Pharmacological effects of intravenous melatonin: comparative studies with thiopental and propofol

Background. Possible utility of high-dose i.v. melatonin asan anaesthetic adjuvant has not been studied. This study comparedits effects with thiopental and propofol. Methods. Sprague Dawley rats were assigned to receive bolusor cumulative i.v. doses of melatonin, thiopental or propofol.Righting reflex, hindpaw withdrawal to a noxious stimulus, responseto tail clamping and haemodynamic effects were assessed. Results. Melatonin caused a dose-dependent increase in paw withdrawalthreshold and the percent of rats displaying loss of the rightingreflex. Melatonin was comparable to thiopental and propofolin terms of its rapid onset of hypnosis. The mean ED₅₀ valuesfor loss of righting reflex were 5.4 (SEM 1.2), 12.5 (1.1) and178 (1.1) mg kg^–1 for propofol, thiopental and melatonin,respectively. The percent of rats displaying loss of responseto tail clamping was greater with propofol than with melatonin(P<0.05). Haemodynamic changes produced by melatonin or propofolwere similar in onset and magnitude. Conclusions. I.V. melatonin can exert hypnotic effects similarto those observed with thiopental and propofol. Melatonin exhibitedsignificant antinociceptive effects but was less effective inabolishing the response to tail clamping. Br J Anaesth 2003; 90: 504–7     

Pre-emptive lidocaine inhibits arterial vasoconstriction but not vasopressin release induced by a carbon dioxide pneumoperitoneum in pigs

Background. We assessed the preventive effects of i.v. or i.p.lidocaine administration on increases in vascular resistanceproduced by carbon dioxide pneumoperitoneum and related thisto vasopressin release. Methods. Carbon dioxide pneumoperitoneum (14 mm Hg intra-abdominalpressure) was performed in 32 anaesthetized young pigs and monitoredusing a pulmonary artery catheter. Animals received lidocaine0.5% (0.5 mg kg^–1) i.v. (n=9) or 2 ml kg^–1 i.p.(n=9) or saline (n=5) 15 min before the pneumoperitoneum andwere compared with a control group (n=9). Results. I.V. and i.p. lidocaine inhibited increases in meansystemic vascular resistance induced by the pneumoperitoneum[2109 (SD 935) and 2282 (895), respectively, vs 3013 (1067)dyne s^–1 cm^–5 in the control group]. Cardiac outputwas increased. Plasma lidocaine concentrations were threefoldhigher after i.p. administration than after i.v. administration.After pneumoperitoneum insufflation, plasma lysine-vasopressinconcentrations increased in all groups (control 74%, saline65%, i.p. lidocaine 57%, i.v. lidocaine 74%). Conclusions. I.V. and i.p. lidocaine blunted systemic vascularresponses to carbon dioxide pneumoperitoneum in pigs, but withoutinfluencing vasopressin release. Br J Anaesth 2003; 90: 343–8     

Comparison of local anaesthetic effects of tramadol with prilocaine for minor surgical procedures

Background. Recent studies have shown that a local anaestheticaction of tramadol 5% was able to induce a sensory block topinprick, touch, and cold similar to that of lidocaine 1%. Theaim of this study was to compare the local anaesthetic effectsof tramadol hydrochloride with prilocaine. Methods. Sixty ASA I or II patients, undergoing excision ofthe cutaneous lesions under local anaesthesia, were includedin the study. Patients were randomly assigned to receive either1 ml of tramadol 5% (Group T, n=30) or 1 ml of prilocaine 2%(Group P, n=30) intradermally, in a double-blinded fashion.The degree of the burning sensation and pain at the injectionsite was documented. Sensory block was assessed 1 min afterinjection. The patient was asked to report the degree of sensationand to grade touch and pinprick sensation. Two minutes afterdrug administration, incision was performed and intensity ofpain, felt by the patient was evaluated on a four-point scale(0–3). Any local adverse effects were recorded. Results. There was no difference in the quality of block betweenthe two groups. Side effects were noted in both groups witha significant increase in the incidence of local reaction (rash)in Group T (seven patients) when compared with Group P (onepatient) (P<0.05). Seven patients in Group T vs four patientsin Group P complained of burning at the injection site (P>0.05). Conclusions. Intradermal tramadol 5% can provide a local anaesthesiasimilar to the prilocaine but the incidence of local adverseeffects is higher. Br J Anaesth 2003; 90: 320–2     

