Ann Radovsky

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)

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)

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)

Outcome Model of Asphyxial Cardiac Arrest in Rats

An outcome model with asphyxial cardiac arrest in rats has been developed for quantifying brain damage. Twenty-two rats were randomized into three groups. Control group I was normal, was conscious, and had no asphyxia (n = 6). Sham group II had anesthesia and surgery but no asphyxia (n = 6). All 12 rats in groups I and II survived to 72 h and were functionally and histologically normal. Arrest group III (the model; n = 10) had light anesthesia and apneic asphyxia of 8 min, which led to cessation of circulation at 3–4 min of apnea, resulting in cardiac arrest (no flow) of 4–5 min. All 10 rats had spontaneous circulation restored by standard external cardiopulmonary resuscitation. Nine rats survived controlled ventilation for 1 h and observation to 72 h, while one rat died before extubation. All nine survivors were conscious at 72 h, with neurologic deficit scores (0% = best; 100% = worst) of 7 ± 69? (2–16%). All brain regions at five coronal levels were examined for ischemic neurons. The prevalence of ischemic neurons in five regions was categorically scored. The average total brain histopathologic damage score in group III (n = 9) was 2.1 (p < 0.05 vs. group I or II). A reproducible outcome model of cardiac arrest in rats was documented. It provides a tool for investigating pathophysiological mechanisms of neuronal death caused by a transient global hypoxic–ischemic brain insult.

Critical Time Window for Intra-Arrest Cooling With Cold Saline Flush in a Dog Model of Cardiopulmonary Resuscitation

Background— Mild hypothermia improves outcome when induced after cardiac arrest in humans. Recent studies in both dogs and mice suggest that induction of mild hypothermia during cardiopulmonary resuscitation (CPR) greatly enhances its efficacy. In this study, we evaluate the time window for the beneficial effect of intra-arrest cooling in the setting of prolonged CPR in a clinically relevant large-animal model. Methods and Results— Seventeen dogs had ventricular fibrillation cardiac arrest no flow of 3 minutes, followed by 7 minutes of CPR basic life support and 50 minutes of advanced life support. In the early hypothermia group (n=9), mild hypothermia (34°C) was induced with an intravenous fluid bolus flush and venovenous blood shunt cooling after 10 minutes of ventricular fibrillation. In the delayed hypothermia group (n=8), hypothermia was induced at ventricular fibrillation 20 minutes. After 60 minutes of ventricular fibrillation, restoration of spontaneous circulation was achieved with cardiopulmonary bypass for 4 hours, and intensive care was given for 96 hours. In the early hypothermia group, 7 of 9 dogs survived to 96 hours, 5 with good neurological outcome. In contrast, 7 of 8 dogs in the delayed hypothermia group died within 37 hours with multiple organ failure (P=0.012). Conclusions— Early application of mild hypothermia with cold saline during prolonged CPR enables intact survival. Delay in the induction of mild hypothermia in this setting markedly reduces its efficacy. Our data suggest that if mild hypothermia is used during CPR, it should be applied as early as possible.

Moderate hypothermia after cardiac arrest of 17 minutes in dogs. Effect on cerebral and cardiac outcome.

Moderate hypothermia (30 degrees C) induced before circulatory arrest is known to improve neurologic outcome. We explored, for the first time in a reproducible dog outcome model, moderate hypothermia induced during reperfusion after cardiac arrest (resuscitation). In three groups of six dogs each (N = 18), normothermic ventricular fibrillation cardiac arrest (no blood flow) of 17 minutes was reversed by cardiopulmonary bypass--normothermic in control group I (37.5 degrees C) and hypothermic to 3 hours in groups II (32 degrees C) and III (28 degrees C). Defibrillation was achieved in less than or equal to 5 minutes and partial bypass was continued to 4 hours, controlled ventilation to 20 hours, and intensive care to 96 hours. All 18 dogs survived. Electroencephalographic activity returned significantly earlier in groups II and III. Mean +/- SD best neurologic deficit between 48 and 96 hours was 44 +/- 8% in group I, 38 +/- 12% in group II, and 35 +/- 7% in group III (differences not significant). Best overall performance category 2 (good outcome) between 48 and 96 hours was achieved in none of the six dogs in group I and in four of the 12 dogs in the combined hypothermic groups II and III (difference not significant). Mean +/- SD brain total histologic damage score was 130 +/- 22 in group I, 93 +/- 28 in group II (p = 0.05), and 80 +/- 26 in group III (p = 0.03). Gross myocardial damage was greater in groups II and III than in group I--numerically higher overall and significantly higher in group III for the right ventricle alone (p = 0.02). Moderate hypothermia after prolonged cardiac arrest may or may not improve cerebral outcome slightly and can worsen myocardial damage.

