Electrophysiological effects of morphine in an in vitro model of the 'border zone' between normal and ischaemic-reperfused guinea-pig myocardium

Background. Morphine is commonly used in clinical practice inpain management. Although morphine has been shown to preconditionthe myocardium, its effects on action potential parameters andischaemia–reperfusion-induced arrhythmias and conductionblocks remain unknown. Methods. In a double-chamber bath, guinea-pig right ventricularmuscle strips were subjected partly to normal conditions andpartly to 30 min of simulated ischaemia (hypoxia, hyperkalaemia,acidosis, and lack of nutritional substrate) followed by 30 minof reperfusion. Action potential parameters were recorded continuouslyin the normal zone and in the ischaemic– reperfused zone.Spontaneous arrhythmias and conduction blocks were noted. Theelectro physiological effects of morphine were studied at 0.01and 0.1 µM. Results. In control conditions, morphine did not modify actionpotential parameters of resting membrane potential, maximalupstroke velocity (V_max), action potential amplitude (APA) andaction potential duration at 50 and 90% of repolarization. Morphinereduced ischaemia-induced depolarization and lessened the ischaemia-induceddecrease in APA and V_max. Morphine significantly decreased theoccurrence of conduction block during simulated ischaemia (20%at 0.01 and 0.1 µM vs 67% in the control group, P<0.05)and reperfusion-induced arrhythmias (40% at 0.01 µMand 30% at 0.1 µM vs 92% in the control group, P<0.05). Conclusions. In ischaemic–reperfused guinea-pig myocardium,morphine at clinically relevant concentrations decreased ischaemia-inducedconduction blocks and reperfusion-induced ventricular arrhythmias. Br J Anaesth 2002; 89: 888–95     

Thiopental and isoflurane attenuate the decrease in hippocampal phosphorylated Focal Adhesion Kinase (pp125FAK) content induced by oxygen-glucose deprivation

Background. Thiopental and isoflurane exhibit neuroprotectiveeffects against cerebral ischaemia. Here, we hypothesized thatoxygen–glucose deprivation decreases the ATP-dependentphosphorylation process of Focal Adhesion Kinase (pp¹²⁵FAK,a functionally important non-receptor tyrosine kinase), andthat this phenomenon is attenuated by thiopental and isoflurane. Methods. Rathippocampal slices were subjected to an anoxic-aglycaemic(or physiologic, control) challenge followed by 3-h reperfusion,and treated with various concentrations of thiopental and isoflurane.PP¹²⁵FAK phosphorylation was measured by immunoblotting. Neuronaldeath was assessed by immunostaining with bis-benzimide. Results. Significant neuronal death was detected after 30 min(but not 10) of anoxia-aglycaemia (40 (4) vs 14 (5)% of control,P<0.05). At 30 min, phosphorylated pp¹²⁵FAK content was significantlydecreased by anoxic glucose-free conditions (55 (27)% of control,P<0.05). This effect was markedly attenuated by thiopental(10 and 100 µM) and isoflurane (1 and 2%). Under controlconditions, thiopental (1, 10, and 100 µM) and isoflurane(0.5, 1, and 2%) increased pp¹²⁵FAK phosphorylation in a concentration-relatedfashion. This effect was blocked by chelerythrin and bisindolylmaleimideI and IX (10 µM, three structurally distinct inhibitorsof protein kinase C, PKC) but not the N-methyl-D-aspartate (NMDA)receptor antagonist MK801 (10 µM). Conclusion. Phosphorylated pp¹²⁵FAK content was markedly decreasedin hippocampal slices subjected to oxygen–glucose deprivation.Thiopental and isoflurane significantly attenuated this phenomenon,possibly via PKC activation.     

