Synergism between halothane and nitrous oxide in the production of nuclear abnormalities in the dividing fibroblast.

When Chinese hamster fibroblasts divide in the presence of halothane there is an increased incidence of cells with abnormal nuclei, both in mitosis and in interphase. The authors compared the effects of halothane and nitrous oxide separately and in combination. Nitrous oxide, 75 percent, alone had no significant effect compared with controls, less than 1.4 per cent of cells showing abnormalities, while halothane alone had a dose-dependent effect on both phases of the cell cycle. Halothane, 1 per cent, caused abnormalities in 7 per cent (SEM +/- 0.32) of cells in interphase and in 12 per cent (SEM +/- 0.95) of cells in mitosis, but the combination of 0.75 per cent halothane with 75 percent nitrous oxide produced 15 per cent (SEM +/- 0.68) abnormal cells in interphase and 22 per cent (SEM +/- 0.51) abnormal mitoses. Similar highly significant differences were obtained throughout the dose-response curves to as much as 4 per cent halothane in air and 2.35 per cent halothane in 75 per cent nitrous oxide. This appears to demonstrate synergism between halothane and nitrous oxide in the production of this particular side effect. In contrast, the effects of halothane and nitrous oxide on growth rate were additive.     

METHOXYFLURANE IN DENTAL ANAESTHESIA: A BLIND TRIAL

Anaesthesia with nitrous oxide and oxygen, alone or supplementedwith methoxyflurane or halothane, was administered for dentalextractions in 256 patients (204 children and 52 antenatal women).Anaesthesia was regarded as "good" in 69 per cent of patientswith methoxyflurane and 75 per cent with halothane, but only50 per cent with unsupplemented nitrous oxide and oxygen. Afurther trial was carried out in 144 children and 8 antenatalwomen, nitrous oxide and oxygen being supplemented in all caseswith methoxyflurane or halothane. There were 59 per cent "good"results with methoxyflurane and 76 per cent with halothane.Methoxyflurane was found to be considerably cheaper than halothane.The shortcomings of purely inhalational anaesthesia for dentalextractions was shown by the finding that in no series was thepercentage of "good" results as high as 80.     

Inhibition of cell-mediated cytotoxicity by halothane and nitrous oxide.

Killing of tumor cells by lymphoid cells is important in cell-mediated immunity and defense against cancer. The authors determined that halothane, in vitro, inhibits the killing of YAAC-1 ascites tumor cells from A/jax mice by sensitized peritoneal exudate cells from C57/Black/6 mice. Lysis of tumor cells was quantitated by release of 51Cr into the culture medium. Inhibition of cell-mediated cytotoxicity ranged from 5 per cent in 0.5 per cent halothane to 44.7 per cent in 2.5 per cent halothane exposure. A 12 per cent inhibition of cytotoxicity by 80 per cent nitrous oxide was not statistically significant, but was of a magnitude near that of an equipotent concentration of halothane. The inhibition of cytotoxicity by halothane and nitrous oxide observed in vitro may partially account for the inhibition of cytotoxicity observed when patients undergo surgical operation.     

Differential effects of sevoflurane, isoflurane, and halothane on Ca2+ release from the sarcoplasmic reticulum of skeletal muscle.

