Impact of peripheral elimination on the concentration-effect relationship of remifentanil in anaesthetized dogs

Background. This study elucidates the impact of sampling sitewhen estimating pharmacokinetic-pharmacodynamic (PK-PD) parametersof drugs such as remifentanil that undergo tissue extractionin the biophase. The interrelationship between the concentrationsof remifentanil predicted for the effect compartment and thosemeasured in arterial, venous, and cerebrospinal fluid were investigatedunder steady-state conditions. Methods. Following induction of anaesthesia with pentobarbital,an arterial cannula (femoral) and two venous catheters (jugularand femoral) were inserted. Electrodes were placed for EEG recordingof theta wave activity. Each dog received two consecutive 5-mininfusions for the PK-PD study and a bolus followed by a 60-mininfusion was started for the steady-state study. Cerebrospinalfluid, arterial and venous blood samples were drawn simultaneouslyafter 30, 40, and 50 min. At the end of the infusion, arterialblood samples were collected for pharmacokinetic analysis. Results. Remifentanil PK-PD parameters based on theta wave activitywere as follows: apparent volume of distribution at steady-state(V_ss) (231±37 ml kg^–1), total body clearance (Cl)(63±16 ml min^–1 kg^–1), terminal eliminationhalf-life (t_1/2ß) (7.71 min), effect compartment concentrationat 50% of maximal observed effect (EC₅₀) (21±13 ng ml^–1),and equilibration rate constant between plasma and effect compartment(k_e0) (0.48±0.24 min). The mean steady-state cerebrospinalfluid concentration of 236 ng ml^–1 represented 52 and74% of that in arterial and venous blood, respectively. Conclusions. Our study re-emphasizes the importance of a samplingsite when performing PK-PD modelling for drugs undergoing eliminationfrom the effect compartment. For a drug undergoing tissue eliminationsuch as remifentanil, venous rather than arterial concentrationswill reflect more exactly the effect compartment concentrations,under steady-state conditions. Declaration of interest. Remifentanil was provided by AbbottLaboratories.     

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.     

Effect of two anaesthetic regimens on airway nitric oxide production in horses

There is evidence that halothane inhibits nitric oxide synthasein vitro, but the effect of intravenous anaesthetic agents isless clear. This study was undertaken to compare the rate ofexhaled nitric oxide production (V_NO) in spontaneously breathinghorses anaesthetized with halothane or an intravenous regimen.Seven adult horses were studied twice in random order. Afterpremedication with romifidine 100 µg kg^–1,anaesthesia was induced with ketamine 2.2 mg kg^–1and maintained with halothane in oxygen (HA) or by an intravenousinfusion of ketamine, guaiphenesin and romifidine (IV). Inhaledand exhaled nitric oxide (NO) concentrations, respiratory minuteventilation (V_E), pulmonary artery pressure (P_PA), fractionalinspired oxygen concentration (FI_O2), end-tidal carbon dioxideconcentration (E'_CO2), cardiac output (Q) and partial pressuresof oxygen and carbon dioxide in arterial blood (Pa_O2, Pa_CO2)were measured. Exhaled nitric oxide production rate was significantlylower (40 min, P<0.01; 60 min, P<0.02) duringHA [40 min, 1.4 (SD 1.4) pmol l^–1 kg^–1 min^–1;60 min, 0.7 (0.7) pmol l^–1 kg^–1 min^–1]than during IV [40 min, 9.3 (9.9) pmol l^–1 kg^–1min^–1; 60 min, 12.5 (13.3) pmol l^–1 kg^–1min^–1). Mean pulmonary artery pressure was significantlyhigher (40 min, P<0.01; 60 min, P<0.001) during HA[40 min, 5.9 (1.1) kPa; 60 min, 5.9 (0.9) kPa] comparedwith IV (40 min, 4.4 (0.4) kPa; 60 min, 4.4 (0.5) kPa].NO is reduced in the exhalate of horses anaesthetized with halothanecompared with an intravenous regimen. It is suggested that increasedmean pulmonary artery pressure during halothane anaesthesiamay be linked to the differences in NO production. Br J Anaesth 2001; 86: 127–30     

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.     

