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PubMed2003

Desflurane inhibits platelet function in vitro similar to halothane.

BACKGROUND AND OBJECTIVE: The effects of the volatile anaesthetic desflurane on platelet activation in vitro were studied and compared to those of halothane. METHODS: Platelet-rich plasma was exposed to 2 MAC of desflurane or halothane, or air only and stimulated by platelet agonists ADP (2.5, 5 and 10 micromol L(-10) and collagen (10 microg m(L-1)). Platelet response was measured by Born aggregometry (maximum aggregation response, area under the curve) and flow cytometry (mean channel fluorescence, percentage of CD62P-positive cells, index of platelet activation for positive platelets). RESULTS: Aggregation response was significantly reduced in platelets exposed to desflurane or halothane; the inhibitory effect was more pronounced when the areas under the curve were analysed: values ranged from 37.5% to 73.3% of control samples for ADP stimulation and 77.1% to 79.8% for collagen stimulation. CD62P expression before and after stimulation with receptor agonists was not statistically different in platelets exposed to desflurane, halothane or air. CONCLUSIONS: By impairing platelet aggregation while not affecting alpha-degranulation desflurane has a differential effect on various aspects of platelet activation similar to halothane. Our results are compatible with the hypothesis of an impairment of platelet thromboxane receptor signalling by halothane. We suggest a similar mechanism for desflurane.

Anesthetics, Inhalation↗
PubMed2004

Similar susceptibility to halothane, caffeine and ryanodine in vitro reflects pharmacogenetic variability of malignant hyperthermia.

BACKGROUND AND OBJECTIVE: To analyse the use of standardized application of ryanodine for in vitro muscle contracture testing to define cut-off values separating malignant hyperthermia susceptible from malignant hyperthermia negative subjects. Furthermore, we compared the results of in vitro muscle-contracture tests following the halothane, caffeine and ryanodine challenges. METHODS: In 113 subjects, halothane, caffeine and ryanodine muscle-contracture tests were performed according to the protocol of the European Malignant Hyperthermia Group. RESULTS: Malignant hyperthermia susceptible subjects (n = 77) had significantly shorter onset times in the ryanodine in vitro muscle-contracture test (1 micromol ryanodine) compared with malignant hyperthermia negative subjects (n = 36), median 4.8 vs. 20.1 min, respectively, without any influence of age or gender. The best cut-off value was 10 min (sensitivity 0.78 and specificity 0.94, respectively). Shorter cut-off values had greater specificity, but lower sensitivity. Groups could not be separated without an overlap. In susceptible subjects, we found a correlation between onset time and threshold concentrations for halothane and caffeine (p = 0.47 and 0.52, respectively). In addition, muscle bundles with high susceptibility to halothane and caffeine also showed high susceptibility to ryanodine. CONCLUSIONS: The ryanodine in vitro muscle-contracture test confirmed the malignant hyperthermia status that was determined using the halothane and caffeine in vitro muscle-contracture tests. Due to an overlap between the two groups, discrimination ability was not always perfect and short cut-off values with higher specificity had reduced sensitivity and vice versa. The correlation of contractures following the halothane, caffeine and ryanodine challenges points towards a similar individual pharmacogenetic effect rather than a specific, different pharmacological action between the three agents.

Adolescent↗
PubMed2003

Identification of nicotinic acetylcholine receptor amino acids photolabeled by the volatile anesthetic halothane.