Survival without brain damage after clinical death of 60-120 mins in dogs using suspended animation by profound hypothermia

ObjectivesThis study explored the limits of good outcome of brain and organism achievable after cardiac arrest (no blood flow) of 60–120 mins, with preservation (suspended animation) induced immediately after the start of exsanguination cardiac arrest. DesignProspective experimental comparison of three arrest times, without randomization. SettingUniversity research laboratory. SubjectsTwenty-seven custom-bred hunting dogs (17–25 kg). InterventionsDogs were exsanguinated over 5 mins to cardiac arrest no-flow of 60 mins, 90 mins, or 120 mins. At 2 mins of cardiac arrest, the dogs received, via a balloon-tipped catheter, an aortic flush of isotonic saline at 2°C (at a rate of 1 L/min), until tympanic temperature reached 20°C (for 60 mins of cardiac arrest), 15°C (for 60 mins of cardiac arrest), or 10°C (for 60, 90, or 120 mins of cardiac arrest). Resuscitation was by closed-chest cardiopulmonary bypass, postcardiac arrest mild hypothermia (tympanic temperature 34°C) to 12 hrs, controlled ventilation to 20 hrs, and intensive care to 72 hrs. Measurements and Main ResultsWe assessed overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, death), neurologic deficit scores (NDS 0–10%, normal; 100%, brain death), regional and total brain histologic damage scores at 72 hrs (total HDS >0–40, mild; 40–100, moderate; >100, severe damage), and morphologic damage of extracerebral organs. For 60 mins of cardiac arrest (n = 14), tympanic temperature 20°C (n = 6) was achieved after flush of 3 mins and resulted in two dogs with OPC 1 and four dogs with OPC 2: median NDS, 13% (range 0–27%); and median total HDS, 28 (range, 4–36). Tympanic temperature of 15°C (n = 5) was achieved after flush of 7 mins and resulted in all five dogs with OPC 1, NDS 0% (0–3%), and HDS 8 (0–48). Tympanic temperature 10°C (n = 3) was achieved after flush of 11 mins and resulted in all three dogs with OPC 1, NDS 0%, and HDS 16 (2–18). For 90 mins of cardiac arrest (n = 6), tympanic temperature 10°C was achieved after flush of 15 mins and resulted in all six dogs with OPC 1, NDS 0%, and HDS 8 (0–37). For 120 mins of cardiac arrest (n = 7), three dogs had to be excluded. In the four dogs within protocol, tympanic temperature 10°C was achieved after flush of 15 mins. This resulted in one dog with OPC 1, NDS 0%, and total HDS 14; one with OPC 1, NDS 6%, and total HDS 20; one with OPC 2, NDS 13%, and total HDS 10; and one with OPC 3, NDS 39%, and total HDS 22. ConclusionsIn a systematic series of studies in dogs, the rapid induction of profound cerebral hypothermia (tympanic temperature 10°C) by aortic flush of cold saline immediately after the start of exsanguination cardiac arrest—which rarely can be resuscitated effectively with current methods—can achieve survival without functional or histologic brain damage, after cardiac arrest no-flow of 60 or 90 mins and possibly 120 mins. The use of additional preservation strategies should be pursued in the 120-min arrest model.

Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats

Although high-dose epinephrine during CPR improves coronary perfusion pressure (CoPP) and rate of return of spontaneous circulation (ROSC) in some models, its impact on long term outcome (> or = 72 h) has not been evaluated. Previous studies of sodium bicarbonate (NaHCO3) therapy during CPR indicate that beneficial effects may be dependent on epinephrine (EPI) dose. We hypothesized that EPI and NaHCO3 given during CPR have a significant impact on long term outcome. One hundred male Sprague-Dawley rats were prospectively studied in a block randomized placebo controlled trial. Rats were anesthetized, paralyzed, mechanically ventilated, instrumented, and each underwent 10 min of asphyxia, resulting in 6.8 +/- 0.4 min of circulatory arrest. Resuscitation was performed by mechanical ventilation and manual external chest compressions. EPI 0.0 (placebo), 0.01, 0.1, or 1.0 mg/kg IV was given at the onset of CPR, followed by NaHCO3 0.0 (placebo) or 1.0 mEq/kg IV. Successfully resuscitated rats were monitored and ventilated for 1 h without hemodynamic support. Neurologic deficit scores (NDS), cerebral histopathologic damage scores (CHDS) and myocardial histopathologic damage scores (MHDS) were determined in rats that survived 72 h. EPI improved CoPP and ROSC in a dose-dependent manner up to 0.1 mg/kg. Rats receiving EPI 0.1 and 1.0 mg/kg during CPR exhibited prolonged post-ROSC hypertension and metabolic acidemia, increased A-a O2 gradient, and an increased incidence of post-ROSC ventricular tachycardia or fibrillation. Overall survival was lower with EPI 0.1 and 1.0 mg/kg compared to 0.01 mg/kg. Although NDS was significantly less with EPI 0.1 mg/kg compared to placebo, there was no difference in CHDS between groups. In contrast, MDS was significantly higher with EPI 0.1 mg/kg compared to placebo or EPI 0.01 mg/kg. There was an overall trend toward improved survival at 72 h in rats that received NaHCO3 which was most evident in the EPI 0.1 mg/kg group. We conclude that (1) EPI during CPR has a biphasic dose/response curve in terms of survival, when post-resuscitation effects are left untreated and (2) NaHCO3 doses greater than 1.0 mEq/kg may be necessary to treat the side-effects of high-dose EPI. Further work is needed to determine if treating the immediate post-resuscitation effects of high-dose EPI can prevent detrimental effects on long-term outcome.