Pharmacokinetics and dynamics of atracurium infusions after paediatric orthotopic liver transplantation{dagger}

We examined the pharmacokinetics and pharmacodynamics of atracuriumbesylate and its metabolites in children after orthotopic livertransplantation (OLT), as a suitable model for critically illchildren. Ten children were studied after OLT on return to theintensive care unit (ICU). The mean (range) age was 36 (7–78)months, and weight 6–24.2 kg. Atracurium was startedat induction of anaesthesia and adjusted in the ICU accordingto clinical need. Neuromuscular block was measured using accelerometry(TOFguard) and the train-of-four (TOF) ratio or count. Arterialplasma samples for atracurium and metabolites taken before,12-hourly during, and at frequent intervals after the infusionwere analysed by HPLC. The mean (range) maximum infusion rateduring steady-state conditions was 1.44 (0.48–3.13) mg kg^–1 h^–1and the duration of infusion 36.9 (22.5–98.4) h. Tachyphylaxiswas not observed. The mean terminal half-life (t_1/2) for atracuriumwas 18.8 (12–32.3) min. The steady-state plasma clearance(CL_ss) was 13.9 (7.9–20.3) ml min^–1 kg^–1and the terminal volume of distribution (V_Z) 390 (124–551)ml kg^–1; both were higher than in adults after successfulOLT. The maximum concentration (C_max) of laudanosine was 1190(400–1890) ng ml^–1 and t_1/2 was 3.9 (1.1–6.7)h. The renal clearance of laudanosine was 0.9 (0.1–2.5) ml min^–1 kg^–1and increased with urine flow, but there was no significantrelationship with serum creatinine. EEG spikes were confirmedin one child only; the corresponding laudanosine C_max was 720 ng ml^–1.Monoquaternary alcohol C_max was 986 (330–1770) ng ml^–1and t_1/2 42.9 (30–57.7) min. Mean recovery time on stoppingthe atracurium infusion to a TOF ratio >0.75 was 23.6 (12–27)min. Atracurium is an effective and safe neuromuscular blockingagent in this population. Laudanosine concentrations are notexcessive if graft function is satisfactory. Br J Anaesth 2000; 85: 850–5     

Effects of xenon anaesthesia on the circulatory response to hypoventilation

Background. Circulatory response to hypoventilation is aimedat eliminating carbon dioxide and maintaining oxygen delivery(DO₂) by increasing cardiac output (CO). The hypothesis thatthis increase is more pronounced with xenon than with isofluraneanaesthesia was tested in pigs. Methods. Twenty pigs received anaesthesia with xenon 0.55 MAC/remifentanil0.5 µg kg^–1 min^–1 (group X, n=10) or isoflurane0.55 MAC/remifentanil 0.5 µg kg^–1min^–1 (groupI, n=10). CO, heart rate (HR), mean arterial pressure (MAP)and left ventricular fractional area change (FAC) were measuredat baseline, after 5 and 15 min of hypoventilation and after5, 15 and 30 min of restored ventilation. Results. CO increased by 10–20% with both anaesthetics,with an equivalent rise in HR, maintaining DO₂ in spite of a20% reduction in arterial oxygen content. Decreased left ventricular(LV) afterload during hypoventilation increased FAC, and thiswas more marked with xenon (0.60–0.66, P<0.05 comparedwith baseline and isoflurane). This difference is attributedto negative inotropic effects of isoflurane. Increased pulmonaryvascular resistance during hypoventilation was found with bothanaesthetics. Conclusion. The cardiovascular effects observed in this modelof moderate hypoventilation were sufficient to maintain DO₂.Although the haemodynamic response appeared more pronouncedwith xenon, differences were not clinically relevant. An increasein FAC with xenon is attributed to its lack of negative inotropiceffects.     

