A phase I, two-center study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children

BACKGROUND: To investigate dexmedetomidine in children, the authors performed an open-label study of the pharmacokinetics and pharmacodynamics of dexmedetomidine. METHODS: Thirty-six children were assigned to three groups; 24 received dexmedetomidine and 12 received no drug. Three doses of dexmedetomidine, 2, 4, and 6 microg x kg x h, were infused for 10 min. Cardiorespiratory responses and sedation were recorded for 24 h. Plasma concentrations of dexmedetomidine were collected for 24 h and analyzed. Pharmacokinetic variables were determined using nonlinear mixed effects modeling (NONMEM program). Cardiorespiratory responses were analyzed. RESULTS: Thirty-six children completed the study. There was an apparent difference in the pharmacokinetics between Canadian and South African children. The derived volumes and clearances in the Canadian children were V1 = 0.81 l/kg, V2 = 1.0 l/kg, Cl1 (systemic clearance) = 0.013 l x kg x min, Cl2 = 0.030 l x kg x min. The intersubject variabilities for V1, V2, and Cl1 were 45%, 38%, and 22%, respectively. Plasma concentrations in South African children were 29% less than in Canadian children. The volumes and clearances in the South African children were 29% larger. The terminal half-life was 110 min (1.8 h). Median absolute prediction error for the two-compartment mammillary model was 18%. Heart rate and systolic blood pressure decreased with time and with increasing doses of dexmedetomidine. Respiratory rate and oxygen saturation (in air) were maintained. Sedation was transient. CONCLUSION: The pharmacokinetics of dexmedetomidine in children are predictable with a terminal half-life of 1.8 h. Hemodynamic responses decreased with increasing doses of dexmedetomidine. Respiratory responses were maintained, whereas sedation was transient.     

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.     

Ketamine Distribution Described by a Recirculatory Pharmacokinetic Model Is Not Stereoselective

Background: Differences in the pharmacokinetics of the enantiomers of ketamine have been reported. The authors sought to determine whether these differences extend to pulmonary uptake and peripheral tissue distribution and to test the hypothesis that tissue distribution of the stereoisomers differs because of carrier-mediated drug transport.

Methods: The dispositions of markers of intravascular space and blood flow (indocyanine green, ICG) and total body water and tissue perfusion (antipyrine) were determined along with S-(+)- and R-(-)-ketamine in five mongrel dogs. The dogs were studied while anesthetized with 2.0% halothane. Marker and drug dispositions were described by recirculatory pharmacokinetic models based on frequent early and less-frequent later arterial blood samples. These models characterize pulmonary uptake and the distribution of cardiac output into parallel peripheral circuits.

Results: Plasma elimination clearance of the S-(+)-ketamine enantiomer, 29.9 ml [middle dot] min-1 [middle dot] kg-1, was higher than that of the R-(-)-enantiomer, 22.2 ml [middle dot] min-1 [middle dot] kg-1. The apparent pulmonary tissue volumes of the ketamine S-(+) and R-(-)-enantiomers (0.31 l) did not differ and was approximately twice that of antipyrine (0.16 l). The peripheral tissue distribution volumes and clearances and the total volume of distribution (2.1 l/kg) were the same for both stereoisomers when elimination clearances were modeled from the rapidly equilibrating peripheral compartment.     

Physicochemical Properties, Pharmacokinetics, and Pharmacodynamics of a Reformulated Microemulsion Propofol in Rats

Background: A newly developed microemulsion propofol consisted of 10% purified poloxamer 188 and 0.7% polyethylene glycol 660 hydroxystearate. The authors studied the physicochemical properties, aqueous free propofol concentration, and plasma bradykinin generation. Pharmacokinetics and pharmacodynamics were also evaluated in rats.

Methods: The pH, particle size, and osmolarity of microemulsion propofol were measured using a pH meter, particle size analyzer, and cryoscopic osmometer, respectively. The aqueous free propofol and plasma bradykinin were measured by a dialysis method and radioimmunoassay, respectively. Microemulsion propofol was administered by zero-order infusion of 0.5, 1.0, and 1.5 mg [middle dot] kg-1 [middle dot] min-1 for 20 min in 30 rats. The electroencephalographic approximate entropy was used as a surrogate measure of propofol effect.

