DECISION-MAKING BEHAVIOUR DURING INHALATION OF SUBANAESTHETIC CONCENTRATIONS OF ENFLURANE

The effect of subanaesthetic concentrations of enflurane ondecision-making behaviour in risk situations was assessed usinga signal detection task. The subject heard noise alone (whitenoise) or a signal superimposed on the noise (1000-Hz tone)and had to report what he heard in each trial. Risk situationswere manipulated by changing the monetary reward and penaltyassociated with correct and incorrect responses. Eight malevolunteers participated in this study. It was found that underanaesthetic influence they did not avoid the same risks whichhad been avoided under control conditions. The findings areexplained in terms of influence of the gas on loss of controland lessened responsibility for the result of behaviour. ^*Present address: Aranne Laboratory of Psychophysiology andNeurobehavioral Studies, Department of Neurology, Hadassah UniversityHospital, Jerusalem, Israel.     

COMPARISON OF CNS EFFECTS OF PROPOFOL AND THIOPENTONE IN CATS

Using cats with chronically implanted brain electrodes, we havecompared the effects of propofol on CNS electrical activitieswith those of thiopentone. Ten cats were allocated to receiveeither propofol (n = 5) or thiopentone (n = 5). Cats were anaesthetizedinitially with 4% halothane in oxygen. The trachea was intubatedand the lungs ventilated mechanically. A femoral artery anda vein in a forepaw were cannulated for arterial pressure monitoringand fluid infusion. After the inspired concentration of halothanewas maintained at 0.5%, EEG in the cortex, the amygdala andthe hippocampus, somatosensory evoked potential (SEP) and reticularmulti-unit activity (R-MUA) were recorded. Incremental dosesof propofol or thiopentone were administered i. v. at 5-minintervals during 0.5% halothane anaesthesia. The cumulativedoses of propofol and thiopentone were 2, 5, 10 and 20mg kg^–1,and 4, 10, 20 and 40 mg kg^–1 respectively. Arterial pressurewas maintained in excess of 100 mm Hg systolic by infusion ofphenylephrine. All cats in the propofol group survived, buttwo in the thiopentone group died after the adminstration ofthiopentone 40mg kg^–1 Changes observed in CNS activitywere dose-related in all cases. The EEG changed with the incrementsof doses of propofol or thiopentone, from fast, small amplitudeto complexes of fast and slow, large amplitude activities, burstsuppression and flat EEG. SEP latency was prolonged by bothagents: the peak latency of N1 changed from 15 (SD 2) ms to20 (5) ms with propofol 20mg kg^–1, and from 14 (1) msto 27(2) ms with thiopentone 40 mg kg^–1. SEP amplitudeswere depressed by both agents: the amplitude of N1 was depressedby 70 (29) % with propofol 20 mg kg^–1 and by 60 (33) %with thiopentone 40mg kg^–1. The R-MUA also was depressedby both agents: 85 (4) % with propofol 20 mg kg^–1 and85 (8) % with thiopentone 40mg kg^–1. The R-MUA was depressedto 50% of control by propofol 3.2 (1.6) mg kg^–1 or thiopentone6.7 (5.0) mg kg^–1. These depressive actions on the EEG,SEP and R-MUA induced by propofol were similar to those inducedby twice the equivalent doses of thiopentone on an mg kg^–1basis. These results indicate that propofol has the same simpledepressant effects as thiopentone on CNS electrical activity.     

