ALS group comparisons with difference P < .05.

1) 5/10 achieved ROSC. 2) 2/10 died 4-24 h. 3) 3/10 survived to 72 h. 4) 3/5 with ROSC survived to 72 h. 5) 2/5 with ROSC achieved OPC 1. 6) 2/3 24 h survivors normal at 72 h. 7) 2/10 achieved OPC 1.

30% with dextran 40 in saline plus Ringers' solution 50:50.

In both groups, normotension was maintained up to 24 hours. Base deficit > 7 mEq/L was corrected wi th N a H C O 3. IPPV wi th N 2 0 / O 2 (50/ 50%) and p a n c u r o n i u m pa ra lys i s (without halothane) were maintained from two to 20 hours. Intensive care was continued for 72 hours. Lidocaine was given IV as needed to control ventricular tachycardia. Tetracycline 50 mg was given IM every eight hours.

Evaluation The variables used to compare dif-

ferences between the control group (Table 1A) and the CPB group (Table

1B) - - in terms of cardiovascular resuscitability, survival, and neurologic r ecove ry - - i nc luded the t ime to ROSC, the n u m b e r of dogs t h a t achieved ROSC, ep inephr ine -coun- t e r s h o c k e n e r g y - n o r e p i n e p h r i n e - NaHCO 3 requirements, and survival t ime. Neurologic assessment at 24, 48, and 72 hours after insult consisted of applying the neurologic deficit (ND) scoring and overall performance cate- g o r i z a t i o n tOPC) used p r e v i o u s - ly, l,5-7,Z3, 24 ND scores range from 0% (normal) to 100% (brain death). OPC reflects cerebral plus extra-cerebral causes of disability. OPC 1 implies normal performance; OPC 2, moderate disability; OPC 3, severe disability,

but conscious; OPC 4, coma or vegetative state; and OPC 5, death or brain death.

OPC and ND were determined by two nonblinded team members who observed the dogs' recovery repeatedly between and at the evaluation times of 24, 48, and 72 hours. Use of CPB made blinding of the exper imenters impossible. In other studies, evaluation of OPC from videotapes by blinded outsiders was identical with that by experimenters. Invest igator vari- ability among our team members in previous blinded placebo studies w a s zero for OPC and _+ 5% for ND.

Complete autopsies were performed immediately in dogs in which spon-


TABLE lB. Course in dogs after ventricular fibrillation cardiac arrest of four minutes followed by CPR basic life support of 30 minutes

(B) CPB Group Insult V Time to

During CPR-BLS (AC) ROSC Dog MAP Pupils for Max No. torr React VF 30 min

11 50 - 125 5 min

12 50 + 50 1 min

13 70 + 125 2 min

14 70 + 225 1 min

15 65 + 125 3 h 30 min

16 20 - 50 1 h 30 min

17 80 + 125 1 h

18 65 ÷ 50 I h

19 65 ÷ 125 1 h

20 65 + 205 2 h

J (DC) for Epinephrine

Defibrillation mg Total 0-4 h

100 1 CPB 4 h NE

100 1 CPB 4 h

100 1 CPB 1 h

100 1 CPB 1 h

350 1 CPB 3V2 NE

200 1 CPB 4 h NE

100 0 CPB 1 h

100 0.5 CPB 1 h NE

100 0.25 CPB 1 h

100 0.3 CPB 1 h

Course After ROSC (CPB to 1 h minimum) 24 h 48 h 72 h 72 h Outcome

4-24 h ND ND ND OPC Survival

Not weaned CPB - - Died 4 h Died 4 h EMD EMD

IPPV, stable 29 14 6 1 Survived 72 h Weaned to SB



IPPV, weaned - - Died 5 h Died 5 h CS CS

IPPV, weaned Died 5 h Died 5 h VF VF

[PPV, stable 3 0 0 1 Survived 72 h Weaned to SB




Mean 60 120 1.9 135 0.7

--SD _+16 -+60 +1.3 +-82 -+0.4

n 10 8/10 10 10 10 10 NE 4/10

Signifi- NS* NS NS t t t t cance

ROSC, restoration of spontaneous circulation; SB, spontaneous breathing; Def, defibrillation; J, joules; NE, norepinephrine requirement; ND, neurological deficit (100% brain death, 0%=normal) ; OPC, overall performance categories (1 normal, 2 moderate disability, 3=severe disability but conscious, 4 -coma, 5=death); CS, cardiogenic shock; EMD, electromechanical dissociation (QRS without pulse); MAP, mean arterial pressure; VF, ventricular fibrillation; BLS, basic life support; ALS, advanced life support; AC, alternating current; DC, direct current *See footnote Table 1A tCPB vs CPR-ALS group comparisons with difference P <.05. *Not statistically significant difference.

