Thomas K. Henthorn

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.

Using the time of maximum effect site concentration to combine pharmacokinetics and pharmacodynamics.

Background To simulate the time course of drug effect, it is sometimes necessary to combine the pharmacodynamic parameters from an integrated pharmacodynamic–pharmacodynamic study (e.g., volumes, clearances, ke0 [the effect site equilibration rate constant], C50 [the steady state plasma concentration associated with 50% maximum effect], and the Hill coefficient) with pharmacokinetic parameters from a different study (e.g., a study examining a different age group or sampling over longer periods of time). Pharmacokinetic–pharmacodynamic parameters form an interlocked vector that describes the relationship between input (dose) and output (effect). Unintended consequences may result if individual elements of this vector (e.g., ke0) are combined with pharmacokinetic parameters from a different study. The authors propose an alternative methodology to rationally combine the results of separate pharmacokinetic and pharmacodynamic studies, based on tpeak, the time of peak effect after bolus injection. Methods The naive approach to combining separate pharmacokinetic and pharmacodynamic studies is to simply take the ke0 from the pharmacodynamic study and apply it naively to the pharmacokinetic study of interest. In the tpeak approach, ke0 is recalculated using the pharmacokinetics of interest to yield the correct time of peak effect. The authors proposed that the tpeak method would yield better predictions of the time course of drug effect than the naive approach. They tested this hypothesis in three simulations: thiopental, remifentanil, and propofol. Results In each set of simulations, the tpeak method better approximated the postulated “true” time course of drug effect than the naive method. Conclusions Tpeak is a useful pharmacodynamic parameter and can be used to link separate pharmacokinetic and pharmacodynamic studies. This addresses a common difficulty in clinical pharmacology simulation and control problems, where there is usually a wide choice of pharmacokinetic models but only one or two published pharmacokinetic–pharmacodynamic models. The results will be immediately applicable to target-controlled anesthetic infusion systems, where linkage of separate pharmacokinetic and pharmacodynamic parameters into a single model is inherent in several target-controlled infusion designs.

A survey of propofol abuse in academic anesthesia programs.

BACKGROUND:Although propofol has not traditionally been considered a drug of abuse, subanesthetic doses may have an abuse potential. We used this survey to assess prevalence and outcome of propofol abuse in academic anesthesiology programs. METHODS:E-mail surveys were sent to the 126 academic anesthesiology training programs in the United States. RESULTS:The survey response rate was 100%. One or more incidents of propofol abuse or diversion in the past 10 yr were reported by 18% of departments. The observed incidence of propofol abuse was 10 per 10,000 anesthesia providers per decade, a fivefold increase from previous surveys of propofol abuse (P = 0.005). Of the 25 reported individuals abusing propofol, 7 died as a result of the propofol abuse (28%), 6 of whom were residents. There was no established system to control or monitor propofol as is done with opioids at 71% of programs. There was an association between lack of control of propofol (e.g., pharmacy accounting) at the time of abuse and incidence of abuse at the program (P = 0.048). CONCLUSIONS:Propofol abuse in academic anesthesiology likely has increased over the last 10 yr. Much of the mortality is in residents. Most programs have no pharmacy accounting or control of propofol stocks. This may be of concern, given that all programs reporting deaths from propofol abuse were centers in which there was no pharmacy accounting for the drug.

Ultrasound-Induced Mild Hyperthermia as a Novel Approach to Increase Drug Uptake in Brain Microvessel Endothelial Cells

AbstractPurpose. Drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Thus, a noninvasive and reversible method to enhance BBB permeation of drugs is highly desirable. In the present work, we studied if ultrasound-induced mild hyperthermia (USHT, 0.4 watts (W)/cm2 at 41°C) can enhance drug absorption in BBB endothelial cells, and we elucidated the mechanism of USHT on cellular accumulation. Methods. To accomplish these aims, we studied the effects of hyperthermia (41°C), USHT, P-glycoprotein (P-gp) modulator (PSC 833), and combination of USHT and PSC 833 on accumulation of P-gp substrate (R123) and non-P-gp substrates (sucrose, 2-deoxyglucose, and antipyrine) in monolayers of primary bovine brain microvessel endothelial cells (BBMEC). Results. USHT, through its thermal effect, produces a significant (relative to controls; no USHT) and comparable increase in R123 accumulation with PSC 833. We also demonstrate that USHT increases permeability of hydrophobic (R123 and [14C]-antipyrine) and not hydrophilic molecules ([14C]-sucrose and 2-[3H]-deoxy-d-glucose). The enhanced permeability is reversible and size dependent, as USHT produces a much larger effect on cellular accumulation of [14C]-antitpyrine (molecular weight of 188 D) than that of R123 (molecular weight of 380.8 D). Although USHT increases membrane permeability, it did not affect P-gp activity or the activity of glucose transporters. Conclusions. Our results point to the potential use of USHT as a reversible and noninvasive approach to increase BBB permeation of hydrophobic drugs, including P-gp-recognized substrates.

