Timothy J. Quill

Preliminary Pharmacokinetics and Pharmacodynamics of an Ultra-short-acting Opioid: Remifentanil (gi87084b)

Remifentanil is a newly synthesized 4-anilidopiperidine with an ester side chain susceptible to esterase metabolism. We evaluated the safety, analgesic efficacy, and pharmacokinetics of remifentanil in 48 male volunteers. Volunteers were randomized to receive increasing doses of remifentanil, alfentanil, or placebo. Analgesic efficacy was evaluated by increasing tolerance to a spring-loaded rod measured at the tibia and sternum at multiple time points. Respiratory depression was measured by changes in arterial blood gas tensions and peripheral hemoglobin oxygen saturation. Hemodynamics were continuously monitored by means of an intra-arterial catheter. Both remifentanil and alfentanil produced a dose-dependent increase in analgesia and respiratory depression. Remifentanil was 20 to 30 times more potent (milligram to milligram) than alfentanil when assessed by either analgesic efficacy or respiratory measures. The pharmacokinetics of remifentanil were best described by a biexponential decay curve. Remifentanil had a small volume of distribution of 0.39 (SD, ±0.25) L/kg (alfentanil, 0.52 ± 2 L/kg), with a rapid distribution phase of 0.94 (SD, ±0. 57) min and an extremely short elimination half-life of 9.5 (SD, ±4) min compared with an elimination half-life of alfentanil of 58 (SD, ±7.6) min. The t1/2 ke0 (half-time for equilibration between plasma and the effect compartment) of remifentanil for analgesia was calculated as 1.3 min. Thus, remifentanil appears to have a pharmacologic profile similar to other potent μ agonists, but with exceptionally short-lasting pharmacokinetics, which is likely to make it a very useful opioid for clinical practice.

Pharmacokinetic model-driven infusion of fentanyl: assessment of accuracy.

Computer-assisted continuous infusion (CACI) is a pharmacokinetic model-driven infusion device that enables physicians to administer intravenous (iv) drugs in a quantitative fashion, specifying a theoretical blood or plasma concentration. This study evaluated the accuracy of CACI administration of fentanyl using a newly developed CACI device programmed with a well-known set of pharmacokinetic parameters for fentanyl. Patients received diazepam 1 or 2 h before surgery. Anesthesia was induced by a combination of 70% N2O and fentanyl administered by CACI to a predicted concentration of 15-25 ng.ml-1. After neuromuscular blockade and tracheal intubation, the desired plasma fentanyl concentration (setpoint) entered into CACI was 3-6 ng.ml-1, and then the setpoint fentanyl concentration was titrated according to strict criteria of adequate or inadequate anesthesia. Plasma samples for subsequent assay of fentanyl concentration then were taken: at predefined stimuli, when inadequate anesthesia occurred, or 5 min before an anticipated decrease in the fentanyl setpoint. The predictive accuracy of CACI was assessed by calculating for each patient the tenth, 50th, and 90th percentile of the performance error and absolute performance error from each measured and predicted plasma sample pair. Cumulative probability functions for each of these were then plotted. Precision was defined as the dispersion of the tenth to 90th percentile of the median percent performance error for the population and was found to be -31-26%. The median population performance error was -4%, and the median population absolute performance error was 21%.(ABSTRACT TRUNCATED AT 250 WORDS)

Onset and duration of neuromuscular blockade following high-dose vecuronium administration.

To determine the onset time and duration of high doses of vecuronium, 40 ASA Physical Status 1 and 2 patients were randomly assigned to receive either 100, 200, 300, or 400 micrograms/kg of vecuronium bromide for muscle relaxation during elective general surgery. Neuromuscular blockade was continuously quantitated by recording the electromyographic response to stimulation of the ulnar nerve train-of-four. The rate of onset of neuromuscular blockade, endotracheal intubating conditions, duration of neuromuscular blockade, and hemodynamic effects of vecuronium at each dose were evaluated and compared. The time from vecuronium administration to complete abolition of twitch tension (T1 = 0%) decreased from 208 +/- 41 to 106 +/- 35 s as the vecuronium dose was increased from 100 to 400 micrograms/kg (P less than 0.01). Corresponding times to endotracheal intubation (T1 less than 20%) also decreased from 183 +/- 24 to 96 +/- 31 s with increasing doses (P less than 0.01). Recovery time (T1 = 25%) increased from 37 +/- 13 to 138 +/- 24 min with increasing doses (P less than 0.01). No significant hemodynamic differences between the four groups were observed. Endotracheal intubating conditions were good or excellent in all patients. High doses of vecuronium may, therefore, be a useful alternative to succinylcholine when a rapid onset of neuromuscular blockade is required.

