Phenotyping malignant hyperthermia susceptibility by measuring halothane-induced changes in myoplasmic calcium concentration in cultured human skeletal muscle cells

Background. Malignant hyperthermia (MH) is a potentially lethaldisease triggered by volatile anaesthetics and succinylcholinein genetically predisposed individuals. Because of the heterogeneticnature of MH, a simple genetic-based diagnostic test is notfeasible and diagnosis requires an invasive open muscle biopsyfollowed by the in vitro contracture test (IVCT). Our aim wasto establish if measurements of halothane-induced increasesin intracellular calcium ion concentration [Ca²⁺]_i in culturedhuman skeletal muscle cells can be used to phenotype MH susceptibilityand if different mutations in the ryanodine receptor (RYR1)gene affect halothane-induced increases in [Ca²⁺]_i. Methods. Primary cultures of human skeletal muscle cells wereestablished from 54 individuals diagnosed by the IVCT accordingto the protocol of the European MH Group as: MH susceptible(n=22), MH negative (n=18) or MH equivocal (n=14). All individualswere screened for the presence of the most common mutationsin the RYR1 gene. [Ca²⁺]_i was measured by fluorescent digitalmicroscopy using fura-2/AM in 10 cells from each patient atfive different halothane concentrations. Results. The halothane-induced increase in [Ca²⁺]_i differedsignificantly between the three diagnostic groups. Differentmutations of the RYR1 gene did not have a specific impact onhalothane-induced increases in [Ca²⁺]_i. Conclusions. Measurements of [Ca²⁺]_i in human skeletal musclecells can be used to phenotype MH susceptibility; however, wedid not observe a specific effect of any mutation in the RYR1gene on the halothane-induced increase in [Ca²⁺]_i. Br J Anaesth 2002; 89: 571–9     

Anaesthetic management of coronary artery bypass grafting in a patient with central core disease and susceptibility to malignant hyperthermia on statin therapy

Central core disease and malignant hyperthermia (MH) are bothassociated with mutations in the RYR1 gene. We report the anaestheticmanagement of one such patient presenting for coronary arterybypass grafting. Her medication included aspirin 75 mg, atorvastatin20 mg, isosorbide mononitrate 60 mg, atenolol 25 mg and glyceryltrinitrite sublingual spray as required. The use of aprotinin,statins and moderate hypothermia in patients with central coredisease and known susceptibility to MH has not been documented. Br J Anaesth 2003; 91: 744–7     

Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia

Malignant hyperthermia (MH) is a potentially fatal pharmacogeneticdisease triggered by several anaesthetic agents. The in vitromuscle contracture test (IVCT) is the standard test to establishan individual’s risk of susceptibility to MH. Clinicalpractitioners and geneticists of the European MH Group haveagreed on the present guidelines for the detection of MH susceptibilityusing molecular genetic techniques and/or IVCT to predict therisk of MH. Br J Anaesth 2001; 86: 283–7 Footnotes ^* for the European Malignant Hyperthermia Group     

Effects of a 5HT(2) receptor agonist on anaesthetized pigs susceptible to malignant hyperthermia

Background. The pathophysiology of the serotoninergic systemin malignant hyperthermia (MH) is not completely understood.The serotonin-2 (5HT_2A) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropanehydrochloride (DOI) induces typical MH symptoms, including skeletalmuscle rigidity, an increase in body temperature, hyperventilationand acidosis in conscious MH-susceptible (MHS) pigs. Whetherthese symptoms are directly generated in skeletal muscle, resultfrom central serotonergic overstimulation or from a porcinestress syndrome remains unresolved. In this study the in vivoeffects of DOI on anaesthetized (and thus stress-protected)MHS and MH-normal (MHN) pigs were investigated. Methods and results. DOI 1 mg kg^–1 was administered threetimes at 40-min intervals to five MHS and five MHN anaesthetizedpigs. Body temperature, heart rate, muscle tone, arterial carbondioxide pressure (Pa_CO2), pH and creatine kinase concentrationswere measured. The clinical occurrence of MH was defined byPa_CO2 above 70 mm Hg and an increase in body temperature ofmore than 2 °C. Intragroup differences were analysed withthe Friedman test as an overall non-parametric ANOVA and, incase of significance, with the Wilcoxon test. Intergroup comparisonswere performed with the Mann–Whitney U-test (statisticalsignificance P<0.05). MHS and MHN pigs developed muscle fasciculations,significant increases in body temperature and Pa_CO2 and a significantdecrease in pH after the administration of DOI. These changeswere comparable in both groups until the third dose of DOI,when in MHS pigs heart rate and Pa_CO2 rose significantly andpH fell significantly compared with MHN pigs. All MHS pigs fulfilledthe MH criteria. Body temperature increased by more than 2 °Cin all MHN pigs and Pa_CO2 exceeded 70 mm Hg in two. Thus, twoMHN pigs fulfilled the criteria of MH. Conclusions. The comparability of the clinical presentationfollowing DOI administration in MHS and MHN animals and theorder of the development of MH-like symptoms favour the hypothesisof a central serotonergic overstimulation, leading to a serotoninsyndrome. Br J Anaesth 2003; 91: 281–4     

