Continuous infusions of propofol administered to dogs: effects on ICG and propofol disposition

We have studied the effects of stepwise increasing infusionrates of propofol 200–500 µg kg^–1 min^–1on blood concentrations of propofol and the disposition andclearance of a bolus dose of indocyanine green (ICG) 0.5 mgkg^–1 in 10 acutely instrumented dogs. Drug concentrationsand ICG clearance were measured 30 min after each change ofinfusion rate and after reverting for 60 min to the basal propofolinfusion rate. Increasing infusion rates resulted in significantprolongation of the elimination half-life of ICG and decreasein ICG clearance at the largest infusion rate (500 µgkg^–1 min^–1) compared with the basal rate. Similarly,there were greater than predicted blood concentrations of propofolat the largest infusion rate. When the infusion rate revertedto 200 µg kg^–1 min^–1, and continued for 60min, there was a significant difference between the initialblood concentration of propofol at this basal infusion rateand this latter value (P < 0.01). These changes reflect thepersistent myocardial depression observed during the recoveryphase. (Br. J. Anaesth. 1994; 72: 451–455) Presented in part at the Annual Meeting of the American Societyof Anesthesiologists, October 1990, Las Vegas, U.S.A.     

CLEARANCE OF ATRACURIUM AND LAUDANOSINE IN THE URINE AND BY CONTINUOUS VENOVENOUS HAEMOFILTRATION

We have measured the steady state urinary clearances of atracurium,given by constant infusion, and laudanosine in eight patientsundergoing artificial ventilation; all had normal renal function(mean creatinine clearance 81 ml min^–1). Mean (so) urinaryclearance of atracurium was 0.55 (0.5) ml kg^–1 min^–1;that of laudanosine was 0.33 (0.2) ml kg^–1 min^–1.Simultaneous plasma clearances were 7.1 (1.4)ml kg^–1 min^–1and3.8 (1.5) ml kg^–1 min^–1, re-spectively. Notionalhaemofiltration clearances of the two substances were measuredalso in seven critically ill patients with renal and respiratoryfailure undergoing continuous venovenous haemofiltration. Mean(SD) clearances of atracurium and laudanosine in the haemofiltratefluid were 0.11 (0.06) ml kg^–1 min^–1 and 0.09 (0.02)ml kg^–1 min^–1, respectively whilst plasma clearanceswere atracurium 6.7 (1.8) mlkg^–1min^–1 and laudanosine4.5 (1.8) ml kg^–1 min^–1. There were no significantdifferences between the plasma clearances of the drugs in thetwo groups, despite the difference in severity of sickness.Urinary clearance rates of atracurium and laudanosine were approximately8 and 9% of that in the plasma, but the haemofiltration clearanceof both substances was only 2 %. Part of this work was presented at meetings of the AnaestheticResearch Society in April and July, 1990.     

Prevention of postoperative nausea and vomiting by continuous infusion of subhypnotic propofol in female patients receiving intravenous patient-controlled analgesia

In this prospective, randomized, double-blind, placebo-controlledstudy, the use of continuous subhypnotic propofol infusion asan antiemetic in fentanyl intravenous patient-controlled analgesia(i.v. PCA) was investigated during the first 24 h after surgery.One hundred female patients, ASA I–II, aged 20–71yr, undergoing major gynaecological or orthopaedic surgery,were included. Either propofol 10 mg or placebo (1 ml of Intralipid)was given and one of the following five regimens was maintainedfor 24 h: propofol 5, 10, 15 or 20 µg kg^–1 min^–1or Intralipid 1 ml h^–1 as a placebo. Fentanyl i.v. PCAwas started in the postanaesthesia care unit for postoperativeanalgesia. Significantly more of the patients given propofol15 and 20 µg kg^–1 min^–1 experienced no nauseaor vomiting compared with those given placebo (65% and 70% versus25%; P<0.05). Patients given propofol 20 µg kg^–1min^–1 reported more sedation than those in the other groups4 h after surgery (P<0.05). Br J Anaesth 2000; 85: 898–900     

