SELECTIVE ADRENERGIC BETA-RECEPTOR BLOCKADE IN THE PREVENTION OF ADRENALINE-EVOKED VENTRICULAR ARRHYTHMIAS IN DOGS ANAESTHETIZED WITH HALOTHANE IN OXYGEN

The effect of selective beta-receptor blockade on adrenaline-evokedventricular arrhythmias was studied in atropinized dogs anaesthetizedwith halothane in oxygen. Cardiac beta-receptors were selectivelyblocked with ICI 50172, while the peripheral vascular beta-receptorswere selectively blocked with H 35/25. ICI 50172 prevented adrenaline-evokedventricular arrhythmias and the increase in sinus rate producedby adrenaline. The blockade produced was surmountable, largerdoses of adrenaline increasing the rate of sinus rhythm andthen ventricular arrhythmias followed. In contrast H 35/25 showedonly a weak anti-arrhythmic activity. This action appears tobe non-specific, since the increase in sinus rate caused byadrenaline was only partially prevented by H 35/25. The resultsare in agreement with the concept that ICI 50172 blocks excitatorybeta-receptors, while H 35/25 blocks inhibitory beta-receptors.     

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.     

INTERACTIONS OF ADRENERGIC BETA-RECEPTOR BLOCKADE (OXPRENOLOL) AND Pco2 IN THE ANAESTHETIZED DOG: INFLUENCE OF INTRINSIC BETA-SYMPATHOMIMETIC ACTIVITY

Effects of change in Pa_co2 on systemic and coronary haemodynamicsand on coronary sinus blood-gases have been studied in 10 open-chesteddogs in which the lungs were ventilated with 0.8% halothanein oxygen, before and after administration of oxprenolol 0.3mg kg^–1 i.v. The hyperdynamic response of the circulationto hypercapnia was only marginally reduced after oxprenolol(cardiac output increased by 10% as opposed to 16% before oxprenolol).Before and after oxprenolol, hypocapnia caused large reductionsof coronary blood flow (–24% and –20% respectively),while hypercapnia caused large increases of coronary blood flow(+59% and +34% respectively). Oxprenolol does not appear tomodify significantly the circulatory response to arterial carbondioxide tension.     

EFFECT OF PROPIOMAZINE, PERPHENAZINE, PROMETHAZINE AND PROMAZINE ON ADRENALINE-INDUCED VENTRICULAR ARRHYTHMIAS DURING NITROUS OXIDE-HALOTHANE ANAESTHESIA IN THE DOG

Ventricular tachycardia was produced in the dog by intravenousinjection of 2–3 µg/kg of adrenaline during nitrousoxide-halothane anaesthesia. On a weight basis, propiomazinewas found to be as effective as perphenazine in preventing thearrhythmias. Promethazine and promazine showed similar effectsin much higher doses. The protection provided by all these drugscould be surmounted by doses of adrenaline of 4–6 µg/kg.Propiomazine did not produce any action on blood pressure whereasthe other drugs tested produced a prolonged fall in pressurein all the experiments. Since the clinical dose of propiomazineis 2–4 times that of perphenazine, it is possible thatthe former may prove superior to the latter in clinical trials.     

EFFECT OF PROPRANOLOL ON THE VENTRICULAR ARRHYTHMIAS INDUCED BY HYPERCARBIA DURING HALOTHANE ANAESTHESIA IN MAN

The effects of propranolol on arterial blood pressure, heartrate, and cardiac rhythm during ventricular arrhythmias initiatedby hypercarbia were investigated in thirteen subjects during1 per cent halothane anaesthesia. Propranolol was consistentlyeffective in the treatment of ventricular arrhythmia inducedby hypercarbia in all subjects. The successful use of propranololsuggests that the mechanism for ventricular arrhythmia producedby respiratory acidosis during halothane anaesthesia was relatedto beta adrenergic receptors. Blockade of these receptors bybeta adrenergic agents decreased markedly the sensitizationof myocardium to sympathetic stimulation.     

