HEPATIC AND EXTRAHEPATIC DISPOSITION OF PROPOFOL IN PATIENTS UNDERGOING CORONARY BYPASS SURGERY

In order to clarify the relative contribution of the liver tothe short term disposition of propofol, hepatic blood flow wasmeasured during induction of anaesthesia with an i.v. bolusdose of propofol 2 mg kg^–1. Total clearance of the drugwas 2390 (SD 340) ml min^–1, hepatic extraction 82% andhepatic clearance 1060 (260) ml min^–1. During the 60-minperiod of observation, hepatic extraction of propofol increasedfrom 79% to 92%. It is concluded that, within 1 h, only 44%of the administered dose is removed by the liver. Consequently,drug accumulation may occur with repeated dosing or infusionof propofol. The increase in extraction results presumably fromslow release of propofol from the soy-bean emulsion. Results presented in part at the 29th Spring Meeting of theGerman Association of Pharmacology, March 8–11, Mainz,FRG. (Abstract (No. 490) in Naunyn-Schmiedebergs Archives ofPharmacology 1988; 337 (Suppl.): R123.)     

PHARMACOKINETICS OF PANCURONIUM IN PATIENTS WITH NORMAL AND IMPAIRED RENAL FUNCTION

Plasma concentrations of pancuronium were measured using a fluorimetricmethod in six patients with normal renal function and sevenpatients in chronic renal failure. A two-compartment open modelwas used in the pharmacokinetic analysis of the data. With thismodel, the clearance of pancuronium was found to be reducedsignificantly in the patients with renal failure, and in theseindividuals the volume of the central (distribution) compartmentwas increased significantly. The clinical implications of thesefindings are discussed.     

DISPOSITION KINETICS OF PANCURONIUM BROMIDE IN PATIENTS WITH TOTAL BILIARY OBSTRUCTION

Plasma concentrations of pancuronium were measured in nine patientsundergoing surgery because of total biliary obstruction. Whencompared with the averaged model-independent pharmacokineticparameters obtained for normal patients, the terminal half-lifeof 270 min was more than twice normal (132 min, P<0.001);the plasma clearance of 59 ml min^–1 was less than halfthe normal rate for pancuronium (123 ml min^–1, P<0.003).These significant alterations to the pharmaco–kineticsof pancuronium were associated with prolongation of neuromuscularblockade. Following a bolus injection of pancuronium 6 mg, therewas a mean time of 114 min (normals 70 min, P <0.05) beforethe evoked twitch response had returned to 5% of the controlvalue. The pattern of urinary excretion of the drug and itsmetabolites did not differ from that of normal patients. Toavoid excessive dosage during prolonged surgery for total biliaryobstruction, it is recommended that supramaximal nerve stimulationbe used to indicate the need for the administration of furtherdoses of pancuronium.     

A PRELIMINARY INVESTIGATION OF THE RENAL AND HEPATIC EXCRETION OF GALLAMINE TRIETHIODIDE IN MAN

The fate of gallamine triethiodide has been investigated inpatients undergoing cholecystectomy with choledochostomy (groupI), pelvic operations (group II) and orthopaedic operations(group III). Following a single i.v. injection of gallamine2.5 mg kg"1 the disappearance of the drug from the serum occurredin three phases with half-lives of less than 5, 30, 138 min,less than 5, 39, 141 and less than 5, 48, 144 min in the respectivegroups. Twenty-four hours after injection the renal excretionof the unchanged drug was 53% (15–100%) of the administereddose in group I, 67% (40–90%) in group II and 95% (89–100%)in group III. The biliary excretion of gallamine appeared tobe negligible in man. The relationship between renal excretionand duration of action of gallamine, and the influence of someintraoperative factors on drug disposition, are discussed. ^*Also at Institute of Anaesthesiology, University Hospital ofNijmegen, and Institute of Clinical and Experimental Anaesthesiology,University Hospital of Groningen.     