Compared to CPR-ALS Group (Table 1A). 1) 10/10 achieved ROSC (P <.02). t 2) 3/10 died 4-24 h (NS). 3) 7/10 survived to 72 h (P <.05).t 4) 7/10 with ROSC survived to 72 h (NS).t 5) 7/10 with ROSC achieved OPC I (P < .025.) 6) 5/7 24 h survivors normal at 72 h (NS). 7) 7/10 achieved OPC 1 (P < .025). t

taneous circulation could not be restored, and in surviving dogs at 24 hours if they had achieved OPC 4 or 5, or at 72 hours if they had OPC 1, 2, or 3.

Experiments were exc luded f rom statistical analysis when they did not follow protocol according to our standard criteria.6, 7 Eight of the 28 dogs were excluded, four from each group. There was CPR trauma with hemor- rhagic shock post-ROSC in five (two with pulmonary lacerations and three wi th liver lacerations). There were

major avoidable technica l complications of CPB in three. The lat ter in- cluded one in which the venae cavae c a n n u l a was m a l p o s i t i o n e d a n d k inked; one in w h i c h m u l t i p l e at- tempts to cannulate the venae cavae failed wi th in the a l lo t ted t ime; and one in which CPB flow was not ob- tained because of major vessel clott ing preceding heparinization.

For stat ist ical comparisons between groups we used the Student t test for i n d e p e n d e n t s a m p l e s . T h e M a n n - Whitney U test was used to compare

r e q u i r e m e n t s for drugs. W h e n OPC scores were d i c h o t o m i z e d in to conscious vs unconscious, Fisher's exact test was used to test t r ea tmen t differences. When OPC was treated as or- dinal outcome (OPC 1, 2, 3, 4, 5) the Wilcox rank sum test was used. P .05 for two-sided t e s t s were reported as significant.

R E S U L T S Twenty experiments went according

to protocol and were used for analysis, ten in the control group (Table 1A) and

16:6 June 1987 Annals of Emergency Medic ine 624 /33

BYPASS & CPR Levine et al

ten in the CPB group (Table 1B). In the CPR-ALS control group, three of ten dogs surv ived to 72 hours , as compared to t he CPB group in w h i c h seven of ten dogs survived to 72 hours (P < .05).

Prearrest baseline variables and insult variables were the same in both g roups (for c o n t r o l l e d l i m i t s , see Methods). Dur ing the 30 minu te s of CPR-BLS, MAP in the control group ranged between 51 -+ 16 m m Hg and 56 + 14 m m Hg, and in the CPB group between 58 +- 18 m m Hg and 63 - 18 m m Hg (NS) (Figure 1). EEG activi ty ceased at ten to 20 seconds of VF. At the end of four minutes of VF- cardiac arrest, pupi ls were fixed and dilated. During CPR-BLS, pupil lary react ivi ty returned in the control group in five of ten dogs by five minutes and in eight of ten dogs by 25 minu te s (Table 1A); and in the CPB group in seven of ten dogs by five minutes and in nine of ten dogs at 25 minutes (Ta- ble 1B) (NS). Thus, pupi l lary ac t iv i ty was restored by CPR-BLS in 16 of 20 dogs. EEG activi ty could not be inter- preted during CPR-BLS due to mot ion artifacts. However, when immedia te ly on ROSC in 15 dogs of both groups the EEG connec t i on was re -es tab l i shed , continuous EEG activi ty was evident immedia te ly in all dogs.

CPR-ALS a c h i e v e d ROSC w i t h i n ten m i n u t e s in five of ten con t ro l dogs. Efforts in the other five dogs, c o n t i n u e d f rom 10 to 30 m i n u t e s , were u n s u c c e s s f u l (Table 1A). One countershock succeeded in defibrillat- ing t h r e e of t en and two coun te r - shocks in one of ten control dogs, but s ix of t en r e q u i r e d m u l t i p l e countershocks of max ima l energy (400 J). Even in those r e susc i t a t ed by CPR- ALS, this refractoriness to defibrilla- t ion de layed s t a b i l i z a t i o n of spontaneous circulation.

