Dawn Lea

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.

Sufentanil and alfentanil pattern of consumption during patient-controlled analgesia: a comparison with morphine.

Pattern of drug consumption and side effects of sufentanil and alfentanil were compared to morphine, using “on-demand” patient-controlled analgesia (PCA). After a non-narcotic general anesthetic, a bolus dose of the narcotic was given intravenously towards the end of surgery. PCA was started in the recovery room. Data were retrieved postoperatively for a total of 24h. Results showed a wide range of pattern of drug consumption and uniform acceptance of therapy by the nurses and the patients in all the groups. The frequency of use of incremental dose was > 2–2.5-fold for the sufentanil and alfentanil groups, respectively, compared with morphine. The bolus dose of the narcotics failed to achieve adequate analgesia for 2h for morphine and sufentanil and for 6h for alfentanil. Overall patients were most sedated with sufentanil. At the time intervals sampled, there was a higher incidence of oxygen desaturation—less < 95% with morphine and alfentanil, compared with sufentanil. There was similar incidence of nausea in all the groups. Further study is needed to determine precisely the best dose regimens for Sufentanil appears to be a promising drug for PCA use.

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.

Cerebral blood flow measurements during blood pressure control with intravenous labetalol following craniotomy.

Cerebral blood flow measurements using a thermal diffusion technique were made in conjunction with an extensive cardiovascular evaluation, during and after administration of intravenous labetalol given for blood pressure control in craniotomy patients. Eighteen patients, ages 30-65 years, ASAII and III, scheduled for elective craniotomy, became hypertensive during emergence and recovery from a pentothal/fentanyl/vecuronium/N2O/isoflurane general anesthesia. Labetalol was administered in a stepwise manner every 10 minutes during an average period of 1 h. After this titration period, an 8-h maintenance period followed. During titration and maintenance periods, comprehensive systemic hemodynamic parameters were collected through intra-arterial and flow-directed pulmonary artery catheters. Cerebral cortical blood flow (CBF) was continuously recorded using a thermal diffusion cortical blood flow probe (Saber System). Data were analyzed using variance F tests to evaluate changes from baseline over time. Labetalol controlled postoperative hypertension in all cases with a total dose range of 0.4-6.8 mg/kg. During titration, statistically significant decreases in blood pressure were obtained, accompanied by a small decrease in systemic vascular resistance (SVR) and slight increase in cardiac index (CI). Heart rate decreased in a manner directly proportional to the dose of labetalol administered. In the maintenance period, further decreases in blood pressure and heart rate were observed, with significant decreases in central venous pressure, pulmonary capillary wedge pressure, and SVR and an increase in CI. All values remained within normal ranges and no adverse effects were observed. CBF decreased slightly during the study period, although not significantly (from 67 +/- 8 to 57 +/- 7 ml 100 g min). Blood pressure control achieved with labetalol in postoperative neurosurgical patients seems to be the result of mild alpha-adrenoceptor blocking effects (i.e., reduced SVR) and beta-adrenoceptor blocking effects (i.e., reduced heart rate) at higher doses. The 6-8 h duration of effect of labetalol was enough to control postoperative hypertension in all patients with no additional therapy. Compared with alternative drugs available for blood pressure control in similar clinical conditions, labetalol appears to be reliable, safe, and effective, by providing a lasting effect with no evidence of rebound hypertension, increased CBF, or cardiac dysfunction.

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.

Pharmacodynamic effects of vecuronium: A dose response study

Vecuronium was administered to patients in dosages of 0.1, 0.2, 0.3, and 0.4 mg/kg to determine the clinical efficacy of large doses of vecuronium. Onset times shortened with larger doses up to 0.3 mg/kg. With 0.4 mg/kg, however, there was no significant improvement in onset time and the duration of action became unpredictable and often prolonged. Mean onset times were 172, 138, 106, and 100 seconds for the four groups, respectively. Prolonged duration of action (43, 96, 111, and 174 minutes, respectively) was observed with increasing dosages. Recovery rates for the first twitch response of the train-of-four stimulus from 10% to 25% were similar in all groups. There were no adverse hemodynamic effects secondary to large doses of vecuronium.

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.