The pharmacokinetics of atracurium isomers in vitro and in humans

Atracurium is a mixture of ten isomers. By high-performance liquid chromatography, using acidified methanol as the mobile phase and silica support, it was separated into its three geometrical isomer groups, cis-cis, cis-trans, and trans-trans, which contain three, four, and three isomers, respectively. The clinically available form of atracurium was made up of 58% cis-cis, 36% cis-trans, and 6% trans-trans isomers. In buffered saline, pH 7.4, at 37 degrees C, the half-lives of the three isomer groups were 57.1 +/- 0.9, 59.7 +/- 0.9, and 66.4 +/- 2.7 min, respectively, for the cis-cis, cis-trans, and trans-trans groups. In whole blood, under similar conditions, the three groups showed different behavior. The cis-cis group broke down in a monoexponential manner with a half-life of 23.3 +/- 2.8 min. The cis-trans group showed bi-exponential breakdown with a rapid phase of 2.3 +/- 0.4 min and a slow phase of 22.1 +/- 2.9 min. The trans-trans group decayed rapidly, but, because of the low concentration of this group in the mixture, kinetic parameters could not be obtained. In eight patients, the mean elimination half-life and apparent clearance of the cis-cis group were 20.6 +/- 1.5 min and 5.3 +/- 0.4 ml.kg-1.min-1, respectively. For the cis-trans group, the apparent elimination half-life and clearance were 17.7 +/- 1.8 min and 9.0 +/- 1.0 ml.kg-1.min-1, but these figures require care in interpretation, as this isomer group contains isomers of widely varying rates of decomposition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of the three isomers of mivacurium in health, in end-stage renal failure and in patients with impaired renal function

We have studied the pharmacokinetics of cis-trans, trans-trans and cis- cis mivacurium in nine healthy patients (creatinine clearance 66-133 ml min-1), in seven patients with end-stage renal failure requiring dialysis (creatinine clearance 4-11 ml min-1) and in seven patients with impaired renal function (creatinine clearance 32-49 ml min-1), during thiopentone-fentanyl-midazolam-nitrous oxide-oxygen anaesthesia. Mivacurium chloride was infused at a rate of 15 micrograms kg-1 min-1 for 10 min, 7.5 micrograms kg-1 min-1 for a further 10 min, and then at a rate adjusted to maintain T1/T0 at 5%. The minimum duration of infusion was 60 min (range 60-235 min). The plasma concentration of the three isomers was measured at regular intervals throughout the infusion, and for up to 300 min after the infusion was stopped. Compartmental analysis of the resulting isomer profiles was undertaken: one- and two-compartment models were fitted to derive clearance, volume of distribution and terminal elimination half-life. Clearance of the cis-cis isomer was reduced significantly in the renal failure (median 2.4 (range 2.1-2.6) ml kg-1 min-1) and intermediate renal function groups (2.1 (2.0-2.9) ml kg-1 min-1), compared with healthy patients (3.8 (2.6-4.9) ml kg-1 min-1) (P < 0.01 in each case). There was no significant difference, within the sample size studied, between the clearance of the cis-trans isomer, in health (106 (26-147) ml kg-1 min-1), in renal failure (80 (22-135) ml kg-1 min-1) or with impaired renal function (87 (58-101) ml kg-1 min-1); or of the trans-trans isomer (57 (18-79) ml kg-1 min-1), (47 (16-88) ml kg-1 min-1) and (44 (40-55) ml kg-1 min-1), respectively). Clearance of each isomer correlated significantly with plasma cholinesterase activity (cis-trans, r = 0.55, P < 0.01; trans-trans, r = 0.62, P < 0.01), although this could be demonstrated only in healthy patients for the cis-cis isomer (r = 0.67, P < 0.05). There was no significant difference in the terminal half-lives of any isomer between the groups: cis-cis, healthy (68 (41-204) min), renal failure (80 (55-153) min), impaired renal function (101 (66-157) min); cis-trans, healthy (2.0 (1.3-4.4) min), renal failure (4.3 (2.3-7.8) min), impaired renal function (3.5 (1.4-10.4) min; trans-trans, healthy (2.3 (1.6-8.1) min), renal failure (4.2 (2.4-7.3) min), impaired renal function (13.4 (2.1-50) min). Volume of distribution was similar for each isomer in all three groups. The median infusion rate required to maintain T1/T0 at 5% was significantly increased in the impaired renal function group, at 10.0 micrograms kg-1 min-1, compared with both healthy patients (5.9 micrograms kg-1 min-1) and renal failure patients (5.0 micrograms kg-1 min-1) (P < 0.05 in each case).      