Effect of lidocaine on ischaemic preconditioning in isolated rat heart

Background. Lidocaine is frequently used as an agent to treatventricular arrhythmias associated with acute myocardial ischaemia.Lidocaine is a potent blocker not only of sodium channels, butalso of ATP-sensitive potassium channels. The opening of thesechannels is a key mechanism of ischaemic preconditioning. Weinvestigated the hypothesis that lidocaine blocks the cardioprotectioninduced by ischaemic preconditioning. Methods. Isolated rat hearts (n=60) were subjected to 30 minof no-flow ischaemia and 60 min of reperfusion. Control hearts(CON) underwent no further intervention. Preconditioned hearts(PC) received two 5-min periods of ischaemia separated by 10min of reflow before the 30 min ischaemia. In three groups,lidocaine was infused at concentrations of 2, 10 or 20 µgml^–1 for 5 min before the preconditioning ischaemia. Leftventricular developed pressure (LVDP) and infarct size (IS)(triphenyltetrazolium choride staining) were measured as variablesof ventricular function and cellular injury, respectively. Results. PC reduced IS from 24.8 (SEM 4.1) % to 4.0 (0.7) %of the area at risk (P<0.05). Adding 2 or 10 µg ml^–1lidocaine had no effect on IS compared with PC alone (3.7 (0.7)%, 6.9 (1.8) %). Adding 20 µg ml^–1 lidocaine increasedIS to 14.1 (2.5) % compared with PC (P<0.05). Baseline LVDPwas similar in all groups (111.4 (2.1) mm Hg). Compared withCON, PC improved functional recovery (after 60 min of reperfusion;52.3 (5.9) mm Hg vs 16.0 (4.0) mm Hg, P<0.01). The improvedventricular function was not influenced by addition of 2 or10 µg ml^–1 lidocaine (47.3 (5.7) mm Hg, not significant;45.3 (7.3) mm Hg, not significant), but was blocked by the infusionof 20 µg ml^–1 lidocaine (22.5 (8.0) mm Hg, P<0.01vs PC). Conclusions. Lidocaine blocks the cardioprotection induced byischaemic preconditioning only at supratherapeutic concentrations.     

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).     

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.      

Differential effects of intravenous anaesthetic agents on the response of rat mesenteric microcirculation in vivo after haemorrhage

Background. The differential effects of i.v. anaesthesia onthe response of the mesenteric microcirculation after haemorrhagein vivo are previously unexplored. Methods. Male Wistar rats (n=56) were anaesthetized intravenouslyeither with propofol and fentanyl (propofol/fentanyl), ketamineor thiopental. A tracheostomy and carotid cannulation were performedand the mesentery surgically prepared for observation of themicrocirculation using fluorescent in vivo microscopy. Animalswere allocated to one of three groups: control, haemorrhageor haemorrhage re-infusion. Results. After haemorrhage, the response of the microcirculationdiffered during propofol/fentanyl, ketamine and thiopental anaesthesia.During propofol/fentanyl anaesthesia there was constrictionof arterioles (–16.7 (3.9)%), venules (–5.9 (1.7))and capillaries (–16.3 (2.8)) (n=12). During ketamineand thiopental anaesthesia both constriction and dilation wasobserved. After haemorrhage and re-infusion, macromolecularleak occurred from venules during propofol/fentanyl and thiopentalanaesthesia (P<0.05), but not during ketamine anaesthesia. Conclusion. In summary, i.v. anaesthetic agents differentiallyalter the response of the mesenteric microcirculation to haemorrhage. Br J Anaesth 2002; 88: 255–63     

Ketamine for treatment of catheter related bladder discomfort: a prospective, randomized, placebo controlled and double blind study

Background. Intraoperative urinary catheterization might causepostoperative catheter related bladder discomfort (CRBD). Weevaluated the efficacy of ketamine as a treatment modality forCRBD. Methods. Fifty-four, ASA physical status I and II, male andfemale adult patients, having CRBD after elective percutaneousnephrolithotomy were randomized into two equal groups of 27each. In the postoperative period, patients who complained ofCRBD received medication depending upon group allocation. Group1 (Control) received placebo, Group II (Ketamine) received i.v.ketamine 250 µg kg^–1. After induction of anaesthesiapatients were catheterized with a 16 Fr Foley's catheter andthe balloon was inflated with 10 ml distilled water. Gradingof CRBD was done as none, mild, moderate and severe by a blindedobserver at 0, 1, 2 and 6 h after operation. Results. Ketamine reduced the incidence of CRBD (P<0.001)at 2 and 6 h along with reduction in severity (P<0.05) at1 h compared with control. Higher incidence of mild sedationwas observed in the ketamine group (P<0.05) which was notassociated with any untoward effects. Operative time and intraoperativefentanyl requirement were similar in both the groups. Conclusion. I.V. ketamine (250 µg kg^–1) is an effectivetreatment for reducing the incidence and severity of postoperativeCRBD.     