Early recovery after remifentanil-pronounced compared with propofol-pronounced total intravenous anaesthesia for short painful procedures

Background. We compared recovery from high-dose propofol/low-doseremifentanil (‘propofol-pronounced’) compared withhigh-dose remifentanil/low-dose propofol (‘remifentanil-pronounced’)anaesthesia. Methods. Adult patients having panendoscopy, microlaryngoscopy,or tonsillectomy were randomly assigned to receive either propofol-pronounced(propofol 100 µg kg^–1 min^–1; remifentanil0.15 µg kg^–1 min^–1) or remifentanil-pronounced(propofol 50 µg kg^–1 min^–1; remifentanil 0.45µg kg^–1 min^–1) anaesthesia. In both groups,the procedure was started with remifentanil 0.4 µg kg^–1,propofol 2 mg kg^–1, and mivacurium 0.2 mg kg^–1.Cardiovascular measurements and EEG bispectral index (BIS) wererecorded. To maintain comparable anaesthetic depth, additionalpropofol (0.5 mg kg^–1) was given if BIS values were greaterthan 55 and remifentanil (0.4 µg kg^–1) if heartrate or arterial pressure was greater than 110% of pre-anaestheticvalues. Results. Patient and surgical characteristics, cardiovascularmeasurements, and BIS values were similar in both groups. Therewere no differences in recovery times between the groups (timeto extubation: 12.7 (4.5) vs 12.0 (3.6) min, readiness for transferto the recovery ward: 14.4 (4.4) vs. 13.7 (3.6) min, mean (SD)). Conclusions. In patients having short painful surgery, lesspropofol does not give faster recovery as long as the same anaestheticlevel (as indicated by BIS and clinical signs) is maintainedby more remifentanil. However, recovery times were less variablefollowing remifentanil-pronounced anaesthesia suggesting a morepredictable recovery. Br J Anaesth 2003; 91: 580–2     

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.     

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     

Xenon increases total body oxygen consumption during isoflurane anaesthesia in dogs

Background. This study was designed to examine whether the couplingbetween oxygen consumption (V^·O₂) and cardiac output(CO) is maintained during xenon anaesthesia. Methods. We studied the relationship between V^·O₂ (indirectcalorimetry) and CO (ultrasound flowmetry) by adding xenon toisoflurane anaesthesia in five chronically instrumented dogs.Different mixtures of xenon (70% and 50%) and isoflurane (0–1.4%)were compared with isoflurane alone (1.4% and 2.8%). In addition,the autonomic nervous system was blocked (using hexamethonium)to study its influence on V^·_O2 and CO during xenon anaesthesia. Results. Mean (SEM) V^·O₂ increased from 3.4 (0.1) ml kg^–1 min^–1during 1.4% isoflurane to 3.7 (0.2) and 4.0 (0.1) ml kg^–1 min^–1after addition of 70% and 50% xenon, respectively (P<0.05),whereas CO and arterial pressure remained essentially unchanged.In contrast, 2.8% isoflurane reduced both, V^·O₂ [from3.4 (0.1) to 3.1 (0.1) ml kg^–1 min^–1]and CO [from 96 (5) to 70 (3) ml kg^–1 min^–1](P<0.05). V^·O₂ and CO correlated closely during isofluraneanaesthesia alone and also in the presence of xenon (r²=0.94and 0.97, respectively), but the regression lines relating COto V^·_O2 differed significantly between conditions, withthe line in the presence of xenon showing a 0.3–0.6 ml kg^–1 min^–1greater V^·O₂ for any given CO. Following ganglionic blockade,50% and 70% xenon elicited a similar increase in V^·O₂,while CO and blood pressure were unchanged. Conclusions. Metabolic regulation of blood flow is maintainedduring xenon anaesthesia, but cardiovascular stability is accompaniedby increased V^·O₂. The increase in V^·_O2 is independentof the autonomic nervous system and is probably caused by directstimulation of the cellular metabolic rate. Br J Anaesth 2002; 88: 546–54     

