HALOTHANE DOES NOT INHIBIT HUMAN NEUTROPHIL FUNCTION IN VITRO

Various indices of function of neutrophils from normal healthyvolunteers have been examined after in vitro exposure to halothane.Random free movement on glass was unaffected, but random migrationthrough millipore filters was slightly increased. There wasno significant change in migra tion in response to casein chemotaxis.Phagocytosis, degranulation and the enhanced non mito chondrialrespiration associated with phagocytosis were unaffected. Electron-microscopicappearance at 30 s after exposure to latex particles was normalin all respects.     

CARDIAC CONDUCTION INTERACTIONS OF PROPRANOLOL AND VERAPAMIL WITH HALOTHANE IN PENTOBARBITONE-ANAESTHETIZED DOGS

We have studied the effects of propranolol 0.25 mg kg^–1and verapamil 0.075 mg kg^–1 on cardiac conduction andrefractoriness in 21 dogs anaesthetized with pentobarbitone30 mg kg^–1 using His bundle electrocardiography and programmedstimulation. After baseline studies under pentobarbitone andhalothane (1.3 MAC) anaesthesia, the dogs were allocated randomlyto two groups: group 1 received verapamil followed by propranolol;group 2 received pro-pranolol followed by verapamil; the drugswere given in a continuous infusion over 10 min. The atrial—His(AH) interval, the atrioventricular node effective (AVERP),and functional (AVFRP) refractory periods, were prolonged byverapamil in both groups, but not the His-ventricle (HV) intervalor the ventricular effective refractory period (VERP). AVFRPand VERP were prolonged by propranolol in both groups. Correctedsinus node recovery times were normal after each drug. Heartrate and the rate required to produce Wenckebach were decreasedby each drug. The combination of verapamil and propranolol duringhalothane anaesthesia in dogs has significant cardiac conductioneffects; however, no spontaneous AV block occurred during thestudy.     

FLUMAZENIL DOES NOT ANTAGONIZE HALOTHANE, THIAMYLAL OR PROPOFOL ANAESTHESIA IN RATS{dagger}

We have studied the effects of flumazenil on sleep time andEEG in rats anaesthetized with 1.5% halothane, propofoi 20 mgkg^–1, thiamylal 30 mg kg^–1, or combinations of diazepam5 mg kg^–1 and anaesthetic agents. We also studied theeffects of flumazenil 0.3, 3 and 30 mg kg^–1 on behaviourand EEG. Flumazenil 0.3 and 3 mg kg^–1 alone had no effecton behaviour or EEG, but flumazenil 30 mg kg^–1 had depressiveeffects similar to those of diazepam on behaviour and EEG. Flumazenil0.3, 3 and 30 mg kg^–1 i.v., antagonized the effects ofdiazepam 10 mg kg^–1 i.v. on behaviour and EEG. Flumazenilhad no antagonistic effect on sleep time induced by anaestheticagents, but flumazenil 30 mg kg^–1 potentiated propofol-inducedanaesthesia. Flumazenil did not affect anaesthesia-induced EEGchanges. Diazepam 5 mg kg^–1 potentiated anaesthesia. Flumazenilantagonism of diazepam potentiation varied with anaestheticagent: flumazenil 0.3 mg kg^–1 antagonized diazepam actionin halothane anaesthesia, but 30 mg kg^–1 was requiredin propofoi anaesthesia; this large dose was insufficient inthiamylal anaesthesia. ^*Present address: Department of Anesthesia, Omiya Medical Center,Omiya 330, Japan.      

PREOPERATIVE CIMETIDINE DOES NOT PREVENT SUBCLINICAL HALOTHANE HEPATOTOXICITY IN MAN

To assess the influence of pretreatment with cimetidine on changesin hepatocellular integrity after halothane anaesthesia, 53patients were allocated randomly to receive either cimetidine1600 mg orally or placebo tablets before anaesthesia. Plasmaconcentrations of glutathione S-transferase (GST) were measuredas an index of hepatic damage. Data from 45 patients were availablefor analysis. Plasma GST concentration increased significantly3 h after induction of anaesthesia in both groups (P < 0.01,both groups) and at 6 h in the cimetidine groups (P < 0.05).Pretreatment with cimetidine did not influence the magnitudeof increase in GST concentration. There was no difference betweenthe groups in the frequency of abnormal GST concentrations atany time. Cimetidine does not appear to prevent release of GSTfrom the liver by halothane anaesthesia in man.     

