Colin A. Shanks

Effects of Etomidate on Hormonal Responses to Surgical Stress

The hormonal responses to surgical stress were examined in 10 patients scheduled for elective gynecologic laparotomy. Anesthesia was induced with either thiopental, 4 mg/kg, or etomidate, 0.35 mg/kg, and maintained with nitrous oxide and enflurane. Plasma cortisol, aldosterone, ACTH, and catecholamines were measured during the 24 h after the induction of anesthesia. The catecholamine responses of the patients whose anesthesia was induced with either drug were similar. The plasma ACTH concentrations for the etomidate group were greater than baseline values and the concentrations in the thiopental group (P < 0.05) in the fourth and fifth hours. In the patients receiving thiopental, both cortisol and aldosterone concentrations were greater than the baseline value (P < 0.05) in the second to fourth hours after induction. In the etomidate group, the plasma concentrations of cortisol were less than baseline values (P < 0.05) in the first and second hours after induction of anesthesia and both cortisol and aldosterone were lower than those in the thiopental group (P < 0.05) in the half to fourth hours after induction. These results confirm an earlier report of the suppression of cortisol after etomidate administration and, because aldosterone also was suppressed, suggests that etomidate exerts its effect by inhibiting early stages of steroidogenesis in the adrenal cortex.

Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant

The purpose of this multicenter, randomized, assessor-blind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular relaxant, ORG 9487, provided both good to excellent tracheal intubating conditions 60 s after administration and a clinical duration of action <20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 micro g/kg) and thiopental (3-6 mg/kg) and maintained with N2 O/O2 and a propofol infusion (50-300 micro g [centered dot] kg-1 [centered dot] min-1). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxograph) commenced immediately after anesthetic induction and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% T1 recovery), and recovery (TOF >or=to 0.7) were measured. Dose-dependent changes were observed in tracheal intubating conditions and neuromuscular block. Good to excellent intubating conditions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses >or=to1.5 mg/kg. Mean clinical durations <20 min were observed in adult patients at doses up to 2.0 mg/kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5-2.0 mg/kg ORG 9487 enabled both rapid tracheal intubation and a short clinical duration of action in adult and elderly patients. (Anesth Analg 1997;84:1011-8)

Statistical methods in anesthesia articles: An evaluation of two American journals during two six-month periods

Simple criteria were used to evaluate the statistical analyses in 243 articles from two American anesthesia journals published in the latter six months of 1981 and 1983. Eighty-two percent of the articles reported the use of control measures and 37% reported randomization of treatment, where they were possible. Data were classified as nominal, ordinal, or interval; as independent or related samples; as two-sample or more-than-two-sample cases. The descriptive, inferential, and correlative tests used were evaluated for appropriate application and primary errors were identified. Nine percent of the 722 descriptive statistics had major errors, most of which were a description of ordinal data as though they were interval. The incidence of erroneous applications of 394 inferential statistical tests was 78%. Nearly three-quarters of the 308 primary inferential statistical errors involved either use of a test for independent samples on related data (and vice versa) or multiple applications of an uncorrected test to the same data. Only 4% of the 113 statistics of association were considered erroneous, most because the method was not identified. No differences were detected in the incidence of errors in either experimental design or statistical analysis across time or across the two anesthesia journals. Fifteen percent of the 243 articles in both journals at both times were without major errors in statistical analysis. Recognition of potential sources of error should make it easier for investigators to use experimental designs and statistical analyses appropriate to their needs.

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.

Continuous intravenous infusion of rocuronium (ORG 9426) in patients receiving balanced, enflurane, or isoflurane anesthesia.

BackgroundRocuronium (ORG 9426) Is a new nondepolarizing neuromuscular blocking agent with a rapid onset and an intermediate duration of action. This study obtains the infusion requirements of rocuronium in 30 patients in whom anesthesia was maintained with barbiturate-nitrous oxide-opioid, nitrous oxide and enflurane, or nitrous oxide and isoflurane. MethodsFor all 30 patients, anesthesia was induced with intravenous thiopental and fentanyl, followed by 0.45 mg/kg rocuronium. Patients were randomly allocated to receive either: 1) nitrous oxide in 40% oxygen supplemented with fentanyl, thiopental, and droperidol (balanced anesthesia), 2) 1.25 MAC enflurane-nitrous oxide, or 3) 1.25 MAC isoflurane-nitrous oxide. Once blockade had recovered to 95% depression of twitch height, muscle relaxation was maintained by continuous Infusion of rocuronium, adjusted to maintain mechanical twitch response at 95% depression. ResultsAt 90 and 120 min, the enflurane and isoflurane groups had lower Infusion requirements than those receiving barbiturate-nitrous oxide-opioid anesthesia (P < 0.02), but these did not differ significantly between the two volatile agents. Final infusion requirements (mean ± SD) were 9.8 ± 3.7, 5.9 ± 3.1, and 6.1 ± 2.7 μg·kg-1·min-1 for the groups receiving barbiturate-nitrous oxide-opioid, enflurane, and isoflurane anesthesia, respectively. Spontaneous recovery began soon after termination of the infusion; in all patients, twitch tension equaled 10% of control within 5 min. ConclusionsThe infusion requirements to maintain 95% twitch depression approximated 10 μg·kg-1·min-1 during barbiturate-nitrous oxide-opioid anesthesia. These requirements were reduced by 40% during anesthesia involving enflurane or isoflurane.

Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia

Mivacurium chloride (BW B1090U) was administered to 72 patients during their elective surgery. The eight groups (nine subjects per cell) in the 2 x 2 x 2 study design differed in three factors: the size of the mivacurium bolus dose administered, whether or not this dose was followed by an infusion of mivacurium, and in the technique used for the maintenance of anesthesia. Four groups received a single bolus dose of mivacurium, 0.15 mg/kg, and the remaining four groups received mivacurium, 0.25 mg/kg, administered iv in 15 s. Precisely 2 min later, tracheal intubation was attempted. Conditions were judged to be good or excellent on most occasions, but intubation was not possible for two of the patients in the low-dose and one in the high-dose groups. Four groups, two at each bolus dose, received no additional mivacurium: there was a dose-dependent decrease in the rate of spontaneous recovery following the bolus dose. The other subdivision of groups was the use of either barbiturate-nitrous oxide-narcotic (balanced) anesthesia, or enflurane-nitrous oxide anesthesia; the anesthetic technique did not affect the pattern of spontaneous recovery from either bolus dose. Four groups, again two at each bolus dose, subsequently received an infusion of mivacurium, adjusted to depress the twitch response by approximately 95%. Infusion rates averaged 6.0 micrograms.kg-1.min-1 in the groups receiving balanced anesthesia and 4.2 micrograms.kg-1.min-1 for those receiving enflurane anesthesia. Recovery following administration by infusion was slower than that observed following a bolus dose of mivacurium, 0.15 mg/kg but did not differ between the anesthetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of parallel erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs

The gamma and Erlang density functions describe a large class of lagged, right-skewed distributions. The Erlang distribution has been shown to be the analytic solution for a chain of compartments with identical rate constants. This relationship makes it useful for the analysis of first-pass pulmonary drug uptake data following intravenous bolus administration and the incorporation of this analysis into an overall systemic drug disposition model. However, others have shown that one Erlang density function characterizes the residence time distribution of solutes in single tissues with significant systematic error. We propose a model of two Erlang density functions in parallel that does characterize well the arterial appearance of indocyanine green, antipyrine, and alfentanil administered simultaneously by right atrial bolus injection. We derive the equations that permit calculation of the higher order moments of a system consisting of two parallel Erlang density functions and use the results of these calculations from the data for all three indicators to estimate pulmonary capillary blood volume and mean transit time in the dog.

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 x min(-1) x kg(-1), was higher than that of the R-(-)-enantiomer, 22.2 ml x min(-1) x 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. CONCLUSIONS Although the elimination clearance of S-(+)-ketamine is 35% greater than that of the R-(-)-enantiomer, there is no difference in the apparent pulmonary tissue volume or peripheral tissue distribution between the stereoisomers, suggesting that physicochemical properties of ketamine other than stereoisomerism determine its perfusion-limited tissue distribution.

Isoflurane alters the recirculatory pharmacokinetics of physiologic markers

Background Earlier studies have demonstrated that physiologic marker blood concentrations in the first minutes after administration, when intravenous anesthetics exert their maximum effect, are determined by both cardiac output and its distribution. Given the reported vasodilating properties of isoflurane, we studied the effects of isoflurane anesthesia on marker disposition as another paradigm of altered cardiac output and regional blood flow distribution. Methods The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1.7%, 2.6%, and 3.5% isoflurane (1.15, 1.7, and 2.3 minimum alveolar concentration, respectively) in a randomized order determined by a Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on very frequent early, and less frequent later, arterial blood samples. These models characterize the role of cardiac output and regional blood flow distribution on drug disposition. Results Isoflurane caused a significant and dose-dependent decrease in cardiac output. Antipyrine disposition was profoundly affected by isoflurane anesthesia, during which nondistributive blood flow was maintained despite decreases in cardiac output, and the balance between fast and slow tissue volumes and blood flows was altered. Conclusions The isoflurane-induced changes in marker disposition were different than those the authors reported previously for halothane anesthesia, volume loading, or hypovolemia. These data provide further evidence that not only cardiac output but also its peripheral distribution affect early drug concentration history after rapid intravenous administration.

Indocyanine green kinetics characterize blood volume and flow distribution and their alteration by propranolol

Although indocyanine green can be used to estimate cardiac output and blood volume independently, a recirculatory multicompartmental indocyanine green model enables description of these and additional intravascular events. Our model was used to describe the effect of propranolol on blood volume and flow distribution in humans.