To identify inhalational anesthetic binding domains in a ligand-gated ion channel, we photolabeled nicotinic acetylcholine receptor (nAChR)-rich membranes from Torpedo electric organ with [(14)C]halothane and determined by Edman degradation some of the photolabeled amino acids in nAChR subunit fragments isolated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-performance liquid chromatography. Irradiation at 254 nm for 60 s in the presence of 1 mM [(14)C]halothane resulted in incorporation of approximately 0.5 mol of (14)C/mol of subunit, with photolabeling distributed within the nAChR extracellular and transmembrane domains, primarily at tyrosines. GammaTyr-111 in ACh binding site segment E was labeled, while alphaTyr-93 in segment A was not. Within the transmembrane domain, alphaTyr-213 within alphaM1 and deltaTyr-228 within deltaM1 were photolabeled, while no labeled amino acids were identified within the deltaM2 ion channel domain. Although the efficiency of photolabeling at the subunit level was unaffected by agonist, competitive antagonist, or isoflurane, state-dependent photolabeling was seen in a delta subunit fragment beginning at deltaPhe-206. Labeling of deltaTyr-212 in the extracellular domain was inhibited >90% by d-tubocurarine, whereas addition of either carbamylcholine or isoflurane had no effect. Within M1, the level of photolabeling of deltaTyr-228 with [(14)C]halothane was increased by carbamylcholine (90%) or d-tubocurarine (50%), but it was inhibited by isoflurane (40%). Within the structure of the nAChR transmembrane domain, deltaTyr-228 projects into an extracellular, water accessible pocket formed by amino acids from the deltaM1-deltaM3 alpha-helices. Halothane photolabeling of deltaTyr-228 provides initial evidence that halothane and isoflurane bind within this pocket with occupancy or access increased in the nAChR desensitized state compared to the closed channel state. Halothane binding at this site may contribute to the functional inhibition of nAChRs.

Amino Acid Sequence↗
PubMed2004

Halothane alters contractility and Ca2+ transport in ventricular myocytes from streptozotocin-induced diabetic rats.

General anaesthetics have previously been shown to have profound effects on myocardial function. Moreover, many patients suffering from diabetes mellitus are anaesthetised during surgery. This study investigated compromised functioning of cardiac myocytes from streptozotocin (STZ)-induced diabetic rats and the additive effects of halothane on these dysfunctions. Ventricular myocytes were isolated from 8 to 12 weeks STZ-treated rats. Contraction and intracellular free calcium concentration ([Ca2+]i) were measured in electrically field-stimulated (1 Hz) fura-2-AM-loaded cells using a video-edge detection system and a fluorescence photometry system, respectively. L-type Ca2+ current was measured in whole cell, voltage-clamp mode. Halothane significantly (p < 0.01) depressed the amplitude and the time course of the Ca2+ transients in a similar manner in myocytes from control and STZ-treated rats. However, the effect of halothane on the amplitude of shortening and L-type Ca2+ current was more pronounced in myocytes from STZ-treated animals compared to age-matched controls. Myofilament sensitivity to Ca2+ was significantly (p < 0.01) increased in myocytes from STZ-treated rats compared to control. However, in the presence of halothane the myofilament sensitivity to Ca2+ was significantly (p < 0.05) reduced to a greater extent in myocytes from STZ-treated rats compared to controls. In conclusion, these results show that contractility, Ca2+ transport and myofilament sensitivity were all altered in myocytes from STZ-treated rats and these processes were further altered in the presence of halothane suggesting that hearts from STZ-induced diabetic rats are sensitive to halothane.

Anesthetics, Inhalation↗
PubMed1999

Sevoflurane causes more postoperative agitation in children than does halothane.

BACKGROUND: An agitated recovery may occur after inhalation anesthesia. The aim of the present study was to assess the recovery quality after mask anesthesia with either halothane or sevoflurane in children. METHODS: Sixty-two children, 8 months to 18 years of age, scheduled for minor surgery, were randomly assigned to receive either halothane or sevoflurane. The patients were premedicated with midazolam and anesthesia was induced i.v. with propofol or by inhalation and maintained with halothane or sevoflurane in N2O/O2 via face mask. Recovery was assessed by a "blinded" observer using a postanesthetic recovery score. Agitation and pain were judged using a visual analog scale. The incidence of vomiting was noted. The day after anesthesia older children and parents of younger children were interviewed about their experience of the anesthesia and recovery period. RESULTS: There were no differences between groups in respect of age, weight, length, or duration of surgery or inhalational gas exposure. Median time from end of administration of inhalational agent to spontaneous eye opening was less after sevoflurane (25 min) than after halothane (48 min), (P < 0.01). Likewise, recovery was faster after sevoflurane anesthesia (P < 0.05). Agitation, but not pain, occurred more frequently after sevoflurane than after halothane (P < 0.05) and agitation was significantly more common in younger children. There was no difference in duration of hospital stay between day-care patients in the two groups. CONCLUSION: Early postanesthetic agitation and recovery was faster after mask anesthesia with sevoflurane than after halothane. There was a higher incidence of agitation in younger children, without correlation to pain.

