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Stroke. 1996;27:105-113

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(Stroke. 1996;27:105-113.)
© 1996 American Heart Association, Inc.

Articles

Improved Cerebral Resuscitation From Cardiac Arrest in Dogs With Mild Hypothermia Plus Blood Flow Promotion

Presented at the American Heart Association Conference on Pediatric Resuscitation in Washington, DC, June 1994, and at the Second CPR Congress of the European Resuscitation Council, Mainz, Germany, October 1994.

Peter Safar, MD; Feng Xiao, MD; Ann Radovsky, DVM, PhD; Koichi Tanigawa, MD; Uwe Ebmeyer, MD; Nicholas Bircher, MD; Henry Alexander S. William Stezoski

From the Safar Center for Resuscitation Research and the Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh (Pa).

Correspondence to Peter Safar, MD, Safar Center for Resuscitation Research, University of Pittsburgh, 3434 Fifth Ave, Pittsburgh, PA 15260.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background and Purpose In past studies, cerebral outcome after normothermic cardiac arrest of 10 or 12.5 minutes in dogs was improved but not normalized by resuscitative (postarrest) treatment with either mild hypothermia or hypertension plus hemodilution. We hypothesized that a multifaceted combination treatment would achieve complete cerebral recovery.

Methods With our established dog outcome model, normothermic ventricular fibrillation of 11 minutes (without blood flow) was followed by controlled reperfusion (with brief normothermic cardiopulmonary bypass simulating low flow and low PaO2 of external cardiopulmonary resuscitation) and defibrillation at <2 minutes. Controlled ventilation was provided to 20 hours and intensive care to 96 hours. Control group 1 (n=8) was kept normothermic (37.5°C), normotensive, and hypocapnic throughout. Experimental group 2 (n=8) received mild resuscitative hypothermia (34°C) from about 10 minutes to 12 hours (by external and peritoneal cooling) plus cerebral blood flow promotion with induced moderate hypertension, mild hemodilution, and normocapnia.

Results All 16 dogs in the protocol survived. At 96 hours, all 8 dogs in control group 1 achieved overall performance categories 3 (severe disability) or 4 (coma). In group 2, 6 of 8 dogs achieved overall performance category 1 (normal); 1 dog achieved category 2 (moderate disability), and 1 dog achieved category 3 (P<.001). Final neurological deficit scores (0% [normal] to 100% [brain death]) at 96 hours were 38±10% (22% to 45%) in group 1 versus 8±9% (0% to 27%) in group 2 (P<.001). Total brain histopathologic damage scores were 138±22 (110 to 176) in group 1 versus 43±9 (32 to 56) in group 2 (P<.001). Regional scores showed similar group differences.

Conclusions After normothermic cardiac arrest of 11 minutes in dogs, resuscitative mild hypothermia plus cerebral blood flow promotion can achieve functional recovery with the least histological brain damage yet observed with the same model and comparable insults.


Key Words: cardiopulmonary resuscitation • cerebral blood flow • heart arrest • hemodilution • hypothermia • dogs


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Only about 50% of CPR attempts for sudden death result in ROSC.1 Many short-term survivors die in permanent coma, and 10% to 30% of long-term survivors suffer permanent brain damage.2 3 4 Despite two decades of research on cerebral resuscitation, the longest normothermic total circulatory arrest the human brain can tolerate with no permanent dysfunction is still believed to be about 5 minutes. Since the average response time of mobile intensive care unit ambulances is unlikely to be reduced below about 10 minutes,1 2 a method of increasing the reversible arrest time from 5 to 10 minutes could have great clinical and socioeconomic importance. This might require mitigating most or all of the components of the cerebral postresuscitation syndrome,3 which include energy failure, ion pump failure, cerebral perfusion failure, excitotoxicity, free radical–triggered lipid peroxidation cascades with calcium loading, and extracerebral organ malfunction.