THE IGNITION RISK WITH MIXTURES OF OXYGEN AND NITROUS OXIDE WITH HALOTHANE

To enable the effect of pressure on the flammability of halothanewith oxygen and with mixtures of oxygen and nitrous oxide tobe studied, the work at atmospheric pressure already reportedin the literature has been extended to find the effect of differenttypes of ignition sources. Particular attention has been paidto those types of ignition most likely to be present when halothaneis in use, such as the cautery and the diathermy knife. Theresults indicate that even with the most flammable mixturesthere is no risk of ignition provided the concentrations ofhalothane recommended for use are not gready exceeded. Furtherwork designed to determine the limiting conditions more preciselywill be reported at a later date. ^*Dr. G. Morris died before submission of this paper.     

NEUROMUSCULAR AND CARDIOVASCULAR EFFECTS OF DOXACURIUM IN CHILDERN ANAESTHETIZED WITH HALOTHANE

The neuromuscular and cardiovascular effects of doxacurium chloride(BW A938U) were evaluated in 27 children (2–12 yr) anaesthetizedwith 1% halothane and nitrous oxide in oxygen. In nine childrenthe incremental technique was used to establish a cumulativedose-response curve by train-of-four stimulation. The remainingchildren received either 30 or 50 µg kg^–1 of thedrug as a single bolus. The median ED₅₀ and ED ₉₅ of doxacuriumin children were 19 and 32 µg kg^–1, respectively.No clinically significant change in heart rate or arterial pressureoccurred. Following doxacurium 30 µg kg^–1 and 50µg kg^–1, recovery to 25% of control occurred in25 (SEM 6) and 44 (3) min, respectively. The recovery index(25–75% of control) was 27 (2) min. The duration of actionof doxacurium is similar to that of tubocurarine and dimethyl-tubocurarinein children. Compared with adults, children seem to requiremore doxacurium (µg kg^–1) to achieve a comparabledegree of neuromuscular depression, and they recover more rapidly. Presented in part at the American Society of AnesthesiologistsAnnual Meeting, October 1987, and the International AnesthesiaResearch Society Meeting, March 1988.     

CIRCULATORY EFFECTS OF ATROPINE IN PATIENTS ANAESTHETIZED WITH NITROUS OXIDE AND TUBOCURARINE

Atropine was given intravenously in a dose of 0.012 mg/kg toten artificially ventilated patients anaesthetized with nitrousoxide and tubocurarine. The heart rate increased from a meanof 68 to a mean of 96 beats/min. This was accompanied by a 31per cent increase in cardiac output and a 12 per cent rise inmean arterial pressure. There was no significant change in strokevolume or left ventricular stroke work. Total peripheral resistancefell by 14 per cent and circulation time by 22 per cent. Useof 0.5 per cent halothane in the inspired mixture in five casesresulted in smaller increases in heart rate and cardiac outputthan were seen in the other five. The results were comparedwith those in an earlier report in which the patients breathedspontaneously during halothane-nitrous oxide anaesthesia (Farman,1967). The response to atropine depends not only on the effectof the drug on the heart, but also on the control state of thecirculation, both of which are heavily influenced by other anaestheticdrugs, by the arterial Pco₂ and by the mechanical effect ofartificial ventilation.     

