Aspirin synergistically potentiates isoflurane minimum alveolar concentration reduction produced by morphine in the rat

BACKGROUND: The combination of opioids and nonsteroidal antiinflammatory drugs is more analgesic than the summed effect of each drug administered separately. This synergism has been used to obtain analgesia in the postoperative period at doses at which side effects are minimal. The aim of this study is to evaluate the analgesic interaction between aspirin and morphine in the rat during isoflurane anesthesia. The reduction in minimum alveolar concentration of isoflurane (MAC(ISO)) was used as an objective measure of the analgesic potency of individual drugs and their use in combination. METHODS: Thirty-seven male Wistar rats were anesthetized with isoflurane in oxygen, and the MAC(ISO) was determined before and after the intravenous administration of aspirin and morphine. Rats were administered morphine alone (1, 3, and 10 mg/kg) or morphine (1 and 3 mg/kg) and aspirin (30 mg/kg). The MAC(ISO) was determined from alveolar gas samples at the time of tail clamp. The duration of MAC(ISO) reduction was recorded. RESULTS: Aspirin did not have an effect on MAC(ISO), (average, 1.35+/-0.1%), whereas the combination of morphine (1 and 3 mg/kg) and aspirin (30 mg/kg) produced a reduction in the dose of morphine needed to produce the same degree of MAC(ISO) reduction. Actual MAC(ISO+drug) data were as follows: 1 mg/kg morphine, 1.17+/-0.14%; 3 mg/kg morphine, 0.98+/-0.15%; 1 mg/kg morphine plus aspirin, 0.90+/-0.04%; 10 mg/kg morphine, 0.63+/-0.13%; and 3 mg/kg morphine plus aspirin, 0.64+/-0.06%. CONCLUSIONS: The synergistic effects of aspirin and morphine allow a clinically significant reduction in the requirements of isoflurane and isoflurane plus morphine, and these drug combinations may decrease the side effects associated with the use of single higher, equianalgesic doses of these drugs.     

Reduction of the minimum alveolar concentration of isoflurane by dexmedetomidine

BACKGROUND: alpha 2-Adrenergic agonists have been shown to reduce anesthetic requirements of other anesthetics, and they may even act as complete anesthetics by themselves at high doses in animal models. The present study was designed to define the interaction of intravenous infusion of dexmedetomidine, an alpha 2-adrenergic agonist, and isoflurane in patients having surgery by using the minimum alveolar concentration (MAC) of isoflurane as the measure of anesthetic potency. METHODS: Forty-nine women scheduled for abdominal hysterectomy were randomly allocated to receive either a placebo infusion (n = 16) or a two-stage infusion of dexmedetomidine with target plasma concentration of 0.3 ng/ml (n = 17) or 0.6 ng/ml (n = 16). The study drug infusion was commenced 15 min before induction of anesthesia with thiopental and alfentanil and was continued until skin incision. The end-tidal concentration of isoflurane for each patient was predetermined according to the "up-down" method of Dixon, and it was maintained for at least 15 min before the patient's response to skin incision was assessed. RESULTS: The MAC of isoflurane was 0.85% end-tidal in the control group, 0.55% end-tidal with the low dose of dexmedetomidine, and 0.45% end-tidal with the high dose of dexmedetomidine. CONCLUSIONS: The MAC of isoflurane in the control group was lower than that reported previously in similar patients having surgery, probably due to anesthesia induction with thiopental and alfentanil. Nevertheless, with the high dose of dexmedetomidine, the MAC of isoflurane was still 47% less than that without dexmedetomidine.     

