Masami Osawa

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.

Naloxone does not Antagonize the Anesthetic‐Induced Depression of Nociceptor‐Driven Spinal Cord Response in Spinal Cats

The effects of several anesthetics on spinal cord nociceptive neural mechanisms and their interactions with the opiate antagonist, naloxone, were studied in acute, spinal cord transected cats. Intra‐arterial injection of bradykinin was used as the noxious test stimulus. Spontaneous activity and the neural response induced by bradykinin were recorded by the multi‐unit activity technique in the lateral funiculus of the spinal cord. Naloxone, 0.1 or 2.0 mg/kg i.v., had little effect on the bradykinin‐induced response, but enhanced the spontaneous firing of the lateral funiculus significantly. Fentanyl, 30 μg/kg i.v., depressed both the bradykinin‐induced response and spontaneous firing. These effects of fentanyl were antagonized completely by naloxone, 0.1 mg/kg i.v. Nitrous oxide, thiamylal, halothane and ether depressed the bradykinin‐induced response considerably, but it was not antagonized by naloxone, 0.1–2.0 mg/kg i.v. Enflurane had little effect on the bradykinin‐induced response. The effects of these anesthetics on spontaneous firing were divergent: nitrous oxide enhanced it while other drugs depressed it, to various degrees. All these data suggest that the neural and/or neurochemical mechanisms of anesthetic‐induced analgesia differ from mechanisms related to opioids.

The divergent actions of volatile anaesthetics on background neuronal activity and reactive capability in the central nervous system in cats

The effects of halothane, isoflurane, and enflurane on background neuronal activity and reactive capability in the central nervous system were studied in cats. The background neuronal activity was assessed by midbrain reticular cell firing, which was measured by the method of multiunit activity, and the EEG in the cortex, amygdala, and hippocampus. The reactive capability was assessed by evoked responses in the visual neuronal pathway. All anaesthetics studied suppressed reticular cell firing in a dosedependent manner, and the suppression by halothane (43.8 ± 10.3% of control, mean ± SD) was less than isoflurane (66.5 ± 5.8%, P < 0.01) and enflurane (73.1 ± 8.8%, P < 0.05) at 1 MAC. Spontaneous EEG spikes developed at 4.8% isoflurane and 3.6% enflurane anaesthesia. Phasic activation of reticular cell firing was associated with EEG spikes during isoflurane and enflurane anaesthesia, and the activation during enflurane anaesthesia was greater than during isoflurane anaesthesia (P < 0.01). Photic stimulation provoked EEG spikes and repetitive stimulation induced seizure activity only at 3.6% enflurane anaesthesia. Halothane and isoflurane suppressed stimulation induced responses in the visual neuronal pathway. The amplitudes of N1 in visual cortical evoked responses induced by photic stimulation were suppressed to 70.1 ± 24.5% of control at 2.4% halothane and 39.3 ± 27.3% at 4.8% isoflurane. Enflurane, at 3.6%, augmented the evoked response induced by photic stimulation (398.4 ± 83.0% of control in the amplitude of N1). These results indicate that all the agents studied had suppressive actions on background neuronal activity in the order halothane < isoflurane = enflurane. The effects on reactive capability were divergent among agents, e.g., enflurane enhanced, halothane suppressed, and the actions of isoflurane were intermediate. We conclude that the anaesthetic effects on background activity and on reactive capability are divergent and that suppression of reactive capability is a factor in determining the ease of clinical application of the anaesthetics.RésuméL’étude porte sur les effets de l’halothane, l’isoflurane et de l’enflurane sur l’activité neuronale de fond et la capacité réactive du système nerveux central chez le chat. L’activité neuronale de fond est mesurée par la décharge des cellules réticulaires mésencéphaliques, ellemême par la méthode de l’activité multiunitaire et l’EEG cortical, amygdalien et hippocampique. La capacité réactive est évaluée les réponses évoquées sur la voie de conduction visuelle neuronale. Tous les anesthésiques suppriment la décharge de la cellule réticulaire proportionnellement à la concentration. La suppression par l’halothane (43,8 ± 10,3% du contrôle, moyenne ± E.T.) a été moindre que par l’isoflurane (66,5 ± 5,8%, P < 0,01) et l’enflurane (73,1 ± 8,8%, P < 0,01) à 1 MAC. Des pointes spontanées sont apparues avec l’anesthésie à l’isoflurane 4,8% et à l’enflurane 3,6%. L’activation phasique de la décharge de la cellule réticulaire est associée à des pointes EEG pendant l’anesthésie à l’isoflurane et à l’enflurane, et l’activation pendant l’enflurane est plus grande que pendant l’isoflurane (P < 0,01). La stimulation photique entraîne des pointes EEG et une stimulation répétée provoque de l’activité épileptique à seulement 3,6% d’enflurane. L’halothane et l’isoflurane suppriment les réponses évoquées induites par stimulation dans la voie de transmission neuronale visuelle. Les amplitudes de N1 pour les réponses évoquées induites au cortex visuel par stimulation photique sont supprimées à 70,1 ± 24,5% du contrôle avec halothane 2,4% et à 39,3 ± 27,3% avec l’isoflurane 4,8%. L’enflurane à 3,6% augmente la réponse évoquée induite par stimulation photique (398,4 ± 83,0 du contrôle dans l’amplitude de N1). Ces résultats indiquent que tous les agents étudiés ont une action suppressive sur l’activité neuronale de fond dans l’ordre halothane < isoflurane = halothane. Les effets sur la capacité réactive divergent parmi les agents, c’estàdire que l’enflurane l’augmente, l’halothane la supprime et l’isoflurane occupe une place intermédiare. Nous en concluons que les effets anesthésiques sur l’activité de fond et la capacité réactive divergent et que la suppression de la capacité réactive est un facteur déterminant sur la facilité de l’utilisation des anesthésiques en clinique.

