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PubMed1993

Role of imidazoline-preferring receptors in the genesis of epinephrine-induced arrhythmias in halothane-anesthetized dogs.

BACKGROUND: Drugs with a central alpha 2-adrenergic action can increase the threshold for halothane-epinephrine-induced arrhythmias. Recently, imidazoline-preferring receptors were shown to play a significant role in the hypotensive effect of alpha 2-adrenergic agonists containing an imidazole ring in their structure. To address the question of whether the antiarrhythmic property of the alpha 2-adrenergic agonists was caused by activation of alpha 2-adrenoceptors or imidazoline-preferring receptors in the central nervous system, the effect of an imidazoline (atipamezole) and a nonimidazoline (L-659,066 and yohimbine) alpha 2-adrenergic antagonist were examined as etiologic factors in the genesis of halothane-epinephrine-induced arrhythmias in dogs. METHODS: Adult mongrel dogs were anesthetized with halothane (1.3%) and monitored continuously for systemic arterial pressure and for premature ventricular contractions. The arrhythmogenic dose (AD) of epinephrine, defined as the smallest dose producing four or more premature ventricular contractions within a 15-s period, was determined in the presence of atipamezole (an imidazoline compound that acrosses the blood-brain barrier), L-659,066 (a nonimidazoline compound that does not penetrate the blood-brain barrier), and yohimbine (a nonimidazoline compound that passes the blood-brain barrier). These drugs were administered either intravenously or into the cisterna magna to assess the site of action for changes in responsiveness. RESULTS: Intravenous atipamezole decreased the AD of epinephrine in the dose-dependent fashion. However, neither L-659,066 nor yohimbine, administered peripherally, decreased the AD of epinephrine. Central administration of atipamezole also decreased the AD of epinephrine, while L-659,066, even if administered centrally, did not affect the AD of epinephrine in the presence of halothane. CONCLUSIONS: Because the imidazoline ring-containing alpha 2-adrenergic antagonist (atipamezole) potentiated the halothane-epinephrine-induced arrhythmias and the nonimidazole alpha 2-adrenergic antagonist (L-659,066 and yohimbine) did not, it is possible that the imidazoline-preferring, rather than the alpha 2-adrenergic, receptor is responsible for the antiarrhythmic property of alpha 2-adrenergic agonists.

Adrenergic alpha-Antagonists↗
PubMed1993

Effects of halothane on global and regional biventricular performances and on coronary hemodynamics before and during right coronary artery stenosis in the dog.

BACKGROUND: Previously, it was suggested that right ventricular (RV) free wall dysfunction does not necessarily elicit global hemodynamic alterations. This was investigated in a canine model of halothane-induced right coronary artery (RCA) insufficiency. METHODS: Two concentrations (0.8% and 1.6% end tidal) of halothane on global and regional RV and left ventricular (LV) performance and on coronary, pulmonary, and systemic hemodynamics were studied in 10 open-chest dogs first before and, subsequently, during critical RCA stenosis. RESULTS: In the absence of stenosis, halothane caused progressive and comparable depression of regional and global RV and LV function and reduction of RCA flow. Halothane administered during RCA stenosis caused disproportionate decreases in RCA flow and segment shortening and increases in systolic segment lengths in the area supplied by the stenosed RCA that were approximately twice as great as before stenosis. Such severe regional RV dysfunction was not accompanied by greater depression of global RV and LV pump function (systolic pressures and stroke volume). CONCLUSIONS: In the canine heart with its dominant left coronary system, RCA insufficiency (on the basis of halothane-induced hypotension) caused regional RV dysfunction suggesting ischemia that was not accompanied by global hemodynamic alteration.

Animals↗
PubMed1993

Pulmonary uptake of propofol in cats. Effect of fentanyl and halothane.