Comparison of isoflurane and propofol-fentanyl anaesthesia in a swine model of asphyxia

Background. There have been few studies comparing the responseto asphyxia and the effectiveness of typical cardiopulmonaryresuscitation (CPR) using exogenous epinephrine administrationand manual closed-chest compression between total intravenousanaesthesia (TIVA) and inhalational anaesthesia. Methods. Twenty pigs were randomly assigned to two study groupsanaesthetized using either 2% end-tidal isoflurane (n=10) orpropofol (12 mg kg^–1 h^–1)–fentanyl (50 µgkg^–1) (n=10). Asphyxia was induced by clamping the trachealtube until the mean arterial pressure (MAP) decreased to 40%of the baseline value (40% MAP time). The tracheal tube wasdeclamped at that point, and CPR was performed. Haemodynamicparameters and blood samples were obtained before the inductionof asphyxia, at 1-min intervals during asphyxia, and 1, 2, 3,5, 10, 30 and 60 min after asphyxia. Results. TIVA maintained the MAP against hypoxia–hypercapniastress significantly longer than isoflurane anaesthesia (mean(SD) 40% MAP time 498 (95) and 378 (104) s respectively). Inall animals in the isoflurane group, spontaneous circulationreturned within 1 min of the start of CPR. In six of the TIVAanimals, spontaneous circulation returned for 220 (121) s; spontaneouscirculation did not return within 5 min in the remaining fouranimals. Conclusions. Although TIVA is less prone than isoflurane anaesthesiato primary cardiovascular depression leading to asphyxia, TIVAis associated with reduced effectiveness of CPR in which resuscitationbecause of asphyxic haemodynamic depression occurs. Br J Anaesth 2003; 91: 871–7     

Fever during anaesthesia

Fever occurs when pyrogenic stimulation activates thermal control centres. Fever is common during the perioperative period, but rare during anaesthesia. Although only a limited number of studies are available to explain how anaesthesia affects fever, general anaesthesia seems to inhibit fever by decreasing the thermoregulatory-response thresholds to cold. Opioids also inhibit fever; however, the effect is slightly less than that of general anaesthesia. In contrast, epidural anaesthesia does not affect fever. This suggests that hyperthermia, which is often associated with epidural infusions during labour or in the post-operative period, may be a true fever caused by inflammatory activation. Accordingly, this fever might be diminished in patients who receive opioids for pain treatment. Post-operative fever is a normal thermoregulatory response usually of non-infectious aetiology. Fever may be important in the host defence mechanisms and should not be routinely treated lest the associated risks exceed the benefits.     

Effect of dexmedetomidine, an alpha2-adrenoceptor agonist, on human pupillary reflexes during general anaesthesia

AIMS: To test the hypothesis that the alpha2-adrenergic agonist, dexmedetomidine, dilates the pupil and does not alter the pupillary light reflex of anaesthetized patients. METHODS: Eight volunteers were administered general anaesthesia with propofol, nitrous oxide and alfentanil. One hour and 25 min after induction of anaesthesia, a 45 min infusion of dexmedetomidine was begun, targeting a plasma concentration of 0.6 ng x ml(-1). Pupil size, pupillary light reflex amplitude, light reflex recovery time, and reflex dilation were measured before and during dexmedetomidine infusion. RESULTS: Dexmedetomidine produced no change in pupil size and light reflex recovery time, increased the light reflex from 0.30 +/- 0.14 to 0.37 +/- 0.12 mm and significantly reduced pupillary reflex dilation by 72 +/- 62%. CONCLUSIONS: These pupillary effects of dexmedetomidine in humans are difficult to reconcile with the findings obtained in cats and rats that have demonstrated a direct inhibitory effect of alpha2-adrenergic agonists on the pupilloconstrictor nucleus. The increase in the magnitude of the light reflex in response to dexmedetomidine does not necessarily involve an anxiolytic mechanism.     

