Halothane decreases the lethal dose of bupivacaine in two-day old pigs
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The influence of the immunoreactive endogenous digoxin-like factor (IEDLF) on the systemic toxic effects of bupivacaine was studied in a rodent model.During 5 weeks, IEDLF secretion was promoted in 10 Wistar male rats by allowing them to drink saline 0.5% in place of water. Ten other animals drank desionized water (control). At the time of experimentation, the two groups of rats were mixed to allow blind observation. Anesthesia was induced with barbiturate, and controlled ventilation was started. A blood sample was drawn for IEDLF assessment just before bupivacaine was infused at a constant rate of 2 mg/kg per minute. Data were analyzed for statistical significance using Student's t-test. A p value less than 0.05 was considered significant.Two rats in the saline group died during the induction of anesthesia. An IEDLF activity was found in the eight remaining rats in this group. Threshold doses of bupivacaine's toxic effects (first ventricular arrhythmia, first seizure activity, 25% fall of baseline heart rate, 25% of baseline mean arterial blood pressure, isoelectric electroencephalogram) were significantly lower for the rats with an endogenous digoxin-like activity. There were, however, no significant differences in the lethal dose of bupivacaine.In hyperoxic nonacidotic male rats, IEDLF increases the cardiac and central nervous system toxicity of bupivacaine.
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Background: Fentanyl is intrathecally used as an adjuvant to bupivacaine in spinal anesthesia, as well as labor analgesia, and in day surgery. The aim of this study was to determine the separate neurotoxic effect of each drug using histological analysis. Methods: Rats (N = 39) received fentanyl at 0.12μl/g body weight (0.05, 0.5, and 1 mg/ml) or bupivacaine (5, 25, and 50 mg/ml) dissolved in saline via an intrathecal catheter. Saline was used as the control solution. Walking behavior and sensory threshold were used as neurofunctional tests. Seven days after the intrathecal injection, the L2 spinal cords, of each rat, with both anterior and posterior roots, including the dorsal ganglion and cauda equina, were examined histologically. Results: No histological abnormalities were observed in any of the rats treated with fentanyl (0.05, 0.5, or 1 mg/ml) or bupivacaine (5 or 25 mg/ml). However, axonal degeneration originating from the posterior root, extending to the posterior white matter, was observed in rats treated with 50-mg/ml bupivacaine. Significantly higher sensory thresholds were observed in rats with 1 mg/ml fentanyl, or 50-mg bupivacaine at 2 hours after the injection. The higher thresholds gradually disappeared in rats with fentanyl after 1 hour even at 1 mg/ml, but remained in rats with 50-mg/ml bupivacaine after 2 hours, and significantly decreased at 7 days after the injection. The rats could walk normally within 15 minutes, 1 hour before, and 1 hour after the injection of fentanyl (0.05, 0.5, and 1 mg/ml), respectively, and within 1, 2, and 4 hours of bupivacaine (5, 25, and 50 mg/ml), respectively. Transient apnea was only observed in 1 rat treated with 0.05-mg/ml fentanyl, while both transient apnea and muscle rigidity were observed in rats treated with 0.5- and 1-mg/ml fentanyl. No rats treated with bupivacaine (5, 25, or 50 mg/ml) showed both side effects. Conclusions: Our results indicated that intrathecal fentanyl does not cause any neurotoxic changes even at more than 40 times the clinical concentration (1 mg/ml), whereas bupivacaine causes nerve damage even when applied at 10 times the clinical concentration (50 mg/ml) in the spinal rat model. Side effects such as respiratory depression and muscle rigidity were seen in rats in the fentanyl group, even at 0.05 mg/ml. These results suggested that intrathecal fentanyl has strong side effects but low neurotoxicity because of the absence of morphological neurotoxicity even at high concentrations, whereas intrathecal bupivacaine induced sensory disturbance associated with axonal degeneration.
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The effect of epidural morphine sulphate (4 mg in 10 ml saline) on the minimum alveolar concentration of halothane was investigated in a double-blind, randomized fashion in ten adult patients undergoing abdominal surgery, and compared with the minimum alveolar concentration of halothane after epidural administration of 10 ml saline in a similar group of patients. Morphine sulphate, administered through the epidural catheter 98 +/- 33 min before to skin incision reduced the minimum alveolar concentration of halothane by 28% (0.57% vs 0.78%, P < 0.05).
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It is known that narcotics reduce the alveolar concentration of inhalation anesthetics in man and animals. However the magnitude and duration of narcotic effect on inhalation anesthesia is not known. Accordingly, I determined in dogs the temporal effect of various doses of pentazocine, a commonly used anesthetic adjuvant, on the minimum alveolar concentration (MAC) of halothane. In addition, I compared plasma pentazocine concentrations in dogs both awake and during halothane anesthesia using an identical intramuscular dose of pentazocine. Intramuscular injection of pentazocine, group II (2.5 mg/kg), group III (5 mg/kg), group IV (10 mg/kg) reduced MAC of halothane required for anesthesia. The magnitude of MAC depression were 19.3% of control halothane MAC in group II, 36.4% of control in group III and 41.7% of control in group IV. Postinjection plasma concentration was fitted by computer with a 2-compartment open pharmacokinetic model. Plasma pentazocine concentration for awake (group I) and anesthetized (group II) dogs given the same dose (2.5 mg/kg) did not differ significantly on biological half-life, total apparent volume of distribution and body clearance. Halothane minimum alveolar concentration (MAC) was correlated to plasma pentazocine concentration (r= -0.60) and cerebrospinal fluid pentazocine concentration (r= -0.74).