Results: The pH, osmolarity, and particle size of microemulsion propofol are 7.5, 280 mOsm/l, and 67.0 +/- 28.5 nm, respectively. The aqueous free propofol concentration in microemulsion propofol was 63.3 +/- 1.2 [mu]g/ml. When mixed with human blood, microemulsion propofol did not generate bradykinin in plasma. Although microemulsion propofol had nonlinear pharmacokinetics, a two-compartment model with linear pharmacokinetics best described the time course of the propofol concentration as follows: V1 = 0.143 l/kg, k10 = 0.175 min-1, k12 = 0.126 min-1, k21 = 0.043 min-1. The pharmacodynamic parameters in a sigmoid Emax model were as follows: E0 = 1.18, Emax = 0.636, Ce50 = 1.87 [mu]g/ml, [gamma] = 1.28, ke0 = 1.02 min-1.     

Remifentanil Requirements during Sevoflurane Administration to Block Somatic and Cardiovascular Responses to Skin Incision in Children and Adults

Background: The authors found no studies comparing intraoperative requirements of opioids between children and adults, so they determined the infusion rate of remifentanil to block somatic (IR50) and autonomic response (IRBAR50) to skin incision in children and adults.

Methods: Forty-one adults (aged 20-60 yr) and 24 children (aged 2-10 yr) undergoing lower abdominal surgery were studied. In adults, anesthesia induction was with sevoflurane during remifentanil infusion, whereas in children remifentanil administration was started after induction with sevoflurane. After intubation, sevoflurane was administered in 100% O2 and was adjusted to an ET% of 1 MAC-awake corrected for age at least 15 min before surgery. Patients were randomized to receive remifentanil at a rate ranging from 0.05 to 0.35 [mu]g [middle dot] kg-1 [middle dot] min-1 for at least 20 min before surgery. At the beginning of surgery, only the skin incision was performed, and the somatic and autonomic responses were observed. The somatic response was defined as positive with any gross movement of extremity, and the autonomic response was deemed positive with any increase in heart rate or mean arterial pressure equal to or more than 10% of preincision values. Using logistic regression, the IR50 and IRBAR50 were determined in both groups of patients and compared with unpaired Student t test. A P value less than 0.05 was considered significant.

Results: The IR50 +/- SD was 0.10 +/- 0.02 [mu]g [middle dot] kg-1 [middle dot] min-1 in adults and 0.22 +/- 0.03 [mu]g [middle dot] kg-1 [middle dot] min-1 in children (P < 0.001). The IRBAR50 +/- SD was 0.11 +/- 0.02 [mu]g [middle dot] kg-1 [middle dot] min-1 in adults and 0.27 +/- 0.06 [mu]g [middle dot] kg-1 [middle dot] min-1 in children (P < 0.001).     

Propofol Pharmacokinetics and Pharmacodynamics for Depth of Sedation in Nonventilated Infants after Major Craniofacial Surgery

Background: To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described.

Methods: After craniofacial surgery, 22 of the 44 evaluated infants (aged 3-17 months) in the pediatric intensive care unit received propofol (2-4 mg [middle dot] kg-1 [middle dot] h-1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD).

Results: In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 [middle dot] (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index.     

Cardiopulmonary Bypass Has Minimal Effects on the Pharmacokinetics of Fentanyl in Adults

Background: Although fentanyl has been widely used in cardiac anesthesia, no complete pharmacokinetic model that has assessed the effect of cardiopulmonary bypass (CPB) and that has adequate predictive accuracy has been defined. The aims of this investigation were to determine whether CPB had a clinically significant impact on fentanyl pharmacokinetics and to determine the simplest model that accurately predicts fentanyl concentrations during cardiac surgery using CPB.

Methods: Population pharmacokinetic modeling was applied to concentration-versus-time data from 61 patients undergoing coronary artery bypass grafting using CPB. Predictive ability of models was assessed by calculating bias (prediction error), accuracy (absolute prediction error), and measured:predicted concentration ratios versus time. The predictive ability of a simple three-compartment model with no covariates was initially compared to models with premedication (lorazepam vs. clonidine), sex, or weight as covariates. This simple model was then compared to 18 CPB-adjusted models that allowed for step changes in pharmacokinetic parameters at the start and/or end of CPB. The predictive ability of the final model was assessed prospectively in a second group of 29 patients.