REDISTRIBUTION OF CARDIAC OUTPUT CAUSED BY OPENING OF ARTERIOVENOUS ANASTOMOSES BY A COMBINATION OF AZAPERONE AND METOMIDATE

The effects of the butyrophenone, azaperone 5 mg kg^–1i.m. alone and after addition of the imidazole derivative metomidate6 mg kg^–1 i.v. were studied in eight conscious pigs. Fifteenminutes after administration of azaperone, systemic arterialpressure was reduced by 35% as a result of a 45 % increase insystemic vascular conductance and 10% decrease in cardiac output(Q). After azaperone, 23% of the radioactive labelled microspheres(15 (SD 1) µm) injected into the left atrium were detectedin the lungs as a result of opening of arteriovenous anastomoses(baseline 3%). The increase in arteriovenous anastomotic bloodflow was at the expense of the nutritional (= capillary) channels.Flow to the brain was maintained, but that to the left ventricledecreased in parallel with the reduction in arterial pressure.Vascular conductance of most other organs, except the skin,increased or was maintained. The addition of metomidate hadno effect on Q because an increase in stroke volume (by 30%)compensated for the decrease in heart rate. Systemic vascularconductance decreased, most noticeably in the brain, left ventricleand skeletal muscle. We conclude that azaperone alone and incombination with metomidate had only a moderate effect on Qbut caused a redistribution in favour of arteriovenous anastomoses.     

TWO-STAGE INFUSION OF CHLORMETHIAZOLE FOR BASAL SEDATION

The effectiveness of chlormethiazole in providing basal sedationwas studied using a two-stage infusion regimen consisting ofan initial loading dose of 60 mg min^–1 25 min (in thelateral position) followed by a maintenance constant-rate infusionof 10 mg min^–1 for 60 min (in the supine position). Theregimen was evaluated in five healthy young volunteers who wereall moderately sedated throughout most of the infusion, lapsinginto sleep when left undisturbed, yet awakened easily to obeycommands. Varying periods of amnesia, corresponding with a meanchlormethiazole ethanedisulphonate blood concentration of 10.3mg litre^–1 (SD 3.8) were obtained. Light sedation occurredduring the first 10 min and the last 20 min of the total infusionperiod, corresponding to chlormethiazole blood concentrationsof 7.9 mg litre^–1 (SD 1.9) and 7.4 mg litre^–1 (SD2.3) respectively. Adverse side-effects were transient nasalirritation, flushing and a coryza-like syndrome. Other side-effectsof tachycardia and hypertension may be beneficial in counteractingcardiovascular depression associated with central neural blockade.A high total body clearance of chlormethiazole (mean 1.39 litremin^–1, SD 0.58) was found and would contribute to thebrief duration of action after termination of the infusion.     

DOSE-DEPENDENT EFFECT OF METOCLOPRAMIDE ON CHOLINESTERASES AND SUXAMETHONIUM METABOLISM

In obstetric patients undergoing postpartum tubal ligation,we found that metoclopramide produced dose-dependent prolongationof suxamethonium-induced neuromuscular block. Mean block timesafter suxamethonium 1 mg kg^–1 were 8.0 min, 9.83 min and12.45 min for control and metoclopramide 10 mg and metoclopramide20 mg groups, respectively. A laboratory study was thereforeconducted on the inhibition of human plasma cholinesterase (PCHE)and erythrocyte acetylcholinesterase (ACHE) activity by varyingconcentrations of metoclopramide using acetylthiocholine assubstrate. PCHE showed a greater sensitivity to inhibition bymetoclopramide; the concentration of metoclopramide producing50% inhibition of activity (I₅₀) was 3.16x10^–7 mol litre^–1,which is within the therapeutic range. ACHE was less sensitiveto inhibition by metoclopramide (I₅₀ 2.24x10^–5 mol litre^–1).Analysis of enzyme kinetics at varying substrate concentrationsrevealed that metoclopramide produced a potent non-competitive,dose-dependent inhibition of both ACHE and PCHE. The inhibitionconstant, ki, was 1.88x10^–7 mol litre^–1 for PCHEand 9.5x10^–8 mol litre^–1 for ACHE. As metoclopramideis a potent inhibitor of PCHE, interactions might be expectedto occur between metoclopramide and drugs that require PCHEfor biotransformation, such as suxamethonium and ester localanaesthetics. ^*Present address: Department of Anaesthesia, Royal HallamshireHospital, Glossop Road, Sheffield S10 2JF.     