Pharmacokinetics of Mivacurium Isomers and Their Metabolites in Healthy Volunteers after Intravenous Bolus Administration

Background: Previous studies report the pharmacokinetics of mivacurium isomers after an infusion using venous blood sampling. Although the extent of the mivacurium arterial-venous gradient is not known, the sampling site is likely to influence mivacurium pharmacokinetic parameters because the drug is rapidly metabolized as it traverses the circulation. The objectives of this study were (1) to determine the pharmacokinetics of mivacurium isomers in healthy persons after intravenous bolus administration using intensive arterial blood sampling, and (2) to characterize the formation and elimination of mivacurium metabolites in human plasma.

Methods: Eight persons classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled to undergo elective surgery under balanced anesthesia received 0.15 mg/kg mivacurium chloride as an intravenous bolus. Arterial blood samples were collected every 10 s during the first 2 min and at frequent intervals for 4 h thereafter. Plasma concentrations of mivacurium isomers and their metabolites were determined by two stereoselective high-performance liquid chromatographic methods coupled with fluorometric detection and noncompartmental pharmacokinetic parameters.

Results: Mean elimination half-lives of the trans-trans, cis-trans, and cis-cis isomers were 2.4, 2, and 28.5 min, respectively, with corresponding mean plasma clearances of 29.2, 45.7, and 6.7 ml [center dot] min-1 [center dot] kg-1. The volumes of distribution at steady state of the trans-trans, cis-trans, and cis-cis isomers were 0.047, 0.054, and 0.189 l/kg, respectively. Plasma concentrations of monoester and alcohol metabolites peaked 25 s (median) after mivacurium injection, with half-lives in the range of 90 min, except for the cis alcohol metabolite, which was only negligibly and transiently formed.     

Pharmacokinetics and pharmacodynamics of mivacurium in patients phenotypically heterozygous for the usual and atypical plasma cholinesterase variants (UA)

BACKGROUND: Mivacurium is hydrolyzed by plasma cholinesterase (pChe). The purpose of this study was to evaluate the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium in patients phenotypically heterozygous for the usual and the atypical pChe variant (UA). METHODS: Thirty-two patients were included in a dose-response study, in which the patients received one of four doses of mivacurium. An additional bolus dose of mivacurium, to a total of 0.1 mg kg-1, was given followed by a continuous infusion adjusted to maintain 91-99% neuromuscular block. The times to different levels of recovery following the infusion were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Twelve of the patients with an estimated duration of anaesthesia of more than 90 min were (randomly) selected for the pharmacokinetic part of the study. Venous samples were taken for determination of the three isomers of mivacurium. These results were compared with results from a previous study in phenotypically normal patients (UU). RESULTS: The estimated ED50 and ED95 were 24 and 69 microg kg-1, respectively. The median (range) infusion rate was 3.7 microg kg-1 min-1 (1.2-2.9) and the time to a TOF ratio of 0.7 was 29.8 min (16.1-44.8). The median clearances of the cis-cis, cis-trans and trans-trans isomers were 3.7, 29 and 28 ml kg-1 min-1, respectively. The elimination half-lives of the isomers were 45, 6.7 and 6.3 min, respectively. CONCLUSION: In patients heterozygous for the usual and the atypical variant (UA), the potency of mivacurium is higher, the infusion requirements lower and the rate of spontaneous recovery prolonged, compared with phenotypically normal patients. The clearances of the active isomers are significantly lower and the elimination half-lives longer in heterozygous patients than in phenotypically normal patients (UU). The pharmacokinetics of the inactive cis-cis isomer was not affected.     