SEVOFLURANE DOES NOT INCREASE INTRACRANIAL PRESSURE IN HYPERVENTILATED DOGS

We have measured the effects of 0.5, 1.0 and 1.5 MAC (minimumalveolar concentration) endtidal concentrations of sevolluraneon intracranial pressure (ICP), cerebral perfusion pressure(CPP), mean arterial pressure (MAP), central venous pressureand heart rate in hypocapnic dogs (Pa_c02, 3.2–3.7 kPa)and compared the data with those produced by equi-MAC concentrationsof enflurane and halothane. Enflurane and halothane caused smallbut significant increases in ICP at 0.5, 1.0 and 1.5 MAC, butthere were no changes with sevoflurane. However, sevofluranecaused a considerable decrease in MAP with consequent decreasein CPP. We conclude that sevollurane should be a suitable agentfor neuroanaesthesia and is preferable to either enflurane orhalothane. (Br. J. Anaesth. 1993; 71: 551–555)     

SOME ACTIONS OF HALOTHANE AND ETHER IN BLED DOGS

A method is described of bleeding dogs under anaesthesia withethylene (79 per cent) and oxygen (21 per cent) to an arbitrarylevel of hypotension. Arterial blood oxygen saturations remainednormal while the hyperventilation of the animals in responseto haemorrhage was unimpaired. In dogs rendered hypotensiveby 30-50 per cent reductions of their circulating blood volume,halothane caused a fall, and di-ethyl ether a rise in the arterialblood pressure, heart rate and respiratory minute volume. Venouspressure fell further on administration of halothane. Acuteexperiments in dogs bled to a mean blood pressure of 50 mm Hgdid not distinguish a lethal effect of halothane due to itshypotensive action. Increasing the severity of the bleedingprocedure demonstrated the lethal effect of impairing the hyperventilationwith halothane in air which caused marked arterial desaturation.Survival experiments might demonstrate a deleterious effectof halothane due to its hypotensive action in severe haemorrhagewhen compared with ether anaesthesia. Preliminary survival experimentsare reported. ^*Present address: University College Hospital, London, W.C.I.     

ISOFLURANE DOES NOT INCREASE THE INCIDENCE OF INTRAOPERATIVE MYOCARDIAL ISCHAEMIA COMPARED WITH HALOTHANE DURING VASCULAR SURGERY

We have studied the incidence of new intra-operative myocardialischaemia (IMI), myocardial infarction (Ml) and cardiac death(CD) in 500 consecutive patients undergoing elective major non-cardiacvascular surgery. Patients were allocated randomly to receiveeither halothane (n = 226) or isoflurane (n = 274) as principalanaesthetic agent. Using real-time ST segment trend analysis(leads V5 and II) IMI (halothane 39%, isoflurane 38%), MI (halothane1.3%, isoflurane 1.5%) and CD (halothane 0.4%, isoflurane 0.7%)did not differ significantly between the two groups. Twenty-threeper cent of IMI episodes were related to haemodynamic disturbances,but unrelated to the type of surgery: 148 supra-aortic (IMI= 39%), 244 abdominal aortic (IMI = 41%) and 108 lower extremityrevascularizations (IMI = 33%). We conclude that the choiceof volatile anaesthetic agent does not influence cardiac morbidityor mortality in this type of patient     

CHRONIC TREATMENT WITH FINASTERIDE DAILY DOES NOT AFFECT SPERMATOGENESIS OR SEMEN PRODUCTION IN YOUNG MEN

PURPOSE: Finasteride, an oral type 2, 5alpha-reductase inhibitor, is used in 1 mg. daily doses for the treatment of male pattern hair loss. A dose of 5 mg. finasteride daily reduces ejaculate volume by approximately 25%, and reduces prostate volume by approximately 20% and serum prostate specific antigen (PSA) by approximately 50% in men with benign prostatic hyperplasia. To our knowledge no data exist on the effect of 1 mg. finasteride daily on ejaculate volume or other semen parameters, or on the prostate in young men. Therefore, we studied the potential effect and reversibility of effect of 1 mg. finasteride daily on spermatogenesis, semen production, the prostate and serum PSA in young men. MATERIALS AND METHODS: In this double-blind, placebo controlled multicenter study 181 men 19 to 41 years old were randomized to receive 1 mg. finasteride or placebo for 48 weeks followed by a 60-week off-drug period. Of the 181 men 79 were included in a subset for the collection and analysis of sequential semen samples. RESULTS: There were no significant effects of 1 mg. finasteride on sperm concentration, total sperm per ejaculate, sperm motility or morphology. Ejaculate volume in subjects on finasteride decreased 0.3 ml. (-11%) compared to a decrease of 0.2 ml. (-8%) for placebo, with a median between treatment group difference of -0.03 ml. (1%, 90% confidence interval -10.4 to 13.1, p = 0.915). There were significant but small decreases in prostate volume (-2.6%) and serum PSA (-0.2 ng./ml.) in the finasteride group, which reversed on discontinuation of the drug. CONCLUSIONS: Treatment with 1 mg. finasteride daily for 48 weeks did not affect spermatogenesis or semen production in young men. The effects of 1 mg. finasteride daily on prostate volume and serum PSA in young men without benign prostatic hyperplasia were small and reversible on discontinuation of the drug.     