BACKGROUND: Although malignant hyperthermia after application of sevoflurane has been reported, little is known about its action on intracellular calcium homeostasis of skeletal muscle. The authors compared the effect of sevoflurane with that of isoflurane and halothane on Ca2+ release of mammalian sarcoplasmic reticulum and applied a novel method to quantify Ca2+ turnover in permeabilized skeletal muscle fibers. METHODS: Liquid sevoflurane, isoflurane, and halothane at 0.6 mM, 3.5 mM, and 7.6 mm were diluted either in weakly calcium buffered solutions with no added Ca2+ (to monitor Ca2+ release) or in strongly Ca2+ buffered solutions with [Ca2+] values between 3 nM and 24.9 microm for [Ca+]-force relations. Measurements were taken on single saponin skinned muscle fiber preparations of BALB/c mice. Individual [Ca2+]force relations were characterized by the Ca2+ concentration at half-maximal force that indicates the sensitivity of the contractile proteins and by the steepness. Each force transient was transformed directly into a Ca2+ transient with respect to the individual [Ca2+]-force relation of the fiber. RESULTS: At 0.6 mM, single force transients induced by sevoflurane were lower compared with equimolar concentrations of isoflurane and halothane (P < 0.05). Similarly, calculated peak Ca2+ transients of sevoflurane were lower than those induced by equimolar halothane (P < 0.05). The Ca2+ concentrations at half maximal force were decreased after the addition of sevoflurane, isoflurane, and halothane in a concentration-dependent manner (P < 0.05). CONCLUSION: Whereas sevoflurane, isoflurane, and halothane similarly increase the Ca2+ sensitivity of the contractile apparatus in skeletal muscle fibers, 0.6 mM sevoflurane induces smaller Ca2+ releases from the sarcoplasmic reticulum than does equimolar halothane.     

Cerebral effects of nitrous oxide in the dog

The cerebral effects of nitrous oxide, 60 per cent, were examined in 27 dogs. During administration of halothane, 0.2 per cent, nitrous oxide increased cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMR02) to a maximum of 203 and 121 per cent of control, respectively. Cerebrospinal fluid pressure paralleled the change in CBF. The electroencephalogram (EEG) showed low-voltage slow-wave activity. With halothane, 0.8 per cent, nitrous oxide increased CBF and CMR02 to maximum values of 164 and 108 per cent of control, respectively. After administration of thiamylal, 8 mg/kg, intravenously, nitrous oxide did not increase CBF or CMR02 for the first 30-min period, but thereafter, CMR02 increased to 11 per cent above control. Pretreatment with reserpine, 0.5 mg/kg, intramuscularly, for two days did not modify the cerebral circulator and metabolic responses to nitrous oxide. These results indicate that nitrous oxide causes cerebral metabolic stimulation accompanied by an increase in CBF and slowing of the EEG. Sympathoadrenal stimulation would appear not to be the mechanism for the increases in CBF and CMR02. The cerebral effects of nitrous oxide are modified by the background anesthesia.     

Differential Effects of Sevoflurane, Isoflurane, and Halothane on Ca (2+) Release from the Sarcoplasmic Reticulum of Skeletal Muscle

Background: Although malignant hyperthermia after application of sevoflurane has been reported, little is known about its action on intracellular calcium homeostasis of skeletal muscle. The authors compared the effect of sevoflurane with that of isoflurane and halothane on Ca2+ release of mammalian sarcoplasmic reticulum and applied a novel method to quantify Ca2+ turnover in permeabilized skeletal muscle fibers.

Methods: Liquid sevoflurane, isoflurane, and halothane at 0.6 mM, 3.5 mM, and 7.6 mM were diluted either in weakly calcium buffered solutions with no added Ca2+ (to monitor Ca2+ release) or in strongly Ca2+ buffered solutions with [Ca2+] values between 3 nM and 24.9 [micro sign]M for [Ca2+]-force relations. Measurements were taken on single saponin skinned muscle fiber preparations of BALB/c mice. Individual [Ca2+]-force relations were characterized by the Ca2+ concentration at half-maximal force that indicates the sensitivity of the contractile proteins and by the steepness. Each force transient was transformed directly into a Ca (2+) transient with respect to the individual [Ca2+]-force relation of the fiber.

Results: At 0.6 mM, single force transients induced by sevoflurane were lower compared with equimolar concentrations of isoflurane and halothane (P < 0.05). Similarly, calculated peak Ca2+ transients of sevoflurane were lower than those induced by equimolar halothane (P < 0.05). The Ca2+ concentrations at half maximal force were decreased after the addition of sevoflurane, isoflurane, and halothane in a concentration-dependent manner (P < 0.05).     

