Ichiro Hase

Propofol decreases the clearance of midazolam by inhibiting CYP3A4: an in vivo and in vitro study

To examine the effect of propofol on the pharmacokinetics of midazolam in vivo and to elucidate the mechanism of the pharmacokinetic changes of midazolam by propofol with the use of human liver microsomes and recombinant CYP3A4.

The short-acting beta1-adrenoceptor antagonists esmolol and landiolol suppress the bispectral index response to tracheal intubation during sevoflurane anesthesia.

In this randomized, double-blind, controlled study, we tested the hypothesis that the short-acting &bgr;1-adrenoceptor antagonists esmolol and landiolol suppress hemodynamic changes and bispectral index (BIS) increases, both of which are induced by tracheal intubation under general anesthesia with sevoflurane alone. Forty-five patients were randomly assigned to the control, esmolol, and landiolol groups (n = 15 each). Anesthesia was induced with sevoflurane in oxygen, with an end-tidal concentration maintained at 1 minimum alveolar anesthetic concentration (MAC). Infusion of saline (control group), esmolol (bolus of 1 mg/kg and then 0.25 mg · kg−1 · min−1; esmolol group), or landiolol (bolus of 0.125 mg/kg and then 0.04 mg · kg−1 · min−1; landiolol group) was started 5 min after the induction of anesthesia and was continued throughout the study. Tracheal intubation was performed 12 min after anesthesia induction. There were no differences in overall changes of mean arterial blood pressure among the three groups, whereas, at 1–5 min after tracheal intubation, heart rate increased in all groups but was significantly slower in the esmolol and landiolol groups than in the control group (P < 0.05). BIS was between 96 and 98 for all patients at baseline and decreased during the induction of anesthesia. There were no differences in BIS among the three groups before laryngoscopy (39 ± 5, 39 ± 5, and 38 ± 4 in the control, esmolol, and landiolol groups, respectively). BIS increased significantly in the control group (54 ± 10; P < 0.05) 1 min after intubation, whereas it remained unchanged in the esmolol and landiolol groups (45 ± 10 and 41 ± 6, respectively). In conclusion, the increase in both heart rate and BIS after tracheal intubation under 1 MAC sevoflurane anesthesia was suppressed by the concomitant administration of either esmolol or landiolol.

Propranolol increases the threshold for lidocaine-induced convulsions in awake rats: a direct effect on the brain.

BACKGROUND:Propranolol is a β-adrenoceptor antagonist used clinically. Local anesthetics are used for controlling pain, whereas propranolol is concomitantly given to treat hypertension and tachycardia. However, there are few studies examining the effects of propranolol on the toxicity of local anesthetics. We investigated the effect of propranolol on lidocaine-induced convulsions in awake, spontaneously breathing rats. METHODS:Male Sprague-Dawley rats were randomly divided into six groups (n = 8, each group). Rats were pretreated with intracerebroventricular saline (cerebroventricle- control: CV-C group), 10 or 30 &mgr;g/kg of (S)-(−)-propranolol (propranolol) (cerebroventricle-small dose: CV-S and cerebroventricle-large dose: CV-L groups, respectively) or IV saline (IV-control: IV-C group), 1 or 3 mg/kg of propranolol (IV-small dose: IV-S and IV-large dose: IV-L groups, respectively). Three minutes later, lidocaine was administered IV at 4 mg · kg−1 · min−1 until tonic-clonic convulsions occurred. RESULTS:The convulsive dose of lidocaine in the CV-L group was significantly larger than that in the CV-C group (30.6 ± 5.1 vs 23.5 ± 2.2 mg/kg, respectively, P = 0.008). Plasma concentrations of total and protein-unbound lidocaine, concentrations of lidocaine in the brain at the onset of convulsions were also significantly higher in the CV-L group than those in the CV-C group (36.1 ± 4.8 vs 26.0 ± 3.8 &mgr;g/mL, 22.5 ± 3.5 vs 13.7 ± 2.6 &mgr;g/mL, 82.7 ± 7.1 vs 57.3 ± 5.7 &mgr;g/g, P < 0.001 for all). The convulsive dose, plasma concentrations of total and protein-unbound lidocaine, and brain lidocaine in the IV-L group were also significantly larger than those in IV-C group and comparable with those in the CV-L group. The plasma concentration of propranolol before starting an infusion of lidocaine in the IV-L group was approximately 60-fold higher than that in the CV-L group (554.7 ± 104.6 and 9.3 ± 6.7 ng/mL, respectively). CONCLUSIONS:Propranolol increased the threshold for lidocaine-induced convulsions by directly acting on the brain.

Nitrous oxide induces paradoxical electroencephalographic changes after tracheal intubation during isoflurane and sevoflurane anesthesia

In this randomized, double-blind, controlled study, we tested the hypothesis that nitrous oxide (N2O) affects bispectral index (BIS) and 95% spectral edge frequency (SEF95) in response to tracheal intubation during anesthesia with isoflurane and sevoflurane. In protocol 1, we randomly allocated 90 ASA physical status I patients to 6 groups (n = 15 each). Anesthesia was induced with isoflurane or sevoflurane with 0%, 33%, or 66% N2O. The concentration of isoflurane and sevoflurane was gradually increased and end-tidal concentrations were maintained at 1.1% and 1.7%, respectively. Tracheal intubation was performed 12 min after induction of anesthesia. BIS was significantly increased 1 min after tracheal intubation compared before laryngoscopy in patients receiving only isoflurane or sevoflurane (P = 0.001 and 0.007, respectively). In patients receiving 66% N2O-isoflurane or 66% N2O-sevoflurane, both BIS and SEF95 were significantly decreased after tracheal intubation and significantly lower than in those patients receiving only isoflurane or sevoflurane, respectively (P < 0.01 for both). In protocol 2, 3 &mgr;g/kg of IV fentanyl completely abolished the decrease of BIS and SEF95 after tracheal intubation during anesthesia with 66% N2O-isoflurane and 66% N2O-sevoflurane (n = 10). We conclude that 66% N2O induced a paradoxical decrease of BIS in response to tracheal intubation during anesthesia with isoflurane and sevoflurane.

