Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma

Background. There are no studies reported on the pharmacokineticsof controlled release morphine (MST) in patients with hepatocellularcarcinoma, the fifth most common cancer in the world. Methods. We have studied the pharmacokinetic profile of MST(30 mg) in 15 patients with liver carcinoma (eight with primarycarcinoma on top of chronic hepatitis C, and seven with secondarymetastatic liver malignancy as a result of other primary) comparedwith our previously published data for 10 healthy controls.Plasma morphine concentrations were measured in venous bloodsamples at intervals up to 12 h by high-pressure liquid chromatography.Total body clearance (Cl) and systemic bioavailability wereestimated using a compartmental method. Results. Morphine bioavailability showed a substantial increasein patients with primary liver and secondary metastatic carcinomathan that of controls (64.8, 62.1, and 16.8%, respectively).The area under the serum concentration–time curve increased4-fold in primary carcinoma (416 [SEM25] µg h^–1litre^–1) and 3-fold (303 [21] µg h^–1 litre^–1)in metastatic liver patients compared with healthy control (92.5[3] µg h^–1 litre^–1). No significant differencewas found in T_max between the two malignant groups but C_maxwas significantly greater in primary liver carcinoma patients.Impaired morphine elimination was noted in primary carcinomaonly (t_1/2 5.99 [0.39] h). Conclusion. Careful administration of morphine is recommendedin patients with liver cancer.     

Cross-tolerance between spinal neostigmine and morphine in the rat

Background. Direct or indirect acting cholinergic muscarinicagonists such as neostigmine, are potent antinociceptives whenadministered intrathecally (i.t.). This study examines whetherspinal neostigmine tolerance and cross-tolerance to spinal morphineoccurs. Methods. Rats (32/group) were implanted with miniosmotic pumpsdelivering either i.t. saline 1 µl h^–1 (S), morphine10 nmol µl^–1 h^–1 (M), or neostigmine 3 nmolµl^–1 h^–1 (N). Latencies (infrared thermalwithdrawal rear paw) were measured daily for 6 days after whichfour animals from each group were given one i.t. challenge doseof morphine (m) 0.1, 1, 10, or 100 nmol, or neostigmine (n)0.3, 3, 10, or 30 nmol. Results. Neostigmine and morphine-infused animals both developedtolerance to spinal neostigmine, but neostigmine-infused animalsshowed no significant cross-tolerance to spinal morphine; meanED₅₀ nmol (CI 95%) dose–response values were Sn 2.6 (1.9–3.5),Mn 15.6 (9.9–24.6)*, Nn 18.7 (11.7–29.8)*, Sm 0.7(0.4–1.1), Nm 1.2 (0.8–2.0), Mm 152 (50–461)*(*significance vs saline infused control group). Conclusion. Thus, unidirectional cross-tolerance from morphineto neostigmine was evident. Previous studies suggest morphinehas a cholinergic mechanism of action partially accounting forits antinociceptive effect, which may explain this observedunidirectional cross-tolerance. Br J Anaesth 2003; 91: 427–9     

Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats

Several lines of evidence suggest that the N-methyl-D-aspartatereceptor (NMDA) and nitric oxide (NO) systems are involved inmorphine tolerance. Cyclooxygenase (COX) inhibitors may alsoplay a role in morphine tolerance by interacting with both systems.In the present study, we examined the effects of the COX inhibitorsN-(2-cyclohexyloxy-4-nitrophenyl) methanesulphonamide (NS-398,selective COX₂ inhibitor) and indomethacin (non-selective COXinhibitor) on the development of antinociceptive tolerance ofmorphine in a rat spinal model. The antinociceptive effect wasdetermined by the tail-flick test. Tolerance was induced byinjection of morphine 50 µg intrathecally (i.t.) twicedaily for 5 days. The effects of NS-398 and indomethacinon morphine antinociceptive tolerance were examined after administeringthese drugs i.t. 10 min before each morphine injection.Neither NS-398 nor indomethacin alone produced an antinociceptioneffect at doses up to 40 µg. NS-398 and indomethacindid not enhance the antinociceptive effect of morphine in naïveand morphine-tolerant rats. However, they shifted the morphineantinociceptive dose–response curve to the left when co-administeredwith morphine during tolerance induction, and reduced the increasein the ED₅₀ of morphine (dose producing 50% of the maximum response)three- to four-fold. Collectively, these findings and previousstudies suggest that COX may be involved in the developmentof morphine tolerance without directly enhancing its antinociceptiveeffect. Br J Anaesth 2000; 85: 747–51 ^* Corresponding author: Department of Anesthesiology, NationalDefense Medical Center and Tri-Service General Hospital, #8Section 3, Tingchow Road, Taipei, Taiwan     

