Sven E. Gisvold

Nimodipine Improves Outcome when Given after Complete Cerebral Ischemia in Primates

Twenty-seven pigtailed monkeys (Macaca nemestrina) were subjected to 17 min of complete cerebral ischemia followed by 96 h of intensive care treatment. Fourteen of the monkeys were assigned randomly to the treatment group and received nimodipine 10 μg·kg−1 5 min postischemia followed by 1 μg·kg−1·min−1 for 10 h. Six monkeys (three treated) failed to meet preestablished protocol criteria and were excluded. The remaining treated and untreated monkeys were well matched for age, sex, and other physiologic variables. Neurologic outcome at 96 h postischemia was significantly better in the nimodipine-treated monkeys than in the controls. Eight of the 11 treated animals had an apparent normal level of consciousness; four of these had no detectable neurologic deficits and a fifth had only a slight motor apraxia. Only two of the 10 untreated animals had an apparent normal level of consciousness, and all had major neurologic deficits. Histopathologic examination showed variable ischemic neuronal change and infarction to involve gray matter in distal arterial perfusion zones. Significant white matter changes were not observed. A histopathologic scoring system yielded a significantly better mean score for the treated group than for the untreated group, and there was significant correlation between neurologic function and histopathologic findings. The authors conclude that nimodipine improves the neurologic outcome when given after an episode of complete cerebral ischemia in primates, and they recommend controlled clinical trials in patients resuscitated after cardiac arrest.

Thiopental Treatment after Global Brain Ischemia in Pigtailed Monkeys

The authors investigated the value of high-dose thiopental (TH) therapy after 16-min complete global brain ischemia (GBI) in three groups of pigtailed monkeys, using a neck cuff model of GBI with 96 h intensive care postischemia (PI). Control group (n18): Normotension was restored within 2 min PI; paralysis/controlled ventilation was maintained for 48 h PI with 50% N2O/O2. Thiopental loading group (n13): Control treatment plus TH-loading with 90 mg/kg iv given from 5 to 65 min PI (mean peak TH plasma level 130 μg/ml). Thiopental anesthesia group (n14): Control treatment plus TH anesthesia with 90 mg/kg iv given over 12 h PI (sustained TH plasma levels of 25–35 μg/ml and EEG burst suppression). Norepinephrine requirement for blood pressure control PI was greater in the TH groups than in the control group (P < 0.05). Lidocaine was needed for control of arrhythmias in the TH loading group. There was no significant difference in mortality or neurologic outcome between the groups. At 96 h PI seven of 11 animals were awake in the control group, compared with seven of 12 and six of 12 in the two TH groups. Neurologic deficit scores (NDS) for the survivors at 96 h PI were 23 ± 6% (mean ± SD) (n10) in the control group, compared with 25 ± 9% (n11) and 26 ± 12% (n10) in the two TH groups (NDS 100% = brain death, 0% = normal). Seizures PI (in 1–2 of each group) were associated with worse neurologic deficits. At 96 h PI, all three groups had developed the same type and distribution of histologic lesions. Thus, the authors were unable to demonstrate any brain-damage-ameliorating effect of TH loading or TH anesthesia after 16 min GBI in pigtailed monkeys.

Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms.

Both the period of total circulatory arrest to the brain and postischemic-anoxic encephalopathy (cerebral postresuscitation syndrome or disease), after normothermic cardiac arrests of between 5 and 20 mins (no-flow), contribute to complex physiologic and chemical derangements. The best documented derangements include the delayed protracted inhomogeneous cerebral hypoperfusion (despite controlled normotension), excitotoxicity as an explanation for selectively vulnerable brain regions and neurons, and free radical-triggered chemical cascades to lipid peroxidation of membranes. Protracted hypoxemia without cardiac arrest (e.g., very high altitude) can cause angiogenesis; the trigger of it, which lyses basement membranes, might be a factor in post-cardiac arrest encephalopathy. Questions to be explored include: What are the changes and effects on outcome of neurotransmitters (other than glutamate), of catecholamines, of vascular changes (microinfarcts seen after asphyxia), osmotic gradients, free-radical reactions, DNA cleavage, and transient extracerebral organ malfunction? For future mechanism-oriented studies of the brain after cardiac arrest and innovative cardiopulmonary-cerebral resuscitation, increasingly reproducible outcome models of temporary global brain ischemia in rats and dogs are now available. Disagreements exist between experienced investigative groups on the most informative method for quantitative evaluation of morphologic brain damage. There is agreement on the desirability of using not only functional deficit and chemical changes, but also morphologic damage as end points.

Asphyxia, cardiac arrest and resuscitation in rats. I. Short term recovery.