No evidence of mutations in the CACNA1S gene in the UK malignant hyperthermia population

Background. Malignant hyperthermia (MH) is an inherited, potentiallyfatal, pharmocogenetic disorder triggered by certain anaestheticagents. In light of the reported genetic heterogeneity for thedisorder and the recent introduction of DNA testing guidelinesfor the trait, we have assessed the role of the CACNA1S genein MH susceptibility in UK patients. Linkage to this locus haspreviously been demonstrated in several European MH families. Methods and results. We screened 200 unrelated MH-susceptibleindividuals for known CACNA1S mutations. With the aim to characterizefurther novel mutations at this locus, functionally relevantregions of the gene were also sequenced in 10 unrelated individualsfrom families where the involvement of other MH susceptibilityloci was unlikely. No sequence variations were detected in anyof the patients investigated. Conclusions. Defects in CACNA1S are not a major cause of MHin the UK population. Diagnostic screening of this gene is unlikelyto be of value to UK MH patients in the near future. Br J Anaesth 2002; 88: 587–9     

Differential effects of propofol, ketamine, and thiopental anaesthesia on the skeletal muscle microcirculation of normotensive and hypertensive rats in vivo

Background. This study utilized the dorsal microcirculatorychamber (DMC) model to determine differential effects of i.v.propofol, ketamine, and thiopental anaesthesia on the skeletalmuscle microcirculation (10–180 µm) of normotensive(Male Wistar Kyoto, WKY) and hypertensive (spontaneously hypertensiveHarlan, SHR) rats, importantly, comparing responses to a consciousbaseline. Methods. Three weeks following implantation of the DMC in WKY(n=8) and SHR (n=6) (130 g) 0.25 ml 100 g^–1 FITC–BSA(i.v.) was administered and the microcirculation viewed usingfluorescent in vivo microscopy for a 30 min baseline (t=0–30min). This was followed by either propofol, thiopental, ketamine,or saline (i.v. bolus induction over 5 min (t=30–35 min)),then maintenance step-up infusion for 60 min (t=45–105min), so that animals received all four agents 1 week apart(56 experiments). Results. Dilation of A3 arterioles (15–30 µm) andV3 venules (20–40 µm) with propofol was greaterin SHR (t=95 min, A3 36.7 (12)%, V3 15.5 (2.3)%) than WKY (t=95min, A3 19.4 (7.4)%, V3 8.0 (2.3)%) (P<0.05). Constrictionof A3 with ketamine was greater in SHR (t=95 min, A3 –29.1(6.4)%) than WKY (A3 –17.5 (8.8)%) (P<0.05). This wasaccompanied by hypotension with propofol in SHR (–32%decrease in systolic arterial pressure), but not WKY (–6%)and hypertension with ketamine in WKY (–15%) and SHR (–24%)(P<0.05). During thiopental anaesthesia there was dilationof A1 (80–180 µm), A3, and V3 in WKY (P<0.05).Conversely, in SHR dilation of venules (29.2 (8.7)%) was accompaniedby constriction of A1 and A3 (t=95 min, A1 –25.1 (5.9)%,A3 –45.2 (3.1)%) (P<0.05). Conclusion. Within the skeletal muscle microcirculation of hypertensiverats there is enhanced dilation with propofol and constrictionwith ketamine, associated with exaggerated changes in arterialpressure. Thus, dysfunctional control mechanisms at the levelof the microcirculation alter responses to anaesthesia duringhypertension.      