EFFECTS OF DIFFERENT HEPATIC PATHOLOGIES ON DISPOSITION OF ALFENTANIL IN ANAESTHETIZED PATIENTS

We have studied the influence of different hepatic pathologieson the disposition of alfentanil in 23 unpremedicated patients(six healthy control subjects, six patients with liver dysfunctionof alcoholic aetiology and 11 patients with non-alcohol relatedliver disease). All patients received a bolus of alfentanil500 fig i.v. as supplement to 67% nitrous oxide and isofluranein oxygen anaesthesia. Plasma drug concentrations were measuredin venous blood samples at intervals up to 24 h by radio-immunoassayand protein binding was determined by equilibrium dialysis.Kinetic estimates were determined using non-compartmental analysis.Patients with non-alcoholic liver disease had lesser plasmaclearance (114.8 (range 66.8–213.5) ml min^–1) thanthe alcoholic group (158.8 (100.0–220.7) ml min^–1)or controls (187.4 (125.2–269.5) ml min^–1). In allthree groups, there was considerable intersubject variability,with a bimodal distribution in the non-alcoholic group. Thisgroup also had a smaller apparent volume of distribution atsteady state. Mean residence time was prolonged in the alcoholicgroup compared with controls (284.9 (217.8–362.2) minvs 226.8 (201.2–250) min). Protein binding was decreasedin the alcoholic group compared with controls (84.9 (SD 4.2)%vs 89.3 (2.1)%); this was attributable to a lesser plasma a,-acidglycoprotein concentration (0.55 (0.18) g litre^–1 vs 0.89(0.21) g litre^–1). Free drug clearance was reduced inboth liver dysfunction groups compared with controls. ^*Department of Anesthesiology, Bowman-Gray Medical School, WinstonSalem, North Carolina, U.S.A. Department of Anaesthesia, Freeman Hospital, Newcastle uponTyne. Presented in part at the Anaesthetic Research Society meeting,Cardiff July 1989 [1].     

DISPOSITION OF PROPOFOL AT CAESAREAN SECTION AND IN THE POSTPARTUM PERIOD

We have compared the pharmacokinetics of a bolus dose of propofol2 mg kg^–1 in eight patients undergoing Caesarean sectionwith those in eight postpartum patients undergoing sterilizationby mini-laparotomy. The Caesarean section group had a totalbody clearance of (median) 31.5 (range 24.4–53.3) ml min^–1kg^–1, apparent volume of distribution at steady state5.10 (2.46–6.61) litre kg^–1 and mean residence time161 (52.3–251) min; values for the postpartum group were33.8 (21.5–47.2) ml min^–1 kg^–1, 5.17 (3.47–8.09)litre kg^–1 and 163 (92.3–238) min, respectively.The 95% confidence interval for the umbilical venous to maternalvenous ratio of propofol at delivery was 0.62–0.86. Plasmaprotein binding studies showed there was less unbound propofolin maternal plasma (1.28–2.29%) compared with umbilicalplasma (2.08–3.88%) (P<0.01). Neonatal concentrationsof propofol were greater than maternal concentrations at 2 hand were in the range 0.05–0.11 µg ml^–1 at4h.     

PHYSIOLOGICAL DISPOSITION OF I.V. MORPHINE IN SHEEP

In a crossover design study we have measured the total bodyand regional clearances of morphine. Thirteen experiments wereperformed in four conscious sheep that had been prepared previouslywith appropriate intravascular cannulae. Morphine (as sulphatepentahydrate) was infused i.v. at 2.5, 5, 10 and 20 mg h^–1to produce constant blood concentrations. Morphine (base) concentrationswere measured in blood, urine and tissues with a specific HPLCmethod. The mean (SEM) total body clearance of morphine was1.63 (0.21) litre min^–1; this comprised 1.01 (0.10) litremin^–1 clearance by the liver and 0.55 (0.06) litre min^–1by the kidneys. There was no evidence of dose-dependent clearanceor significant extraction of morphine by the lungs, brain, heart,gut or hindquarters at any dose. The kidney clearance of morphinewas greater than the 0.21 (0.06) litre min^–1 renal clearancedetermined from the product of the mean total body clearanceand the 12.3 (2.4)% of the administered dose recovered as unmetabolizedmorphine from 48 h urine collection (P <0.05). It was concludedthat the liver and kidneys account for the majority of morphineclearance, and that the kidneys both excrete and metabolizemorphine. An abstract of this work was presented in part at the Vlth WorldCongress on Pain, April 1990, Adelaide, Australia and publishedin Pain 1990; (Suppl. 5): S175     