SYSTEMIC EFFECTS OF NITROUS OXIDE WHEN USED WITH HALOTHANE AND OXYGEN ANAESTHESIA AT NORMAL BODY TEMPERATURE

Observations made during thirty-five routine operations, using0.5–2.0 per cent halothane in a 70–80 per cent mixtureof nitrous oxide with oxygen, indicate that addition of nitrousoxide to halothane and oxygen may be associated with decreasein blood pressure, heart rate, tidal volume and muscle tone,and increase in respiratory rate; reversal of these changesmay be obtained by withdrawal of nitrous oxide. In three offive observations the rise in respiratory rate was inadequateto compensate for the fall in tidal volume, and minute volumefell by 16–37 per cent. In patients with chronic respiratorydisease, a fall in minute volume of this order might resultin serious arterial oxygen desaturation, particularly when oxygenconstitutes 25 per cent or less of the inspired gas. When halothane,which also depresses ventilation, is used together with highconcentrations of nitrous oxide, this might result in seriousrespiratory depression. Present address: Institute of Orthopaedics, Stanmore, Middlessex.     

Direct effect of halothane and isoflurane on the function of the sarcoplasmic reticulum in intact rabbit atria

The negative inotropic effect of halothane and isoflurane on potentiated-state contractions of isolated rabbit atria in a normal Ca2+ (2.5 mM) medium was compared with the force depression in low Ca2+ media without an anesthetic. When this comparison was made in the presence of 1 microM ryanodine so that the force of contraction was dependent only upon transsarcolemmal Ca2+ influx with no Ca2+ contribution from the sarcoplasmic reticulum (SR), the force of contraction was depressed equally by 0.6% halothane in a normal Ca2+ medium and by a 1.5 mM Ca2+ medium without the anesthetic. Similarly, 1.0% halothane or 1.5% isoflurane and a 1.0 mM Ca2+ medium were equally depressant as were 2.4% isoflurane and a 0.5 mM Ca2+ medium. In the absence of ryanodine, where the atrial contractile activity is largely dependent on Ca2+ released from the SR, 0.6% halothane in the normal Ca2+ medium depressed contractile force by 32%, whereas the force was depressed by only 16% in the 1.5 mM Ca2+ medium without the anesthetic. Similar results were obtained when the effects of 1.0% halothane and of 1.0 mM Ca2+ were compared. In contrast, the force of contraction measured in the absence of ryanodine was not at all inhibited by 1.5% isoflurane and minimally (11%) inhibited by 2.4% isoflurane. Consequently, the force depression by isoflurane was less than that found in the low Ca2+ media.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arterial air embolism of venous origin in dogs: effect of nitrous oxide in combination with halothane and pentobarbitone

The effects of using nitrous oxide (N2O) with halothane or pentobarbitone anaesthesia on the filtration of venous air emboli (VAE) by the pulmonary circulation were studied in dogs. Dogs anaesthetized with either pentobarbitone, pentobarbitone/N2O, halothane, or halothane/N2O were embolized with venous air into the right atrium at 0.25 to 0.35 ml.kg-1.min-1 for 30 min. The animals were in a supine, head down position. A Doppler ultrasonic probe located over the suprarenal aorta detected arterial bubbles that escaped filtration by the lungs. No bubbles were detected at 0.25 ml.kg-1.min-1, but at 0.30 ml.kg-1.min-1 the incidence was 11 per cent (pentobarbitone), 0 per cent (pentobarbitone/N2O), 33 per cent (halothane), and 63 per cent (halothane/N2O) and at 0.35 ml.kg-1.min-1, 44 per cent (pentobarbitone), 14 per cent (pentobarbitone/N2O), and 56 per cent (halothane). Half of the dogs receiving VAE with halothane/N2O at 0.30 ml.kg-1.min-1 died within the first 10 min of the air infusion. Thus, no animals were studied at the next higher dose (0.35 ml.kg-1.min-1). The results suggest that the occurrence of VAE with nitrous oxide anaesthesia may result in greater haemodynamic consequence and increased likelihood for spillover of the venous bubbles into the arteries if used with halothane as compared to pentobarbitone.     

