Scott Howell

Measured Context-sensitive Half-times of Remifentanil and Alfentanil

BackgroundThe context-sensitive half-time, rather than the terminal elimination half-life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context-sensitive half-time is derived from computer modelling using

The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the bispectral index

The Bispectral Index (BIS) correlates well with the level of consciousness with single anesthetic drugs.We studied the effect of the interaction of propofol with alfentanil on propofol concentration and BIS associated with 50% probability of loss of consciousness and lack of recall (Cp50 and BIS50,

Determination of plasma concentrations of propofol associated with 50% reduction in postoperative nausea

Background: Subhypnotic doses of propofol possess direct antiemetic properties. The authors sought to determine the plasma concentration of propofol needed to effectively manage postoperative nausea and vomiting. Methods: Patients aged 18–70 yr who were classified as American Society of Anesthesiologists physical status 1 or 2 and had surgery during general anesthesia were approached for the study. Only patients who had nausea (verbal rating score > 5 on a 0‐ to 10‐point scale), retching, or vomiting in the postanesthetic care unit participated. Propofol was administered to these patients to achieve target plasma concentrations of 100, 200, 400, and 800 ng/ml using a computer‐assisted continuous infusion device. Target concentrations were increased every 15 min until patients described at least a 50% reduction in symptoms on the verbal rating score. An arterial blood sample was obtained at each step. The measured plasma propofol concentrations were used to analyze data. Blood pressure, heart and respiratory rates, arterial blood saturation, sedation score, and overall satisfaction with treatment were recorded. Results: Of the 89 patients who consented to the study, 15 patients met entry criteria and were enrolled. Five of these patients also had retching or vomiting when they entered the study. Fourteen patients responded successfully to treatment. One patient did not achieve the required response at plasma concentrations of 830 ng/ml. Hence the success rate for the treatment of postoperative nausea and vomiting was 93%. Among patients who responded, the median plasma concentration associated with an antiemetic response was 343 ng/ml. There was no difference in sedation scores from baseline and no episodes of desaturation. Hemodynamic parameters were stable during the study. Conclusions: Propofol is generally efficacious in treating postoperative nausea and vomiting at plasma concentrations that do not produce increased sedation. Simulations indicate that to achieve antiemetic plasma propofol concentrations of 343 ng/ml, a bolus dose of 10 mg followed by an infusion of approximately 10 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1 are necessary.

Targeting Effect Compartment or Central Compartment Concentration of Propofol What Predicts Loss of Consciousness

BACKGROUND An effect compartment has been postulated, and the ke0 has been quantified for several intravenous anesthetic drugs using electroencephalography (EEG) as the measure of effect. The authors wanted to validate that loss of responsiveness (LOR) was related to targeting an effect compartment concentration rather than a central compartment (plasma) concentration. METHODS Twenty American Society of Anesthesiologists physical status I and II patients were randomized to receive propofol administered to a target central compartment or target effect compartment site concentration of 5.4 microg/ml propofol administered by a target-controlled infusion (TCI) using a previously validated set of pharmacokinetic parameters and a ke0 of 0.63 min(-1). Every 30 s for the first 5 min and every minute for the second 5 min the patients were asked to open their eyes. The time to LOR was measured by a blinded investigator. The authors also simulated the time to reach the desired target effect site concentration using varying ke0 values. RESULTS The median time to LOR in the group targeted to a predicted plasma propofol concentration was 3.02 min and 1.23 min in the group targeted to a predicted effect compartment propofol concentration (P < 0.05). LOR to command in both groups occurred at a predicted median effect compartment concentration of 4.55 microg/ml. Simulations demonstrated that the time predicted to LOR targeting an effect site concentration of 5.4 microg/ml is markedly altered by the value chosen for the ke0. CONCLUSIONS This study confirms the utility of the ke0 value to describe the effect compartment for propofol. The authors also illustrate the importance of selecting the correct ke0 value for the pharmacokinetic parameters used within the TCI system.

Drug Interactions: Volatile Anesthetics and Opioids

Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided.

Pharmacokinetic Model-driven Infusion of Fentanyl in Children

Background This study determined the accuracy of previously defined adult fentanyl pharmacokinetics in children having surgery; from this population, the pharmacokinetics of fentanyl were characterized in children when administered via a computerized assisted continuous-infusion device. Methods Twenty children between the ages of 2.7 and 11 y scheduled to undergo elective noncardiac surgery were studied. After induction, anesthesia was maintained with 60% nitrous oxide in oxygen supplemented with fentanyl (n = 10) or fentanyl plus isoflurane (n = 10). Fentanyl was administered via computerized assisted continuous-infusion to target concentrations determined by clinical requirements. Plasma fentanyl concentrations were measured and used to evaluate the performance of the fentanyl pharmacokinetics and then to determine a new set of pharmacokinetic parameters and the variance in the context-sensitive half-times simulated for these patients. Results The original adult fentanyl pharmacokinetics resulted in a positive bias (10.4%), indicating that measured concentrations were mostly greater than predicted. A two-compartment model with age and weight as covariates provided the optimal pharmacokinetic parameters. These resulted in a residual performance error of -1.1% and a median absolute performance error of 17.4%. The context-sensitive times determined from this pediatric population were considerably shorter than the context-sensitive times previously published for adults. Conclusions The pharmacokinetics of fentanyl administered by computerized assisted continuous-infusion differ between adults and children. The newly derived parameters are probably more suitable to determine infusion schemes of up to 4 h in children between the ages of 2 and 11 y.

How to manage drug interactions.

Multiple drugs are used to provide anaesthesia. On average, four to six drugs are used during anaesthesia and, therefore, drug interactions are common. These interactions are primarily either pharmacokinetic or pharmacodynamic. Due to the relatively short duration of drug administration for anaesthesia, pharmacokinetic drug interactions resulting from alterations in drug metabolism do not generally produce clinically significant effects. Pharmacodynamic-drug interactions between anaesthetic drugs, however, are potentially serious. This may reflect that anaesthesia is not a single entity, but a process provided by a combination of drugs; i.e. loss of consciousness, analgesia and neuromuscular blockade. An understanding of each drugs pharmacokinetics, pharmacodynamics and drug interactions will allow clinicians to administer drugs to provide a more optimal anaesthetic.