Treatment of ischaemic left ventricular dysfunction with milrinone or dobutamine administered during coronary artery stenosis in the presence of beta blockade in pigs

Background. This study examines the effects of phosphodiesterasetype III (PDEIII) inhibition vs beta stimulation on global functionof the left ventricle (LV) and systemic haemodynamics in a porcinemodel of acute coronary stenosis with beta blockade. Methods. A total of 18 adult swine were anaesthetized. Micromanometer-tippedcatheters were placed in the ascending aorta and LV. Two pairsof ultrasonic dimension transducers were placed in the subendocardiumon the short axis proximal to a left anterior descending (LAD)artery occluder and the long axis of the LV. Before ischaemia,i.v. esmolol was infused to decrease baseline heart rate (HR)by approximately 25%, and all animals received an esmolol infusion(150 µg kg^–1 min^–1). Ischaemia was producedby reducing the flow in the LAD artery by approximately 80%,from 17(4) to 3(2) ml min^–1. Animals were randomized toreceive (after esmolol) one of the following: no drug, shamonly (Group 1, n=6), control (C); 50 µg kg^–1 i.v.milrinone (Group 2, n=6) followed by 0.375 µg kg^–1min^–1 (M); or incremental doses of dobutamine (Group 3,n=6) every 10 min (5, 10 and 20 µg kg^–1 min^–1)(D). Left ventricular function data obtained included HR, arterialand LV pressures, cardiac output (CO), Emax and dP/dT. Measurementswere taken during five time periods: before ischaemia (at baseline,after esmolol) and every 10 min during ischaemia (at 10, 20and 30 min). Results. The effects of beta blockade and ischaemia had a significantimpact on contractility (Emax) in Group M and myocardial performance(left ventricular end-diastolic pressure, LVEDP) in all groups.Left ventricular function (Emax, CO, LVEDP and SVR) was betterpreserved when milrinone was added in Group M. A moderate doseof dobutamine (10 µg kg^–1 min^–1) increasedCO. Only the high dose (20 µg kg^–1 min^–1)improved contractility (Emax), but at the expense of increasedSVR. Also, LVEDP with either dose of dobutamine remained highand unchanged. Conclusions. From our limited findings, it would appear thatthere may, theoretically, be some benefit for using milrinonein preference to other inotropic drugs in the presence of betablockade. Milrinone administration should be considered in patientswith acute ischaemic LV dysfunction and preexisting beta blockadebefore using other inotropic drugs such as beta stimulants. Presented in part at: the 27th Annual Meeting of the Societyof Cardiovascular Anesthesiologists, May 14–18, 2005,Baltimore, MD, USA (Anesth Analg 2005; 100: 5CA60).     

HAEMODYNAMIC EFFECTS OF THE PHOSPHODIESTERASE INHIBITOR ENOXIMONE IN COMPARISON WITH DOBUTAMINE IN ESMOLOL-TREATED CARDIAC SURGERY PATIENTS

In a randomized study, the haemodynamic effects of the new phosphodiesterase-III-inhibitor,enoximone, were compared with dobutamine in acutely ß-adrenoceptorblocked patients. Twenty patients scheduled for aorto-coronarybypass grafting suffering from tachycardia (heart rate (HR)> 100 beat min^–1) were treated by infusion of esmolol,an ultra-short acting, selective ß₁-blocker. Twentyminutes after the start of esmolo, either enoximone 0.5 mg kg^–1as a bolus (n = 10) or dobutamine 5 µg kg^–1 min^–1was administered. Haemodynamic effects were monitored for 40min, including measurement of left ventricular haemodynamics.Esmolol reduced HR (–27%) and dP/dt_max (–38%) significantlyin both groups. Cardiac index (Cl) was decreased also. Enoximoneincreased Cl (+35%) and dP/dt_max (+39%) significantly, whileno change in dobutamine-treated patients was observed. Systemicvascular resistance increased only in the dobutamine group (+44%).     