BACKGROUND: Many drugs are removed by the lung. The pulmonary uptake of one drug can be inhibited when a second, highly accumulated drug is administered parenterally or as a chronic oral treatment. The effect of inhalational anesthetics on pulmonary drug uptake has not been extensively studied and may alter pharmacokinetics of intravenously administered drugs. METHODS: The uptake of propofol by the lung during a single passage through the pulmonary circulation was studied in four groups of anesthetized cats: spontaneously breathing cats (control group, n = 6), cats whose lungs were mechanically ventilated (n = 6), and cats whose lungs were mechanically ventilated and that were anesthetized with 1% (n = 6) or 1.5% (n = 6) halothane. In an additional group, the single-pass pulmonary uptake of propofol was studied in six spontaneously breathing cats pretreated with fentanyl. The amount of propofol taken up by the lung during the first pass was measured from double indicator-dilution outflow curves using indocyanine green (ICG) as the intravascular reference indicator. RESULTS: The first-pass uptake of propofol (mean +/- SEM) was 61.3 +/- 4.9% and 60 +/- 3.7% of the injected dose in control cats and in cats whose lungs were mechanically ventilated, respectively. Although exposure of the animals to 1% halothane had no significant effect on pulmonary extraction of propofol, the first-pass uptake decreased significantly to 38.8 +/- 6.9% in cats exposed to 1.5% halothane compared with control cats and to cats undergoing mechanical ventilation of the lungs without exposure to halothane. Also, in animals pretreated with fentanyl, propofol uptake was reduced to 40 +/- 5% compared with the control group. CONCLUSIONS: The results demonstrate a substantial extraction of propofol by the lung that is not affected by mechanical ventilation. Inhibition of propofol uptake by 1.5% halothane and by fentanyl provides a potential mechanism of drug-drug interaction that may interfere with the pharmacokinetic profile of propofol, and may alter the amount of propofol needed to achieve or supplement a given depth of anesthesia.

Anesthesia, Inhalation↗
PubMed1993

Amrinone attenuates airway constriction during halothane anesthesia.

BACKGROUND: Phosphodiesterase (PDE) inhibitors should, in theory, be useful in patients with both cardiac and reactive airway disease who require anesthesia. The effects of the PDE inhibitor, amrinone, on the release of endogenous catecholamines and on airway reactivity to aerosol methacholine challenge were evaluated during thiopental/fentanyl and halothane anesthesia in five mongrel dogs. METHODS: Responses to methacholine aerosol challenge (0.03, 0.075, 0.15, 0.30, 0.75, and 3.0 mg/ml) were measured during four conditions: thiopental/fentanyl anesthesia, thiopental/fentanyl anesthesia with amrinone infusion, halothane anesthesia, and halothane anesthesia with amrinone infusion. Increase in pulmonary resistance (RL) and decreases in dynamic compliances (Cdyn) were calculated for each methacholine dose. Plasma epinephrine and norepinephrine concentrations were measured during thiopental/fentanyl anesthesia with amrinone infusion. RESULTS: Before aerosol challenge, baseline RL and Cdyn did not differ in the four groups. Amrinone significantly attenuated the pulmonary response to methacholine during both thiopental/fentanyl and halothane anesthesia. Plasma catecholamine concentrations did not increase during amrinone infusion. CONCLUSIONS: Amrinone attenuates methacholine-induced airway responses even during halothane anesthesia. These data indicate that isozyme-selective PDE inhibitors hold promise for the perioperative treatment of bronchospasm.

Amrinone↗
PubMed1993

Halothane and temperature interact to increase succinylcholine-induced jaw contracture in the rat.

BACKGROUND: The agonist actions of succinylcholine (SCh) have recently come under study because of their involvement in the clinical problem of masseter muscle rigidity, and their possible involvement in malignant hyperthermia. The authors investigated factors affecting SCh-induced contractures in an animal preparation. METHODS: Rats were anesthetized with either halothane (1-2%) or pentobarbital. Resting and twitch isometric tension were measured from the jaw muscles. Succinylcholine (500 or 750 micrograms/kg) was administered intravenously, producing increases in resting tension (i.e., contractures). Jaw muscle temperature was controlled by radiant heat. RESULTS: Succinylcholine increased jaw muscle tension for several seconds. These contractures exhibited tachyphylaxis, and were antagonized by vecuronium (0.8-1.5 mg/kg), indicating mediation by acetylcholine receptors (AChR). In the presence of 2% halothane, contractures were tenfold greater at a rectal temperature of 41 degrees C than at 37 degrees C. In contrast, under 50 mg/kg intraperitoneal pentobarbital anesthesia, contractures were not affected by rectal temperature. Neither the half-decay time of contracture nor twitch tension (0.2 Hz, preceding SCh) were increased in the presence of halothane at 41 degrees C. In a set of experiments in which rectal temperature was maintained at 37 degrees C but jaw temperature was varied between 36-41 degrees C, there was a significant regression of SCh-induced jaw contracture on temperature in the presence of halothane. In contrast, there was no significant relationship between jaw temperature and contracture in the presence of pentobarbital. CONCLUSIONS: These results in the rat demonstrate a temperature-dependent interaction between halothane and SCh that has not previously been described.

Animals↗
PubMed1994

Recovery characteristics of desflurane versus halothane for maintenance of anesthesia in pediatric ambulatory patients.