Between 1987 and 1991, using reproducible dog models with 10 or 12.5 minutes of normothermic cardiac arrest (without blood flow), we found that mild cerebral hypothermia induced before arrest5 or immediately after reperfusion for 1 to 2 hours6 7 8 9 significantly improved but did not normalize cerebral functional and morphological outcome. Hypothermia was less effective when cooling was induced 15 minutes after reperfusion.9 Induced after cardiac arrest, mild hypothermia (34°C) proved safer and more effective than moderate hypothermia (30°C)8 10 despite the knowledge that protection with intra-arrest hypothermia improves with lower temperatures.11 Mild resuscitative hypothermia also mitigates postarrest brain damage in rat models.12 13 14 15 The mechanism of therapeutic hypothermia is multifaceted and includes preserving energy charge; decreasing oxygen demand, excitotoxicity, free radical reactions, and deleterious enzyme reactions; and tightening membranes.3 6

Normotensive reperfusion is accompanied by a transient, diffuse increase in CBF followed by a protracted reduction in CBF and thus in cerebral oxygen delivery.16 17 18 19 20 The reduction in CBF is accompanied by the return of cerebral oxygen uptake to baseline values or higher.17 18 19 20 This mismatching, reflected in critically low cerebral venous PO2 values of about 20 mm Hg (2.7 kPa) or less,21 22 lasts from 2 to 12 hours after reperfusion.23 24 In dogs, postarrest hypertension plus hemodilution normalized CBF18 and improved but did not normalize cerebral functional25 26 and morphological26 outcome. In an exploratory study, a postarrest change of hypocapnia to normocapnia increased cerebral venous PO2.27

This study tested the hypothesis that complete functional and morphological cerebral recovery after normothermic cardiac arrest of 11 minutes can be achieved with a physical combination treatment that mitigates the multifactorial cerebral postresuscitation syndrome.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
This study was approved by the Animal Care and Use Committee of the University of Pittsburgh. Male hunting dogs (coon hounds) from the same breeding colony, aged 8 to 12 months and weighing 20 to 25 kg, were used. The established outcome model used3 6 28 29 meets all our 10 goals for evaluating novel cerebral resuscitation potentials. These goals (see Reference 3, Table 1Down) include a controlled insult in the therapeutic window, controlled reperfusion without adding variable low-flow states, concurrent randomized control experiments, intensive care for at least 72 hours after arrest with control of extracerebral variables that might influence cerebral outcome, all control experiments resulting in survival with brain damage, and exclusion of postarrest deaths due to extracerebral complications.


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  		Table 1. Neurological Deficit Scoring in Dogs

After normothermic VF of 11 minutes without blood flow, the dogs were reperfused with brief CPB used as an experimental tool for controlling blood pressure, flow, temperature, and composition.28 For reperfusion of <=2 minutes, low blood flow and low PaO2 were used to simulate the low oxygen delivery of clinical external CPR. External CPR has been associated with variable low flow and frequent inability to achieve ROSC.3 5 7 25 28 After ROSC, controlled IPPV with 50% oxygen was used until an RT of 20 hours was reached. Intensive care was provided to RT 96 hours. The same team performed 25 experiments in a block-randomized sequence: group 1 (n=9) received normothermic standard life support including hypocapnia. Group 2 (n=8) received standard life support plus mild hypothermia (34°C) for 12 hours and CBF promotion by induced hypertension, mild hypervolemic hemodilution, and normocapnia. Group 3 (n=8) received a complicated combination of six drugs in addition to the group 2 treatment protocol. Group 3 versus group 2 comparisons will be reported separately because it would complicate this report. Placebo control of treatments was not possible.

The surgical preparation, insult, intensive care, and outcome evaluation have been described in detail previously.6 9 Briefly, preparation included induction of sedation with ketamine, light anesthesia with N2O:O2-halothane (0.2% to 1.0%, adjusted to prevent mydriasis or hypertension), intubation, IPPV, pancuronium for immobilization, gastric tube and bladder catheter insertion, sterile cut-downs and catheterizations of vessels, and continuous monitoring of cardiovascular-pulmonary variables. Core temperature was monitored in the pulmonary artery, esophagus, and rectum; brain temperature was monitored at the tympanic membrane. For later venoarterial closed-chest CPB,28 cannulas were inserted into the right external jugular vein (to be advanced into the vena cava later) and a femoral artery. Control of prearrest and standard postarrest variables to RT of 20 hours included MAP at 110±20 mm Hg (14.6±2.7 kPa), central venous and pulmonary artery occlusion pressure at 5 to 15 mm Hg (0.7 to 2.0 kPa), and temperature at the tympanic membrane at 37.5°C. Blood gas tensions were controlled according to temperature-uncorrected determinations at 37°C (alpha-stat mode).

