Questioning the cardiocirculatory excitatory effects of opioids under volatile anaesthesia

Background. Opioid-induced hyperalgesia has been demonstratedin awake animals. We observed an increased haemodynamic reactivityin response to noxious stimuli in rats under sevoflurane anaesthesiatreated with a very low dose of sufentanil. The aim of thisinvestigation was to determine whether the two phenomena sharea common origin: an opioid-induced excitatory reaction. To addressthis, we administered several drugs with proven efficacy inopioid hyperalgesia to rats presenting with haemodynamic hyper-reactivity. Methods. The MACbar of sevoflurane was measured in controlsand in animals treated with sufentanil 0.005 µg kg^–1min^–1 before and after administration of i.v. (0.25, 0.5mg kg^–1) and intrathecal (i.t.) (250 µg) ketamine,i.v. (0.5, 1 mg kg^–1) and i.t. (30 µg) MK-801(NMDAantagonist), i.v. (0.1, 0.5 mg kg^–1) naloxone, i.v. (10mg kg^–1) and i.t. (50, 100 µg) ketorolac or i.t.(100, 150 µg) meloxicam (COX-2 inhibitor). Results. Sufentanil 0.005 µg kg^–1 min^–1 significantlyincreased MACbar (3.2 (SD 0.3) versus 1.9 (0.3) vol%). Withthe exception of naloxone, all drugs displayed a significantMACbar-sparing effect (>50%) in controls. Naloxone completelyprevented haemodynamic hyperactivity. Two patterns of reactionwere recorded for the other drugs: either hyper-reactivity wassuppressed and the MACbar-sparing effect was maintained (i.t.ketamine, i.t. MK-801, i.t. ketorolac [100 µg], i.t. meloxicam[150 µg]) or hyper-reactivity was blocked but MACbar-sparingeffect was lost (i.v. ketamine [0.5 mg kg^–1], i.v. MK-801[0.5, 1 mg kg^–1], i.v. ketorolac [10 µg kg^–1],i.t. ketorolac [50 µg], i.t. meloxicam [100 µg]). Conclusions. We have demonstrated that low-dose sufentanil-inducedhaemodynamic hyper-reactivity is an excitatory µ-opiate-relatedphenomenon. This effect is reversed by drugs effective in treatingopiate-induced hyperalgesia.     

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.     

INTERACTION OF KETAMINE WITH ATRACURIUM

The effect of ketamine on the duration of atracurium-inducedneuromuscular blockade was studied in 40 healthy patients anaesthetizedwith midazolam, fentanyl and nitrous oxide. Twenty received,in addition, i.v. ketamine 2 mg kg^–1 followed by an infusionof 2 mg kg^–1 h^–1. Atracurium 0.5 mg kg^–1 wasinjected i.v. and the time to 25% recovery of the twitch heightwas measured. It was 8.0 min longer in the ketamine group (P< 0.005), with a 95% confidence interval of from 2.3 to 11.8min.     

KETAMINE AND E.E.G. SEIZURE WAVES: INTERACTION WITH ANTI-EPILEPTIC DRUGS

When unrestrained cats were injected with ketamine 2–6mgkg^–1i v., anaesthesia was associated with seizure waves inducedin the cortical e.e.g. After cats were pretreated with trimethadione500 mg kg^–1 1 p., ketamine did not induce seizure waves.Pretreatment with diphenylhydantoin 25 or 100 mg kg^–1i.p slightly enhanced seizure waves following ketamine. In bothsituations the anaesthetic effect of ketamine remained unaffected     

PHARMACOKINETICS AND ANALGESIC EFFECT OF KETAMINE IN MAN

The pharmacokinetics and analgesic effect of i.v. ketamine indoses of 125 µg kg^–1 and 250 µg kg^–1were determined in five healthy volunteers. Analgesia was measuredwith the submaximal effort tourniquet test. Both doses of ketamineprolonged the period of pain-free ischaemic exercise while theplasma ketamine concentration was greater than 100 ng ml^–1.Ketamine was distributed rapidly (T^z=17 min). The eliminationhalf-life was 186 min.     

PREMEDICATION DETERMINES THE CIRCULATORY RESPONSES TO RAPID SEQUENCE INDUCTION WITH SUFENTANIL FOR CARDIAC SURGERY

Thirty-three patients undergoing elective aortocoronary bypasswere allocated randomly to receive morphine 0.1 mg kg^–1i.m. and either lorazepam 50 µg kg^–1 by mouth orhyoscine 6 µg kg^–1 i.m. before rapid sequence inductionof anaesthesia with sufentanil 5 µg kg^–1 i.v. andsuxamethonium 1 mg kg^–1 i.v. Following induction and trachealintubation, patients premedicated with hyoscine had a significantlyhigher mean heart rate, mean arterial pressure, cardiac indexand left ventricular stroke-work index than patients premedicatedwith lorazepam. The incidence of new myocardial ischaemia waslow in both groups.     