The relative accuracies of two automated noninvasive arterial pressure measurement devices

We compared the accuracies of two types of noninvasive blood pressure devices. Thirty-two patients requiring an intraarterial catheter for anesthetic management underwent simultaneous monitoring with Dinamap 1846SX and Ohmeda Finapres 3700 devices. For the first 10 minutes of recording, new Dinamap determinations were performed every 60 seconds; subsequent recordings were made at 3-minute intervals. Data were obtained at the time of new Dinamap readings, and twice between new readings to approximate the real-time performance of the two monitors. We defined superior accuracy as a statistically significant difference in mean absolute error greater than 5 mm Hg. With these criteria, pooled data from all patients revealed no difference in performance, even in real time. Pooled data can be misleading since there was a significant amount of variation in accuracy for both monitors. Therefore, we used nonparametric analysis to determine how many individual patients were monitored better by either device. When we compared only data from new Dinamap readings, the Finapres monitor showed superior performance for systolic readings in 13 patients, versus 6 patients for the Dinamap (P<0.05, chi-square test). Similar analysis for diastolic and mean pressure performance did not reach statistical significance. However, in real time, the Finapres unit monitored more patients more accurately for systolic (14 Finapres versus 3 Dinamap), diastolic (11 Finapres versus 3 Dinamap), and mean (10 Finapres versus 3 Dinamap) pressure determinations. The magnitude of these differences were, however, less dramatic than expected. This was probably due to stabilization of arterial pressure during the anesthetic, which minimized the error due to intermittent sampling. We conclude that continuous Finapres readings and new Dinamap determinations are equally accurate for diastolic and mean arterial pressures. The accuracy of Finapres appears to be slightly superior for systolic pressure. The intermittent sampling of oscillometric devices compromises their performance relative to the Finapres in many, but not all, cases.

Effect of altering pump flow rate on cerebral blood flow and metabolism in infants and children

The effects of reduced pump flow rate (PFR) on cerebral blood flow, cerebral oxygen consumption (CMRO2), oxygen extraction, cerebral vascular resistance, and total body vascular resistance were examined in 27 pediatric patients during hypothermic cardiopulmonary bypass (hCPB). During steady state hCPB the extracorporeal flows were randomly adjusted to a conventional PFR and a reduced PFR for each patient. The reduced pump flow rates were dictated by surgical needs. Cerebral blood flow measured using Xenon 133 clearance, and CMRO2 and oxygen extraction were calculated. Our results demonstrated that cerebral blood flow and CMRO2 are unchanged if pump flow rates are reduced by 35% to 45% of conventional PFRs at moderate and deep hypothermic temperatures. Reductions in PFR of 45%-70% from conventional PFRs affect the brain differently during either moderate or deep hCPB. At moderate hCPB (26 degrees to 29 degrees C), reductions in PFRs of 45% to 70% resulted in a significant decrease in cerebral blood flow and CMRO2, whereas oxygen extraction increased in a compensatory manner. During deep hCPB (18 degrees to 22 degrees C), PFR reductions of 45% to 70% of conventional PFR significantly reduced cerebral blood flow and CMRO2 but did not increase oxygen extraction, suggesting that at deep hypothermic temperatures, cerebral blood flow and CMRO2 exceed cerebral metabolic needs. Cerebral vascular resistance increased significantly with decreasing temperature but was not affected by pump flow reductions. We have derived indices for minimal acceptable low-flow cardiopulmonary bypass based on the known effects of temperature on cerebral metabolism and have speculated on its utility based on our limited data and a literature review.

CLINICAL RESPONSES TO ORG 9426 DURING ISOFLURANE ANESTHESIA

&NA; To determine average dose requirements and pharmacodynamic characteristics before general clinical use, the doseresponse curve, onset time, and recovery time for the neuromuscular relaxant ORG 9426 were determined in 72 adult patients given doses of 120, 160, 200, or 240 μg/kg after establishment of a steady‐state expired isoflurane concentration of approximately 1%. Neuromuscular blockade was continuously recorded using the ulnar evoked electromyogram. Using the log probit method, ED95 was 268 μg/kg, ED90 was 251 μg/kg, and ED50 was 144 μg/kg. The time until 80% blockade was 1.9 min at 240μg/kg, and the average time to peak effect was 4.6 min, which did not vary with dose. The clinical duration (injection until T1 returned to 25%) was 20.5 min, and the recovery index (T1 increased from 25% to 75% of control) was 15.4 min, after a total dose of 300 μg/kg. The duration of 75‐μg/kg and 100‐μg/kg repeat (maintenance) dose was 14.6 and 17.8 min, respectively, and no cumulative effect was apparent after as many as five maintenance doses. No cardiovascular side effects were seen at doses used in the study. We conclude that ORG 9426 is a nondepolarizing muscle relaxant with a rapid onset and short duration of action that deserves further clinical evaluation.