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     

Norepinephrine kinetics and dynamics in septic shock and trauma patients

Background. There is considerable variability in the inter-patientresponse to norepinephrine. Pharmacokinetic studies of dopamineinfusion in volunteers and in patients have also shown largevariability. The purpose of this study was to define the pharmacokineticsof norepinephrine in septic shock and trauma patients. Methods. After Ethical Committee approval and written informedfamily consent, 12 patients with septic shock and 11 traumapatients requiring norepinephrine infusion were studied. Norepinephrinedose was increased in three successive steps of 0.1 mg kg^–1min^–1 at 15-min intervals (20% maximum allowed increasein arterial pressure). Arterial blood was sampled before andat 0.5, 13, and 15 min after each infusion rate change and 30s, 1, 2, 5, 10, and 15 min after return to baseline dosing.Norepinephrine was assayed by HPLC. The pharmacokinetics weremodelled using NONMEM (one-compartment model). The effects ofgroup, body weight (BW), gender and SAPS II (Simplified AcutePhysiology Score II) [Le Gall JR, Lemeshow S, Saulnier F. Anew Simplified Acute Physiology Score (SAPS II) based on a European/NorthAmerican multicenter study. J Am Med Assoc 1993; 270: 2957–63]patients score on clearance (CL) and volume of distribution(V) were tested. Results. Group, gender, and BW did not influence CL or V. CLwas negatively related to SAPS II. CL and T_1/2 varied from 3litre min^–1 and 2 min, respectively, when SAPS II=20 to0.9 litre min^–1 and 6.8 min when SAPS II=60. Conclusion. In trauma patients and in septic shock patients,norepinephrine clearance is negatively related to SAPS II.     

Propacetamol augments inhibition of platelet function by diclofenac in volunteers

Background. Acetaminophen (paracetamol) enhances the analgesiceffect of non-steroidal anti-inflammatory drugs (NSAIDs). Acetaminophenis a weak inhibitor of cyclooxygenase (COX), and its combinationwith an NSAID may augment COX inhibition-related side effects. Methods. Ten healthy male volunteers (21–30 yr) were givendiclofenac 1.1 mg kg^–1 alone, a combination of propacetamol30 mg kg^–1 (which is hydrolysed to 50% acetaminophen)and diclofenac 1.1 mg kg^–1 or placebo intravenously ina double blind, crossover study. Platelet function was assessedat 5 min, 90 min and 22–24 h by photometric aggregometry,platelet function analyser (PFA-100^TM) and by measuring therelease of thromboxane B₂ (TxB₂). Analgesia was assessed withthe cold pressor test. Results. Platelet aggregation induced with arachidonic acidwas fully inhibited by both diclofenac alone and the combinationat the end of the 30-min drug infusion. Propacetamol augmentedthe inhibition by diclofenac at 90 min (P=0.014). At 22–24h, platelet function had fully recovered. TxB₂ release was inhibitedby the combination of propacetamol and diclofenac at 90 minin comparison with diclofenac alone (P=0.027). PFA-100^TM detectedno difference in platelet function between these two groups.No analgesic effect was detected with the cold pressor test. Conclusions. The combination of propacetamol and diclofenacinhibits platelet function more than diclofenac alone. Thisshould be considered when assessing the risk of surgical bleeding. Br J Anaesth 2003; 91: 357–62     

EFFECT OF DOBUTAMINE ON OXYGEN SUPPLY AND UPTAKE IN HEALTHY VOLUNTEERS

We have measured the changes in Vo₂ and the Vo₂; D_o2 relationshipduringinfusion of dobutamine in healthy volunteers. Nine healthy,adult, non-obese, male physicians were infused with an incrementalinfusion of dobutamine starting at 2.5 µg kg^–1 min^–1increasing to 5.0 and then 7.5 y.g kg^–1 min^–1 for15 min each. Vo ₂ and cardiac index were measured every fiveminutes. Vo₂/(VO₂ m^–2) increased from a baseline of 128(SEM 6.1) ml min^–1 m^–2 to 159 (8.0)ml min¹ m^–2(P< 0.05) at 7.5 fig kg^–1 min^–1. The correspondingchanges for Do₂l (Do₂m^–2) were from 643 (35) ml min^–1m^–2 to 1240 (142) ml min^–1 m^–2 (P<0.05).The coefficient of correlation for pairs of Vo₂ and DO₂ values,at baseline and each dobutamine infusion in individual subjects,range from 0.89 to 0.99 (mean 0.95, SD 0.03). Dobutamine haspotent calorigenic effects; demonstration of a positive correlationbetween Vo₂ and Do₂ after infusion of dobutamine does not necessarilyimply an underlying tissue oxygen debt.     

