INFLUENCE OF "PRIMING" ON THE POTENCY OF NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS

Dose-response curves have been constructed to determine theED₅₀ and ED₉₅ (doses required to produce a 50% and a 95% block,respectively) following administration of a small "priming"dose of atracurium 50 µg kg-¹, vecuronium 10 µgkg-¹ or pancuronium 10 µg kg-¹ The myoneural blockerswere administered subsequently as a single bolus. The resultswere compared with previously published work on these drugs,in which no priming dose had been administered. The respectiveED₅₀ and ED₉₅ values in the primed and control groups were 122and 126µg kg-¹ and 208 and 226µg kg-¹, respectively,for atracurium; 26 and 23 µg kg-¹ and 42 and 39 µgkg-¹, respectively, for vecuronium; and 31 and 30 fµgkg-¹ and 56 and 60 µg kg-¹, respectively, for pancuronium.The values showed no significant differences between the respectiveprimed and control groups. Contrary to previous suggestions,our results show no enhancement of blockade when these drugswere administered in divided doses.     

ACUTE "TOLERANCE" TO THE CENTRAL RESPIRATORY EFFECTS OF MIDAZOLAM IN THE DOG

The effect of repeated doses of midnTinlam 0.1 mg kg^–1on efferent activity in the phrenic nerve was observed in sevenartificially ventilated dogs, anaesthetized with chloraloseand paralysed with suxamethonium. PaO₂, .PaCo₂ arterial pH andcore temperature were adjusted to constant values throughouteach experiment. The first dose of midazolam caused a relativelyprolonged reduction in phrenic activity, after complete recoverya second dose was administered and so on for four doses. Peakphrenic efferent activity returned to initial values on average69 4min after the first dose of miHnTnlam The effects of successivesubsequent doses lasted progressively shorter times (mean values49.4, 38.7 and 25.3min). In four preparations, 2 h after recoveryfrom the fourth doses a second "train" of four doses was administered.The response to the first dose of this second "train" showedthat 90% recovery had occurred from the effect of the first"train" and there wts a similar sequence of decreasing responsesto successive doses. This study demonstrated acute toleranceto the central respiratory effects of midazolam. ^*Present address: Department of Anaesthetics, Brompton Hospital,Fulham Road, London SW3 6HP.     

ALTERATIONS OF "SLEEPING TIME" IN THE RAT INDUCED BY DRUGS WHICH MODULATE CENTRAL MONOAMINERGIC SYSTEMS

The effects of adrenoceptor agonists and antagonists have beendetermined on "sleeping time" in the rat—that is, withthe animal immobile and adopting a sleeping posture. Alterationsin their gross behaviour patterns were assessed also. The specific₂-adrenoceptor agonists (yohimbine, WY 26393, RX 781094 andRS 21361) decreased sleeping time, as did the ß-adrenoceptoragonist clenbuterol. The specific ₂-adrenoceptor agonist clonidinegave a large increase in sleeping time at doses in excess of25 ug kg^–1. The same effect was seen with the ß-antagonistpropranolol and the specific B2-antagonist ICI 118551.     

ANALYSIS OF UNCERTAINTY IN THEORETICAL METHODS OF CARDIAC OUTPUT MEASUREMENT USING THE "MONTE CARLO" TECHNIQUE

We have developed three models which describe the relationshipbetween cardiac output and the uptake of volatile anaestheticagents, based on the Fick equation, and determined if thesemodels could provide useful methods of cardiac output measurement.Because many variables are involved in the calculation of cardiacoutput using these methods, a "Monte Carlo" simulation was performedto investigate the combined effect of uncertainties in severalvariables on the resultant cardiac output estimate. We foundthat the single-breath model was most accurate when the inspiredconcentration was large, while the rebreathing model was betterwith smaller inspired concentrations. The three-breath modelwas the least accurate under all conditions studied. Volatileanaesthetics were generally more accurate than nitrous oxide,with both enflurane and halothane more accurate than isoflurane.The "Monte Carlo" technique provides a valuable tool for analysisof errors in measurement methods. ^*Department of Anaesthesia, The Christchurch School of Medicine,PO Box 4345, Christchurch, New Zealand.      