腹腔镜在婴幼儿阻塞性黄疸诊治的价值

目的探讨腹腔镜胆道造影技术在婴儿阻塞性黄疸诊治中的应用。方法首先由脐部置入腹腔镜观察及肝脏情况,如果胆囊形态基本正常,通过右肋缘下Trocar孔拖出胆囊底,切开胆囊插管行胆道造影,如果胆囊呈纤维闭锁状态,不能拖出腹腔外则中转进腹手术。结果 25例均利用腹腔镜技术行胆道探查、胆道造影明确诊断,其中胆道闭锁18例、胆汁淤积症4例,3例胆道发育不良,据情况分别行胆道冲洗、胆囊造瘘、胆道重建等手术及肝活检术,所有胆道闭锁患儿均行Kasai手术。结论腹腔镜技术用于阻塞性黄疸的早期鉴别诊断及治疗有较高的临床实用价值,对胆汁淤积的患儿,可免除开腹手术。     

肝静脉阻断技术在紧邻第二肝门部肝肿瘤切除术中的应用

目的评估肝静脉主干血流控制在第二肝门部肿瘤切除中的作用和意义。方法回顾分析2008年1月至2009年9月在我科实施第二肝门部肿瘤切除患者的临床资料,术前肝功能Child-PughA级9例,B级2例,单独阻断肝右静脉6例,左中肝静脉共干3例,阻断肝右静脉+左中肝静脉共干1例,阻断肝右静脉+下腔静脉1例。结果 11例患者术中失血量在300～2000ml,住院天数13.5±2.1天,术中血管阻断时间29±10.1min。术后并发症:胸腔积液1例,胆漏1例,腹水2例。11例患者随访时间2～18月,目前无患者死亡。结论熟练掌握和应用肝静脉主干阻断技术,可以提高复杂肝脏肿瘤切除的安全性。     

PHARMACOKINETICS AND PHARMACODYNAMICS OF VERCURONUIUM IN PATIENTS WITH CHOLESTASIS

pharmacokinetics and pharmacodynamics of vecuronium were studiedin nine surgical patients with cholestasis, and in 14 patientswithout hepatic or renal disease. After the administration ofvecuronium 0.2 mg kg^–1 the plasma concentration of vecuroniumand the degree of neuromuscular blockade were measured. Theplasma clearance of vecuronium was decreased significantly (P< 0.01) from 4.30± 1.56 ml min^–1 kg^–1(mean±SD) in normal patients to 2.36± 0.80 mlmin^–1 kg^–1 in patients with cholestasis. The eliminationhalf-life was of 58±22 min in normal patients and wasprolonged to 98±57 min (P < 0.05) in patients withcholestasis. The total apparent volume of distribution was unchangedin patients with cholestasis. A prolonged neuromuscular blockadeinduced by vecuronium was observed in patients with cholestasis:the duration of effect from injection to 75% recovery of thetwitch height was prolonged from 74 ± 19 min in normalpatients to 111 ± 13 min in patients with cholestasis.The plasma concentration corresponding to 50% recovery fromparalysis did not differ significantly between the two groups.Vecuronium has a prolonged effect in patients with cholestasiswhich is caused by a delay in its elimination.     

PHARMACOKINETICS OF MIVACURIUM N NORMAL PATIENTS AND IN THOSE WITH HEPATIC OR RENAL FAILURE

We have determined the pharmacokinetics and duration of actionof a bolus dose of mivacurium (0.15 mg kg^–1) during isofluraneand nitrous oxide anaesthesia in nine patients with normal renaland liver function, nine patients undergoing cadaveric kidneytransplantation and nine patients undergoing cadaveric livertransplantation. Total plasma concentrations of mivacurium weremeasured for 2.5 h after administration using a high-pressureliquid chromatographic assay. Plasma concentration vs time datafor what were presumed to be the two active mivacurium isomerswere analysed by a non-compartmental method based on statisticalmoments. Neuromuscular block was assessed by measuring the electromyographicevoked response of the adductor pollicis muscle to train-of-fourstimulation of the ulnar nerve. The mean time to recovery of25% neuromuscular transmission, T₂₅, was greater in the patientswith liver failure (57.2 min) than in control patients (18.7min). The volume of distribution at steady rate (Vd^ss) was comparablein the three groups. Patients with impaired liver function hadsignificantly longer mean residence time and smaller plasmaclearance than did patients with renal failure or control patients.There were significant negative correlations between plasmacholinesterase activity and both T₂₅ (r = 0.79) and mean residencetime (x = 0.62)     

