Enhancing a sedation score to include truly noxious stimulation: the Extended Observer's Assessment of Alertness and Sedation (EOAA/S).

BACKGROUND: Although the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) is frequently used in sedation-related drug and device studies, a major shortcoming is that it does not differentiate between lighter and deeper levels of general anaesthesia because the only noxious stimulus of the MOAA/S is a trapezius squeeze. The primary aim of this investigation was to expand the MOAA/S score to include truly noxious stimulation, thereby extending the dynamic range of the assessment to include sedation states consistent with deeper levels of general anaesthesia. METHODS: Twenty healthy volunteers received target controlled infusions of fentanyl (target=0.8 ng ml(-1)) and propofol (starting at 0.5 µg ml(-1) and gradually increasing to 5 µg ml(-1)). At each propofol concentration, a MOAA/S score was obtained before and after tetanic electrical stimulation. The tetanic electrical stimulation current was gradually increased until the subject responded or until 50 mA was delivered without a response. A pharmacodynamic model was constructed to characterize the concentration-effect relationship between propofol and the MOAA/S scores. RESULTS: All subjects required a significantly higher propofol concentration to produce unresponsiveness to tetanic electrical stimulation at 50 mA compared with a standardized trapezius squeeze. The pharmacodynamic model adequately characterized the concentration-effect relationship. CONCLUSIONS: The Extended Observer's Assessment of Alertness and Sedation (or EOAA/S) extends the range of the widely used MOAA/S score to include truly noxious stimulation, thereby enabling the identification of drug-induced central nervous system depression representative of surgical anaesthesia.

Remifentanil by bolus injection: a safety, pharmacokinetic, pharmacodynamic, and age effect investigation in human volunteers.

BACKGROUND: Although remifentanil's short-acting pharmacokinetic profile makes it well suited for procedures during which a brief period of intense analgesia is required, setting up an infusion pump for brief procedures is inconvenient. The clinical pharmacology of remifentanil administered by bolus injection, a more convenient alternative, has not been explored in detail. The primary aim of this study was to examine the safety of single bolus doses of remifentanil in conscious, healthy, adult volunteers breathing room air. Secondary aims included the evaluation of remifentanil pharmacokinetics and analgesic effects after bolus injection and a comparison of these issues in younger vs older adults. METHODS: Using a randomized, double-blind, placebo-controlled, dose-escalation, crossover study design, 64 subjects (16 over 60 years old) received remifentanil or placebo by bolus injection in a fixed unit dose separated by a 1 h washout period. Respiratory effects were assessed using a respiratory intervention scale. Analgesic effects were assessed using pressure algometry. A population pharmacokinetic model was constructed using non-linear, mixed-effects modelling techniques based on arterial blood samples. Computer simulations were performed to illustrate the clinical application of the pharmacokinetic model. RESULTS: Dose-related increases in both respiratory and analgesic effects were observed. In general, the respiratory depression observed was mild and easily treated with requests to breathe or the administration of oxygen, although the older cohort (and some younger subjects) experienced more substantial respiratory depression at lower doses. The pharmacokinetics of bolus-dose remifentanil were adequately described by a two-compartment model. The pharmacokinetic simulations illustrated the potential utility of bolus-dose remifentanil. CONCLUSIONS: Bolus injection could potentially be a safe and effective means of administering remifentanil in clinical situations requiring a brief period of intense analgesia. Because some subjects, both old and young, experienced significant respiratory depression even at low doses, careful monitoring of respiratory function is essential.

Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model.

BACKGROUND: The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic-pharmacodynamic model of propofol infusions in ICU patients. METHODS: With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2-5. Propofol administration in the first 20 subjects was based on a previously derived pharmacokinetic model for propofol. The last 10 subjects were given propofol based on a pharmacokinetic model derived from the first 20 subjects. Plasma propofol concentrations were measured, together with sedation score. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then prospectively tested in the last 10 subjects. An integrated pharmacokinetic-pharmacodynamic model was used to construct dosing regimens for light and deep sedation with propofol in ICU patients. RESULTS: The pharmacokinetics of propofol were described by a three-compartment model with lean body mass and fat body mass as covariates. The pharmacodynamics of propofol were described by a sigmoid model, relating the probability of sedation to plasma propofol concentration. The pharmacodynamic model for propofol predicted light and deep levels of sedation with 73% accuracy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3, 4, and 5 were 0.25, 0.6, 1.0, and 2.0 microg/ml. Predicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 --> 2) with propofol were 13, 34, 198, and 203 min, respectively. Corresponding emergence times from deep sedation (sedation score = 5 --> 2) with propofol were 25, 59, 71, and 74 h. CONCLUSIONS: Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient's body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.