Attenuation of contraction of isolated canine coronary arteries by enflurane and halothane

Contraction of vascular smooth muscle such as that existing in coronary arteries is regulated in part by Ca++ entry into cells via Ca++ channels. Volatile anaesthetics are known to attenuate agonist-induced coronary artery constriction. The purpose of this experiment was to determine if 1.5 MAC concentrations of halothane or enflurane attenuated contractions evoked by activation of one type of Ca++ channel--the potential operator channel. In the current experiment, potential operator channels were activated by depolarizing isolated canine coronary artery rings with high concentration of K+, causing Ca++ entry and vessel contraction. Rings without endothelium were suspended for isometric force measurement in organ chambers containing aerated Krebs-Ringer solution. Maximum response to Ca++ in rings depolarized with K+ was 120 +/- 5 per cent in untreated versus 101 +/- 3 per cent in rings treated with enflurane (P less than 0.01). The maximum response was 123 +/- 6 per cent in untreated versus 111 +/- 5 per cent during halothane administration (P less than 0.05). In contrast, nifedipine 10(-9) M depressed maximum contractions from 114 +/- 5 per cent to 37 +/- 4 per cent (P less than 0.01) and nifedipine 10(-8) M depressed contractions to 30 +/- 4 per cent (P less than 0.01). In a further series of experiments, sustained contractions were depressed by continued administration of the anaesthetics, indicating no loss of anaesthetic effect with time. The results indicate that 1.5 MAC halothane and enflurane attenuate contractions of canine coronary arteries evoked by depolarization and Ca++ entry through potential operated channels. However, neither halothane nor enflurane exhibited the marked depressant effect exerted by nifedipine.     

THE IMMEDIATE CARDIAC DEPRESSION BY ANAESTHETICS IN CONSCIOUS DOGS

The time course of circulatory changes during induction withhalothane and/or nitrous oxide was studied in six healthy awakedogs. Beat-to-beat changes in cardiac performance were measuredwith chronically implanted aortic electromagnetic flowmeters,and pressures were recored from atria, pulmonary artery, anddescending aorta. The dogs were trained to wear masks designedfor delivering gases, and to acclimatize to the odour of halothane.Both 3 per cent halothane and 60 per cent nitrous oxide reducedpeak aoritc flow and maximum acceleration within 4–8 secondsafter the first breath. This depression was more pronouncedwith halothane than nitrous oxide, and was even more severewith the combinaton of halothane and nitrous oxide, and waseven more severe with the combination of halothane and nitrousoxide. and was even more severe with the combination of halothaneand nitrous oxide. Cardiac denervation when halothane and nitrousoxide olone and in combination produced the same immediate cardiacdepression ^*Supported in part by United States Public Health,Grant Number2T01GM00063-09 and the WellcomeTrust. Present address: Departmentof Anesthesia,Stanford Medical School, Palo Alto, California,U.S.A.     

Nitrous oxide added to halothane reduces coronary flow and myocardial oxygen consumption in patients with coronary disease

The haemodynamic and myocardial metabolic effects of adding 50 per cent nitrous oxide to 0.5 per cent halothane were studied in 13 patients, before the surgical incision for coronary artery vein grafts. Cardiac output and coronary sinus blood flow were determined by thermodilution, along with haemodynamic measurements. Measurements 15 minutes after addition of nitrous oxide revealed a significant decrease in heart rate, arterial pressure, cardiac index, coronary sinus blood flow and myocardial oxygen consumption. There was a significant increase in coronary sinus lactate content, and a significant decrease, from 27 to 11 per cent, in myocardial lactate extraction. We conclude that these circulatory changes were likely to be due to a depression of ventricular function by the nitrous oxide. The myocardia of these patients with severe coronary disease were becoming globally ischaemic while they were receiving 50 per cent oxygen, in the presence of hypotension. Nitrous oxide should be turned off when hypotension occurs in coronary patients.     

