Masahiro Murakawa

Isoflurane and Sevoflurane Augment Norepinephrine Responses to Surgical Noxious Stimulation in Humans

Background Suppression of hypertensive response to noxious stimulation by volatile anesthetics may be a result of suppression of the stimulation‐induced norepinephrine response or that of the cardiovascular response to catecholamines, or both. The suppression of the cardiovascular response is established, but that of norepinephrine response has not been confirmed. The authors hypothesized that the suppression of cardiovascular response but not that of norepinephrine response plays a major role in suppressing the noxious stimulation‐induced hypertensive response by volatile anesthetics. Methods Forty healthy donors for living‐related liver transplantation were allocated to four groups: receiving 1.2% (end‐tidal) isoflurane in oxygen and nitrogen, 2.0% isoflurane, 1.7% sevoflurane, or 2.8% sevoflurane. The intraoperative plasma norepinephrine and epinephrine concentrations, arterial blood pressure and pulse rate were measured for the first 15 min of surgery and were compared with the preoperative values. Results Norepinephrine and epinephrine concentrations both increased intraoperatively in all four groups. The values of maximum increase the area under the concentration‐versus‐time curve of norepinephrine were greater in the high dose groups of both anesthetics. The intraoperative blood pressure did not differ by different doses of anesthetics, and the degree of increase of blood pressure was not proportional to the plasma catecholamine concentrations. Conclusion The effects of isoflurane and sevoflurane on the surgical noxious stimulation‐induced norepinephrine response were inversely proportional to the dose. The suppression of noxious stimulation‐induced blood pressure response by anesthetics that were studied may be the result of suppression of the responses of vascular smooth muscle and myocardium to catecholamines.

Effects of sevoflurane on central nervous system electrical activity in cats.

We analyzed the effect of a new volatile anesthetic, sevoflurane (2%-5% in oxygen) on the electroencephalogram (EEG) of the neocortex, amygdala, and hippocampus, cortical somatosensory evoked potential (SEP), and brainstem reticular multiunit activity (R-MUA) in cats. Sevoflurane suppressed the background activity of the neocortex more than the amygdala and hippocampus. With increasing concentration of sevoflurane, the cortical EEG progressed from high-amplitude slow waves to a suppression-burst pattern, which was followed by an isoelectric pattern and then spikes with isoelectricity. The amplitude of the SEP was augmented and the R-MUA was suppressed by sevoflurane in a dose-related manner. Repetitive peripheral electrical stimulation induced generalized seizures at 5% sevoflurane in 2 of 13 cats. These results suggest that sevoflurane suppresses the background central nervous system electrical activities in a dose-related manner, leaving the reactive capabilities facilitated at deep anesthesia.

Nitric Oxide Synthase Inhibitor Does Not Reduce Minimum Alveolar Anesthetic Concentration of Halothane in Rats

Nitric oxide (NO) synthase inhibitor (Nω-nitro-L-arginine methyl ester [L-NAME]) has been reported to reduce minimum alveolar anesthetic concentration (MAC) of halothane when administered intravenously (IV) and to reduce thermal hyperalgesia, or produce antinociception in the formalin test, when administered intracerebroventricularly (ICV) or intrathecally (IT). This study attempts to identify the site(s) in the central nervous system (CNS) where L-NAME acts to reduce the halothane MAC. For this purpose, we examined the effects of IV, ICV, and IT administration of L-NAME on the halothane MAC in rats. In contrast to an earlier study, we did not observe any decrease in the halothane MAC after IV (10–30 mg/kg) administration of L-NAME. ICV (100 pg) and IT (100 pg and 1 mg) administration of L-NAME also did not alter the halothane MAC. These findings indicate that the L-arginine-NO pathway is not involved in the mechanism of action of halothane to suppress mechanical nociceptive response or in the nociceptive neural mechanism of mechanical stimulation.

Activation of the cortical and medullary dopaminergic systems by nitrous oxide in rats: a possible neurochemical basis for psychotropic effects and postanesthetic nausea and vomiting.