Rapacuronium recovery characteristics and infusion requirements during inhalation versus propofol-based anaesthesia

We examined the effect of four maintenance anaesthetics on theneuromuscular blocking activity and spontaneous recovery characteristicsafter a short-term infusion of rapacuronium. Eighty ASA I–IIIadult patients undergoing elective surgery were studied at fourcentres. Anaesthesia was induced with propofol 1.5–2.5 mg kg^–1and fentanyl 1–2 µg kg^–1, followedby a bolus of rapacuronium 1.5 mg kg^–1. Thepatients were randomized to receive either desflurane (2–4%end-tidal, ET), sevoflurane (0.75–1.5% ET), isoflurane(0.4–0.8% ET), or a propofol infusion (75–150 µg kg^–1 min^–1)for maintenance of anaesthesia in combination with nitrous oxide(60–70%) in oxygen. When the first twitch (T₁) of a train-of-fourstimulus (using the TOF Guard^® accelerometer) returned to5%, an infusion of rapacuronium was started at 3 mg kg^–1 h^–1and adjusted to maintain T₁/T₀ at 10%. The duration of infusionlasted between 45 and 60 min, and the average infusionrates of rapacuronium were similar in all groups, ranging from1.6 to 2.5 mg kg^–1 h^–1. There wereno significant differences among the groups in the times forT₁/T₀ to return to 25%, 75% or 90%, or for T₄/T₁ to return to70% and 80% upon discontinuation of the infusion. When potentinhalation anaesthetics are used in clinically relevant concentrationsfor maintenance of anaesthesia, the neuromuscular recovery profileof rapacuronium administered as a variable-rate infusion forup to 1 h is similar to that found with a propofol-basedanaesthetic technique. Br J Anaesth 2000; 85: 302–5     

Glycopyrrolate during sevoflurane-remifentanil-based anaesthesia for cardiac catheterization of children with congenital heart disease

Background. Remifentanil is recommended for use in procedureswith painful intraoperative stimuli but minimal postoperativepain. However, bradycardia and hypotension are known side-effects.We evaluated haemodynamic effects of i.v. glycopyrrolate duringremifentanil–sevoflurane anaesthesia for cardiac catheterizationof children with congenital heart disease. Methods. Forty-five children undergoing general anaesthesiawith remifentanil and sevoflurane were randomly allocated toreceive either saline, glycopyrrolate 6 µg kg^–1or glycopyrrolate 12 µg kg^–1. After induction ofanaesthesia with sevoflurane, i.v. placebo or glycopyrrolatewas administered. An infusion of remifentanil at the rate of0.15 µg kg^–1min^–1 was started, sevofluranecontinued at 0.6 MAC and cisatracurium 0.2 mg kg^–1 wasgiven. Heart rate (HR) and non-invasive arterial pressures weremonitored and noted every minute for the first 10 min and thenevery 2.5 min for subsequent maximum of 45 min. Results. Baseline HR [mean (SD)] of 117 (20) beats min^–1decreased significantly from 12.5 min onwards after startingthe remifentanil infusion in the control group [106 (18) at12.5 min and 99 (16) beats min^–1 at 45 min]. In the groupsreceiving glycopyrrolate, no significant decrease in HR wasnoticed. Glycopyrrolate at 12 µg kg^–1 induced tachycardiabetween 5 and 9 min after administration. Systolic and diastolicarterial pressures decreased gradually, but there were no significantdifferences in the pressures between groups. Conclusion. I.V. glycopyrrolate 6 µg kg^–1 preventsbradycardia during general anaesthesia with remifentanil andsevoflurane for cardiac catheterization in children with congenitalheart disease. Administering 12 µg kg^–1 of glycopyrrolatetemporarily induces tachycardia and offers no additional advantage.     