Pharmacokinetics of remifentanil and its major metabolite, remifentanil acid, in ICU patients with renal impairment

Background. The pharmacokinetics of remifentanil, an opioidanalgesic metabolized by non-specific esterases, and its principalmetabolite, remifentanil acid (RA), which is excreted via thekidneys, were assessed as part of an open-label safety studyin intensive care unit (ICU) patients with varying degrees ofrenal impairment. Methods. Forty adult ICU patients with normal/mildly impairedrenal function (creatinine clearance [CL_cr] 62.9 (SD) 14.5 mlmin^–1; n=10) or moderate/severe renal impairment (CL_cr14.7 (15.7) ml min^–1; n=30) were included. Remifentanilwas infused for up to 72 h, at a starting rate of 6–9µg kg^–1 h^–1 titrated to achieve a target sedationlevel, with additional propofol (0.5 mg kg^–1 h^–1)if required. Intensive arterial sampling was performed for upto 72 h after infusion. Pharmacokinetic parameters obtainedby simultaneous modelling of remifentanil and RA data were statisticallycompared between the two groups. Results. Remifentanil pharmacokinetics were not significantlyaffected by renal status. RA clearance in the moderate/severegroup was reduced to about 25% that of the normal/mild group(41 (29) vs 176 (49) ml kg^–1 h^–1, P<0.0001).Metabolic ratio, a predictor of the ratio of RA to remifentanilconcentrations at steady state, was approximately eight-foldhigher in the moderate/severe group relative to the normal/mildgroup (116 (110) vs 15 (4), P<0.0001). Maximum RA levelsapproached 700 ng ml^–1 in the moderate/severe group. Conclusions. Although RA accumulates in patients with moderate/severerenal impairment, pharmacokinetic modelling predicts that RAconcentrations during a 9 µg kg^–1 h^–1 remifentanilinfusion for up to 15 days would not exceed those reported inthe present study, for which no associated prolongation of µ-opioideffects was observed. Br J Anaesth 2004; 92: 493–503     

Genotype and interleukin-10 responses after cardiopulmonary bypass

Background. The pro- and anti-inflammatory cytokine balancehas been implicated in outcome from inflammatory conditions,and cardiopulmonary bypass is associated with a marked inflammatoryresponse. Interleukin-10 (IL-10) is an anti-inflammatory cytokineand levels have been shown to be highest in those patients whodevelop sepsis after trauma or surgery. IL-10 levels vary betweenindividuals and genotype may dictate the IL-10 response. Wetherefore investigated IL-10 genotype, circulating IL-10 concentrationsand outcome in terms of organ dysfunction 24 h after cardiopulmonarybypass. Methods. Blood samples were obtained from 150 patients before,and 3, and 24 h after cardiopulmonary bypass. IL-10 wasmeasured by enzyme immunoassay. The single nucleotide polymorphismat –1082 base pairs was detected by restriction fragmentlength polymorphism analysis. Post-bypass organ system dysfunctionwas defined prospectively. Results. IL-10 concentrations were increased 3 h afterbypass (P<0.0001) and were still increased at 24 h (P<0.0001).Homozygosity for the G allele was associated with lower median(range) maximal IL-10 levels at 3 h (44 (13–136)pg ml^–1) compared with the A allele (118 (39–472)pg ml^–1; P=0.042). Those patients who developed atleast one organ dysfunction (n=33) had higher IL-10 levels 3 hafter surgery (242 (18–694) pg ml^–1) comparedwith those without organ dysfunction (77 (7–586) pg ml^–1;P=0.001, n=117). Conclusions. The G allele of the –1082 base pair singlenucleotide polymorphism in the IL-10 gene is associated withlower IL-10 release after cardiopulmonary bypass. High levelsof IL-10 secretion are associated with organ dysfunction 24 hafter surgery. Br J Anaesth 2003; 91: 424–6     