Hypoxemia decreases the shivering threshold in rabbits anesthetized with 0.2 minimum alveolar anesthetic concentration isoflurane

Shivering has been proposed as an etiology of postoperative hypoxemia. The difficulty with this theory is that hypoxemia inhibits shivering in unanesthetized cats, rats, and humans. However, anesthesia inhibits many protective reflexes, including the ventilatory response to hypoxemia. We therefore tested the hypothesis that arterial hypoxemia fails to inhibit shivering in lightly anesthetized rabbits. Rabbits were intubated and instrumented during exposure to surgical concentrations of anesthesia, and anesthesia was then maintained with 0.2 minimum alveolar anesthetic concentration isoflurane. The core was cooled at a rate of 2-3 degrees C/h by perfusing water at 10 degrees C through a colonic thermode. Core temperatures were recorded from the distal esophagus. Sustained, vigorous shivering was considered physiologically significant. The core temperature that triggering significant shivering identified the thermoregulatory threshold for this response. Arterial blood was sampled for gas analysis at the shivering threshold in each rabbit. Hypoxemia linearly reduced the shivering threshold from 36.7 degrees C at 130 mm Hg to 35.4 degrees C at 50 mm Hg (threshold = PaO2.0.019 + 34.3; r2 = 0.49). We failed to confirm our hypothesis: instead, even mild hypoxemia reduced the shivering threshold >1 C. A 1 C decrease in the shivering threshold is likely to prevent or stop most postoperative shivering because it exceeds the reduction produced by many effective anti-shivering drugs. These data do not support the theory that shivering causes postoperative hypoxemia. IMPLICATIONS: Shivering has been proposed as an etiology of postoperative hypoxemia. Our data, in contrast, show that mild hypoxemia inhibits shivering. Shivering is thus unlikely to be a cause of postoperative hypoxemia.     

Oleamide potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor activity but does not alter minimum alveolar anesthetic concentration

Short-term exposure to ozone at peak ambient levels induces neutrophil influx and impairs lung function in healthy humans. In order to investigate the mechanisms contributing to neutrophil recruitment and to examine the role of T-cells in the acute inflammatory response, we exposed 12 healthy humans to 0.2 parts per million (ppm) of ozone and filtered air on two separate occasions for 2 h with intermittent periods of rest and exercise (minute ventilation = 30 L x min(-1)). Fibreoptic bronchoscopy was performed 6 h after the end of exposures. Total protein, tryptase, histamine, myeloperoxidase, interleukin (IL)-8 and growth-related oncogene-alpha (Gro-alpha) were measured and total and differential cell counts were performed in bronchoalveolar lavage (BAL) fluid. Flow cytometry was performed on BAL cells to study total T-cells, T-cell receptors (alphabeta and gammadelta), T-cell subsets (CD4+ and CD8+ cells) and activated T-cell subsets (CD25+). Using immunohistochemistry, neutrophils, mast cells, total T-cell numbers, T-cell subsets, CD25+ T-cells and leukocyte endothelial adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were quantified in the bronchial biopsies. Paired samples were available from nine subjects. Following ozone exposure there was a threefold increase in the proportion of polymorphonuclear neutrophils (PMNs) (p=0.07) and epithelial cells (p=0.05) in BAL fluid. This was accompanied by increased concentrations of IL-8 (p=0.01), Gro-alpha (p=0.05) and total protein (p=0.058). A significant positive correlation was demonstrated between the two chemokines and proportion of PMNs in BAL fluid. After ozone exposure there was a significant decrease in the CD4/CD8 ratio (p=0.05) and the proportion of activated CD4+ (p=0.01) and CD8+ T-cells (p=0.04). However, no significant changes were demonstrable in any of the inflammatory markers studied in the biopsies. Short-term exposure of healthy humans to 0.2 ppm ozone induced a neutrophil influx in peripheral airways at 6 h post exposure, but no apparent inflammatory response in proximal airways. This response seems to be mediated at least in part by interleukin-8 and growth-related oncogene-alpha.     