Determinants of thiopental induction dose requirements

Dose requirements for thiopental anesthetic induction have significant age- and gender-related variability. We studied the association of the patient characteristics age, gender, weight, lean body mass, and cardiac output with thiopental requirements. Doses of thiopental, infused at 150 mg/min, required to reach both a clinical end-point and an electroencephalographic (EEG) end-point were determined in 30 males and 30 females, aged 18--83 yr. Univariate least squares linear regression analysis revealed outliers in the relationships of age, weight, lean body mass, and cardiac output to thiopental dose at clinical and EEG endpoints. Differential weighting of data points minimized the effect of outliers in the construction of a robust multiple linear regression model of the relationship between several selected independent variables and the dependent variables thiopental dose at clinical and EEG endpoints. The multiple linear regression model for thiopental dose at the clinical end-point selecting the regressor variables age, weight, and gender (R2 = 0.76) was similar to that for age, lean body mass, and gender (R2 = 0.75). Thiopental dose at the EEG end-point was better described by models selecting the variables age, weight, and cardiac output (R2 = 0.88) or age, lean body mass, and cardiac output (R2 = 0.87). Although cardiac output varied with age, age always remained a selected variable. Because weight and lean body mass differed with gender, their selection as variables in the model eliminated gender as a selected variable or minimized its importance.

The relationship of age to the pharmacokinetics of early drug distribution: the concurrent disposition of thiopental and indocyanine green

The optimal dose of thiopental depends both on its initial distribution kinetics, which determine its concentrations at sites of action after iv administration, and on its pharmacodynamics. The disposition of concomitantly administered thiopental and indocyanine green (ICG), a marker of intravascular space, was determined in 21 patients, aged 20-80 yr, to determine the pharmacokinetic basis of increased reactivity of the elderly to thiopental. Data obtained from frequent early arterial blood samples and the simultaneous modelling of thiopental disposition with that of ICG allow a rigorous description of early drug distribution. Their disposition is described by a two-compartment ICG model and a four-compartment thiopental model that have a common central volume, V1, the central blood pool. ICG distributes, by intravascular mixing, from V1 to a peripheral blood volume that is a subset of a rapidly equilibrating (fast) peripheral thiopental compartment; elimination clearance of both drugs is modelled from these peripheral compartments. In contrast to the results of others, the results of this study demonstrate that V1 does not decrease with increasing age. The only pharmacokinetic variable that changed with age is the intercompartmental clearance (Cl21) from V1 to the rapidly equilibrating peripheral volume, V2, which decreased 35% between the ages of 20-80 yr. The authors suggest that V1 and the intercompartmental clearances may be used together to explain smaller dose requirements in individuals with increased reactivity to thiopental; such an analysis does not predict that dose adjustments should be made on the basis of age alone.

The pharmacokinetics of bupivacaine when injected intra-articularly after knee arthroscopy

Bupivacaine pharmacokinetics were determined in 11 patients receiving the drug intra-articularly after knee arthroscopy performed under general anesthesia. Forty ml 0.25% bupivacaine was given at the end of surgery aid the thigh tourniquet was released 2 to 3 minutes after injection. Blood samples were obtained up to 5 hours after tourniquet release and plasma bupivacaine concentrations were determined. Pharmacokinetic parameters determined were (mean ± SD): volume of distribution (Vd beta) 206 ± 88 L, clearance (Cl) 0.826 ± 0.378 L/min, terminal half-life (T1/2) beta 189 ± 84 minutes, absorption rate constant (ka) 9.92 ± 6.79/min, estimated peak plasma concentrations (Cpmax) 0.48 ± 0.20 μg/mL, and time to peak concentration (tmax) 43.4 ± 23.1 minutes. Results indicate that injections of 100 mg bupivacaine intra-articularly after knee arthroscopy produce peak blood concentrations within the first hour after surgery, and that these will be well below concentrations associated with toxic reactions. Peak concentrations can be minimized with shorter tourniquet inflation times and with longer intervals between injection and tourniquet release.