The Pharmacokinetics and Steady State Pharmacodynamics of Mivacurium in Children

Background: The authors previously showed that children require larger infusion rates of mivacurium than adults to maintain target twitch depression. Here, they determined whether there are differences between children and adults in mivacurium's pharmacokinetic and pharmacodynamic properties.

Methods: Twenty-seven patients aged 1-58 yr were anesthetized with nitrous oxide and isoflurane. Cholinesterase activity and adductor pollicis twitch tension in response to train-of-four stimuli were measured. Mivacurium was infused, targeting 90% twitch depression. When twitch was stably depressed 85%-95% for 10 min with no change in infusion rate for 15 min, plasma was sampled to determine concentrations of mivacurium's stereoisomers. Clearance of the trans-trans (Cltrans-trans) and cis-trans (Clcis-trans) isomers was determined as the mivacurium infusion rate (adjusted for isomer composition) divided by the concentration of that isomer. Using the Hill equation, assuming equipotency of the trans-trans and cis-trans isomers, and ignoring the contribution of the nonpotent cis-cis isomer, the authors estimated the steady state plasma concentration yielding 90% twitch depression, C90. The effect of age on cholinesterase activity, the infusion rate depressing twitch tension by 90% (IR90), C90, Cltrans-trans, and Clcis-trans was determined using linear regression.

Results: Cholinesterase activity, IR90, and C90 did not vary with age. Both Cltrans-trans (r2 = 0.19, P = 0.01) and Cl sub cis-trans (r2 = 0.19, P = 0.02) decreased with age.     

Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs

To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3%, anesthesia was maintained with isoflurane (0.5% in oxygen) and fentanyl (4 micrograms.kg-1.hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5 degrees C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95% twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 micrograms.kg-1.min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 micrograms/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 micrograms/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 micrograms/ml, despite a 90-min duration of liver exclusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacology of laudanosine in dogs

The authors determined the pharmacokinetics (including transfer into cerebrospinal fluid [CSF]) and the cardiovascular and central nervous system (CNS) effects of laudanosine, a metabolite of atracurium. Eight dogs were anesthetized with halothane; blood pressure and a fronto-occipital electroencephalographic lead were monitored. Laudanosine (1 mg . kg-1 iv) was administered as a bolus, and its concentrations in plasma, CSF, urine, and bile were determined by liquid chromatography. Three-compartment modeling of plasma laudanosine concentrations yielded an elimination half-life for laudanosine of 113 +/- 24 min (mean +/- SD) and a clearance of 25 +/- 8 ml . kg-1 . min-1. CSF concentrations of laudanosine were highest 5-10 min after iv injection of laudanosine and ranged in concentration from 208 to 572 ng . ml-1 (i.e., 36-87% of the corresponding plasma concentrations). Unchanged laudanosine was found in urine (0.5-12% of injected dose) and bile (less than 0.1%); metabolites of laudanosine were found in both fluids. After a 6-h sampling period, dogs were hyperventilated with halothane (FIO2 = 0.2) to a PaCO2 of 26-28 mmHg. Laudanosine was then administered 2 mg . kg-1 iv every 5 min. With cumulative doses of 2-8 mg . kg-1, all dogs showed signs of "awakening" from anesthesia. Cumulative doses of 14-22 mg . kg-1 produced seizure activity in all animals. Mean arterial blood pressure decreased significantly to 86% of control levels at 1 min following administration of laudanosine (1 mg . kg-1 iv) and returned to control levels 4 min later.(ABSTRACT TRUNCATED AT 250 WORDS)     

Convulsive effects and pharmacokinetics of laudanosine in the rat

Laudanosine, which is a degradation product of atracurium, is a convulsant drug in the rat. Laudanosine plasma concentrations were measured by high performance liquid chromatography after administration of both laudanosine and atracurium; protein binding and renal excretion of laudanosine were also determined. A continuous laudanosine infusion of 25 mg kg-1h-1, or less, did not cause convulsions. Eight times ED90 for twitch depression of atracurium gave rise to a laudanosine plasma concentration of less than 8 micrograms ml-1. The convulsive plasma-concentration level for laudanosine was over 17 micrograms ml-1 in the rat. The protein binding of laudanosine was 80%. The kidney excreted 15-20% laudanosine. We conclude that convulsive levels of laudanosine will be very unlikely in any species provided that normal atracurium doses are used no matter how long the procedure.     

