Fritz Sterz

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.

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.

Hypertension with or without hemodilution after cardiac arrest in dogs

We studied blood flow-promoting therapies after cardiac arrest in 18 dogs. Our model consisted of ventricular fibrillation (no blood flow) lasting 12.5 minutes, controlled reperfusion with cardiopulmonary bypass and defibrillation within 5 minutes, controlled intermittent positive-pressure ventilation to 20 hours, and intensive care to 96 hours. Group I (control, n = 6) dogs were reperfused under conditions of normotension (mean arterial blood pressure 100 mm Hg) and normal hematocrit (greater than or equal to 35%). Group II (n = 6) and III (n = 6) dogs were treated with norepinephrine at the beginning of reperfusion to induce hypertension for 4 hours. In addition, group III dogs received hypervolemic hemodilution to a hematocrit of 20% using dextran 40. There were no differences in the time to recovery of electroencephalographic activity among groups. All six group I dogs remained severely disabled; in groups II and III combined, six of the 12 dogs achieved good outcome (p less than 0.01). Some regional histopathologic damage scores at 96 hours were better in groups II and/or III than in group I (neocortex: p less than 0.05 group II different from group I; hippocampus: p less than 0.01 both groups II and III different from group I). Total histopathologic damage scores were similar among the groups. A hypertensive bout with a peak mean arterial blood pressure of greater than or equal to 200 mm Hg beginning 1-5 minutes after the start of reperfusion was correlated with good outcome (p less than 0.01). Our results support the use of an initial bout of severe hypertension, but not the use of delayed hemodilution.

Regional Prevalence and Distribution of Ischemic Neurons in Dog Brains 96 Hours After Cardiac Arrest of 0 to 20 Minutes

BACKGROUND AND PURPOSE In this established outcome model of cardiac arrest in dogs, we have used total (summed regional) brain histopathologic damage scores. The present study describes the regional progression of necrotic (ischemic) neuron prevalence with increasing duration of cardiac arrest. It tests the hypothesis that increases in the total prevalence of necrotic neurons better correspond to increasing arrest duration and better correlate with neurological deficit than do any individual regional scores. METHODS Blinded evaluation with light microscopy was used to score the prevalence (five categories) and note the distribution of necrotic neurons in dog brains 96 hours after normothermic ventricular fibrillation cardiac arrest followed by standard reperfusion and control of extracerebral variables. Six coronal brain sections including 19 regions were examined from dogs subjected to 0 (n = 2), 5 (n = 5), 10 (n = 6), 12.5 (n = 12), 15 (n = 8), 17 (n = 5), or 20 (n = 1) minutes of cardiac arrest. Dogs were neurologically evaluated before death. RESULTS Necrotic neurons were widespread and scattered among normal neurons. Individual regions varied in their sensitivity to different durations of cardiac arrest. There were consistent increases in the mean prevalence of necrotic neurons with increased arrest duration in the hippocampal dentate gyrus and for cerebellar granule neurons. Regionally, the caudate nucleus had the best correlation with clinical neurological deficit (rho = +.85, P < .01). CONCLUSIONS Compared with total (summed regional) necrotic neuron prevalence scores, increased regional prevalence scores for cerebellar granule neurons with increasing arrest duration were equally significant, and scores for the caudate nucleus had nearly the same correlation with individual clinical neurological deficit.

Hypertension with hemodilution prevents multifocal cerebral hypoperfusion after cardiac arrest in dogs.

Background Improved neurological outcome with postarrest hypertensive hemodilution in an earlier study could be the result of more homogeneous cerebral perfusion and improved O2 delivery. We explored global, regional, and local cerebral blood flow by stable xenon-enhanced computed tomography and global cerebral metabolism in our dog cardiac arrest model. Methods Ventricular fibrillation cardiac arrest of 12.5 minutes was reversed by brief cardiopulmonary bypass, followed by life support to 4 hours postarrest We compared control group I (n=5; mean arterial blood pressure, 100 mm Hg; hematocrit, ≥35%) with immediately postarrest reflow-promoted group II (n=5; mean arterial blood pressure, 140–110 mm Hg; hypervolemic hemodilution with plasma substitute to hematocrit, 20–25%). Results After initial hyperemia in both groups, during the “delayed hypoperfusion phase” at 1–4 hours postarrest, global cerebral blood flow was 51–60% of baseline in group I versus 85–100% of baseline in group II (p<6.01). Percentages of brain tissue voxels with no flow, trickle flow, or low flow were lower (p<0.01) and mean regional cerebral blood flow values were higher in group II (p<0.0l). Global cerebral oxygen uptake recovered to near baseline values at 3–4 hours postarrest in both groups. Postarrest arterial O2 content, however, in hemodiluted group II was 40–50% of that in group I. Thus, the O2 uptake/delivery ratio was increased (worsened) in both groups at 2–4 hours postarrest. Conclusions After prolonged cardiac arrest, immediately induced moderate hypertensive hemodilution to hematocrit 20–25% can normalize cerebral blood flow patterns (improve homogeneity of cerebral perfusion), but does not improve cerebral O2 delivery, since the flow benefit is offset by decreased arterial O2 content Individualized titration of hematocrit or hemodilution with acellular O2 carrying blood substitute (stroma-free hemoglobin or fluorocarbon solution) would be required to improve O2 uptake/delivery ratio.

Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs. Reperfusion with open-chest CPR or cardiopulmonary bypass

Using the stable xenon-enhanced computed tomography (Xe-CT) method in dogs, we studied local, regional and global cerebral blood flow (LCBF, rCBF and gCBF) in two sham experiments and nine cardiac arrest experiments. Within the same experiments without arrest, gCBF and rCBF values were reproducible and stable. LCBF values varied over time. In group I (n = 4), ventricular fibrillation cardiac arrest (no blood flow) of 10 min was reversed by open-chest cardiopulmonary resuscitation (CPR). In group II (n = 5), ventricular fibrillation cardiac arrest of 12.5 min was reversed by brief closed-chest cardiopulmonary bypass. This was followed by controlled ventilation, normotension, normoxia, normocarbia and normothermia to 4 h (n = 7) or 20 h (n = 2) postarrest. The postarrest CBF patterns were similar in both groups. Open-chest CPR during ventricular fibrillation generated near-baseline gCBF and lower LCBF ranges. During postarrest spontaneous circulation, transient diffuse hyperemia was without low-flow regions, longer in brain stem and basal ganglia than in neocortex. During delayed hypoperfusion at 1-4 h postarrest (n = 9), mean gCBF was 44-60% baseline, rCBF in primarily gray matter regions was 15-49 ml/100 cm3 per min and LCBF voxels with trickle-flow and low-flow values, in percent of CT cut area, were increased over baseline. Global CMRO2 (n = 3 of group II) recovered to near baseline values between 1 and 4 h postarrest, while gCBF and O2 delivery were about 50% baseline (mismatching of O2 uptake and O2 delivery).

Cerebral and systemic arteriovenous oxygen monitoring after cardiac arrest. Inadequate cerebral oxygen delivery

BACKGROUND After prolonged cardiac arrest, under controlled normotension, cardiac output and cerebral blood flow are reduced for several hours. This dog study documents for the first time the postarrest reduction in oxygen (O2) delivery in relation to O2 uptake for brain and entire organism. METHODS In eight dogs we used our model of ventricular fibrillation (VF) cardiac arrest of 12.5 min, reperfusion with brief cardiopulmonary bypass, and controlled normotension, normoxemia, and mild hypocapnia to 24 h. RESULTS Between 4 and 24 h after cardiac arrest, cardiac output decreased by about 25% and the systemic arteriovenous O2 content difference doubled, while the calculated systemic O2 utilization coefficient (O2 UC) increased and the systemic venous PO2 decreased, both not to critical levels. The cerebral arteriovenous O2 content difference however, which was 5.6 +/- 1.7 ml/dl before arrest, increased between 1 and 18 h, to 10.8 +/- 3.2 ml/dl at 4 h. The cerebral O2 UC increased and the cerebral venous PO2 decreased, both to critical levels. CONCLUSIONS After prolonged cardiac arrest in dogs with previously fit hearts, the reduction of O2 transport to the brain is worse than its reduction to the whole organism. Monitoring these values might help in titrating life-support therapies.

Mild hypothermia after cardiac arrest in dogs does not affect postarrest multifocal cerebral hypoperfusion.

