Naofumi Iwatsuki

Hyperbaric oxygen therapy accelerates neurologic recovery after 15-minute complete global cerebral ischemia in dogs

Background and MethodsAlthough hyperbaric oxygen therapy is clinically used for the treatment of several types of ischemic brain injury, few basic animal studies are available that provide a rationale for this therapy for complete global brain ischemia. Therefore, we investigated the effect of hyperbaric oxygen therapy on neurologic recovery after 15-min complete global cerebral ischemia in a canine model. Complete global ischemia was induced in 19 dogs by occlusion of the ascending aorta and the caval veins. Nine dogs were randomized to treatment with hyperbaric oxygenation (3 atmospheres absolute, 100% oxygen for 1 hr) at 3, 24, and 29 hrs after ischemia under spontaneous respiration, while the other ten dogs served as the control group without hyperbaric oxygen therapy (group C). Neurologic recovery was evaluated based on the electroencephalogram (EEC) activity score (1 = normal; 5 = isoelectric) and the neurologic recovery score (100 = normal; 0 = brain death) over a 14-day postischemic period. ResultsThe survival rates were 3/10 (30%) in the control group vs. 7/9 (78%) in the group treated with hyperbaric oxygen (p < .05). Over the 14-day postischemic period, the best (lowest) EEG scores of each dog were significantly (1.7 ± 0.2 vs. 2.9 ± 0.3; mean ± SE, p < .01) lower in the hyperbaric oxygen-treated group. The best neurologic recovery scores of each dog were significantly (69 ± 6 vs. 48 ± 5; mean ± SE, p < .05) higher in the treated animals. The number of dogs that recovered to a neurologic recovery score of >65 (assessed as a slight disability) were 1/10 in the control group and 6/9 in the group treated with hyperbaric oxygen (p < .02). ConclusionsHyperbaric oxygen therapy performed in the early postischemic period accelerated neurologic recovery and improved the survival rate in dogs after 15-mins of complete global cerebral ischemia.

Hyperbaric oxygen combined with nicardipine administration accelerates neurologic recovery after cerebral ischemia in a canine model.

ObjectiveTo evaluate the efficacy of combined therapy—hyperbaric oxygenation with nicardipine administration—for neurologic recovery after complete cerebral ischemia. DesignRandomized, prospective, controlled, unblinded study, with 14-day postischemic observation. SettingLaboratory of the Department of Anesthesiology, Tohoku University School of Medicine. SubjectsNineteen healthy mongrel dogs (mean weight 10.4 kg) divided randomly into two groups—ten dogs in the untreated group and nine dogs in the treated group. InterventionsFifteen minutes of complete global cerebral ischemia was achieved by occlusion of the ascending aorta and the caval veins. Dogs in the treated group each received a 0.01-mg/kg bolus injection of nicardipine immediately after the reestablishment of circulation, followed by a 0.03-μg/kg/min continuous infusion of nicardipine for 3 days and hyperbaric oxygen therapy with 3 atmospheres absolute pressures in an FIO2 of 1.0 for 1 hr at 3, 24, and 29 hrs after ischemia. Neurologic recovery was evaluated based on the survival time and rate, the Electroencephalogram (EEG) Score (1 = normal, 5 = isoelectric), and the Neurologic Recovery Score (100 = normal, 0 = brain dead) over a 14-day postischemic period. Measurements and Main ResultsNeurologic Recovery Scores of the treated group were always higher than those scores of the untreated group throughout the 14-day period. The best Neurologic Recovery Score was 83.1 ± 5.3 in the treated group and 46.9 ± 5.2 in the untreated group (p < .01). The numbers of dogs that recovered to a Neurologic Recovery Score of >85 (assessed as almost normal) was five of nine in the treated group and none of ten in the untreated group (p < .01). Recovery of EEG over 14-day period was better in the treated group. The survival rate and the predicted survival rate were 78% and 13.6 days in the treated group and 30% and 9.0 days in the untreated group, respectively (p < .04 for the survival rate and p < .05 for the survival time).Conclusion: Combined therapy, using hyperbaric oxygenation with nicardipine administration, given after 15 mins of complete global cerebral ischemia, accelerates neurologic recovery in dogs. (Crit Care Med 1994; 22:858–863)

A Weak Negative Inotropic Effect of Protamine Sulfate upon the Isolated Canine Heart Muscle

The direct effect of protamine sulfate upon myocardial inotropism was studied using an isolated canine heart muscle preparation. Isometric force (F) was decreased to 87.6 ± 1.2% of control values by a concentration of 50 × 10−3 g/L protamine, which is approximately equal to the estimated serum concentration of protamine when administered clinically in doses of 4 mg/kg. The decrease in F was accompanied by a decrease in the maximum velocity of force development (dF/dt) but no alteration in time to peak force. Administration of the preservative of protamine sulfate did not alter F and dF/dt. This suggests that protamine produces a direct negative inotropic effect, mediated by a decrease in intensity but not by a decrease in duration of the active state.