Adolescent↗
PubMed1999

Halothane decreases bacterial adherence in vitro.

BACKGROUND: Adherence of pathogenic bacteria to host epithelial cells is thought to be the initial step in infection, while the presence of the commensal flora is an important host defence mechanism. Anything altering bacterial adherence to human epithelial cells may contribute to bacterial infections. The impact of anaesthesia on this first step to infection is not known. In this study the effect of halothane on bacterial adherence was investigated. METHODS: Human epithelial cells (HEp-2) and two strains of Escherichia coli were exposed to halothane 2% for 2 h. Then HEp-2 cells were coincubated with bacteria for 3 h. Bacteria attached to the epithelial cells were evaluated by light microscopy. RESULTS: Compared to the control, bacterial adherence was reduced by 37% to 56% with the different strains when HEp-2 cells were exposed to halothane. No significant difference was found when only bacteria were treated with halothane. CONCLUSION: Our results show that halothane reduces bacterial adherence to human epithelial cells in vitro. Reduced number or function of epithelial cell surface receptors may be responsible for the reduced adherence as no changes were observed when only the bacteria were exposed to halothane.

Anesthetics, Inhalation↗
PubMed2000

Does halothane or isoflurane affect hypoxic and post-hypoxic vascular response in rabbit aorta?

BACKGROUND: Halothane and isoflurane affect differently endothelium-dependent and -independent vasorelaxation at 95% O2. In addition, hypoxic vascular response might involve endothelium-dependent and -independent mechanisms. Therefore, we investigated, in rabbit aortic rings, 1) the influence of halothane and isoflurane on vasodilation at 95% O2 and on hypoxic-induced vasorelaxation at 0% O2 and 2) the influence of halothane and isoflurane on endothelium-dependent and -independent post-hypoxic vascular response. METHODS: Endothelium-intact and endothelium-denuded rabbit aortic rings were used. Phenylephrine precontracted rings were exposed, at 95% O2, to acetylcholine (ACh, 10(-9) to 10(-4) M) or sodium nitroprusside (SNP, 10(-9) to 10(-4) M) in the presence or absence of anaesthetic at 1 or 2 MAC. Precontracted rings were also exposed to an acute reduction in O2 from 95% to 0% followed by an acute reoxygenation with 95% O2 in the absence or presence of anaesthetic at 1 or 2 MAC. RESULTS: At 95% O2, halothane decreased endothelium-dependent relaxation to ACh, while endothelium-independent relaxation to SNP was decreased only at 2 MAC. Isoflurane did not modify ACh- or SNP-induced relaxation. At 0% O2, neither halothane nor isoflurane altered the hypoxic vascular relaxation. Post-hypoxic response was not changed either. CONCLUSION: Our results indicate that halothane and isoflurane do not alter vascular hypoxic response in conductance arteries.

Acetylcholine↗
PubMed1999

Protein kinase C co-expression and the effects of halothane on rat skeletal muscle sodium channels.

1. Voltage-gated Na channels, which are potential targets for general anaesthetics, are substrates for PKC, which phosphorylates a conserved site in the channel inactivation gate. We investigated the idea that PKC modulates the effect of volatile anaesthetics on Na channels via phosphorylation of this inactivation gate site. 2. Na currents through rat skeletal muscle Na channel alpha-subunits expressed in Xenopus oocytes were measured by two-microelectrode voltage clamp in the presence of the volatile anaesthetic agent halothane (2-bromo-2-chloro-1,1,1-trifluroethane). PKC activity was modulated by co-expression of a constitutively active PKC alpha-isozyme. 3. Halothane (0.4 mM) had no effect on Na currents. With co-expression of PKC, however, halothane dose-dependently enhanced the rate of Na current decay and caused a small, but statistically significant reduction in Na current amplitude. 4. The enhancement of Na current decay was absent in a Na channel mutant in which the inactivation gate phosphorylation site was disabled. Effects of halothane on amplitude were independent of this mutation. 5. Co-expression of a PKC alpha-isozyme permits an effect of halothane to hasten current decay and reduce current amplitude, at least in part through interaction with the inactivation gate phosphorylation site. We speculate that the interaction between halothane and Na channels is direct, and facilitated by PKC activity and by phosphorylation of a site in the channel inactivation gate.