Pharmacodynamics and atracurium and laudanosine concentrations during a fixed continuous infusion of atracurium in mechanically ventilated patients with acute respiratory distress syndrome

The present study was designed to assess the pharmacodynamics and the plasma levels of atracurium and laudanosine found during a 72-hour fixed rate infusion of atracurium in acute respiratory distress syndrome patients without renal or liver failure. Nine sedated and mechanically ventilated acute respiratory distress syndrome patients without renal or liver failure were paralysed with a bolus of atracurium (1 mg x kg(-1)) followed by a 72-hour continuous infusion (1 mg x kg(-1) x h(-1)). The count of train-of-four (TOF) and TOF ratio were monitored by an accelerograph until full neuromuscular recovery (T4/T1 > or = 0.7). Atracurium and laudanosine concentrations were measured from the onset to four days after cessation of the infusion. An electroencephalogram was recorded daily. Analysis showed that TOF count was always < or = 3 until cessation of the infusion. Following cessation, neuromuscular recovery occurred between 31 and 96 minutes (median value = 45 min). The highest atracurium and laudanosine concentrations ranged from 3.3 to 5.8 microg x ml(-1) and from 3 to 20 microg x ml(-1) respectively. In four patients with renal impairment, the highest laudanosine concentration was > 10 microg x ml(-1). No seizure was recorded. A fixed infusion rate of atracurium in acute respiratory distress syndrome patients provided an effective muscle paralysis with a rapid neuromuscular recovery but can lead to accumulation of laudanosine in patients with renal impairment.     

胸腔镜胸交感神经切断术病人舒芬太尼复合异丙酚麻醉的效果

目的 评价胸腔镜胸交感神经切断术病人舒芬太尼复合异丙酚麻醉的效果.方法 择期行胸腔镜胸交感神经切断术的手汗症病人20例,ASA Ⅰ或Ⅱ级,静脉注射舒芬太尼0.5 μg/kg、异丙酚2.0～2.5 mg/kg和阿曲库铵0.6 mg/kg麻醉诱导,麻醉维持:静脉输注舒芬太尼0.2～0.3 μg·kg-1·h-1、异丙酚2～4 mg·kg-1·h-1,间断静脉注射阿曲库铵0.3 mg/kg.手术结束前30 min舒芬太尼输注速率减至0.1 μg·kg-1·h-1,异丙酚减至1～2 mg·kg-1·h-1.分别于麻醉诱导前(基础状态)、气管插管时、CO2充气时、CO2充气5 min、30min、放气后5min、拔管时记录SP、DP、HR,并于上述时点采集静脉血样,测定血浆皮质醇、醛固酮和血糖浓度,记录自主呼吸恢复时间、呼之睁眼时间和拔管时间.结果 术中SP、DP和HR波动在正常范围内;与基础值比较,血浆皮质醇、醛固酮和血糖浓度升高(P＜0.05),自主呼吸恢复时间、呼之睁眼时间和拔管时间分别为4.5±1.9、6.4±2.7、(12.6±1.5)min.结论 胸腔镜胸交感神经切断术病人舒芬太尼0.1～0.3 μg·kg-1·h-1复合异丙酚1～4mg·kg-1·h-1麻醉能维持血液动力学的稳定,可减轻应激反应.     