VARIATION IN ARTERIAL PRESSURE DURING ANAESTHESIA WITH HALOTHANE IN DIFFERENT GAS MIXTURES

Seventeen patients were anaesthetized with halothane vaporizedin oxygen, air, and 75 per cent nitrous oxide in oxygen,forthe performance of prolonged superficial operations. With oxygenthere was an average fall in arterial pressure of 17 per centfrom pre-operative value. When air was next substituted foroxygen in seven patients pressure changes were negligible, butsubstitution of nitrous oxide then resulted in falls averaging20 per cent. When oxygen was followed first by nitrous oxidein ten patients falls averaging 23 per cent were observed whichwere substantially reversed on return to anas the vaporizingmedium.     

THE ANTI-EMETIC EFFECT OF HALOTHANE

A study was undertaken to evaluate the anti-emetic propertiesof halothane. One hundred and thirty female patients undergoingdiagnostic dilatation and curettage, and cystoscopy, were givena standard premedication of atropine 0.65 mg and pethidine 50mg. Of these, 42 patients were anaesthetized with thiopentoneand anaesthesia was maintained using nitrous oxide and trichloroethylene;in 44 patients induction and maintenance were identical buteach received 1 per cent halothane for the last 5 minutes ofthe procedure; and in 44 patients anaesthetic induction wassimilar but halothane and nitrous oxide were used for maintenance.As many variables as possible known to influence nausea andvomiting were excluded. The results show that a short exposureto halothane reduces the vomiting incidence following trichloroethyleneby 50 per cent. Halothane alone was followed by a vomiting incidenceof only one-eighth that of trichloroethylene.     

ANAESTHESIA FOR CAESAREAN SECTION: An Evaluation of a Method using Low Concentrations of Halothane and 50 per cent of Oxygen

The addition of 0.5 per cent of halothane vapour to a basicthiopentone, nitrous oxide, muscle relaxant anaesthetic techniquedoes not increase blood loss at Caesarean section, does notaffect the incidence of hypotension, and is likely to ensureunconsciousness. By permitting the administration of 50 percent of oxygen with nitrous oxide, the condition of the newborninfant is likely to be improved. The use of 0.8 per cent ofhalothane vapour does not increase blood loss but is associatedwith a high incidence of hypotension and for this reason isnot advisable.     

THE EFFECTS OF CLINICAL CONCENTRATIONS OF HALOTHANE ON THE BLOOD FLOW AND OXYGEN UPTAKE OF THE CEREBRAL CORTEX

Clinical concentrations of halothane vaporized in nitrous oxide-oxygencaused vasodilatation in the cerebral cortex of anaesthetizeddogs at constant arterial carbon dioxide tension. The vasodilatoryaction on the cerebral circulation was greater the higher theconcentration of halothane. Consequently 2 per cent halothaneincreased blood flow through the cerebral cortex more than did0.5 per cent halothane. However, the administration of 4 percent halothane reduced mean blood pressure so markedly thatblood flow was not elevated above the control value. The oxygenuptake of the cerebral cortex was depressed by halothane andthis depression was greater with 2 per cent halothane than with0.5 per cent. These results are discussed with reference tothe effects of halothane on intracranial pressure and on theoxygenation of the brain.     

EVALUATION OF THE EFFECT OF HALOTHANE ON POSTOPERATIVE VOMITING

Observations on the frequency and severity of postanaestheticnausea and vomiting were made in 252 women undergoing minorgynaecological operations under general anaesthesia consistingof thiopentone, nitrous oxide and oxygen. Anaesthesia lastedfor 10 minutes in all patients. One per cent halothane in oxygenwas given for 5 minutes at the end of anaesthesia to two groupsof cases, one with and one without atropine premedication. Thisdid not lead to a statistically significant reduction of theincidence and severity of sickness as compared with the unpremedicatedcontrol group. The administration of halothane in this way did,however, lead to a significant reduction in emergence vomitingin atropine-premedicated patients. The incidence and severityof sickness after chlorpromazine premedication was significantlylower than in the control group. Trichloroethylene supplementationof nitrous oxide and oxygen anaesthesia did not materially influencesickness as compared with the control group. The major partof postoperative sickness occurred in the first postoperativehour in patients without effective anti-emetic premedication.     

