PATIENT-CONTROLLED ANALGESIA WITH EXTRADURAL MORPHINE OR PETHIDINE

Two groups of patients were allowed to self-administer morphine(n = 17) or pethidine (n = 15) extradurally after abdominalsurgery, for a mean period of 16 h. Bolus increments of morphine1 mg or pethidine 20 mg were administered by programmable pump.Pain relief from extradural patient-controlled analgesia (PCA)was excellent in all but two patients in the morphine group.Pain relief was not qualitatively different between the twogroups. No clinical respiratory depression was seen. The averageconsumption of extradural morphine was 0.52 ± 0.29 mgh^–1 (range 0.19–1.04 mg h^–1) and of pethidine18.0±8.1 mg h^–1 (5.8–35.4 mg h^–1).This yields an equianalgesic dose relationship of 1:35. Morphineconsumption was more irregular than pethidine consumption. Morphineand pethidine plasma concentrations measured during PCA werewell below the reported minimum analgesic plasma concentrationsin most cases. Several patients, particularly in the pethidinegroup, tended to increase their opioid consumption during PCA.This could be explained by an increasingly smaller fractionof the pethidine bolus being absorbed to the subarach-noid spaceduring frequent repetitive dosing. The large inter-individualvariation in consumption makes it impossible to recommend astandard dose of extradural morphine or pethidine for analgesiaof predictable duration and with a minimum of adverse effects.     

DOUBLE-BLIND COMPARISON BETWEEN DOXAPRAM AND PETHIDINE IN THE TREATMENT OF POSTANAESTHETIC SHIVERING

Sixty patients who shivered after routine surgery under generalanaesthesia were allocated randomly to receive normal saline(n = 20), doxapram 1.5mg kg^–1 (n = 20) or pethidine 0.33mgkg^–1 (n = 20). Both doxapram and pethidine were effectivein treating postoperative shivering 2–3 mm after i.v.administration. In the group who received normal saline, 15patients were still shivering 10 min after treatment, whilstin the doxapram group only three patients were shivering atthat time. In the pethidine group, all patients had stoppedshivering by 7 min after treatment. We conclude that both doxapramand pethidine were effective in the treatment of postoperativeshivering. (Br. J. Anaesth. 1993; 71: 685–688)     

NORPETHIDINE TOXICITY AND PATIENT CONTROLLED ANALGESIA

Patient-controlled analgesia (PCA) with i.v. opioids is prescribedincreasingly. We report three cases of norpethidine toxicityin patients receiving pethidine by PCA. (Br. J. Anaesth. 1993;71: 738–740) ^*Present address: Department of Anaesthesia, Western Infirmary,Glasgow G11 6NT     

COMPARATIVE PLASMA CONCENTRATION PROFILES AFTER I.V., I.M. AND RECTAL ADMINISTRATION OF PETHIDINE IN CHILDREN

Plasma concentration—time curves of pethidine and norpethidinewere studied in 25 children allocated after operation to threegroups to receive pethidine 1 mg kg^–1 i.v., i.m. or rectally.Peak concentrations occurred after 5± 1, 10 ±2, and 60 ± 10 min, respectively, while the maximum concentrationsamounted to 2800±462, 1609 ± 367 and 531 ±179nmol litre^–1, respectively. The area under the curve (0–240min) was similarly reduced in the group with rectal administration(P < 0.05). Compared with the i.v. data, approximately 40%systemic availability occurred after rectal application, althoughconsiderable individual variastion was noted. In one child veryhigh plasma concentrations were observed after rectal administration,possibly as a result of redistribution/recirculation phenomena.The average results are similar to those obtained when otheropioids are given rectally.     

PHARMACOKINETICS OF I.V. AND RECTAL PETHIDINE IN CHILDREN UNDERGOING OPHTHALMIC SURGERY

We have studied the pharmacokinetics of i.v. and rectal pethidinein 20 children age 4–8 yr under going ophthalmic surgery.After i.v. administration, the clearance of pethidine was mean10.4 (SD 1.7) ml kg^–1 min^–1, volume of distributionat steady state 2.8 (0.6) litre kg^–1 and elimination haff-ilfe3.0 (0.5) h. After rectal administration, plasma pethidine concentrationsvaried greatly and peak concentrations appeared late, at 147(44) mm. The mean systemic bioavailabiity after rectal administration was approximately 55%. Because the bioavailabiityof rectal pethidine varies greatly, this route is not encouragedin the management of acute pain. (Br. J. Anaesth. 1993; 71:823–826)     