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

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

Influence of acute normovolaemic haemodilution on the dose-response relationship, time-course of action and pharmacokinetics of rocuronium bromide

Background. Acute normovolaemic haemodilution (ANH) is an effectivestrategy for avoiding or reducing allogeneic blood transfusion.We aimed to study its effect on the pharmacological profileof rocuronium. Methods. In two study centres, 28 patients undergoing majorsurgery with ANH were matched with 28 control patients. In thedose–response groups, using the mechanomyograph, neuromuscularblock of six consecutive incremental doses of rocuronium 50µg kg^–1, followed by 300 µg kg^–1, wasevaluated. In the pharmacokinetics groups, serial arterial bloodsamples were withdrawn for rocuronium assay after a single doseof rocuronium 600 µg kg^–1. Results. ANH resulted in a shift to the left of rocuronium dose–responsecurve. Rocuronium effective dose₉₅ (ED₉₅) was 26% lower (P<0.05)in the ANH group [283.4 (92.0) µg kg^–1] comparedwith the control group [383.5 (127.3) µg kg^–1].Times from administration of last incremental dose until 25%of first response of train-of-four (TOF) recovery (Dur₂₅) and0.8 TOF ratio recovery (Dur_0.8) were 28% longer in the ANH group[39.9 (8.4), 66.7 (14.2) min] compared with the control group[31.1 (6.6), 52.1 (15.8) min] (P<0.01, P<0.05), respectively.Volume of distribution was higher (P<0.01), central clearancewas lower (P<0.05) and terminal elimination half-life waslonger (P<0.0001) in the ANH group [234.97 (47.11) ml kg^–1,4.70 (0.94) ml kg^–1 min^–1, 77.29 (12.25) min] comparedwith the control group [181.22 (35.73) ml kg^–1, 5.71 (1.29)ml kg^–1 min^–1, 56.86 (10.05) min, respectively]. Conclusion. ANH resulted in prolongation of rocuronium time-courseof action, thus careful monitoring of neuromuscular block isrecommended in patients who undergo ANH.     

Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery

Background. In this double-blind, randomized, placebo-controlledstudy we compared the effects of three different dose regimensof magnesium on intraoperative propofol and atracurium requirements,and postoperative morphine consumption in patients undergoinggynaecological surgery. Methods. Eighty women were allocated to four equal groups. Thecontrol group received normal saline; magnesium groups received40 mg kg^–1 of magnesium before induction of anaesthesia,followed by i.v. infusion of normal saline, magnesium 10 mgkg^–1 h^–1 or magnesium 20 mg kg^–1 h^–1for the next 4 h. Propofol infusion was targeted to keep bispectralindex values between 45 and 55. Postoperative analgesia wasachieved using PCA with morphine. Results. Magnesium groups required significantly less propofol[mean (SD) 121.5 (13.3), 102.2 (8.0) and 101.3 (9.7) µgkg^–1 min^–1 respectively] than the control group(140.7 (16.5) µg kg^–1 min^–1). Atracurium usewas significantly higher in the control group than magnesiumgroups [0.4 (0.06) vs 0.34 (0.06), 0.35 (0.04), 0.34 (0.06)mg kg^–1 h^–1 respectively]. Morphine consumptionwas significantly higher in control group than magnesium groupson the first postoperative day [0.88 (0.14) vs 0.73 (0.17),0.59 (0.23), 0.53 (0.21) mg kg^–1 respectively]. The heartrate was lower in magnesium groups and 20 mg kg^–1 h^–1infusion group demonstrated the lowest values. Conclusion. Magnesium 40 mg kg^–1 bolus followed by 10mg kg^–1 h^–1 infusion leads to significant reductionsin intraoperative propofol, atracurium and postoperative morphineconsumption. Increasing magnesium dosage did not offer any advantages,but induced haemodynamic consequences.     