Normothermic no-flow VF was induced for 11 minutes in all dogs (see "Discussion" for selection of insult time). After two baseline measurements during paralysis and controlled ventilation with N2O:O2 50:50% and 0.5% halothane, N2O and halothane were discontinued, and anesthesia was reduced by IPPV with 100% oxygen for 1 minute followed by room air for 4 minutes. With tympanic membrane temperature controlled at exactly 37.5°C, VF was induced by external transthoracic electric shock with 100 to 120 V AC for 2 seconds, repeated as needed. IPPV was stopped simultaneously.

After VF for 11 minutes (without heparin), reperfusion was performed with closed-chest CPB for 2 to 5 minutes. The CPB circuit had been primed with about 300 mL dextran 40 (10% in isotonic saline) and Ringer's solution 50:50%. Heparin (0.75 mg/kg [75 U/kg]) and NaHCO3 (1 mmol/kg) were added. At the start of CPB, epinephrine (0.02 mg/kg) was given through the arterial cannula. CPB was started (RT, 0 minute) with 38°C fluid at low flow (ie, 50 mL/kg for the first and 75 mL/kg for the second minute) and low oxygen flow of 5 L/min (resulting in PaO2 of about 60 mm Hg [8.0 kPa]). (In previous less "clinically realistic" protocols with the same outcome, we used VF of 12.5 minutes, CPB priming with 500 mL dextran–Ringer's solution, 1.5 mg/kg heparin, flow >100 mL/kg per minute, and PaO2 >200 mm Hg.) IPPV during CPB was at a rate of 10 per minute with 100% oxygen. A second dose of epinephrine (0.01 mg/kg) was given through the arterial cannula to intensify VF and increase MAP to >80 mm Hg (10.6 kPa). After CPB of about 90 seconds, an external defibrillating countershock of 200 J was delivered and repeated as needed with 200, 300, and 360 J. When ROSC was accomplished, usually after one or two countershocks, CPB flow was rapidly decreased and IPPV increased to achieve CO2 washout and a PaCO2 of 30 to 35 mm Hg (4.0 to 4.7 kPa). All dogs were weaned from CPB before RT of 5 minutes.

Intensive care (as before) included IPPV with 100% oxygen from RT 0 to 2 hours and N2O:O2 50:50% from RT 2 to 20 hours. For sedation and additional analgesia, diazepam (0.25 mg/kg IV) plus morphine (0.1 to 0.3 mg/kg IV) were given between RT 6 and 16 hours, whenever mydriasis or unwanted hypertension occurred. Pancuronium was given for immobilization and lidocaine for ventricular tachycardia. After RT 20 hours, relaxant effects were reversed with intravenous neostigmine plus atropine.6 9 After extubation, oxygen was given by face mask, hydration and dextrose were given intravenously, intravenous diazepam was repeated as needed for seizures or opisthotonos, and water and food were supplied by mouth as tolerated.6 9

Outcome evaluation involved three measurements3 6 7 8 9 29 : (1) OPC (1, normal; 2, moderate disability; 3, severe disability but conscious; 4, coma; and 5, death or brain death), (2) NDS (0%, normal; 100%, brain death) (Table 1Up), and (3) total and regional brain HDS. OPC and NDS were evaluated between RT 20 and RT 96 hours by a technician every 8 hours and by a physician every 24 hours. In addition, an evaluation was conducted at RT 96 hours by a physician blinded to the therapy. The average score of all three observers was used to determine the final OPC and NDS at RT 96 hours. Interobserver differences were about ±5% for final NDS and ±0% for final OPC.