AUTORADIOGRAPHIC DISTRIBUTION STUDY OF "SHORT ACTING" AND "LONG ACTING" BARBITURATES: 35S-THIOPENTONE AND 14C-PHENOBARBITONE

The distribution of ³⁵S-thiopentone and ¹⁴C-phenobarbitone hasbeen studied after intravenous injection in the mouse wholebody and in the cat brain, using an auto-radiographic technique.Thirty seconds after injection ³⁵S-thiopentone reached the highestconcentration in the brain and liver of the mice, leaving theblood very rapidly. The adipose tissue built up increasing levelsof radioactivity up to 20 minutes after the injection of ³⁵S-thiopentone.¹⁴C-phenobarbitone showed a more even distribution in parenchymatousand lean tissues. A rather constant level of radioactivity waspresent in the blood during 4 hours after the administrationof ¹⁴C-phenobarbitone. ¹⁴C-pheno-barbitone penetrated the bloodbrain barrier at a much slower rate than ³⁵S-thiopentone. Thebrain distribution of both compounds was studied in furtherdetail in the cat brain. Experiments with pregnant mice revealedsome differences in the placental passage and foetal distributionof these two barbiturates.     

POSSIBLE INTERACTION BETWEEN MUSCLE RELAXANTS AND THE KALLIKREIN-TRYPSIN INACTIVATOR "TRASYLOL"

The administration of proteolytic enzyme inhibitor, Trasylol,during or shortly after operation, appeared to influence theeffect of muscle relaxants in three patients. ^* The first and second cases described here were presented tothe Congress of Association of European Anaesthesiologists andthe Greek Society of Anaesthesiologists (Athens, September 9–13,1965).     

"SELF-TAMING" OF SUXAMETHONIUM AND SERUM POTASSIUM CONCENTRATION

Fifty patients undergoing routine surgery were randomly dividedinto two groups. Group 1 were pretreated with a small (10-mg)dose of suxamethonium ("self-taming") before administrationof suxamethonium 1 mg kg^–1, while group 2 received nopretreatment. Potassium concentrations were measured immediatelybefore induction of anaesthesia and, subsequently, for 7 min.A small increase in mean plasma potassium concentration wasseen in the group who were not pretreated, while the patientswho received a "self-taming" dose of suxamethonium showed asustained decrease below pre-induction values. Mean plasma potassiumconcentrations were significantly less in the "self-taming"group than in the group not pretreated     

Efficiency of the Carden "Ventmasta" in A and D modes during controlled ventilation in children

We have determined the efficiencies of the enclosed MaplesonA and Mapleson D modes of the Carden "Ventmasta" ventilatorduring controlled ventilation in 19 anaesthetized children.In addition, we determined the suitability for the A mode ofthe fresh gas formula, VF = 0.6xweight^0.5. Efficiency was assessedin terms of the fraction of fresh gas delivered to the alveoli.When the minute volume to fresh gas flow ratio exceeded 1 .5,fractional delivery of fresh gas was 23% greater in the A modethan in the D mode (0.74 vs 0.60) (P<0.0001). Under the sameconditions, mean end-tidal carbon dioxide concentration in 27children undergoing ventilation in the A mode with VF = 0.6xweight^0.5was 4.6% (range 3.5–5.4%). We conclude that the Cardensystem is up to 23% more efficient in the A mode than in theD mode, and that under the conditions of this study, normocapniaor mild hypocapnia was produced accurately using the formulaVF = 0.6xweight^0.5.     