USE OF VECURONIUM AND DOXAPRAM IN PATIENTS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA

Neuromuscular blockade was obtained with vecuronium 108 µgkg^–1 in 44 patients under-going diagnostic muscle biopsyas part of an investigation of malignant hyperthermia (MH) susceptibility.At the termination of anaesthesia doxapram 1.43 mg kg^–1was given in an attempt to antagonize postoperative respiratorydepression. Rectal, muscle and skin temperatures, blood lactateconcentration and venous PCO₂ were measured before, during andafter anaesthesia. Susceptibility to MH was established by invitro contracture tests according to the protocol of the EuropeanMH Group. Twenty patients were susceptible to MH (MHS), 19 wereMH nonsusceptible (MHN) and five MH equivocal (MHE). No adverseeffects of the drugs were observed. There were no differencesbetween the three groups in rectal or muscle temperature, bloodlactate concentration or venous PCO₂ at any time. Doxapram didnot prevent an increase in postoperative PCO₂. It is concludedthat vecuronium and doxapram may be safely administered to patientssusceptible to MH.     

Target concentrations of remifentanil with propofol to blunt coughing during intubation, cuff inflation, and tracheal suctioning

Background. The target blood concentrations of propofol andremifentanil, when used in combination, required to blunt thecough response to tracheal intubation, cuff inflation, and trachealsuctioning without neuromuscular blocking agents are not known. Methods. In a randomized prospective study, 81 patients wereenrolled to determine which of three target remifentanil bloodconcentrations was required to blunt coughing during intubation,cuff inflation, and tracheal suctioning. Anaesthesia was achievedwith propofol at a steady effect-site concentration of 3.5 µgml^–1. The target blood remifentanil concentrations were5, 10, or 15 ng ml^–1. These concentrations were maintainedfor 12 min before intubation. Results. There was no cough response to intubation in more than74% of patients and no significant difference in the incidenceof coughing with intubation between the three groups. Significantdifference in coughing, diminishing with increasing remifentaniltarget concentration, was observed with cuff inflation (P=0.04)and tracheal suctioning (P=0.007). Bradycardia and hypotensionwas more frequent with the remifentanil target concentrationof 15 ng ml^–1. Tracheal suctioning resulted in more coughingthan intubation (P=0.01) or cuff inflation (P=0.004). Conclusion. Target remifentanil blood concentrations of 5, 10,and 15 ng ml^–1 associated with a 3.5 µg ml^–1propofol target blood concentration provided good intubatingconditions and absence of cough about 75% of the time. Highertarget remifentanil concentrations were associated with lesscoughing during tracheal tube cuff inflation and tracheal suctioning.     

Predictive performance of computer-controlled infusion of remifentanil during propofol/remifentanil anaesthesia

Background. The predictive performance of the available pharmacokineticparameter sets for remifentanil, when used for target-controlledinfusion (TCI) during total i.v. anaesthesia, has not been determinedin a clinical setting. We studied the predictive performanceof five parameter sets of remifentanil when used for TCI ofremifentanil during propofol anaesthesia in surgical patients. Methods. Remifentanil concentration–time data that hadbeen collected during a previous pharmacodynamic interactionstudy in 30 female patients (ASA physical status I, aged 20–65 yr)who received a TCI of remifentanil and propofol during lowerabdominal surgery were used in this evaluation. The remifentanilconcentrations predicted by the five parameter sets were calculatedon the basis of the TCI device record of the infusion rate–timeprofile that had actually been administered to each individual.The individual and pooled bias [median performance error (MDPE)],inaccuracy [median absolute performance error (MDAPE)], divergenceand wobble of the remifentanil TCI device were determined fromthe pooled and intrasubject performance errors. Results. A total of 444 remifentanil blood samples were analysed.Blood propofol and remifentanil concentrations ranged from 0.5to 11 µg ml^–1 and 0.1 to 19.6 ng ml^–1respectively. Pooled MDPE and MDAPE of the remifentanil TCIdevice were –15 and 20% for the parameter set of Mintoand colleagues (Anesthesiology 1997; 86: 10–23), 1 and21%, –6 and 21%, and –6 and 19% for the three parametersets described by Egan and colleagues (Anesthesiology 1996;84: 821–33, Anesthesiology 1993; 79: 881–92, Anesthesiology1998; 89: 562–73), and –24 and 30% for the parameterset described by Drover and Lemmens (Anesthesiology 1998; 89:869–77). Conclusions. Remifentanil can be administered by TCI with acceptablebias and inaccuracy. The three pharmacokinetic parameter setsdescribed by Egan and colleagues resulted in the least biasand best accuracy. Br J Anaesth 2003; 90: 132–41     