In the CPB group there were good venous returns and flows, according to protocol; the first countershock of 100 J del ivered after one m i n u t e of CPB was effect ive in e ight of ten dogs; ROSC was achieved in all ten wi th in five minutes (P < .05); eight of ten required only .one dose of epinephr ine (vs two of ten wi th CPR-ALS) (P < .01), and six of ten required only one countershock for spontaneous cardiac con t r ac t i ons genera t ing MAP > 50 m m Hg wi th in 30 seconds (vs 0 of ten wi th CPR-ALS) (P < .01). After ROSC, NaHCO 3 and norepinephrine requirements were not significantly different

between the five control and ten CPB dogs tha t survived. T i m e to ROSC wi th CPB was 1.9 minutes mean vs 17 minutes mean in the control group (P < .05)(Tables 1A and 1B).

Two dogs in the control group died wi th in 24 hours of ROSC due to cardiogenic shock (Table 1A). In the CPB group, one dog (#11) remained in elec- t romechanical dissociation and could n o t be w e a n e d f rom CPB at four hours ; one (#15) cou ld be w e a n e d f rom CPB after four hours , but remained in cardiogenic shock and died at five hours. A third could be weaned after four hours to spontaneous nor- motens ion , but at five hours sudden r e f r a c t o r y VF d e v e l o p e d (Table 1B). Thus, t he re was no s ign i f i can t difference be tween groups in the inci- dence of secondary cardiovascular de- terioration between four hours and 24 hours.

A u t o p s i e s were m a c r o s c o p i c a l l y negative, except for gross morphologic changes in all but one heart of either group, w h i c h showed s u b e p i c a r d i a l hemorrhages (contusions) and myocardial necroses. In particular, the hearts of dogs that died f rom cardiac com- p l i ca t ions dur ing the f irst 24 hours showed infarctions.

Of the three dogs in the CPR-ALS c o n t r o l g roup t h a t s u r v i v e d a f t e r weaning from IPPV at 24 hours, two regained consciousness immediate ly . Both achieved an N D score of near zero at 48 hours, and an OPC 1 (normal) at 72 hours; the third survivor was comatose at 24 hours, improved somewha t by 48 hours, deter iorated again and achieved a final ND score at 72 hours of 40%, wi th an OPC 3 (severe disabil i ty but responsive)(Tables 1A and 1B; Figure 2). In contrast, of the seven survivors in the CPB group, all achieved a 72-hour ou tcome of N D 0% to 6% and OPC 1 (normal). Thus consciousness was achieved in seven of ten CPB dogs vs two of ten controls (P = .025) (Table 1B). The number of control dogs that survived to 72 hours was too small (three of ten) to allow meaningful s ta t i s t ica l compar ison of neurologic outcome (NDs and OPCs) between groups. Applying the Wilcox- on rank sum test according to the best OPC achieved, in all ten dogs in each group (with no ROSC l is ted as worse than OPC 5) (Figure 2), we again found P < .05 in favor of the CPB group. The same compar ison wi th only the five control dogs that achieved ROSC was not significant.

D I S C U S S I O N A majori ty of VF cardiac arrests oc-

cur outside of hospitals. In urban areas it should be possible to achieve in the majori ty of vic t ims of sudden cardiac death a start of CPR-BLS by bystanders w i th in five minutes , and ROSC wi th CPR-ALS by paramedics wi th in ten to 15 m i n u t e s of col lapse.I , z In rural areas, however, lay people and emergency medical technicians mus t often provide CPR-BLS at the scene and during t ransportat ion over longer periods, as in our an imal model . In this clinical scenario, our study demonstrated that emergency CPB is superior to CPR-ALS in achieving ROSC and s u r v i v a l w i t h good n e u r o l o g i c outcome. The causes of this improve- men t in survivorship are unclear, but may include the improved vital organ p e r f u s i o n g e n e r a t e d by e m e r g e n c y CPB, and the dilut ion of ischemic tox- ins. In this study, group differences in su rv iva l and ce reb ra l o u t c o m e are h ighly s ignif icant because mos t prearrest var iables k n o w n to in f luence o u t c o m e w e r e t h e s a m e in b o t h groups and there was no interexperi- ment variabil i ty of CPR-BLS and post- CPR (or post-CPB) life support.