To provide a neurochemical basis for the central nervous system actions of nitrous oxide, the changes of brain dopamine (DA), serotonin (5‐HT), norepinephrine (NE), and metabolites of DA and 5‐HT were studied in rats. Thirty male Wistar rats were assigned to one of five groups according to the type of gas and the duration of gas exposure. The rats in one group, which served as control, were exposed to air for 30 min, and the rats in four other groups were exposed to 75% nitrous oxide in oxygen for 0.5, 1, 2, and 4 h, respectively. Animals were killed with microwave irradiation, and the brains were divided into seven sections: the cerebral cortex, cerebellum, striatum, hippocampus, midbrain‐thalamus, hypothalamus, and medullapons. The contents of NE, DA, 3,4‐dihydroxyphenylalanine (DOPAC), homovanillic acid (HVA), 5‐HT, and 5‐hydroxyindoleacetic acid (5‐HIAA) in each discrete area were measured with high‐performance liquid chromatography. Nitrous oxide had no significant effect on the contents of NE, 5‐HT, nor 5‐HIAA, but decreased that of DA in the striatum and midbrainthalamus after 4 h of exposure (P < 0.05). Levels of DOPAC, but not DA, in the cerebral cortex and medulla‐pons were increased significantly at exposures up to 2 h (P < 0.05), but were not significant from control levels after a 4‐h exposure. Increased levels of DOPAC indicate that nitrous oxide increases dopaminergic neuronal activities in the mesocortical projection and the medullary network. The euphoric properties of nitrous oxide may be a reflection of the activation of mesocortical dopaminergic projection, whereas the increased incidence of postexposure emesis may be a reflection of the activation of the medullary dopaminergic system. The attenuation after 4 h of exposure may correlate with development of acute tolerance to nitrous oxide actions.

Chronic Treatment with Nitric Oxide Synthase (NOS) Inhibitor Profoundly Reduces Cerebellar NOS Activity and Cyclic Guanosine Monophosphate but Does Not Modify Minimum Alveolar Anesthetic Concentration

We previously found that acute administration of a nitric oxide synthase (NOS) inhibitor (Nomega-nitro-L-arginine methyl ester [L-NAME]) does not reduce the minimum alveolar anesthetic concentration (MAC) of halothane in rats. However, a recent study has suggested that brain NOS activity could not be inhibited by more than approximate equals 50% by acute administration of L-NAME. To investigate the effect of marked inhibition of NOS activity on the MAC of halothane, we measured cerebellar NOS activity, cerebellar cyclic guanosine monophosphate (cGMP) levels, and halothane MAC in rats chronically treated with L-NAME and compared the results to those of the saline-treated control group. Although the cerebellar NOS activity and cGMP levels were significantly decreased (14% and 2.7% of control, respectively) by L-NAME, the value of the halothane MAC was not significantly affected. These results suggest that the anesthetic action of halothane, as measured by its MAC in rats, is not related to NOS activity or cGMP levels in the brain. (Anesth Analg 1995;81:862-5)

The effect of xenon on spinal dorsal horn neurons : A comparison with nitrous oxide

We compared the effects of xenon (Xe) on the spinal cord dorsal horn neurons with those of nitrous oxide (N2 O) in cats anesthetized with chrolarose and urethane.We assessed the potency of both anesthetics by the inhibition of wide dynamic range neuron responses evoked by cutaneous noxious (pinch) stimulation to a hindpaw. During 70% Xe inhalation, the responses of 7 of 11 neurons to pinch stimulation were suppressed. N2 O, 70%, suppressed it in 8 of 11 neurons. The potency of Xe and N2 O was compared in six neurons that were suppressed by both anesthetics. After 20 min of Xe inhalation, the response to pinch was suppressed to 49.5% +/- 8.2% (mean +/- SE), while N2 O, 70% in oxygen, suppressed it to 45.9% +/- 7.9%. The difference between N2 O and Xe was not significant. We conclude that Xe and N2 O suppress the spinal cord dorsal horn neurons to a similar degree. (Anesth Analg 1997;84:1372-6)