Comparison of relaxant effects of propofol on methacholine-induced bronchoconstriction in dogs with and without vagotomy

Propofol has been suggested to have in vivo airway relaxanteffects, although the mechanism is still unclear. In this study,we determined whether propofol could antagonize methacholine-inducedbronchoconstriction and determined whether vagotomy modifiesthis relaxant effect. Fourteen mongrel dogs anaesthetized withpentobarbital and pancuronium were assigned to a control group(n=7) and a vagotomy group (n=7). The trachea was intubatedwith a special endotracheal tube that had a second lumen forinsertion of the bronchoscope. Bronchial cross-sectional area,which was monitored continuously through the bronchoscope, wasmeasured with image analysis software. Bronchoconstriction waselicited with methacholine (0.5 µg kg^–1 + 5.0 µg kg^–1 min^–1)until the end of the experiment. Thirty minutes after the startof methacholine infusion, propofol 0, 0.2, 2.0 and 20 mg kg^–1was administered. Changes in bronchial cross-sectional areawere expressed as percentages of the basal area. Plasma concentrationsof propofol and catecholamine were measured by high-performanceliquid chromatography. Maximal inhibition (bronchoconstriction= 0%, baseline = 100%) and IC₅₀ (concentration producing 50%inhibition of maximal effect) produced by propofol was obtainedfrom each concentration–response curve using a curve-fittingprogram. Methacholine decreased bronchial cross-sectional areato 49.3% (95% confidence interval 38.5–60.1%) and 45.3%(34.8–55.7%) of the baseline value. Propofol 20 mg kg^–1significantly reversed this effect: bronchial cross-sectionalarea was reduced to 77.8% (66.2–89.6%) and 75.9% (64.0–87.9)in the control and vagotomy groups respectively. The two groupsdid not differ significantly in the maximal inhibitory effectof propofol [control group, 61.1% (46.3–75.9%), vagotomygroup, 64.2% (40.1–88.3%)] or pIC₅₀ [control group 5.03(4.55–5.51), vagotomy group 4.86 (4.49–5.24)]. Therefore,the relaxant effects of propofol on methacholine-induced bronchoconstrictionmay not be mediated centrally. Propofol may relax airway smoothmuscles directly or through the peripheral vagal pathway. Br J Anaesth 2001; 86: 249–53     

Can isoflurane mimic ischaemic preconditioning in isolated rat heart?

Ischaemic preconditioning can protect the myocardium againstischaemic injury by opening of the adenosine triphosphate (ATP)-sensitivepotassium (K_ATP) channel. Isoflurane is also thought to openthis channel. The present investigation tested the hypothesisthat pre-ischaemic treatment with isoflurane mimics ischaemicpreconditioning (producing chemical preconditioning) and therebyprotects the myocardium against ischaemic injury in an isolatedrat heart model. Control hearts underwent 30 min of globalno-flow ischaemia followed by 60 min of reperfusion. Thehearts of the preconditioning group underwent two 5 minperiods of no-flow ischaemia interspersed with 5 min ofreperfusion before the sustained ischaemia. In three additionalgroups, hearts were subjected to 15 min of 1.5 minimalalveolar concentration (MAC) of isoflurane (ISO-1), 15 min 3MAC (ISO-2) or 25 min 1.5 MAC (ISO-3) of isoflurane followedby 5 min washout before the global ischaemia. Left ventricular(LV) developed pressure and creatine kinase release were measuredas variables of myocardial performance and cellular injury,respectively. Recovery of LV developed pressure was improvedafter ischaemic preconditioning [after 60 min reperfusion,mean 63 (SEM 6)% of baseline] compared with the control group[18 (4)% P<0.01] but not by isoflurane, independently ofconcentration or duration of administration [ISO-1, 17 (2)%,P=0.99 vs control; ISO-2, 12 (3)%, P=0.64; ISO-3, 4 (1)%, P=0.06].Total creatine kinase release over 1 h of reperfusion wasnot significantly different between control [251 (36) U g^–1dry weight] and all isoflurane groups [ISO-1, 346 (24) U g^–1,P=0.30; ISO-2, 313 (33) U g^–1, P =0.73; ISO-3, 407(40) U g^–1, P=0.03]. These results indicate thatpre-ischaemic administration of isoflurane does not cause anaesthetic-inducedpreconditioning in the isolated rat heart. Br J Anaesth 2001; 86: 269–71     

