Dennis M. Fisher

Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine.

Dexmedetomidine is a selective alpha2-adrenoceptor agonist with centrally mediated sympatholytic, sedative, and analgesic effects. This study evaluated: 1) pharmacokinetics of dexmedetomidine in plasma and cerebrospinal fluid (CSF) in surgical patients; 2) precision of a computer-controlled infusion protocol (CCIP) for dexmedetomidine during the immediate postoperative period; and 3) dexmedetomidines sympatholytic effects during that period. Dexmedetomidine was infused postoperatively by CCIP for 60 min to eight women, targeting a plasma concentration (Cp) of 600 pg/mL. Before, during, and after infusion, blood was sampled to determine plasma concentrations of norepinephrine, epinephrine, and dexmedetomidine, and CSF was sampled to determine dexmedetomidine concentrations (CCSF). Heart rate and arterial blood pressure were measured continuously from 5 min before until 3 h after the end of infusion. During the infusion, Cp values generally exceeded the target value: median percent error averaged 21% and ranged from -2% to 74%; median absolute percent error averaged 23% and ranged from 4% to 74%. After infusion, CCSF was 4% +/- 1% of Cp. Because CCSF barely exceeded the assays limit of quantitation, CSF pharmacokinetics were not determined. During the infusion, norepinephrine decreased from 2.1 +/- 0.8 to 0.7 +/- 0.3 nmol/L; epinephrine decreased from 0.7 +/- 0.5 to 0.2 +/- 0.2 nmol/L; heart rate decreased from 76 +/- 15 to 64 +/- 11 bpm; and systolic blood pressure decreased from 158 +/- 23 to 140 +/- 23 mm Hg. We conclude that infusion of dexmedetomidine by CCIP using published pharmacokinetic parameters overshoots target dexmedetomidine concentrations during the early postoperative period. Hemodynamic and catecholamine results suggest that dexmedetomidine attenuates sympathetic activity during the immediate postoperative period. Implications: We studied the pharmacokinetic and sympatholytic effects of dexmedetomidine during the immediate post-operative period and found that during this period, the published pharmacokinetic data slightly overshoot target plasma dexmedetomidine concentrations. We also found that heart rate, blood pressure, and plasma catecholamine concentrations decrease during dexmedetomidine infusion. (Anesth Analg 1997;85:1136-42)

twenty-four-hour Pharmacokinetics of Rectal Acetaminophen in Children : an Old Drug with New Recommendations

Background: Rectal acetaminophen is often administered during operation to provide supplemental analgesia or antipyresis in children. Recent studies examining current dose guidelines are limited by short sampling times. The authors extended the drug sampling period to more clearly define acetaminophen pharmacokinetics in children having surgery. Methods: Children (n = 28) were randomized to receive a single dose of 10, 20, or 30 mg/kg rectal acetaminophen after induction of anesthesia. Venous blood samples were taken every 30 min for 4 h, every 60 min for 4 h, and every 4 h for 16 h. Data were analyzed using a mixed‐effects modeling technique (using NONMEM software) to determine the volume of distribution and clearance normalized for bioavailability. Additional models accounted for suppository dissolution followed by acetaminophen absorption. Results: Age, weight, estimated blood loss, volume of intravenous fluid administered, and anesthesia time were similar in the three groups. Most patients did not achieve peak or sustained serum values in the 10–20 micro gram/ml serum concentration range associated with antipyresis. The volume of distribution was 385 ml/kg, and clearance normalized for bioavailability, F, was 5.46 ml [center dot] kg sup ‐1 [center dot] min sup ‐1. Pharmacokinetic models suggest that absorption of acetaminophen is a function of zero‐order dissolution of suppositories and first‐order absorption from the rectum. Suppository dose size also may affect absorption characteristics. Conclusions: The current recommended rectal acetaminophen dose of 10–15 mg/kg yields peak serum concentrations less than the antipyretic serum concentration of 10–20 micro gram/ml. Based on the observed kinetics, the authors recommend that the initial dose should be approximately 40 mg/kg.

Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children.