Halothane and Diazepam Inhibit Ketamine-induced c-fos Expression in the Rat Cingulate Cortex

Background Ketamine, a noncompetitive N‐methyl‐D‐aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N‐methyl‐D‐aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c‐fos protein (c‐Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established. Methods The effects of diazepam and halothane on c‐Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c‐Fos expression was detected using immunohistochemical methods. Results Ketamine induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices in a dose‐dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose‐dependent manner, leaving the thalamus relatively unaffected. Conclusion Halothane and diazepam inhibited ketamine‐induced c‐Fos expression in the cingulate and retrosplenial cortices, leaving the thalamus relatively unaffected.

Effects of isoflurane on in vivo release of acetylcholine in the rat cerebral cortex and striatum.

Background: Acetylcholine (ACh) is one of the major excitatory neurotransmitters in the central nervous system, and changes in neural activity induced by anesthesia alter the release of ACh. However, the effects of isoflurane, one of the most widely used volatile anesthetics, on ACh release are not known. The present study attempts to clarify the dose–effect relationship of isoflurane on the in vivo release of ACh in rat brains.

Perioperative plasma concentrations of endothelin and natriuretic peptides in children undergoing living-related liver transplantation

To investigate the clinical significance of endothelin (ET), natriuretic peptides, and the renin-angiotensin-aldosterone system in pediatric liver transplantation, we measured plasma levels of ET, atrial and brain natriuretic peptides (ANP, BNP), aldosterone, and plasma renin activity in 18 patients (aged 0.5-12 yr; median 1 yr) undergoing living-related liver transplantation due to congenital biliary atresia and severe liver cirrhosis. Before transplantation, the plasma ET level (28.9 +/- 2.5 [mean +/- SEM] pg/mL) was increased compared with that of healthy children (10-18 pg/mL), but decreased during the anhepatic phase (22.5 +/- 1.6 pg/mL). It increased again after reperfusion and remained at high levels in the early postoperative period (postoperative day 3, 27.8 +/- 3.0 pg/mL). Plasma levels of ANP and BNP and aldosterone and plasma renin activity were also high before surgery. Plasma ANP and BNP did not change significantly during surgery. After transplantation, plasma BNP significantly increased, and plasma ANP tended to increase. Plasma aldosterone increased markedly during the anhepatic phase, although plasma renin activity decreased. After transplantation, plasma aldosterone and plasma renin activity both decreased to within normal levels. Mean arterial blood pressure increased gradually after reperfusion and surgery (postoperative day 3, 35.7 +/- 5.2% increase). No substantial differences in these variables occurred between the younger (<or=to1.0 yr, n = 9) and older patients (>1.0 yr, n = 9). These results suggest that ET production in the cirrhotic liver is augmented and ET, natriuretic peptides, and the renin-angiotensin-aldosterone system all play some role in the circulatory regulation during perioperative periods of pediatric liver transplantation. (Anesth Analg 1996;82:235-40)

Factors associated with postoperative respiratory complications in pediatric liver transplantation from living-related donors

Factors associated with respiratory complications (RCs) after pediatric living-related liver transplantation were statistically analyzed in the first 100 cases where surgery was performed at Kyoto University. The overall incidence of postoperative RCs was 45%, including atelectasis (23%), pleural effusion (23%), and pneumonia (12%). Univariate and multivariate analyses were performed with regard to the association between postoperative RCs and 13 pre- and intraoperative variables that were considered to represent the preoperative medical status of the patients and the severity of operative insult. The following four independent variables were found to have prognostic significance with regard to the postoperative RCs: (1) history of preoperative RCs, (2) height < or = -2 SD from the mean for the age, (3) United Network for Organ Sharing score = 1, and (4) intraoperative blood loss > or = 20% of body weight. Postoperative death was highly affected by postoperative RCs: 8 of 11 deaths during the study period were directly or closely related to postoperative RCs. We conclude that postoperative RCs are major contributing factors to operative morbidity and mortality in pediatric living-related liver transplantation, which may possibly be reduced by intensive respiratory management of patients with the above risk factors for postoperative RCs.