Pharmacodynamics and pharmacokinetics of rocuronium in intensive care patients

We have studied dose requirements, recovery times and pharmacokinetics of rocuronium in 32 intensive care patients. After an initial dose of 50 mg, rocuronium was administered as maintenance doses of 25 mg whenever two responses to train-of-four (TOF) stimulation reappeared (bolus group; n = 27) or by continuous infusion to maintain one response in the TOF (infusion group; n = 5). Median requirements for rocuronium were 27.4 (range 14.5-68.3) mg h-1 and 43.7 (30.9-50.3) mg h- 1 in patients in the bolus and infusion groups, respectively. Median total duration of rocuronium administration was 29.0 (12.4-95.5) h and 63.4 (24.0-140.3) h, respectively. Median time from administration of the last bolus dose and end of infusion to recovery of the fourth twitch in the TOF was 100 (45-300) min and 60 (15-155) min, respectively. Arterial blood samples were obtained for up to 10 h after cessation of rocuronium administration, and concentrations of the parent compound and its putative metabolites were measured using high pressure liquid chromatography (HPLC). The plasma concentration profile (n = 12) was described adequately by a two-compartment model. Mean plasma clearance (Cl), steady-state distribution volume (Vss), mean residence time (MRT) and elimination half-life (T1/2 beta) were 3.16 (SD 1.15) ml kg-1 min-1, 769 (334) ml kg-1, 262 (120) min and 337 (163) min, respectively. Recovery times, Vss, MRT, and T1/2 beta differed from previously published data obtained after rocuronium infusion of moderate duration in surgical patients.      

Continuous infusion of atracurium in children

Atracurium infusion requirements were determined in 28 children anesthetized with N2O:O2 narcotic, N2O:O2 halothane (1% inspired), and N2O:O2 enflurane (2% inspired). When the patient was recovering from a bolus dose of 0.4 mg/kg atracurium, a continuous infusion of atracurium was started and the rate was adjusted to maintain 90-99% muscle twitch depression. Patients receiving enflurane anesthesia required atracurium at an infusion rate of 4.9 +/- 0.3 micrograms X kg-1 X min-1 which was a significantly lower rate (P = 0.0001) than those anesthetized with halothane (8.3 +/- 0.4 micrograms X kg-1 X min-1) or with N2O:O2 and narcotic (9.3 +/- 0.5 micrograms X kg-1 X min-1). At the onset of neuromuscular blockade, the twitch response disappeared faster after train-of-four stimulation repeated every 10 s than after single twitch rates of stimulation at 0.1 Hz. In children, during halothane anesthesia after 0.4 mg/kg atracurium, the response of the adductor of the thumb was ablated in 2.0 +/- 0.3 min with train-of-four stimulation, and in 3.7 +/- 0.4 min with single twitch stimulation. The authors recommend the use of a nerve stimulator during continuous infusion of atracurium because of the marked interpatient differences in infusion-rate requirements.     

妇科腹腔镜手术患者右美托咪啶或瑞芬太尼复合七氟醚麻醉效果的比较

目的 比较妇科腹腔镜手术患者使用右美托咪啶复合七氟醚与瑞芬太尼复合七氟醚麻醉的效果.方法 择期拟行妇科腹腔镜手术患者40例,年龄18～64岁,BMI 18～30 kg/m2,ASA分级Ⅰ或Ⅱ级.采用随机数字表法,将患者随机均分为2组(n=20):右美托咪啶复合麻醉组(D组)和瑞芬太尼复合麻醉组(R组).D组和R组麻醉诱导前5 min时静脉输注右美托咪啶0.05μg·kg·min-1或瑞芬太尼0.1μg·kg-1·min-1,10 min后输注速率为右美托咪啶0.3μg·kg-1·h-1,瑞芬太尼0.15μg·kg-1·min-1.麻醉诱导:静脉注射异丙酚1.5～2.0 mg/kg、顺阿曲库铵0.15 mg/kg和芬太尼2 μg/kg,气管插管后行机械通气,维持PET CO2 35～40 mm Hg.麻醉维持:吸人3%七氟醚,并调节其吸入浓度维持Narcotrend指数40～50,气腹开始时静脉注射芬太尼1 μg/kg,按需静脉注射顺阿曲库铵.分别于给药前、气管插管后5 min、气腹10 min和气管拔管后5 min时,抽取颈外静脉血样,测定血清皮质醇、去甲肾上腺素和肾上腺素的浓度,并行血气分析,记录pH值、乳酸和葡萄糖的浓度.记录呼吸恢复时间、睁眼时间、气管拔管时间和定向力恢复时间.记录围术期不良反应的发生情况和术后2 h内镇痛药的使用情况.结果 与R组比较,D组气腹10 min时血清去甲肾上腺素和肾上腺素的浓度降低,呼吸恢复时间缩短,睁眼时间延长,气管拔管期间心动过速、术后寒战和恶心呕吐的发生率降低,术后芬太尼的使用率降低(P＜0.05).结论 妇科腹腔镜手术患者右美托咪啶复合七氟醚麻醉的效果优于瑞芬太尼复合七氟醚.