Sevoflurane preconditions stunned myocardium in septic but not healthy isolated rat hearts

Background. Recent evidence indicates that sevoflurane treatmentbefore prolonged ischaemia reduces infarct size in normal hearts,mimicking ischaemic preconditioning. We examined whether exposureto sevoflurane before brief ischaemia, inducing a ‘stunnedmyocardium’, provided such protective effects in an isolatedworking heart from normal or septic rats. Methods. With institutional approval, 91 rats were randomlyallocated into one of either caecal-ligation and perforation(CLP: n=50) or sham (Sham: n=41) procedure groups 24 h beforethe study. After determination of baseline measurements, includingcardiac output (CO), myocardial oxygen consumption (mV^·O₂)and cardiac efficiency (CE; COxpeak systolic pressure/mV^·O₂),each isolated heart was perfused with or without 2% sevofluranefor 15 min before global ischaemia (pre-ischaemia). After 15min ischaemia and 30 min reperfusion, all hearts were assessedfor functional recovery of myocardium (post-reperfusion). Results. During the pre-ischaemia period, 2% sevoflurane causeda significant reduction of CO in the CLP group compared withthe Sham group. During the post-reperfusion period, both CO(16.9 vs 11.0 ml min^–1) and CE (11.2 vs 7.7 mm Hg ml^–1(µl O₂)^–1) was higher in the sevoflurane-treatedvs -untreated hearts from CLP rats, and was accompanied by lowerincidence of reperfusion arrhythmia compared with control hearts(8 vs 32%). In contrast, 2% sevoflurane did not provide cardioprotectiveeffects in normal rats. Conclusions. The current study demonstrates that pre-treatmentwith sevoflurane minimizes myocardial dysfunction and the incidenceof reperfusion arrhythmia after brief ischaemic insults in septichearts. Br J Anaesth 2002; 89: 896–903     

Efficacy of prophylactic ketamine in preventing postoperative shivering

Background. Treatment with ketamine and pethidine is effectivein postoperative shivering. The aim of this study was to comparethe efficacy of low-dose prophylactic ketamine with that ofpethidine or placebo in preventing postoperative shivering. Methods. A prospective randomized double-blind study involved90 ASA I and II patients undergoing general anaesthesia. Patientswere randomly allocated to receive normal saline (Group S, n=30),pethidine 20 mg (Group P, n=30) or ketamine 0.5 mg kg^–1(Group K, n=30) intravenously 20 min before completion of surgery.The anaesthesia was induced with propofol 2 mg kg^–1, fentanyl1 µg kg^–1 and vecuronium 0.1 mg kg^–1. It wasmaintained with sevoflurane 2–4% and nitrous oxide 60%in oxygen. Tympanic temperature was measured immediately afterinduction of anaesthesia, 30 min after induction and beforeadministration of the study drug. An investigator, blinded tothe treatment group, graded postoperative shivering using afour-point scale and postoperative pain using a visual analoguescale (VAS) ranging between 0 and 10. Results. The three groups did not differ significantly regardingpatient characteristics. The number of patients shivering onarrival in the recovery room, and at 10 and 20 min after operationwere significantly less in Groups P and K than in Group S. Thetime to first analgesic requirement in Group S was shorter thanin either Group K or Group P (P<0.005). There was no differencebetween the three groups regarding VAS pain scores. Conclusion. Prophylactic low-dose ketamine was found to be effectivein preventing postoperative shivering.     

Cardioprotective effects of desflurane: effect of timing and duration of administration in rat myocardium