BACKGROUND: Desflurane is a new potent, inhaled anesthetic agent with low blood-gas solubility that should allow for the rapid induction of and emergence from anesthesia. However, its extreme pungency makes desflurane unacceptable for induction of anesthesia in children. This study was undertaken to determine the airway properties of desflurane administered by mask after anesthetic induction with halothane and nitrous oxide, and to compare the emergence and recovery properties of minimum alveolar concentration (MAC)-equivalent concentrations of desflurane or halothane in nitrous oxide in pediatric patients undergoing ambulatory surgery. METHODS: Forty-five children undergoing ambulatory surgery for inguinal hernia repair, orchiopexy, and/or circumcision were randomized into two groups. Both groups were premedicated with intranasal midazolam and given halothane and nitrous oxide by mask to induce anesthesia. A caudal block was placed in children in both groups after anesthetic induction. For maintenance of anesthesia, group I patients (n = 22) were switched over to desflurane (1 MAC) and nitrous oxide, and group II patients (n = 23) continued to receive halothane (1 MAC) and nitrous oxide. All patients breathed spontaneously throughout the entire procedure, and all anesthetics were terminated abruptly at the conclusion of surgery. Recovery indicators (time to first response, length of time in the recovery room and length of time in the hospital) and the quality of the anesthetic emergence were assessed by a nurse blinded to each patient's anesthetic. This observer was present with the patient throughout his or her ambulatory hospitalization and continuously assessed the recovery indicators according to preset criteria. RESULTS: The groups did not differ with respect to age, weight, or dose of midazolam. Although group I (desflurane) had a longer anesthesia time (52 +/- 12 min vs. 42 +/- 10 min), their time to first response (9.5 +/- 6.8 min vs. 20.9 +/- 14.7 min) and their recovery room time (21 +/- 10.7 min vs. 29 +/- 14.6 min) were less than those in group II (halothane). There was a trend for patient emergence from desflurane anesthesia to be associated with a higher incidence of emergence delirium (50% vs. 21%). The two groups were similar with respect to overall duration of postoperative ambulatory hospitalization. CONCLUSIONS: In children premedicated with intranasal midazolam, desflurane maintenance anesthesia allows for a faster recovery. However, depending on the institution's criteria for ambulatory surgical patient discharge, desflurane may or may not affect the overall hospitalization time.

Ambulatory Surgical Procedures↗
PubMed1994

Effect of halothane on large-conductance calcium-dependent potassium channels in cerebrovascular smooth muscle cells of the rat.

BACKGROUND: Patch-clamp methods were used to examine the effects of the volatile general anesthetic halothane on large-conductance calcium-dependent potassium channels (BK channels) in dispersed cerebrovascular smooth muscle cells of adult rats. METHODS: Inside-out membrane patches were used for recordings at 21-23 degrees C. Halothane was administered at aqueous concentrations of 0.5-2.8 mM in conjunction with free cytoplasmic calcium concentrations of 1 or 100 microM and at a membrane potential of -60 mV or +60 mV. RESULTS: At a free cytoplasmic calcium concentration of 1 microM, the clinically relevant dose of 0.5 mM (2 MAC) halothane reduced the open probability of large-conductance calcium-dependent potassium channels without altering the single-channel conductance. This effect was blocked by increasing the concentration of cytoplasmic free calcium to 100 microM, but was not intrinsically voltage dependent. CONCLUSION: The marked dilation of cerebral vessels seen during surgical anesthesia with halothane cannot be attributed to direct effects of the drug on large-conductance calcium-dependent potassium channels. The protective effect of calcium suggests that halothane exerts its effects at channel sites located within the cell membrane.

Animals↗
PubMed1994

Ischemic depolarization during halothane-nitrous oxide and isoflurane-nitrous oxide anesthesia. An examination of cerebral blood flow threshold and times to depolarization.