HEPATIC DISPOSITION OF METHOHEXITONE IN PATIENTS UNDERGOING CORONARY BYPASS SURGERY

In order to clarify the relative contribution of hepatic metabolismto the short term disposition of metho-hexitone, we have measuredhepatic blood flow during induction of anaesthesia with a 1.5-mgkg^–1 i. v. bolus dose of methohexitone. Median hepaticclearance was 1.01 litre min^–1 and hepatic extraction87%. As a consequence of the high hepatic extraction, the hepaticclearance of methohexitone was closely dependent on hepaticplasma flow. (Br. J. Anaesth. 1992; 69: 478–481)     

THIOPENTONE-NITROUS OXIDE-HALOTHANE ANAESTHESIA AND SUXAMETHONIUM: PRETREATMENT WITH PANCURONIUM AND GALLAMINE

Eighty healthy adult patients randomly allocated to four groupsreceived pancuronium 0.01, 0.015, 0.02 mg kg^–1 or gallamine0.3 mg kg^–1 i.v. 3 min before induction. Just before inductionof anaesthesia, the patients were examined for signs and symptomsof neuromuscular blockade. After induction of anaesthesia withthiopentone, suxamethonium 1.5 mg kg^–1 was administeredi.v. Five minutes later the second dose was injected. No seriousarrhythmia was seen in any of the four groups following therepeated dose of suxamethonium. However, the highest dose ofpancuronium (0.02 mg kg^–1) caused an unacceptably highfrequency of partial neuromuscular blockade.     

CHOLESTASIS AND RENAL FAILURE IN A PATIENT WITH SECONDARY AMYLOIDOSIS

Amyloid, was first described in the 19th century by Virchow, which means starch or cellulose. Extracellular deposition of this unique protein fibrils in tissues, often leading organ dysfunction is known as amyloidosis. In systemic amyloidosis, amyloid fibrils may deposit in different organs including kidneys, heart and liver. Although liver is effected frequently, clinical liver disease is rare. There are a few cases that secondary amyloidosis presented with hepatic involvement and cholestasis which seems to be limited to primary amyloidosis. Hepatic amyloidosis with cholestasis may be a predictor of involvement of other organs and thus of poor prognosis. We report a case of a 67 year old man with renal failure and prominent cholestasis due to AA amyloid deposition in the liver.     

PHARMACOKINETICS OF ATRACURIUM AND ITS METABOLITES IN PATIENTS WITH NORMAL RENAL FUNCTION, AND IN PATIENTS IN RENAL FAILURE

The plasma pharmacokinetic profiles of atracurium and its derivatives,lafdanosine and monoquaternary alcohol, were studied in sixpatients with renal failure after a bolus dose of atracurium0.3–0.4 mg kg^–1. The pharmacokinetics of the derivativesonly were studied in a group of four normal patients receivingatracurium 0.3 mg kg^–1. Measurements of plasma and urineconcentrations were performed by high pressure liquid chromatography.Pharmacokinetics of atracurium were not significantly differentin the renal failure group when compared with those obtainedin a previous study on six normal patients. Although 2–10%of the dose was recovered in the urine of normal patients asunchanged atracurium, and 3–4% as lafdanosine, renal failureproduced no significant differences in plasma pharmacokinetics,with mean plasma elimination half-lives of 20 min for atracurium,234 min for lafdanosine and 39 min for quaternary alcohol. ^*Southend Hospital, Prittlewell Chase, Westcliff-on-Sea, EssexSSO ORY. Upjohn Limited, Fleming Way, Crawley, West Sussex RH10 2NJ.     