NON-COMPETITIVE EFFECTS OF DISOPYRAMIDE AT THE NEUROMUSCULAR JUNCTION: EVIDENCE FOR ENDPLATE ION CHANNEL BLOCK

The effects of disopyramide were studied at the neuromuscularjunction in an attempt to elucidate the mechanism of its blockingaction at this site. Disopyramide 5 x 10^–5-10^–3mol litre^–1 produced a concentration-dependent reductionof twitch amplitude in the indirectly stimulated chick biventercervicis preparation, but greater concentrations were requiredto reduce twitches elicited directly in the presence of erabutoxin-b1µg ml^–1. Equieffective twitch blocking doses ofeither disopyramide or tubocurarine greatly reduced agonistresponses to acetylcholine and carbachol, but the reductionwas less for magnesium-blocked twitches. Neostigmine antagonizedtubocurarine-induced, but not diso-pyramide-induced, blockadeof twitches. Concentration-response profiles to acetylcholineand carbachol were shifted to the right in a non-parallel fashionand the maximal response was depressed by disopyramide 5 x 10^–5-5x 10^–4 mol litre^–1. Intracellular recording studiescarried out in the cut, voltage-clamped costo-cutaneous muscleof the garter snake showed that disopyramide 5 x 10^–5-5x 10^–4 mol litre^–1 produced a concentration- andvoltage-dependent reduction of the amplitude of neurally evokedendplate-currents (EPC) and of the time constant of decay ()of EPC. We conclude that disopyramide possesses a non-competitiveblocking action at the neuromuscular junction, which is notreversible by anticholinesterase agents. The voltage-dependentnature of the block suggests that it is mediated via blockadeof the open form of the acetylcholine-activated receptor-ionchannel complex.     

EFFECT OF ANAESTHETIC AGENTS ON BILE FLOW AND BILIARY EXCRETION OF 131I- CHOLYLGLYCYLTYROSINE IN THE RAT

We have compared in the rat the effects of i.v. anaestheticagents on bile flow rate and on the biliary excretion of a novelbile acid, ^131l-cholylglycyltyrosine (¹³¹l-cholylgly.tyr.).Etomidate 1-mg bolus and 2-mg h^–1 infusion, Althesin 3-mgbolus and 14.5-mg h^–1 infusion and propofol 3.3-mg bolusand 3.3-mg h^–1 were given via a tail vein cannula andpentobarbitone 50 mg kg^–1 was given by the intraperitonealroute, to groups of six rats. Each animal received only oneanaesthetic agent. One hour after cannulation of the commonbile duct, ¹³¹l-cholylgly.tyr. 5 µCi was injected intothe jugular vein and bile was collected every 1 min for 10 min.The mean (SD) percentage cumulative biliary excretion of ¹³¹l-cholylgly.tyr.at the end of 10 min was: propofol group 74.1 (5.2)% Althesingroup 82.3 (2.2)%; etomidate group 69.4 (17.6)%; pentobarbitonegroup 76.4 (3.2)%. Propofol and Althesin were relatively morecholeretic, causing bile flow rates twice that produced by pentobarbitone.Only Althesin caused a significant increase in biliary excretionof ¹³¹l-cholylgly.tyr. relative to that in rats that receivedpentobarbitone. Bile flow rates for the respective anaesthetictechniques (µl min^–1/100 g body weight) (mean (SD))were: propofol group 14.1 (1.8); Althesin group 12.5 (1.7);etomidate 8.5 (1.4); pentobarbitone group 7.3 (1.0). There wasa marked metabolic acidosis in all rats except in the propofolgroup, in which normal acid-base status and oxygenation wereobserved. Previously presented at the Medical Research Society and published(abstract form) in Clinical Science and Molecular Medicine 1986;71: 71–72.     