BACKGROUND: Isoflurane-N2O anesthesia (as compared with halothane-N2O) reduces the cerebral blood flow (CBF) at which electroencephalographic changes occur in humans subjected to carotid occlusion. In contrast, no differences were seen in rats when cortical depolarization (instead of the electroencephalogram) was used as the ischemic marker during equi-MAC isoflurane-N2O and halothane-N2O anesthesia. To extend these findings, we used laser-Doppler flowmetry to continuously examine CBF (CBFLDF) and attempted to better define the relation between CBF and the time to depolarization (as a measure of the rate of energy depletion after ischemia). METHODS: Cortical CBFLDF was measured in normothermic, normocarbic rats, and the cortical direct-current potential was recorded using glass microelectrodes. Animals were anesthetized with 0.75 MAC halothane or 0.75 MAC isoflurane, both in 60% N2O. After baseline recordings, both carotid arteries were occluded. Five minutes later mean arterial pressure was rapidly reduced to and held at target values of 50, 45, 40, 30 or 0 mmHg. This mean arterial pressure was maintained (and CBFLDF was continually monitored) until depolarization occurred, or for a maximum of 20 min. RESULTS: CBFLDF values before and after carotid occlusion (but before hypotension) were similar in the two groups. As intended, CBFLDF decreased as postocclusion mean arterial pressure was reduced and the incidence of cortical depolarization increased. The delay until depolarization, defined as the interval between the moment CBFLDF reached 25% of the preocclusion baseline until depolarization occurred, decreased as CBFLDF was reduced. However, there were no intergroup differences except after a circulatory arrest (CBF = 0), where cortical depolarization was seen approximately 30 s later in isoflurane-N2O-anesthetized rats. CONCLUSIONS: The CBF threshold for cortical depolarization as measured by laser-Doppler flowmetry did not differ significantly between halothane-N2O- and isoflurane-N2O-anesthetized rats. There were also no important differences in the times until depolarization, other than a small difference when flow = 0. If the time to depolarization is reflects the potential ischemic injury, the it is unlikely that isoflurane-N2O conveys any protective advantage relative to halothane-N2O.

Anesthesia, Inhalation↗
PubMed1994

Halothane enhances suppression of spinal sensitization by intrathecal morphine in the rat formalin test.

BACKGROUND: Injection of formalin in the hindpaw of the rat induces intense C-fiber activity accompanied by brief flinching of the injected paw (phase 1) and gives rise to facilitated spinal processing characterized by renewed flinching beginning 15 min after injury and lasting 40 min or more (phase 2). In previous work, isoflurane, administered during phase 1, slightly reduced phase-2 activity, whereas the addition of intrathecal morphine dramatically inhibited phase 2, even with naloxone reversal 6 min after the formalin injection. We used a similar model to determine whether intrathecal morphine could block spinal sensitization in the absence of inhalation anesthetic. METHODS: Hot plate tests at 52 degrees C and radiant heat-evoked hindpaw withdrawal tests were used to determine optimal doses of agonists and antagonists. The formalin test was carried out on male Sprague-Dawley rats, which were divided into five groups. A combination of naloxone 0.5 mg/kg and naltrexone 0.5 mg/kg was administered subcutaneously 6 min after the formalin injection to all animals except controls (group 1) to prevent ongoing opioid effect. Groups 1-3 received intrathecal saline, and groups 4 and 5 received intrathecal morphine 30 micrograms 20 min before formalin injection. Halothane was administered for 1-2 min to facilitate formalin injection for groups 1, 2, and 4. In groups 3 and 5 halothane was administered from 5 min before to 6 min after formalin injection. The number of flinches per minute was counted 1 and 5 min after formalin administration and thereafter at 5-min intervals for 1 h. The total number of flinches at 1 and 5 min was considered as phase-1 activity, and the total number of flinches during the 10-60-min interval was considered as phase 2. RESULTS: Phase-2 activity for groups 1 and 2 was nearly identical, demonstrating no appreciable effect of the opioid antagonists alone. Groups 3 (halothane alone) and 4 (morphine alone) exhibited a significant decrease in phase-2 activity. Group 5 (morphine plus halothane) demonstrated a profound decrease in phase-2 activity, which was significantly more profound than that of groups 3 or 4. CONCLUSIONS: Intrathecal morphine, administered before formalin injection but antagonized before the onset of phase 2 of the formalin test, significantly suppresses sensitization of dorsal horn neurons. This suppression is significantly increased by coadministration of halothane anesthesia.

Animals↗
PubMed1995

Halothane and isoflurane decrease the open state probability of K+ channels in dog cerebral arterial muscle cells.