BUPRENORPHINE DISPOSITION IN PATIENTS WITH RENAL IMPAIRMENT: SINGLE AND CONTINUOUS DOSING, WITH SPECIAL REFERENCE TO METABOLITES

The disposition of buprenorphine has been studied in two patientgroups to assess the influence of impaired renal function onthe metabolism of buprenorphine and two of its metabolites,buprenorphine-3-glucuronide (B3G) and norbuprenorphine (NorB).A single i.v. dose of 0.3 mg was given to 15 patients (ninewith dialysis-dependent renal failure) undergoing lower abdominalor peripheral body surface surgery. Blood was sampled up to24 h. Concentrations of buprenorphine, B3G and NorB were assayedby a differential radio-immunoassay technique. There were nodifferences in buprenorphine kinetics between anaesthetizedhealthy patients and those with renal impairment: mean eliminationhalf-lives 398 and 239 min; clearance 651 and 988 ml min^–1apparentvolume of distribution at steady state 313 and 201 litre, respectively.Both metabolites were undetectable following the single i.v.dose. In a second group of 20 patients (eight with renal impairment),buprenorphine was administered by continuous infusion for provisionof analgesia and control of ventilation in the ITU (median infusionrate 161 µg h^–1 (range 36–230 µg h^–1)for a median duration of 30 h (2–565 h). Buprenorphineclearance in patients with normal and impaired renal functionwas similar (934 and 1102 ml min^–1, respectively), aswere dose-corrected plasma concentrations of buprenorphine.In patients with renal failure, plasma concentrations of NorBwere increased by a median of four times, and B3G concentrationsby a median of 15 times.     

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].     

SENSITIVITY TO GALLAMINE AND PANCURONIUM WITH SPECIAL REFERENCE TO SERUM PROTEINS

In 100 females undergoing lower abdominal surgery, the requirementof pancuronium (mg/m² body surface) showed no notable correlationwith any serum protein fraction. In a comparable series of 100female patients the requirement of gallamine (mg/m² body surface)displayed a positive correlation with the serum albumin levelboth with diazepam as induction agent (r=0.34) and with thiopentoneas the induction agent (r=0.25). The doses of both relaxantswere 7–8 per cent lower and displayed a lower inter-individualvariation with diazepam compared with thiopentone. It is suggestedthat charge-dissipating ethyl quaternization present in thegallamine molecule is responsible for the correlation of thisrelaxant with the serum albumin level.     

CIRCULATORY EFFECTS OF ATROPINE IN PATIENTS ANAESTHETIZED WITH GALLAMINE TRIETHIODIDE AND NITROUS OXIDE

Circulatory responses to the intravenous injection of acceleratingdoses of atropine sulphate were studied in ten patients anaesthetizedwith nitrous oxide, oxygen and gallamine triethiodide and ventilatedartificially. Small but significant increases in heart rateand cardiac output were accompanied by lowering of total peripheralresistance and circulation time. Arterial pressures, strokevolumes and stroke work were unchanged. Initial heart ratesand pressures were high, due to the use of gallamine, and itis suggested that the control levels of cardiac output werealso high. This would account for the smaller changes seen comparedwith earlier reports of the effect of atropine in patients artificiallyventilated using tubocurarine and in those spontaneously breathingnitrous oxide, oxygen and halothane.     

PHARMACOKINETICS OF ATRACURIUM AND LAUDANOSINE IN PATIENTS WITH HEPATIC CIRRHOSIS

The pharmacokinetic profiles of atracurium and one of its derivatives,laudanosine were studied following an i.v. bolus of atracurium0.6 mg kg^–1 administered to eight patients with hepaticcirrhosis and to seven healthy controls. The central volumeof distribution of atracurium was greater in the patients withcirrhosis (104.6 ml kg^–1) compared with the controls (69.6ml kg^–1) (P < 0.05), as was the total volume of distribution(281.8 ml kg^–1 and 202.1 ml kg^–1, respectively)(P < 0.05). There was no significant difference in the eliminationhalf-life of atracurium between the two groups. The total volumeof distribution of laudanosine was increased in cirrhotic patients(2.68 litre kg^–1) compared with healthy controls (1.97litre kg^–1) (P < 0.05), as was its elimination half-life(277 min in cirrhotic individuals; 168 min in controls) (P <0.05). There was no significant difference in the clearanceof laudanosine between the two groups.     