Propofol-alfentanil vs propofol-remifentanil for posterior spinal fusion including wake-up test

Background. Wake-up test can be used during posterior spinalfusion (PSF) to ensure that spinal function remains intact.This study aims at assessing the characteristics of the wake-uptest during propofol–alfentanil (PA) vs propofol–remifentanil(PR) infusions for PSF surgery. Methods. Sixty patients with scoliosis and candidates for PSFsurgery were randomly allocated in either alfentanil (PA) orremifentanil (PR) group. After an i.v. bolus of alfentanil 30µg kg^–1 in the PA group or remifentanil 1 µgkg^–1 in the PR group, anaesthesia was induced with thiopentaland atracurium. During maintenance, opioid infusion consistedof alfentanil 1 µg kg^–1 min^–1 or remifentanil0.2 µg kg^–1 min^–1, in the PA group and thePR group, respectively. All patients received propofol 50 µgkg^–1 min^–1. Atracurium was given to maintain therequired surgical relaxation. At the surgeon's request, allinfusions were discontinued. Patients were asked to move theirhands and feet. Time from anaesthetic discontinuation to spontaneousventilation (T₁), and from then until movement of the handsand feet (T₂), and its quality were recorded. Results. The average T₁ and T₂ were significantly shorter inthe PR group [3.6 (2.5) and 4.1 (2) min] than the PA group [6.1(4) and 7.5 (4.5) min]. Quality of wake-up test, however, didnot show significant difference between the two groups studied. Conclusion. Wake-up test can be conducted faster with remifentanilcompared with alfentanil infusion during PSF surgery.     

Efficacy and respiratory effects of low-dose spinal morphine for postoperative analgesia following knee arthroplasty

A randomized, double-blind study of 38 patients undergoing totalknee replacement was undertaken to compare the efficacy andrespiratory effects of low-dose spinal morphine and patient-controlledi.v. morphine against patient-controlled i.v. morphine alone.Patients received either morphine 0.3 mg or saline 0.3 mlwith 0.5% heavy spinal bupivacaine 2–2.5 ml. Respiratoryeffects were measured continuously for 14 h postoperativelywith an Edentec 3711 respiratory monitor. There was an improvementin pain relief in the intrathecal morphine group, with significantlylower median VAS pain scores on movement at 4 h (0 (median0–1.5) vs 5 (1.25–7.75) P<0.01), 12 h (2(1–5) vs 6 (3–8) P<0.01) and 24 h (3 (1–5)vs 5 (3–7) P<0.05) postoperatively, despite using significantlyless patient-controlled morphine (20 mg (10.25–26.25)vs 38.5 mg (27–51) P<0.01) in the first 24 h.There was a small but statistically significant reduction inthe median oxygen saturation (Sp_O2) in the intrathecal morphinegroup 97 (95–99)% compared with the placebo group 99 (97–99)%(P<0.05). Although marked disturbances in respiratory patternwere observed in both groups, none of the patients in the studyhad severe hypoxaemia (Sp_O2 <85% >6 min h^–1)and there was no significant difference in the incidence ofmild (Sp_O2 <94% >12 min h^–1)or moderate (Sp_O2 <90% >12 min h^–1)hypoxaemia or in the incidence of episodes of apnoea or hypopnoeain the two groups. Br J Anaesth 2000; 85: 233–7 ^* Corresponding author     

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.     