Evaluation of pentamorphone in humans: a new potent opiate

We evaluated the analgesic properties of 14-beta-n-pentylaminomorphinone (pentamorphone), a new morphinan derivative, in 23 male volunteers divided into 6 groups who were given either placebo (1 per group) or 0.015, 0.03, 0.06, 0.12, 0.24, 0.48 ug-kg−1 pentamorphone intravenously. Analgesia was evaluated by the maximal tolerance to a spring-loaded rod on the tibia and manubrium. Analgesic assessments and arterial blood samples were taken prior to and at set time intervals following drug administration. Pentamorphone produced a linear increase in pain tolerance with increasing dose as well as a dose-dependent depression of ventilation. Pentamorphone had no effect on blood pressure or heart rate in the doses used. Plasma histamine levels at 5 minutes were not elevated with any of the dosages. Pentamorphone appears to be an analgesic with clinically tolerable side effects in the range 0.12 to 0.24 Hg-kg-1 that merits further evaluation under clinical conditions.

Accuracy of drug infusion pumps under computer control

Infusion rates demanded of the infusion pump in many computer-controlled drug delivery applications are made to change at intervals much shorter than those encountered under routine clinical use. The purpose of this study was to validate the volumetric accuracy of three commercially available infusion pumps operating in a demanding computer-controlled application. In independent 2-h evaluations, the infusion rate demanded of each pump changed as often as every 5, 10, or 15 s using an algorithm for computer-controlled pharmacokinetic model-driven intravenous infusion. Accuracy of the infusion devices was determined gravimetrically. At all measurement times, each of the infusion pumps was accurate to within approximately +or-5% of the expected volumetric output under each of the infusion rate intervals tested. Flow rate accuracy of +or-5% is equal to the nominal expected accuracy of these infusion pumps in conventional clinical use.<<ETX>>

A Comparison of Mivacurium Dosage Requirements During Isoflurane and Desflurane Anesthesia

STUDY OBJECTIVE To evaluate the dose requirement and recovery characteristics of mivacurium infusions during anesthesia with equipotent concentrations of either desflurane or isoflurane. DESIGN Randomized, open-study comparing the effects of desflurane and isoflurane on mivacurium-induced neuromuscular blockade. SETTING Operating suite of a university-affiliated medical center. PATIENTS 41 ASA status I, II, and III adult patients, requiring more than 45 minutes of neuromuscular blockade for surgery. INTERVENTIONS Following a standardized induction sequence and established steady desflurane-nitrous oxide (DES group) or isoflurane-nitrous oxide (ISO group) anesthesia at 1 minimum alveolar concentration (MAC), an intubating dose of 0.2 mg/kg of mivacurium chloride was administered. Ventilation was maintained with a face mask until the first twitch (T1) of the evoked train-of-four (TOF) reached 10% or less of control when tracheal intubation was performed. T1 was allowed to return to 10% of its control value. An infusion of mivacurium at the initial rate of 5 micrograms/kg/min was then started and adjusted to maintain T1 at 10% +/- 2% of control. Within 20 minutes of completion of surgery, the mivacurium infusion was stopped, and the time for the evoked electromyograph (EMG) to return to 25% and 75% of the original baseline was noted. MEASUREMENTS AND MAIN RESULTS Neuromuscular function was monitored continuously by an evoked EMG. The average infusion rate was 5.7 +/- 2.4 micrograms/kg/min (mean +/- SD) for DES group (n = 20) and 6.6 +/- 2.7 micrograms/kg/min for ISO group (n = 21) (p = NS). There was no change in the infusion rate of mivacurium over time for both groups. However, there was an inverse relationship in both groups between the time to recovery following a bolus dose and the subsequent mean infusion rate of mivacurium (correlation coefficient = -5.0; p < 0.005). The spontaneous recovery index (T25-75) for the two groups was identical, 11.5 +/- 4.9 min (mean +/- SD) for DES group and 11.5 +/- 7.9 min for ISO group (p = NS). CONCLUSION There were no differences in the dose requirement and recovery indices of mivacurium during either desflurane or isoflurane-based anesthesia. Patients who took longer to recover from the bolus dose in both groups showed a subsequent reduction in dose requirements of mivacurium.

Pharmacokinetic basis of intravenous drug delivery

Summary We have seen in recent years the release of numerous intravenous anaesthetic agents whose duration of action is relatively short, thus lending themselves to administration via continuous infusion. Clinical studies have clearly demonstrated the advantages of continuous infusion over repeated bolus dosing. These two factors have prompted pump manufacturers to produce devices that simplify the administration of intravenous anaesthetics by continuous infusion. It is concentration rather than dose that results in the desired effect. Utilizing pharmacokinetic principles, it is possible to provide automated drug delivery systems whereby the device can produce a clinician-specified drug concentration. In addition, where there is an easily measurable end-point, closed-loop feedback control can be implemented automatically to control the desired parameter within a very narrow range. With this rapid development in intravenous drug delivery, it becomes imperative that clinicians familiarize themselves with these new drug delivery devices so that they can use them optimally to care for their patients.