Propofol pharmacokinetics in children with biliary atresia

We studied the pharmacokinetics of an i.v. bolus dose of propofol2.5–3.0 mg kg^–1 in eight children (age 4–24months) with biliary atresia and in six control (ASA I) children(age 11–43 months). Blood samples were obtained for 4h after administration of propofol. Blood concentrations ofpropofol were measured by high pressure liquid chromatography.Systemic clearance of propofol (Cl) and volume of distributionat steady state (V^ss) showed a highly significant correlationwith body weight. Propofol Cl and V^ss, normalized for body weight,were similar in children with biliary atresia (mean 37.5 (SD8.3) ml min^–1 kg^–1 and 3.5 (1.6) litre kg^–1,respectively) compared with control children (38.7 (6.8) mlmin^–1 kg^–1 and 2.4 (0.8) litre^–1 kg^–1,respectively). We conclude that in children with biliary atresiathe pharmacokinetics of propofol are similar to those of healthychildren.     

EFFECTS OF PROPOFOL AND OF THIOPENTONE ANAESTHESIA ON THE REGIONAL KINETICS OF PETHIDINE IN THE SHEEP

We have examined the extraction ratios, net fluxes and clearancesof pethidine by the liver, kidneys and hindquarters in sheepbefore, during and after continuous anaesthesia (70 min) withpropofol or thiopentone. Before anaesthesia, the overall meanrespective regional pethidine extraction ratios were 0.98 (SD0.01), 0.20 (0.06) and 0.44 (0.13), the corresponding net fluxeswere 47 (7), 5 (2) and 20 (10)% dose min^–1 and the clearances1.44 (0.22), 0.17 (0.07) and 0.80 (0.39) litre min^–1.During propofol anaesthesia, arterial blood concentrations ofpethidine approximately doubled (P < 0.05), mean pethidinehepatic extraction ratio was unchanged, flux was increased to145 (20)% and clearance decreased to 79 (10)% (P < 0.05)of baseline values; mean pethidine renal extraction ratio, fluxand clearance were 73 (34), 112 (43) and 69 (31)% of baselinevalues; mean hindquarter pethidine extraction ratio decreasedto 65 (25)% (P < 0.05) of baseline values. During thiopentoneanaesthesia, arterial blood concentrations of pethidine approximatelydoubled (P < 0.01), mean pethidine hepatic extraction ratiowas 97 (2)% of baseline values and flux and clearance were unchanged,mean pethidine renal extraction ratios, flux and clerance decreasedto 37 (21), 54 (18) and 27 (19)% (all P < 0.05) of baselinevalues and mean pethidine hindquarter extraction ratio was 81(20)% of baseline values. In spite of only modest changes inhepatic and renal blood flow during anaesthesia, blood concentrationsof pethidine doubled and pethidine kinetics were disturbed forseveral hours after anaesthesia. Overall, however, the changeswere of smaller magnitude and shorter duration than those thathave been described for anaesthesia with the volatile anaestheticagents. ^*Present address: Department of Anaesthesia and Intensive Care,Royal Adelaide Hospital, The University of Adelaide, AdelaideSA 5000, Australia.     

A SHEEP PREPARATION FOR STUDYING INTERACTIONS BETWEEN BLOOD FLOW AND DRUG DISPOSITION: VI: EFFECTS OF GENERAL OR SUBARACHNOID ANAESTHESIA ON BLOOD FLOW AND CHLORMETHIAZOLE DISPOSITION

Blood flow through and chlormethiazole extraction ratios acrosslungs, liver, kidneys and gut were measured in awake unrestrainedsheep (controls) and with the same animals anaesthetized with1.5% halothane or whilst undergoing high thoracic subarachnoidblockade with amethocaine. In the control-drug studies, chlormethiazoleinfused to sub-sedative blood concentrations produced no significantchanges in haemodynamics or in the kinetics of iodohippurate(renal and hepatic blood flows). Chlormethiazole was eliminatedpredominantly by the liver (mean extraction ratio and clearance,respectively, 0.90 and 1.3 litre min^–1) and lungs (0.15;0.6 litre min^–1). Renal clearance was absent or neglible(>0.1 litre min^–1). Because of pulmonary clearance,mean total body clearance was derived from analysis of pulmonaryarterial concentrations. Under general anaesthesia, there weresignificant reductions in mean cardiac output, hepatic and renalblood flow (to 54%, 63% and 43% of control); chlormethiazolemean hepatic extraction ratios and clearance were reduced, respectively,to 82% and 56% of control, and its pulmonary and renal clearanceswere abolished. With subarachnoid anaesthesia there were nosignificant changes in haemodynamics or in chlormethiazole extractionratios or clearances.     

