James C. Scott

Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil.

The authors compared the pharmacodynamics of sufentanil with those of fentanyl using the electroencephalogram (EEG) as a measure of opioid drug effect. Sixteen patients were given a rapid infusion of sufentanil (18.75 micrograms/min) during EEG recording. To quantitate the opioid-induced slowing of the EEG, the authors analyzed its power spectrum and calculated the spectral edge. An inhibitory sigmoid Emax model of the maximal decrease in spectral edge produced by the opioid related spectral edge values to serum concentrations of sufentanil. The resulting data for the pharmacodynamic parameters of sufentanil were compared with fentanyl parameters that were obtained by reanalysis from an identically conducted, previously published study. The half-time of blood-brain equilibration (T1/2Keo) was not statistically different between sufentanil and fentanyl (6.2 +/- 2.8 vs. 6.6 +/- 1.7 min, mean +/- SD, respectively). The intrinsic potency of sufentanil, as measured by the serum concentration needed to cause half the maximal EEG slowing (IC50), was 12-fold greater (0.68 +/- 0.31 ng/ml) than that of fentanyl (8.1 +/- 2.2 ng/ml). The second part of the study verified the hypothesis that administration of equipotent bolus doses would produce equal onset times. Bolus injections of either 125 micrograms of sufentanil or 1,250 micrograms of fentanyl were given during EEG recording. The time from injection to 50% maximal EEG slowing (T50) was calculated for each patient. The values for T50 for the two groups did not differ. The authors conclude that fentanyl and sufentanil have similar pharmacodynamic profiles, the former being 12 times more potent than the latter.

Pharmacokinetics of fentanyl administered by computer-controlled infusion pump.

Fentanyl was administered to 21 patients using a computer-controlled infusion pump (CCIP) based on a pharmacokinetic model. Eleven of the patients were dosed according to the pharmacokinetics described by McClain and Hug, and ten of the patients were dosed according to the pharmacokinetics described by Scott and Stanski. The authors measured the difference between the measured arterial fentanyl concentrations and the concentrations predicted by the CCIP for each pharmacokinetic parameter set. The median absolute performance error (MDAPE) in patients dosed according to McClain and Hugs parameters was 61%, and the MDAPE in patients dosed according to Scott and Stanskis parameters was 33%. The population pharmacokinetics in these 21 patients were analyzed using a pooled data technique. The pharmacokinetics of fentanyl in this population showed a smaller central compartment volume and a more rapid initial distribution half-life than previously estimated for fentanyl. The derived pharmacokinetic parameters described these patients well and also predicted the observed fentanyl concentrations from four previously published fentanyl studies with reasonable accuracy. Comparison of the parameters used by the authors with those of McClain and Hug demonstrated that dosing regimens designed from pharmacokinetic models can be fairly accurate at the times sampled in the original study but may not be accurate at time points not sampled in the original research. The authors concluded that although the pharmacokinetics of fentanyl administered by CCIP are the same as the pharmacokinetics of fentanyl administered by a bolus or constant rate infusion, a pharmacokinetic study using a CCIP may be particularly effective at characterizing the most rapid distribution pharmacokinetic parameters, and thus may provide parameters appropriate for subsequent use in a CCIP.

Testing Computer-controlled Infusion Pumps by Simulation

The pharmacokinetic behavior of intravenous anesthetic drugs can be described by two- or three-compartment models. Rapid achievement and maintenance of steady plasma concentrations of these drugs requires a complicated delivery scheme, perhaps best controlled by a computer. The authors developed a method of simulating the performance of a computer-controlled infusion pump from the differential equations describing drug transfer between compartments. They also derived a mathematically simple and flexible approximate solution to these equations using Eulers numerical method. They incorporated this approximate solution into a computer-controlled infusion pump for intravenous drugs. They tested their pump by simulating the administration of fentanyl to a hypothetical patient whose fentanyl pharmacokinetics were described by a three-compartment model. The exact analytical solution served as the standard of comparison. The approximation technique, using a 15-s interval between model updates, had a maximum error of 0.35 ng.ml-1, and rapidly converged on the exact solution. The simulations revealed oscillations in the system. The authors suggest that such simulations be used to evaluate computer-controlled infusion pumps prior to clinical trials of these devices.