At 96 hours, the experiment was terminated for morphological studies.6 29 30 31 Perfusion fixation of the brain under anesthesia and euthanasia were followed by a total body necropsy, removal of the fixed head, and removal and further immersion fixation of the brain. Coronal sections 3 mm thick were examined for gross lesions. Six to 10 of these sections were embedded in paraffin, cut to 6 µm thick, stained with hematoxylin-eosin-phloxine, and examined with light microscopy (x40 to x400 magnifications) for 19 anatomic areas bilaterally by the pathologist (A.R.), who was blinded as to group identity. Each anatomic area was scored for severity and extent of ischemic neuronal changes, infarcts, and edema according to measure of involvement: none (0), minimal (1+), mild (2+), moderate (3+), or severe (4+). The categorical score was multiplied by 2 for ischemic neuronal changes and by 4 for infarctions. The total numerical score was the sum of all area scores from both sides. Previously, total HDS correlated well with final NDS (r=.8 to .96).6 7 8 9 26 29 30 31 Total HDS was between 0 and 10 in the sham experiments, >30 with significant NDS, and >100 with high NDS.

Hypothermia
Both groups were reperfused with CPB at 38°C. In the control group, tympanic membrane temperature was controlled at 37.5±0.5°C to RT 96 hours. In the experimental group, the head and neck were covered with ice bags, starting with reperfusion.9 In addition, peritoneal cold lavage was performed immediately after ROSC, starting at approximately RT 2 minutes, through a preplaced, multihole plastic tube (8 mm OD) inserted into the peritoneal cavity through a small incision below the umbilicus. Ringer's solution (2 L) at 4°C was instilled into the abdominal cavity over 1 minute and allowed to dwell. More peritoneal cold solution was added as needed. When tympanic temperature reached 35°C, the peritoneal fluid was drained by gravity, and ice was removed from the head and neck. Tympanic temperature was maintained at 34.0±0.5°C for 12 hours by external surface cooling or warming. After 12 hours at tympanic temperature of 34°C, the dogs were externally warmed over 3 to 5 hours to 37.5°C. Normothermia was maintained to RT 96 hours.

CBF Promotion
In group 1, a spontaneous hypertensive bout as a response to epinephrine was allowed to occur immediately after ROSC. Then, MAP was maintained at 110±20 mm Hg (14.6±2.7 kPa) to RT 20 hours with intravenous titrated norepinephrine or trimethaphan. Hematocrit was controlled at about 40% throughout with CPB circuit blood given intravenously after RT 5 minutes. PaCO2 was controlled at 30 mm Hg (4.0 kPa) from RT 0 to 20 hours by adjusting the rate of IPPV.

In group 2, previously effective hypertension,18 25 26 hemodilution,18 25 26 and normocapnia27 were combined. Hypertension consisted of an obligatory systolic arterial pressure bout of >200 mm Hg (26.6 kPa) over 1 to 5 minutes26 ; if not spontaneous, it was induced with titrated intravenous norepinephrine. Thereafter, MAP was maintained at 140±10 mm Hg (18.6±1.3 kPa) with norepinephrine by intravenous titration to RT 4 hours,25 26 followed by 110±20 mm Hg (14.6±2.7 kPa) to RT 20 hours as in group 1. In group 2, mild hypervolemic hemodilution was with intravenous dextran 40 (10% in isotonic saline) immediately after ROSC25 26 in volumes sufficient to lower the hematocrit from about 0.40 (40%) to 0.30 (30%) until RT 12 hours, the duration of cerebral hypoperfusion18 ; the maximal volume of dextran given was 20 mL/kg. Circuit blood was reinfused slowly after RT 12 hours if hematocrit was less than 0.30 (30%). In group 2, PaCO2 was controlled at 30 mm Hg (4.0 kPa) only until RT 3 hours (to combat washout acidosis as in group 1) and then at 40 mm Hg (5.3 kPa) from RT 3 to 20 hours, the time of lowest CBF in previous studies.17 18 19 23 24