PHARMACOKINETICS OF FENTANYL DURING CONSTANT RATE I.V. INFUSION FOR THE RELIEF OF PAIN AFTER SURGERY

Forty-five patients in four groups undergoing orthopaedic, upperabdominal, prolonged or cardiac surgery received a constantrate i.v. infusion of fentanyl 100 µg h^–1 for 24h starting 2 h before surgery. A single bolus dose was giveni.v. at the induction of anaesthesia. Plasma fentanyl concentrations,measured by radio-immunoassay were between 1 and 3 ng ml^–1until the infusions were discontinued. Clearance of fentanylwas decreased in the cardiac surgery group only. The eliminationhalf-life was 7.3–9.7 This simple regimen produced effectiveanalgesia.     

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.     

HYPOXAEMIA AND PAIN RELIEF AFTER UPPER ABDOMINAL SURGERY: COMPARISON OF I.M. AND PATIENT-CONTROLLED ANALGESIA

Forty patients recovering from upper abdominal surgery wereallocated randomly to receive i.m. morphine 0.15 mg kg^–1as required or patient-controlled analgesia (PCA), with i.v.morphine 1 mg and a 5-min lock out time. Arterial oxygen saturation(Sp⁰²) was measured continuously the night before and for 24h immediately after surgery. A significantly greater proportionof patients in the PCA group (nine of 19) rated their analgesiaas excellent compared with the i.m. group (two of 20) (P <0.05). There was no significant difference in the incidenceof postoperative hypoxaemia in the two treatment groups. Severepostoperative hypoxaemia (Sp02 <85% for more than 6 min h^–1) was seen in three patients receiving i.m. analgesia and onepatient in the PCA group. ^*Present address: Royal Hallamshire Hospital, Sheffield     

POSTOPERATIVE ANALGESIA WITH FENTANYL: PHARMACOKINETICS AND PHARMACODYNAMICS OF CONSTANT-RATE I.V. AND TRANSDERMAL DELIVERY

We have investigated the use of constant-rate delivery of fentanylby i.v. and transdermal routes for the treatment of pain aftermajor surgery. Forty-five males, ASA I–III, received ina doubleblinded fashion either placebo (n = 6) or fentanyl (n= 39) i.v. at one of four dose rates (25, 50, 100 or 125 µgh^–1). Stable serum concentrations of fentanyl were producedby the end of surgery and were maintained for a total of 24h. Calculated clearance of fentanyl was 1.05±0.38 litremin^–1 and was not related to weight or age. Both the 100-and 125-µg h^–1 dose rates produced significant analgesicefficacy as assessed by postoperative morphine requirements.Mean serum concentrations of fentanyl in these groups were 1.42±0.14(SD) and 1.90±0.30 ng ml^–1, respectively. One of10 patients receiving fentanyl 100 µg h^–1 and threeof nine patients receiving 125 µg h^–1 had evidenceof respiratory depression. Eight additional patients were treatedwith a transdermal drug delivery system containing fentanyl(TTS-fentanyl). Steady-state serum concentrations in this groupwere 2.15±0.92 (SD) ng ml^–1. Postoperative morphinerequirements were minimal (< 0.5 mg h^–1) and Pa_CO2remained acceptable in all patients. Serum concentrations offentanyl increased slowly (15 h to plateau) and decreased slowly(apparent half-life, 21 h). We conclude that delivery of analgesicdoses of fentanyl is feasible by the transdermal route. Presented, in part, at the Annual Meeting of the American Societyof Anesthesiologists, Las Vegas, Nevada, October, 1986.     

PREVENTION OF HISTAMINE-INDUCED CARDIOVASCULAR REACTIONS DURING THE INDUCTION OF ANESTHESIA FOLLOWING PREMEDICATION WITH H1- + H2-ANTAGONISTS I. M.