Preanesthetic medication in children: a comparison of oral transmucosal fentanyl citrate versus placebo

Initial studies have suggested that oral transmucosal fentanyl citrate (OTFC) in a dose of 15-20 micrograms/kg may be a safe and effective preanesthetic medication in children and adults, but this has not been demonstrated in a randomized, double-blind fashion. The purpose of this study was to determine in a randomized, double-blind manner, the efficacy of a lollipop containing fentanyl citrate as a preanesthetic medication before surgery in children. Forty health ASA physical status 1 or 2 children 3-12 yr of age were divided randomly and in double-blind fashion into two groups. Group 1 received the lollipop containing OTFC and group 2 received a placebo lollipop. An appropriate size lollipop was chosen so that if the patient received fentanyl, the total dose would be 15-20 micrograms/kg. Anxiety, sedation, and separation scores were assessed preoperatively and ease of induction was rated. Oxygen saturation and respiratory rate were monitored. Time intervals from preanesthetic to induction and from recovery room (PACU) admission to discharge were noted. Recovery room behavior was assessed upon admission and discharge. Complications and the need for postoperative opioids were noted. OTFC produced significantly more sedation and less anxiety compared with that following placebo. Respiratory rate was significantly decreased in the OTFC group, but oxygen saturation was not significantly different between groups. Anxiety and separation scores and the quality of induction were better in the OTFC group. There was a higher incidence of nausea and pruritus in the fentanyl group. OTFC did not prolong the PACU stay.

Anesthetic mishaps and the cost of monitoring: A proposed standard for monitoring equipment

Review of insurance data indicates that approximately 1.5 claims are paid per 10,000 anesthetic procedures, a conservative estimate of the incidence of preventable serious injury associated with anesthesia. Insurance data permit estimation of the premium cost for the anesthesiologist and hospital, per operating room per year, of

Simultaneous measurements of cardiac output by thermodilution, esophageal Doppler, and electrical impedance in anesthetized patients.

69,429.00. We propose the use of an enhanced monitoring standard requiring a pulse oximeter, capnograph, spirometer, halometer, automatic sphygmomanometer, breathing circuit oxygen analyzer, stethoscope, electrocardiographic monitor, and temperature monitor. We suggest that this premium cost, together with the estimate that 50% of incidents would be avoided, predicts a resultant saving of over

Improved Radioreceptor Assay of Opiate Narcotics in Human Serum: Application to Fentanyl and Morphine Metabolism

27,000/operating room/year, a savings equal to the entire cost of the enhanced monitoring system in approximately 8 months, or a yearly savings of over five times the annualized expense of the monitoring system. Thus, in addition to the moral imperative to monitor a patient during anesthesia to avoid injury and death, there is an economic incentive to monitor effectively.

EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil.

Simultaneous intraoperative measurements of cardiac output were obtained in nine patients with transesophageal Doppler, transthoracic impedance, and pulmonary artery thermodilution techniques to evaluate the utility of the noninvasive methods. Pairs of noninvasive and thermodilution measurements were obtained 25 times with transesophageal Doppler and 58 times with transthoracic impedance. Correlation of the noninvasive measurements with thermodilution was poor, with r = 0.43 for transthoracic impedance and r = .68 for transesophageal Doppler. The average difference between the noninvasive and the thermodilution values was -0.4 +/- 1.4 L/min (mean +/- SD) and -0.1 +/- 1.6 L/min for impedance and Doppler, respectively. Changes in cardiac output at sequential time points as measured by thermodilution were predicted with 95% confidence only when a change of >4 L/min was observed by transesophageal Doppler or >8 L/min was observed by transthoracic impedance. Therefore, it is concluded that neither noninvasive technique reliably estimated cardiac output as determined by thermodilution, and neither tracked trends.

Seizure-like Movements during a Fentanyl Infusion with Absence of Seizure Activity in a Simulataneous EEG Recording

A recently developed radioreceptor assay (RRA) (1) that employs 3H-naloxone and rat brain membrane homogenates was improved two ways. First, the brain membranes were preincubated in the presence of sodium ions, and second, manganase-II ions were added to the sample incubations. These changes enhanced the assay sensitivity and reproducibility with stored membrane preparations and reduced the effects of serum constituents (Na+) on ligand–receptor binding. Patient sera were assayed by radioimmunoassay (RIA) and RRA after fentanyl administration and by high-performance liquid chromatography (HPLC) and RRA after morphine administration. The results with both fentanyl assays were comparable, and no fentanyl metabolites were detectable by RRA after HPLC of serum extracts. In contrast, preliminary results with the HPLC-RRA procedure suggest the presence of an active morphine metabolite of unknown structure in sera obtained from patients on morphine therapy.