This study was conducted to investigate the degree of insult from asphyxia leading to total body circulatory arrest, as a model for brain resuscitation studies in rats. Of 78 male rats, 68 were anesthetized with halothane in O2/N2O, controlled ventilated, paralyzed with pancuronium and asphyxiated, 5, 7.5, 10, 12.5 and 15 min, respectively. Asphyxiation led to circulatory arrest in 244 +/- 22 s (mean +/- S.E.M.). Resuscitation was successful in 65% within 60 s using controlled ventilation with 100% O2, extrathoracic compressions and epinephrine intravenously. Subsequent intensive care to 6, 12 or 24 h was successful in 50% of resuscitated rats. At 6, 12 and 24 h of recovery, neurologic deficit scores and light microscopic neuropathology scores of the brain after in vivo fixation of the total body with intraventricular paraformaldehyde 3%, revealed a large scatter variability without a clear pattern. Lesions were located mostly in the frontal cortex and hippocampus (footplate) with ischemic neuronal change as the most frequent structural change. Brain cell necrosis was not seen after successful resuscitation. It seems that both scores were influenced by post-insult stress, as indicated by paroxysmal hypertension and motor activity, by complications, such as obstruction of the tracheotomy cannula by abundant sputum production, and by partial sedation with N2O and paralysis with pancuronium. This study indicates the feasibility of an asphyxial insult in rats for use in resuscitation studies of short duration. Although 24 h post-insult recovery is possible, up to 6 h seems most practical, with asphyxia of 7.5-10 min most successful and controllable. Questions are raised about the effects of irritation during the post-insult intensive care on both neurological deficit and neuropathology scores.

Predictors of electromechanical dissociation during cardiac arrest

ECG patterns observed during cardiac arrest were analyzed in 261 comatose cardiac arrest survivors. Forty-seven patients (18%) exhibited electromechanical dissociation (EMD) at some point before restoration of stable spontaneous circulation. These patients had a higher mortality (P = .05) and a lower rate of cerebral recovery (P = .01) during the one-year follow-up than study patients who did not exhibit EMD. Patients who developed EMD subsequent to defibrillation had better outcome than patients presenting with EMD. Multivariate analysis revealed that age more than 70 years old (P = .007), pulmonary disease (P less than .001), diabetes (P = .013, in-hospital arrests only), and prearrest hypoxemia (P = .013, outside-hospital arrests only) were independently predictive of the occurrence of EMD. Although the generalizability of these findings is limited, they may offer new clues to the pathophysiology of EMD.

Prolonged immobilization and controlled ventilation do not improve outcome after global brain ischemia in monkeys.

This study is a therapeutic evaluation of prolonged immobilization and controlled intermittent positive-pressure ventilation (IPPV) after global brain ischemia (GBI) in pigtailed monkeys. Sixteen min of GBI was produced with a high-pressure neck cuff, while the lungs were being continuously ventilated. Normotension was restored within 2 min postischemia (PI). The control group of 13 monkeys was weaned from IPPV 4 to 6 h PI. The treatment group of 18 animals was paralyzed and ventilated with a 50:50 nitrous oxide-oxygen mixture for 48 h PI. Intensive care was maintained for 96 h PI. In the control group, 8 of 10 animals were awake at 96 h PI compared to 7 of 11 in the treatment group. Neurologic deficit scores for the survivors in the 2 groups were also not significantly different. Histologic examination supported this conclusion. Paralysis/IPPV for 48 h post-GBI with 50% N2O facilitates control of blood gases and blood pressure, but does not improve the neurologic outcome over that achieved with only 4 to 6 h of controlled ventilation.

Thiopental after brain ischemia in monkeys. Cardiovascular and electroencephalographic effects.

The cardiovascular and electroencephalographic (EEG) effects of thiopental were investigated, with and without preceding global brain ischemia (GBI). Four groups of pigtailed monkeys were used: Group I received thiopental 90 mg/kg over 1 h after 16 min GBI. Group II received thiopental 90 mg/kg over 1 h without preceding brain ischemia. Group III received 90 mg/kg over 1, 3, 6, or 8 h with varying infusion rates and no brain ischemia. Group IV, after 16 min GBI, received thiopental 90 mg/kg over 12 h with a gradually reduced infusion rate, keeping thiopental serum levels around 120–140 μmol‐1‐1 throughout the infusion. Large doses of thiopental (Group II) produced serious cardiovascular side‐effects. With co‐existing brain ischemia (Group I), these side‐effects were much worse; five of six animals not receiving lidocaine prophylaxis suffered circulatory arrest. A prolongation of the Q‐T interval on the electrocardiogram may be of pathogenetic importance. In contrast, lower thiopental blood levels, sufficient to depress the EEG to burst suppression or isoelectricity, were well tolerated with and without preceding brain ischemia (Groups IV and III).

Systematic Studies of Cerebral Resuscitation Potentials after Global Brain Ischemia (GBI)

Resuscitation of the brain after ischemic-anoxic brain injury remains a controversial topic. There is, however, presently a certain therapeutic optimism in this field. Ours is partly based on the recognition of a post-resuscitation disease, that is, treatable pathologic processes in all organs after restoration of adequate perfusion pressure and arterial oxygenation. Also, Hossmann has shown that neurons can survive longer periods of anoxia than previously assumed. There have been reports on experimental focal ischemia indicating beneficial effects of barbiturates and moderate hemodilution before and after initiation of focal ischemia. After complete temporary global brain ischemia (GBI), as in cardiac arrest, however, results so far have been conflicting and controversial.