To determine the induction and maintenance characteristics of desflurane in pediatric patients, the authors anesthetized 206 infants and children aged 1 month to 12 yr with nitrous oxide plus desflurane and/or halothane in oxygen. Patients were assigned to one of four groups: anesthesia was 1) induced and maintained with desflurane after premedication with an oral combination of meperidine, diazepam, and atropine; 2) induced and maintained with desflurane; 3) induced with halothane and maintained with desflurane; or 4) induced and maintained with halothane. An unblinded observer recorded time to loss of consciousness (lid reflex), time to intubation, and clinical characteristics of the induction and maintenance of anesthesia. Moderate-to-severe laryngospasm (49%) and moderate-to-severe coughing (58%) occurred frequently during induction of anesthesia with desflurane; the incidence of these was not altered by premedication. In contrast, laryngospasm and coughing were rare during induction of anesthesia with halothane. In unpremedicated patients, time to loss of lid reflex (mean +/- SD) was similar for desflurane (2.4 +/- 1.2 min) and halothane (2.1 +/- 0.8 min). During induction of anesthesia, before laryngoscopy and intubation, mean arterial pressure less than 80% of baseline was more common with halothane; heart rate and mean arterial pressure greater than 120% of baseline were more common with desflurane. Intraoperatively, heart rate greater than 120% of baseline was more common with desflurane; blood pressures were similar for the two anesthetics. The authors conclude that the high incidence of airway complications during induction of anesthesia with desflurane limits its utility for inhalation induction in pediatric patients. Anesthesia can be safely maintained with desflurane if induced with a different anesthetic.

Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination

Atracurium, a nondepolarizing muscle relaxant, is eliminated through several pathways, including Hofmann elimination (spontaneous degradation in plasma and tissue at normal body pH and temperature) and ester hydrolysis (catalysis by nonspecific esterases). Because elimination of atracurium occurs in both tissue and plasma, traditional pharmacokinetic models assuming elimination from a single central compartment are inaccurate for atracurium. The authors developed a two-compartment pharnacokinetic model in which hepatic and/or renal elimination occurs from the central compartment (Clorgan), and Hofmann elimination and ester hydrolysis occur from both central and peripheral compartments (Clnonorgan). To determine the in vitro rate constant for Hofmann elimination and ester hydrolysis, atracurium was added to whole blood kept at each patients pH and temperature. The values for this rate constant ranged from 0.0193 to 0.0238 per min. When these values were applied to the pharmacokinetic model, Cltotal, Clorgan, and Clnonorgan were 4.8 ± 1.1, 3.0 ± 0.9, and 1.9 ± 0.6 ml.kg−1. min−1, respectively. The authors conclude that more than one-half of the clearance of atracurium occurs via pathways other than Hofmann elimination and ester hydrolysis.

Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil.

To evaluate nasally administered sufentanil, 1.5–4.5 μg/kg, for pre-induction (i.e., pre-medication/induction) of anesthesia in pediatric patients, the authors studied ASA PS1 or 2 patients scheduled for elective surgery. Eighty children, ages 6 months to 7 yr, were randomized to receive sufentanil (1.5, 3.0, or 4.5 μg/kg) or placebo (normal saline, 0.03 ml/kg) nasally over 15–20 s. Induction of anesthesia was completed with 5% halothane and O2 via facemask. After tracheal intubation, anesthesia was maintained with N2O (60–70%) and halothane, as clinically indicated. A blinded observer remained with the child from prior to drug administration until discharge from the recovery room. Patients given sufentanil were more likely to separate willingly from their parents and be judged as calm at or before 10 min compared to those given saline. Ventilatory complicance during induction of anesthesia decreased markedly in 25% of subjects given sufentanil, 4.5 μg/kg. Subjects given sufentanil moved or coughed less during tracheal intubation and required less halothane compared to those given placebo. During recovery, patients given sufentanil cried less and fewer needed anal gesics; recovery times were similar for all groups. However, patients given sufentanil, 4.5 μg/kg, had a higher incidence of vomiting in the recoyery room and during the first postoperative day. The authors conclude that nasally administered sufentanil, 1.5 or 3.0 μg/kg, facilitates separation of children from parents, has minimal side effects, may improve intubating conditions, and can provide postoperative analgesia.

Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation.