Effects of different speeds of induction with sevoflurane on the EEG in man.

The effects of two kinds of induction speed of sevoflurane anesthesia on the EEG pattern were compared in the same individual using medical student volunteers: a first exposure of 4% was given, followed after full recovery, by incremental doses of 1, 2 and 4% successively, each being administered for 10 min. The arterial blood level of the anesthetic was measured using gaschrornatograph. The changes of EEG pattern during fast induction with 4% were not represented by the abbreviation of those observed during the slow induction with the incremental doses. The administration of 4% induced a sudden appearance of high voltage, rhythmic slow waves of 2–3 Hz at 1–3 min when the arterial blood anesthetic level increased maximally, which was then followed by a pattern of faster activities of 10—14 Hz mixed with 5–8 Hz slow waves. In contrast, the administration of incremental doses induced an increase in frequency and amplitude of EEG activities in the light plane, followed by their decreases in deeper planes. The final EEG patterns were identical for both these methods of induction. These findings confirmed our previous hypothesis that not only the arterial blood level of anesthetics but the rate of its increase are important factors determining the EEG pattern of anesthesia.

Boron neutron capture therapy : Preliminary study of BNCT with sodium borocaptate (Na2B12H11SH) on glioblastoma

To plan the optimal BNCT using BSH for glioblastoma patients, the10B concentration in tumor and blood was investigated in 11newly diagnosed glioblastoma patients. All patients received 20 mg BSH/kgbody weight 2.5–16 hrs prior to tumor removal. The quantitativedistribution of 10B was determined by prompt gamma rayspectrometry and/or α-track autoradiography. 10Bdistribution in tumors was heterogeneous, ± 25% of scatteringat the microscopic level, and the distribution was also heterogeneous at thetissue level. 10B concentration in blood decreased inbi-exponential decay as a function of the time after the end of theadministration. The T/B ratio showed non-exponential increase with largevariation. The maximum T/B ratio would be around 1. The tumor/normal brain(T/N) ratio of 10B concentration was 11.0 ± 3.2. The10B content in normal brain is originated in vascular10B in parenchyma, since the 10B content innormal brain to blood (N/B ratio) being compatible with the blood content inparenchyma. These values allow for BNCT, using thermal neutrons, on braintumors located less than approximately 3.3 cm in depth from the brainsurface of neutron incidence, providing that the dose on the normalendothelium is controlled to less than the tolerance limit. In ourpreliminary study of BNCT, a 31% 3-year survival was achieved overall for 16 glioblastoma patients and a 50% 2-year survival wasachieved on 8 glioblastoma patients in our recent dose escalation studybased on these data.

The bilateral effect of stellate ganglion block on the facial skin blood flow.