Background. We compared the cardioprotective effects of 1 minimumalveolar concentration (MAC) desflurane administered before,during or after ischaemia, or throughout the experiment (before,during and after ischaemia) on myocardial infarct size following30 min occlusion of the left anterior descending coronary arteryand 3 h reperfusion in adult rats. Methods. Fifty male Sprague–Dawley rats were anaesthetizedwith pentobarbital, intubated and mechanically ventilated. Bloodgases, pH and body temperature (37.5–38°C) were controlled.Heart rate and arterial pressure were measured continuously.Animals were randomly assigned to the following groups (n=10in each group): pentobarbital only (‘Pento’); 15min desflurane administration followed by 10 min of washoutbefore 30 min ischaemia and 3 h reperfusion (‘Precond’);30 min desflurane administration during ischaemia period (‘Isch’);desflurane administration during the 15 first min of reperfusion(‘Reperf’) and desflurane administration throughoutthe experiment (before, during and after ischaemia; ‘Long’).Volumes at risk and infarct sizes were assessed by Indian inkand with 2,3,5-triphenyltetrazolium chloride staining, respectively. Results. Physiological parameters and volumes at risk were notsignificantly different between groups. In the Pento group,mean myocardial infarct size was 65 (SD 15)% of the volume atrisk; myocardial infarct size was reduced to a significant andcomparable extent in the desflurane-treated groups (Precond42 (14)%; Isch 34 (11)%; Reperf 41 (15)%; Long 33 (10)%; P<0.0002vs Pento group). Conclusions. In rats, desflurane 1 MAC significantly decreasedmyocardial infarct size whatever the period and duration ofadministration. Br J Anaesth 2004; 92: 552–7     

Local anaesthetics inhibit signalling of human NMDA receptors recombinantly expressed in Xenopus laevis oocytes: role of protein kinase C

Background. N-methyl-D-aspartate (NMDA)-receptor activationcontributes to postoperative hyperalgesia. Studies in volunteershave shown that intravenous local anaesthetics (LAs) preventthe development of hyperalgesic pain states. One potential explanationfor this beneficial effect is the inhibition of NMDA receptoractivation. Therefore, we studied the effects of LA on NMDAreceptor function. Methods. The human NR1A/NR2A NMDA receptor was expressed recombinantlyin Xenopus laevis oocytes. Peak currents were measured by voltageclamp in Mg- and Ca²⁺-free, Ba²⁺-containing Tyrode's solution.Holding potential was –70 mV. Oocytes were stimulatedwith glutamate/glycine (at EC₅₀) with or without 10 min priorincubation in bupivacaine, levobupivacaine, S-(–)-ropivacaine,or lidocaine (all at 10^–9–10^–4 M), procaine(10^–4 M), R-(+)-ropivacaine (10^–4 M), QX314 (permanentlycharged, 5x10^–4 M) extracellularly or intracellularlyor benzocaine (permanently uncharged, 5x10^–3 M). We alsodetermined the effect of the protein kinase C (PKC) inhibitorschelerythrine (5x10^–5 M), calphostin C (3x10^–6 M)and Ro 31-8220 (10^–7 M), and the effect of PKC activationwith phorbolester (10^–6 M). Results. Non-injected oocytes were unresponsive to agonist application,but oocytes expressing NMDA receptors responded with inwardcurrents (1.1±0.08 µA). All LA concentration-dependentlyinhibited agonist responses. The inhibition was reversible andstereoselective. Intracellular QX314 reduced responses to 59%of control, but extracellular QX314 was without effect. Benzocainereduced responses to 33% of control. PKC inhibitors had no additionalinhibitory effect beyond that of bupivacaine. The effect ofPKC activation was abolished in the presence of bupivacaine. Conclusion. All LA tested inhibited the activation of humanNMDA receptors in a concentration dependent fashion. This effectmay contribute to reduced hyperalgesia and opiate toleranceobserved after systemic administration of LA. The effect isindependent of the charge of LA; site of action is intracellular.The mechanism of action may be mediated by inhibition of PKC.     

Propofol metabolism is enhanced after repetitive ketamine administration in rats: the role of cytochrome P-450 2B induction