Volume kinetics of glucose 2.5% solution and insulin resistance after abdominal hysterectomy

Background. We hypothesized that volume kinetics can be usedto predict the rate of infusion of glucose 2.5% solution requiredto yield any predetermined plasma glucose level and degree ofplasma dilution during the postoperative period. Methods. In 15 women, mean age 50 yr (range 37–63), 2days after an abdominal hysterectomy, a volume kinetic analysiswas performed on an i.v. infusion of 12.5 ml kg^–1 (900ml) of glucose 2.5% given over 45 min. The insulin resistancewas measured by a glucose clamp, and it was compared with dailybioimpedance analyses, which indicated the hydration of theintra/extracellular body fluid spaces. Results. The clearance of glucose was 0.42 litre min^–1(0.60 litre min^–1 is normal) while the other five parametersin the kinetic model were similar to those obtained in healthyvolunteers. Computer simulations indicated that in a 70-kg female,at steady state, the rate of infusion (ml min^–1) shouldbe three times the allowed increase in plasma glucose (mmollitre^–1). To maintain a predetermined plasma dilutionthe corresponding rate factor was 160. The glucose uptake duringclamping was 3.9 mg kg^–1 min^–1 (7.0 is normal),which, during the second day after hysterectomy, correlatedwith the dehydration of the intracellular space (r=0.77; P<0.002)and with the protein catabolism as indicated by the urinaryexcretion of 3-methylhistidine (r=–0.76, P<0.002). Conclusion. The anaesthetist can prescribe postoperative administrationof glucose 2.5% to reach any desired plasma glucose level anddilution by using the two presented nomograms. Insulin resistancecorrelated with intracellular dehydration and protein catabolism.     

IN VITRO EFFECT OF EPHEDRINE, ADRENALINE, NORADRENALINE AND ISOPRENALINE ON HALOTHANE-INDUCED CONTRACTURES IN SKELETAL MUSCLE FROM PATIENTS POTENTIALLY SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA

We have measured the effects of ephedrine, adrenaline, noradrenalineand isoprenaline on halothaneinduced contractures in musclebiopsies from patients potentially susceptible to malignanthyperthermia (MH). At concentrations of 4–24 mmol litre^–1,ephedrine induced in vitro contractures in halothane 0.44 mmollitre^–1-prechallenged muscle, whilst adrenaline, noradrenalineand isoprenaline had no effect. There was a shift of the ephedrineconcentration-response curve to theleft and an increased maximummuscle contracturein the MH susceptible group compared withthe MH negative group (P < 0.001). We conclude that ephedrineincreased halothane-induced muscle contractures in vitro eitherby an unknown pharmacological mechanism or by an adrenergicstimulation which was different from those of the other investigatedadrenoceptoragonists.(Br. J. Anaesth. 1993; 70:76–79)     

Effects of intramuscular administration of lidocaine or bupivacaine on induction and maintenance doses of propofol evaluated by bispectral index

Background. Interest in combining local and general anaesthesiahas lead to studies investigating possible interactions. Ina prospective, randomized, double-blind study, we tested whetherlocal anaesthetics administered i.m. potentiate the hypnoticeffect of propofol. Methods. Sixty patients (three groups, n=20) undergoing lowerabdominal surgery with total i.v. propofol anaesthesia wereinvestigated. Patients in Group B received i.m. bupivacaine(5 mg ml^–1) 1 mg kg^–1, patients in Group Lreceived i.m. lidocaine (100 mg ml^–1) 2 mg kg^–1and patients in Group C received i.m. saline 5 ml beforeoperation. Hypnosis was measured with bispectral index (BIS). Results. The induction (BIS <45), and the maintenance dosesof propofol (BIS between 40 and 50) were significantly lessin Group B and Group L compared with the control group. Inductiondoses were 1.58 (SD 0.39), 1.56 (0.24) and 2.03 (0.33) mg kg^–1respectively; P<0.0001. Maintenance doses were 6.33 (2.06),7.08 (1.23) and 9.95 (2.02) mg kg^–1 respectively in thefirst hour; P<0.0001. Groups B and L were associated withan attenuated haemodynamic response to both induction and intubation. Conclusion. I.M. administered local anaesthetics are associatedwith a decrease in both the induction and maintenance dosesof propofol during total i.v. anaesthesia and a reduction inhaemodynamic responses. Br J Anaesth 2002; 89: 849–52     