In a prospective controlled double-blind study, 60 electivesurgical patients were randomly assigned to three premedicationgroups. Twenty patients received promethazine 0. 5 mg kg^–1i.m. 45 min before induction of anaesthesia; a further 20 patientsreceived an additional i. m. injection of cimetidine 400 mg120 min before induction. The third group (n = 20) served asthe control group. Following vecuronium 0.02 mg kg^–1,anaesthesia was induced with fentanyl, and etomidate. All patientsthen received suxamethonium 1.5 mg kg^–1 i. v. The combinedadministration of H₁- + H₂-antagonists as premedication ledto a significant reduction in the increase in heart rate whencompared with the effects in the other groups.     

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.     

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

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

Evaluation of effects of magnesium sulphate in reducing intraoperative anaesthetic requirements

Background. The present randomized, placebo-controlled, double-blindstudy was designed to assess the effect of peroperatively administeredi.v. magnesium sulphate on anaesthetic and analgesic requirementsduring total i.v. anaesthesia. Methods. Eighty-one patients (36 women, 45 men) undergoing electivespinal surgery were included in one of two parallel groups.The magnesium group received magnesium sulphate 30 mg kg^–1as a bolus before induction of anaesthesia and 10 mg kg^–1h^–1 by continuous i.v. infusion during the operation period.The same volume of isotonic solution was administered to thecontrol group. Anaesthesia was maintained with propofol (administeredaccording to the bispectral index) and remifentanil (adjustedaccording to heart rate and arterial blood pressure) infusions. Results. A significant reduction in hourly propofol consumptionwas observed with magnesium administration. For example, themean infusion rate of propofol in the second hour of the operationwas 7.09 mg kg^–1 h^–1 in the controlgroup vs 4.35 mg kg^–1 h^–1 in themagnesium group (P<0.001). The magnesium group required significantlyless remifentanil (P<0.001) and vecuronium (P<0.001).No side-effects were observed with magnesium administration. Conclusion. The administration of magnesium led to a significantreduction in the requirements for anaesthetic drugs during totali.v. anaesthesia with propofol, remifentanil and vecuronium. Br J Anaesth 2002; 89: 594–8     

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.     

COMPARISON OF INFUSIONS OF ALFENTANIL OR PETHIDINE FOR SEDATION OF VENTILATED PATIENTS ON THE ITU

Sedation was studied in 30 patients requiring overnight ventilationin the intensive therapy unit (ITU). Patients received an infusionof either alfentanil or pethidine, supplemented with midazolam.The infusion rates were adjusted to provide optimal sedationas judged by a nurse, and measurements were made of qualityof sedation, recovery and serum cortisol concentration. In addition,blood concentrations of alfentanil were measured to permit pharmacokineticand pharmacodynamic analysis. Satisfactory sedation was achievedin both groups. The required infusion rate for alfentanil wasbetween 0.4 and 0.5 µ kg^–1 min^–1. Recoverywas good in both groups, apart from one patient in the alfentanilgroup, in whom recovery was greatly prolonged and alfentanilpharmacokinetics were abnormal. A difference was found in themetabolic response to surgery between the two groups, the responsein the alfentanil group being significantly less marked.     

INFLUENCE OF PRETREATMENT WITH A MONOAMINE OXIDASE INHIBITOR (PHENELZINE) ON THE EFFECTS OF BUPRENORPHINE AND PETHIDINE IN THE CONSCIOUS RABBIT

The existence of a severe toxic interaction (occasionally fatal)from the clinical use of pethidine and monoamine oxidase (MAO)inhibitors is well established. The present study evaluatesthe possibility of such an interaction existing for the opioidpartial agonist buprenorphine. Conscious rabbits (n = 6 in eachgroup) pretreated 18–24 h previously with physiologicalsaline or the MAO inhibitor phenelzine 20 mg kg^–1 s.c.were subsequently given physiological saline, pethidine 5 mgkg^–1 i.v. or buprenorphine 0.1 or 1.0 mg kg_–1 i.v.Whilst saline was without effect and phenelzine produced onlya small increase in the rabbit temperature, the combinationof phenelzine and pethidine produced a marked, prolonged hyperpyrexia(+4.4±0.19 °C; P < 0.001), hypertension (+33.9±3.1mm Hg; P < 0.01) and agitation. Three rabbits died, at 35,45 and 55 min after the pethidine–phenelzine combination.Buprenorphine was without significant effect on any parameterwhen given after phenelzine. In the model used buprenorphine,in contrast to pethidine, showed no interaction with the MAOinhibitor phenelzine.     