For CPR-BLS, our s tudy gives sug- gestive evidence that this method can provide for long periods the more than 20% normal cerebral blood flow required for mainta in ing cerebral viabil- i ty zs if CPR is performed op t imal ly (by our laboratory standard) and started promptly. Sixteen of 20 dogs had pupil lary constr ict ion and 15 had EEG activi ty restored during CPR-BLS, and n ine of 20 achieved c o m p l e t e long- t e rm neuro log ic recovery. A l t h o u g h this also has been observed occasion- ally in patients, l-3, z6 it is not always seen even in animal studies3,7 In rabbits, we have shown that the longer the per iod of cardiac arrest, the less l ike ly i t is that the needed cerebral blood flow of more than 20% normal w i l l be a c h i e v a b l e du r ing e x t e r n a l CPRA 7 Epinephrine during CPR can raise m y o c a r d i a l pe r fus ion pressure and t he r e by improve ROSC rates, z8 and a l so i m p r o v e c e r e b r a l b l o o d flow. 29

C o n c e r n i n g CPR-ALS, our s tudy t e s t e d i t s a b i l i t y to r e s t o r e spontaneous circulation. After the 34:min - u t e i n s u l t , CPR-ALS a t t e m p t s at ROSC longer than ten minutes were invariably ineffective. Protracted CPR- ALS at tempts added a period of low- flow insul t of one to ten minutes in


the CPR-ALS group, which could have influenced outcome (Table 1A). Great- er need for e p i n e p h r i n e and countershocks in the CPR-ALS group could have been a factor in refractory VE This is unlikely, however, because the dogs in which ROSC at tempts of more than ten minu tes failed developed a progressively weaker VF pat tern rather than an increased epinephr ine effect on the ECG.

Logistic obstacles to the use of CPB for emergency r e susc i t a t i on inc lude the t ime needed for vascular access. Our study was designed to evaluate the physiologic efficacy of CPB if performed correctly, Therefore, the three of 14 dogs assigned to the CPB group in which CPB was not ready at the al- lotted t ime were excluded from analysis. A separate s imulated clinical performance s tudy would be needed to test the t ime needed and the c o m - plications encountered wi th cannulat- ing and init iating CPB in pat ients undergoing active external CPR.

Heparinization after cardiopulmonary-cerebral resuscitat ion offers ben- efits and risks. We have p rev ious ly shown in dogs that cardiac arrest of more than t en m i n u t e s can cause large vessel clotting.13,14 Some clinicians consider external CPR t rauma to be a r e l a t i v e c o n t r a i n d i c a t i o n to heparinizat ion. Our dogs tha t were heparinized after CPR did not show excessive b l e e d i n g f r o m c u t d o w n wounds and there was no gas t ro in- testinal bleeding. Clinicians have used h e p a r i n i z a t i o n for CPB a f t e r CPR w i t h o u t m a j o r b l e e d i n g p r o b - lems.11, I7-21 In fu tu r e s tud ie s , systemic heparinization during CPB may not be necessary, because non th rom- bogenic sur faces c r ea t ed by c h e m - ically bonded heparin have been developed for t h e e n t i r e CPB c i r c u i t , including membrane oxygenator (per- sonal communica t ion , O Norlander, Stockholm, Sweden, October 1986).

Our CPB l abora to ry s tud ies were encouraged by t h e i m p r o v e d resuscitability from prolonged cardiac arrest that we had encountered earlier wi th use of ao r t i c pe r fu s ion w i t h heparinization, hemodilut ion, and hy- pertension; 23 and others' results wi th hepar inizat ion alone, go MAP, hemo- dilution, and heparinizat ion were the same in both groups of this study. We can assume that after prolonged cardiac arrest, CPB can con t ro l hemo- dilution, hepar in iza t ion , and hyper- tension better than can CPR-ALS.

