Bideshwar Kataria

The pharmacokinetics of propofol in children using three different data analysis approaches.

BackgroundAccurate dosing of propofol in children requires accurate knowledge of propofol pharmacokinetics in this population. Improvement in pharmacokinetic accuracy may depend on the incorporation of individual patient factors into the pharmacokinetic model or the use of population approaches to estimating the pharmacokinetic parameters. We investigated whether incorporating individual subject covariated (e.g., age, weight, and gender) into the pharmacokinetic model improved the accuracy. We also investigated whether the use of a mixed-effects population model (e.g., the computer program NONMEM) improved the accuracy of the pharmacokinetic model beyond the accuracy obtained with models estimated using two simple approaches. MethodsWe studied 53 healthy, unpremedicated children (28 boys and 25 girls) ranging from 3 to 11 yr of age. Twenty children only received an initial loading dose of 3 mg/kg intravenous propofol. In the remaining 33 children, an initial intravenous propofol dose of 3.5 mg/kg was followed by a propofol maintenance infusion. Six hundred fifty-eight venous plasma samples were gathered and assayed for propofol concentrations. Three different regression techniques were used to analyze the pharmacokinetics: the “standard two-stage‘’ approach, the “naive pooled-data‘’ approach, and the nonlinear mixed-effects modeling approach (as implemented in NONMEM). In both the pooled-data and mixed-effects approaches, individual covariates (age, weight, height, body surface area, and gender) were added to the model to examine whether they improved the quality of the fit. Accuracy of the model was measured by the ability of the model to describe the observed concentrations. ResultsThe pharmacokinetics of propofol in children were best described by a three-compartment pharmacokinetic model. There were no appreciable differences among the pharmacokinetics estimated using the two-stage, pooled-data, and mixed-effects approaches. Weight was a significant covariate, and the weight-proportional model was supported by all three regression approaches. The pharmacokinetic parameters of the weight-proportional pharmacokinetic model (pooled-data approach) were: central compartment (V1) = 0.52 1.kg−1 rapid-distribution compartment (V2) = 1.01.kg−1; slow-distribution compartment (V3) = 8.2 1.kg−1; metabolic clearance (Cl1) = 34 ml.kg−1.min−1; rapid-distribution clearance (Cl2) = 58 ml.kg−1.min−1; and slow-distribution clearance (Cl3) = 26 ml.kg−1.min−1. The inclusion of age as an additional covariate of V2 statistically improved the model, but the actual improvement in the fit was small. ConclusionsThe pharmacokinetics of propofol in children are well described by a standard three-compartment pharmacokinetic model. Weight-adjusting the volumes and clearances significantly improved the accuracy of the pharmacokinetics. Adjusting the pharmacokinetics for inclusion of additional patient covariates or using a mixed-effects model did not further improve the ability of the pharmacokinetic parameters to describe the observations.

A comparison of sevoflurane to halothane in paediatric surgical patients: results of a multicentre international study

Induction, emergence and recovery characteristics were compared during sevoflurane or halothane anaesthetic in a large (428) multicentre, international study of children undergoing elective inpatient surgical procedures. Two hundred and fourteen children in each group underwent inhalation induction with nitrous oxide/oxygen and sevoflurane or halothane. Incremental doses of either study drug were added until loss of eyelash reflex was achieved. Steady state concentrations of anaesthesia were maintained until the end of surgery when anaesthetic agents were terminated simultaneously. Time variables were recorded for induction, emergence and the first need for analgesia in the recovery room. In addition, in 86 of the children in both groups, venous blood samples were drawn for plasma fluoride levels during and after surgery. There was a trend toward smoother induction (induction of anaesthesia without coughing, breath holding, excitement laryngospasm, bronchospasm, increased secretion, and vomiting) in the sevoflurane group with faster induction (2.1 min vs 2.9 min, P= 0.037) and rapid emergence times (10.3 min vs 13.9 min, P= 0.003). Among the children given sevoflurane, 2% developed bradycardia compared with 11% in the halothane group. Postoperatively, 46% of the children in the halothane group developed nausea and or vomiting versus 31% in the sevoflurane group (P= 0.002). Two children in the halothane group developed cardiac dysrhythmia and were dropped from the study. In addition, a child in the halothane group developed malignant hyperthermia, received dantrolene, and had an uneventful recovery. Mean maximum inorganic fluoride concentration was 18.3 μM˙l−1. The fluoride concentrations peaked within one h of termination of sevoflurane anaesthetic and returned rapidly to baseline within 48 h. This study suggests that sevoflurane may be the drug of choice for the anaesthetic management of children.