BACKGROUND: Both halothane and isoflurane evoke cerebral vasodilation. One of the potential mechanisms for arterial vasodilation is enhanced K+ efflux resulting from an increased opening frequency of membrane K+ channels. The current study was designed to determine the effects of volatile anesthetics on K+ channel current in single vascular smooth muscle cells isolated from dog cerebral arteries. METHODS: Patch clamp recording techniques were used to investigate the effects of volatile anesthetics on macroscopic and microscopic K+ channel currents. RESULTS: In the whole-cell patch-clamp mode, in cells dialyzed with pipette solution containing 2.5 mM EGTA and 1.8 mM CaCl2, depolarizing pulses from -60 to +60 mV elicited an outward K+ current that was blocked 65 +/- 5% by 3 mM tetraethylammonium (TEA). Halothane (0.4 and 0.9 mM) depressed the amplitude of this current by 18 +/- 4% and 34 +/- 6%, respectively. When 10 mM EGTA was used in the pipette solution to strongly buffer intracellular free Ca2+, an outward K+ current insensitive to 3 mM TEA was elicited. This K+ current, which was reduced 51 +/- 4% by 1 mM 4-aminopyridine, was also depressed by 17 +/- 5% and 29 +/- 7% with application of 0.4 and 0.9 mM halothane, respectively. In cell-attached patches using 145 mM KCl in the pipette solution and 5.2 mM KCl in the bath, the unitary conductance of the predominant channel type detected was 99 pS. External application of TEA (0.1 to 3 mM) reduced the unitary current amplitude of the 99 pS K+ channel in a concentration-dependent manner. The open state probability of this 99 pS K+ channel was increased by 1 microM Ca2+ ionophore (A23187). These findings indicate that the 99 pS channel measured in cell-attached patches was a TEA-sensitive, Ca(2+)-activated K+ channel. Halothane and isoflurane reversibly decreased the open state probability (NPo), mean open time, and frequency of opening of this 99 pS K+ channel without affecting single channel amplitude or the slope of the current-voltage relationship. CONCLUSIONS: Halothane and isoflurane suppress the activity of K+ channels in canine cerebral arterial cells. These results suggest that mechanisms other than K+ channel opening likely mediate volatile anesthetic-induced vasodilation.

Animals↗
PubMed1995

Halothane and isoflurane alter the Ca2+ binding properties of calmodulin.

BACKGROUND: Ca2+ plays an important role in signal transduction and anesthetic mechanisms. To date, no one has observed a direct effect of volatile anesthetics on a Ca(2+)-binding protein. We therefore examined the effects of halothane and isoflurane on the Ca(2+)-binding properties of bovine brain calmodulin. METHODS: The fluorescence emission of calmodulin was obtained over a range of Ca2+ concentrations (10(-7)-10(-4)M) in the presence and absence of halothane and isoflurane. The intrinsic tyrosine fluorescence of calmodulin was measured at an excitation wavelength of 280 nm and an emission wavelength of 320 nm. Fluorescence measurements were carried out in 50 mM hydroxyethylpiperazineethane sulfonic acid, 100 mM KC1, and 2 mM ethyleneglycol-bis-(beta-aminoethyl ether) tetraacetic acid at pH 7.0 and 37 degrees C. Experiments were performed in polytetrafluorethylene-sealed cuvettes so that the volatile anesthetic concentrations remained constant. The titration data were analyzed in two ways. The data were fit to the Hill equation by using nonlinear regression analysis to derive the Hill coefficient and the dissociation constant. The data were also analyzed by two-way analysis of variance with multiple comparisons to determine statistically significant effects. Volatile anesthetic concentrations were measured by gas chromatography. RESULTS: The presence of volatile anesthetics altered the Ca(2+)-binding affinity of calmodulin in a dose-dependent fashion. At 0.57% (0.25 mM) halothane and 1.7% (0.66 mM) isoflurane, the affinity of calmodulin for Ca2+ relative to control was decreased. However, at higher concentrations of both anesthetics, the affinity for Ca2+ was increased. When the volatile anesthetics were allowed to evaporate from the experimental solutions, the observed rightward shift of the calmodulin-Ca2+ binding curve for Ca2+ at low concentrations of the anesthetics returned to the control position. The leftward shift seen at high concentrations of the anesthetics was irreversible after evaporation of 8.7% (3.3 mM) isoflurane and 5.7% (2.5 mM) halothane. CONCLUSIONS: These data demonstrate a complex interaction of two hydrophobic volatile anesthetics with calmodulin. A biphasic effect was observed both for halothane and for isoflurane. Calmodulin, an EF-hand Ca(2+)-binding protein, undergoes a conformational shift when binding Ca2+, exposing several hydrophobic residues. These residues may be sites at which the anesthetics act.

Animals↗
PubMed1995

A system model for halothane closed-circuit anesthesia. Structure considerations and performance evaluation.