Background and Objectives It is our hypothesis that stellate ganglion block increases regional blood flow on the blocked side, but does not change cardiac output, suggesting that the corresponding regional blood flow on the contralateral side may decrease, which would be disadvantageous for patients with bilateral sympatheticallymaintained pain. The aim of this study is to examine the effect of stellate ganglion block on facial skin blood flow. Methods Skin blood flow on the right and left forehead was measured by a laser blood flowmeter before stellate ganglion block and 15 minutes after the block. The block was performed for 8 outpatients with acute or chronic pain in the head or neck using a 24-gauge needle, 5 mL of 1% mepivacaine, and a paratracheal approach at the C6 transverse process. Time control without the block was obtained with 9 healthy volunteers. Results All the patients developed the Horners syndrome on the blocked side, but not on the contralateral side. The facial skin blood flow increased from 7.5 ± 1.1 mL/min/100 g to 14.5 ± 1.4 mL/min/100 g on the blocked side (P < .01) and from 8.8 ± 1.2 mL/min/100 g to 12.8 ± 1.7 mL/min/100 g on the contralateral side (P < .05). The healthy volunteers without the block showed no significant change (from 10.1 ± 0.8 mL/min/100 g to 10.3 ± 0.7 mL/min/100 g). Conclusions Our study suggests that stellate ganglion block may increase the contralateral regional skin blood flow.

Acute Tolerance to the Analgesic Action of Nitrous Oxide Does Not Develop in Rats

The time course of nitrous oxide analgesia was studied in rats with a behavioral criterion, the tail-flick test to radiant heat. All rats were placed individually in a Plexiglas tube and exposed to either nitrous oxide, 75% in oxygen, or room air (control) for 2 hr. Analgesic potency was evaluated by prolongation of the time required to induce tail-flick. Although individual animals showed variability in the tail-flick time during exposure to nitrous oxide, no animal showed a tendency toward the development of tolerance, and a statistically significant sustained prolongation of tail-flick time was produced.

Compound A concentration is decreased by cooling anaesthetic circuit during low-flow sevoflurane anaesthesia

PurposeIn the presence of carbon dioxide absorbents, sevoflurane is degraded to CF2=C(CF3)OCH2F, an olefin compound A. There remains some concern of the hepatic and renal toxicity that compound A poses when using low-flow anaesthetic techniques. We investigated a device to decrease the concentration of compound A products by decreasing the temperature of exhaled air and soda lime in semi-closed low-flow anaesthesia technique in surgical patients.MethodsTen patients, ASA 1 or 2, were studied. Five received anaesthesia using a cooling circuit, that consisting of an anaesthetic circuit and an intercooler device interposed in the expiratory tube. The intercooler was dipped in an iced water tank. Anaesthesia was given through this circuit from induction to emergence. Another five patients received anaesthesia without cooling. Anaesthesia was maintained with sevoflurane and O2 50%/N2O during four to six hours of operation. A fixed concentration of sevoflurane 2% at a total flow of 1 L·min−1 was administered. Gas samples were taken every hour and compound A was quantitated by gas chromatography. The temperatures of canister, circuit and body were measured every hour.ResultsThe device effectively lowered the temperatures [24 ± 3.4 to 5 ± 1,3°C] and the concentrations of compound A [27.1 ± 3.8 ppm to 16.3 ± 2.08 ppm,P < 0.05] in the circuit. The body temperatures were not lowered.ConclusionCompound A concentrations were reduced by cooling the anaesthetic circuit in clinical settings.ObjectifEn présence d’absorbants du gaz carbonique, le sévoflurane se dégrade en CF2=C(CF3)OCH2F, un composé oléfine A. Ce qui nous fait toujours craindre une certaine toxicité hépatique et rénale possible lors de l’emploi de techniques anesthésiques à débit lent. Nous avons fait l’essai d’un dispositif qui diminuerait la concentration du composé A en abaissant la température de l’air expiré et de la chaux sodée dans un circuit anesthésique semi-fermé à débit lent.MéthodeDix patients, ASA I ou II, ont été étudiés. Cinq d’entre eux ont reçu une anesthésie avec l’emploi d’un appareil refroidisseur interposé sur le tube d’expiration du circuit d’anesthésie. Le refroidisseur était plongé dans un réservoir d’eau glacée. L’anesthésie a été administrée par ce circuit depuis l’induction jusqu’au réveil. Les cinq autres patients ont reçu une anesthésie sans refroidissement. Lanesthésie a été maintenue avec du sévoflurane et un mélange d’O2 et de N2O à 50 % pendant les quatre à six heures de l’intervention. Une concentration fixe de 2 % de sévoflurane à un débit total de 1 L·min−1 a été administrée. Des échantillons de sang ont été prélevés à chaque heure et le composé A a été mesuré par Chromatographie en phase gazeuse. Les températures de la chaux, du circuit et du corps ont été mesurées à chaque heure.RésultatsLe dispositif a efficacement réduit les températures [de 24 ± 3,4 à 5 ± 1,3°C] et les concentrations du composé A [de 27,1 ± 3,8 ppm à 16,3 ± 2,08 ppm,P < 0,05] dans le circuit. La température du corps n’a pas baissé.ConclusionLes concentrations de composé A ont été réduites par le refroidissement du circuit anesthésique en pratique clinique.