Effect of a subanesthetic minimum alveolar concentration of isoflurane on two tests of the hypoxic ventilatory response

BACKGROUND: These experiments were designed to study the effect of 0.1 minimum alveolar concentration isoflurane on the hypoxic ventilatory response as measured by two common methods of hypoxic testing: when normocapnic hypoxia was induced abruptly and when it was induced gradually. We hypothesized that any disparity in results would be due to an isoflurane effect that was manifested differently in the two tests. METHODS: After 20 min for uptake and equilibration of 0.1 minimum alveolar concentration end-tidal isoflurane or carrier gas in hyperoxia, isocapnic hypoxia was induced either abruptly over 60-80 s ("step" test) or gradually over 10 min ("ramp" test), followed by 20 min of isocapnic hypoxia at 45 mmHg end-tidal oxygen. Control of the hypoxic and isocapnic stimuli was accomplished accurately by a computer-controlled dynamic end-tidal forcing system. Eight subjects performed each test in the presence and absence of isoflurane. RESULTS: For both step tests and ramp tests, 0.1 minimum alveolar concentration isoflurane had no effect on minute ventilation during the defined periods of hypoxia. With isoflurane, delta VE45, the acute change in ventilation from hyperoxia to hypoxia, was 97 +/- 20% (mean +/- SEM) of the control response for step tests and 100 +/- 25% of the control response for ramp tests. The step tests produced significantly larger acute hypoxic responses than did the ramp tests, but by the end of 20 min of hypoxia, ventilation was similar for both tests. CONCLUSIONS: Neither method of hypoxic testing demonstrated the level of isoflurane effect reported by others. A comparison of the two methods of hypoxic testing suggests that ramp tests, as commonly performed, do not allow adequate time for full expression of the acute hypoxic ventilatory response. Step tests also better separated the opposing hypoxic effects of carotid body stimulation and central ventilatory depression.     

Increasing isoflurane from 0.9 to 1.1 minimum alveolar concentration minimally affects dorsal horn cell responses to noxious stimulation

BACKGROUND: The spinal cord appears to be the site at which isoflurane suppresses movement that occurs in response to a noxious stimulus. In an attempt to localize its site of suppressant action, the authors determined the effect of isoflurane on dorsal horn neuronal responses to supramaximal noxious stimulation at end-tidal concentrations that just permitted and just prevented movement. METHODS: Rats (n = 14) were anesthetized with isoflurane, and after lumbar laminectomy, the minimum alveolar concentration (MAC) for each rat was determined using a supramaximal mechanical stimulus. In these same rats, after extracellular microelectrode placement in the lumbar spinal cord, dorsal horn neuronal responses to the supramaximal stimulus were determined at the concentrations of isoflurane that bracketed each rat's MAC (0.1% higher and lower than MAC). The MAC of isoflurane was then re-determined. RESULTS: Dorsal horn neuronal response was 1,757+/-892 impulses/min at 0.9 MAC and 1,508+/-988 impulses/min at 1.1 MAC, a 14% decrease (P < 0.05). Cell responses varied, with some cells increasing their response at the higher concentration of isoflurane. The MAC of isoflurane was 1.38+/-0.2% before and 1.34+/-0.2% after determination of dorsal horn neuronal responses. CONCLUSIONS: Isoflurane, at concentrations that bracket MAC, has a variable and minimal depressant effect on dorsal horn cell responses to noxious mechanical stimulation. These data suggest that the major action of isoflurane to suppress movement evoked by a noxious stimulus might occur primarily at a site other than the dorsal horn.     

Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies

This study investigated the effect of lidocaine i.v. on halothane minimum alveolar concentration (MAC) in ponies. Six ponies were anaesthetised with thiopentone and succinylcholine, intubated and anaesthesia maintained with halothane. Ventilation was controlled and blood pressure maintained within clinically acceptable limits. Following a 2 h equilibration period, baseline halothane MAC was determined. The ponies were then given a loading dose of lidocaine (2.5 or 5 mg/kg bwt) or saline over 5 min, followed by a constant infusion of lidocaine (50 or 100 microg/kg/min, or saline, respectively). The halothane MAC was redetermined after a 60 min infusion of lidocaine or saline. The baseline halothane MAC for the control group was mean +/- s.d. 0.94 +/- 0.03%, and no significant decrease occurred following saline infusion. Lidocaine decreased halothane MAC in a dose-dependent fashion (r = 0.86; P < 0.0003). The results indicate that i.v. lidocaine may have a role in equine anaesthesia.     