Background. In a series of ex vivo and in vivo studies we investigatedthe ability of repetitive ketamine administration to alter themetabolism and anaesthetic effect of propofol and the role ofketamine-mediated P-450 2B induction in rats. Methods. Male Wistar rats were pretreated with 80 mg kg^–1ketamine i.p. twice daily for 4 days. Pentoxyresorufin O-dealkylation(PROD), P-450 2B protein and mRNA were determined. Residualpropofol concentration was measured after incubating hepaticmicrosomes with 100 µM propofol. Sleeping times inducedby i.p. 80 mg kg^–1 propofol were determined. Orphenadrine,a P-450 2B inhibitor, was added in both ex vivo and in vivostudies. Finally, serial whole blood propofol concentrationswere determined after i.v. infusion of 15 mg kg^–1 propofol. Results. Ketamine pretreatment produced 5.4-, 3.4- and 1.7-foldincreases in hepatic PROD activity, P-450 2B protein and mRNA,respectively. Residual propofol concentration was 46% lowerafter incubation with microsomes from ketamine-pretreated ratsthan in the control group. The addition of orphenadrine to ketamine-pretreatedmicrosomes produced an increase in residual propofol concentrationin a concentration-dependent manner. Ketamine pretreatment reducedpropofol sleeping time to 12% of the control, which was reversedby orphenadrine. The whole blood propofol concentration in ketamine-pretreatedrats was significantly lower than that of control rats at 1,2, 4 and 8 min after cessation of propofol infusion. Conclusions. Repetitive ketamine administration enhances propofolmetabolism and reduces propofol sleeping time in rats. We suggestthat P-450 2B induction may produce ketamine–propofolinteraction in anaesthetic practice.     

Neuroprotective and neurotoxic properties of the 'inert' gas,xenon

Background. Antagonists of the N-methyl-D-aspartate (NMDA) subtypeof glutamate receptors have been shown not only to have neuroprotectiveeffects but also to exhibit neurotoxic properties. In this study,we used c-Fos, a protein product of an immediate early gene,as a marker of neuronal injury to compare the neuroprotectiveeffects of xenon and the neurotoxic properties of xenon, nitrousoxide, and ketamine, three anaesthetics with NMDA receptor antagonistproperties. Methods. We used an in vivo rat model of brain injury in whichN-methyl-DL-aspartic acid (NMA) is injected subcutaneously (s.c.)and c-Fos expression in the arcuate nucleus is used as a measureof injury. To examine the neurotoxic potential of each of thethree anaesthetics with NMDA receptor antagonist properties,c-Fos expression in the posterior cingulate and retrosplenial(PC/RS) cortices was measured. Results. Xenon dose-dependently suppressed NMA-induced c-Fosexpression in the arcuate nucleus with an IC₅₀ of 47 (2)% atm.At the highest concentration tested (75% atm) NMA-induced neuronalinjury was decreased by as much as that observed with the prototypicalNMDA antagonist MK801 (0.5 mg kg^–1 s.c.). Both nitrousoxide and ketamine dose-dependently increased c-Fos expressionin PC/RS cortices; in contrast, xenon produced no significanteffect. If the dopamine receptor antagonist haloperidol wasgiven before either nitrous oxide or ketamine, their neurotoxiceffects were eliminated. Conclusions. Uniquely amongst anaesthetics with known NMDA receptorantagonist action, xenon exhibits neuroprotective propertieswithout co-existing neurotoxicity. The reason why ketamine andnitrous oxide, but not xenon, produce neurotoxicity may involvetheir actions on dopaminergic pathways. Br J Anaesth 2002; 89: 739–46     

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     

Influence on platelet aggregation of i.v. parecoxib and acetaminophen in healthy volunteers

Background. Acetaminophen (paracetamol) alone or in combinationwith other analgesics is widely used for postoperative analgesia.While acetaminophen and non-steroidal anti-inflammatory drugsinhibit platelet function, the cyclooxygenase-2 (COX-2) selectivelyinhibiting coxibs show no interference with platelet function.The authors studied the effect of a combination of i.v. parecoxiband acetaminophen on platelet function in healthy volunteers. Methods. Eighteen healthy, male volunteers (22–33 yr)received i.v. acetaminophen 1 g, parecoxib 40 mg+acetaminophen1 g or placebo in a double-blind, crossover study. Plateletfunction was assessed by photometric aggregometry and by measuringthe release of thromboxane B₂. Plasma acetaminophen concentrationswere measured by high-performance liquid chromatography. Results. Platelet aggregation (median area under the curve)triggered with arachidonic acid 500 µM was 24.6, 3.9 and4.2x10³ area units (P=0.02, all groups) after placebo, acetaminophenand parecoxib+acetaminophen, respectively. Inhibition of plateletaggregation showed no difference between acetaminophen aloneand the combination (P=0.82). Aggregation triggered with arachidonicacid 750 or 1000 µM, adenosine diphosphate (ADP) 1.5 or3 µM, or epinephrine 5 µM showed no differencesbetween the groups. Release of thromboxane B₂ in response toADP was inhibited similarly by both acetaminophen and the combination.Plasma acetaminophen concentrations were similar after acetaminophenand the combination. Conclusions. Acetaminophen and parecoxib showed no interactionin inhibiting platelet function. In combination they cause amild degree of COX-1 inhibition corresponding to that of acetaminophenalone.     