Abstract：

Objective To compare the efficacy of dexmedetomidine versus remifentanil in combination with sevoflurane for gynecological laparoscopy. Methods Forty ASA Ⅰ or Ⅱ patients aged 18-64 yr with body mass index of 18-30 kg/m2 undergoing gynecological laparoscopy were randomly assigned to one of two groups ( n =20 each): dexmedetomidine group (group D) and remifentanil group (group R). Starting from 5 min before induction of anesthesia, dexmedetomidine was infused at 0.05 μg · kg - 1 · min- 1 in group D and remifentanil at 0.1 μg· kg- 1· min-1 in group R for 10 min, then dexmedetomidine infusion rate was increased to 0. 3 μg· kg-1 · h-1 and remifentanil infusion rate was increased to 0.15 μg· kg-1 · min-1 . Anesthesia was induced with propofol 1.5-2.0 mg/kg and fentanyl 2 μg/kg. Tracheal intubation was facilitated with cis-atracurium 0.15 mg/kg. Anesthesia was maintained with sevoflurane and fentanyl 1 μg/kg and intermittent iv boluses of cis-atracurium. Narcotrend index was maintained at 40-50. Blood sample was taken from external jugular vein for blood gas analysis and determination of serum concentrations of corticosteroid, norepinephrine and epinephrine before administration, at 5 min after intubation, at 10 min of aeroperitoneum and at 5 min after extubation. The pH value and concentrations of lactic acid and glucose were recorded. The time for recovery of spontaneous breathing, eye-opening time, extubation time, orientation time and perioperative side-effects were recorded. Numeric rating scale was used to assess the intensity of pain during 2 h after operation. The analgesics used were also recorded. Results The serum concentrations of norepinephrine and epinephrine were significanfly lower at 10 min of aeroperitoneum, the time for recovery of spontaneous breathing was shorter, eye-opening time longer and the incidence of shivering and nausea and vomiting lower, the percentage of patients requiring rescue opioids lower in group D than in group R ( P ＜ 0.05). Conclusion The efficacy of dexmedetomidine combined with sevoflurane anesthesia is better than remifentanil combined with sevoflurane anesthesia for gynecological laparoscopy.     

Cumulation and reversal with prolonged infusions of atracurium and vecuronium

A randomized, double-blind study was undertaken to compare the tendencies for cumulation, and reversal characteristics of atracurium (ATR) and vecuronium (VEC) when administered by continuous infusion for long surgical procedures under balanced anaesthesia. Eligible subjects were between 50 and 75 yr of age and were free of neuromuscular disease. Patients in the ATR group (n = 25) received a loading dose of atracurium 0.25 mg.kg-1, followed by an infusion initially set at 5.0 micrograms.kg-1.min-1. In the VEC group (n = 25) patients received a loading dose of vecuronium 0.05 mg.kg-1, followed by an infusion at 1.0 microgram.kg-1.min-1. During surgery, the infusions of both ATR and VEC were titrated in increments or decrements of 12.5% to maintain first twitch (T1) suppression of 90-95%. Neuromuscular block was measured by recording the integrated evoked electromyographic response (EMG) of the first dorsal interosseous muscle in response to supramaximal TOF stimuli on the ulnar nerve. The durations of infusion were similar for the two groups (164 +/- 42 and 183 +/- 67 min for ATR and VEC, respectively). The infusion rates of ATR (mean +/- SD) remained between 4.0 +/- 0.7 and 5.0 +/- 1.0 microgram.kg-1.min-1 throughout the study period. In contrast, a progressive decrease (P less than 0.05) in the infusion rate of VEC, from 1.0 to 0.47 +/- 0.13 micrograms.kg-1.min-1, was observed during the study period. The number of adjustments required to maintain 90-95% T1 suppression decreased between the second and fourth hours of administration, but were similar at corresponding times when comparing the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of Propofol Infusions in Critically Ill Neonates, Infants, and Children in an Intensive Care Unit

Background: Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children.

Methods: Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4-6 mg [middle dot] kg-1 [middle dot] h-1 of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography.