PHARMACODYNAMICS OF ATRACURIUM DURING PROPOFOL, THIOPENTONE AND OPIOID ANAESTHESIA

We have assessed in 20 patients the accuracy and precision ofan infusion profile for atracurium, which continually set theinfusion rate to maintain stable muscle paralysis and a targetsteady state plasma concentration, when equilibrium betweenthe biophase and plasma had occurred. Muscle paralysis was stableafter 20 min, with a mean absolute drift in muscle paralysisin the succeeding 40 min of 0.13 (SD 0.07)% T1/Tc (height offirst twitch/height of control twitch) per min. The plasma samplesafter 30 min, which were assessed empirically as being in equilibriumwith the biophase, had an overall mean bias of 8.0 (SEM 3.7)% (P < 0.05) and an overall mean absolute prediction errorof 16.4 (SEM 2.5)% from the target steady state concentrationbeing delivered by the infusion. The profile was then used toestimate the steady state plasma concentration of atracuriumrequired to maintain 90% paralysis (C_p^ss₉₀), by manually adjustingthe delivered target concentration of the infusion until muscleparalysis was stable at 88–92% inhibition of T1/Tc for15–20 min, with three plasma samples taken over the next10 min. Measurements were completed within 60–90 min.The mean C^ss_p90 of atracurium with propofol was 1.039 (SD 0.224)ug ml^–1 (n = 10), with thiopentone 1.334 (0.378) µgml–1 (n = 10), and with opioidanaesthesia 0.915 (0.221)ug ml^–1 (n = 10). These differences in the C^ss_p90 explainsome of the variability in response which occurs with neuromuscularblocking drugs. The technique enables the Cpss90 of a myoneuralblocker to be determined by a simple model-independent method.     

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.     

SUFENTANIL DISPOSITION IN PATIENTS UNDERGOING RENAL TRANSPLANTATION: INFLUENCE OF CHOICE OF KINETIC MODEL

We studied the disposition of sufentanil in 10 patients undergoingrenal transplantation, and compared the data with those fromeight healthy anaesthetized patients undergoing lower abdominalsurgery. Patients received sufentanil 2.5 µg kg^–1as part of a balanced anaesthetic technique. Central venousblood samples were collected at intervals up to 600 min, andplasma sufentanil concentrations assayed by radioimmunoassay.Pharmacokinetic parameters were calculated from drug concentration—timeprofiles by extended least squares non-linear regression analysis(ELSFIT) and by a model independent (Ml) approach using AUCand its first moment, AUMC. There were no differences (basedon Ml results) between the two groups for elimination half-life(T^ß) (renal failure: 188 min; anaesthetized controls:195 min), clearance (Cl) (1030 and 1093 ml min^–1) andapparent volume of distribution at steady state (V^ss) (223.0and 215.3 litre). Sufentanil binding to plasma proteins was91.4% in the renal patients and 92.2% in the healthy group (ns).Comparison of kinetic methods showed significant correlationof the individual estimates for T^ß, Cl and V^ss (P< 0.01). The mean absolute differences between methods were:T^ß2.7 min (95%limits: –26.2 to 31.5), Cl 36.5ml min^–1 (–5.5 to 78.4), V^ss –18.4 litre (–47.7to 10.9). When the mean estimate for the two methods ((ELSFIT+ Ml)/2) was compared with the difference, there was no correlationfor the estimates of Cl and V^ss. Ml tended to overestimate clearanceand underestimate volume of distribution. There was a significantrelationship between estimates for elimination half-life, witha slope greater than zero. Presented in part at the Anaesthetic Research Society, BristolMeeting, June 1988.     