SUFENTANIL DISPOSITION IN PATIENTS UNDERGOING RENAL TRANSPLANTATION: INFLUENCE OF CHOICE OF KINETIC MODEL

We studied the disposition of sufentanil in 10 patients undergoingrenal transplantation, and compared the data with those fromeight healthy anaesthetized patients undergoing lower abdominalsurgery. Patients received sufentanil 2.5 µg kg^–1as part of a balanced anaesthetic technique. Central venousblood samples were collected at intervals up to 600 min, andplasma sufentanil concentrations assayed by radioimmunoassay.Pharmacokinetic parameters were calculated from drug concentration—timeprofiles by extended least squares non-linear regression analysis(ELSFIT) and by a model independent (Ml) approach using AUCand its first moment, AUMC. There were no differences (basedon Ml results) between the two groups for elimination half-life(T^ß) (renal failure: 188 min; anaesthetized controls:195 min), clearance (Cl) (1030 and 1093 ml min^–1) andapparent volume of distribution at steady state (V^ss) (223.0and 215.3 litre). Sufentanil binding to plasma proteins was91.4% in the renal patients and 92.2% in the healthy group (ns).Comparison of kinetic methods showed significant correlationof the individual estimates for T^ß, Cl and V^ss (P< 0.01). The mean absolute differences between methods were:T^ß2.7 min (95%limits: –26.2 to 31.5), Cl 36.5ml min^–1 (–5.5 to 78.4), V^ss –18.4 litre (–47.7to 10.9). When the mean estimate for the two methods ((ELSFIT+ Ml)/2) was compared with the difference, there was no correlationfor the estimates of Cl and V^ss. Ml tended to overestimate clearanceand underestimate volume of distribution. There was a significantrelationship between estimates for elimination half-life, witha slope greater than zero. Presented in part at the Anaesthetic Research Society, BristolMeeting, June 1988.     

SEDATION DURING SPINAL ANAESTHESIA: COMPARISON OF PROPOFOL AND MIDAZOLAM

Propofol and midazolam were compared in 40 patients undergoingorthopaedic surgery under spinal anaesthesia. An infusion ofeither 1% propofol or 0.1% midazolam was given at a rate adjustedto maintain a similar level of sedation. The mean time to reachthis required level was similar in both groups. Quality andease of control of sedation were good in all patients. A meaninfusion rate of 3.63 mg kg^–1 h^–1 was required forpropofol and 0.26 mg kg^–1 h^–1 for midazolam. Immediaterecovery, as judged by ability to open eyes and recall dateof birth, was significantly more rapid following propofol (P< 0.0001). Similarly, restoration of higher mental functionwas significantly faster following propofol, measured by choicereaction time and critical flicker fusion threshold. Amnesiafor the immediate postoperative period was significantly greaterafter midazolam (P = 0.0001). ^*Present address: Department of Anaesthetics, Royal Infirmary,Edinburgh. Present address: Intensive Therapy Unit, Western General Hospital,Edinburgh.     

Pharmacokinetics of the three isomers of mivacurium and pharmacodynamics of the chiral mixture in hepatic cirrhosis