Anesthetics, Inhalation↗
PubMed1998

Anaesthesia and the QT interval. Effects of isoflurane and halothane in unpremedicated children.

The effects of isoflurane and halothane on the QT interval were investigated during induction of anaesthesia. Fifty-one unpremedicated, ASA grade 1 children were studied. Anaesthesia was induced with either isoflurane (n = 25) or halothane (n = 26) and was maintained to the end of the study with end-tidal concentrations of between 2.5% and 3%. Recording of the electrocardiograph, heart rate and systolic arterial pressure were obtained at the following times: before induction of anaesthesia; 1 min and 3 min after stable end-tidal concentrations of anaesthetic agent had been reached; 1 min and 3 min following vecuronium administration; at the time of tracheal intubation and 1 min and 3 min later. Isoflurane significantly prolonged the QT interval (p < 0.001), in contrast to halothane which shortened it (p < 0.01). Heart rate remained largely unchanged during isoflurane anaesthesia but it decreased in the presence of halothane (p < 0.001). In both groups, systolic arterial pressure decreased significantly after induction of anaesthesia (p < 0.001) and remained so to the end of the study. In the isoflurane group, 12 children developed ECG repolarisation abnormalities and in one child an arrhythmia was noticed. In the halothane group, one child developed repolarisation changes while arrhythmias were observed in 10 children. There were no adverse sequelae. It is concluded that halothane may be a better anaesthetic agent than isoflurane for use in children with a prolonged QT interval.

Anesthetics, Inhalation↗
PubMed1998

Sevoflurane anaesthesia in paediatric patients: better than halothane?

Forty-two children (aged 2-16 years) were randomly assigned to receive either sevoflurane (n = 21) or halothane (n = 21) in nitrous oxide/oxygen. After pre-medication with midazolam, anaesthesia was induced by facemask and the anaesthetic concentration was increased until loss of eyelash reflex (sevoflurane, 6%; halothane, 2.5%). Thereafter, 1-1.5 MAC of the inhalational agents were maintained until skin closure. Intra-operative analgesia was provided either by intermittent intravenous (i.v.) bolus doses of fentanyl (2-3 micrograms kg-1) or by a regional blockade. Induction was smooth and the time to loss of eyelash reflex was slightly shorter with sevoflurane than with halothane, the difference not quite reaching statistical significance (P = 0.06). In both groups, heart rate remained stable and blood pressure decreased significantly during induction. Haemodynamic parameters remained stable during anaesthetic maintenance; no cardiac dysrhythmias were observed. Emergence time with sevoflurane was 12.9 min vs. 16.3 min with halothane, but this difference was not statistically significant. It is concluded that sevoflurane is as suitable for paediatric patients as halothane. The slightly faster emergence time offered by sevoflurane over halothane was of no clinical significance in the present study.

Adolescent↗
PubMed1997

Evaluation of awakening and recovery characteristics following anaesthesia with nitrous oxide and halothane fentanyl or both for brief outpatient procedures in infants.

