EFFECT OF MEPTAZINOL ON NEUROMUSCULAR TRANSMISSION IN THE ISOLATED RAT PHRENIC NERVE-DIAPHRAGM PREPARATION*

Meptazinol has been shown to have significant effects on neuromusculartransmission in the isolated rat phrenic nerve-diaphragm preparation.The response of the preparation to indirect electrical stimulationwas increased in a concentration-dependent manner by meptazinolhydrochloride 2–32 µg ml^–1. Meptazinol 0.5–2µg ml^–1 antagonized the effects the tubocurarineon this preparation, and in concentrations of 1 µg ml^–1andgreater, potentiated suxamethonium. These effects were similarto those obtained with neostigmine and it was demonstrated thatmeptazinol had significant anti-cholinesterase activity in theconcentrations used. Inhibition of cholinesterase with ecothio-paterevealed a neuromuscular blocking activity of meptazinol inconcentrations as low ^*A preliminary account of some of this work was presented tothe Anaesthetic Research Society, June 31, 1984.     

FUNCTIONAL AND METABOLIC EFFECTS OF BUPIVACAINE AND LIGNOCAINE IN THE RAT HEART-LUNG PREPARATION

We have examined the effects of bupivacaine and lignocaine onmyocardial metabolism in the rat isolated heart-lung preparation.Bupivacaine 1, 5 or 25 µg ml^–1 or lignocaine 4,20 or 100 µg ml^–1 was administered 5 min after thestart of perfusion. Both bupivacaine 25 µg ml^–1and lignocaine 100 µg ml^–1 reduced heart rate significantly.Bupivacaine 25 µg ml^–1 was associated with a higherincidence of arrhythmias than the other groups. Three heartsin the bupivacaine 25 µg ml^–1 group (n = 8) andtwo hearts in the lignocaine 100 µg ml^–1 group (n= 8) failed (zero cardiac output) at the end of the experiment.Although there were no significant differences in myocardiallactate and glycogen concentrations between groups, ATP contentin the bupivacaine 25 µg ml^–1 and lignocaine 100µg ml^–1 groups was significantly less than thatin the control group. The results suggest that myocardial depressionand subsequent metabolic deterioration occurred with both thehigh doses of local anaesthetics; these findings do not accountfor the apparent increased cardiotoxicity of bupivacaine.     

Spinal anaesthesia for Caesarean section with bupivacaine 5 mg ml(-1) in glucose 8 or 80 mg ml(-1)

The standard spinal preparation of bupivacaine contains a highconcentration of glucose (80 mg ml^–1). However,the addition of only a small amount of glucose (8 mg ml^–1)to plain solutions of bupivacaine results in a solution which,although no more than marginally hyperbaric, produces a morepredictable block when used for spinal anaesthesia in non-pregnantpatients. However, bupivacaine 5 mg ml^–1 inglucose 8 mg ml^–1 has a density [1.00164 (SD0.00008) at 37°C] which is relatively greater than thatof the cerebrospinal fluid (CSF) of the pregnant patient atterm (1.0003 at 37°C) because CSF density decreases duringpregnancy. Therefore, a double-blind, randomized, controlledstudy was carried out to compare intrathecal bupivacaine (glucose8 mg ml^–1) with bupivacaine (glucose 80 mg ml^–1)in 40 pregnant patients at term. Although there was no differencebetween groups in onset of sensory block, dose of ephedrineor patient satisfaction, patients receiving bupivacaine (5 mg ml^–1)with glucose (8 mg ml^–1) had persistently highersensory blocks between 60 and 120 min after intrathecalinjection, suggesting that the spread of spinal solutions inthe pregnant patient at term is not dependent on density. Br J Anaesth 2001; 86: 805–7     

Fentanyl inhibits the release of [3H]noradrenaline from SH-SY5Y human neuroblastoma cells