COMPARISON OF HAEMODYNAMIC EFFECTS OF METOCURINE AND PANCURONIUM IN PATIENTS WITH CORONARY ARTERY DISEASE

The haemodynamic effects of large bolus doses of metocurine0.45 mg kg^–1 and pancuronium 0.1 mg kg^–1 were comparedin patients with coronary artery disease anaesthetized withdiazepam, anileridine and nitrous oxide. Hypotension occurredmore frequently after metocurine and was a result of a decreasein systemic vascular resistance. After pancuronium there wasno increase in arterial pressure or heart rate, but a smallincrease in cardiac index. The decrease in heart rate aftermetocurine was the principal cause of the statistically significantdifference in cardiac index between the two groups. Contraryto previous findings, metocurine did not attenuate circulatoryresponses to tracheal intubation. During surgical stimulation,two of the 10 patients of the pancuronium group developed significantST segment depression and three patients had a rate-pressureproduct greater than 12000mm Hg beat min^–1. However, thedifference in rate-pressure product between the groups was notstatistically significant.     

CARDIAC EFFECTS OF ATROPINE AND GALLAMINE IN PATIENTS RECEIVING SUXAMETHONIUM

Eighty healthy patients were randomly allocated to four groups.Atropine 0.01 mg kg^–1 i.v. (group I), gallamine 0.3 mgkg^–1 i.v. (group II), atropine 0.01 mg kg^–1 i.m.and gallamine 0.3 mg kg^–1 i.v. (group III), or atropine0.01 mg kg^–1 i.v. and gallamine 0.3 mg Lrg^–1 i.v.(group IV) were given before operation. After induction of anaesthesiawith thiopentone, suxamethonium 1 mg kg^–1 was given i.v.The lungs were ventilated with halothane in nitrus oxide inoxygen. Five minutes later the same dose of suxamrthonium wasrepeated. E.c.g. was monitored continuously. No serious bradycardiawas observed following a second injection of suxamethonium inany group. The results suggest that thiopentone protects againstsuxamethonium-induced bradycardia during halothane anaesthesia.     

DISPOSITION OF INFUSIONS OF ATRACURIUM AND ITS METABOLITE, LAUDANOSINE, IN PATIENTS IN RENAL AND RESPIRATORY FAILURE IN AN ITU

A study of plasma atracurium and laudanosine concentrationswas undertaken in 14 critically ill patients who received abolus dose of atracurium 0.6 mg kg^–1 followed by an infusionof 0.6mg kg^–1 h^–1 for a period of 11–47 h.Seven of the patients had normal renal function and seven werein acute renal failure. In both groups plasma concentrationsof atracurium reached a plateau of approximately 1300 ng ml^–1within30 min of the bolus dose. The drug disappeared from the plasmawithin 120 min after discontinuation of the infusion. Therewas no difference between the two groups with respect to thepharmacokinetic parameters derived for atracurium. In the patientswith normal renal function, plasma laudanosine concentrationreached a plateau of apprpximately 1200ng ml^–1 within10h. In patients with renal failure there was a greater variationin the plasma laudanosine concentration: the highest value recordedwas 4300 ng ml^–1. Patients with renal failure had a significantlylonger mean elimination half-life for laudanosine (1418 minv. 375min; P < 0.05) and Vd (4.52 litre kg^–1 v. 240litre kg^–1; P < 0.01) than the patients with normalrenal function. ^*Present address: Southport General Hospital, Scarisbrick NewRoad, Southport, Merseyside PR8 6LF.