Bispectral index changes following etomidate induction of general anaesthesia and orotracheal intubation

Background. Etomidate-associated hypnosis has only been studiedusing standard clinical criteria and raw EEG variables. We conducteda BIS-based investigation of etomidate induction of generalanaesthesia. Methods. Thirty hydroxyzine-premedicated ASA I patients wererandomly allocated to receive etomidate 0.2, 0.3, or 0.4 mgkg^–1 intravenously over 30 s. The BIS was continuouslyrecorded. A tourniquet was placed on a lower limb to recordpurposeful movements and myoclonia. Tracheal intubation wasfacilitated using rocuronium 0.6 mg kg^–1 when the BISvalue was 50. The times to disappearance of the eyelash reflex,to a decrease in the BIS to 50, and to tracheal intubation werecompared. The BIS values 30 s following tracheal intubation,and mean arterial pressure (MAP) and heart rate (HR) at alltime points were also recorded. Results. The BIS value decreased to 50 for tracheal intubationwith no purposeful movement in all but one patient in the 0.2mg kg^–1 group. There was no difference between the etomidategroups (0.2, 0.3, and 0.4 mg kg^–1) in regards to timeto loss of the eyelash reflex (103 (67), 65 (34), 116 (86) s,P=0.2), or to a decrease in BIS to 50 (135 (81), 82 (36), 150(84) s, P=0.1). Also, the BIS value 30 s after intubation (41(10), 37 (4), 37 (4), P=0.4), and plasma etomidate concentrations(161 [29–998], 308 [111–730], 310 [90–869]ng ml^–1, P=0.2) did not differ between groups. The timeto loss of the eyelash reflex was 12–140 s shorter thanthe time to a decrease in BIS to 50 in three patients in eachgroup who received etomidate 0.2 and 0.4 mg kg^–1, andin four patients who received 0.3 mg kg^–1. No awarenesswas recorded. MAP and HR increases following tracheal intubationwere comparable between groups. Conclusions. Etomidate induction doses do not predict the timefor BIS to decrease to 50 as this variable varies markedly followingthree etomidate dose regimen. Br J Anaesth 2003; 91: 341–6     

Effects of three different L-type Ca2+ entry blockers on airway constriction induced by muscarinic receptor stimulation

Background. The crucial role of L-type Ca²⁺ channels in airwaysmooth muscle contraction suggests that these channels couldbe an important therapeutic target. There are three separatedrug binding sites on this channel: those for dihydropyridines,benzothiazepines and phenyl alkylamines. In this study, we examinedthe effects of the dihydropyridines nifedipine and nicardipine,the benzothiazepine diltiazem, and the phenylalkylamine verapamilon airway constriction. Methods. Tension of guinea-pig tracheal strips was measuredisometrically in vitro with a force displacement transducer.Strips were precontracted with carbachol 10^–7 M with orwithout 4-aminopyridine 10^–3 M, a voltage-sensitive K⁺channel blocker. Then, nifedipine 10^–8–10^–4M, diltiazem 10^–8–3x10^–4 M or verapamil 10^–8–3x10^–4M was added cumulatively to the organ bath (n=6 each). The bronchialcross-sectional area of pentobarbital-anaesthetized dogs wasassessed using a bronchoscopy method. Bronchoconstriction waselicited with methacholine 0.5 µg kg^–1 plus 5 µgkg^–1 min^–1, and then nicardipine 0–1000 µgkg^–1, diltiazem 0–3000 µg kg^–1 or verapamil0–3000 µg kg^–1 were given i.v. (n=7 each). Results. In the in vitro experiments, nifedipine and diltiazemfully reversed carbachol-mediated tracheal contraction withlogIC₅₀ values of 4.76 (SEM 0.22) (mean 17.5 µM) and 4.60(0.33) (mean 24.8 µM), respectively. Although verapamil10^–6–10^–4 M reversed the contraction by 87.2%,strip tension re-increased by 18.1% following maximal relaxationwith verapamil 3x10^–4 M. This re-increase was almost fullyabolished by pretreatment with 4-aminopyridine. In the in vivoexperiments, nicardipine and diltiazem dose-dependently reversedmethacholine-induced bronchoconstriction, with logID₅₀ valuesof 3.22 (0.05) (mean 0.60 mg kg^–1) and 1.85 (0.32) (mean14.0 mg kg^–1), respectively. Verapamil worsened methacholine-inducedbronchoconstriction. Conclusions. Although supraclinical doses of dihydropyridinesand benzothiazepines can produce airway relaxant effects, theseagents are unlikely to be used in the treatment of bronchoconstriction.In addition, verapamil may aggravate airway constriction. Br J Anaesth 2003; 90: 671–5     