The relationship between alfentanil distribution kinetics and cardiac output

The relationship between cardiac output and the tissue distribution of alfentanil was investigated in seven healthy volunteers. Subjects were given 10 µg/kg alfentanil and 0.5 mg/kg indocyanine green. Arterial blood samples were obtained at baseline, 1 minute, every ½ minute until 5 minutes, and then every minute until 15 minutes after the drug injection was begun. Subsequent samples were collected to 6 hours. Cardiac output was measured continuously by use of thoracic bioimpedance. Alfentanil pharmacokinetics were modeled with both a standard three‐compartment model and a four‐compartmental model based in part on the two‐compartmental pharmacokinetics of indocyanine green. The sum of intercompartmental clearances for both the three‐ and four‐compartment models were significantly correlated with the measured cardiac outputs, r = 0.93 and r = 0.88, respectively. These findings indicate that the intercompartmental clearance (i.e., tissue distribution) of alfentanil is largely determined by cardiac output (i.e., tissue blood flow).

Premedication of pediatric tonsillectomy patients with oral transmucosal fentanyl citrate

We assessed the safety and efficacy of oral transmucosal fentanyl citrate (Fentanyl Oralet[registered sign]; Abbott Laboratories, Abbott Park, IL), administered preoperatively to provide both preoperative sedation and postoperative analgesia, in a randomized, double-blind, placebocontrolled study in 40 children, 2-10 yr of age, scheduled for tonsillectomy. In the preoperative holding area, one group (Group O) received Fentanyl Oralet[registered sign] (fentanyl 10-15 micro g/kg), and the other (Group IV) received only the candy matrix. Patients in Group O received an IV injection of saline, and those in Group IV received an IV injection of fentanyl (2 micro g/kg) after removal of the first tonsil. Except for the opioid, patients received a standard anesthetic. Preoperative sedation and cooperation were assessed. Postoperative pain was evaluated using an objective pain scale. Patients in Group O were more sedated but no more cooperative at the induction of anesthesia compared with those in Group IV. No patient vomited preoperatively or experienced preoperative or postoperative desaturation. Time to postanesthesia care unit (PACU) discharge was not different between groups. There was no significant difference in the number of patients requiring morphine in the PACU (6 of 21 in Group O versus 10 of 19 in Group IV). Plasma fentanyl concentrations were not a reliable indicator of the need for postoperative morphine. Among the patients who required morphine postoperatively, there was an 11-fold variation in plasma fentanyl concentrations at the time of morphine administration. Derived pharmacokinetic parameters were similar to those previously reported in children; bioavailability of the fentanyl in Fentanyl Oralet[registered sign] was 0.33. We conclude that premedication with Fentanyl Oralet[registered sign] did not differ with IV fentanyl in regard to the induction of anesthesia and postoperative analgesia. Implications: In this double-blind, randomized study, we studied the efficacy of Fentanyl Oralet[registered sign] (10-15 micro g/kg) preoperatively for providing postoperative analgesia in children undergoing tonsillectomy. We found no incidence of preoperative desaturation or vomiting in any patient. This is in contrast to other studies, in which there was a longer time interval between Fentanyl Oralet[registered sign] completion and induction of anesthesia. The bioavailability of the fentanyl in Fentanyl Oralet[registered sign] was estimated to be 33%, which is less than that reported in adults (approximately 50%). There was no difference in postoperative opioid requirements between patients who received 2 micro g/kg of fentanyl IV and those who received Fentanyl Oralet[registered sign].

Assessment of the debrisoquin and dextromethorphan phenotyping tests by gaussian mixture distributions analysis

From a sample of 149 unrelated Spaniards, individuals were phenotyped for their ability to hydroxylate debrisoquin and O‐demethylate dextromethorphan. The distribution of urinary metabolic ratios for each test was analyzed by univariate gaussian mixture distributions analysis to determine the number of populations, the mean and standard deviation of the metabolic ratios for each population, and the proportion belonging to each population. For the 124 subjects phenotyped with both the debrisoquin and dextromethorphan tests a bivariate analysis was performed. The results demonstrate that both tests similarly separated this sample into two populations, with 10% belonging to poor metabolizer phenotypes. In addition, the correlation between the metabolic ratios from each test is significant, indicating that they are measuring the same biologic trait and the certainty of correctly identifying the debrisoquin oxidation phenotype of an individual is improved by using the results of both tests.