Improvement of 'dynamic analgesia' does not decrease atelectasis after thoracotomy

There is still controversy concerning the beneficial aspectsof ‘dynamic analgesia’ (i.e. pain while coughingor moving) on the reduction of postoperative atelectasis. Inthis study, we tested the hypothesis that thoracic epiduralanalgesia (TEA) prevents these abnormalities as opposed to multimodalanalgesia with i.v. patient controlled analgesia (i.v. PCA)after thoracotomy. Fifty-four patients undergoing thoracotomy(lung cancer) were randomly assigned to one of the two groups.Clinical respiratory characteristics, arterial blood gas, andpulmonary function tests (forced vital capacity and forced expiratoryvolume in 1 s) were obtained before surgery and on the next3 postoperative days. Atelectasis was compared between the twogroups by performing computed tomography (CT) scan of the chestat day 3. Postoperative respiratory function and arterial bloodgas values were reduced compared with preoperative values (mean(SD) FEV₁ day 0: 1.1 (0.3) litre; 1.3 (0.4) litre) but therewas no significant difference between groups at any time. PCAand TEA provided a good level of analgesia at rest (VAS day0: 21 (15/100); 8 (9/100)), but TEA was more effective for analgesiaduring mobilization (VAS day 0: 52 (3/100); 25 (17/100)). CTscans revealed comparable amounts of atelectasis (expressedas a percentage of total lung volume) in the TEA (7.1 (2.8)%)and in the i.v. PCA group (6.71 (3.2)%). There was no statisticaldifference in the number of patients presenting with at leastone atelectasis of various types (lamellar, plate, segmental,lobar). Br J Anaesth 2001; 87: 564–9     

Loss of volition and pain response during induction of anaesthesia with propofol or sevoflurane

We compared the time to reach two anaesthetic end-points duringinduction of anaesthesia with a potent inhalation agent (sevoflurane)and an i.v. agent (propofol). We used a method to ensure steadybreathing during inhalation induction, and measured loss oftone in the outstretched arm and loss of response to a painfulstimulus. Thirty-eight female patients (age 39 (9) yr, weight65 (11) kg, and height 165 (8) cm) (mean (SD)) were randomlyallocated to receive either propofol or sevoflurane. The predictedinduction dose of propofol, estimated from age and weight foreach patient, was given at a rate of 1% of the induction doseper second, to a possible maximum of 2.5 times the predictedinduction dose. Sevoflurane was given with an inhaled concentrationof 8%, which was anticipated to cause loss of arm tone within90–120 s. After loss of consciousness, we applied a painfulelectrical stimulus to a finger at 15-s intervals and measuredthe time to loss of motor response. The median times and interquartilevalues for loss of arm tone were 105 (88–121) s for sevofluraneand 65 (58–80) s for propofol. This was equivalent to0.65 of the ED₅₀ of propofol. The time to loss of response topain was 226 (169–300) s for sevoflurane. The variancesof these three measurements were not significantly different,indicating that these dose–response relationships weresimilar. In contrast, only 11 of the patients given propofollost the response to pain after 2.5xED₅₀ had been given. Theseresults support previous evidence of substantial differencesbetween anaesthetic end-points, and show that this evidencecan be obtained using a simple and rapid method. Br J Anaesth 2001; 87: 283–6