This study compared recovery characteristics and postoperative ventilatory function when halothane, fentanyl or combination of halothane and fentanyl in addition to N2O were used for intraoperative anaesthesia in term infants undergoing hernia repair as outpatients. Sixty-six full term ASA PS I infants ages 1-12 months were studied. All received inhalation induction with N2O, O2 and halothane, followed by intravenous atropine and atracurium, tracheal intubation, and controlled ventilation. For anaesthesia maintenance, patients were randomized into one of three groups. Group I received 70% N2O, 30% O2 and halothane. Group II received 70% N2O, 30% O2, halothane and 2 micrograms.kg-1 fentanyl. Group III received 70% N2O, 30% O2 and 10 micrograms.kg-1 fentanyl. Awakening times were similar in all three groups, however, Group I patients had significantly shorter recovery and discharge times than those of Group II and III. None of the patients experienced postoperative apnoea or periodic breathing. One patient in Group III experienced two brief episodes of bradycardia not associated with apnoea or arterial desaturation (SpO2 > 90% for greater than 30 s). Decreased SpO2 occurred less frequently in Group I (5.9%) compared to Group II (22.7%) and Group III (19.0%) patients, however, the group differences were not significant. Transcutaneous CO2 (TcCO2) values were not statistically different among the three groups. Pain scores were initially lower in Groups II and III, but at 120 min the differences were not significant. Postoperative apnoea was not observed in this study. SpO2 < 90% and TcCO2 > 9 kPa (70 mmHg) was more common in infants receiving 2 and 10 micrograms.kg-1 fentanyl than in infants receiving halothane and nitrous oxide anaesthesia. Infants < 3 months old did not have a higher incidence of SpO2 < 90% or significantly higher TcCO2 values when compared to infants > 3 months old. Fentanyl in doses used in this study did not prolong awakening time but did prolong recovery and discharge times in outpatient infants.

Ambulatory Surgical Procedures↗
PubMed1992

Saturable binding of halothane to rat brain synaptosomes.

The hypothesis that volatile anesthetics act directly on or bind specifically to membrane proteins remains controversial. In earlier in situ electron probe microanalysis studies in cardiac muscle we showed preferential partitioning of halothane into mitochondria. To determine whether partitioning represents saturable binding or simple solubility, a photoaffinity labeling method was developed for halothane to examine binding in rat brain synaptosomes. Radioligand binding assays were then used to determine binding parameters for this important inhalational anesthetic. UV-light exposure of synaptosomes incubated with clinical concentrations of [14C]halothane resulted in sufficient labeling to allow characterization of binding sites. Analysis of saturation and competition curves showed that greater than 60% of [14C]halothane photolysis product binding to synaptosomes was specific, with low affinity (Kd = 0.49 +/- 0.16 mM) and high binding site concentration (Bmax = 1.87 +/- 0.75 nmol/mg of protein). Halothane photoaffinity labeling was partially inhibited by isoflurane (20%), chloroform (44%), 2-bromotrifluoroethane (20%), and dichlorotrifluoroethane (20%) but not by ethanol. The Kd measured with this photoaffinity approach is similar to the concentration of halothane required to produce anesthesia in rats.

Affinity Labels↗
PubMed1998

Effects of halothane on mechanical response of skeletal muscle from malignant hyperthermia susceptible patients.

The purpose of this investigation was to compare the effects of halothane on malignant hyperthermia (MH) and normal isolated muscle bundle performance during isometric contraction and relaxation phases. Mechanical parameters were measured: peak tension (PT), time to peak tension (TPT) and positive peak of isometric tension derivative (+dP/dtmax) characterized the contraction phase. Half-relaxation time (RT1/2) and negative peak of isometric tension derivative (-dP/dtmax) characterized the relaxation phase. The ratio R = (+dP/dtmax)/(-dP/dtmax) was used to study the coupling between contraction and relaxation under isometric condition. In normal muscle, halothane increased PT by nearly 40% without altering TPT. The +dP/dtmax value increased concomitantly with the -dP/dtmax values, thus no changes in R was observed. In MH muscle, PT was first potentiated (0.5-1.0 vol% halothane) and then depressed (2.0-3.0 vol% halothane). TPT and +dP/dtmax were not altered whereas RT1/2 increased progressively with concomitant decrease in -dP/dtmax, thus R increased by nearly 40%. The amplitude of MH muscle contracture with stepwise concentrations of halothane was correlated with the increase of RT1/2 and R, and the decrease of -dP/dtmax. These results suggest that halothane alters the relaxation phase more than the contraction phase in MH human skeletal muscle compared to normal muscle.

Anesthetics, Inhalation↗
PubMed1975

Calcium uptake into muscle of pigs susceptible to malignant hyperthermia: in vitro and in vivo studies with and without halothane.