HAEMODYNAMIC EFFECTS OF OXPRENOLOL AND PRACTOLOL IN DOGS UNDER HALOTHANE ANAESTHESIA

The effects of beta-adrenergic blockade produced by either oxprenololor practolol in dogs anaesthetized with nitrous oxide and halothanewere studied. The main changes were a fall in cardiac output,heart rate and stroke work index, and an increase in centralvenous pressure. These changes were more marked with practololthan with oxprenolol but this difference was probably due toa higher degree of beta-adrenergic stimulation during the controlperiod in the dogs receiving practolol. The changes seen could,in the main, be attributed solely to beta-blockade. The possibilitythat the drugs are also direct myocardial depressants couldnot be ruled out as in some dogs showing no evidence of beta-stimulationin the control period negative inotropic effects were producedby both drugs.     

NORMALIZATION OF HEMATOCRIT IN HEMODIALYSIS PATIENTS DOES NOT AFFECT SILENT ISCHEMIA

Background. In clinical practice, the glomerular filtration rate (GFR) is often estimated by the Modification of Diet in Renal Disease (MDRD) or Cockcroft-Gault (CG) formulae. No data are available, however, on the performance of these formulae in Arab individuals. Methods. Plasma creatinine samples were obtained from 90 consecutive normal Arab kidney donors for the estimation of GFR (eGFR) using the simplified MDRD and CG formulae. The GFR was measured in these donors with chromium labelled EDTA {[51Cr] EDTA). Bias was assessed by calculating the difference between the measured GFR and the calculated GFR using each of the two formulae; precision was calculated using the r value of the regression analysis. Results. The group studied consisted of 90 donors, of whom 64 were males (71%). The mean age was 30.8 years (± 9.8) and mean BMI was 25.7 (± 5.7). The measured GFR (mean 112.4 ± 17.5) correlated better with the calculated GFR by CG formula (mean 107.7 ± 29.7) and showed poor correlation with the GFR estimated by the MDRD (mean 89.2 ± 13.8); bias?=?4.8 and 23.3, respectively (p?=?0.1 and < 0.0001, respectively). The correlation with CG formula was better in males (bias?=?2, p?=?0.5) and those under 30 years of age (bias?=?1.0, p?= 0.9). Based on our data, we calculated a correction factor to the CG formula to improve the correlation with the measured GFR in Arab individuals. By multiplying the CG formula by 1.0446, the bias was reduced from 4.8 (p?= 0.1) to 0.0 (p?=?0.5) with an increase in precision from 0.2 (p?= 0.05) to 0.43 (p?=?0.0001). Using CG formula, the frequency for values within 30% of the mean of the measured value was 75%, which improved to 80% using the revised formula. Conclusions. CG formula was found to be the most appropriate for calculation of GFR in Arab individuals. It is possible to reduce the bias and improve precision in Arab individuals with normal renal function by multiplying the result obtained by CG formula by 1.0446.     

NITROUS OXIDE INHALATION DOES NOT INFLUENCE PLASMA CONCENTRATIONS OF (3-ENDORPHIN OR MET-ENKEPHALIN-LIKE IMMUNOREACTIVITY

The possibility that nitrous oxide releases endogenous opioidpeptides into the circulation has been tested in 10 pain-free,unstressed volunteers breathing 30% nitrous oxide in oxygen.Despite achieving plateau concentrations in venous blood, accompaniedby subjective effects, there were no significant changes inplasma concentrations of immunoreactive ß-endorphin,methionine-enkephalin or ACTH. These results indicate that,in the absence of nociceptive input, the effects of the inhalationof nitrous oxide are unrelated to alterations in peripheralconcentrations of these endogenous opioid peptides. ^*Present address: Hospital for Sick Children, Melbourne, Australia.     