We have examined the effect of fentanyl on [³H]noradrenalinerelease in a human neuroblastoma cell preparation, SH-SY5Y.Fentanyl produced a significant, concentration-dependent inhibitionof [³H]noradrenaline release with IC₅₀ values of 5.5 x 10^–6mol litre^–1 and 15.5 x 10^–6 mol litre^–1 forcarbachol- and potassium- evoked release, respectively. Thesmall difference in IC₅₀ between the two evoking stimuli maybe explained by the weak binding affinity of fentanyl to muscarinicreceptors (K_i = 570 nmol litre^–1). The minimum concentrationsat which a significant effect was observed were 0.3 x 0.10^–6mol litre^–1 and 10.0 x 10^–6 mol litre^–1 forcarbachol- and potassium-evoked release, respectively; thesevalues are considerably in excess of the serum concentrationof fentanyl required to produce analgesia. Naloxone failed toantagonize the fentanyl inhibition and, furthermore, morphineand an enkephalin had no effect on evoked release, implyinga non-opioid receptor mediated effect. (Br. J. Anaesth. 1994;72: 98–103)     

FENTANYL BY CONSTANT RATE I.V. INFUSION FOR POSTOPERATIVE ANALGESIA

Fentanyl by continuous i.v. infusion (1.5 µg kg^–1min^–1 or 0.5 µg kg^–1 min^–1) was comparedwith placebo infusion as an analgesic regimen for 24 h afterhysterectomy. The drugs were infused using a new disposabledevice which required no external power source. All patientswere allowed morphine i.m. if they experienced pain. Patientsin the higher dose fentanyl group demanded less i.m. morphineand had better pain relief after operation, without importantrespiratory depression. ^* Present address: University Department of Anaesthesia, MedicalSchool, Beech Hill Road, Sheffield S10 2RX.     

I.V. FLUIDS DURING SURGERY

During an attempt to measure renal function during operationin six patients undergoing major abdominal surgery involvingintestinal resection and blood loss in excess of 300 ml, itbecame apparent that the conventional recommendation for i.v.crystalloid fluid of 5–10 ml kg^–1 h^–1 wasnot sufficient to maintain cardiovascular stability and urineoutput, but a volume of 15 ml kg^–1 h^–1, given toa subsequent six patients, was adequate. Administration of lowsodium (glucose) solutions also produced biochemical abnormalitiesof a severity not documented previously. A survey of the publishedliterature on volumes of crystalloid fluids used supports thecontention that, during major surgery, crystalloid requirementsmay be of the order of 10–15 ml kg^–1 h^–1 ratherthan 5–10 ml kg^–1 h^–1.     

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.     

PROPOFOL AND ALFENTANIL IN CHILDREN: INFUSION TECHNIQUE AND DOSE REQUIREMENT FOR TOTAL I.V. ANAESTHESIA

We estimated the dose of propofol (initial dose followed bya stepped infusion) when given with two different infusion ratesof alfentanil for total i. v. anaesthesia in 59 children aged3–12 yr. Patients in series 1 (four groups) received analfentanil loading dose of 85g kg^–1 and an infusion of65 g kg^–1 h^–1. Patients in series 2 (groups 5 and6) received an alfentanil loading dose of 65 g kg^–1 andinfusion of 50 g kg^–1 h^–1. Parents gave their informedconsent. Premedication comprised temazepam 0.3 mg kg^–1.Glycopyrronium 5 g kg^–1 was administered and anaesthesiainduced and maintained with alfentanil (loading dose and infusion)followed by propofol (loading dose and three-stage manual infusionscheme). Suxa-methonium 1 mg kg^–1 was used to facilitatetracheal intubation and the lungs were ventilated artificiallyto normocapnia with 30% oxygen in air. Probit analysis was usedto determine the dose requirement of propofol. In series 1.the ED₅₀ was 6.0 mg kg^–1 h^–1 (95% confidence limits5.5-6.2 mg kg^–1 h^–1) and ED₉₅ 8.6 (6.8-7.8) mg kg^–1h^–1. Corresponding values for series 2 were ED₅₀ 7.5 (8.0-9.8)mg kg^–1 h^–1 and ED₉₅ 10.5 (9.6^–13.1) mg kg^–1h^–1. ^*Department of Anaesthesia, University of Newcastle upon Tyne,Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP.      