Exclusion criteria, as previously,3 29 included sudden death from noncerebral causes. Groups 1 and 2 were block randomized with a third group (n=8) that received six drugs in addition to the group 2 therapy. Group 3 results will be reported separately because they are complex and worsened group 2 outcome.32 Statistical analyses were performed for comparison of group 1 versus 2, as well as all three groups. OPC and other variables not normally distributed were analyzed by the Kruskal-Wallis one-way ANOVA for all three groups and by the Mann-Whitney test for differences between group 1 and 2. NDS and HDS were analyzed by one-way ANOVA for all three groups and by Scheffé's procedure for group 1 versus 2. Significance was defined as P<.05.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
*Results
down arrowDiscussion
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One dog (from group 1) of the 17 was eliminated because of sudden apnea and absence of pulse at RT 26 hours, 2 hours after weaning and extubation. All 16 dogs that followed protocol survived to 96 hours. There were no group differences in prearrest body weight, anesthesia time, or in controlled (Table 2Down), observed (Table 3Down), or resuscitation variables (Table 4Down). In all dogs, ROSC was achieved after 1.5 to 2.5 minutes of CPB, with one to three countershocks. All dogs were weaned from CPB by RT 5 minutes.


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  		Table 2. Controlled Variables in Group 1 (n=8) Versus Group 2 (n=8)


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  		Table 3. Observed Variables in Group 1 (n=8) Versus Group 2 (n=8)


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  		Table 4. Resuscitation Variables

In both groups, tympanic membrane temperature was controlled according to protocol (Table 2Up). In group 2, head and neck surface cooling alone during the first 2 minutes decreased temperatures in the tympanic membrane and pulmonary artery by only 0.3°C (0.15°C/min). Starting with peritoneal instillation, tympanic temperature decreased by 0.3°C/min, while core temperature decreased more rapidly. Tympanic temperature reached 34°C in about 9 minutes. By 15 minutes after ROSC, all group 2 temperatures had reached 33°C to 34°C and were maintained until RT 12 hours. Rewarming restored normothermia by RT 16 hours.

After ROSC, all but 1 dog (from group 1) spontaneously achieved an initial hypertensive bout, with brief (<=2 minutes) systolic arterial pressure peaks >200 mm Hg (26.6 kPa) (Table 2Up). At RT 15 minutes, MAP was 119±13 mm Hg (15.8±1.7 kPa) in group 1 and 136±8 mm Hg (18.1±1.1 kPa) in group 2 (P<.05). Thereafter, MAP leveled off around 130 mm Hg (17.3 kPa) in group 1 and 140 mm Hg (18.6 kPa) in group 2 (NS). This partial nonadherence to protocol was because in group 1 trimethaphan was used too sparingly and only in 3 dogs for fear of causing previously encountered hypotensive accidents.

In group 1, hematocrit remained around 40% (Table 2Up). In group 2, hemodilution decreased hematocrit to 0.30±0.04 (30±4%) by RT 30 minutes. Hematocrit was then successfully controlled between 0.30 (30%) and 0.33 (33%) to RT 12 hours. The total amount of dextran required was 500±246 mL. PaCO2 was well controlled according to protocol (Table 2Up). Norepinephrine was needed primarily in the first few hours, numerically more in group 2 (NS). Heart rates were lower and cardiac outputs higher in group 2 (Table 3Up). Dysrhythmias were about the same in both groups. Activated clotting time was higher in group 2, but no bleeding tendency was evident. Lidocaine was needed in 4 of the 8 dogs in both groups. There was no significant difference between groups in the doses of pancuronium, morphine, diazepam, or NaHCO3 required. No significant pulmonary shunt effect, acidemia, or serum electrolyte abnormalities were found in either group. Urine volume was larger in group 2 in the first 24 hours (P<.05). All dogs were weaned from IPPV by RT 24 hours.

Mean OPC, NDS, and total HDS at RT 96 hours were better in group 2 in three-group (P<.05) and two-group (P<.001) comparisons. All final OPC and NDS were best values achieved.

Concerning overall performance (Fig 1Down), all 8 dogs in group 1 remained severely disabled (OPC 3) or comatose (OPC 4). In group 2, 6 of the 8 dogs rapidly improved to normal performance (OPC 1), one remained moderately disabled (OPC 2), and one was severely disabled but conscious (OPC 3) (P<.001, group 1 versus 2).



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  		Figure 1. Chart shows final OPC at 96 hours after 11 minutes of normothermic VF cardiac arrest. Each circle represents one 96-hour dog experiment.