We have studied the pharmokinetics of cis-trans, trans-transand cis-cis mivacurium in 10 healthy subjects and 11 patientswith mild or moderate hepatic cirrhosis, during nitrous oxide-oxygen-isofluraneanaesthesia. Mivacurium 15µgkg^–1 min^–1 wasinfused for 10 min (total dose 0.15 mg kg^–1) and the plasmaconcentration of the three isomers measured at regular intervalsfor 190 min. The electromyographic response to the drug wasalso measured. Compartmental analysis of the resulting isomerprofiles was undertaken: one- and two-compartment models werefitted to derive clearance, volume of distribution and half-life.Clearance of the cis-trans and trans-trans isomers was reducedsignificantly in the cirrhotic compared with the healthy group:cis-trans (median (range)) 44 (15–121) ml kg^–1 min^–1vs 95 (57–213) ml kg^–1 min^–1 (P<0.05);trans-trans 32 (12–64) ml kg^–1 min^–1 vs 70(34–101) ml kg^–1 min^–1 (P<0.05). The differencein the clearance of the cis-cis isomer in the cirrhotic (4.2(2.9–12.1) ml kg^–1 min^–1) compared with thehealthy group (5.2 (2.9–8.9) ml kg^–1 min^–1)was not significant with this sample size. Clearance of eachisomer correlated significantly with plasma cholinesterase activity:cis-trans r = 0.73, P<0.001; trans-trans r=0.69, P<0.001;cis-cis r = 0.48, P<0.05. Terminal half-life was prolongedsignificantly for the cis-trans and trans-trans isomers in thecirrhotic patients compared with the healthy subjects: cis-trans2.5 (1.3–64.6) min vs 1.5 (0.7–2.2) min (P<0.05);trans-trans 11.1 (2.8–36.9) min vs 2.3 (1.2–7.8)min (P<0.001), but was not statistically significant forthe cis-cis isomer: 60.8 (8.7–155) min vs 50.3 (12.6–237)min. Volume of distribution was similar for all three isomersin the healthy and cirrhotic groups. Onset and recovery fromneuromuscular block were slower in the cirrhotic compared withthe healthy group: time to 90% depression of T1/T0 6.8 (5.8–11.5)min vs 5.9 (5.3–10.3) min (P<0.05); recovery index(25–75% recovery of T1/T0) 11.8 (5.6–26.3) min vs7.4 (4.7–9.6) min (P<0.01). There was a significantnegative correlation between all recovery variables and plasmacholinesterase activity.      

Effects of propofol on functional activities of hepatic and extrahepatic conjugation enzyme systems

The effect of propofol on the hepatic and extrahepatic conjugationenzyme systems was assessed in vitro using microsomal and cytosolicpreparations of human liver, hamster kidney, lung and gut. Thefunctional activities of phase-II enzymes, including uridinediphosphate-glucuronosyltransferase (UDPGT), glutathione S-transferase(GST) and N-acetyltransferase (NAT) were evaluated in the presenceof various concentrations of propofol (0.05–1.0 mmol litre^–1),using 1-naphthol, 1-chloro-2,4-dinitrobenzene and p-aminobenzoicacid as substrates respectively. Propofol produced concentration-dependentinhibition of UDPGT activity in human liver microsomes. Propofoldid not produce significant inhibition of human hepatic GSTactivity at concentrations below 1.0 mmol litre^–1. Incontrast, NAT activity was unaffected by propofol 0.05–1.0mmol litre^–1 in human liver cytosolic preparations. Inextrahepatic tissues, hamster renal and intestinal UDPGT activitieswere significantly inhibited by propofol at 0.25–1.0 mmollitre^–1. In these tissues, GST and NAT were unaffectedby propofol at 1.0 mmol litre^–1. Propofol produced differentialinhibition of human liver and hamster extrahepatic conjugationenzymes as a result of different substrate and tissue specificities.The potential interference of the metabolic profile of phase-IIenzymes as a result of inhibition by propofol (especially ofUDPGT and GST) should be considered when using propofol withother drugs for anaesthesia.     