DIURETIC-INDUCED HYPOKALAEMIA, PANCURONIUM NEUROMUSCULAR BLOCKADE AND ITS ANTAGONISM BY NEOSTIGMINE

The effect of hypokalaemia on a neuromuscular blockade inducedby pancuronium and its antagonism by neostigmine was studiedin the cat anterior tibialis-peroneal nerve preparation usingthe constant infusion of pancuronium technique. Hypokalaemiawas induced by chronic administration of chlorothiazide. Theinfusion rate of pancuronium required to maintain a 90% depressionof twitch tension was reduced from 0.72 ±0.06 µgkg^–1 min^–1 in the cats with a normal serum concentrationof potassium (K⁺ = 4.4±0.2 mmol litre^–1; n = 7)to 0.41±0.07 µg kg^–1 min^–1 in the hypokalaemiccats (K⁺ = 2.3±0.1 mmol litre^–1; n = 8). The doseof neostigmine necessary for 50% antagonism of the pancuronium-induceddepression of twitch tension (ED₅₀) was 10.0 µg kg^–1in the cats with a normal potassium concentration and 18.5 µgkg^–1 in hypokalaemic cats. We conclude that hypokalaemiadecreases the dose of pancuronium required for neuromuscularblockade and increases the dose of neostigmine required forantagonism of the block.     

EFFECT OF SOME I.V. ANAESTHETIC AGENTS ON CANINE GASTROINTESTINAL MOTILITY

Thiopentone 20 mg kg^–1, ketamine 8 mg kg^–1 and minaxolone2 mg kg^–1 were administered to fasting greyhound dogs.Mechanical and electrical activities from stomach, duodenum,jejunum and ileum were recorded using strain gauge force transducersand implanted bipolar electrodes. Thiopentone and minaxolonecaused intense activity in the duodenum and jejunum (phase Iand phase II of the interdigestive cycle), but not the stomachor ileum. The activity following injection of thiopentone orminaxolone was prevented by premedication with either atropine0.05 mg kg^–1 or pentolinium 0.2 mg kg^–1. Ketaminehad no influence on gastrointestinal activity or the responseto thiopentone or minaxolone. None of these drugs altered thebasal electrical rhythm of the intestine     

Comparison of patient-controlled analgesia in children by i.v. and s.c. routes of administration

Sixty children undergoing appendicectomy were allocated randomlyto receive one of two PCA regimens with morphine. Group IV receivedstandard i.v. PCA with a bolus dose of morphine 20 µgkg^–1 and a background infusion of 4 µg kg^–1h^–1 while group SC received PCA by the s.c. route witha bolus dose of morphine 20 µg kg^–1 and a backgroundinfusion of 5 µg kg^–1 h^–1. In both groupsthere was a lockout interval of 5 min. Group SC self-administeredsignificantly less morphine (P < 0.05) and had a significantly(P < 0.07) greater percentage of valid demands for analgesiathan group IV. There were no differences in pain scores betweenthe groups at rest or during movement. Group IV suffered significantly(P<0.01) more hypoxic episodes than group SC. There wereno differences between groups in the incidence of postoperativenausea and vomiting or oversed-ation. S.c. PCA appears to beas effective and safe as i.v. PCA. By giving patients feedbackon the occurrence of valid demands for analgesia, s.c. PCA mayproduce more appropriate and effective use of PCA. (Br. J. Anaesth.1994; 72: 533–536) ^*Present address: Department of Anaesthesia, Royal Infirmaryof Edinburgh, 1 Lauriston Place, Edinburgh.     

VENOUS SEQUELAE FOLLOWING I.V. ADMINISTRATION OF DICLOFENAC

Diclofenac sodium (Voltarol) was administered i.v. to 149 consecutivepatients who were thought likely to benefit from its anti-inflammatoryaction. Patients were allocated randomly to one of two groups:group A received the undiluted i.m. preparation (25 mg ml^–1)and group B the i.m. preparation diluted in normal saline (5mg ml^–1). Diclofenac 1 mg kg^–1 administered overa 10-min period via a 23-gauge needle into a vein at eitherthe antecubital fossa or the dorsum of the hand. No local orsystemic problems were encountered in either group, at the timeof injection. A high incidence of painless local venous thrombosisoccurred in both hand and arm veins, 72 h after administrationin group A (85% and 58%, respectively). The incidence of thrombosiswas reduced markedly after administration of the diluted drug:38% hand veins; 8% antecubital fossa veins.     