An investigation to show the effect of lung fluid on impedance cardiac output in the anaesthetized dog

Background. Accumulation of lung fluid in the critically illpatient is believed to attenuate impedance cardiac output (CO_IC)measurements. However, this phenomenon has never been shownexperimentally. Methods. In eight anaesthetized and ventilated dogs (weight15–22 kg) a high-precision flow probe was placed on theascending aorta via a left thoracotomy incision and the directcardiac output (CO_FP) was measured. Simultaneous CO_IC measurementswere made using a RheoCardioMonitor (ACMA, Singapore). Lungoedema was induced by intravenous oleic acid 0.1 mg kg^–1.Lung fluid was assessed by the decrease in basal thoracic impedance(Z_b). Percentage errors between the two methods (CO_IC–CO_FP)were calculated and compared as Z_b decreased at 1 intervals. Results. During the experiment mean Z_b decreased from 35.9 (SD5.2) to 27.8 (6.5) (P=0.0037). This occurred over a periodof 225 (range 112–338) min and Z_b decreased by 1 every51 (22–68) min. The presence of excessive lung fluid wasconfirmed at post-mortem. Before lung oedema was induced, CO_ICwas 1.5 (0.6) litre min^–1 and the corresponding valueof CO_FP was1.5 (0.7) litre min^–1 (data from eight dogs).As Z_b decreased, and lung fluid accumulated, the error betweenCO_IC and CO_FP widened (P<0.0001, ANOVA for repeated measures).Eventually, CO_IC decreased to 0.7 (0.3) litre min^–1 andthe corresponding value of CO_FP was1.2 (0.3) litre min^–1(Z_b=5 , data from six dogs). Mean arterial pressure, centralvenous pressure and systemic vascular resistance were kept constant. Conclusion. The presence of lung fluid attenuates CO_IC measurementswith respect to CO_FP.     

Differential effects of thiopental on methacholine- and serotonin-induced bronchoconstriction in dogs

Background. Thiopental sometimes causes bronchospasm duringinduction of anaesthesia. In addition, we have reported previouslythat thiopental produced transient bronchospasm, which was blockedby atropine pretreatment, and worsened histamine-induced bronchoconstrictionin dogs. Previous in vitro reports suggest that synthesis ofcontractile cyclooxygenase products, such as thromboxane A₂,may be involved in the mechanism of bronchospasm. However, thein vivo spastic effects have not been defined comprehensively. Methods. Twenty-seven mongrel dogs were anaesthetized with pentobarbital.Bronchoconstriction was elicited with methacholine (0.5 µg kg^–1+5.0µg kg^–1 min^–1; Mch group, n=7) orserotonin (10 µg kg^–1+1 mg kg^–1 h^–1;5HT group, n=20), and assessed as percentage changes in bronchialcross-sectional area (BCA, basal=100%) using a bronchoscope.In the 5HT group, dogs were subdivided into four groups of fiveeach: S-5HT, I-5HT, 5HT-S and 5HT-A. In the S-5HT and I-5HTgroups, 30 min before serotonin infusion dogs were given salineand indomethacin respectively at 5 mg kg^–1 i.v. Inall groups, 30 min after bronchoconstrictor infusion started,dogs were given thiopental at doses between 0 (saline) and 20mg kg^–1. In the 5HT-S and 5HT-A groups, dogs weregiven saline or atropine 0.2 mg kg^–1 i.v. 5 min afterthiopental 20 mg kg^–1. Results. Methacholine and serotonin reduced BCA by about 50and 40% respectively. Thiopental 20 mg kg^–1 increasedand decreased BCA by about 20 and 10% in the Mch and 5HT groupsrespectively. Indomethacin and atropine did not attenuate thepotentiation of serotonin bronchoconstriction produced by thiopental. Conclusion. The present study indicates that thiopental mayattenuate or worsen bronchoconstriction induced by muscarinicor serotonin receptor stimulation, respectively. The synthesisof contractile cyclooxygenase products and cholinergic stimulationmay not be involved in the contractile effect of thiopentalon serotonin bronchoconstriction. Br J Anaesth 2003; 91: 379–84     

Pharmacokinetics and clinical efficacy of long-term epidural ropivacaine infusion in children