The action of halothane on spontaneous contractile waves and stimulated contractions in isolated rat and dog heart cells

The cell length of single, isolated rat and dog heart cells was monitored during exposure to halothane-containing solution to define the cellular mechanism of halothane's negative inotropic effect. Spontaneous contractile waves, which reflect spontaneous Ca release from the sarcoplasmic reticulum (SR) in resting rat heart cells, exhibited a significant increase in frequency and a decrease in amplitude in the presence of halothane 0.27 mM (0.9 vol%) and 0.55 mM (1.7 vol%). Electrically stimulated dog and rat heart cells abruptly exposed to halothane (0.47-0.55 mM or 1.5-1.7 vol%) revealed a transient increase in twitch amplitude (significantly different from control). Twitch amplitude then declined to values significantly below control as halothane exposure continued. This decrease in twitch reached 42 +/- 13% (mean +/- SD) of control in rat cells and 50 +/- 14% in dog cells beating at 60 beats per min. In dog cells the magnitude of the transient increase in twitch amplitude was greater at faster beating rates compared with lower rates in the same cells (P less than 0.01) and the transient increase was insensitive to verapamil. Halothane 0.55 mM (1.7 vol%) also significantly accelerated the rate of decline in the twitch amplitude of successive beats in rat cells stimulated after a rest interval (negative staircase). The findings regarding spontaneous contractile waves indicate a direct effect of halothane at the SR in resting cells, occurring independently of any changes in the slow inward current. The halothane-induced changes in beating cells can be explained by an enhancement of Ca release from the SR with an eventual reduction of SR Ca stores.     

Differential effects of halothane, enflurane, and isoflurane on Ca2+ transients and papillary muscle tension in guinea pigs.

These studies were designed to examine the effects of inhalational anesthetics on rapid changes in myocardial intracellular Ca2+ and Ca2+ sensitivity of the contractile apparatus. The effects of halothane, enflurane, and isoflurane on rapid changes in intracellular Ca2+ (Ca2+ transients as measured with bioluminescent protein aequorin) and contractile characteristics were compared in guinea pig right ventricular papillary muscles. In addition to examination of their potencies at equianesthetic concentrations, the effects of these agents on alterations in Ca2+ sensitivity at myofilaments were also investigated. The negative inotropic effects of halothane (0.65 and 1.15%) and enflurane (1.0 and 2.2%) were dose-dependent and closely related to a decrease in Ca2+ transients. In the presence of isoflurane (0.77 and 1.6%), the contractile force decreased in a dose-dependent manner, but the decrease was significantly less as compared to that with equianesthetic concentrations of halothane and enflurane. An additional feature observed in the presence of isoflurane was a dissociation between intracellular Ca2+ availability and contractile force. Although the magnitude of the Ca2+ transients did not change when the percentage of isoflurane was increased from 0.77 to 1.6, the contractile force decreased. Because of these findings, the effects of halothane (1.2%), enflurane (2.2%), and isoflurane (1.6%) on the relationship between intracellular Ca2+ and tension developed in the papillary muscle were examined in order to assess myofibrillar responsiveness to Ca2+. The results indicate that only isoflurane slightly but significantly shifted the Ca2+/isometric tension curve toward higher intracellular Ca2+ concentrations; no differences were observed in the absence and presence of equianesthetic concentrations of halothane and enflurane.(ABSTRACT TRUNCATED AT 250 WORDS)     

CEREBRAL BLOOD FLOW DURING HALOTHANE ANAESTHESIA

Cerebral blood flow has been measured in dogs using the methodof Lassen and Ingvar (1961), and Ingvar and Lassen (1962), whichinvolves measurement of the rate of clearance of krypton 85from an area of exposed cerebral cortex after injection intothe internal carotid artery. In every measurement during halothaneanaesthesia there was a considerable reduction in cerebral bloodflow compared with the flows obtained with nitrous oxide andoxygen. The average reduction in flow was 46 per cent and thiswas accompanied by an average increase in cerebrovascular resistanceof 50 per cent. Measurements were also made of the cerebraloxygen uptake (CMRO2) and halothane produced an average decreasein uptake of 49 per cent. Possible mechanisms for the observedresults are discussed.