Results: None of the covariate (premedication, sex, weight) models nor any of the CPB-adjusted models significantly improved prediction error or absolute prediction error, compared to the simple three-compartment model. Thus, the simple three-compartment model was selected as the final model. Prospective assessment of this model yielded a median prediction error of +3.8%, with a median absolute prediction error of 15.8%. The model parameters were as follows: V1, 14.4 l; V2, 36.4 l; V3, 169 l; Cl1, 0.82 l [middle dot] min-1; Cl2, 2.31 l [middle dot] min-1; Cl3, 1.35 l [middle dot] min-1.     

Dose-Response Relationship and Infusion Requirement of Cisatracurium Besylate in Infants and Children during Nitrous Oxide-Narcotic Anesthesia

Background: To determine the effect of age on the dose-response relation and infusion requirement of cisatracurium besylate in pediatric patients, 32 infants (mean age, 0.7 yr; range, 0.3-1.0 yr) and 32 children (mean age, 4.9 yr; range, 3.1-9.6 yr) were studied during thiopentone-nitrous oxide-oxygen-narcotic anesthesia.

Methods: Potency was determined using a single-dose (20, 26, 33, or 40 [mu]g/kg) technique. Neuromuscular block was assessed by monitoring the electromyographic response of the adductor pollicis to supramaximal train-of-four stimulation of the ulnar nerve at 2 Hz.

Results: Least-squares linear regression analysis of the log-probit transformation of dose and maximal response yielded median effective dose (ED50) and 95% effective dose (ED95) values for infants (29 +/- 3 [mu]g/kg and 43 +/- 9 [mu]g/kg, respectively) that were similar to those for children (29 +/- 2 [mu]g/kg and 47 +/- 7 [mu]g/kg, respectively). The mean infusion rate necessary to maintain 90-99% neuromuscular block during the first hour in infants (1.9 +/- 0.4 [mu]g [middle dot] kg-1 [middle dot] min-1; range: 1.3-2.5 [mu]g [middle dot] kg-1 [middle dot] min-1) was similar to that in children (2.0 +/- 0.5 [mu]g [middle dot] kg-1 [middle dot] min-1; range: 1.3-2.9 [mu]g [middle dot] kg-1 [middle dot] min-1).     

Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats

Background: Central [alpha] adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, [alpha]2 adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective [alpha]2-adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats.

Methods: Sprague-Dawley rats received a cocaine infusion (1.25 mg [middle dot] kg-1 [middle dot] min-1) followed 15 min later by the coinfusion of either dexmedetomidine (20-[mu]g/kg intravenous bolus followed by an infusion of 1 [mu]g [middle dot] kg-1 [middle dot] min-1, CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 [mu]m) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) via retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group.

Results: Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold.     

Effects of Propofol and Remifentanil on Phrenic Nerve Activity and Nociceptive Cardiovascular Responses in Rabbits

Background: The effects of propofol, remifentanil, and their combination on phrenic nerve activity (PNA), resting heart rate (HR), mean arterial pressure (MAP), and nociceptive cardiovascular responses were studied in rabbits.

Methods: Basal anesthesia and constant blood gas tensions were maintained with [alpha]-chloralose and mechanical ventilation. PNA, HR, MAP, and maximum changes in HR and MAP ([DELTA]HR, [DELTA]MAP) evoked by electrical nerve stimulation of tibial nerves were recorded. The comparative effects were observed for propofol at infusion rates from 0.05 to 3.2 mg [middle dot] kg-1 [middle dot] min-1 (group I) and remifentanil from 0.0125 to 12.8 [mu]g [middle dot] kg-1 [middle dot] min-1 alone (group II), and during constant infusions of propofol at rates of 0.1 and 0.8 mg [middle dot] kg-1 [middle dot] min-1 (groups III and IV, respectively). Finally, the effect of remifentanil on propofol blood levels was observed (group V).