Compound A concentration and the temperature of CO2 absorbents during low-flow sevoflurane anesthesia in surgical patients.

Sevoflurane, a new inhalational anesthetic, is metabolically broken down into several decomposition products in the presence of CO2 absorbents. One of the products, CF2=C (CF3) OCH2F (compound A), which appears to be the most toxic, was quantitated in 20 surgical patients subjected to more than 3 h of anesthesia using a low-flow anesthesia circuit. To minimize the variables in the reaction velocity between sevoflurane and the CO2 absorbents, we maintained the sevoflurane concentration at 2%. Wakolime-A, one type of soda lime, resulted in the highest increase in compound A concentration. The peak concentration was 27.1±3.1 ppm, less than one-tenth of the LC50 (50% lethal concentration) of compound A, which was previously reported as 420 or 400 ppm in rats. We also measured the temperature in CO2 absorbents, which had been reported to influence compound A production. The elevation in the temperature was 27.9±1.3°C in Wakolime-A, 29.4±8.4°C in Baralyme, and 31.0±5.0°C in Sodasorb II. Further studies are needed to assess the safety and efficacy of sevoflurane.

An Adverse Effect of Carboxymethylcellulose in Lidocaine Jelly

To the Editor:—Lidocaine jelly is widely used as a local anesthetic and a lubricant. Lidocaine jelly is composed of lidocaine, preservatives (methyl paraben and propyl paraben) and a suspending agent (carboxymethylcellulose). Systemic adverse effects of lidocaine jelly usually are caused by an overdose or an allergic reaction to lidocaine or its preservatives (parabens). An allergic reaction to carboxymethylcellulose in lidocaine jelly has not been known, although carboxymethylcellulose can cause anaphylaxis in cattle. However, recently, it has been reported that carboxymethylcellulose in triamcinolone acetonide and barium sulfate induced anaphylaxis in humans. We report a case in which an allergic reaction to carboxymethylcellulose in lidocaine jelly may have been involved. A 69-yr-old woman was seen in our pain clinic department with a history of three gastroscopic examinations using lidocaine jelly. These were followed each time by hyposthenia of the upper and lower limbs lasting several hours. The symptom suggests that overdose of lidocaine jelly may have been possible. Unfortunately, the concentration of lidocaine in the blood was not evaluated during the episodes. However, the recurrent episodes suggest that an allergic reaction to lidocaine jelly may have contributed, although the symptom is atypical of an allergic reaction. Therefore, carried out allergy tests with the components of lidocaine jelly. Before the allergy tests, the patient provided written informed consent. Results of intradermal tests on the forearm with lidocaine, methyl paraben, propyl paraben, and carboxymethylcellulose were negative. Results of nasal provocation tests with lidocaine, methyl paraben, and propyl paraben were also negative, but tests with carboxymethylcellulose induced ipsilateral nasal congestion and dysthesia of the tongue and the ipsilateral temporal region within 30 min. The results of the two in vivo allergy tests with carboxymethylcellulose were inconsistent. The potential explanation is that the nasal mucosa may be more sensitive than the skin of the forearm because the nasal mucosa is rich in blood flow and is next to the pharynx, which was exposed to lidocaine jelly during the gastroscopic evaluations. To support the results of the nasal provocation test, we carried out an in vitro allergy test, the drug-induced lymphocyte stimulation test (DLST), which has been reported to be useful for the diagnosis of a drug allergy. Results of the drug-induced lymphocyte stimulation test with methyl paraben and propyl paraben were negative, but results of tests with carboxymethylcellulose were positive (fig. 1). The nasal provocation test and the drug-induced lymphocyte stimulation test showed that the patient has hypersensitivity to carboxymethylcellulose. We have no direct evidence supporting that hypersensitivity to carboxymethylcellulose can induce hyposthenia of upper and lower limbs. However, the three recurrent episodes and the results of allergy tests suggest that an allergic reaction to carboxymethylcellulose in lidocaine jelly may have contributed to this case.