Peter Safar

Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study.

ObjectivePreviously, we documented that mild hypothermia (34°C) induced immediately with reperfusion after ventricular fibrillation cardiac arrest in dogs improves functional and morphologic cerebral outcome. This study was designed to test the hypothesis that a 15-min delay in the initiation of cooling after reperfusion would offset this beneficial effect. DesignProspective, randomized, controlled study. SettingAnimal intensive care unit. SubjectsA total of 22 custom-bred coonhounds. InterventionsEighteen dogs underwent normothermic ventricular fibrillation arrest (no blood flow) of 12.5 mins, reperfusion with brief cardiopulmonary bypass, defibrillation within 5 mins, intermittent positive-pressure ventilation to 20 hrs, and intensive care to 96 hrs. Three groups of six gogs each were studied: group 1, normothermic controls; group 2, core temperature 34°C from reperfusion to 1 hr; and group 3, delayed initiation of cooling until 15 mins after normothermic reperfusion, and 34°C from 15 mins to 1 hr 15 mins after cardiac arrest. Measurements and Main ResultsTympanic membrane temperature (which represented brain temperature) in group 2 reached 34°C at 6 ± 3 (SD) mins after reperfusion; and in group 3 at 29 ± 1 mins after reperfusion. Best overall performance categories achieved (1, normal; 5, brain death) compared with group 1, were better in group 2 (p <.05) but not in group 3 (NS). Similar results were found with best neurologic deficit scores (0%, normal; 100%, brain death), i.e., 44 ± 4% in group 1, 19 ± 15% in group 2 (p<.01), and 38 ± 9% in group 3 (NS). Total brain histologic damage scores (< 30 minimal damage; > 100 severe damage), however, were 150 ± 32 in group 1, 81 ± 13 in group 2 (p<.001 VS. group 1), and 107 ± 17 in group 3 (p<.05 VS. group 1). ConclusionsMild, resuscitative cerebral hypothermia induced immediately with reperfusion after cardiac arrest improves cerebral functional and morphologic outcome, whereas a delay of 15 mins in initiation of cooling after reperfusion may not improve functional outcome, although it may slightly decrease tissue damage. (Crit Care Med 1993;21:1348–1358)

The Physician's Responsibility toward Hopelessly Ill Patients

Abstract Physicians have a specific responsibility toward patients who are hopelessly ill, dying, or in the end stages of an incurable disease. In a summary of current practices affecting the care of dying patients, we give particular emphasis to changes that have become commonplace since the early 1980s. Implementation of accepted policies has been deficient in certain areas, including the initiation of timely discussions with patients about dying, the solicitation and execution in advance of their directives for terminal care, the education of medical students and residents, and the formulation of institutional guidelines. The appropriate and, if necessary, aggressive use of pain-relieving substances is recommended, even when such use may result in shortened life. We emphasize the value of a sensitive approach to care — one that is adjusted continually to suit the changing needs of the patient as death approaches. Possible settings for death are reviewed, including the home, the hospital, the intensive ...

The physician's responsibility toward hopelessly ill patients. A second look.

Physicians have a specific responsibility toward patients who are hopelessly ill, dying, or in the end stages of an incurable disease. In a summary of current practices affecting the care of dying patients, we give particular emphasis to changes that have become commonplace since the early 1980s. Implementation of accepted policies has been deficient in certain areas, including the initiation of timely discussions with patients about dying, the solicitation and execution in advance of their directives for terminal care, the education of medical students and residents, and the formulation of institutional guidelines. The appropriate and, if necessary, aggressive use of pain-relieving substances is recommended, even when such use may result in shortened life. We emphasize the value of a sensitive approach to care--one that is adjusted continually to suit the changing needs of the patient as death approaches. Possible settings for death are reviewed, including the home, the hospital, the intensive care unit, and the nursing home. Finally, we consider the physicians response to the dying patient who is rational and desires suicide or euthanasia.