SITE OF ACTION OF FENTANYL IN INHIBITING THE PITUITARY-ADRENAL RESPONSE TO SURGERY IN MAN

To determine the site of action of fentanyl in attenuating thepituitary—adrenal response to surgery, we have measuredserum concentrations of cortisol and growth hormone during andafter a standardized surgical procedure in two groups of patients.One group received fentanyl 15µg kg^–1 i.v. immediatelybefore the start of surgery; a second group received fentanyl15 µg kg^–1 i.v. together with corticotrophin releasingfactor 100 µg i.v., growth hormone releasing hormone 100µgi. v. and arginine vasopressin 10 units i.m. The concomitantadministration of the releasing factors with the opioid resultedin a significantly greater serum concentration of cortisol 30,60, 120 and 240 min after surgery commenced, compared with thegroup which received fentanyl alone. Similarly, the growth hormoneresponse in the combined group was significantly greater thanin the fentanyl-alone group 30 min after the start of surgery.We conclude that the inhibitory effect of fentanyl on surgically-inducedsecretion of pituitary hormone was mediated directly or indirectlyvia the hypothalamus.     

COMPARISON OF THE ANAESTHETIC AND HAEMODYNAMIC EFFECTS OF CHLORMETHIAZOLE AND THIOPENTONE

Two groups of eight women (60 – 85 yr) undergoing gynaecologicaloperations of 50 to 130 min duration were compared. Anaesthesiawas induced with either thiopentone (mean 4.5mg kg^–) orchlormethiazole(mean 6.0 ing kg^–1) and maintained withnitrous oxide and pethidine in combination with the drug usedfor the induction. The hourly maintenance dose and the plasmaconcentration determined at equilibrium were greater for chlormethiazole(means 4.7mg kg^–1 h^–1 and 27(µmol litre^–1)compared with 1.3 mgkg ^–1h ^–1 (P< 0.01) and 16µmollitre^–1 respectively for thiopentone (P< 0.02). Impedancecardiography showed that cardiac output was decreased by 30–40%in the thiopentone group (P < 0.01), whereas ho significantchange was observed in the chlormethiazole group. Chlormethiazoleanaesthesia was followed by a significant increase (P<0.02)in stroke volume. No correlations were found between the plasmaconcentrations and changes in the haemodynamic indices for eitherof the drugs.     

MYONEURAL EFFECTS OF PETHIDINE AND DROPERIDOL

In vitro experiments on the rat phrenic nerve - hemidiaphragmpreparation, stimulated directly or indirectly with supramaximalimpulses at 0.1 Hz revealed that pethidine in concentrationsgreater than 5µgml^–1 caused a rapid increase ofthe twitch. This was maximal (60% increase during direct and70% increase during indirect stimulation) with pethidine 75µgml^–1.With concentrations of pethidine greater than 40µgml^–1,the initial increase was followed by a slowly developing inhibitionof the twitch (50% depression with 46.0 and 50.4µgml^–1during direct and indirect stimulation, respectively). Droperidolcaused no increase in twitch, but it depressed the twitch by50% at concentrations of 9.8 and 6.9µgml^–1 duringdirect and indirect stimulation, respectively. The increasein twitch produced by pethidine was augmented by 4-aminopyridineand inhibited by verapamil during both direct and indirect stimulation.Tubocurarine antagonized the augmentation of the twitch by pethidineonly during indirect stimulation. The pethidine- and droperidol-inducedinhibition of the twitch could be reversed by washout, but itwas not antagonized by neostigmine or 4-aminopyridine. The inhibitoryeffect of pethidine and droperidol were additive. Sub-effectiveinhibitory concentrations of pethidine and droperidol, and thoseof tubocurarine, pancuronium and suxamethonium, independentlyof the sequence of their administration, mutually increasedthe myoneural effects of one another. The resulting twitch depressioncould be reversed by washout. The inhibition caused by the combinationof pethidine with tubocurarine or pancuronium was partiallyantagonized by neostigmine or 4-aminopyridine. That of pethidinewith suxamethonium was not affected by neostigmine or 4-aminopyridine.The findings indicate that the main site of both the facilitatingand inhibitory effect of pethidine, and that of the inhibitoryeffect of droperidol, it the muscle fibre. In addition, droperidolhas a moderate inhibitory and pethidine a weak stimulating effectat the neuromuscular junction.     

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

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