Results: The infusion rates for 50% depression (ED50) of PNA, [DELTA]HR, and [DELTA]MAP were 0.41, 1.32, and 1.58 mg [middle dot] kg-1 [middle dot] min-1 for propofol, and 0.115, 0.125, and 1.090 [mu]g [middle dot] kg-1 [middle dot] min-1 for remifentanil, respectively. The ratios for the ED50 values of [DELTA]HR and [DELTA]MAP to PNA were 3.2 and 3.9 for propofol, and 1.1 and 9.5 for remifentanil, respectively. Analysis of the expected and observed responses and isobologrms showed that although their combined effects on PNA, resting HR, and MAP, and [DELTA]MAP were synergistic for [DELTA]HR, they were merely additive. Remifentanil had no effect on propofol blood levels.     

Pharmacokinetics of Tranexamic Acid during Cardiopulmonary Bypass

Background: Tranexamic acid (TA) reduces blood loss and blood transfusion during heart surgery with cardiopulmonary bypass (CPB). TA dosing has been empiric because only limited pharmacokinetic studies have been reported, and CPB effects have not been characterized. We hypothesized that many of the published TA dosing techniques would prove, with pharmacokinetic modeling and simulation, to yield unstable TA concentrations.

Methods: Thirty adult patients undergoing elective coronary artery bypass grafting, valve surgery, or repair of atrial septal defect received after induction of anesthesia: TA 50 mg/kg (n = 11), TA 100 mg/kg (n = 10), or TA 10 mg/kg (n = 10) over 15 min, with 1 mg [middle dot] kg-1[middle dot] hr-1 maintenance infusion for 10 h. TA was measured in plasma using high performance liquid chromatography. Pharmacokinetic modeling was accomplished using a mixed effects technique. Models of increasing complexity were compared using Schwarz-Bayesian Criterion (SBC).

Results: Tranexamic acid concentrations rapidly fell in all three groups. Data were well fit to a 2-compartment model, and adjustments for CPB were supported by SBC. Assuming a body weight of 80 kg, our model estimates V1 = 10.3 l before CPB and 11.9 l during and after CPB; V2 = 8.5 l before CPB and 9.8 l during and after CPB; Cl1 = 0.15 l/s before CPB, 0.11 l/s during CPB, and 0.17 l/s after CPB; and Cl2 = 0.18 l/s before CPB and 0.21 l/s during and after CPB. Based on simulation of previous studies of TA efficacy, we estimate that a 30-min loading dose of 12.5 mg/kg with a maintenance infusion of 6.5 mg [middle dot] kg-1[middle dot] hr-1 and 1 mg/kg added to the pump prime will maintain TA concentration greater than 334 [mu]m, and a higher dose based on 30 mg/kg loading dose plus 16 mg[middle dot]kg-1 [middle dot]h-1 continuous infusion and 2 mg/kg added to the pump prime would maintain TA concentrations greater than 800 [mu]m.     

The Pharmacokinetics of Milrinone in Pediatric Patients after Cardiac Surgery

Background: Milrinone has been shown to increase cardiac output in children after cardiac surgery, but pharmacokinetic analysis has not been used to identify effective dose regimens. The purpose of this study was to characterize the pharmacokinetics of milrinone in infants and children and to apply the results of the issue of dosing.

Methods: Twenty children were studied after they underwent repair of congenital cardiac defects. Control hemodynamic measurement was made after the children were separated from cardiopulmonary bypass, and each patient was given a loading dose of 50 [micro sign]g/kg progressively in 5 min. Hemodynamic measurements were recorded again at the end of the loading dose and when a blood sample was taken to determine milrinone plasma concentrations. Further blood samples were taken during the next 16 h for milrinone plasma concentration analysis. The pharmacokinetics of milrinone were analyzed using the population pharmacokinetic program NONMEM.

Results: The loading dose of milrinone resulted in a mean decrease in mean blood pressure of 12% and a mean increase in cardiac index of 18% at a mean peak plasma concentration of 235 ng/ml. The pharmacokinetics of milrinone were best described by a three-compartment model. In the optimal model, all volumes and distribution clearances were proportional to weight, and weight-normalized elimination clearance was proportional to age; i.e., Cl1 = 2.5 [middle dot] weight [middle dot] (1 + 0.058 [middle dot] age) where Cl1 is expressed as ml/min, and the units of weight and age are kg and months, respectively.     

Temperature-dependent Pharmacokinetics and Pharmacodynamics of Vecuronium

Background: The authors evaluated the influence of temperature on the pharmacokinetics and pharmacodynamics of vecuronium because mild core hypothermia doubles its duration of action.