Pharmacokinetics of Lidocaine, Bupivacaine, and Levobupivacaine in Plasma and Brain in Awake Rats

Background:We have compared the pharmacokinetics and brain distribution of lidocaine, racemic bupivacaine (bupivacaine), and levobupivacaine in awake, spontaneously breathing rats. Methods:Lidocaine (0.5 mg · kg−1 · min−1), bupivacaine (0.1 mg · kg−1 · min−1), or levobupivacaine (0.1 mg · kg−1 · min−1) was continuously administered to rats for 2 h (n = 12, each anesthetic). Blood samples and cerebral dialysate were collected during infusion and for 2 h after termination of infusion. Concentrations of anesthetics in the cerebral extracellular fluid were measured by microdialysis using the retrodialysis calibration method. Tissue-to-plasma partition coefficients calculated from the total (protein-bound and unbound) and unbound concentrations in plasma and brain as well as pharmacokinetic parameters in plasma and cerebral extracellular fluid were compared among the three anesthetics. Results:There were no differences in plasma total or unbound concentrations between bupivacaine and levobupivacaine. Concentrations of bupivacaine in the cerebral extracellular fluid were significantly higher than levobupivacaine (P < 0.001). Despite no differences in the ratio of total brain concentration to total plasma concentration among the three anesthetics, the ratio of cerebral extracellular fluid concentration to plasma unbound fraction of bupivacaine was significantly higher than lidocaine and levobupivacaine (0.58 ± 0.09, 0.47 ± 0.18, and 0.40 ± 0.09, respectively; P = 0.03 and 0.003, respectively). Conclusions:Although the ratio of total brain concentration to total plasma concentrations of lidocaine, bupivacaine, and levobupivacaine was similar, concentration ratio of bupivacaine in the cerebral extracellular fluid to plasma unbound fraction was significantly higher than lidocaine and levobupivacaine.

The use of intravenous nitroglycerin in a case of spasm of the sphincter of Oddi during laparoscopic cholecystectomy.

Spasm of the sphincter of Oddi still occurs during cholecystectomy. Some reports indicate that the spasm, induced by morphine, can be reversed by injection of naloxone, nalbuphine, and glucagon. Others maintain that nitroglycerin or nifedipine can relax the sphincter of Oddi muscle. We recently encountered spasm of the sphincter of Oddi during a laparoscopic cholecystectomy and treated it successfully with intravenous nitroglycerin.

Area under the plasma concentration-time curve of inorganic fluoride following sevoflurane anesthesia correlates with CYP2E1 mRNA level in mononuclear cells

Background Because the amount of inorganic fluoride released after anesthesia with sevoflurane depends on the dose of administered sevoflurane and cytochrome P450 (CYP) 2E1 activity in the liver, a reliable and noninvasive probe for CYP2E1 would be useful for predicting plasma inorganic fluoride levels after anesthesia. In this study, the authors evaluated the relation between plasma concentration of inorganic fluoride after sevoflurane anesthesia and CYP2E1 mRNA level in mononuclear cells. Methods Twenty patients (American Society of Anesthesiologists physical status I), aged 20–68 yr undergoing body surface surgery with general anesthesia with sevoflurane were enrolled. One milliliter of blood was obtained before administration of sevoflurane and mononuclear cells were obtained. Levels of CYP2E1 mRNA in mononuclear cells were measured by competitive reverse transcription polymerase chain reaction with a specific primer and competitor for CYP2E1 mRNA. Results There was a significant correlation between level of CYP2E1 mRNA in mononuclear cells and the area under the plasma concentration–time curve of plasma inorganic fluoride from the beginning of sevoflurane administration to infinity in uninduced and uninhibited patients (r2 = 0.56;P < 0.01). Conclusions Area under the plasma concentration–time curve of inorganic fluoride after sevoflurane anesthesia correlates with CYP2E1 mRNA in mononuclear cells in peripheral blood.

Successful elimination of intractable anal pain associated with rectal cancer by combination of subarachnoid phenol block with sacral nerve root thermocoagulation

【目的】直腸がん術後の旧肛門部の疼痛に対し, くも膜下フェノールブロックと仙骨部神経根高周波熱凝固術が著効した症例を経験したので報告する.【症例】61歳, 男性. 直腸がん再発の旧肛門部の疼痛に対し, オピオイドなどの鎮痛薬が投与されていたが, 疼痛管理が困難な状態であった. これに対し, くも膜下フェノールブロックを施行することでオピオイドを中止できる程度に疼痛が軽減した. しかし, 数週間後, 第3仙髄神経の支配領域である旧肛門深部の疼痛が増悪してきたため, 仙骨部神経根高周波熱凝固術を施行したところ, 疼痛の消失が得られた.【結論】直腸がん術後の骨盤内再発における旧肛門部の疼痛は, くも膜下フェノールブロックのみでは疼痛管理に難渋することがあるが, 仙骨部神経根高周波熱凝固術を併用することで疼痛緩和を得られる可能性がある. Palliat Care Res 2010; 5(2): 314-316