Concerning neurological function (Fig 2Down), NDS improved (decreased) progressively between RT 24 and 96 hours in both groups. From RT 40 hours, group 2 achieved significantly better NDS than group 1. Final NDS at RT 96 hours were 38±10% (22% to 45%) in group 1 versus 8±9% (0% to 27%) in group 2 (P<.001, group 1 versus 2). In group 1, all 8 dogs remained severely disabled, and those with OPC 4 had opisthotonos and running movements. In group 2, complete functional recovery (NDS, 0% to 10%, as seen after sham experiments) was achieved in 6 of the 8 dogs (those with OPC 1), and low NDS (16% and 27%) were seen in the 2 others.



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  		Figure 2. Graph shows NDS at 24 to 96 hours (x axis) after 11 minutes of VF cardiac arrest (VFCA). NDS, 0% to 100% on y axis. Values are mean±SD. BL indicates baseline; CA, cardiac arrest.

Macroscopic necropsy findings at RT 96 hours were negative in both groups, except for scattered myocardial necroses in the free walls of both ventricles in both groups, as described with this model previously.31 32 33 34 All brains were macroscopically normal. Total brain HDS (Fig 3Down) were 138±22 (110 to 176) in group 1 versus 43±9 (32 to 56) in group 2 (P<.001, group 1 versus 2). Regional HDS showed similar significant group differences. All scores were attributable to ischemic neurons (ie, pyknotic nuclei and shrunken eosinophilic cytoplasm) alongside normal-appearing neurons. There were no microinfarcts or morphological evidence of cerebral edema. There were scattered ischemic neurons in most regions examined, with the exception of the midbrain and medulla. All the neocortical areas examined were somewhat affected. Regional HDS in the hippocampus were 21±6 (14 to 30) in group 1 versus 5±2 (4 to 8) in group 2 (P<.001). Regional HDS of cerebellar Purkinje cells were 20±6 (10 to 30) in group 1 versus 5±3 (0 to 10) in group 2 (P<.001), with 1 dog in group 2 having no changes in the cerebellum. In 2 sham-operated dogs without arrest, total HDS were 0 and 2.



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  		Figure 3. Bar graph shows HDS (0 to 160 on y axis) at 96 hours after 11 minutes of VF cardiac arrest, including neocortex (frontal, parietal, occipital, and temporal), insular cortex, hippocampus (including dentate gyrus), basal ganglia (average of scores of caudate nucleus, putamen, globus pallidus, and amygdala), thalamus, and cerebellum (dentate nucleus, granular cells, and Purkinje cells). Regional HDS of midbrain (including substantia nigra), pons, and medulla are not shown because HDS were all zero (no damage). *P<.001 compared with group 1.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
up arrowResults
*Discussion
down arrowReferences
 
The OPC, NDS, and total and regional HDS in group 2 were the lowest (best) achieved in any outcome experiments in dogs we have conducted over the past 15 years with comparable insults and models.3 It is uncertain whether the remaining minimal number of neurons with ischemic changes would have any significant neurological or psychological relevance in humans. Outcome variables in group 2 were better than in previous studies with comparable insults that used mild hypothermia of 1 to 2 hours alone,6 7 8 9 hypertensive hemodilution alone,26 or special drug treatments.3 32 33 In one previous study of mild postarrest hypothermia plus hypertensive hemodilution after 12.5 minutes of VF,6 we achieved the same OPC but less favorable NDS and HDS than in the present study. Resuscitation was more favorable and less "clinical" in the former study,6 in which surface cooling was already started during VF and reperfusion was with high flow, high PaO2, and cold CPB fluid. In the present study, we used brief, normothermic, low-flow CPB with PaO2 of 60 mm Hg to simulate the low arterial oxygen delivery of external CPR, while being able to reproducibly "jump start" the heart, which would not be possible with external CPR. This brief use of CPB does not invalidate the clinical significance of the model.

Even 5 minutes of no-flow VF and normothermic standard life support are followed by some histological brain damage.3 5 31 An insult of 11 minutes of VF, reversed by reproducible reperfusion with brief CPB as an experimental tool using low flow and low PaO2, was selected because it is clinically more realistic than 12.5 minutes of VF and high PaO2 reperfusion, which gave the same outcome. The insult used in this study proved to be in the therapeutic window. Control protocols after shorter insults sometimes gave good cerebral recovery.5 31 34 VF of 10 minutes and external CPR5 7 33 34 or VF of 12.5 minutes and brief high-flow CPB6 8 9 26 reproducibly gave the same poor outcome in control groups as in this study and also gave improved outcome with certain special treatments.