DISPOSITION OF MEPIVACAINE AND BUPIVACAINE ENANTIOMERS IN SHEEP

Mepivacaine and bupivacaine are used clinically as racemic mixturesof enantiomers. In these studies the enantiomers of each agentwere administered separately to sheep by i.v. bolus injectionon separate occasions. Enantioselective disposition was deemedif the R:s ratio of the relevant pharmacokinetic parameter differedsignificantly from unity. Both enantiomers of both agents werecleared principally by the liver; urinary excretion of unmetabolizedagents accounted for < 2% of the doses. For R(–)- andS( +)-mepivacaine. respective mean (SEM) values of parameterswere: total body clearance 1.20 (0.29) litre min^–1 and0.97 (0.20) litre min^–1 (ns); total volume of distribution144 (39) litre and 80 (21) litre (P < 0.05); slow half-life120 (40) min and 84 (22) min (ns); mean hepatic extraction ratio0.50 (0.14) and 0.52 (0.09) (ns); mean hepatic clearance 0.75(0.23) litre min1 and 0.75 (0.18) litre min1 (ns). For R(+)-and s(–)-bupivacaine, respective values were: total bodyclearance 0.77 (0.33) litre m nd 0.53 (0.26) litre min (P<0.05);total volume of distribution 40 (10) litre and 43 (10) litre(ns); slow half-life 57 (10) min and 104 (21) min (P<0.05);mean hepatic extraction ratio 0.46 (0.15) and 0.29 (0.13) (P< 0.05); mean hepatic clearance 0.85 (0.31) litre min and0.54 (0.26) litre min (P < 0.05). Thus there was enantioselectivedistribution of mepivacaine and enantioselective clearance ofbupivacaine, but the magnitude of the effect was relativelysmall. This paper is dedicated to the memory of friend and colleagueDr Peter J. Meffin (1943-1987), who made major contributionsto our knowledge of the disposition of mepivacaine and of otherenantiomeric drugs before his untimely death     

FENTANYL PHARMACOKINETICS IN ANAESTHETIZED PATIENTS WITH CIRRHOSIS

Fentanyl kinetics were studied in patients with cirrhosis andin patients with normal hepatic and renal function undergoingsurgery under general anaesthesia, the latter group served asthe controls. Plasma fentanyl concentrations declined bi-exponentiallyin the controls with an average elimination half-life (T^ß)of 263 mm; total plasma clearance (C7) was 10.8mlmin^–1kg^–1,and total apparent volume of distribution (V^ß) 3 81litre kg^–1. No significant change was observed in patientswith cirrhosis: T( T^ß) was 304mm, Cl 11.3 ml min^–1kg^–1 and V^ß 4.41 litre kg^–1. These datasuggest that the elimination half-life of fentanyl is not primarilyinfluenced by the rate at which it is metabolized in the liver.     

Changes in apparent systemic clearance of propofol during transplantation of living related donor liver

Background. Propofol is used during living-related donor livertransplantation because its metabolism is not greatly affectedby liver failure. However, the pharmacokinetics of propofolduring liver transplantation have not been fully defined. Thepurpose of this study was to evaluate the apparent systemicclearance of propofol during the dissection, anhepatic and reperfusionphases of living-related donor liver transplantation, and toestimate the role of the small intestine and lung as extrahepaticsites for propofol disposition. Methods. Ten patients scheduled for living-related donor livertransplantation were enrolled in the study. Anaesthesia wasinduced with vecuronium 0.1 mg kg^–1 and propofol 2 mgkg^–1, and then maintained by 60% air, 0.5–1.5% isofluranein oxygen and a constant infusion of propofol at 2 mg kg^–1h^–1. Apparent systemic clearance during the dissection,anhepatic and reperfusion phases was calculated from the pseudo-steady-stateconcentration for each phase. Disposition in the small intestinewas determined by measuring arteriovenous blood concentrationin 10 liver transplantation donors. Pulmonary disposition wasdetermined by measuring the arteriovenous blood concentrationin 10 recipients during the anhepatic phase. The data are expressedas mean (SD). Results. Apparent systemic clearances in the dissection, anhepaticand reperfusion phases were 1.89 (SD 0.48) litre min^–1,1.08 (0.25) litre min^–1 and 1.53 (0.51) litre min^–1,respectively. The concentration of propofol in the portal veinwas lower than in the radial artery. The intestinal extractionratio calculated from the concentration in the radial arteryand portal vein was 0.24 (0.12). There were no significant differencesin propofol concentrations between the radial and pulmonaryarteries. Conclusion. Apparent systemic clearance was decreased by     

PHARMACOKINETICS OF ATRACURIUM IN ANAESTHETIZED INFANTS AND CHILDREN

The pharmacokinetics of atracurium were studied in infants andchildren anaesthetized with isoflurane and nitrous oxide inoxygen. There were no significant differences in volume of distribution(area) (139 v. 152 ml kg^–1), clearance (5.1 v. 5.3 mlkg^–1 min^–1), T (2.1 v. 2.0 mim), or T^ß(19.1 v. 20.3 min) between children with normal hepatic andrenal function and those with moderately impaired hepatic functionpresenting for hepatic transplantation. There were significantdifferences in volume of distribution (area) (176 v. 139 mlkg^–1) and in clearance of atracurium (9.1 v.5.1 ml kg^–1min^–1) between infants and children with normal excretoryfunction. In infants the clearance of atracurium in ml m^–1min^–1 (153 v. 133) tended to be greater and the T andT^ß tended to be shorter (1.0 v. 2.0 and 13.6 v. 19.1)than in children with normal excretory function; however, thesetrends did not reach statistical significance. Plasma laudanosineconcentration was around 100 ng ml^–1 greater in patientswith liver disease than in normal children from 15–45min following a bolus of atracurium 0.5 mg kg^–1.     