STIMULANT AND DEPRESSANT EFFECTS OF KETAMINE ON NEOCORTICAL ACTIVITY IN CATS

Electroencephalographic (EEG) and behavioural effects of ketaminewere examined in chronically-prepared cats carrying recordingelectrodes for neocortical EEG and a stimulating electrode inthe optic chiasma for producing evoked potentials. Ketamine3–5 mg kg^–1 alone acted as a stimulant upon thecortical electrical activity with induced immobility. However,when ketamine was given in combination with barbiturate, itappeared to be a depressant in the sense that the anaestheticeffect of barbiturate was potentiated. Ketamine also failedto excite the neocortex of cats whose mesencephalic reticularformation had been destroyed. These results suggest that ketamine,administered in cats with no pretreatment or lesion, enhancedthe neocortical activity via the ascending reticular activatingsystem of the brain stem.     

Double-blind randomized controlled trial of caudal versus intravenous S(+)-ketamine for supplementation of caudal analgesia in children

Background. The postoperative analgesic efficacy of S(+)-ketamineafter caudal or i.v. administration following sub-umbilicalsurgery in children was studied to investigate its principalsite of analgesic action. Methods. Sixty children undergoing caudal block during generalanaesthesia for hernia repair or orchidopexy were prospectivelyrandomized to one of three groups: the bupivicaine group receivedplain bupivacaine 0.25% 1 ml kg^–1; the caudal ketaminegroup received caudal plain bupivacaine 0.25% 1 ml kg^–1with S(+)-ketamine 0.5 mg kg^–1; the i.v. ketamine groupreceived caudal plain bupivacaine 0.25% 1 ml kg^–1 plusS(+)-ketamine 0.5 mg kg^–1 i.v.. Postoperative measurementsincluded analgesic requirements and modified objective painscore for the first 24 h. Results. The median time to first analgesia was significantlylonger in the caudal ketamine group (10 h) than in the i.v.ketamine (4.63 h) or bupivacaine (4.75 h) groups (P=0.01). Significantlyfewer doses of analgesia were required over the first postoperative24 h by subjects in the caudal ketamine group (median 1) comparedwith the i.v. ketamine (median 2) or bupivacaine (median 2.5)groups (P<0.05). There was no difference between the groupsin the incidence of postoperative nausea and vomiting or psychomotorreactions. Conclusions. We have demonstrated that the addition of caudalS(+)-ketamine to bupivacaine prolongs the duration of postoperativeanalgesia. However, the same dose of i.v. S(+)-ketamine combinedwith a plain bupivacaine caudal provides no better analgesiathan caudal bupivacaine alone, indicating that the principalanalgesic effect of caudal S(+)-ketamine results from a localneuroaxial rather than a systemic effect. Br J Anaesth 2004; 92: 344–7     

KETAMINE INFUSIONS: PHARMACOKINETICS AND CLINICAL EFFECTS

The clinical effects and pharmacokinetics of ketamine, administeredas an i.v. infusion, were studied in 31 patients. Anaesthesiawas induced with ketamine 2 mg kg^–1 i.v. and maintainedusing an i.v. infusion of ketamine, supplemented by nitrousoxide. The plasma concentrations of ketamine, nor-ketamine anddehydro-nor-ketamine were analysed using gas-liquid chromatography.The average maintenance dose of ketamine was 41 ± 21µg kg^–1 min^–1, but there was an obvious decreasein the dose required as anaesthesia progressed. This dose gavea stable plasma concentration of ketamine of 9.3 ± 0.8µmol litre^–1. Patients recovered at 2.7 ±0.9 µmol litre^–1. Plasma half-life of ketamine was79 ±8 min. Maximum concentration of nor-ketamine was4.7 ± 2.4 µmol litre^–1 and of dehydro-nor-ketamine3.2 ± 1.9 µmol litre^–1. There were transientincreases (15–30% of pre anaesthetic values) in arterialpressure, heart rate and cardiac output during operation. Nopostoperative respiratory depression was seen.     

KETAMINE DISPOSITION IN CHILDREN AND ADULTS

The pharmacokinetics of ketamine 2 mg kg^–1 i.v. and 6mg kg^–1 i.m. were investigated in nine children undergoingminor surgery. After either route of administration plasma ketamineconcentrations were similar to those found in adult patientsreceiving the same dose, except at later times after i.v. injection,when concentrations were smaller in children. Also, absorptionafter i.m. injection appeared to be more rapid in children.Substantially larger concentrations of the metabolite norketaminewere found in children than in adults after the injection ofketamine. Concentrations of ketamine upon awakening in a furthergroup of nine children receiving ketamine as the sole anaestheticshowed large inter-individual variation. The concentrationswere greater than those previously reported for adults. Thegreater dose requirements in children, compared with adults,are probably attributable to pharmacodynamic rather than pharmacokineticfactors.     

Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury

Background. Ketamine is used as an anaesthetic agent for shortsurgical procedures, and as a sedative and analgesic in intensivecare patients. Intensive care patients with brain or spinalcord injury may have physiological changes that could alterthe pharmacokinetics of ketamine. The pharmacokinetics of ketaminehave been studied in healthy volunteers and in patients undergoingdifferent types of surgery, but no data are available in intensivecare patients. Methods. We determined the pharmacokinetics of ketamine andits active metabolites, norketamine and dehydronorketamine,in 12 intensive care patients with brain or spinal cord injury.The effect of ketamine on haemodynamic variables was also investigated. Results. The total clearance of ketamine, mean (SD), was 36.0(13.3) ml min^–1 kg^–1, the volume of distribution(Vß) was 16.0 (8.6) litre kg^–1, and the eliminationhalf-life was 4.9 (1.6) h. Ketamine did not alter any haemodynamicvariables in the patients studied. Conclusions. Pharmacokinetic variables of ketamine in intensivecare patients are greater than in healthy volunteers and insurgical patients. The increase in the volume of distributionis greater than the increase in clearance, resulting in a longerestimated half-life of ketamine in this patient group. Br J Anaesth 2003; 90: 155–60     

Serotonergic receptor antagonists alter responses to general anaesthetics in rats

Serotonergic neurotransmission is involved in controlling arousallevels in humans and other animals. Here, the effects of serotonergicreceptor antagonists on the induction and depth of anaesthesiaproduced by three different general anaesthetics were investigated.Rats were pre-treated (i.p.) with either methiothepin (1.5 mgkg^–1), mianserin (5 mg kg^–1), ketanserin (7 mg kg^–1)or saline. Subsequently, successive, cumulative doses (i.p.)of either ketamine (final, cumulative dose of 350 mg kg^–1),sodium pentobarbital (final dose 77 mg kg^–1), or chloralhydrate (final dose 600 mg kg^–1) were administered. Theresponse to the anaesthetics was measured using a behaviouraltest battery assessing nocifensive reflexes and hypnotic state.Pre-treatment with methiothepin enhanced responses to all threeanaesthetics; mianserin enhanced responses to chloral hydrate.These results show that some serotonergic receptor antagonistschange anaesthetic requirements, resulting in enhanced anaesthesiato hypnotics with different mechanisms of action. Br J Anaesth 2000; 85: 904–6     

ANALGESIC EFFECT OF INTRATHECHAL KETAMINE IN RATS

The analgesic effect of ketamine hydrochloride 200,400, 800and 1600 µg kg^–1, administered intrathecally inrats, was evaluated using the tail-flick test. A short-livedanalgesic effect was demonstrated with the larger doses andthis could be abolished by pretreatment with naloxone hydrochloride200 µg kg^–1. Intrathecal morphine 100 µg kg^–1produced a more profound analgesic effect than intrathecal ketamine1600 µg kg^–1. There were three deaths shortly afterintrathecal injection of ketamine. Histopathological examinationof the spinal cords and nerve roots of these rats revealed thepresence of vacuoles in the cells of the posterior root ganglion.Other rats sacrificed for histopathological examination showedno changes attributed to the injectate.     

Effects of AM281, a cannabinoid antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality in septic shock in rats

Introduction. The purpose of this study was to examine the effectsof AM281, a cannabinoid receptor antagonist, on systemic haemodynamics,internal carotid artery blood flow and mortality during septicshock in rats. Methods. The study included three sets of experiments: measurementsof changes in systemic haemodynamics and left internal carotidartery flow (30 animals divided into three groups of 10); measurementsof biochemical variables (n=30); assessment of mortality (n=30).Male Wistar rats (7 weeks old) were randomly divided into threegroups: group 1, control; group 2, lipopolysaccharide (LPS)i.v., Escherichia coli endotoxin 10.0 mg kg^–1 i.v., bolus;group 3, LPS 10.0 mg kg^–1 i.v.+AM281 1 mg kg^–1 i.v.Systemic haemodynamics, carotid artery flow changes and biochemicalvariables were assessed at pretreatment and 1, 2 and 3 h afterthe treatment was performed. Results. Administration of AM281 could prevent the haemodynamicchanges induced by sepsis. Tumour necrosis factor-     