BACKGROUND: Previously, the authors described a physiologic model for closed-circuit inhalational anesthesia. The basic version of this system model was clinically validated for isoflurane. An extended version adopted nonpulmonary elimination causing a constant fraction of anesthetic to be irreversibly lost. This version improved the accuracy of the model for enflurane. The model's performance for other inhalational anesthetics that are not biochemically inert, such as halothane, remained to be evaluated. METHODS: The current study quantified the predictive performance of four versions of the model by comparison of the predicted and measured alveolar halothane concentration-time profiles in 53 patients. Version A did not incorporate nonpulmonary elimination, whereas version D adopted a nonlinear hepatic nonpulmonary elimination following Michaelis-Menten kinetics. A and D used fixed partition coefficients. Their counterparts, A' and D', were formulated to examine the impact of age-adjusted partition coefficients on the accuracy of our model. Each concentration measured by mass spectrometry was compared to four predicted concentrations calculated by four computer simulations (one per version). For each patient, the authors calculated the root mean squared error (rmse; typical error size), bias (systematic component), and scatter of the prediction errors. RESULTS: Fifty-three patients were anesthetized with 330 ml of liquid halothane via 426 bolus injections during more than 61 h; 21,890 alveolar concentrations (average 0.6 vol%) were measured. Version D' showed the best overall performance with an rmse of 19.6 +/- 7.2%, a bias of 0.5 +/- 15.9%, and a scatter of 13.2 +/- 3.5% (mean +/- SD). CONCLUSIONS: The model incorporating nonpulmonary elimination and age-adjusted partition coefficients (D') is sufficiently reliable and accurate to represent halothane closed-circuit anesthesia. This system model, with its various versions, is a valuable tool to predict the dynamics of isoflurane, enflurane, and halothane for clinical, educational, and research purposes.

Adult↗
PubMed1995

Direct cerebrovasodilatory effects of halothane, isoflurane, and desflurane during propofol-induced isoelectric electroencephalogram in humans.

BACKGROUND: The effect of volatile anesthetics on cerebral blood flow depends on the balance between the agent's direct vasodilatory action and the indirect vasoconstrictive action mediated by flow-metabolism coupling. To compare the intrinsic action of volatile anesthetics, the effect of halothane, isoflurane, and desflurane on flow velocity in the middle cerebral artery during propofol-induced isoelectricity of the electroencephalogram was examined. METHODS: In 21 ASA physical status 1-2 patients, anesthesia was induced with 2.5 mg/kg propofol, 3 micrograms/kg fentanyl, and 0.1 mg/kg vecuronium and maintained with a propofol infusion to preserve an isoelectric electroencephalogram. End-tidal carbon dioxide and blood pressure were maintained constant throughout the study period. A transcranial Doppler was used to measure blood flow velocity in the middle cerebral artery, and a catheter was inserted in a retrograde direction into the jugular bulb for oxygen saturation measurements. After 15 min of isoelectric electroencephalogram, arterial and jugular venous blood samples were drawn, and flow velocity in the middle cerebral artery was recorded. Patients were randomly allocated to receive 0.5 MAC halothane, isoflurane, or desflurane, and after 15 min of equilibration, all variables were measured again. The concentration of the volatile agent was increased to 1.5 MAC, and after 15 min of equilibration, the measurements were repeated. RESULTS: Halothane, isoflurane, and desflurane significantly increased flow velocity in the middle cerebral artery (baseline 28 +/- 4, 30 +/- 4, and 29 +/- 3 cm/s, respectively) at 0.5 MAC (19 +/- 1.5%, 21 +/- 2%, and 23 +/- 3%, respectively; P < 0.05) and at 1.5 MAC (48 +/- 3%, 75 +/- 7%, and 74 +/- 4%, respectively; P < 0.05). Changes in the cerebral arteriovenous oxygen content difference are consistent with these findings. CONCLUSIONS: Halothane, isoflurane, and desflurane have intrinsic, dose-related cerebral vasodilatory effects. Whereas all three agents are similar at 0.5 MAC, isoflurane and desflurane have greater vasodilatory effects than halothane at 1.5 MAC.

Adult↗
PubMed1995

Vasomotor responses of rat coronary arteries to isoflurane and halothane depend on preexposure tone and vessel size.