To determine the effect of end-stage renal disease on the pharmacokinetics of reocuronium bromide (ORG 9426), a new nondepolarizing monoquaternary steroidal neuromuscular blocking drug, the authors administered 600 micrograms/kg rocuronium (2 x ED95) intravenously to ten patients undergoing cadaver renal transplantation and ten healthy patients undergoing elective minor surgery (controls). All patients were anesthetized with nitrous oxide (50-70% in oxygen) and isoflurane (end-tidal concentrations of 1.2 +/- 0.5% and 0.8 +/- 0.2%, mean +/- SD, for control and transplant groups, respectively). Plasma concentrations of rocuronium were determined by capillary gas chromatography. A population-based pharmacokinetic analysis (NONMEM) was used to determine typical values, standard errors, and interindividual variability for the pharmacokinetic parameters and to determine whether these values differed between control and renal transplant patients. Total plasma clearance (2.89 +/- 0.25 ml.kg-1.min-1, mean +/- SE) and volume of the central compartment (76.9 +/- 10.6 ml/kg) did not differ between control and renal transplant patients, whereas volume of distribution at steady state was greater in renal transplant patients (264 +/- 19 ml/kg) than in control patients (207 +/- 14 ml/kg). This resulted in a longer elimination half life in renal transplant patients (97.2 +/- 17.3 min) compared to controls (70.9 +/- 4.7 min). The authors conclude that renal failure and renal transplantation alter the distribution but not the clearance of rocuronium.

Pharmacokinetics and Pharmacodynamics of d-Tubocurarine in Infants, Children, and Adults

&NA; The pharmacokinetics and pharmacodynamics of d‐tubocurarine (dTc) were determined in neonates (0–2 months, n = 7), infants (212 months, a = 7), children (1–12 years, n = 9), and adults (12–30 years, n = 8) during 70% nitrous oxide, 0.58 MAC halothane anesthesia. dTc was administered by infusion, while blood for determination of plasma dTc concentrations was obtained, and the EMG of the adductor pollicis recorded. The plasma dTc concentration at which 50% depression of EMG twitch height occurs (Cpss(50)) was 0.18 ± 0.09 &mgr;g/ml in neonates, and 0.27 ± 0.06 &mgr;g/ml in infants, both significantly lower than the values of 0.42 ± 0.14 and 0.53 ± 0.14 &mgr;g/ml for children and adults, respectively. The steady‐state distribution volume (Vdss) was 0.74 ± 0.33 l/kg in neonates, significantly greater than the values of 0.52 ± 0.22, 0.41 ± 0.12, and 0.30 ± 0.10 1/kg in infants, children, and adults, respectively. The elimination half‐life (t&bgr;1/2) was 174 ± 60 min in neonates, significantly longer than the values of 90 ± 23 and 89 ± 18 min in children and adults, respectively. Plasma clearance did not differ with age. We also determined D50, the product of Vdss and Cpss(50). D50, the quantity of drug present at steady‐state to produce 50% paralysis, did not differ between groups. The authors conclude that during comparable nitrous oxide‐halothane anesthesia, neonates and infants have an increased sensitivity to dTc, as determined by Cpss(50). However, because of he larger Vdss in younger patients, dose size should not differ with age. In addition, because of the longer t&bgr;1/2 in neonates, second and subsequent doses should be required at less frequent intervals.

Clinical Pharmacology of Vecuronium and Atracurium

Vecuronium and atracurium provide addition flexibility to the clinician using neuromuscular blocking drugs. The shorter duration of action, lack of significant cardiovascular effects, and the lack of dependence on the kidney for elimination provide clinical advantages over, or alternatives to, currently available nondepolarizing neuromuscular blocking drugs.

Initial and subsequent dosing of rectal acetaminophen in Children : A 24-hour pharmacokinetic study of new dose recommendations

Background Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors’ previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10–20 &mgr;g/ml, without evidence of accumulation. Methods Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration. Results All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 ± 25% of the time. With subsequent dosing, the target range was maintained 60 ± 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 &mgr;g/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses. Conclusions A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10–20 &mgr;g/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period.

The Pharmacokinetics and Pharmacodynamics of Atracurium in Patients with and without Renal Failure

To determine the influence of renal function on the pharmacology of atracurium, 10 patients with normal renal function and 10 with renal failure (scheduled for cadaver kidney transplant) were anesthetized with nitrous oxide and halothane. Atracurium besylate, 0.5 mg·kg−1, was given as an iv bolus and plasma samples were collected over a 4-h period. These samples were assayed for atracurium (all patients) and laudanosine, one of the principal metabolites (eight of the normal group), using an ion-exchange liquid chromatographic assay. The plasma concentrations of atracurium for each patient were fitted to a two-compartment pharmacokinetic model. The onset time, duration of action, and recovery time of atracurium neuromuscular blockade were measured. There were no differences found in the pharmacokinetics or pharmacodynamics of atracurium between patients with normal renal function and those with renal failure. There were measurable levels of laudanosine following atracurium administration with peak levels of 199 ± 31 ng·ml−1 at 2 min. The authors conclude that the pharmacokinetics and pharmacodynamics of atracurium are not altered by renal failure.