Intrathecal morphine and clonidine for coronary artery bypass grafting

Background. After cardiac surgery adequate postoperative analgesiais necessary. We assessed analgesia using intrathecal morphineand clonidine. Methods. In a double-blind randomized study, 45 patients havingcoronary artery bypass graft surgery were allocated randomlyto receive i.v. patient-controlled analgesia (PCA) morphine(bolus, 1 mg; lock-out interval, 7 min) (control group), eitheralone or combined with intrathecal morphine 4 µg kg^–1or with both intrathecal morphine 4 µg kg^–1and clonidine 1 µg kg^–1. Intrathecal injectionswere performed before the induction of general anaesthesia.Pain was measured after surgery using a visual analogue scale(VAS). We recorded i.v. PCA morphine consumption during the24 h after operation. Results. Morphine dosage [median (25th–75th percentiles)]was less in the first 24 h in the patients who were given intrathecalmorphine + clonidine [7 (0–37) mg] than in other patients[40.5 (15–61.5) mg in the intrathecal morphine group and37 (30.5–51) mg in the i.v. morphine group]. VAS scoreswere lower after intrathecal morphine + clonidine compared withthe control group. Time to extubation was less after intrathecalmorphine + clonidine compared with the i.v. morphine group [225(195–330) vs 330 (300–360) min, P<0.05]. Conclusion. Intrathecal morphine and clonidine provide effectiveanalgesia after coronary artery bypass graft surgery and allowearlier extubation. Br J Anaesth 2003; 90: 300–3     

Effects of halothane, sevoflurane and propofol on left ventricular diastolic function in humans during spontaneous and mechanical ventilation

Background. There is limited knowledge of the effects of anaestheticson left ventricular (LV) diastolic function in humans. Our aimwas to evaluate these effects in humans free from cardiovasculardisease. Methods. Sixty patients (aged 18–47 yr) who had no historyor signs of cardiovascular disease were randomized to receivegeneral anaesthesia with halothane, sevoflurane or propofol.Echocardiography was performed at baseline and during spontaneousrespiration at 1 minimum alveolar concentration (MAC) of theinhalational agents or propofol 4 µg ml^–1 (step1), and repeated during positive-pressure ventilation with 1and 1.5 MAC of the inhalational agents or with propofol 4 and6 µg ml^–1 (steps 2A and 2B). Analysis of echocardiographicmeasurements focused on heart rate corrected isovolumic relaxationtime (IVRT_c) and early diastolic peak velocity of the lateralmitral annulus (E_a). Results. IVRT_c decreased from baseline to step 1 in the halothanegroup (82 [95% CI, 76–88] ms and 74 [95% CI, 68–80]ms respectively; P=0.02), remained stable in the sevofluranegroup (78 [95% CI, 72–83] ms and 73 [95% CI, 67–81]ms; n.s.) and increased in the propofol group (80 [95% CI, 74–86]ms and 92 [95% CI, 84–102] ms; P=0.02). E_a decreased inthe propofol group only (18.8 [95% CI, 16.5–19.9] cm s^–1and 16.0 [95% CI, 14.9–17.9] cm s^–1; P=0.003). Fromstep 2A to step 2B, IVRT_c increased further in the propofolgroup (109 [95% CI, 99–121] ms and 119 [95% CI, 99–135]ms; P=0.04) but remained stable in the other two groups. E_adid not change from step 2A to step 2B. Conclusions. Halothane and sevoflurane did not impair LV relaxation,whereas propofol caused a mild impairment. However, the impairmentby propofol was of a magnitude that is unlikely to cause clinicaldiastolic dysfunction.      

Comparison of the role of endothelin, vasopressin and angiotensin in arterial pressure regulation during sevoflurane anaesthesia in dogs