Volume kinetics of glucose 2.5% solution and insulin resistance after abdominal hysterectomy

Background. We hypothesized that volume kinetics can be usedto predict the rate of infusion of glucose 2.5% solution requiredto yield any predetermined plasma glucose level and degree ofplasma dilution during the postoperative period. Methods. In 15 women, mean age 50 yr (range 37–63), 2days after an abdominal hysterectomy, a volume kinetic analysiswas performed on an i.v. infusion of 12.5 ml kg^–1 (900ml) of glucose 2.5% given over 45 min. The insulin resistancewas measured by a glucose clamp, and it was compared with dailybioimpedance analyses, which indicated the hydration of theintra/extracellular body fluid spaces. Results. The clearance of glucose was 0.42 litre min^–1(0.60 litre min^–1 is normal) while the other five parametersin the kinetic model were similar to those obtained in healthyvolunteers. Computer simulations indicated that in a 70-kg female,at steady state, the rate of infusion (ml min^–1) shouldbe three times the allowed increase in plasma glucose (mmollitre^–1). To maintain a predetermined plasma dilutionthe corresponding rate factor was 160. The glucose uptake duringclamping was 3.9 mg kg^–1 min^–1 (7.0 is normal),which, during the second day after hysterectomy, correlatedwith the dehydration of the intracellular space (r=0.77; P<0.002)and with the protein catabolism as indicated by the urinaryexcretion of 3-methylhistidine (r=–0.76, P<0.002). Conclusion. The anaesthetist can prescribe postoperative administrationof glucose 2.5% to reach any desired plasma glucose level anddilution by using the two presented nomograms. Insulin resistancecorrelated with intracellular dehydration and protein catabolism.     

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).     

EFFECT OF ANAESTHETIC AGENTS ON BILE FLOW AND BILIARY EXCRETION OF 131I- CHOLYLGLYCYLTYROSINE IN THE RAT

We have compared in the rat the effects of i.v. anaestheticagents on bile flow rate and on the biliary excretion of a novelbile acid, ^131l-cholylglycyltyrosine (¹³¹l-cholylgly.tyr.).Etomidate 1-mg bolus and 2-mg h^–1 infusion, Althesin 3-mgbolus and 14.5-mg h^–1 infusion and propofol 3.3-mg bolusand 3.3-mg h^–1 were given via a tail vein cannula andpentobarbitone 50 mg kg^–1 was given by the intraperitonealroute, to groups of six rats. Each animal received only oneanaesthetic agent. One hour after cannulation of the commonbile duct, ¹³¹l-cholylgly.tyr. 5 µCi was injected intothe jugular vein and bile was collected every 1 min for 10 min.The mean (SD) percentage cumulative biliary excretion of ¹³¹l-cholylgly.tyr.at the end of 10 min was: propofol group 74.1 (5.2)% Althesingroup 82.3 (2.2)%; etomidate group 69.4 (17.6)%; pentobarbitonegroup 76.4 (3.2)%. Propofol and Althesin were relatively morecholeretic, causing bile flow rates twice that produced by pentobarbitone.Only Althesin caused a significant increase in biliary excretionof ¹³¹l-cholylgly.tyr. relative to that in rats that receivedpentobarbitone. Bile flow rates for the respective anaesthetictechniques (µl min^–1/100 g body weight) (mean (SD))were: propofol group 14.1 (1.8); Althesin group 12.5 (1.7);etomidate 8.5 (1.4); pentobarbitone group 7.3 (1.0). There wasa marked metabolic acidosis in all rats except in the propofolgroup, in which normal acid-base status and oxygenation wereobserved. Previously presented at the Medical Research Society and published(abstract form) in Clinical Science and Molecular Medicine 1986;71: 71–72.