Pharmacodynamics of rocuronium with and without prior administration of succinylcholine

STUDY OBJECTIVES To compare succinylcholine (S) and rocuronium (R) used for endotracheal intubation, and to assess the possible action of S on subsequently administered R. DESIGN Double-blind, randomized, phase III study. SETTING University Medical Center. PATIENTS 24 ASA physical status I and II patients, ages 28 to 65, undergoing general anesthesia for abdominal procedures. INTERVENTION Double-blind administration of R 600 mcg/kg (Group A) or S 1 mg/kg was achieved with open label R 150 mcg/kg. Standardized general anesthetic technique with sodium thiopental, fentanyl, and nitrous oxide in oxygen was administered. MEASUREMENTS AND MAIN RESULTS Neuromuscular junction was tested by ulnar nerve stimulation and mechanomyograph. Intubation was attempted at 80% first twitch depression of train-of-four. Heart rate and blood pressure were recorded throughout. Onset times were 74 +/- 37 seconds for S and 130 +/- 46 seconds for R. Intubation times were 76 +/- 29 seconds for S and 85 +/- 23 seconds for R (no significant difference). Good to excellent intubation conditions were achieved in both groups. S given prior to R decreased onset time and increased duration of R, when compared with R given alone. No drug related cardiovascular events were noted. CONCLUSION Rapid intubation conditions can be obtained after both S and R. Given its overall safety profile, R can be used when S is contraindicated, or in healthy patients with no apparent difficult airway, when procedures are expected to last more than 25 minutes.

Pharmacodynamic effects of three doses of ORG 9426 used for endotracheal intubation in humans

STUDY OBJECTIVE To determine the pharmacodynamic characteristics of three incremental doses of ORG 9426 used for endotracheal intubation in patients. DESIGN Double-blind, randomized administration of one of three doses of intravenous ORG 9426. SETTING Inpatients requiring surgery at Georgetown University Medical Center. PATIENTS Thirty-six patients, ages 18 to 65, ASA physical status I, II, and III, scheduled for general surgery. INTERVENTIONS After Georgetown University Institutional Review Board approval and patient consent, patients were premedicated with midazolam or droperidol. Anesthesia was induced with thiopental sodium and fentanyl. Anesthesia was maintained with 60% nitrous oxide in oxygen. The ulnar nerve was stimulated supramaximally with a 2 Hz train-of-four (TOF) every 20 seconds. Thumb contractions were measured with a force transducer. When TOF and anesthesia were stable, 2, 2.5, or 3 times the ED95 of ORG 9426 (570 micrograms/kg, 710 micrograms/kg, or 850 micrograms/kg) was administered randomly. Tracheal intubation was attempted at maximal depression of the first TOF response (T1). MEASUREMENTS AND MAIN RESULTS The following parameters were measured: time interval from the injection of ORG 9426 to 90% depression of T1 (T1 90% block), maximal T1 depression (onset time), intubating conditions, clinical duration (time for return of T1 to 25% of control), heart rate (HR), blood pressure (BP), and any adverse clinical experience. ORG 9426 provided adequate intubating conditions in all patients but two, independent of the dose used. Its onset time was rapid, but increasing the dose did not shorten the onset. T1 90% block was achieved rapidly (75 +/- 25 seconds to 78 +/- 18 seconds, means +/- SD). The clinical duration of ORG 9426 was relatively short and lengthened with increasing doses (from 36 +/- 18 minutes at 570 micrograms/kg to 42 +/- 10 minutes at 850 micrograms/kg. Spontaneous twitch recovery from 10% to 25% was similar in all dosage groups (5 +/- 1 minutes to 6 +/- 4 minutes). No clinically significant changes in HR and BP and no adverse clinical experiences were noted in any group. CONCLUSION These findings warrant further clinical evaluation of ORG 9426 for induction and maintenance of muscle relaxation in humans.

Evaluation of intravenous esmolol for treatment of postoperative hypertension

The efficacy and safety of intravenous (IV) esmolol to treat postoperative hypertension was studied in 30 adult patients, during emergence and recovery from anesthesia after general surgery. Esmolol was given as an IV infusion when the patient developed systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (OBP) ≥95 mm Hg and heart rate (HR) ≥70 beats/min in the recovery room. Patients received a dose ranging from 100 to 2,104 mg of esmolol. Mean duration of the infusion was 63.6 ± 28.3 minutes. There were statistically significant differences between the control measurements and the end of esmolol titration for SBP, DBP, and HR. Side effects such as HR less than 60 beats/min or a decrease in SBP greater than 25% were observed in 33% (10/30) of the patient population; however, these effects were temporary and self-limiting. Hypotension (SBP β -adrenergic blocker esmolol was 90% (27/30) efficacious (ie, at least a 10% decrease in SBP or DBP) in controlling postoperative hypertension. As a fastacting, short-lasting antihypertensive drug, it joins the armamentarium of other drugs in the treatment of postoperative hypertension during emergence from anesthesia after general surgery.