DIFFERENTIAL EFFECTS OF VECURONIUM ON DIAPHRAGM AND GENIOHYOID MUSCLE IN ANAESTHETIZED DOGS

We have examined the sensitivity of the geniohyoid, an upperairway dilating muscle, to vecuronium in 12 anaesthetized dogsundergoing mechanical ventilation of the lungs and comparedit with that of the diaphragm. Dogs were allocated randomlyto two groups: pentobarbitone alone (group 1, n = 7); pentobarbitonecombined with 0.2 MAC (0.44%) of enflurane anaesthesia (group2, n = 5). Supramaximal single twitch stimulations (0.1 Hz)were applied to the phrenic nerves in the upper thorax and thegeniohyoid branches of the hy-poglossal nerves at the neck.The evoked responses were assessed by the transdiaphragmaticpressure (Pdi) and the isometric force of the geniohyoid muscles(Tgh) until complete recovery of these variables after i.v.administration of vecuronium 0.02 mg kg^–1. In both groups,the magnitude of the depression of twitch response was greaterand time required to reach control amplitude was longer in thegeniohyoid than the diaphragm. The depression of Tgh. was significantlygreater in group 2 than in group 1, whereas no change was observedin Pdi between the two groups. We conclude that the geniohyoidis more sensitive to vecuronium than the diaphragm and the differentialeffects of vecuronium are facilitated by a low concentrationof enflurane.     

EFFECTS OF CHRONIC INHALATION OF HALOTHANE, ENFLURANE OR ISOFLURANE IN RATS

Male Fischer 344 rats were exposed to halothane, enflurane orisoflurane vapour 20 p.p.m., or air, for up to 30 weeks. Noneof the anaesthetic agents led to hepatocellular necrosis. Exposureto halothane resulted in slight increases in serum alanine aminotransferaseactivity, an increase in the size of the liver, an increasein hepatic microsomal cytochrome P-450 content and a minimalamount of fatty change in the liver. None of these effects wereobserved during exposure to enflurane or isoflurane. Urinaryfluoride excretion was increased during exposure to either enfluraneor isoflurane. Using this increase as an index of anaestheticbiotransformation, we found that the extent of bsiotransformationof isoflurane was only slightly lower than that of enflurane. ^*Histopathology, Flinders Medical Centre, Bedford Park, SouthAustralia 5042     

EFFECT OF OXPRENOLOL ON ADRENALINE-EVOKED VENTRICULAR ARRHYTHMIAS IN DOGS ANAESTHETIZED WITH HALOTHANE IN OXYGEN

The effect of oxprenolol (CIBA 39,089-Ba), a recently introducedadrenergic beta-receptor antagonist, on adrenaline-evoked ventriculararrhythmias was studied in atropinized dogs anaesthetized withhalothane in oxygen. The anti-arrhythmic activity of oxprenololwas due to specific blockade of beta-receptors. The block producedwas surmountable in nature and larger doses of adrenaline re-evokedventricular arrhythmias. Its potency was very similar to thatof propranolol. However, in contrast to propranolol, oxprenololadministration following electrical defibrillation of the heartdid not precipitate cardiocirculatory collapse. In this respectoxprenolol may have important therapeutic advantages over propranolol.     

AN EXPERIMENTAL STUDY OF PULMONARY DAMAGE ASSOCIATED WITH INTRAVENOUS INJECTION OF HALOTHANE IN DOGS

Halothane was injected intravenously into two groups of dogsand the effects on the lungs noted. The nine dogs of group Iwere unanaesthetized and received no ventilatory support followinginjection. The dogs were killed at varying time intervals afterinjection and the macroscopic and microscopic appearances werestudied. In the six dogs of group II the chests were open andthey were artificially ventilated with 30 per cent oxygen and70 per cent nitrous oxide at the time of injection. Serial biopsieswere taken. The predominant lesions produced were generalizedoedema and patchy alveolar haemorrhages. These changes weremore severe in dogs of group I. The aetiology is conjectural,possibly being due to direct capillary damage or to embolization.The danger of accidental intravenous injection of halothane,a not unknown occurrence, is stressed. Present address: Department of Pathology, Mallory InstituteBoston, U.S-A.     

PULMONARY ARTERIOVENOUS SHUNTS DURING HALOTHANE ANAESTHESIA IN DOGS*

The fraction of cardiac output flowing through pulmonary arteriovenousanastomoses (Q_av/Q_t) was measured in dogs during halothane anaesthesiaand compared with results obtained in normal awake dogs. Flowthrough arteriovenous anastomoses was measured using ^$$mTc-labelledpolystyrene microspheres (50 µm diameter). The fractionof cardiac output perfusing pulmonary arteriovenous anastomosesduring halothane anaesthesia was 4.1% (±SD 1.75) comparedwith 4.6% (±SD 0.73) in air-breathing awake control dogs.In spite of variations in arteriovenous shunt fraction, no significantrelationship between the Q_av/Q_t and Q_a/Q_t was detected. Theseresults suggest that pulmonary arteriovenous anastomoses donot contribute significantly to the physiological shunt observedduring halothane anaesthesia. ^*Presented at the American Society of Anesthesiologists AnnualMeeting, Chicago, Illinois, 1975.     