Influence of hemorrhagic shock on remifentanil: a pharmacokinetic and pharmacodynamic analysis.

BACKGROUND: Hemorrhagic shock is known to alter significantly the pharmacokinetics of fentanyl, an opioid that requires delivery to the liver for metabolism. The authors hypothesized that the pharmacokinetics and pharmacodynamics of remifentanil, an esterase metabolized opioid that does not require delivery to a metabolic organ, would be altered less by hemorrhagic shock that those of fentanyl. METHODS: Sixteen pigs were assigned randomly to control and shock groups. The shock group was bled using an isobaric hemorrhage model. Remifentanil 10 microg x kg(-1) x min(-1) was infused for 10 min to both groups. Arterial samples were collected for remifentanil concentration assay. Pharmacokinetic parameters were estimated using a three-compartment model. The electroencephalogram spectral edge was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. RESULTS: Remifentanil blood levels were higher in the shocked group. The central clearance was slower and the central compartment was smaller in shocked animals. No difference between groups was observed in the magnitude or time course of the remifentanil-induced decrease in spectral edge. CONCLUSIONS: Hemorrhagic shock altered the pharmacokinetics of remifentanil, suggesting that less remifentanil would be required to maintain a target plasma concentration. However, because of its rapid metabolism, the impact of hemorrhagic shock on the concentration decline of remifentanil after termination of the infusion was minimal. Hemorrhagic shock did not alter the pharmacodynamics of remifentanil.

The use of remifentanil for Cesarean section in a parturient with recurrent aortic coarctation.

PURPOSE: To illustrate the clinical utility of a short acting opioid (remifentanil) based general anesthetic for Cesarean section in a parturient with compromised cardiac function. CLINICAL FEATURES: A 23-yr-old primigravida, complicated by a recurrent aortic coarctation with an approximate 50% narrowing of the aortic arch, presented for elective Cesarean section at 37 wk gestational age. Initially asymptomatic, her clinical condition had deteriorated as the pregnancy progressed, with worsening episodes of mild chest pain and shortness of breath. A semi-elective Cesarean section under general anesthesia was planned at 37 wk to minimize the potential for aortic complications associated with the hemodynamic stress of labour. Remifentanil was infused at 0.05 to 0.1 microg x kg(-1) x min(-1) with good sedation and analgesia for the placement of invasive monitors. The infusion was increased to 0.2 microg x kg(-1) x min(-1) for induction, and combined with isoflurane 0.4 to 0.6% for maintenance of anesthesia. The patient maintained stable hemodynamics throughout and her trachea was extubated without difficulty at the end of the procedure. The newborn did not require tracheal intubation, mask ventilation or naloxone and was in excellent condition upon transfer to the well baby nursery. CONCLUSION: Remifentanil, when used as part of an opioid-based general anesthetic for Cesarean section, can provide maternal hemodynamic stability with minimal neonatal respiratory depression and should allow for immediate postoperative tracheal extubation of the mother.

Multiple dose pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers.

BACKGROUND: Oral transmucosal fentanyl citrate (OTFC) is a solid form of fentanyl that delivers the drug through the oral mucosa. The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain is under evaluation. The aim of this study was to test the hypothesis that the pharmacokinetics of OTFC do not change with multiple dosing. METHODS: Twelve healthy adult volunteers received intravenous fentanyl (15 microg/kg) or OTFC (three consecutive doses of 800 microg) on separate study sessions. Arterial blood samples were collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maximum concentration) were identified from the raw data and subjected to a nonparametric analysis of variance. Population pharmacokinetic models for all subjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. RESULTS: The shapes of the profiles of plasma concentration versus time for each dose of OTFC were grossly similar. No change was noted for maximum concentration or time to maximum concentration over the three doses, while minimum concentration did show a significantly increasing trend. Terminal half-lives for intravenous fentanyl and OTFC were similar. A two-compartment population pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models demonstrated rapid and substantial absorption of OTFC that did not change systematically with time and multiple dosing. CONCLUSIONS: The pharmacokinetics of OTFC were similar among subjects and did not change with multiple dosing. Multiple OTFC dosing regimens within the dosage schedule examined in this study can thus be formulated without concern about nonlinear accumulation.

Teaching sedation and analgesia with simulation.