Potentiation by ketamine of fentanyl antinociception. I. An experimental study in rats showing that ketamine administered by non-spinal routes targets spinal cord antinociceptive systems

Background. Ketamine has been found to exert antinociceptiveeffects in animals and to be analgesic at subanaesthetic dosesin humans. This study was designed to investigate the involvementof spinal cord mechanisms in the potentiation of opioid analgesiaby parenteral non-spinal administration of ketamine. Methods. Thresholds for nociception were measured in an acutepain model in rats that allowed identification of antinociceptiveeffects due to drug action in the spinal cord. Dose–responsecurves for the antinociceptive effects of ketamine alone andketamine in conjunction with the µ opioid fentanyl wereconstructed. Results. Intraperitoneal ketamine up to 3.75 mg kg^–1caused no sedative or antinociceptive effects and intrathecalketamine caused dose-dependent, spinally mediated antinociceptiveeffects. Injections of ketamine doses that caused no antinociceptiveeffects when given alone (intrathecal 25 µg and intraperitoneal3.75 mg/kg) significantly increased spinally mediated antinociceptionproduced by intrathecal fentanyl injections when assessed usingnoxious heat (tail-flick test) but not when assessed by noxiouselectrical current (electrical current threshold test). Conclusions. We conclude that ketamine can potentiate the effectsof fentanyl by an interaction at the level of the spinal cordeven when ketamine is given via a non-spinal route of administration. Br J Anaesth 2002; 88: 685–91     

Epinephrine and clonidine do not improve intrathecal sufentanil analgesia after total hip replacement

Background. We compared analgesia after intrathecal sufentanilalone, sufentanil with epinephrine 200 µg and sufentanilwith clonidine 30 µg in patients after total hip replacement,the endpoints being onset and duration of action. Methods. We performed a randomized double-blind study of 45patients for elective total hip arthroplasty using continuousspinal anaesthesia. As soon as a pain score higher than 3 ona 10 cm visual analogue scale was reported, sufentanil 7.5 µgalone, sufentanil 7.5 µg + epinephrine 200 µg orsufentanil 7.5 µg + clonidine 30 µg in 2 ml normalsaline was given intrathecally. Pain scores, rescue analgesia(diclofenac and morphine) and adverse effects (respiratory depression,postoperative nausea and vomiting, itching) were observed for24 h after surgery. Results. Time to a pain score of <3 [6 (SD 1) vs 6 (1) vs5 (1) min], time to the lowest pain score [7 (2) vs 8 (2) vs8 (2) min] and time to the first dose of systemic analgesicfor a pain score >3 [281 (36) vs 288 (23) vs 305 (30) min]were similar in all three groups. Adverse effects and analgesicrequirements during the first 24 h were also similar. Conclusion. After total hip replacement, all three analgesicregimens gave good analgesia with comparable onset and durationof action, and minor adverse effects. Br J Anaesth 2002; 89: 562–6     

Naloxone improves functional recovery of myocardial stunning in conscious dogs through its action on the central nervous system

This study tests the hypothesis that naloxone, but not its quarternarysalt, naloxone methiodide (which does not enter the centralnervous system), improves recovery from myocardial stunningin conscious dogs. Twenty dogs were chronically instrumentedfor measurement of heart rate, left atrial, aortic and leftventricular pressure (LVP), LV dP•dt_max^–1 and myocardialwall thickening fraction (WTF). Regional myocardial blood flowwas determined with coloured microspheres. Occluder around theleft anterior descending artery (LAD) allowed induction of reversibleLAD ischaemia. Each of the 20 dogs underwent two LAD ischaemicchallenges. Experiments (performed on separate days, in crossoverfashion) were: (i) 10 min of LAD occlusion after applicationof naloxone 63 µg kg^–1 or naloxone methiodide 63µg kg^–1 and (ii) occlusion without naloxone or naloxonemethiodide. WTF was measured at baseline and until completerecovery occurred. LAD ischaemia significantly reduced LAD WTFwith (mean (SD) 54 (15)% lower than baseline) and without naloxone(55 (16)% lower than baseline), without significant haemodynamicdifferences. Between 1 to 30 min of reperfusion, WTF was significantlyhigher with naloxone (P<0.05). There was no difference inWTF with or without naloxone methiodide. We conclude that naloxoneimproved recovery from myocardial stunning in conscious dogs,and that this was centrally mediated. Br J Anaesth 2001; 86: 545–9     