BACKGROUND: The authors previously reported that in rabbits, isoflurane exhibited a heterogeneous vasomotor effect, constricting small resistance coronary arteries and dilating larger conductance arteries. The novelty of isoflurane-induced constriction of small coronary arteries raised the question of whether the finding depended on the unique experimental setup or species used. The purpose of this study was to address these questions. Therefore, a second species was studied, namely rats, as well as a second volatile anesthetic, halothane. In addition, the dependence of the vasomotor effect on the preexisting tone of the vessels was examined. METHODS: Thirty-six large coronary arteries (262 +/- 23 microns) and 42 small coronary arteries (99 +/- 15 microns) from 31 Wistar rats were isolated. Each vessel was placed in a microvessel chamber and was (1) submaximally preconstricted with the thromboxane analog U46619; (2) submaximally predilated with sodium nitroprusside; or (3) neither preconstricted nor predilated. The vessel was then subjected to increasing concentrations of either isoflurane or halothane, 0-3%. Changes in inner diameter were monitored and recorded with optical density video detection system. RESULTS: Isoflurane constricted predilated or untreated small coronary arteries, but had no effect on preconstricted small arteries. Isoflurane dilated large coronary arteries, with the preconstricted vessels dilating the most. In contrast, halothane dilated both the small and large coronary arteries to a similar extent. Preconstricted vessels dilated more to halothane than vessels with no added tone. CONCLUSIONS: Whereas isoflurane has a heterogeneous vasomotor effect in rat coronary arteries, constricting the small vessels and dilating the large ones, halothane dilates both the small and large arteries. The vasoconstriction effect was most evident in vessels with no added tone, whereas the vasodilatory effect was most significant in preconstricted vessels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Preservation of the ration of cerebral blood flow/metabolic rate for oxygen during prolonged anesthesia with isoflurane, sevoflurane, and halothane in humans.

BACKGROUND: In several animal studies, an increase in cerebral blood flow (CBF) produced by volatile anesthetics has been reported to resolve over time during prolonged anesthesia. It is important to investigate whether this time-dependent change of CBF takes place in humans, especially in clinical situations where surgery is ongoing under anesthesia. In this study, to evaluate the effect of prolonged exposure to volatile anesthetics (isoflurane, sevoflurane, and halothane), the CBF equivalent (CBF divided by cerebral metabolic rate for oxygen (CMRO2) was determined every 20 min during anesthesia lasting more than 4h in patients. METHODS: Twenty-four surgical patients were assigned to three groups at random to receive isoflurane, sevoflurane, or halothane (8 patients each). End-tidal concentration of the selected volatile anesthetic was maintained at 0.5 and 1.0 MAC before surgery and then 1.5 MAC for the 3 h of surgical procedure. Normothermia and normocapnia were maintained. Mean arterial blood pressure was kept above 60 mmHg, using phenylephrine infusion, if necessary. CBF equivalent was calculated every 20 min as the reciprocal of arterial-jugular venous oxygen content difference. RESULTS: CBF equivalent at 0.5 MAC of isoflurane, halothane, and sevoflurane was 21 +/- 4, 20 +/- 3, and 21 +/- 5 ml blood/ml oxygen, respectively. All three examined volatile anesthetics significantly (P<0.01) increased CBF equivalent in a dose-dependent manner (0.5, 1.0, 1.5 MAC). AT 1.5 MAC, the increase of CBF equivalent with all anesthetics was maintained increased with minimal fluctuation for 3 h. The mean value of CBF equivalent at 1.5 MAC in the isoflurane group (45 +/- 8) was significantly (P<0.01) greater than those in the halothane (32 +/- 8) and sevoflurane (31 +/- 8) groups. Electroencephalogram was found to be relatively unchanged during observation periods at 1.5 MAC. CONCLUSIONS: These results demonstrate that CBF/CMRO2 ratio is markedly increased above normal and maintained during prolonged inhalation of volatile anesthetics in humans. It is impossible to determine whether these data indicate a stable CBF or whether CBF and CMRO2 are changing in parallel during the observation period. The unchanging electroencephalographic pattern suggests that the former possibility is more likely and that the increase of CBF produced by volatile anesthetics is maintained over time without decay, which has been reported in several animal studies. It also is suggested that isoflurane possesses greater capability to maintain global CBF relative to CMRO(2) than does halothane or sevoflurane. time.)

Adult↗
PubMed1996

Simulation of an epidural test dose with intravenous isoproterenol in awake and in halothane-anesthetized children.