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The anaesthetic properties of a halothane-in-fat solution given either as a single i.v. dose or as a continuous i.v. infusion were investigated in rats. 0.3 ml of a 5% solution of halothane in fat emulsion was injected i.v. into 15 awake rats. At the end of the 30 s injection, all rats had collapsed from the upright position and showed no response to a firmly applied tail clamp. Breathing usually became shallow and irregular just after injection. Two rats died. In the surviving rats, movement in response to clamping of the tail reappeared after some 30 s (range 15-90 s). The rats regained the upright position after about 100 s, and appeared fully awake about 3 min (range 2-5 min) after injection. Surviving rats behaved normally after the experiment, and gained in weight. They were killed 1-29 days later. The lungs, kidneys, heart, brain and liver had a normal macroscopic and microscopic appearance. In a second set of experiments (n = 9), a 10% solution of halothane was continuously infused i.v. (3.75 microliters min-1). The anaesthetic depth, as well as the mean arterial pressure, heart rate, respiratory rate and arterial PCO2 and PO2 were similar to values observed during inhalation of halothane in air at an inspired concentration of 1.1%. By doubling the infusion rate, MAP was reduced by 23%. It was easy to adjust anaethestic depth by changing the infusion rate and recovery was fast.
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Desbutylbupivacaine, a major metabolite of bupivacaine, is known to accumulate during long‐term continuous infusion blocks in man. Its acute toxicity in comparison with that of bupivacaine has not been studied. In a lightly anaesthetized rat model, bupivacaine (2 mg/kg/min, N = 10) or desbutylbupivacaine (4 mg/kg/min, N = 10) was infused i.v. until asystole. Arterial blood pressure, ECG and EEG were continuously recorded. The mean doses of bupivacaine producing cardiac toxicity, i.e. arrhythmia (12.4 mg/kg) and asystole (24.0 mg/kg), were approximately half of those of desbutylbupivacaine. Seizure activity on the EEG was observed in only one of the desbutylbupivacaine‐infused rats while all rats receiving bupivacaine developed seizures (mean dose 5.2 mg/kg). Desbutylbupivacaine infusion caused a decrease in arterial blood pressure greater than that resulting from bupivacaine infusion. When desbutylbupivacaine 0.67 mg/kg/min was coinfused with bupivacaine 2 mg/kg/min, the cardiovascular toxicity of bupivacaine was clearly potentiated. The EEG parameters were affected in a similar fashion as when bupivacaine alone was infused. In this rat model, desbutylbupivacaine was about half as toxic as bupivacaine judged by cardiac parameters, and clearly less toxic to the central nervous system than bupivacaine.
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SUMMARY Inhalation anesthetics decrease the clearance of some drugs that are eliminated by renal excretion. The purpose of the study reported here was to investigate the effects of halothane anesthesia on the pharmacokinetics and urinary excretion of gentamicin sulfate, using the horse as a model. Using a crossover design, pharmacokinetic values after a single iv dose of gentamicin (4 mg/kg) were compared in halothane-anesthetized and unanesthetized horses. Compared with unanesthetized horses, the anesthetized horses had significant decreases in total body clearance ( P < 0.01) and apparent volume of distribution ( P < 0.05), and a significant increase in half-life ( P < 0.05) of gentamicin.
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We examined nimodipine modification of bupivacaine toxicity in anesthetized male rats. Three minutes after pretreatment, group 1 (n = 11), group 3 (n = 10), and their respective control groups (n = 11 and n = 9) received intravenous bupivacaine LD50 (median lethal dose). After pretreatment, group 2 (n = 10), group 4 (n = 8), and their respective control groups (n = 10 and n = 8) received intravenous bupivacaine LD90, (90% lethal dose). Pretreatment was 200 μg/kg intravenous nimodipine in groups 1 and 2 and 500 μg/kg in groups 3 and 4. Control animals were pretreated with intravenous saline solution. Data were analyzed by χ2-analysis and analysis of variance. Survival increased after 200 μg/kg nimodipine (P < 0.05). In group 1, 9 (81%) of 11 survived compared with control animals (4 [36%] of 11). In group 2, 8 (80%) of 10 survived compared with control animals (2 [20%] of 10). Survival was not increased after 500-μg/kg nimodipine pretreatment. In group 3, 2 (22%) of 9 survived compared with control animals (4 [40%] of 10). In group 4, 4 (50%) of 8 survived compared with control animals (2 [25%] of 8). We conclude that nimodipine pretreatment with 200 μg/kg protects against fatal toxicity from LD50 and LD90 bupivacaine, but 500 μg/kg does not.
Nimodipine
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Halothane 5% (0.6 ml/kg) and isoflurane 10% (0.4 ml/kg) in intralipid injected intravenously over one minute were the minimum doses that consistently abolished movement in response to tail clamping in dogs. The depth of anaesthesia was controlled by adjusting the infusion rate. Blood pressure decreased during induction and regained progressively during maintenance with low doses especially with isoflurane. The heart and respiratory rates were increased during maintenance with low doses while a decrease was observed by increasing the depth of anaesthesia that was more prominent with halothane. Recovery achieved after infusion of halothane 5% or isoflurane 10% for 30 minutes, was fast and survivors behaved normally. Lung tissues were macro and microscopically normal. It was concluded that, intravenous administration of halothane 5% or isoflurane 10% induced ultra short general anaesthetic effect and had a safe hemodynamic and respiratory responses especially with isoflurane.
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