Assessment of neurological prognosis in comatose survivors of cardiac arrest

When a patient resuscitated from cardiac arrest remains unconscious the clinician would like to have a reliable early method for predicting the outcome. The objective of our study was to predict cerebral outcome after cardiac arrest by clinical neurological examination. The data were drawn from an international multicentre controlled clinical trial of thiopentone. Twelve hospitals in nine countries took part. 262 comatose cardiac arrest survivors were followed up for one year. These patients were given advanced life support (American Heart Association guidelines) followed by intensive care to a standardised protocol. Glasgow and Glasgow-Pittsburgh coma scores and their constituent signs were recorded at fixed times. Outcome was taken to be the best cerebral performance at any time during follow-up, and for that purpose we used cerebral performance categories (CPC 1-5) of the Glasgow outcome categories. A poor outcome (CPC 3-5) could be predicted immediately after reperfusion (at entry into the study) with an accuracy ranging from 52% to 84% for various signs and scores. On the third day it was possible to identify severely disabled or permanently comatose survivors without false predictions using both coma scores and several of their constituent variables. The best predictor was absence of motor response to pain. This modelling exercise now needs to be repeated on a new series of patients but the results do suggest that, after 3 days, stringent ethical criteria can be met and used in decision-making about termination of care in comatose cardiac arrest survivors.

Mild Cerebral Hypothermia during and after Cardiac Arrest Improves Neurologic Outcome in Dogs

We previously found mild hypothermia (34–36°C), induced before cardiac arrest, to improve neurologic outcome. In this study we used a reproducible dog model to evaluate mild hypothermia by head cooling during arrest, continued with systemic cooling (34°C) during recirculation and for 1 h after arrest. In four groups of dogs, ventricular fibrillation (no flow) of 12.5 min at 37.5°C was reversed with cardiopulmonary bypass and defibrillation in ≤5 min, and followed by controlled ventilation to 20 h and intensive care to 96 h. In Study A we resuscitated with normotension and normal hematocrit; Control Group A-I (n = 12) was maintained normothermic, while Treatment Group A-II (n = 10) was treated with hypothermia. In Study B we resuscitated with hypertension and hemodilution. Control Group B-I (n = 12) was maintained no rmo thermic (6 of 12 were not hemodiluted), while Treatment Group B-II (n = 10) was treated with hypothermia. Best overall performance categories (OPCs) achieved between 24 and 96 h postarrest were in Group A-I: OPC 1 (normal) in 0 of 12 dogs, OPC 2 (moderate disability) in 2, OPC 3 (severe disability) in 7, and OPC 4 (coma) in 3 dogs. In Group A-II, OPC 1 was achieved in 5 of 10 dogs (p < 0.01), OPC 2 in 4 (p < 0.001), OPC 3 in 1, and OPC 4 in 0 dogs. In Group B-I, OPC 1 was achieved in 0 of 12 dogs, OPC 2 in 6, OPC 3 in 5, and OPC 4 in 1 dog. In Group B-II, OPC 1 was achieved in 6 of 10 dogs (p < 0.01), OPC 2 in 4 (p < 0.05), and OPC 3 or 4 in 0 dogs. Mean neurologic deficit and brain histopathologic damage scores showed similar significant group differences. Morphologic myocardial damage scores were the same in all four groups. We conclude that mild brain cooling during and after insult improves neurologic outcome after cardiac arrest.

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

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 degrees C), normotensive, and hypocapnic throughout. Experimental group 2 (n = 8) received mild resuscitative hypothermia (34 degrees 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.

MILD HYPOTHERMIC CARDIOPULMONARY RESUSCITATION IMPROVES OUTCOME AFTER PROLONGED CARDIAC ARREST IN DOGS

Background and Methods.This study was designed to explore the effect of mild cerebral and systemic hypothermia (34°C) on outcome after prolonged cardiac arrest in dogs. After ventricular fibrillation with no flow of 10 min, and standard external CPR with epi-nephrine (low flow) from ventricular fibrillation time of 10 to 15 min, defibrillation and restoration of spontaneous normotension were between ventricular fibrillation time of 16 and 20 min. This procedure was followed by controlled ventilation to 20 hr postarrest and intensive care to 72 hr postarrest. In control group 1 (n = 10), core temperature was 37.5°C; in control group 2 (n = 10), cooling was started immediately after restoration of spontaneous normotension; and in group 3 (n = 10), cooling was initiated with start of CPR. Cooling was by clinically feasible methods. Results.Best overall performance categories achieved (1 = normal; 5 = brain death) were better in group 2 (p = .012) and group 3 (p = .005) than in group 1. Best neurologic deficit scores were 36 ± 14% in group 1, 22 ± 15% in group 2 (p = .02), and 19 ± 18% in group 3 (p = .01). Brain histopathologic damage scores were also lower (better) in groups 2 (p = .05) and 3 (p = .03). Myocardial damage was the same in all three groups. Conclusion.Mild cerebral hypothermia started during or immediately after external CPR improves neurologic recovery. (Crit Care Med 1991; 19:379)