Laboratory exploration of emergency CPB for cardiac arrest started wi th the work of Bozhiev et al, l~ who reported in 1976 that after fifteen-minute VF-cardiac arrest, five of six dogs treated wi th CPB for 20 minutes sur- v ived w i t h n e a r - n o r m a l n e u r o l o g i c function. The use of barbiturate anesthesia, prearrest heparinization, priming of the bypass circuit wi th blood, the p o s s i b i l i t y of h y p o t h e r m i a , and the lack of concurrent controls and post-CPR in tens ive care made these results only sugg&stive. In short- term studies using CPB, we restored stable spontaneous circulation after up to 20 minutes of normothermic VF-cardiac ar res t , I3 and up to 90 m i n u t e s of hypo the rmic asphyxial cardiac arrest (ice water submersion). I4 In the normothermic s tudy I3 the heart was per- mi t ted to fibrillate for 20 minutes during CPB. In this study, we defibrillated early during CPB and cont inued wi th ass i s ted c i r cu l a t i on to p reven t left- sided heart and lung congestion ~2 and fibri l lat ion-induced myocardial hyper- metabol ism.

Clinical use of emergency CPB has been effective in the t empora ry sup- por t of pa t i en t s af ter ca rd io tho rac i c surgery, 17 wi th cardiogenic shock,19, 2o a n d w i t h h y p o t h e r m i a . 18 T h e s e c l in ica l repor ts l acked con t ro l s and neurologic evaluation. Femoral vessels could be cannulated in five minutes, or even less, by c u tdow n 17 or per- cutaneously. 21 All these clinical trials were wi th systemic heparinization.

In the p re sen t study, CPB significant ly increased cardiovascular resusci tabi l i ty (Tables 1A and 1B). However, after weaning from CPB at four to 24 hours, secondary cardiovascular dete- rioration occurred in two control and three CPB dogs. Thus, insult- induced myocardial i schemia and CPR-induced myocardial t rauma were not compen- sated for by CPB of one to four hours. Had we cont inued or resumed CPB for assisted c i rcula t ion after four hours, the c a r d i o v a s c u l a r causes of d e a t h might have been prevented. In our par- allel s tudy of CPB wi thout preceding CPR, 15 we found greater myocard ia l morphologic damage in the CPR-ALS control group t h a n i n the CPB only group. In the present; study, CPR-BLS damaged the hea r t s 'of bo th groups. Avoiding external CPR during trans- port, however, cannot be justified, par- t icu lar ly since we demons t ra ted pro- l o n g e d e x t e r n a l CPR-BLS to be potent ia l ly efficacious.,

In our p rev ious s tudies , af ter 20 m i n u t e s of no f low in dogs, even when CPR-ALS achieved ROSC, secondary ca rd iovascu la r de t e r io ra t i on i n v a r i a b l y followed.S, 13 Thus , prolonged CPB seems essential to give the heart a chance to recover after ten to 20 m i n u t e s of cardiac ar res t (no flow), which cerebral neurons could survive wi th complete recovery if re- pe r fus ion and r eoxygena t i on in ju ry could be prevented, s

Cerebral resusci tabi l i ty could not be s tat is t ical ly assessed in this s tudy because only three dogs in the control group survived to 72 hours - - one se- verely brain damaged but conscious (OPC 3) and two normal (OPC 1). All s even CPB s u r v i v o r s to 72 h o u r s achieved OPC 1.

CONCLUSION After prolonged cardiac arrest wi th

CPR-BLS, e m e r g e n c y CPB (wi thou t t ho raco tomy) enhances ROSC over that achieved by CPR-ALS. CPB can reperfuse and assist c i rcula t ion relia- bly and thereby enhance survival and c e r e b r a l r e c o v e r y ra tes . T h e Bio- m e d i c u s s e l f - r e gu l a t i ng c e n t r i f u g a l pump and the Bard hollow-fiber membrane oxygenator, when pr imed wi th p lasma subst i tute , are s imple to use and effective in control l ing pressure, flow, oxygenation, and composi t ion of blood. Methods should be developed for rapid vascular access in pat ients undergoing closed-chest CPR. Further studies are needed.

Drs Nicholas Bircher, Paul Paris, Michael Pinsky, and Ernesto Pretto made valuable suggestions. Dr Ralph Siewers of the De- partment of Surgery and Ken Litzie, Craig Roberts, and Michael Gioffredi of the Bard Company were consultants on cardiopulmonary bypass. Henry Alexander, Frank Houghton, Wilson Choy, and An- drew Miller helped with animal intensive care. Lisa Cohn, Fran Mistrick, and Gale Foster helped prepare the manuscript.

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cardiopulmonary bypass after cardiac arrest and prolonged closed-chest cpr in dogs

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