Results: A propofol infusion rate of 4 mg [middle dot] kg-1 [middle dot] h-1 achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml [middle dot] kg-1 [middle dot] min-1 and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery.     

Comparative pharmacokinetics of pipecuronium bromide, pancuronium bromide and vecuronium bromide in anesthetized man

The pharmacokinetics of pipecuronium bromide was studied in 9 male patients (ASA class 1-2, 20-65 years of age). Following a single intravenous dose of pipecuronium 0.08 mg.kg-1, plasma levels were measured by capillary gas chromatography. Plasma concentration-time curves were evaluated by fitting the data to a bi-exponential equation. The pharmacokinetic parameters of pipecuronium were compared with those of pancuronium (0.08 mg.kg-1) and vecuronium (0.08 mg.kg-1) previously obtained under the same anesthesia (66% N2O, 33% O2 and 1% halothane). With pipecuronium, following pharmacokinetic parameters were obtained; distribution half-life; T1/2 alpha = 3.9 +/- 0.7 min (mean +/- SEM), elimination half-life; T1/2 beta = 102 +/- 12 min, volume of the central compartment; V1 = 95 +/- 13 ml.kg-1, volume of distribution at steady state; Vdss = 264 +/- 41 ml.kg-1, clearance; Cl = 1.8 +/- 0.2 ml.min-1.kg-1. Microconstants of two-compartment open models (k12, k21, k10) were also calculated. Using Mann-Whitney's U-test, these parameters of pipecuronium were compared with those of pancuronium (n = 3) and vecuronium (n = 4). V1 and Vdss of pipecuronium were significantly larger than those of pancuronium (V1; 38 +/- 12 ml.kg-1 and Vdss; 120 +/- 4 ml.kg-1) (both P less than 0.10). Reflecting the larger central volume of pipecuronium, pipecuronium tended to have a larger clearance than that of pancuroniumu (Cl; 1.1 +/- 0.2 ml.min-1.kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of methohexital given by constant rate intravenous infusion]

The pharmacokinetic characteristics of a constant rate methohexitone infusion were studied in young ASA 1 patients undergoing maxillofacial surgery. They were randomly assigned to two groups; group M patients (n = 7) were given 9 mg.kg-1.h-1 of methohexitone for one hour, and group MF patients (n = 7) 9 mg.kg-1.h-1 of methohexitone with 7 micrograms.kg-1.h-1 of fentanyl, also for one hour. Blood samples for determining methohexitone concentrations were obtained at various times, from before the start of the methohexitone infusion up to 19 h afterwards. In twelve patients, a two-compartment model was appropriate to characterize the decrease of methohexitone concentration; for the other two (one in each group), a three-compartment model was applied. There were no statistically significant differences between the two groups. Elimination half-life in group M was 3.22 +/- 1.96 h, and total plasma clearance 8.54 +/- 2.8 ml.kg-1.min-1. The wide variations in pharmacokinetic parameters between subjects may explain some unpredictable variations in duration of action of methohexitone. Fentanyl did not modify methohexitone pharmacokinetics, which remained of the first order. However, it potentiated the barbiturate's action: extubation was only possible after stopping the infusion for 39.4 min +/- 22 min in group MF, and 15.4 min +/- 6 min in group M (p less than 0.01). At that time, plasma concentrations were respectively 3.12 +/- 0.99 mg.l-1 (group MF) and 5.71 +/- 2.09 mg.l-1 (group M), (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of propofol and isoflurane on the neuromuscular block induced by atracurium]

Speed of onset, duration of action and recovery time for a bolus injection of atracurium were measured in two groups of patients. In group I anaesthesia considered of propofol, fentanyl, nitrous oxide and oxygen mixture. The induction dose of propofol was 2 mg/kg-1 followed by an infusion of 9.0 mg/kg-1/h-1 for first half hour and 4.5 mg/Kg-1/h-1 subsequently. In group II anaesthesia consisted of isoflurane, fentanyl, nitrous oxide and oxygen mixture. Isoflurane was given upon clinical needs. Speed of onset, duration of action, and recovery time for atracurium were measured in the two groups. No statistically significant differences between speed of onset and duration of action between the two groups were found. The recovery period from T1 = 10% to T1 = 70% twitch response was considerably longer with isoflurane (25 min +/- 6) than with propofol (18 min +/- 3) (p less than 0.01). Results obtained suggest that for adequate relaxation during tracheal intubation smaller doses of atracurium are not needed during isoflurane than propofol administration. Because of the longer recovery period of residual neuromuscular blockade during isoflurane anaesthesia decreasing doses of atracurium and careful monitoring of twitch depression tension are also suggested.     