TOTAL I.V. ANAESTHESIA WITH PROPOFOL AND ALFENTANIL: DOSE REQUIREMENTS FOR PROPOFOL AND THE EFFECT OF PREMEDICATION WITH CLONIDINE

We determined in 51 healthy patients undergoing body surfacesurgery the dose requirements for propofol, as part of a totali.v. anaesthesia technique with an alfentanil infusion. Afterpremedication with temazepam, patients received alfentanil 50µg kg^–1 followed by an infusion of 50 µg kg^–1h^–1. Patients were anaesthetized with a loading dose ofpropofol followed by a three-stage infusion designed to reachone of five preselected blood concentrations of propofol. Themotor response to the initial surgical incision was noted andprobit analysis was used to derive the ED₅₀ (2.94 mg kg^–1h^–1; 95% confidence limits: 2.35–3.37 mg kg^–1h^–1). and ED₉₅ (4.98 mg kg^–1 h^–1; 95% limits:4.13–8.8 mg kg^–1 h^–1) for the final propololinfusion rate under these conditions. Whole blood concentrationof propofol at the time of the incision was related linearlyto the infusion rate and the EC₅₀ and EC₉₅ (probit analysis)were derived as 1.44 (95% confidence limits 0.62–1.87)and 4.05 (95% confidence limits 2.78–30.5) µg ml^–1,respectively. Postoperative recovery was rapid, uncomplicatedand uneventful. In a subgroup of eight patients, the additionof clonidine 0.6mg to the premedication significantly decreasedthe requirement for propofol (P <0.05) during surgery, butresulted in prolonged recovery times. Pilot study presented to the Anaesthetic Research Society, June24, 1988 [1].     

OESOPHAGEAL CONTRACTILITY DURING TOTAL I.V. ANAESTHESIA WITH AND WITHOUT GLYCOPYRRONIUM

Somatic movement and spontaneous and provoked oesophageal contractionswere noted at time of incision in 51 patients receiving totali.v. anaesthesia with alfentanil and propofol. Probit analysisof the dose of propofol required to prevent spontaneous movementrevealed an ED₅₀ (95% confidence limits) of 2.5 (1.8-2.9) mgkg^–1 h^–1 and ED₉₅ of 4.7 (4.0-7.5) mg kg^–1h^–1. Corresponding venous blood concentrations gave anEC₅₀ of 1.2 (0.4-1.6) µg ml^–1 and an EC₉₅ of 4.0(2.8-18.5) µg ml^minus;1. ED₅₀ of propofol for preventingspontaneous oesophageal contraction was 3.0 (1.9-3.6) mg kg^–1h^–1. ED₉₅ was 6.9 (5.0-27.3) mg kg^–1 h^–1;EC₅₀ for oesophageal contractions was 1.7 (0.7-2.3) µgml^–1 and EC₉₅ was 5.9 (3.7-70.6) µg ml^–1.Another group of 10 patients were given glycopyrronium 5 µgkg^–1 at induction; oesophageal contractility was significantlyreduced in this group. Preliminary results of this research were presented to the AnaestheticResearch Society, Nottingham, July 1990. ^*Department of Anaesthesia, Derriford Hospital, Plymouth, DevonPL6 8DH. Department of Anaesthesia, Darlington Memorial Hospital, Darlington,Durham DL3 6HX.     

EFFECT OF I.V. LIGNOCAINE ON PAIN AND THE ENDOCRINE METABOLIC RESPONSES AFTER SURGERY

Pain intensity, and blood glucose and plasma cortisol concentrationswere measured following abdominal hysterectomy in 18 patientsallocated randomly to receive either i.v. lignocaine 1.5 mgkg^–1 plus 2 mg kg^–1 h^–1, or saline. The administrationof lignocaine resulted in plasma conentrations between 1.5 and2.0 µg ml^–1 during the 2-h study period. However,the administration of lignocaine i.v. had no effect on the intensityof pain after surgery, or on the adrenocortical and hyperglycaemicresponses to surgery.     

PHARMACOKINETICS OF I. V. AND RECTAL METHOHEXITONE IN CHILDREN

The pharmacokinetics of methohexitone were investigated in 15healthy children undergoing minor surgery under inhalation anaesthesia.Six received 1% methohexitone 1–2 mg kg^–1 i.v. andnine received 10% methohexitone 20–25 mg kg^–1 perrectum. On i. v. administration, three-compartment pharmacokineticsgenerally applied. The mean elimination half-life of methohexitonewas 193 ± 75 min; that is, considerably longer than previouslyreported for children, but in good agreement with findings inadults. The mean clearance was 17.9 ± 8.3 ml min^–1kg^–1, the volume of distribution at steady state was 2.1± 0.24 litre kg^–1 and the mean residence time was134 ± 47 min. The pharmacokinetic model used for thei.v. data was easily modified to suit the plasma concentrationcurves obntained on rectal administration. The mean bioavailabilityof methohexitone administered per rectum was 17% with a six-foldvariation between individuals.     