EFFECTS OF ATRACURIUM, VECURONIUM OR PANCURONIUM PRETREATMENT ON LIGNOCAINE SEIZURE THRESHOLDS IN CATS

Among the non-depolarizing neuromuscular blocking drugs, atracuriumappears to be unique in its ability to produce cerebral stimulationin lightly anaesthetized animals. This effect is attributedto the atracurium metabolite, laudanosine. The following studieswere performed to determine if pretreatments with the non-depolarizingneuromuscular blockers pancuronium, atracurium or vecuroniumwould differ in their effects on the seizure threshold of lignocaine.Adult mongrel cats were anaesthetized with 1.0 MAC halothanein oxygen and nitrogen. Ventilation, blood-gas tensions, acidbasebalance and temperature were controlled. Cats received pancuronium0.2 mg kg^–1 i.v. (n= 7), atracurium 1.0 mg kg^–1i.v. (n = 7) or vecuronium 0.2 mg kg^–1 i.v. (n = 7). Tenminutes after the administration of the myoneural blocker, allcats received lignocaine 4 mg kg^–1 min^–1 i.v. untilthe onset of EEG evidence of generalized seizure activity. Atseizure onset, there were no statistically significant differencesamong the cumulative lignocaine doses or the serum lignocaineconcentrations in cats pretreated with pancuronium, atracuriumor vecuronium.     

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.     

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.      

CARDIAC EFFECTS OF ATROPINE AND GALLAMINE IN PATIENTS RECEIVING SUXAMETHONIUM

Eighty healthy patients were randomly allocated to four groups.Atropine 0.01 mg kg^–1 i.v. (group I), gallamine 0.3 mgkg^–1 i.v. (group II), atropine 0.01 mg kg^–1 i.m.and gallamine 0.3 mg kg^–1 i.v. (group III), or atropine0.01 mg kg^–1 i.v. and gallamine 0.3 mg Lrg^–1 i.v.(group IV) were given before operation. After induction of anaesthesiawith thiopentone, suxamethonium 1 mg kg^–1 was given i.v.The lungs were ventilated with halothane in nitrus oxide inoxygen. Five minutes later the same dose of suxamrthonium wasrepeated. E.c.g. was monitored continuously. No serious bradycardiawas observed following a second injection of suxamethonium inany group. The results suggest that thiopentone protects againstsuxamethonium-induced bradycardia during halothane anaesthesia.     

PRELIMINARY STUDY OF A PREGNANOLONE EMULSION (KABI 2213) FOR I.V. INDUCTION OF GENERAL ANAESTHESIA

Pregnanolone emulsion was administered i.v. to 13 healthy malevolunteers to assess its potential as an agent for i.v. inductionof general anaesthesia and to establish a pharmacokinetic profileat two doses. Each subject received 0.5mg kg^–1 0.75mgkg^–1 and 1.0 mg kg^–1 on successive occasions, therate of administration being constant for each dose. Pregnanoloneemulsion was found to produce smooth and reliable inductionof general anaesthesia with cardiorespiratory effects comparableto those of other i. v. induction agents.     

METHOHEXITONE ANAESTHESIA FOR MICROLARYNGOSCOPY: CIRCULATORY MODULATION WITH METROPROLOL AND DIHYDRALAZINE

Anaesthesia for microlaryngoscopy was induced and maintainedwith fentanyl 3 µg kg^– and methohexitone (initialbolus of 1–1.5 mg-kg^–1 plus subsequent infusionof 4 mg kg^–1 h^–1). Suxamethonium was used to induceneuro-muscular blockade. Twenty minutes before induction ofanaesthesia, previously normotensive patients (n = 35), andpatients with hypertension well controlled by beta-receptorantagonists (n = 16) were pretreated with metoprolol (M) 0.2mg kg^–1i.v. and dihydralazine (DH) 0.2 mg kg^–1i.v.,dihydralazine 0.2 mg kg^–1 i.v. alone, or saline. Arterialpressure (AP) and heart rate (HR) were monitored: any arrhythmiaand ST₆₀T changes were noted. After the methohexitone infusionwas stopped, the times for emergence and full recovery wereshort (median 2 min 15s and 5 min later, respectively). Pretreatmentwith M+DH abolished increases in AP and HR during endoscopy.Arrhythmias were observed in fewer pretreated patients thanin controls (P < 0.05). ST₆₀-Tchanges in the ECG indicatingmyocardial ischaemia were found in two of 19 M+DH and in sixof 21 saline-pretreated patients. One of these six patientsdeveloped a myocardial infarction. Pretreatment with dihydralazinealone attenuated the pressor response to microlaryngoscopy,but was associated with consistently high HR and an incidenceof arrhythmias as well as ST₆₀T changes similar to that foundafter saline.