Measurement of motor evoked potentials following repetitive magnetic motor cortex stimulation during isoflurane or propofol anaesthesia

Background. Isoflurane and propofol reduce the recordabilityof compound muscle action potentials (CMAP) following singletranscranial magnetic stimulation of the motor cortex (sTCMS).Repetition of the magnetic stimulus (repetitive transcranialmagnetic stimulation, rTCMS) might allow the inhibition causedby anaesthesia with isoflurane or propofol to be overcome. Methods. We applied rTCMS (four stimuli; inter-stimulus intervalsof 3, 4, 5 ms (333, 250, 200 Hz), output 2.5 Tesla) in 27 patientsand recorded CMAP from the hypothenar and anterior tibial muscle.Anaesthesia was maintained with fentanyl 0.5–1 µgkg^–1 h^–1 and either isoflurane 1.2% (10 patients)or propofol 5 mg kg^–1 h^–1 with nitrous oxide 60%in oxygen (17 patients). Results. No CMAP were detected during isoflurane anaesthesia.During propofol anaesthesia 333 Hz, four-pulse magnetic stimulationevoked CMAP in the hypothenar muscle in 75%, and in the anteriortibial muscle in 65% of the patients. Less response was obtainedwith 250 and 200 Hz stimulation. Conclusions. In most patients, rTCMS can overcome suppressionof CMAP during propofol/nitrous oxide anaesthesia, but not duringisoflurane anaesthesia. A train of four magnetic stimuli ata frequency of 333 Hz is most effective in evoking potentialsfrom the upper and lower limb muscles. The authors concludethat rTCMS can be used for evaluation of the descending motorpathways during anaesthesia. Br J Anaesth 2003; 91: 487–92     

Randomized controlled trial to investigate influence of the fluid challenge on duration of hospital stay and perioperative morbidity in patients with hip fractures

Background. A prospective, randomized controlled trial comparingconventional intraoperative fluid management with two differingmethods of invasive haemodynamic monitoring to optimize intraoperativefluid therapy, in patients undergoing proximal femoral fracturerepair under general anaesthesia. Methods. Ninety patients randomized to three groups; conventionalintraoperative fluid management (Gp CON, n=29), and two groupsreceiving additional repeated colloid fluid challenges guidedby central venous pressure (Gp CVP, n=31) or oesophageal Dopplerultrasonography (Gp DOP, n=30). Primary outcome measures weretime to medical fitness to discharge, hospital stay and postoperativemorbidity. Results. The fluid challenge resulted in significantly greaterperioperative changes in central venous pressure between GpCVP and Gp CON (mean 5 (95% confidence interval 3–7) mmHg) (P<0.0001). Important perioperative changes were alsoshown in Gp DOP with increases of 49.4 ms (19.7–79.1 ms)in the corrected flow time, 13.5 ml (7.4–19.6 ml) in strokevolume, and 0.9 (0.49–1.39) litre min^–1 in cardiacoutput. As a result, fewer patients in Gp CVP and Gp DOP experiencedsevere intraoperative hypotension (Gp CON 28% (8/29), Gp CVP9% (3/31), Gp DOP 7% (2/30), P=0.048 (chi-squared, 2 degreesof freedom (df)). No differences were seen between the threegroups when major morbidity and mortality were combined, P=0.24(chi-squared, 2 df). Postoperative recovery for survivors, asdefined by time to be deemed medically fit for discharge, wassignificantly faster, in comparison with Gp CON, in both theGp CVP (10 vs 14 (95% confidence interval 8–12 vs 12–17)days, P=0.008 (t-test)), and Gp DOP (8 vs 14 (95% confidenceinterval 6–12 vs 12–17) days, P=0.023 (t-test).There were no significant differences between groups, for survivors,with respect to acute orthopaedic hospital and total hospitalstay. Conclusions. Invasive intraoperative haemodynamic monitoringwith fluid challenges during repair of femoral fracture undergeneral anaesthetic shortens time to being medically fit fordischarge. Br J Anaesth 2002; 88: 65–71     