Intraobserver consistency for HDS evaluations was again ascertained in this study: blinded resubmission of five group 2 brains to the same pathologist (A.R.) resulted in total HDS between 36 and 56, which varied by only 2 points (range, 0 to 6) from the original HDS. To detect subtle damage, HDS was used instead of tedious and costly evaluations of learning and memory in dogs.

Comparison with past studies by the same investigator and technicians (different fellows) revealed that the poor OPC, NDS, and HDS achieved in all 8 dogs in control group 1 were also achieved in 47 of 50 normothermic control group dogs in past studies using the same model, after VF of 12.5 minutes and high-flow CPB,3 5 6 8 9 26 VF of 11 minutes and high-flow or low-flow CPB,35 or VF of 10 minutes and external CPR3 5 7 33 34 ; no dog achieved OPC 1. Final NDS in group 2 (8±9%) were better than in past studies after comparable insults with mild hypothermia alone (27±19%)9 or hypertensive hemodilution alone (33±6%).26 All total HDS values in group 2 (43±9; range, 32 to 56) were better than the best HDS values after mild hypothermia alone (81±13; range, 70 to 104)9 or hypertensive hemodilution alone (101±21; range, 80 to 136).26 Although comparisons with historical data should be considered with caution, our previous studies were by the same team leaders and, over the past 6 years, yielded reproducible outcome data.3 35

Mild hypothermia was with ideal but, we feel, clinically realistic methods and timing: head surface cooling with ice starting with reperfusion plus peritoneal cooling starting 2 minutes after reperfusion (ie, immediately after ROSC). Normothermic peritoneal lavage was not used in control group 1 to avoid hemodilution. We doubt that peritoneal lavage had a therapeutic effect, since other detoxification methods failed to improve cerebral outcome.36 Hypothermia of 12 hours alone might have improved the outcome over that of the 2 hours used in a previous study.9 The optimal duration of hypothermia remains to be determined. The therapeutic mechanism cannot be explained merely by a reduction in cerebral oxygen demand,37 which after arrest and mild hypothermia is minimal.19 24 Many molecular-cellular beneficial effects have been reviewed.3 6 The possibilities of transient ischemia triggering "apoptosis"38 and of hypothermia merely delaying the inevitable necrosis39 or inhibiting regeneration triggers40 are interesting but remain to be examined in a reproducible cardiac arrest outcome model in a higher species. Inevitable necrosis39 would be disappointing, but hypothermia would still provide more time for additive treatments to be introduced.41

CBF promotion was multifaceted. The exact mechanism of the delayed cerebral postarrest hypoperfusion remains to be clarified, but vasospasm, blood sludging, and endothelial or astrocyte edema are suspected.42 This study does not reveal whether hypertension, hemodilution, or normocapnia was responsible for the better outcome than hypothermia alone. Evaluations of multifaceted treatments are more difficult and expensive than evaluations of single therapies. Higher postarrest cardiac output in group 2 might have been beneficial also for the brain,34 but CBF depends more on perfusion pressure than cardiac output. Brief postarrest hypertension correlates with better cerebral outcome in dogs26 and humans43 44 but does not prevent the delayed protracted hypoperfusion.18 Beneficial effects of postischemic hypertension have been established.18 25 26 42 43 44 45 After RT 15 minutes, MAP in control group 1 was only numerically lower than in group 2 (reason given in "Results"). The optimal degree and duration of postarrest hypertension and hemodilution remain to be determined. Hemodilution improves the microcirculation and mitigates focal brain ischemia.46 We used a hematocrit level of 0.30 (30%) rather than 0.20 (20%)26 because the latter had reduced arterial oxygen content so much that cerebral oxygen delivery was not increased.18