OBJECTIVE: This study reports on the efficacy of using the anesthesia simulator to teach sedation and analgesia to nurses. This provision of sedation and analgesia to a patient is accomplished with the goal of maintaining the ability of the patient to respond purposefully to auditory or tactile stimuli. METHODS: Nurses working in areas of the hospital where conscious sedation is performed were the participants in this sedation and analgesia training course. Prior to the training session, the participants read the American Society of Anesthesiology Practice guidelines for sedation and analgesia by non-anesthesiologists. At the time of the training session, each participant completed a written pretest, had an introduction to sedation and analgesia with four clinical crisis teaching scenarios using the anesthesia simulator, a practical exam using the simulator, and a written post-test. Each participant was also given the opportunity to complete an evaluation of the session. RESULTS: Twenty nurses completed the training session. The written tests had a maximum possible score of 30. Mean score on the written pretest was 22.9 +/- 3.54, and mean score on the written post-test was 26.0 +/- 4.24 (p < 0.001). Seventeen of the twenty subjects scored higher on the post-test. Mean practical exam score was 5.5 of a possible 6.0. Mean participant rating of the education session was 3.75 (1 = poor, 4 = excellent). All but one participant rated the length of the training session as "about right." CONCLUSIONS: The anesthesia simulator provides an excellent tool for teaching conscious sedation skills to hospital nurses. The participants' test performance improved following the session, and they also rated the educational experience as excellent.

Pharmacokinetics and pharmacodynamics of remifentanil: an update in the year 2000.

Remifentanil is still in its infancy in terms of postmarketing development. Its appropriate role in modern anesthesia care is still being defined and reports of novel clinical applications for remifentanil are frequently appearing in the anesthesia literature. This review will focus on selected advances in our understanding of remifentanil pharmacokinetics and pharmacodynamics and on newly proposed clinical applications for remifentanil.

Remifentanil for conscious sedation and analgesia during awake fiberoptic tracheal intubation: a case report with pharmacokinetic simulations.

We report a case of awake, fiberoptic tracheal intubation of a difficult airway (Ludwig's angina) using remifentanil as part of the sedation-analgesia regimen. Remifentanil's rapid onset-rapid offset pharmacokinetic profile enabled precise control of the level of opioid effect. In combination with other drugs, remifentanil may offer some clinical advantages compared to the other fentanyl congeners in providing the opioid component of conscious sedation-analgesia for awake tracheal intubation in patients with difficult airways.

Fentanyl pharmacokinetics in hemorrhagic shock: a porcine model.

BACKGROUND: It is common clinical practice to administer reduced doses of opioid to patients suffering from hemorrhagic shock to minimize adverse hemodynamic consequences and to prevent prolonged opioid effect However, the scientific foundation supporting this practice is not well established. The aim of this study was to test the hypothesis that hemorrhagic shock alters both the distribution and clearance of opioids using fentanyl in a porcine isobaric hemorrhage model. METHODS: Eighteen pigs were randomized to shock or control groups. The animals in the shock group were subjected to hemorrhage using an isobaric method. Pigs in both groups received fentanyl (50 microg/kg) intravenously over 5 min. Frequent arterial blood samples were obtained for radioimmunoassay. Each animal's pharmacokinetic parameters were estimated by fitting a three-compartment model to the concentration versus time data Nonlinear mixed-effects population pharmacokinetic models examining the influence of mean arterial pressure and cardiac index were also constructed. Clinical simulations using the final population model were performed. RESULTS: The shock cohort reached substantially higher fentanyl concentrations. The shock group's central clearance and central- and second-compartment distribution volumes were significantly reduced. The most useful population model scaled all pharmacokinetic parameters to mean arterial pressure. The simulations illustrated that hemorrhagic shock results in higher fentanyl concentrations for any given dosage scheme. CONCLUSION: The essential finding of the study is that fentanyl pharmacokinetics are substantially altered by hemorrhagic shock. The reduced opioid requirement commonly observed during hemorrhagic shock is at least partially attributable to pharmacokinetic mechanisms.

Influence of arteriovenous sampling on remifentanil pharmacokinetics and pharmacodynamics.

INTRODUCTION: Remifentanil is a new, short-acting, rapidly metabolized opioid. Because remifentanil is metabolized in blood and tissues by nonspecific esterases, there is a substantial difference between arterial and venous remifentanil concentrations. This difference may greatly affect the estimation of pharmacokinetic and pharmacodynamic parameters. OBJECTIVES: To assess the effects of sampling site on the pharmacokinetic and pharmacodynamic characteristics of remifentanil. METHODS: Ten healthy female subjects received intravenous remifentanil at an infusion rate of 3 microg/kg/min for 10 minutes. Serial blood samples were collected during and after drug administration from the radial artery and antecubital vein. A spectral edge measure was derived from the processed electroencephalographic and used as a measure of opioid effect. RESULTS: Venous concentrations were lower than arterial concentrations during the infusion of remifentanil. Pharmacokinetic parameters estimated from venous and arterial data differed significantly. When arterial concentrations were plotted against electroencephalographic effect, a classic counterclockwise hysteresis loop was observed, indicating a time-lag between changes in concentration and changes in effect. However, concentrations from venous blood produced a clockwise hysteresis loop that would classically suggest the development of acute tolerance. CONCLUSIONS: If this study had been conducted with venous samples alone, inappropriate conclusions such as acute tolerance could have been inferred. When designing studies to measure the acute time course (ie, non-steady state) of concentration and effect, the potential effects of sampling site on pharmacokinetic and pharmacodynamic characteristics must be carefully considered, particularly when the arteriovenous drug concentration difference is large.