Methods: Anesthesia was induced with alfentanil and propofol and maintained with nitrous oxide and isoflurane in 12 healthy volunteers. Train-of-four stimuli were applied to the ulnar nerve, and the mechanical response of the adductor pollicis was measured. Volunteers were actively cooled or warmed until their distal esophageal temperatures were in one of four ranges: < 35.0[degrees]C, 35.0-35.9[degrees]C, 36.0-36.9[degrees]C, and >= 37.0[degrees]C. With temperature stabilized, vecuronium was infused at 5 [mu]g [middle dot] kg-1 [middle dot] min-1 until the first response of each train-of-four had decreased by 70%. Arterial blood (for vecuronium analysis) was sampled at intervals until the first response recovered to at least 90% of its prevecuronium level. Vecuronium, 20 [mu]g [middle dot] kg-1 [middle dot] min-1, was then infused for 10 min, and arterial blood was sampled at intervals for up to 7 h. Population-based nonlinear mixed-effects modeling was used to examine the effect of physical characteristics and core temperature on vecuronium pharmacokinetics and pharmacodynamics.

Results: Decreasing core temperature over 38.0-34.0[degrees]C decreases the plasma clearance of vecuronium (11.3% per [degrees]C), decreases the rate constant for drug equilibration between plasma and effect site (0.023 min-1 per [degrees]C), and increases the slope of the concentration-response relationship (0.43 per [degrees]C).     

Pharmacokinetics of Dopamine in Healthy Male Subjects

Background: Dopamine is an agonist of [alpha], [beta], and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model.

Methods: Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 [mu]g [middle dot] kg-1 [middle dot] min-1 for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 [mu]g [middle dot] kg-1 [middle dot] min-1 for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine.

Results: Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 [mu]g [middle dot] kg-1 [middle dot] min-1. Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-[mu]g [middle dot] kg-1 [middle dot] min-1 infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion.     

Population Pharmacokinetics of Piritramide in Surgical Patients

Background: Piritramide is a synthetic opioid used for post-operative analgesia in several European countries. The authors present a mixed-effects model of its population pharmacokinetics in patients undergoing surgery.

Methods: After institutional approval and informed patient consent was obtained, 29 patients who were classified as American Society of Anesthesiologists physical status I or II and aged 21-82 yr were enrolled in the study. They received 0.2 mg/kg piritramide as an intravenous bolus before anesthesia was induced. Central venous blood samples were drawn for as long as 48 h after administration of the drug. The plasma concentration of piritramide was determined by gas chromatography. The concentration-time data were analyzed by mixed-effects modeling. Target-controlled infusions and intermittent bolus regimens were simulated to identify a regimen suitable for patient-controlled analgesia based on population pharmacokinetics and published pharmacodynamic data.

Results: The pharmacokinetics of piritramide were described adequately by a linear three-compartment model. Patient age and weight were significant covariates. The values of the pharmacokinetic parameters are: V1 = 50.5 [1], V2 = 150 [middle dot] (1 + 9.32 [middle dot] 10-3 [middle dot] (age - 47 yr)) [1], V3 = 212 [middle dot] (1 + 6.37 [middle dot] 10-3 [middle dot] (age - 47 yr)) [1], Cl1 = 0.56 [middle dot] (1 - 6.14 [middle dot] 10-3 [middle dot] (age - 47 yr)) [1/min], Cl2 = 8.25 [middle dot] (1 + 2.02 [middle dot] 10-2 [middle dot] (Wt - 74 kg)) [1/min], Cl3 = 0.80 [1/min]. The age of 47 yr and the weight of 74 kg refer to the median values for these factors in the patients studied. Rapid distribution, slow distribution, and elimination half-lives for the median patient are 0.05, 1.34, and 10.43 h, respectively. The context-sensitive half-time after a 24-h infusion is predicted at 10.5 h in a 75-yr-old patient compared with 7 h for the median patient.     

Acute Pain Induces Insulin Resistance in Humans

Background: Painful trauma results in a disturbed metabolic state with impaired insulin sensitivity, which is related to the magnitude of the trauma. The authors explored whether pain per se influences hepatic and extrahepatic actions of insulin.