INFLUENCE OF HALOTHANE AND ENFLURANE ON RESPIRATORY AIRFLOW RESISTANCE AND SPECIFIC CONDUCTANCE IN ANAESTHETIZED MAN

We have developed a method for the measurement of respiratoryresistance and specific airways conductance (s.G_aw) using theforced airflow oscillation method, and have used it to studythe effects of halothane and enflurane on airway mechanics inanaesthetized patients. Resistance (R_rs) was determined overa range of lung volumes and s.G_aw was obtained by computer-aidedanalysis of the hyperbolic relationship between R_rs and lungvolume. Patients received diazepam orally, followed by thiopentoneand pancuronium. The trachea was intubated and the lungs ventilatedwith 70% nitrous oxide in oxygen. After obtaining three baselinemeasurements of s.G_aw, 1.3% halothane (10 patients) or 2.5%enflurane (10 patients) was added to the inspired gas. Halothanecaused an increase in s.G_aw (bronchodilatation) of 47% (P<0.05;paired t test) at 3 min and a non-significant increase of 72%at 15 min. Enflurane produced no significant increase in s.G_awat 3 and 8 min, but a 56% increase (P<0.02) at 15 min. Onepatient responded to halothane with an increase in bronchomotortone, manifest by a significant reduction in s.G_aw (P<0.01;two-sample t test). Enflurane did not cause bronchoconstrictionin any patient. There was a significant reduction in resistancewith halothane (P<0.05; paired t test) and enflurane (P<0.01).Expiratory reserve volume (ERV) was found to be small, and contributedto the high resistances observed: mean resistance 0.59 kPa litre^–1s, range 0.15–1.71. Small changes in ERV were also shownto produce changes in resistance independent of changes in bronchomotortone. Neither halothane nor enflurane produced significant meanchanges in ERV.     

CIRCULATORY EFFECTS OF ATROPINE IN PATIENTS ANAESTHETIZED WITH GALLAMINE TRIETHIODIDE AND NITROUS OXIDE

Circulatory responses to the intravenous injection of acceleratingdoses of atropine sulphate were studied in ten patients anaesthetizedwith nitrous oxide, oxygen and gallamine triethiodide and ventilatedartificially. Small but significant increases in heart rateand cardiac output were accompanied by lowering of total peripheralresistance and circulation time. Arterial pressures, strokevolumes and stroke work were unchanged. Initial heart ratesand pressures were high, due to the use of gallamine, and itis suggested that the control levels of cardiac output werealso high. This would account for the smaller changes seen comparedwith earlier reports of the effect of atropine in patients artificiallyventilated using tubocurarine and in those spontaneously breathingnitrous oxide, oxygen and halothane.     

EFFECTS OF NITROUS OXIDE ON CEREBRAL METABOLIC RATE IN RATS ANAESTHETIZED WITH ISOFLURANE

It has been demonstrated in several species that a significantincrease in cerebral blood flow (CBF) occurs when nitrous oxideis added to a volatile anaesthetic. This blood flow responsecould result from an increase in cerebral metabolic rate orfrom a direct effect of nitrous oxide on cerebral vessels. Toinvestigate this, the cerebral metabolic rate for glucose (CMRglu)was determined autoradiographically in rats receiving isofluraneanaesthesia with or without nitrous oxide. An increase in anaestheticdepth from 0.5 to 1.0 MAC achieved with isoflurane alone causeda significant reduction in CMRglu (52 (SD11) µmol/100gmin^–1 vs 39 (8) µmol/100 g min^–1). In contrast,the addition of 70% nitrous oxide (0.5 MAC) to 0.5 MAC isofluraneanaesthesia (1 MAC total) left CMRglu unchanged (54 (4) µmol/100g min^–1). We conclude that 70% nitrous oxide does notalter cerebral metabolic rate when administered with 0.5 MACisoflurane. Because CBF increases substantially under very similarconditions, our data indicate that the CBF effects of nitrousoxide, when administered with a volatile agent, were directand mediated by factors other than changes in cerebral metabolicrate. Presented at the American Society of Anesthesiologists AnnualMeeting 1989, New Orleans, U.S.A.     

EFFECTS OF NITROUS OXIDE ON RESPIRATION DURING HALOTHANE ANAESTHESIA IN THE DOG

The pattern of ventilation was studied in eight greyhounds anaesthetizedwith halothane in 50% oxygen with nitrogen and in eight withthe same concentration of halothane in 50% oxygen with nitrousoxide. There was a significant reduction in both inspiratoryand expiratory times in the animals breathing nitrous oxideand an increase in the negative pressures developed in the obstructedairway during inspiration. Measurements during the additionof carbon dioxide to the inspired gases also suggested lessrespiratory depression in the nitrous oxide breathing group.It was concluded that nitrous oxide may counteract the respiratorydepressant effects of halothane.     