Blood flow increases in common carotid artery, lower lip and palate elicited by lingual nerve stimulation in anesthetized cats

The purpose of the present study was to examine whether changes in blood flow in the common carotid artery (CCA) reflect those in individual extracranial tissues (lower lip and palate). Changes were evoked at the three sites simultaneously using a somato-parasympathetic reflex activation method in urethane-α-chloralose anesthetized, vago-sympathectomized cats. Somato-parasympathetic reflex activation was induced by electrical stimulation of the central cut end of the ipsilateral lingual nerve. The blood flow changes evoked in CCA, lower lip and palate changed in parallel when the stimulus to the blood vessels was changed (by changing the stimulus applied to the afferents or by blocking the efferent pathway). However, when drugs were given intravenously which would act directly on receptors in the blood vessels (including the endothelium) or alter the systemic blood pressure level, the evoked responses in CCA reacted in a quantitatively different manner from those evoked in lower lip and palate. These results suggest that evoked changes in CCA blood flow cannot be regarded as an accurate reflection of changes occurring simultaneously in individual extracranial tissues, at least when examining the effect of such drugs on parasympathetic mediated vasodilatation.

Prevention of postischemic hypoperfusion after canine cardiac arrest by nicardipine.

We studied the effect of nicardipine (NC) on canine cerebral blood flow (CBF) after cerebral ischemia induced by cardiac arrest. Cerebral ischemia was produced by 10 min of electrically mediated ventricular fibrillation. An iv injection of NC (10 μg/kg) bolus was followed by continuous NC infusion (0.33 μg/kg min) immediately after the circulation re-established itself. Local CBF was measured using the hydrogen-gas clearance method. The administration of NC maintained CBF at the pre-arrest level during postischemia, thus preventing the hypoperfusion observed in the control group with no NC. However, in the controls, CBF, reduced at 180 min after re-circulation, was not improved by NC infusion. Consequently, administering NC immediately after re-establishment of circulation may help maintain CBF during the postresuscitation period.

Inotropic Effects of Non-depolarizing Muscle Relaxants in Isolated Canine Heart Muscle

The inotropic effects of five non-depolarizing muscle relaxants were examined using an isolated canine heart muscle preparation. Except for fazadinium, all drugs were studied in their commercially available forms. d-Tubocurarine chloride (dTc) and metocurine iodide (MTC) produced dose-dependent decreases in isometric force (F) and the maximum velocity of force development (dF/dt) at concentrations greater than 22.5 × 10−3 g/L for dTc and greater than 15.0 × 10−3 g/L for MTC, concentrations which are 3 and 6 times higher than estimated clinical serum concentrations, respectively. Myocardial depression was about 3 times less with MTC than with dTc at equipotent concentrations. The degree of depression in F and dF/dt produced by MTC was almost identical with that produced by phenol, a preservative of MTC, indicating that MTC-induced myocardial depression may be due to the effect of the preservative. Pancuronium bromide (PC) produced a dose-dependent increase in F and dF/dt and decrease in the time to peak force. PC-induced changes in F, dF/dt, and time to peak force were inhibited by administration of propranolol 10−6 M. The results indicate that PC possesses a positive inotropic effect mediated by beta-adrenergic stimulation. Alcuronium chloride did not change F or dF/dt at concentrations from 5.0 × 10−3 to 60.0 × 10−3 g/L. Fazadinium bromide increased F and dF/dt slightly at a low concentration (1.875 × 10−2 g/L), but further increases in its concentration returned the values of F and dF/dt to control levels. F and dF/dt were not altered in vitro by concentrations of relaxants that would be anticipated in plasma in vivo in patients given clinically effective doses of 0.3 mg/kg of dTc, 0.1 mg/kg of MTC or PC, 0.2 mg/kg of alcuronium chloride, or 0.75 mg/kg of fazadinium bromide.

Antiarrhythmic effect of diltiazem during halothane anesthesia in dogs and in humans.