Background. In this study we aimed to clarify the role of endothelinin arterial pressure regulation during anaesthesia with increasingconcentrations of sevoflurane (1–3 MAC) and compare itwith those of vasopressin and angiotensin. Methods. After an awake control period, on different days, sixdogs underwent each of the following four interventions: sevofluraneanaesthesia alone (1–3 MAC), sevoflurane after block ofeither endothelin receptors using tezosentan (3 mg kg^–1followed by 3 mg kg^–1 h^–1), vasopressinV_1a receptors using [d(CH₂)₅Tyr(Me²)]AVP (40 µg kg^--1)or angiotensin receptors using losartan (6 mg kg^–1 h^–1).Plasma concentrations of endothelin, big endothelin, vasopressinand renin were measured. Effects of sevoflurane in the presenceand absence of the respective receptor block were analysed andcompared using analysis of variance for repeated measures (ANOVAfollowed by Fisher’s PLSD (protected least significantdifference) (P<0.05)). Results. Mean arterial pressure decreased in a dose-dependentmanner with sevoflurane during all interventions. At 1 MAC,this decrease was greatest during angiotensin receptor block(mean (SEM), –41 (3) mm Hg), intermediate duringvasopressin and endothelin receptor block (–31 (4) and–30 (2) mm Hg respectively), and least during sevofluranealone (–24 (3) mm Hg). The course of systemic vascularresistance mirrored the course of arterial pressure, while cardiacoutput did not differ between groups. Plasma concentrationsof endothelin, big endothelin and renin did not change duringany intervention, whereas vasopressin concentration increasedfrom     

Effect of prophylactic bronchodilator treatment with i.v. carperitide on airway resistance and lung compliance after tracheal intubation

Background. Lung resistance increases after induction of anaesthesia.We hypothesized that prophylactic bronchodilation with i.v.carperitide before tracheal intubation would decrease airwayresistance and increase lung compliance after placement of thetracheal tube in both smokers and nonsmokers. Methods. Ninety-seven adults aged between 24 and 59 yr wererandomized to receive i.v. normal saline (0.9% saline) (control)or carperitide, 0.2 µg kg^–1 min^–1 throughoutthe study. The 97 patients included smokers and nonsmokers.Thus the patients were allocated to one of the four groups:smokers who received normal saline (n=21), nonsmokers who receivednormal saline (n=27), smokers who received carperitide (n=19)or nonsmokers who received carperitide (n=30). Thirty minutesafter starting normal saline or carperitide infusion, we administeredthiamylal 5 mg kg^–1 and fentanyl 5 µg kg^–1to induce general anaesthesia and vecuronium 0.3 mg kg^–1for muscle relaxation. Continuous infusion of thiamylal 15 mgkg^–1 h^–1 followed anaesthetic induction. Mean airwayresistance (R_awm), expiratory airway resistance (R_awe) and dynamiclung compliance (C_dyn) were determined 4, 8, 12 and 16 min aftertracheal intubation and compared between the four groups. Results. At 4 min after intubation, R_awm and R_awe were higherand C_dyn lower in smokers than in nonsmokers in the controlgroup. R_awm and R_awe were lower and C_dyn higher in smokers inthe carperitide group than in smokers in the control group.R_awm and R_awe were lower in nonsmokers in the carperitide groupthan in nonsmokers in the control group. Conclusions. Marked bronchoconstriction occurred in the controlgroups (smokers and nonsmokers) 4 min after tracheal intubation.Prophylactic treatment with carperitide before induction ofanaesthesia and tracheal intubation was advantageous, particularlyin smokers.     

Comparison of different bolus doses of morphine for patient-controlled analgesia in children

Forty children undergoing appendicectomy were allocated randomlyto receive one of two PCA regimens with morphine. Group B10received bolus doses of 10 µg kg^–1 and group B20received bolus doses of 20 µg kg^–1. In both groupsthere was a lockout interval of 5 min and a background infusionof 4 µg kg^–1 h^–1. Group B20 self-administeredconsiderably more morphine (P < 0.01) than group B10. Therewas no difference between the pain scores of the groups at rest.Group B20 had significantly (P < 0.05) smaller pain scoresduring movement than group B10 and the latter group sufferedsignificantly (P < 0.01) more hypoxaemic episodes than groupB20. There were no differences between the groups in the incidenceof vomiting, excess sedation or the amount of time spent asleepat night. (Br. J. Anaesth. 1994; 72: 160–163)     

Relation between fentanyl dose and predicted EC50 of propofol for laryngeal mask insertion