DEPRESSION OF HYPOXIC VENTILATORY RESPONSE BY HALOTHANE, ENFLURANE AND ISOFLURANE IN DOGS

The ventilatory responses to isocapnic hypoxia and hypercapniawere studied in six dogs each with a tracheostomy, awake andduring anaesthesia with halothane, enflurane and isoflurane(1–2.5 MAC). Isocapnic hypoxic ventilatory response (HVR)was expressed as the parameter A, such that the greater thevalue of A, the greater the hypoxic response. In the anaesthetizeddogs HVR (A) was reduced significantly from the awake valueof 2010±172 (mean+SEM) to 630±173 by 1 MAC halothane,495± 105 by 1 MAC enflurane and 952±157 by 1 MACisoflurane (P<0.05). All three anaesthetic agents producedsignificant depression of HVR at 1 MAC, but enflurane was moredepressant than isoflurane. At 1.5 MAC all three anaestheticsproduced equal and significant depression of HVR at equianalgesicconcentrations. Further increases in anaesthetic concentrationcaused no increase in depression. Hypercapnic drive, as measuredby the slope of the VE/PA_co2 response curve, was reduced significantlyfrom 9.75 litre min^–1 kPa^–1 ± 2.4 in awakedogs to 0.83 ± 0.56 after 1 MAC halothane, 0.68 ±0.53after 1 MAC enflurane and 1.58 ±0.75 after 1 MAC isoflurane.In addition, hypercapnia-induced augmentation of the hypoxicdrive was abolished by 1 MAC halothane or enflurane and diminishedmarkedly by 1 MAC isoflurane. It may be clinically significantthat hypoxia and hypercapnia during anaesthesia with these agentsdid not produce optimal stimulation of ventilation.     

DETERMINATION OF THE PARTIAL PRESSURE OF HALOTHANE (OR ISOFLURANE) IN BLOOD

A gas chromatographic method is described for the direct quantitativedetermination of the partial pressure of halothane {or isoflurane)in blood as well as the blood-gas partition coefficient. A headspace technique and a flame ionization detector were used. Standardblood was obtained by equilibrating patients' blood with knowngas concentrations in a tonometer. Using an infra-red analyserto measure the halothane gas concentration in the tonometerand within the anaesthetic system allowed for the direct comparisonof the partial pressure in blood to the partial pressure inthe inspired gas. Technical problems associated with this procedure,and with comparable methods, are discussed.     

DOES A SUBPARALYSING DOSE OF VECURONIUM ENHANCE DIAPHRAGM FATIGUE?

We have examined, in six healthy volunteers, the effect of asubparalysing dose of vecuronium on the development of diaphragmfatigue. Vecuronium was given as a 0.5-mg bolus i.v. followedby 0.5 mg infused over 30 min; as a control, saline was givenin random order. Diaphragm strength was assessed by measuringtransdiaphragm pressure and by electromyography. Diaphragm fatiguewas induced by breathing against an inspirator resistance. Theplasma concentration of vecuronium varied between 15 and30 ngml^–1 15 min after administration of vecuronium was started.Peripheral neuromuscular block was not detected in any subject.Diaphragm fatigue developed within the same period in both groups:mean 334 (SD 166) s after saline and 345 (190) s after vecuronium.The electromyographic pattern of diaphragm fatigue and the timeconstant of relaxation of transdiaphragm pressure after fatiguewere similar in both groups. We conclude that, at low plasmaconcentrations of vecuronium, similar to those present in thepostoperative period, there was no predisposition to diaphragmfatigue.     

A PROSPECTIVE STUDY OF HEPATOCELLULAR FUNCTION AFTER REPEATED EXPOSURES TO HALOTHANE OR ENFLURANE IN WOMEN UNDERGOING RADIUM THERAPY FOR CERVICAL CANCER

Ninety-nine Black females receiving radium therapy for carcinomaof the cervix uteri under either halothane (50 patients) orenflurane (49 patients) anaesthesia were studied. Thirty-sixreceived a second and 13 a third exposure to halothane or enflurane.There were no significant changes from the control values inthe serum concentrations of aspartate aminotransferase (s.g.o.t.),gamma glutamyl transpeptidase (GT), lactic dehydrogenase (SLD),alkaline phosphatase (SAP) and proteins. Total serum bilirubin(TSB) decreased significantly during the first exposure to enflurane(P< 0.01). This trend was reversed with subsequent anaestheticsin both the halothane and enflurane groups.