Desflurane affords greater protection than halothane against focal cerebral ischaemia in the rat

Background. We studied the potential neuroprotective effectsof halothane and desflurane, compared with the awake state,on infarct size following 2 h of intraluminal middle cerebralartery occlusion (MCAo) and 22 h of reperfusion. Methods. Male Sprague–Dawley rats were anaesthetized withdesflurane or halothane, intubated, and mechanically ventilated.Mean arterial pressure (MAP), blood gases, and pH were controlled.Body temperature was maintained at 37.5–38°C. Animalswere assigned to one of four groups according to the anaesthetictype (halothane or desflurane) and the duration of anaesthesia:‘short-duration’, during the preparation only; ‘long-duration’,during both preparation and ischaemia. Twenty-four hours afterMCAo, infarcts were visualized by staining with 2,3,5-triphenyltetrazoliumchloride. Two additional groups of rats were subjected to thesame protocol as that of long-duration halothane and long-durationdesflurane with additional pericranial temperature measurementsmade. Results. Physiological parameters were comparable between thegroups but MAP was higher (P<0.0001) in the short-durationgroups. In the short-duration groups, cerebral infarct volumeswere not significantly different between anaesthetics (short-durationhalothane: 288 (61) mm³, mean (SD); short-duration desflurane:269 (71) mm³, P>0.56). Compared with the awake state (short-durationgroups), halothane and desflurane significantly reduced infarctvolumes (long-duration halothane: 199 (54) mm³, P<0.0047vs short-duration halothane; long-duration desflurane: 121 (55)mm³, P<0.0001 vs short-duration desflurane). The mean infarctvolume in the long-duration desflurane group was significantlylower than that in the long-duration halothane group (P<0.0053).Pericranial temperatures were similar in the desflurane andhalothane long-duration groups (P>0.17). Conclusions. In rats, desflurane-induced neuroprotection againstfocal cerebral ischaemia was greater than that conferred byhalothane. Br J Anaesth 2003; 91: 390–6     

Comparison of intrathecal isobaric bupivacaine-morphine and ropivacaine-morphine for Caesarean delivery

Background. This study was designed to evaluate the effectsof intrathecal isobaric bupivacaine 0.5% plus morphine and isobaricropivacaine 0.5% plus morphine combinations in women undergoingCaesarean deliveries. Method. Twenty-five parturients received ropivacaine 15 mg andmorphine 150 µg (RM group) and twenty-five parturientsreceived bupivacaine 15 mg and morphine 150 µg (BM group)for spinal anaesthesia. Sensory and motor block, haemodynamics,postoperative analgesia, fetal outcomes, and side-effects wereevaluated. Results. Intrathecal bupivacaine–morphine and ropivacaine–morphineprovided effective sensory anaesthesia and motor block. Timeto reach complete motor block was shorter and time to completerecovery from motor block was longer in the BM group than theRM group (P<0.05). The time to regression of two dermatomesand time for the block to recede to the S2 dermatome were similarin both groups (P>0.05). Time to first complaint of painand the mean total consumption of tenoxicam were similar inboth groups (P>0.05). APGAR scores at 1 and 5 min were similarin the two groups, as were mean umbilical blood pH values (P>0.05).Hypotension and pruritus were the most common side-effects inboth groups during the operation. Conclusion. Intrathecal isobaric ropivacaine 0.5% 15 mg plusmorphine 150 µg provides sufficient anaesthesia for Caesareandelivery. The ropivacaine–morphine combination resultedin shorter motor block, similar sensory and postoperative analgesia. Br J Anaesth 2003; 90: 659–64