COMPARISON OF PHYSICAL AND FLOW CHARACTERISTICS OF "STREAMLINE" AND "NORMAL" CUFFED TRACHEAL TUBES

A comparative study was undertaken of the physical and flowcharacteristics of "streamline" cuffed tracheal tubes (SCT;Medishield) and "normal" cuffed tracheal tubes (NCT) of sizes6.0, 6.5, and 9.0 mm. The embedding of the pilot tube withinthe wall of SCT imparts a D-shaped lumen which is more markedin 6.0- and 6.5-mm tubes. As a result there is a 15% reductionin the lumen of a 6.5-mm SCT. All sizes of SCT studied had asmaller outer diameter compared with the corresponding sizesof NCT and thus occupied less space in the trachea. In sizes6.0 and 6.5mm, the SCT was found to have distinct disadvantages,such as increased resistance to ventilation of up to twice thatof NCT, and turbulent flow even at a minute volume of 5 litremin^–1. SCT, size 9.0 mm, however offered marginally lessresistance compared with NCT of the same size.     

EVALUATION OF GLYCOPYRROLATE AND ATROPINE AS ADJUNCTS TO REVERSAL OF NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS IN A "TRUE-TO-LIFE" SITUATION

Glycopyrrolate, a quaternary ammonium anticholinergic compound,and atropine were evaluated in combination with neostigminefor antagonism of non-depolarizing neuromuscular block. A totalof 641 patients were investigated in a "true-to-life" situation.The patients receiving glycopyrrolate with neostigmine had smallerchanges in heart rate than those who received atropine. Thiswas particularly apparent in patients with cardiovascular disease. ^* Present address: Department of Anaesthesia, University CentralHospital, 00290 Helsinki, 29, Finland.     

PERFORMANCE OF THE PORTABLEASE AND THE FLUOXAIR PORTABLE ANAESTHETIC EQUIPMENT: WITH REFERENCE TO USE UNDER ADVERSE CONDITIONS

The problems of anaesthesia with portable equipment are reviewedand apparatus previously described is discussed. Two recentmachines, the Fluoxair and the Portablease, were investigatedto assess vapour concentration outputs and resistance to respiratoryairflows. In addition, the work rates of breathing through theequipment were analysed. Tests under varying environmental conditionssuch as changes in atmospheric pressure and ambient temperaturewere made. The general handling of the equipment is described.Results of these investigations show that the calibration ofthe vaporisers and the respiratory resistance of both thesemachines are acceptable for the majority of clinical purposes.Both are suitable for anaesthesia under field service conditionsand in other circumstances which prevent the use of conventionalequipment. ^*The Fluoxair was formerly known as the Haloxair. Present address: St. Paul's Hospital, Endell Street, London,W.C.2.     

THE CONCEPT OF DEADSPACE WITH SPECIAL REFERENCE TO THE SINGLE BREATH TEST FOR CARBON DIOXIDE

We present a review and a theoretical analysis of factors determiningairway deadspace (VD^aw) and alveolar deadspace (VD^alv), thetwo constituents of physiological deadspace (VD^phys). VD^aw isthe volume of gas between the lips and the alveolar/fresh gasinterface, the location of which is determined by inspiratoryflow pattern and airway geometry. VD^alv can be caused by incompletealveolar gas mixing and associated / mismatching within the terminal respiratoryunits, temporal / mismatching within units, spatial / mismatching between units, and venous admixture. Most causes of VD^phys are influencedby inspiratory flow pattern and the time available for gas diffusionand distribution. Analysis can be made from the single breathtest for carbon dioxide (SBT–CO₂) which is the plot offraction of carbon dioxide in expired gas against expired volume.The common causes of VD^alv are associated with a sloping SBT-CO₂phase III. Combination of SBT-CO₂ with PaCO₂ yields VD^phys andVD^alv. A sloping phase III with a negative arterial-end-tidalPco₂ gradient implies compensation by perfusion for early emptying,overventilated alveoli.     