Oral clonidine premedication reduces minimum alveolar concentration of sevoflurane for tracheal intubation in children

BACKGROUND: Sevoflurane is a useful anesthetic for inhalational induction in children because of its low solubility in blood and relatively nonpungent odor. Clonidine has sedative and anxiolytic properties and reduces the requirement for inhalation agents. Nitrous oxide (N2O) also decreases the requirement of inhaled anesthetics, but the effect is variable. The minimum alveolar concentration for tracheal intubation (MAC(TI)) of sevoflurane was assessed with and without N2O and clonidine premedication. METHODS: Seventy-two patients, aged 3-11 yr, were assigned to one of six groups (n = 12 each). They received one of three preanesthetic medications (two groups for each premedication): placebo (control), 2 microg/kg oral clonidine or 4 microg/kg oral clonidine. In one group of each premedication, anesthesia was induced with sevoflurane in oxygen; in the other group, anesthesia was induced with sevoflurane in the presence of 60% N2O. Each concentration of sevoflurane at which tracheal intubation was attempted was predetermined according to Dixon's up-and-down method and held constant for at least 20 min before the trial RESULTS: The MAC(TI) of sevoflurane in the absence of N2O (mean +/- SEM) was 3.2 +/- 0.2%, 2.5 +/- 0.1%, and 1.9 +/- 0.2% in the control, 2-microg/kg clonidine, and 4-microg/kg clonidine groups, respectively. Nitrous oxide (60%) decreased the MAC(TI) of sevoflurane by 26%, 24%, and 27% in the control, 2-microg/kg clonidine, and 4-microg/kg clonidine groups. CONCLUSIONS: Oral clonidine premedication decreased the MAC(TI) of sevoflurane. Nitrous oxide also decreased the MAC(TI). The combination of clonidine and N2O lessened the MAC(TI) of sevoflurane more than did either drug alone.     

Absence of renal and hepatic toxicity after four hours of 1.25 minimum alveolar anesthetic concentration sevoflurane anesthesia in volunteers

Sevoflurane is degraded by CO2 absorbents to Compound A. The delivery of sevoflurane with a low fresh gas flow increases the generation of Compound A. The administration of Compound A to rats can produce injury to renal tubules that is dependent on both the dose and duration of exposure to Compound A. The present study evaluated renal and hepatic function in eight volunteers after a 1-L/min delivery of 3% (1.25 minimum alveolar anesthetic concentration) sevoflurane for 4 h. Volunteers gave their informed consent and provided 24-h urine collections before and for 3 days after sevoflurane anesthesia. Urine samples were analyzed for glucose, protein, albumin, and alpha- and pi-glutathione-S-transferase. Daily blood samples were analyzed for markers of renal and liver injury or dysfunction. Circuit Compound A and plasma fluoride concentrations were determined. During anesthesia, the average maximal inspired Compound A concentration was 39 +/- 6 (mean +/- SD). The median mean arterial pressure, esophageal temperature, and end-tidal CO2 were 62 +/- 6 mmHg, 36.5 +/- 0.3 degrees C, and 30.5 +/- 0.5 mm Hg, respectively. Two hours after anesthesia, the plasma fluoride concentration was 50 +/- 9 micromol/L. All markers of hepatic and renal function were unchanged after anesthesia (repeated-measures analysis of variance P > 0.05). Low-flow sevoflurane was not associated with renal or hepatic injury in humans based on unchanged biochemical markers of renal and liver function. IMPLICATIONS: Sevoflurane delivered in a 3% concentration with a fresh gas flow of 1 L/min for 4 h generated an average maximal Compound A concentration of 39 ppm but did not result in any significant increase in sensitive markers of renal function or injury, including urinary protein, albumin, glucose, and alpha- and pi-glutathione-S-transferase.     