The antiarrhythmic effects of diltiazem (DL), a slow channel inhibitor, were evaluated in the presence of epineph-rine-halothane-induced arrhythmias in dogs, of premature ventricular contractions (PVCs) during anesthesia in patients (n=10), and of tachyarrhythmias with associated atrial fibrillation (AF) during anesthesia in patients (n=9). The arrhythmogenic dose of epinephrine CADE) during one MAC of halothane in dogs was increased from 1.13 ± 0.21 to 3.14 ± 0.89 μg·kg−l ± min−1 by the administration of 0.3 mg/kg of DL. This suggests that DL significantly increases the threshold for the induction of arrhythmias associated with epinephrine and halothane. In 10 patients, PVCs that appeared spontaneously during halothane anesthesia were eliminated by the intravenous administration of DL (0.1 mg/kg). With an additional nine patients who had had AF preoperatively and suffered tachyarrhythmias during anesthesia, the intraoperative intravenous administration of DL significantly decreased heart rate (to less than 100 beats/min) within 10–15 min. Diltiazem is an effective means for the treatment of PVCs and AF–mediated tachyarrhythmias during anesthesia. Because of the pharma-cologic properties of DL (e.g., depressing sinus and atrio-ventricular (AV) node function), DL should be used with caution in patients with a sick sinus syndrome or an AV block, or in the presence of β-adrenergic antagonists.

The effects of nicardipine given after 10-minutes complete global cerebral ischemia on neurologic recovery in dogs.

The effect of nicardipine (NC) on neurologic recovery from ischemic insult after 10-minutes complete global cerebral ischemia was evaluated in dogs by examination of neurologic recovery score (NRS: complete recovery=100, death = 0). Ischemia was achieved by occlusion of ascending aorta, and NC, 10 I1g·kg-1 in bolus followed by infusion of 0.33μg·kg−1·min−1 for 2 hours, was administered immediately after re-establishment of circulation. The mortality at 7th day was 2/9 in the control (C) and 1/9 in the NC group (ns). NRS on 2nd day was 52.3 ±6.8 in the C and 70.6±6.5 in the NC (P<0.05), but that on 7th day did not differ between the two groups. The numbers of dogs recovered to over 80 in NRS on the 2nd day was 1/9 in the C and 5/9 in the NC (P<0.05), but that on the 7th day increased to 3/9 in the C and remained at 5/9 in the NC (ns). These results suggest that NC accelerates the early neurologic recovery from ischemic damage, but influences little the final outcome.

Comparison of the placental transfer of halothane, enflurane,sevoflurane, and isoflurane during cesarean section

The concentrations of placental transfer of halothane (H), enflurane (E), sevoflurane (S), and isoflurane (I) were measured in 46 patients during cesarean section. The mean inhalation times of H (0.5%), E (1%), S (0.8%), and I (0.6%) were 13 min 27 s, 13 min 49s, 13 min 20s, and 8 min 8s, respectively. The mean concentrations in the maternal artery (MA) were 5.2mg·dl−1 in H, 12.3 mg·dl−1 in E, 5.2mg·dl−1 in S, and 2.4mg·dl−1 in I. The concentration ratio between the MA and the fetal umbilical vein (UV) was 0.44 for H, 0.49 for E, and 0.38 for S, and these ratios were not significantly different for these anesthetics. Although the concentration ratio for I (0.27) was significantly lower than those of the other three anesthetics, the UV:MA ratio was calculated to be 0.4 for an inhalation time 13 min. Our result, therefore, suggests that if the inhalation times were equal, the ratios of placental transfer would not differ among these four inhalational anesthetics. The Apgar scores in these four groups were not different from that in the group given only 66% nitrous oxide in oxygen as anesthetic (N2O group). The cardiovascular changes induced by skin incision were bigger in the N2O group than in the other groups. The use of a low concentration of H, E, S, or I is, therefore, suggested to be a useful and acceptable anesthetic method for cesarean section.

Effects of stellate ganglion block on cardiac coronary circulation

Since the stellate ganglion contains cardiac sympathetic nerves, stellate ganglion block (SGB) may influence cardiac and coronary hemodynamics. We investigated this influence of SGB by measuring the heart rate (HR), the left circumflex coronary artery blood flow (CBF), the maximum rate of increase of the left ventricular pressure (LV max dP/dt), the cardiac output (CO), the myocardial oxygen consumption (MVO2), and the myocardial oxygen extraction ratio (MOER) in nine dogs before and after performing SGB by means of injection of 2 ml 1% mepivacaine. Left SGB resulted in a decrease of 10% in CBF and a decrease of 15% in LV max dP/dt, but HR, CO, and MVO2 remained unchanged. On the other hand, right SGB resulted in a decrease of 30% in CBF and a decrease of 25% in LV max dP/dt, as well as a decrease of 20% in HR, 15% in CO, and 25% in MVO2. SGB on either side resulted in an increase in MOER that was slight but nonetheless significant (P<0.05) in that it suggested a relative deficit in CBF with respect to MVO2. Inhalation of 100% oxygen decreased MOER to the pre-SGB level in either side, thus improving the myocardial oxygen supply-demand relationship. This study suggests the possibility that SGB has deteriorative effects on the myocardial oxygen supply-demand relationship. Those effects were counteracted by the inhalation of 100% oxygen.