The optimal PaCO2 after arrest is unclear.47 Although CBF autoregulation seems attenuated after cardiac arrest,48 the CO2 response of CBF seems variable but not abolished.49 50 51 In group 2 at RT 3 hours, after CO2 washout, we used normocapnia instead of hypocapnia because in pilot experiments with the same model we could normalize the otherwise very low sagittal sinus PO2.27 We avoided hypercapnia because acidosis might be damaging.52

The clinical application of a group 2–type protocol will be demanding. Efforts should begin by monitoring brain (tympanic membrane or nasopharyngeal) and heart (esophageal) temperatures outside the hospital.53 Spontaneous mild cooling of CPR patients is not uncommon.53 The goal is to achieve about 34°C for the brain and prevent a risky decrease in heart temperature below 30°C.8 11 A variety of rapid cooling methods for use should be explored during CPR attempts inside and outside hospitals.3 7 53 Whole-body immersion in ice water is impractical.11 Head-neck surface cooling is of adjunctive value,7 but alone it is too slow.6 7 8 9 10 54 Cooling by CPB is most rapid once vessel access is achieved.6 8 9 Induction of mild cerebral hypothermia with intracarotid cold flush would be very rapid53 55 (F. Sterz, K. Lechleuthner, personal communications, 1994) but not readily accepted. In an informal opinion poll, emergency department physicians considered the rapid insertion of a peritoneal catheter in the field as feasible. Caution is advised, however, because peritoneal cold lavage lowered core temperature in the esophagus more rapidly than the tympanic membrane temperature. A combination of semi-invasive methods, complex but feasible in the hands of paramedics, was effective in large dogs.7 Shivering must be prevented. Although initiation of cooling as soon as possible with reperfusion seems desirable,9 some benefit might be achieved by slightly lowering brain temperature even later.56 In humans, 12 hours of even moderate hypothermia seems safe.57 Titrated intravenous infusion of a vasopressor and administration of a plasma substitute by physician-guided paramedics are currently feasible practices. In the hospital, mixed cerebral venous PO2 values could then be monitored via a superior jugular bulb catheter and maintained above approximately 30 mm Hg (4.0 kPa),21 22 23 24 with titrated adjustments of arterial pressure, hematocrit, and PaCO2. Emergency CPB of 1 to 2 minutes was used merely as a research tool for achieving reproducible reperfusion and ROSC, which would not have been possible with external CPR. Rapid "jump starting" of the heartbeat was achieved despite having used CPB with low flow and low PaO2 to simulate the low oxygen delivery of external CPR.

We conclude that after normothermic cardiac arrest of 11 minutes in dogs, resuscitative mild hypothermia plus CBF promotion can achieve functional recovery with the least histological brain damage yet observed with the same model and comparable insults. We recommend that the feasibility, acceptability, and side effects of various practical methods for inducing mild resuscitative hypothermia, with or without CBF-promoting measures, should be explored in patients who receive external CPR for prolonged cardiac arrests inside and outside hospitals. The clinical methods will not be exactly the same as in the protocol of this study.


*    Selected Abbreviations and Acronyms
 
CBF = cerebral blood flow
CPB = cardiopulmonary bypass
CPR = cardiopulmonary resuscitation
HDS = histopathologic damage score(s)
IPPV = intermittent positive-pressure ventilation
MAP = mean arterial pressure
NDS = neurological deficit score(s)
OPC = overall performance category
ROSC = restoration of spontaneous circulation
RT = reperfusion (resuscitation) time
VF = ventricular fibrillation


*    Acknowledgments
 
This study was supported in part by a grant from the A.S. Laerdal Foundation and a grant (NS-24446) from the National Institutes of Health. Dr Sheryl Kelsey advised on statistical analyses. Drs Mickey Eisenberg, Patrick Kochanek, Andrew Kofke, John Moossy, Norman Paradis, Fritz Sterz, Samuel Tisherman, and Peter Winter made valuable suggestions. Dr Yuanfan Wang, Dr Antonio Capone, Annette Pastula, Elron Wallace, and Jason Stezoski helped with the experiments. Francie Siegfried helped with editing. Linda Kalcevic and Fran Mistrick helped with manuscript preparation.

Received June 1, 1995; revision received September 26, 1995; accepted October 16, 1995.


*    References
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*References
 

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