POSTOPERATIVE HYPOXAEMIA: COMPARISON OF EXTRADURAL, I.M. AND PATIENT-CONTROLLED OPIOID ANALGESIA

Arterial oxygen saturation (Sa_o2) was analysed continuouslybefore and for 24 h after lower abdominal surgery in 30 patientsbreathing air using one of three postoperative analgesic regimens:i.v. diamorphine using a patient-controlled analgesia system(PCAS), extradural diamorphine or i.m. morphine. Hypoxaemiawas defined as Sa_O2 < 94% for more than 6 min h^–1.Before operation there was no difference between the three analgesiagroups assessed by the duration when Sa_o2 was less than 94%.After operation the pattern of Sa_O2 vs time distribution waseither stable, with little variation from hour to hour withno hypoxaemia, or unstable with large variation with 30% ofpatients hypoxaemic. Thus three patterns of Sa₀₂ distributionwere seen in the postoperative period: stable without hypoxaemia(4/10 PCAS, 0/10 extradural, and 1/10 i.m. patients), unstablewithout hypoxaemia (4/10 PCAS, 5/10 extradural and 7/10 i.m.patients) and unstable with prolonged nocturnal periods withSa_o2 <94% for a mean of 17.7 min h^–1, 95% confidencelimits (CL) 10–25 min h^–1, (2/10 PCAS, 2/10 i.m.and 5/10 extradural patients). Before operation, the unstablegroup with hypoxaemia spent longer at < 94% Sa_o2 (mean 4.8min h^–1 95% CL 1.0–8.6 min h^–1) than the stablegroup (mean 0.4 min h^–1, 95% CL 0.17–0.61 min h^–1)and this was a predictor of postoperative hypoxaemia. Hypoxaemiaoccurred in all analgesia groups, but extradural diamorphinetended to cause longer periods. Some patients at risk of postoperativehypoxaemia may be predicted by preoperative monitoring of Sa_o2although extradural diamorphine boluses were associated withhypoxaemia in patients with normal preoperative values.     

RELATIONSHIPS BETWEEN INSPIRED OXYGEN CONCENTRATION AND VENOUS ADMIXTURE DURING NITROUS OXIDE-OXYGEN-HALOTHANE ANAESTHESIA

The inspired oxygen concentration (Fl_O²) was changed on 43 occasionsat about 30-min intervals in 13 patients during artificial ventilationwith mixtures of nitrous oxide (N₂O), oxygen and halothane.Ventilator settings remained unchanged for each patient andat the end of each period, samples of arterial and central venousblood (and, in six patients, pulmonary arterial blood) and inspiredand expired gases were collected. Oxygen tension was measuredwith a dedicated electrode shown to be unaffected by N₂O. Venousadmixture (Qva/Qt) was calculated at each Fl_O². There was ahighly significant correlation between the direction of changeof Fl_O² and that of Qva/Qt, irrespective of whether Fl_O² increasedor decreased. In 10 patients, there was a progressive increasein Qva/Qt as Fl_O² increased above 40%, and in all patients Qva/Qton nearly 100% oxygen was greater than that measured at thenext lowest concentration (60-80%). These results are at variancewith the pattern of behaviour predicted from the "critical Va/Q"theory and support the concept of an oxygen-dependent redistributionof perfusion. ^*Present address: Department of Anaesthesia, Prince Henry Hospital,Sydney, Australia     

ENHANCEMENT OF BUPIVACAINE TOXICITY BY DILTIAZEM IN ANAESTHETIZED DOGS

We have studied the cardiovascular effects of graded doses ofbupivacaine in the absence or presence of clinical concentrations(approximately 250 ng litre^–1) of diltiazem in fentanyl-pentobarbi-toneanaesthetized dogs. Bupivacaine was given, increasing in a stepwisemanner, as a loading dose (200, 400 or 600 pig kg^–1) followedby a 30-min i. v. infusion (25, WO or 200 pig kg^–1 min^–1,respectively). Thereafter, bupivacaine was infused at 400 pigkg^–1 min^–1 until each animal died. Group AB (n=5) 7 2 fig kg^–1(n = 7) received bupivacaine, group diltiazem(400 fig kg^–1 followed bymin^–1) and group C (n =7) received diltiazem followed by bupivacaine given as in groupA. Lethal plasma concentrations of bupivacaine were significantlysmaller (P < 0.01) in group C (7.1 (SEM 0.7) vs 12.6 (1.5)mg litre^–1). Bupivacaine produced similar decreases incardiac index, left ventricular (LV) segmental work and thefirst derivative of LV pressure (LV dP/dX) in the absence andpresence of diltiazem. In group A, bivacaine increased systemicvascular resistance index (SVRI) and thus mean arterial pressure(MAP) was maintained. In group C, SVRI, reduced by diltiazemper se, did not increase in response to bupivacaine, so MAPwas not maintained. Death resulted from a progressive decreasein cardiac contractility and MAP. Plasma concentrations of bupivacaineattained at the three doses were similar in the absence andpresence of diltiazem. This study has shown that the toxicityof bupivacaine was increased approximately two-fold by diltiazem.(Br. J. Anaesth. 1992; 69:492–497) Presented in part to the Anaesthesia Research Society, April1990[1]     