Opposite effects of depressant and convulsant barbiturate stereoisomers on acetylcholine release from the rat hippocampus in vivo

Background. It has been shown that the R(–) isomer of1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) induces lossof the righting reflex (LRR), while S(+)-MPPB causes pure excitatoryeffects, including convulsions, in vivo. Methods. We studied the effects of the depressant and convulsantMPPB stereoisomers on rat hippocampal acetylcholine (ACh) releasein vivo, using a brain microdialysis technique in freely movinganimals. Results. R(–)-MPPB 60 and 90 mg kg^–1 i.p. decreasedACh release from the rat hippocampus by 44.1 (8.2)% and 60.8(8.2)%, respectively. In the hippocampus, the local applicationof bicuculline, a -aminobutyric acid (GABA)_A receptor antagonist,1 µmol litre^–1 antagonized the inhibitory effectsof R(–)-MPPB 90 mg kg^–1 i.p. In contrast, R(–)-MPPB,S(+)-MPPB 60 and 90 mg kg^–1 i.p. increased ACh releaseto 151.8 (6.8)% and 169.6 (11.1)% of the basal release, respectively. Conclusions. Our results demonstrated that R(–)-MPPB decreased,while S(+)-MPPB increased, rat hippocampal ACh release and thatthe inhibitory effects of R(–)-MPPB may involve the GABA_Areceptor in vivo. These data imply that changes in hippocampalACh due to these agents may be related to their central inhibitoryand stimulatory actions in vivo. Br J Anaesth 2004; 92: 424–6     

Effect of remifentanil infusion rate on stress response to the pre-bypass phase of paediatric cardiac surgery

Background. Opioids are used routinely to eliminate the stressresponse in the pre-bypass phase of paediatric cardiac surgery.Remifentanil is a unique opioid allowing a rapidly titratableeffect. No data are available regarding a suitable remifentanildose regimen for obtunding stress and cardiovascular responsesto such surgery. Methods. We recruited 49 infants and children under 5 yr oldwho were randomized to receive one of four remifentanil infusionrates (0.25, 1.0, 2.5, or 5.0 µg kg^–1 min^–1).Blood samples were obtained at induction, pre-surgery, 5 minafter opening the chest, and immediately pre-bypass. Whole bloodglucose was measured at all time points while cortisol and neuropeptideY (NPY) were measured in the first and last samples. Heart rateand arterial pressure were also recorded. Results. There was a significant increase in whole blood glucose5 min after opening the chest and pre-bypass (P=0.009, P=0.002)in patients receiving remifentanil 0.25 µg kg^–1min^–1, but not in those receiving higher doses. Increasedremifentanil dosage was associated with reduced plasma cortisolduring surgery (P<0.001). Baseline NPY showed considerablevariation and there was no association between pre-bypass NPYand remifentanil dose. There was a significantly higher heartrate at the pre-bypass stage of surgery in the remifentanil0.25 µg kg^–1 min^–1 group compared with higherdoses (P=0.0006). Four out of five neonates with complex cardiacconditions showed severe bradycardia associated with remifentanil. Conclusions. In infants and children under 5 yr, remifentanilinfusions of 1.0 µg kg^–1 min^–1 and greatercan suppress the glucose increase and tachycardia associatedwith the pre-bypass phase of cardiac surgery, while 0.25 µgkg^–1 min^–1 does not. Remifentanil should be usedwith caution in neonates with complex congenital heart disease. Br J Anaesth 2004; 92: 187–94