Background. This study sought to determine the effective concentrationfor 50% of the attempts to secure laryngeal mask insertion (predictedEC_50LMA) of propofol using a target-controlled infusion (Diprifusor^TM)and investigated whether fentanyl influenced these requiredconcentrations, respiratory rate (RR) and bispectral index (BIS). Methods. Sixty-four elective unpremedicated patients were randomlyassigned to four groups (n = 16 for each group) and given saline(control) or fentanyl 0.5, 1 or 2 µg kg^–1.Propofol target concentration was determined by a modificationof Dixon’s up-and-down method. Laryngeal mask airway insertionwas attempted without neuromuscular blocking drugs after equilibrationhad been established for >10 min. Movement was defined aspresence of bucking or gross purposeful muscular movement within1 min after insertion. EC_50LMA values were obtained by calculatingthe mean of 16 patients in each group. Results. Predicted EC_50LMA of the control, fentanyl 0.5, 1 and2 µg kg^–1 groups were 3.25 (0.20), 2.06 (0.55),1.69 (0.38) and 1.50 (0.54) µg ml^–1 respectively;those of all fentanyl groups were significantly lower than thatof control. RR was decreased in relation to the fentanyl doseup to 1 µg kg^–1. BIS values after fentanyl1 and 2 µg kg^–1 were significantly greaterthan in the control and 0.5 µg kg^–1 groups. Conclusions. A fentanyl dose of 0.5 µg kg^–1is sufficient to decrease predicted EC_50LMA with minimum respiratorydepression and without a high BIS value. Br J Anaesth 2004; 92: 238–41     

Effects of sevoflurane and propofol on left ventricular diastolic function in patients with pre-existing diastolic dysfunction

Background. The effects of anaesthetics on left ventricular(LV) diastolic function in patients with pre-existing diastolicdysfunction are not well known. We hypothesized that propofolbut not sevoflurane will worsen the pre-existing LV diastolicdysfunction. Methods. Of 24 randomized patients, 23 fulfilled the predefinedechocardiographic criterion for diastolic dysfunction. Theyreceived general anaesthesia with sevoflurane 1 MAC (n=12) orpropofol 4 µg ml^–1 (n=11). Echocardiographic examinationswere performed at baseline and in anaesthetized patients underspontaneous breathing and under positive pressure ventilation.Analysis focused on peak early diastolic velocity of the mitralannulus (E_a). Results. During spontaneous breathing, E_a was higher in thesevoflurane than in the propofol group [mean (95% CI) 7.0 (5.9–8.1)vs 5.5 (4.7–6.3) cm s^–1; P<0.05], reflectingan increase of E_a from baseline only in the sevoflurane group(P<0.01). Haemodynamic findings were similar in both groups,but the end-tidal carbon dioxide content was more elevated inthe propofol group (P<0.01). During positive pressure ventilation,E_a was similarly low in the sevoflurane and propofol groups[5.3 (4.2–6.3) and 4.4 (3.6–5.2) cm s^–1, respectively]. Conclusions. During spontaneous breathing, early diastolic functionimproved in the sevoflurane but not in the propofol group. However,during positive pressure ventilation and balanced anaesthesia,there was no evidence of different effects caused by the twoanaesthetics.     

Pharmacokinetics of levobupivacaine 0.25% following caudal administration in children under 2 years of age

Background. Levobupivacaine, the S(–)enantiomer of racemicbupivacaine is less cardiotoxic than racemic bupivacaine andthe R(+)enantiomer dexbupivacaine, while retaining similar localanaesthetic properties and potency to racemic bupivacaine. Thepharmacokinetic profiles of the two bupivacaine enantiomersdiffers and that of racemic bupivacaine may be age dependent.We examined the pharmacokinetics of levobupivacaine after itssingle shot caudal epidural administration in children. Methods. An open-label phase 2 study was undertaken to examinethe pharmacokinetics of levobupivacaine 0.25% 2 mg kg^–1in 49 children aged less than 2 yr, after single shot caudalepidural administration. Plasma concentrations were determinedat intervals up to 60 min after caudal injection. Results. Time to peak plasma concentration (T_max) ranged between5 and 60 min (median 30 min) and was reached later in childrenaged less than 3 months (P<0.005). Peak plasma concentration(C_max) ranged between 0.41 and 2.12 µg ml^–1 (median0.80, mean (SD) 0.91 (0.40) µg ml^–1). Conclusion. After the caudal epidural administration of levobupivacaine2 mg kg^–1 in children less than 2 yr of age, C_max waswithin the accepted safe range for racemic bupivacaine. T_maxvaried and occurred later in some children, particularly thoseaged less than 3 months. Sampling in future pharmacokineticstudies in this age group should extend beyond 60 min. Br J Anaesth 2004; 92: 218–22     