BACKGROUND: An epidural test dose containing epinephrine does not reliably produce hemodynamic responses in children under halothane anesthesia. The purpose of this study was to determine hemodynamic responses to intravenous isoproterenol in both awake and halothane-anesthetized children. METHODS: After obtaining institutional review board approval and parental informed consent, 72 ASA physical status 1 or 2 children (2.8 +/- 1.7 yr) undergoing elective minor surgery were studied before and during anesthesia with 1.2 minimum alveolar concentration halothane. A bolus containing 0.25 mg/ kg bupivacaine and 0.05 microgram/kg, 0.075 microgram/kg, or 0.1 microgram/kg isoproterenol, or bupivacaine and saline was injected via a peripheral arm vein to simulate intravascular injection of an epidural test dose. RESULTS: Before induction of anesthesia, all patients showed a positive test response after isoproterenol injection (heart rate increase > or = 20 beats/min). During anesthesia, 79% of patients receiving 0.05 microgram/kg, 89% of patients receiving 0.075 microgram/kg, and 100% of patients receiving 0.1 microgram/kg met the criterion of a positive test response. Among each treatment group, all infants showed a positive test response. Blood pressure did not differ among the groups at any time. Transient benign dysrhythmias occurred in only one patient under halothane anesthesia receiving 0.075 microgram/kg isoproterenol. CONCLUSION: Isoproterenol at a dose of 0.1 microgram/kg is a sensitive indicator for intravascular injection of a test dose in children anesthetized with halothane and nitrous oxide. Isoproterenol at a dose of 0.05 microgram/kg approximates a minimal effective dose in awake children and in infants. After detailed studies on neural toxicity, isoproterenol could be of value as an epidural test agent in children.

Adrenergic beta-Agonists↗
PubMed1996

A beta-adrenoceptor agonist evokes a nitric oxide-cGMP relaxation mechanism modulated by adenylyl cyclase in rat aorta. Halothane does not inhibit this mechanism.

BACKGROUND: The objective of this study was to characterize the effects of halothane on the agonist-induced nitric oxide-cyclic GMP (NO-cGMP) mechanisms by comparing the intracellular signal transduction mediating isoproterenol- and acetylcholine-induced nitric oxide formation. METHODS: Isoproterenol-induced relaxations of rat aortic rings with and without endothelia were examined in the absence and presence of halothane. Studies were also done in the presence of inhibitors of nitric oxide-synthase, adenylyl cyclase, calmodulin, protein kinase A, and intracellular Ca2+ release mechanism. The relaxations under some of these conditions were compared with those induced by acetylcholine. Cyclic nucleotide contents of the rings were also measured. RESULTS: Isoproterenol relaxed aortic rings via the endothelium-dependent nitric oxide-cyclic GMP mechanism. Inhibition of adenylyl cyclase or of protein kinase A attenuated the isoproterenol-induced relaxations significantly but did not affect those induced by acetylcholine. Inhibition of intracellular Ca2+ release abolished the acetylcholine-induced relaxations but did not affect those induced by isoproterenol. Calmodulin inhibition attenuated both agonist-induced relaxations significantly. Unlike acetylcholine-induced relaxation, that induced by isoproterenol was not affected by halothane. Isoproterenol increased both the cyclic adenosine monophosphate and cGMP contents of rings significantly when endothelia were intact. Inhibition of nitric oxide synthase attenuated the isoproterenol-induced cGMP content increases significantly but did not affect the cyclic adenosine monophosphate content increases. Halothane (2%) did not affect isoproterenol-induced increases in nucleotide content. CONCLUSIONS: Isoproterenol-induced nitric oxide formation requires the activation of constitutive nitric oxide synthase, but the Ca2+ release mechanism is not involved in activating this enzyme. Halothane can inhibit the nitric oxide-cyclic GMP mechanism only when Ca2+ release is greatly involved in the activation of constitutive nitric oxide synthase.

Acetylcholine↗
PubMed1996

Halothane blocks synaptic excitation of inhibitory interneurons.

BACKGROUND: Activation of principal hippocampal neurons is controlled by feedforward and feedback inhibition mediated by gamma-aminobutyric acidergic interneurons. The effects of halothane on glutamate receptor-mediated synaptic excitation of inhibitory interneurons have not been reported yet. METHODS: The effects of halothane on glutamatergic excitatory postsynaptic currents and on spike threshold in visually identified interneurons were studied with tight-seal, whole-cell voltage- and current-clamp recordings in thin slices from adult mouse hippocampus. The excitatory postsynaptic currents were pharmacologically isolated into their N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated components using selective antagonists. RESULTS: Halothane (0.37-2.78 mM) reversibly blocked non-N-methyl-D-aspartate and N-methyl-D-aspartate excitatory postsynaptic currents in hippocampal oriens-alveus interneurons. Half-maximal inhibition was observed at similar concentrations (0.59 mM and 0.50 mM, respectively). Halothane inhibited synaptically generated action potentials at concentrations that did not elevate the spike threshold. CONCLUSIONS: Halothane blocks glutamate receptor-mediated synaptic activation of inhibitory interneurons in the mouse hippocampus.

Action Potentials↗