The clinical efficacy and pharmacokinetics of long-term epiduralropivacaine infusion were investigated in 18 postoperative childrenaged between 0.3 and 7.3 yr. A lumbar or thoracic epiduralcatheter was inserted after the anaesthetic induction. Sixtyminutes following a bolus dose of ropivacaine 1 mg kg^–1,0.2% ropivacaine was infused at a fixed rate of 0.4 mgkg^–1 h^–1 for a mean of 61.3 h (range 36–96 h).Clinical evaluation comprised hourly recording of pain, sedation,motor block, nausea/vomiting, pruritus-scores, Sp_O2, pulse andrespiratory rates, and recording of non-invasive arterial pressureevery 4 h. Total and free plasma concentrations were measuredby high-performance liquid chromatography at 0, 1, 6, 12, 24,36, 48, 72 and 96 h. Analgesia was of high quality andside effects were minor. No clinical signs of local anaesthetictoxicity were seen. Total (100–3189 µg litre^–1)and free (10–56 µg litre^–1) ropivacaineconcentrations were within the range reported to be ‘safe’in previous studies in adults. Mean (95% CI) volume of distributionwas 3.1 litre kg^–1 (2.1–4.2 litrekg^–1), total clearance was 8.5 ml kg^–1 min^–1(5.8–11.1 ml kg^–1 min^–1), free clearancewas 220 ml kg^–1 min^–1 (170–270 mlkg^–1 min^–1) and elimination half-life was 4.9 h(3.0–6.7 h). Br J Anaesth 2000; 85: 347–53 ^* Corresponding author: Department of Anaesthesia and IntensiveCare, Odense University Hospital, DK-5000 Odense C, Denmark     

Treatment of ischaemic left ventricular dysfunction with milrinone or dobutamine administered during coronary artery stenosis in the presence of beta blockade in pigs

Background. This study examines the effects of phosphodiesterasetype III (PDEIII) inhibition vs beta stimulation on global functionof the left ventricle (LV) and systemic haemodynamics in a porcinemodel of acute coronary stenosis with beta blockade. Methods. A total of 18 adult swine were anaesthetized. Micromanometer-tippedcatheters were placed in the ascending aorta and LV. Two pairsof ultrasonic dimension transducers were placed in the subendocardiumon the short axis proximal to a left anterior descending (LAD)artery occluder and the long axis of the LV. Before ischaemia,i.v. esmolol was infused to decrease baseline heart rate (HR)by approximately 25%, and all animals received an esmolol infusion(150 µg kg^–1 min^–1). Ischaemia was producedby reducing the flow in the LAD artery by approximately 80%,from 17(4) to 3(2) ml min^–1. Animals were randomized toreceive (after esmolol) one of the following: no drug, shamonly (Group 1, n=6), control (C); 50 µg kg^–1 i.v.milrinone (Group 2, n=6) followed by 0.375 µg kg^–1min^–1 (M); or incremental doses of dobutamine (Group 3,n=6) every 10 min (5, 10 and 20 µg kg^–1 min^–1)(D). Left ventricular function data obtained included HR, arterialand LV pressures, cardiac output (CO), Emax and dP/dT. Measurementswere taken during five time periods: before ischaemia (at baseline,after esmolol) and every 10 min during ischaemia (at 10, 20and 30 min). Results. The effects of beta blockade and ischaemia had a significantimpact on contractility (Emax) in Group M and myocardial performance(left ventricular end-diastolic pressure, LVEDP) in all groups.Left ventricular function (Emax, CO, LVEDP and SVR) was betterpreserved when milrinone was added in Group M. A moderate doseof dobutamine (10 µg kg^–1 min^–1) increasedCO. Only the high dose (20 µg kg^–1 min^–1)improved contractility (Emax), but at the expense of increasedSVR. Also, LVEDP with either dose of dobutamine remained highand unchanged. Conclusions. From our limited findings, it would appear thatthere may, theoretically, be some benefit for using milrinonein preference to other inotropic drugs in the presence of betablockade. Milrinone administration should be considered in patientswith acute ischaemic LV dysfunction and preexisting beta blockadebefore using other inotropic drugs such as beta stimulants. Presented in part at: the 27th Annual Meeting of the Societyof Cardiovascular Anesthesiologists, May 14–18, 2005,Baltimore, MD, USA (Anesth Analg 2005; 100: 5CA60).