MHS and normal pigs were anaesthetized with nitrous oxide and diazepam. Halothane 1% was then administered for 1 hr. Immediately before and immediately after the halothane inhalation, 10 g of vastus lateralis muscle was excised. SR was isolated from this muscle. Calcium accumulation by the MHS sarcoplasmic reticulum in the absence of halothane was greater than normal. Halothane in vitro produced a similar increase in calcium uptake into both the MHS and the normal SR. Halothane in vivo significantly reduced calcium accumulation by hyperthermic SR but had no significant effect on calcium uptake into the normal SR. Thus the action of halothane on the MHS sarcoplasmic reticulum is indirect, occurring only in the intact cell. It is possibly a result of the deleterious effect which lack of ATP, a low pH or a high temperature is likely to have on the calcium accumulating mechanism of the SR membrane. Our results suggest that the primary defects of porcine and human malignant hyperthermia are not entirely synonymous.

Anesthesia, Inhalation↗
PubMed1977

Inadvertent contamination of anaesthetic circuits with halothane.

All halothane vaporizers tested for leakage when turned off, leaked significant amounts of halothane and this may represent a hazard to patients liable to develop halothane hepatitis or malignant hyperpyrexia. The hazard from leaking vaporizers may be reduced considerably by the use of well-designed bypass units. Circuit contamination by halothane may still result from such sources as neoprene seals around flowmeters, breathing bags and anaesthetic hose which have had previous contact with halothane vapour, whether or not an apparatus is in use. The hazard from contaminated hoses and bags may be reduced considerably by washing and then hanging in a halothane-free atmosphere for a day. The hazard from contamined rubber or plastic components of the anaesthetic machine can be eliminated only by using one apparatus without the vaporizers having been attached at any time during its working life. Similarly, hazards may arise from trichloroethylene vaporizers and from circuit components contaminated with trichloroethylene.

Accident Prevention↗
PubMed1980

Oxygen-linked binding of halothane to human adult haemoglobin.

The affinity for oxygen of normal human haemoglobin (Hb) solutions was measured in the presence of increasing concentrations of halothane. We observed a maximum increase in P50 of 25% with halothane 40 kPa compared with control (oxygen-argon gas mixtures) indicating the oxygen-linked character of the binding of halothane to the Hb molecule. The effect of halothane on P50 was independent of pH between 7.0 and 8.0 and of chloride concentration between 10 and 100 mmol litre-1. This suggests that halothane-Hb interactions may occur through hydrophobic linkage as occurs with short chain aliphatic hydrocarbons. The oxygen-linked binding of halothane appears of minor importance in altering oxygen binding to Hb in vivo compared with other factors such as chloride ion or 2, 3-DPG.

Adult↗
PubMed1981

The polarographic measurement of halothane.

The polarographic reduction of halothane on silver cathodes was studied. Silver catalyses the reduction of halothane: two electrons are exchanged in the reduction process. Experiments using a rotating disc electrode showed a linear relationship between observed current and halothane concentration. A Silastic membrane-covered polarographic electrode was constructed using a silver cathode which gave a good linear response to changes in halothane concentration over the range 0.5% v/v halothane in nitrogen. Oxygen interferes with the measurement of halothane, but can be removed from a gas sample before analysis.

Electrodes↗
PubMed1985

Changes in ventilatory patterns during halothane anaesthesia in children.

Changes in ventilatory variables (VE, VE, f, Tl/Ttot, VT/Tl, PE'CO2) were studied in 12 unpremedicated children, weighing between 10 and 20 kg, during halothane anaesthesia. At an inspired concentration of 0.5% halothane, respiratory rate increased, VT decreased, and VE did not change markedly. When the inspired halothane concentration increased further, there was a significant decrease in VE, mainly as a result of a marked decrease in VT. PE'CO2 increased significantly and inspiratory duty cycle decreased at high inspired halothane concentrations. On return to baseline (0.5% halothane), there was a significant decrease in inspiratory timing and a significant increase in PE'CO2. The relations between these changes and the effect of halothane on inspiratory muscles are discussed.

Anesthesia, Inhalation↗