Intraoperative modulation of alveolar macrophage function during isoflurane and propofol anesthesia

BACKGROUND: Alveolar macrophages are a critical part of the defense against pulmonary infection. Thus the authors determined time-dependent changes in alveolar macrophage functions in patients having surgery who were anesthetized with isoflurane or propofol. METHODS: Patients anesthetized with propofol (n = 30) or isoflurane (n = 30) during orthopedic surgery were studied. Alveolar macrophages were harvested by bronchoalveolar lavage immediately, and 2, 4, and 6 h after induction anesthesia and at the end of surgery. The fraction of aggregated and nonviable macrophages was determined. Then phagocytosis was measured by ingestion of opsonized and unopsonized particles. Finally, microbicidal activity was determined as the ability of the macrophages to kill Listeria monocytogenes directly. RESULTS: Demographic and morphometric characteristics of the patients given propofol and isoflurane were similar, as were their levels of pulmonary function and hemodynamic responses. The fraction of alveolar macrophages ingesting opsonized and unopsonized particles, and the number of particles ingested, decreased significantly over time, with the decrease slightly but significantly greater during isoflurane anesthesia. Microbicidal function decreased progressively during anesthesia and surgery, with the decrease almost twice as great during isoflurane compared with propofol anesthesia. The fraction of aggregated macrophages and recovered neutrophils increased over time in the patients given each anesthetic. CONCLUSIONS: Pulmonary immunologic function changed progressively during anesthesia and surgery. The data from this study suggest that pulmonary defenses are modulated by the type of anesthesia and by the duration of anesthesia and surgery.     

Ethanol concentrations approaching minimum alveolar anesthetic concentration are required to suppress learning in a fear-potentiated startle paradigm in rats

We previously demonstrated that desflurane and two nonimmobilizers dose-dependently decrease learning and memory in rats. This suggests that although they do not suppress movement in response to noxious stimuli, nonimmobilizers act like inhaled anesthetics in their effects on learning and memory. Like most conventional anesthetics, nonimmobilizers have a greater affinity for lipid than for aqueous phases. In the present study, we examined the effect of ethanol on learning and memory to test the hypothesis that a large part of the capacity of anesthetics to affect learning depends on an action on a lipid (nonpolar) phase. Unlike volatile anesthetics and nonimmobilizers, ethanol has a greater affinity for water than for lipids. Thus, if our hypothesis is correct, ethanol should be relatively less potent in its suppression of memory. Rats receiving various doses of ethanol were conditioned to fear a light followed by a footshock. Fear conditioning to the light was subsequently assessed by measurement of potentiation of the acoustic startle reflex in the presence, compared with the absence, of light. Ethanol up to 0.54 minimum alveolar anesthetic concentration (MAC) did not abolish fear, but 0.82 MAC ethanol did abolish learning. Expressed as a fraction of MAC or predicted MAC, ethanol is less potent than desflurane or the nonimmobilizer 1,2-dichlorohexafluorocyclobutane in suppressing learning. This finding is consistent with the hypothesis that the capacity of anesthetics and nonimmobilizers to impair learning and memory depends mostly on an action at a nonpolar site. IMPLICATIONS: Abolition of learning and memory is an important property of inhaled anesthetics. This effect primarily results from an action at a lipid (nonpolar) site, rather than a polar site or a water-lipid interface.     

Minimum alveolar anesthetic concentrations for airway occlusion in cats: a new concept of minimum alveolar anesthetic concentration-airway occlusion response

The role of ergosterol in yeast stress tolerance, together with heat shock proteins (hsps) and trehalose, was examined in a sterol auxotrophic mutant of Saccharomyces cerevisiae. Ergosterol levels paralleled viability data, with cells containing higher levels of the sterol exhibiting greater tolerances to heat and ethanol. Although the mutant synthesised hsps and accumulated trehalose upon heat shock to the same levels as the wild-type cells, these parameters did not relate to stress tolerance. These results indicate that the role of ergosterol in stress tolerance is independent of hsps or trehalose.     