PHARMACOKINETICS OF ATRACURIUM AND LAUDANOSINE IN THE ELDERLY

The pharmacokinetics of a bolus dose of atracurium 0.6 mg kg^–1and its metabolite laudanosine were studied in 11 elderly (meanage 80.9 yr) and 10 young patients (mean age 23.8 yr) undergoingelective surgery. The elimination half-'life (T^ß)of atracurium was significantly longer in the elderly group(23.1 v. 20.1 min), but there was no significant differencebetween the two groups in clearance (Cl), the volume of distribution(Vß) or the mean residence time (MRT) of atracurium.Laudanosine T^ß was also significantly longer (229.1v. 173.1 min) and the clearance significantly slower (4.85 v.7.29 ml min^–1 kg^–1) in the elderly. There was, however,no significant difference in V^ß for laudanosine betweenthe two groups. These data suggest that atracurium depends toa small extent on the liver or the kidney for its metabolismand excretion, and that, as these routes of excretion are lessefficient in the elderly, T^ß is prolonged in thisage group. The deteriorating function of these organs with increasingage may also explain the altered pharmacokinetics of laudanosine. ^*Present address: Broadgreen Hospital, Thomas Drive, LiverpoolL14 3LB.     

THE SENSITIVITY OF THE RESPIRATORY TRACT DURING ANAESTHESIA IN THE CAT

In cats the sensitivity of the respiratory tract to stimulationwith diethyl ether was studied during nitrous oxide, cyclopropane,halothane and trichloroethylene anaesthesia. Nitrous oxide causedlittle change in sensitivity; halothane and trichloroethylenecaused a gradually decreasing sensitivity; and cyclopropanedepressed the response only in deep anaesthesia. In addition,following stimulation, the severity of breath-holding was markedwith cyclopropane but not with the other agents. ^*At present at the Department of Anaesthetics, Welsh NationalSchool of Medicine, Cardiff, Wales. At present at Stobhill Hospital, Glasgow, Scotland.     

THE ROLE OF {alpha}1-ADRENOCEPTORS IN ADRENALINE INDUCED HYPERKALAEMIA

The hyperkalaemic action of adrenaline was investigated in 44anaesthetized domestic pigs. Plasma and epicardial concentrationsof K⁺ were measured, in the latter case with an ion-selectiveelectrode. Adrenaline 10 µg kg^–1 caused a rapidincrease in the plasma concentration of K⁺ from 4.2 to 5.9 mmollitre^–1. The magnitude and the time course of epicardialconcentration of K⁺ were similar. Alpha-adrenoceptor block witheither phentolamine 5 mg kg^–1 (non-selective block) orprazosin 0.1 mg kg^–1 (selective 1-adrenoceptor block)abolished the hyperkalaemic effect of adrenaline in the plasmaand on the epicardium. The 1-adrenoceptor agonist phenylephrineincreased the K⁺ concentration, but the 2-adrenoceptor agonistUK 14.304 did not cause any change in concentration. These resultssuggest that the hyperkalaemia induced by adrenaline occursin the interstitial fluid of the myocardium and is mediatedby 1-adrenoceptors. These findings may be important in patientsat risk of hyperkalaemia, with implications, for example, inthe use of suxamethonium during induction of anaesthesia.     

STIMULATION OF THE PERIPHERAL CHEMORECEPTORS WITH SODIUM BICARBONATE

The i.v. administration of sodium bicarbonate was found to causean increase in arterial pH, followed by an increase in Paco,-This caused a large increase in lung ventilation and in Pao,.Oxygen administration in human subjects, and anatomical denervationof the chemoreceptors in dogs, caused a substantial delay inthe ventilatory responses to sodium bicarbonate. It was concludedthat the i.v. administration of sodium bicarbonate providesa method of testing the presence of peripheral chemoreflexeswhich has the advantage of being independent of alveolar ventilation. ^*Present addresses: Institute of Bio-medical Electronics, Universityof Toronto, Toronto, Ontario, Canada. Department of Anaesthetics, Harefield Hospital, Harefield, Middlesex. Department of Anaesthetics, Burnley General Hospital, Lancashire.     