The role of prefrontal cortex CB1 receptors in the modulation of fear memory

Understanding the mechanism of how fear memory can be extinguishedcould provide potential therapeutic strategies for the treatmentof posttraumatic stress disorders. Here we show that infusionof CB1 receptor antagonist into the infralimbic (IL) subregionof the medial prefrontal cortex (mPFC) retarded cue-alone–inducedreduction of fear-potentiated startle. Conversely, cannabinoidagonist WIN55212-2 (WIN) facilitated the extinction. Unexpectedly,administration of WIN without cue-alone trials reduced startlepotentiation in a dose-dependent manner. The effect of cannabinoidagonists was mimicked by endocannabinoid uptake or fatty acidamide hydrolase inhibitors. Rats were trained with 10 conditionedstimulus (CS⁺) (yellow light)–shock pairings. Extinctiontraining with CS⁺ (yellow light)-alone but not CS^– (bluelight)-alone trials decreased fear-potentiated startle. Intra-ILinfusion of WIN before CS^–-alone trials decreased startlepotentiation, suggesting that the cannabinoid agonist decreasedconditioned fear irrespective of whether the rats underwentCS⁺- or CS^–-alone trials. Cannabinoid agonists activatedextracellular signal-regulated kinases (ERKs) in mPFC slices,and ERK inhibitor blocked the effect of cannabinoid agonistson fear-potentiated startle. These results suggest that CB1receptors acting through the phosphorylation of ERK are involvednot only in the extinction of conditioned fear but also in theadaptation to aversive situations in general.     

PATTERN OF CHANGE OF BRONCHOMOTOR TONE FOLLOWING REVERSAL OF NEUROMUSCULAR BLOCKADE: Comparison between atropine and glycopyrrolate

Specific airways conductance (s. Gn) was measured using theforced airflow oscillation method, to study the effect of tworegimens, commonly used for the reversal of neuromuscular blockade,on bronchomotor tone. Patients who had received neuromuscularblockers and had undergone elective surgery were randomly allocatedto receive neostigmine 50 ßg kg^–1 given concurrentlywith either atropine 20 µg kg^–1 (10 patients) orglycopyrrolate 10 µg kg^–1 (10 patients). Beforeadministration, five baseline measurements of s.G_gw were obtainedand measurements were then made at intervals of 1 min for thenext 10 min At 3 min there was a significant difference in s.G_gwbetween the two groups, higher values being found in the atropinegroup. At 10 min, no significant difference was seen betweenthe groups, although both showed a significant decrease in s.G_gw,compared with baseline values (P < 0.05).     