Pharmacokinetics of [Greek small letter epsilon]-aminocaproic Acid in Patients Undergoing Aortocoronary Bypass Surgery

Background: [Greek small letter epsilon]-Aminocaproic acid (EACA) is commonly infused during cardiac surgery using empiric dosing schemes. The authors developed a pharmacokinetic model for EACA elimination in surgical patients, tested whether adjustments for cardiopulmonary bypass (CPB) would improve the model, and then used the model to develop an EACA dosing schedule that would yield nearly constant EACA blood concentrations.

Methods: Consenting patients undergoing elective coronary artery surgery received one of two loading doses of EACA, 30 mg/kg (group I, n = 7) or 100 mg/kg (group II, n = 6) after CPB, or (group III) a 100 mg/kg loading dose before CPB and a 10 mg [middle dot] kg-1 [middle dot] h-1 maintenance infusion continued for 4 h during and after CPB (n = 7). Two patients with renal failure received EACA in the manner of group III. Blood concentrations of EACA, measured by high-performance liquid chromatography, were subjected to mixed-effects pharmacokinetic modeling.

Results: The EACA concentration data were best fit by a model with two compartments and corrections for CPB. The elimination rate constant k10 fell from 0.011 before CPB to 0.0006 during CPB, returning to 0.011 after CPB. V1 increased 3.8 l with CPB and remained at that value thereafter. Cl1 varied from 0.08 l/min before CPB to 0.007 l/min during CPB and 0.13 l/min after CPB. Cl2 increased from 0.09 l/min before CPB to 0.14 l/min during and after CPB. Two patients with renal failure demonstrated markedly reduced clearance. Using their model, the authors predict that an EACA loading infusion of 50 mg/kg given over 20 min and a maintenance infusion of 25 mg [middle dot] kg-1 [middle dot] h-1 would maintain a nearly constant target concentration of 260 [micro sign]g/ml.     

Continuous infusions of atracurium and vecuronium,compared with intermittent boluses of pancuronium: dose requirements and reversal

This study was designed to determine the effect of prolonged infusion on the ease of reversal of atracurium and vecuronium, and whether factors which potentiate the block delayed reversal. In phase one, 40 patients were randomized (double blind) to determine the steady state conditions for atracurium and vecuronium. Fourteen atracurium patients and 17 vecuronium patients were evaluable. The unblinded second phase involved the steady state conditions using halothane or isoflurane and atracurium infusions. The infusion required for 95% twitch depression (TD95) for atracurium was 7.6 +/- 1.1 micrograms.kg-1 x min-1. The requirement for vecuronium changes with time: TD95 at 30 min was 1.01 +/- 0.16, at 60 min 0.89 +/- 0.12 and after 90 min 0.85 +/- 0.17 micrograms.kg-1 x min-1 (P < 0.05). The mean TD95 was 0.94 +/- 0.23 micrograms.kg-1 x min-1. Multivariate regression analysis of the infusion data revealed a vecuronium model predicting TD95 by the duration of infusion (P < 0.05) and weight (P = 0.05). Atracurium TD95 was predicted by age (P = 0.05). The addition of an inhalation agent to atracurium reduced the infusion rate by 2.01 +/- 0.28 micrograms.kg-1 x min-1 (P = 0.0001) for each increase in MAC. The mean reversal times for atracurium with three different anaesthetics and for vecuronium were not different. Reversal of pancuronium blockade, from less profound twitch depression (86.4 vs 95%) took twice as long as for atracurium and vecuronium for which the following predictors were identified: age, weight, duration of infusion, level of blockade, and type of anaesthetic, using a stepwise regression model.(ABSTRACT TRUNCATED AT 250 WORDS)