Background and Purpose Although mild resuscitative hypothermia (34°C) immediately after cardiac arrest improves neurological outcome in dogs, its effects on cerebral blood flow and metabolism are unknown. Methods We used stable xenon-enhanced computed tomography to study local, regional, and global cerebral blood flow patterns up to 4 hours after cardiac arrest in dogs. We compared a normothermic (37.5°C) control group (group I, n=5) with a postarrest mild hypothermic group (group II, n=5). After ventricular fibrillation of 12.5 minutes and reperfusion with brief cardiopulmonary bypass, the ventilation, normotension, normoxia, and mild hypocapnia were controlled to 4 hours after cardiac arrest. Group II received (minimal) head cooling during cardiac arrest, followed by systemic bypass cooling (to 34°C) during the first hour of reperfusion after cardiac arrest. Results The postarrest homogeneous transient hyperemia was followed by global hypoperfusion from 1 to 4 hours after arrest, with increased “no-flow” and “trickle-flow” voxels (compared with baseline), without group differences. At 1 to 4 hours, mean global cerebral blood flow in computed tomographic slices was 55% of baseline in group I and 64% in group II (NS). No flow (local cerebral blood flow < 5 mL/100 cm3 per minute) occurred in 5±2% of the voxels in group I versus 9±5% in group II (NS). Trickle flow (5 to 10 mL/100 cm3 per minute) occurred in 10±3% voxels in group I versus 16±4% in group II (NS). Cerebral blood flow values in eight brain regions followed the same hyperemia-hypoperfusion sequence as global cerebral blood flow, with no significant difference in regional values between groups. The global cerebral metabolic rate of oxygen, which ranged between 2.7 and 4.5 mL/100 cm3 per minute before arrest in both groups, was at 1 hour after arrest 1.8±0.3 mL in normothermic group I (n=3) and 1.9±0.4 mL in still-hypothermic group II (n=5); at 2 and 4 hours after arrest, it ranged between 1.2 and 4.2 mL in group I and between 1.2 and 2.6 mL in group II. Conclusions After cardiac arrest, mild resuscitative hypothermia lasting 1 hour does not significantly affect patterns of cerebral blood flow and oxygen uptake. This suggests that different mechanisms may explain its mitigating effect on brain damage.

Cardiac resuscitability with cardiopulmonary bypass after increasing ventricular fibrillation times in dogs

Previous studies in dogs have shown resuscitation from prolonged cardiac arrest to conscious survival to be more effective with the use of cardiopulmonary bypass (CPB) than with standard advanced cardiac life support. This study compared cardiovascular resuscitability with CPB only after varying periods of cardiac arrest without artificial circulatory support in a canine model. Group 1 (ten) was subjected to ventricular fibrillation for 15 minutes; group 2 (ten) for 20 minutes; and group 3 (ten) for 30 minutes. All received total CPB after ventricular fibrillation without advanced cardiac life support to defibrillation at two to five minutes and partial CPB to four hours. In all three groups CPB with epinephrine generated normal coronary perfusion pressure and increased ventricular fibrillation amplitude significantly. In groups 1 and 2, CPB reperfusion allowed for successful defibrillation in less than five minutes, weaning from CPB in all dogs at four hours, and stable spontaneous circulation thereafter. In group 3, only five of ten dogs could be weaned from bypass at four hours, and all died early with myocardial necroses. It was concluded that CPB may be of value in the setting of prolonged cardiac arrest when advanced cardiac life support has not been provided or is unable to restore spontaneous heart-beat.

Systematic Development of Cerebral Resuscitation After Cardiac Arrest. Three Promising Treatments: Cardiopulmonary Bypass, Hypertensive Hemodilution, and Mild Hypothermia

Since 1970 we have investigated postischemic anoxic encephalopathy and potential treatments for cerebral resuscitation after cardiac arrest by cardiopulmonary-cerebral resuscitation (CPCR). The post-resuscitation syndrome has been studied at the levels of cell, organ, organism and community. Short-term and long-term models in rats, dogs, and monkeys have been developed, and an international multicenter randomized clinical trial mechanism was established. Clinical studies disproved the 5-min limit of reversible cardiac arrest and yielded other valuable data on treatments and prognostication. Thiopental loading or calcium entry blocker therapy (lidoflazine) gave no significant improvement in patients. Free radical scavengers are under investigation in the laboratory. We hypothesize that post-arrest perfusion failure and necrotizing cascades require etiology-specific combination treatments. Standard (control) therapy in a current dog model of cardiac arrest (no flow) of 12.5-20 min, reperfusion with cardiopulmonary bypass, and intensive care for 72-96 h has consistently resulted in survival with brain damage. After ventricular-fibrillation (VF) arrest of 17 min, moderate hypothermia (28-32 degrees C) inconsistently improved cerebral outcome. After VF arrest of 12.5 min, hypertension plus hemodilution normalized the local (multifocal) cerebral hypoperfusion post-arrest and, again, inconsistently improved cerebral outcome. Additional mild hypothermia (34-36 degrees C), however, consistently improved cerebral outcome, whether induced before or during and after arrest.