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.      

CONTINUOUS I.V. INFUSION OF LABETALOL FOR POSTOPERATIVE HYPERTENSION: Haemodynamic Effects and Plasma Kinetics

Labetalol is a combined -and ß-adrenoreceptor blockingagent. A loading dose may be used to antagonize sympatheticoveractivity rapidly after surgery and be followed by a continuousinfusion to achieve a stable effect. The haemodynamic effectsand pharmacokinetics of this method of labetalol administrationwere studied in six rewarmed, extubated and sedated patients15±2 h after aortobifemoral bypass surgery. Patientswere monitored with radial and thermistor-tipped pulmonary arterycatheters. Labetalol 1.5 mg kg^–1 was injected i.v. over5 min and a maintenance infusion of 0.2 mg kg ^–1 h^–1was started 30 min later and continued for 5.5 h. Within 5 minof the loading dose, i.v. labetalol induced significant (P <0.05) decreases in mean arterial pressure (–32 ±11%),in heart rate (–20±11%) and in cardiac index (–26± 15%) that lasted throughout the infusion. Changes insystemic vascular resistance were not uniform, but an increasewas not observed in any patient. Mean stroke volume index andventricular filling pressures were not significantly affectedby labetalol administration. The mean measured steady stateplasma concentration (C^ss) (264 ±46 ng ml^–1) washigher than predicted (170 ng ml^–1) because the clearance(13.1 ±2.4 ml kg^–1 min^–1) was lower thanthat used to calculate the infusion rate. We conclude that labetalolis an effective antihypertensive agent in the postoperativeperiod. A C^ss can be achieved rapidly by such i.v. administrationand this offers the advantage of inducing rapid and stable haemodynamiceffects. However, calculation of the infusion rate must be basedon a clearance of 13 ml kg^–1 min^–1.     

Intravenous clonidine infusion in critically ill children: dose-dependent sedative effects and cardiovascular stability

Clonidine is used for analgesia and sedation in paediatric anaesthesia,but there are no data on its sedative properties and side effectsin critically ill children. We studied 30 ventilated childrenaged 10 yr and under to determine an effective i.v. dosing rangeand to assess its cardiovascular effects. Twenty non-paralysed,ventilated children were given a background infusion of midazolam50 µg kg^–1 h^–1 combined with a variable clonidineinfusion (0.1–2 µg kg^–1 h^–1) to maintainoptimal sedation. The effects of clonidine 1 µg kg^–1h^–1 on cardiac index were measured in 10 postoperativecardiac patients using a reverse Fick method. Dose-dependentsedation was achievable (713 out of 861 h) without cardiovascularside effects, but an infusion limit of clonidine 1 µgkg^–1 h^–1 was inadequate in two patients. An increaseddose limit of 2 µg kg^–1 h^–1 combined withmidazolam 50 µg kg^–1 h^–1 achieved satisfactorysedation scores for 602 out of a total of 672 h studied withno failures. Clonidine in combination with midazolam at 1 µgkg^–1 h^–1 was not associated with significant changesin heart rate arterial pressure or cardiac index.     

PHARMACOKINETICS OF ALFENTANIL DURING AND AFTER A FIXED RATE INFUSION

Twenty-nine patients (age range 14–81 yr) undergoing orthopaedicsurgery received alfentanil 100 µg kg^–1 given astwo i.v. boluses followed by a fixed rate infusion of 1 µgkg^–1 min^–1 for 44–445 min. Additional 1-mgbolus doses of alfentanil were administered as required. Plasmasamples were assayed for alfentanil using radio-immunoassay.Pharmacokinetic parameters were estimated by a model-independentapproach and by curve-fitting. Regression analysis showed nostatistical relationship between T, CI or Vd and the durationof the infusion, total dose or body weight. We found no significantcorrelation between age and T of alfentanil for patients youngerthan 40 yr. For patients older than 40 yr, T increased linearlywith age. There was no significant decrease in Cl with age,although the lower values for CI (100–200 ml min^–1)were generally found in subjects older than 60 yr. The presentstudy demonstrated that a 100-µg kg^–1 loading doseand a 1-µg kg^–1 min^–1 infusion may be appropriatefor analgesia in general surgical procedures.