Global Ischemia in Dogs: Intracranial Pressures, Brain Blood Flow and Metabolism

Our earlier studies showed no secondary postischemic (PI) rise in cisterna magna pressure (CMP) for ten hours and no significant reduction in CBF (integrated N2O desaturation technique) for three and one-half hours after 15 minutes of systemic circulatory arrest. However, transtentorial pressure gradients may have developed, and CBF changes may have been masked by limitations of the N2O method in low flow states. In this study, 12 dogs were subjected to 15 minutes of aortic occlusion and studied for two hours PI. Immediately after restoration of circulation, cisterna magna, supracortical and lateral ventricle pressures rose to 35 to 40 torr, concomitant with a threefold increase in cerebral blood flow (133Xe clearance technique). By 30 minutes postischemia, cisterna magna and supracortical pressures had returned to control values but lateral ventricular pressures normalized slower. CBF decreased to and remained at 50% of preischemic values after 40 minutes PI. Cerebral glucose uptake increased markedly immediately PI, then fell significantly below control values at 45 minutes. Cerebral O2 uptake was significantly reduced, although less than for glucose, between 30 and 60 minutes PI. Global ischemia for 15 minutes is followed neither by a secondary rise in intracranial pressure nor by a cerebrospinal fluid pressure gradient but rather by hypoperfusion and defective glucose metabolism.

Resuscitation from clinical death: pathophysiologic limits and therapeutic potentials

Modern cardiopulmonary-cerebral resuscitation (CPCR) for the reversal of clinical death (i.e., prolonged cardiac arrest) is a sequence of basic, advanced and prolonged life-support steps. This system was initiated by research that started in the 1950s. Present community-wide results are encouraging, but suboptimal. Maximal benefit from CPCR will be achievable: a) by minimizing response times; and b) by extending reversible arrest times—the topic of this symposium. For reperfusion, closed chest CPR is more readily available than, but physiologically inferior to, open chest CPR and emergency cardiopulmonary bypass. To optimize outcome, four components of the postresuscitation syndrome are being investigated: a) perfusion failure; b) reoxygenation injury cascades; c) self-intoxication; and d) blood derangements. Results from animal outcome studies so far suggest significant but still inconsistent benefit from several special postarrest treatments. The longest normothermic no-flow time yet reversed to good functional survival of heart, brain and the entire organism appears to be not 5 min, but between 10 and 20 min. The following is recommended and in part has been initiated: a) simultaneous investigation of patho-physiologic limits, therapeutic potentials, and prognosticating measurements; b) simultaneous basic research at cellular, organ, and organism levels; c) increased communication and consensus on research models between research centers; d) use of short-term and long-term animal models for systematic mechanism-oriented and empirical outcome-oriented studies; e) development of etiology-specific combination treatments; and f) community-wide case registries combined with epidemio-logic studies and randomized clinical treatment trials.

Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs.

Background and Purpose: Mild cerebral hypothermia (34°C) induced immediately after cardiac arrest improves outcome. Deep postarrest hypothermia (15°C) has not been studied. Methods: We used our dog model of normothermic ventricular fibrillation (no blood flow) of 12.5 minutes, reperfusion by brief cardiopulmonary bypass, controlled ventilation to 20 hours, and intensive care to 72 hours. Head surface cooling and bypass cooling were performed from start of reperfusion to 1 hour. Five groups of six dogs each were compared: group I, normothermic controls; group II, deep hypothermia (15°C); group III, moderate hypothermia (30°C); group IV, mild hypothermia (34°C); and group V, mild hypothermia with head surface cooling begun during no flow. Results: In control group I, five dogs remained comatose (overall performance category [OPC] 4) and one severely disabled (OPC 3). In group II, four dogs achieved OPC 4 and two dogs OPC 3 (NS versus group I). Compared with group I, OPCs were better in group III (p<0.05), group IV (p<0.05), and group V (p<0.05). Neurological deficit scores were also better in groups III, IV, and V than in groups I or II (p<0.05). Total brain histological damage scores were better in group III (p=0.02), group IV (p=0.06), and group V (p<0.05) than in group I. In group II, OPC and neurological deficit scores were the same and histological damage scores numerically worse than in group I and all were worse than in groups III, IV, and V (p<0.05). Cardiovascular complications and myocardial morphological damage in groups II and III were worse than in groups I, IV, and V (p<0.05). Conclusions: Mild or moderate cerebral hypothermia induced immediately after cardiac arrest improves cerebral outcome, more likely when initiated during arrest, whereas deep postarrest hypothermia can worsen cerebral and cardiac outcome. (Stroke 1992;23:1454‐1462)