Methods: Ten healthy male volunteers underwent two randomly sequenced hyperinsulinemic-euglycemic (insulin infusion rate, 0.6 mU [middle dot] kg-1 [middle dot] min-1 for 180 min) clamp studies 4 weeks apart. Self-controlled painful electrical stimulation was applied to the abdominal skin for 30 min, to a pain intensity of 8 on a visual analog scale of 0-10, just before the clamp procedure (study P). In the other study, no pain was inflicted (study C).

Results: Pain reduced whole-body insulin-stimulated glucose uptake from 6.37 +/- 1.87 mg [middle dot] kg-1 [middle dot] min-1 (mean +/- SD) in study C to 4.97 +/- 1.38 mg [middle dot] kg-1 [middle dot] min-1 in study P (P < 0.01) because of a decrease in nonoxidative glucose disposal, as determined by indirect calorimetry (2.47 +/- 0.88 mg [middle dot] kg-1 [middle dot] min-1 in study P vs. 3.41 +/- 1.03 mg [middle dot] kg-1 [middle dot] min-1 in study C;P < 0.05). Differences in glucose oxidation rates were not statistically significant. The suppression of isotopically determined endogenous glucose output during hyperinsulinemia tended to be decreased after pain (1.67 +/- 0.48 mg [middle dot] kg-1 [middle dot] min-1 in study P vs. 2.04 +/- 0.45 mg [middle dot] kg-1 [middle dot] min-1 in study C;P = 0.06). Pain elicited a twofold to threefold increase in serum cortisol (P < 0.01), plasma epinephrine (P < 0.05), and serum free fatty acids (P < 0.05). Similarly, circulating concentrations of glucagon and growth hormone tended to increase during pain.     

Pharmacokinetics of Midazolam in Neonates Undergoing Extracorporeal Membrane Oxygenation

Background: Although the pharmacokinetics of midazolam in critically ill children has been described, there are no such reports in extracorporeal membrane oxygenation.

Methods: The pharmacokinetics of midazolam and 1-hydroxy midazolam after continuous infusion (50-250 [mu]g [middle dot] kg-1 [middle dot] h-1) were determined in 20 neonates undergoing extracorporeal membrane oxygenation. Patients were randomized into two groups: group 1 (n = 10) received midazolam extracorporeally (into the circuit), and group 2 received drug via central or peripheral access. Blood samples for determination of plasma concentrations were taken at baseline, 2, 4, 6, 12, 18, and 24 h, then every 12 h. Population pharmacokinetic analysis and model building was conducted using WinNonMix (Pharsight Corporation, Mountain View, CA). The 1-hydroxy midazolam/midazolam metabolic ratio was determined as a surrogate marker of cytochrome P450 3A activity.

Results: The parameter estimates (n = 19) were based on a one-compartment model with time-dependent change in volume of distribution. Volume (mean +/- standard error) expanded monoexponentially from the onset of extracorporeal membrane oxygenation to a maximum value, 0.8 l +/- 0.5 and 4.1 +/- 0.5 l/kg, respectively. Consequently, plasma half-life was substantially prolonged (median [range]) from onset to steady-state: 6.8 (2.2-39.8) and 33.3 (7.4-178) h, respectively. Total body clearance was determined as (mean +/- standard error) 1.4 +/- 0.15 ml [middle dot] kg-1 [middle dot] min-1. The median metabolic ratio was 0.17 (0.03-0.9). No significant differences were observed between the two groups with respect to parameter estimates. Simulations of plasma concentration profiles revealed excess levels at conventional doses.     

Dobutamine Antagonizes Epinephrine's Biochemical and Cardiotonic Effects: Results of an In Vitro Model Using Human Lymphocytes and a Clinical Study in Patients Recovering from Cardiac Surgery

Background: Patients may receive more than one positive inotropic drug to improve myocardial function and cardiac output, with the assumption that the effects of two drugs are additive. The authors hypothesized that combinations of dobutamine and epinephrine would produce additive biochemical and hemodynamic effects.

Methods: The study was performed in two parts. Phase 1 used human lymphocytes in an in vitro model of cyclic adenosine monophosphate (cAMP) generation in response to dobutamine (10-8 to 10-4 M) or epinephrine (10-9 M to 10-5 M), and dobutamine and epinephrine together. Phase 2 was a clinical study in patients after aortocoronary artery bypass in which isobolographic analysis compared the cardiotonic effects of dobutamine (1.25, 2.5, or 5 [micro sign]g [middle dot] kg-1 [middle dot] min-1) or epinephrine (10, 20, or 40 ng [middle dot] kg-1 [middle dot] min-1), alone or in combination.