EFFECTS OF INCREASING DOSES OF ALFENTANIL, FENTANYL AND MORPHINE ON MID-LATENCY AUDITORY EVOKED POTENTIALS

We have studied dose-dependent effects of alfentanil, fentanyland morphine on mid-latency auditory evoked potentials (MLAEP).Anaesthesia was induced with alfentanil 100 µg kg^–1every 5 mm to a total dose of 500 µg kg^–1 (groupI, n = 10), fentanyl 10 µg kg^–1 every 7 min to atotal dose of 50 µg kg^–1 (group II, n = 10) or morphine1 mg kg^–1 for induction and 0.5 mg kg^–1 every 15min to a tota l dose of 3mg kg^–1 (group III, n = 10).MLAEP were recorded before and 3–15 min after every opioiddose on vertex (positive) and mastoids on both sides (negative).Latencies of the peaks V, Na, Pa, Nb, P1 (ms) and amplitudesNa/Pa, Pa/Nb and Nb/P1 (µV) were measured. Fast-Fouriertransformation was used to calculate power spectra of the AEP.In the awake state, MLAEP had high peak-to-peak amplitudes anda periodic waveform. Power spectra indicated high energy inthe 30–40 Hz frequency range. During general anaesthesiawith increasing doses of alfentanil, fentanyl and morphine,the brainstem response V was stable. There was a marked increaseonly in latency and decrease in amplitude of P1. In contrast,for the early cortical potentials Na and Pa, only small increasesin latencies and decreases in amplitudes were observed. Afterthe largest doses of affentanil (500 µg kg^–1), fentanyl(50 µg kg^–1) and morphine (3 mg kg^–1) Na,Pa and Nb showed a similar pattern as in awake patients. Inthe power spectra, high energy persisted in the 30-Hz frequencyrange. There were no dose-dependent effects of opioids on MLAEPand no differences between alfentanil, fentanyl, and morphinecould be found. (Br. J. Anaesth. 1993; 71: 622–628)     

COMPARATIVE EFFECTS OF PIPECURONIUM AND TUBOCURARINE ON PLASMA CONCENTRATIONS OF HISTAMINE IN HUMANS

We have examined the effects of a rapid bolus dose of pipecuronium0.1 mg kg^–1 or tubo-curarine 0.5mg kg^–1 on plasmahistamine concentration, heart rate and arterial pressure in20 patients (n = 10 in each group). Anaesthesia was inducedwith thiopentone 6 mg kg^–1 i.v. and maintained with 70%nitrous oxide and halo-thane in oxygen. Neuromuscular blockingdrugs were administered 4 min after administration of thiopentone.Venous blood samples were obtained before induction, 1 min afterthiopentone and 1, 3 and 5 min after the administration of theneuromuscular blocking drugs. Tubocurarine caused 240% and 210%increases in plasma concentration of histamine at 1 and 3 min,respectively. These changes were significant (P < 0.05) at1 min and associated with a decrease in mean arterial pressureand an increase in heart rate. None of the 10 patients receivingpipecuronium had a significant change in plasma concentrationof histamine or in haemo-dynami variables. ^*Present addresses: Department of Anaesthesia, Al-Kasr El-AniHospital, Cairo University, Cairo, Egypt. Present addresses: Department of Pharmacology, Lund University,Lund, Sweden.     

EFFECT OF GRADED INFUSION RATES OF PROPOFOL ON REGIONAL AND GLOBAL LEFT VENTRICULAR FUNCTION IN THE DOG

We have studied the effects of graded infusion rates of propofol(0.2–0.5 mg kg^–1 min^–1) on left ventricularglobal and regional function, in eight acutely instrumenteddogs. Global function was assessed by measurement of aorticand left ventricular pressure, L V dP/dt_max, aortic blood accelerationand stroke volume. Regional function was assessed by measurementof systolic shortening and the endsystolic pressure-length relationship.The response of the coronary circulation to short periods ofocclusion was also assessed. Administration of propofol significantlyreduced left ventricular preload, as indicated by reductionsin end-diastolic pressure and length; contractility was depressed,the depression being greater in the apex than in the base ofthe left ventricle. High infusion rates impaired relaxation.Regulation of coronary blood flow was not disrupted. Reductionsin preload and contractility contributed to the propofol-inducedhypotension. After 60 min, recovery from the greatest infusionrate was incomplete. ^*Present address: Department of Anaesthesiology, Universityof the Orange Free State, Bloemfontein, SA.