VARIATION IN THE DISPOSITION OF MORPHINE AFTER I.M. ADMINISTRATION IN SURGICAL PATIENTS

The disposition of morphine when administered by i.m. injectionwas studied in 36 patients receiving morphine as part of premedicationbefore general anaesthesia, and in five patients who receivedmorphine as a postoperative analgesic after median sternotomyfor coronary artery surgery (PCA group). Maximum plasma concentrationof morphine (Cp_max) was 75.3 ± 6.0 (mean±standarderror (SEM)) ng ml^–1 (range 30–160 ng ml(^–1),mean elimination rate constant (k) 4.85 x 10^–3 min^–1and half-life (T₁₂) = 143 min for the preanaesthetic group.The corresponding values for PCA group were Cp_max = 58.0 ±18.0 ng ml^–1 (range 30–130 ng ml^–1), k = 5.63x 10^–3 min^–1 and T₁₂ = 123 min. Analysis of varianceshowed no differences between the groups. Within the preanaestheticgroup, there was a significant difference in k between males(k = 4.01 x 10^–3 min^–1) and females (6.30 x 10^–3min^–1, P<0.01). The corresponding T₁₂ for males was173 min; and 110 min for females. The variation in the dispositionof morphine is thought to be the result of variations in restingmuscle blood flow and inadvertent injection into adipose tissue.There were no significant differences between males and femalesin the preanaesthetic group with respect to age, CP_max timefrom injection to Cp_max.     

DETERMINATION OF THE BLOOD-GAS FACTOR OF THE OXYGEN ELECTRODE USING A NEW TONOMETER

A completely thermostatted bubble tonometer for the determinationof the blood-gas factor of oxygen electrodes is described andits performance evaluated. Equilibration of 3-ml samples ofblood at 37°C with a gas flow of about 100 ml/min takes5 minutes. The blood-gas factor for two oxygen electrode systemshas been determined and some problems in this measurement areoutlined. ^* In receipt of a grant from the Wellcome Trust. In receipt of a grant from the Bayer Products Company.     

EFFECTS OF TEMPERATURE ON THE INTERACTION OF MORPHINE WITH OPIOID RECEPTORS

The electrically stimulated guineapig ileum preparation wasused to determine the effects of temperature on the affinityof morphine for opioid receptors. The potency of morphine (expressedas the concentration which produces 50% inhibition—IC₅₀)was significantly decreased at 30C (IC₅₀ 41.0x10^–8 mollitre^–1) and increased at 40C (IC₅₀ 5.1x10^–1 mollitre^–1) when compared with its potency at 37C (IC₅₀,8.8x10^–8 mol litre^–1). Experiments carried out inthe presence of naloxone (a competitive opioid antagonist) indicatedthat the affinity of opioid receptors for this antagonist wasnot affected by temperature. Further studies using B-funaltrexamine(a mu-specific, non-reversible opioid antagonist) revealed anincrease in morphine receptor affinity when temperature wasincreased from 30 to 37C. The data demonstrated that the potencyof morphine increased with temperature; the affinity of naloxonefor opioid receptors was unaltered by temperature; and the affinityof morphine for mu-receptors reached an optimal value withinthe range 30–37C. Presented in part to the American Society of AnesthesiologistsAnnual Meeting, Las Vegas, Nevada, U.S.A., 1986.     

EFFECTS OF HIGHER OXIDES OF NITROGEN ON THE ANAESTHETIZED DOG

The physiological derangements during and following the administrationof higher oxides of nitrogen have been studied in dogs anaesthetizedwith pentobarbitone. The dogs were exposed to concentrationsof nitric oxide or nitrogen dioxide between 0.1 and 2.0 percent over periods between 5 and 136 minutes. Despite the inhalationof 98 per cent oxygen, death was always associated with a criticalreduction in arterial oxygen content. This was caused by oneor more of the following three factors: methaemoglobinaemia,low arterial Po₂, and acidaemia which caused a shift of theoxyhaemoglobin dissociation curve. The reduction of arterialPo₂ was caused by an outpouring of fluid into the alveoli. ^* In receipt of a Leverhulme Research Fellowship. In receipt of a grant from the Wellcome Foundation. Supported by U.S.P.H.S. Fellowship No. 1-F3-GM-31, 742-01,National Institute of General Medical Sciences. Seconded by the University of Washington, Seattle.