Results: In phase 1, dobutamine increased cAMP production 41%, whereas epinephrine increased cAMP concentration [almost equal to] 200%. However, when epinephrine (10-6 M) and dobutamine were combined, dobutamine reduced cAMP production at concentrations between 10-6 to 10-4 M (P = 0.001). In patients, 1.25 to 5 [micro sing]g [middle dot] kg-1 [middle dot] min-1 dobutamine increased the cardiac index (CI) 15-28%. Epinephrine also increased the CI with each increase in dose. However, combining epinephrine with the two larger doses of dobutamine (2.5 and 5 [micro sign]g [middle dot] kg-1 [middle dot] min-1) did not increase the CI beyond that achieved with epinephrine and the lowest dose of dobutamine (1.25 [micro sign]g [middle dot] kg-1 [middle dot]-1 min (-1)). In addition, the isobolographic analysis for equieffective concentrations of dobutamine and epinephrine suggests subadditive effects.     

The Anabolic Effect of Epidural Blockade Requires Energy and Substrate Supply

Background: The authors examined the hypothesis that continuous thoracic epidural blockade with local anesthetic and opioid, in contrast to patient-controlled intravenous analgesia with morphine, stimulates postoperative whole body protein synthesis during combined provision of energy (4 mg [middle dot] kg-1 [middle dot] min-1 glucose) and amino acids (0.02 ml [middle dot] kg-1 [middle dot] min-1 Travasol(TM) 10%, equivalent to approximately 2.9 g [middle dot] kg-1 [middle dot] day-1).

Methods: Sixteen patients were randomly assigned to undergo a 6-h stable isotope infusion study (3 h fasted, 3 h feeding) on the second day after colorectal surgery performed with or without perioperative epidural blockade. Protein synthesis, breakdown and oxidation, glucose production, and clearance were measured by l-[1-13C]leucine and [6,6-2H2]glucose.

Results: Epidural blockade did not affect protein and glucose metabolism in the fasted state. Parenteral alimentation decreased endogenous protein breakdown and glucose production to the same extent in both groups. Administration of glucose and amino acids was associated with an increase in whole body protein synthesis that was modified by the type of analgesia, i.e., protein synthesis increased by 13% in the epidural group (from 93.3 +/- 16.6 to 104.5 +/- 11.1 [mu]mol [middle dot] kg-1 [middle dot] h-1) and by 4% in the patient-controlled analgesia group (from 90.0 +/- 27.1 to 92.9 +/- 14.8 [mu]mol [middle dot] kg-1 [middle dot] h-1;P = 0.054).     

Concentration-Effect Relation of Succinylcholine Chloride during Propofol Anesthesia

Background: The pharmacokinetics and pharmacodynamics of succinylcholine were studied simultaneously in anesthetized patients to understand why the drug has a rapid onset and short duration of action. A quantitative model describing the concentration-effect relation of succinylcholine was proposed. The correlation between in vitro hydrolysis in plasma and in vivo elimination was also examined.

Methods: Before induction of anesthesia, blood was drawn for in vitro analysis in seven adults. Anesthesia was induced with propofol and remifentanil. Single twitch stimulation was applied at the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis was measured. Arterial blood was drawn frequently after succinylcholine injection to characterize the front-end kinetics. Plasma concentrations were measured by mass spectrometry, and pharmacokinetic parameters were derived using compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic relations were estimated.

Results: The mean in vitro degradation rate constant in plasma (1.07 +/- 0.49 min-1) was not different from the in vivo elimination rate constant (0.97 +/- 0.30 min-1), and an excellent correlation (r2 = 0.94) was observed. Total body clearance derived using noncompartmental (37 +/- 7 ml [middle dot] min-1 [middle dot] kg-1) and compartmental (37 +/- 9 ml [middle dot] min-1 [middle dot] kg-1) approaches were similar. The plasma-effect compartment equilibration rate constant (keo) was 0.058 +/- 0.026 min-1, and the effect compartment concentration at 50% block was 734 +/- 211 ng/ml.