Comparison of propofol/remifentanil and sevoflurane/remifentanil for maintenance of anaesthesia for elective intracranial surgery

Background. Propofol and sevoflurane are suitable agents formaintenance of anaesthesia during neurosurgical procedures.We have prospectively compared these agents in combination withthe short-acting opioid, remifentanil. Methods. Fifty unpremedicated patients undergoing elective craniotomyreceived remifentanil 1 µg kg^–1 followed by an infusioncommencing at 0.5 µg kg^–1 min^–1 reducing to0.25 µg kg^–1 min^–1 after craniotomy. Anaesthesiawas induced with propofol, and maintained with either a target-controlledinfusion of propofol, minimum target 2 µg ml^–1 orsevoflurane, initial concentration 2%_ET. Episodes of mean arterialpressure (MAP) more than 100 mm Hg or less than 60 mm Hg formore than 1 min were defined as hypertensive or hypotensiveevents, respectively. A surgical assessment of operating conditionsand times to spontaneous respiration, extubation, obey commandsand eye opening were recorded. Drug acquisition costs were calculated. Results. Twenty-four and twenty-six patients were assigned topropofol (Group P) and sevoflurane anaesthesia (Group S), respectively.The number of hypertensive events was comparable, whilst morehypotensive events were observed in Group S than in Group P(P=0.053, chi-squared test). As rescue therapy, more labetolol[45 (33) vs 76 (58) mg, P=0.073] and ephedrine [4.80 (2.21)vs 9.78 (5.59) mg, P=0.020] were used in Group S. Between groupdifferences in recovery times were small and clinically unimportant.The combined hourly acquisition costs of hypnotic, analgesic,and vasoactive drugs appeared to be lower in patients maintainedwith sevoflurane than with propofol. Conclusion. Propofol/remifentanil and sevoflurane/remifentanilboth provided satisfactory anaesthesia for intracranial surgery.     

Remifentanil infusion in association with fentanyl-propofol anaesthesia in patients undergoing cardiac surgery: effects on morphine requirement and postoperative analgesia

Background. We have prospectively assessed the effects of remifentanilon morphine requirement in the first hour after emerging fromgeneral anaesthesia after elective coronary artery bypass surgeryand in the first 12 h postoperatively, and pain and agitationscores in the first hour after emerging from general anaesthesia. Methods. Twenty patients undergoing off-pump coronary arterybypass surgery, receiving standardized propofol–fentanyl-basedanaesthesia, randomly received infusions of either remifentanil0.1 µg kg^–1 min^–1 (Group R, n=10) or saline(Group S, n=10), each infused at 0.12 ml kg^–1 h^–1.Propofol and trial drug infusion were continued into the postoperativeperiod until the patients were ready to be woken up. Postoperativeanalgesia was provided with morphine infusion commenced immediatelyafter operation, and was additionally nurse controlled on thebasis of a visual analogue scale (VAS) score (0–10). Agitationscore was recorded using a VAS of 0–3. Results. In the first hour after discontinuing propofol andtrial infusion, morphine requirements were significantly higherin the remifentanil group (8.15 (SD 3.59) mg) compared withthe saline group (3.29 (2.36) mg) (P<0.01). There was nodifference in the total morphine given during the period afterstopping propofol or in the total requirement in the first 12h postoperatively. There was no significant difference in eitherpain scores or agitation scores between the two groups. Conclusion. Use of remifentanil is associated with increasedopioid requirement in the first hour after it has been discontinued.