CEREBRAL RESPONSES TO THE ADDITION OF NITROUS OXIDE TO HALOTHANE IN MAN

Cerebral responses to the substitution of 60% nitrous oxidefor nitrogen during halothane anaesthesia (0.84%, end-tidal)were studied in four patients during surgery. The mean (±SEM)cerebral blood flow equivalent and internal jugular venous oxygentension during halothane anaesthesia, 27±3 ml blood/mloxygen and 41±2 mm Hg respectively, increased significantlyto 45±3ml blood/ml oxygen and 54±3 mm Hg followingthe introduction of nitrous oxide. On the withdrawal of nitrousoxide, the mean cerebral blood flow equivalent and internaljugular venous oxygen tension returned gradually to the controlvalues. Cerebral perfusion pressure and blood-gas values, otherthan the internal jugular venous oxygen tension, did not changesignificantly. Marked slowing of the e.e.g. was observed followingthe addition of nitrous oxide to halothane. Upon the withdrawalof nitrous oxide the e.e.g. returned to the control pattern.These results indicate that cerebral blood flow was in excessof oxygen demand during nitrous oxide/halothane anaesthesiain man. This work was performed at the Department of Anaesthesiology,Yamaguchi University Hospital.     

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.     

EFFECT OF PROPRANOLOL ON CATECHOLAMINE-INDUCED ARRHYTHMIAS DURING NITROUS OXIDE-HALOTHANE ANAESTHESIA IN THE DOG

In dogs under nitrous oxide-halothane anaesthesia, ventriculararrhythmias were produced by intravenous injection of adrenalineand noradrenaline 2–3 µg/kg or isoprenaline 1µg/kg,and completely prevented by propranolol 0.3 mg/kg. Adrenalineor noradrenaline (20–30 µg/kg) produced slow rateventricular extrasystoles and ventricular bigeminy, withoutincrease in the rate of sinus rhythm. Doses of 100 to 150 µg/kgproduced ventricular tachycardia in all and ventricular fibrillationin some experiments. Increase in sinus rate always precededventricular tachycardia. Isoprenaline 10 µ/kg producedventricular tachycardia preceded by an increase in sinus rate.Very large doses (50 µg/kg) produced a greater increasein sinus rate, and later ventricular tachycardia and even ventricularfibrillation resulted in all the experiments. Dosages of catecholamineswhich did not produce any increase in the rate of sinus rhythmnever produced ventricular tachycardia or fibrillation.     

INFUSIONS OF MINAXOLONE TO SUPPLEMENT NITROUS OXIDE-OXYGEN ANAESTHESIA. A COMPARISON WITH ALTHESIN

In 19 patients, minaxolone citrate, a water-soluble steroidanaesthetic agent, has been used as a continuous infusion tosupplement nitrous oxide anaesthesia. The minimum infusion rate(MIR) was found to be 11.3 µg kg^–1 min^–1 forpatients premedicated with morphine 10mg i.m. and breathingspontaneously 66% nitrous oxide in oxygen. The cardiovascularand respiratory effects were similar to those described in aprevious study for Althesin administered under comparable conditions.Recovery from minaxolone was prolonged compared with Althesin,and this may be related both to the water-solubility of thedrug, and to its greater apparent volume of distribution.     

POTENTIATION OF THE NEUROMUSCULAR BLOCKADE PRODUCED BY ALCURONIUM WITH HALOTHANE, ENFLURANE AND ISOFLURANE

The potentiation of alcuronium by halothane, enflurane and isofluranewas investigated using electromyography. In the first study,cumulative dose-response curves were constructed in four groupsof 10 patients anaesthetized with one of the inhalation agentsand nitrous oxide, or with fentanyl and droperidol (control).All three agents reduced the ED₅₀ of alcuronium; the effectwas marked with isoflurane (P < 0.005) but less so with halothane(P < 0.05) and enflurane (ns). In the second part of theinvestigation, designed primarily to test the duration of actionof alcuronium with each agent, a single bolus dose of alcuronium0.2 mg kg^–1 was given to four similar groups (n = 5).The duration of action was significantly prolonged by enflurane(P < 0.01) and isoflurane (P < 0.05), but not by halothane.The possible reasons for this are discussed.     

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.