Apneic oxygenation associated with patient-controlled analgesia.

We report a case in which morphine in combination with intravenous diazepam delivered via patient-controlled analgesia resulted in complete apnea and carbon dioxide narcosis in a patient admitted for cervical traction. A patent airway and high flow oxygen face mask maintained oxygenation despite complete apnea, thus rendering the pulse oximeter useless in detecting the respiratory depression. The case illustrates the limitations of pulse oximetry in detecting opioid induced respiratory depression when the conditions necessary for apneic oxygenation are present.

Remifentanil pharmacokinetics in obese versus lean patients.

BACKGROUND: Remifentanil is a short-acting opioid whose pharmacokinetics have been characterized in detail. However, the impact of obesity on remifentanil pharmacokinetics has not been specifically examined. The goal of this study was to investigate the influence of body weight on remifentanil pharmacokinetics. METHODS: Twelve obese and 12 matched lean subjects undergoing elective surgery received a 1-min remifentanil infusion after induction of anesthesia. Arterial blood samples were collected for determination of remifentanil blood concentrations. Each subject's pharmacokinetic parameters were estimated by fitting a two-compartment model to the concentration versus time curves. Nonlinear mixed-effects population models examining the influence of lean body mass (LBM) and total body weight (TBW) were also constructed. Clinical simulations using the final population model were performed. RESULTS: The obese patient cohort reached substantially higher remifentanil concentrations. The individual pharmacokinetic parameters of a two-compartment model were not significantly different between the obese versus lean cohorts (unless normalized to TBW). The final population model scaled central clearance and the central and peripheral distribution volumes to LBM. The simulations illustrated that remifentanil pharmacokinetics are not grossly different in obese versus lean subjects and that TBW based dosing in obese patients can result in excessively high remifentanil concentrations. CONCLUSIONS: The essential findings of the study are that remifentanil's pharmacokinetics are not appreciably different in obese versus lean subjects and that remifentanil pharmacokinetic parameters are therefore more closely related to LBM than to TBW. Clinically this means that remifentanil dosing regimens should be based on ideal body weight (or LBM) and not TBW.

Dose proportionality and pharmacokinetics of oral transmucosal fentanyl citrate.

BACKGROUND: The pharmacokinetics of a single dose (15 microg/kg) of oral transmucosal fentanyl citrate (OTFC) have been characterized. A range of doses may eventually be used in clinical practice. The goal of this study was to determine if the pharmacokinetics of OTFC are dose proportional for doses ranging from 200 to 1,600 microg. METHODS: Twelve healthy male volunteers were studied on four different occasions, receiving 200, 400, 800, and 1,600 microg OTFC in a double-blind, randomized protocol. Venous blood samples were collected at selected times during and after dosing for a 24-h period and assayed for fentanyl using a radioimmunoassay. Maximum concentration, time to maximum concentration, area under the curve, and elimination half-life were determined for each dose administered. In addition, respiratory rate, need for verbal prompting to breathe, and supplemental oxygen requirements were noted. RESULTS: Mean fentanyl concentration time curves were similarly shaped with increasing doses. Both peak concentrations and area under the curve increased linearly with an increase in dose, whereas time to reach peak serum concentrations did not vary significantly between doses. Except for the 200-microg dose, the apparent elimination half-life remained relatively constant (358-386 min). The incidence of low respiratory rate, supplemental oxygen requirement, and number of breathing prompts significantly increased with increasing doses. CONCLUSIONS: Oral transmucosal fentanyl citrate exhibits dose-proportional pharmacokinetics over the dose range of 200-1,600 microg.

Remifentanil and propofol combination for awake craniotomy: case report with pharmacokinetic simulations.

Remifentanil and propofol infusions were used to provide neuroleptanalgesia during an awake craniotomy to resect a left frontoparietal glioblastoma near the motor speech center. This operation presented anesthetic requirements ranging from adequate analgesia during bone flap removal to an appropriate level of consciousness during cortical speech mapping. We performed pharmacokinetic simulations to estimate the effect site concentrations of propofol and remifentanil as the infusion rates were modulated to meet the dynamic sedation and analgesic needs of the operation. Simulations revealed that changes in infusion rates were quickly followed by changes in the effect site concentrations which corresponded well with the desired changes in patient sedation and analgesia. We propose that remifentanil and propofol in combination may be a useful technique for awake craniotomy.