Harvey Reich

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.

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.

Dynamic heterogeneity of cerebral hypoperfusion after prolonged cardiac arrest in dogs measured by the stable xenon/CT technique: a preliminary study

After prolonged cardiac arrest and reperfusion, global cerebral blood flow (gCBF) is decreased to about 50% normal for many hours. Measurement of gCBF does not reveal regional variation of flow or permit testing of hypotheses involving multifocal no-flow or low-flow areas. We employed the noninvasive stable Xenon-enhanced Computerized Tomography (Xe/CT) local CBF (LCBF) method for use in dogs before and after ventricular fibrillation (VF) cardiac arrest of 10 min. This was followed by external cardiopulmonary resuscitation (CPR) and control of cardiovascular pulmonary variables to 7 h postarrest. In a sham (no arrest) experiment, the three CT levels studied showed normal regional heterogeneity of LCBF values, all between 10 and 75 ml/100 cm3 per min for white matter and 20 and 130 ml/100 cm3 per min for gray matter. In four preliminary CPR experiments, the expected global hyperemia at 15 min after arrest, was followed by hypoperfusion with gCBF reduced to about 50% control and increased heterogeneity of LCBF. Trickle flow areas (LCBF less than 10 ml/100 cm3 per min) not present prearrest, were interspersed among regions of low, normal, or even high flow. Regions of 125-500 mm3 with trickle flow or higher flows, in different areas at different times, involving deep and superficial structures migrated and persisted to 6 h, with gCBF remaining low. These preliminary results suggest: no initial no-reflow foci (less than 10 ml/100 cm3 per min) larger than 125 mm3 persisting through the initial global hyperemic phase; delayed multifocal hypoperfusion more severe than suggested by gCBF measurements; and trickle flow areas caused by dynamic factors.

Effect of Excitatory Amino Acid Receptor Blocker MK-801 on Overall, Neurologic, and Morphologic Outcome after Prolonged Cardiac Arrest in Dogs

Excitatory amino acids accumulating in the brain during ischemia may cause selective neuronal damage postischemia. This hypothesis was tested in a series of studies using MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in a reproducible outcome model of prolonged cardiac arrest in dogs. After normothermic ventricular fibrillation cardiac arrest, the dogs were resuscitated with closed-chest femoral veno-arterial cardiopulmonary bypass. At 4 h they were separated from bypass, ventilation was controlled for 20 h, and intensive care was continued to 96 h. In Study I, ventricular fibrilation cardiac arrest (no-flow) was 17 min; starting immediately with reperfusion, MK-801 1200 mg/kg (n = 5) or an equal volume of placebo (n = 5) was infused over 12 h in blinded, randomized fashion. In Study II, the duration of the no-flow period was reduced to 15 min, and MK-801 2400 mg.kg-1 (n = 4) or placebo (n = 4) was infused. In Study III, no-flow lasted for 15 min, and MK-801 2400 mg/kg was started 30 min before ventricular fibrillation (n = 4); comparison was with Study II controls. In all three studies, MK-801 plasma concentrations peaked at greater than 50 ng/ml and were 15-30 ng/ml over 12 h. All 22 dogs of experiments within protocol survived with severe brain damage. MK-801 delayed return of pupillary reactivity, EEG activity, consciousness, and respiration, necessitating longer periods of controlled ventilation. Neurologic deficit scores, overall performance categories, and brain and heart morphologic damage scores at 96 h did not differ between placebo and MK-801 pretreatment or post-treatment groups. These negative outcome results after prolonged cardiac arrest do not negate the hyperexcitability hypothesis of selective vulnerability, but suggest the existance of additional mechanisms of secondary brain damage.

A comparison of cardiopulmonary resuscitation with cardiopulmonary bypass after prolonged cardiac arrest in dogs. Reperfusion pressures and neurologic recovery

Resuscitability and outcome after prolonged cardiac arrest were compared in dogs with standard external cardiopulmonary resuscitation (CPR) vs. closed-chest emergency cardiopulmonary bypass (CPB). Ventricular fibrillation (VF) was with no blood flow from VF 0 min to VF 10 min. Subsequent CPR basic life support (BLS) was from 10 min to VF 15 min. Then, group I (n = 13) received CPR advanced life support (ALS) from VF 15 min until restoration of spontaneous circulation to occur not later than VF 40 min. Group II (n = 14) received CPR-ALS from VF 15 min to VF 20 min without defibrillation, and then total CPB to defibrillation attempts started at VF 20 min, followed by assisted CPB to 2 h. Total ischemia time (no-flow time plus CPR time of MAP less than 50 mmHg) was unexpectedly shorter in group I (14.3 +/- 2.5 min) than in group II (18.6 +/- 2.3 min) (P less than 0.01). During CPR-BLS, coronary perfusion pressures were 25 +/- 9 mmHg in group I and 18 +/- 8 mmHg in group II (NS). Epinephrine during CPR-ALS, before countershock, raised coronary perfusion pressure to 40 +/- 10 mmHg in group I and 27 +/- 10 mmHg in group II (NS). In group II, coronary perfusion pressure increased during total CPB to 58 +/- 16 mmHg (P less than 0.01 vs. group I). Spontaneous normotension was restored in 11/13 dogs of group I and all 14 dogs of group II (NS). Ten dogs in each group followed protocol and survived to 96 h. Five of ten in group I and six of ten in group II were neurologically normal (NS). We conclude that: (1) Reperfusion with CPB yields higher coronary perfusion pressures than reperfusion with CPR-ALS; and (2) even after no blood flow for 10 min, optimized CPR can result in cardiovascular resuscitability and neurologic recovery, similar to those achieved by CPB.

Factors influencing variable outcomes after ventricular fibrillation cardiac arrest of 15 minutes in dogs

Animal experiments with cardiac arrest and cardiopulmonary resuscitation (CPR) despite controlled insult and postinsult life support, have yielded variable individual outcomes. This report concerns 10 dog experiments with a standardized model of VF cardiac arrest with no flow for 10 min followed by CPR basic life support (BLS) from VF 10 to 15 min and then CPR advanced life support (ALS) with epinephrine at 15 min. Defibrillating countershocks began at 17 min, for restoration of spontaneous circulation. After controlled ventilation to 20 h and intensive care to 96 h, outcome was evaluated using the overall performance category (OPC) 1 (normal) (n5) vs. OPC 2-4 (impaired) (n5) (P less than 0.001). We searched for correlations between normal vs. impaired outcome in various prearrest, arrest and postarrest factors that are suspected to influence postarrest neurologic deficit. Prearrest variables were similar in the normal and impaired groups. Resuscitation variables were similar in both. Coronary perfusion pressure during CPR-ALS was higher in the normal outcome group (P = 0.03). Among postarrest variables, postarrest reperfusion pressure pattern (initial hypertensive bout), blood glucose, cardiac output, Hct, pHa, PaO2 and PaCO2 were the same. Our data support the importance of maximizing coronary perfusion pressure not only for restoration of heart beat but also as a possible predictor of improved cerebral outcome.