Theanine-induced reduction of brain serotonin concentration in rats

Following the administration of theanine, the brain tryptophan content significantly increased or tended to increase, but the contents of serotonin and 5-hydroxyindole acetic acid (5HIAA) decreased. The use of inhibitors of serotonin metabolism enable us to speculate that theanine reduced serotonin synthesis and also increased serotonin degradation in the brain.     

A new method for determining the minimum inhibitory concentration of essential oils

A new microdilution method has been developed for determining the minimum inhibitory concentration (MIC) of oil-based compounds. The redox dye resazurin was used to determine the MIC of a sample of the essential oil of Melaleuca alternifolia (tea tree) for a range of Gram-positive and -negative bacteria. Use of 0.15% (w/v) agar as a stabilizer overcame the problem of adequate contact between the oil and the test bacteria and obviated the need to employ a chemical emulsifier. A rapid version of the assay was also developed for use as a screening method. A comparison of visual and photometric reading of the microtitre plates showed that results could be assessed without instrumentation; moreover, if the rapid assay format was used, rigorous asepsis was not necessary. Accuracy of the resazurin method was confirmed by plate counting from microwells and MIC values were compared with results obtained using an agar dilution assay. The MIC results obtained by the resazurin method were slightly lower than those obtained by agar dilution.     

Comparison of automated and traditional minimum inhibitory concentration procedures for microbiological cosmetic preservatives

Minimum inhibitory concentration (MIC) is used to test resistance of microorganisms against antibiotics and to test cosmetic preservatives. This research expanded traditional MIC with automation and application of colorimetric endpoint MIC. All experiments included common cosmetic preservatives and microorganisms used in testing preservative efficacy. An autodilutor using three 96-well microtiter plates processed 6 preservatives against 1 microorganism in 15 min. The unique tip design made it possible to accurately deliver viscous test materials that cannot be dispensed accurately with vacuum or fluid-filled systems. Tetrazolium violet, a redox indicator, provided a visual color change from clear to purple at the MIC. Optimum concentration of tetrazolium violet was 0.01% with addition of 0.2% glucose to Mueller-Hinton broth for both gram-positive and gram-negative bacteria. The colorimetric endpoint was evident after 24 h from previously cryogenically stored organisms that were thawed before use and after 4 h for 18-24 h broth cultures subcultured from agar plates. The autodilutor accurately pipetted viscous cosmetic products such as hand lotion and shampoo, which cannot be pipetted with a traditional micropipetter.     

Reversible reduction in plasma concentration of nitric oxide induced by cigarette smoking in young adults

The concentration of nitrate plus nitrite, metabolic end products of nitric oxide, in serum prepared from systemic venous blood was significantly (p <0.001) decreased in both heavy (14.5 +/- 1.3 micromol/L) and moderate (17.6 +/- 2.3 micromol/L) smokers relative to that in nonsmokers (22.6 +/- 0.4 micromol/L).     

Minimum alveolar concentration of desflurane for tracheal extubation in deeply anaesthetized, unpremedicated children

We have studied 25 children, aged 4-9 yr, to determine the minimum alveolar concentration (MAC) of desflurane at which safe tracheal extubation can be performed in deeply anaesthetized children. The end-tidal concentration of desflurane was noted at tracheal extubation. Successful extubation was defined as one in which there was no coughing or bucking on the tracheal tube during suctioning of the pharynx, no movement or coughing within 1 min of tracheal extubation and no breath-holding or laryngospasm after extubation. Successful extubation was followed by extubation at a concentration of 0.5% less, and so on in subsequent subjects, until unsuccessful extubation occurred. After a reaction, the percentage was increased in the next patient, continuing up and down in pairs, until the required number of subjects was achieved. In 50% of children aged 4-9 yr, tracheal extubation may be accomplished without coughing or moving at an end-tidal concentration of 7.7%. The end-tidal concentration of desflurane to achieve satisfactory extubation in 95% of children was 8.5%.