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.

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.

Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam.

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.

Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal.

Remifentanil is a novel, short-acting mu-receptor opioid agonist currently in the late stages of development. A member of the 4-anilidopiperidine class, it is unique among the currently marketed agents because of its ester structure. Remifentanil undergoes widespread extrahepatic metabolism by blood and tissue nonspecific esterases, resulting in an extremely rapid clearance of approximately 3 L/min (180 L/h). Like the other members of this class of drugs, remifentanil is lipophilic and is widely distributed in body tissues with a steady-state volume of distribution of approximately 30L. Because of its unique metabolic pathway (among this group of drugs) and rapid clearance, remifentanil represents a new pharmacokinetic class of opioid. Unlike the other fentanyl congeners, termination of the therapeutic effect of remifentanil mostly depends on metabolic clearance rather than on redistribution. The context-sensitive half-time [defined as the time necessary to achieve a 50% decrease in blood (or plasma) concentration after termination of a variable-length, continuous infusion targeted to maintain a steady-state concentration, where the 'context' is the duration of the infusion] is strikingly short for remifentanil, and this is perhaps the most compelling evidence of the pharmacokinetic singularity of the drug. Determined by computer simulation, the context-sensitive half-time of remifentanil is approximately 3 minutes, and is independent of infusion duration. Pharmacodynamically, remifentanil is similar to the other fentanyl congeners. The drug produces physiological changes consistent with potent mu-receptor agonist activity, including analgesia and sedation. Its adverse effect profile (like that of the other drugs of this class) includes ventilatory depression, nausea, vomiting, muscular rigidity, bradycardia and pruritus. Because it does not release histamine upon injection, remifentanil has fewer haemodynamic adverse effects than morphine. The therapeutic potency of remifentanil is somewhat less than that of fentanyl, with an effective concentration (producing 50% of maximal effect, as measured by electroencephalography) of approximately 15 to 20 micrograms/L. Speed of onset of effect is very rapid and is similar to that of alfentanil, which is reflected in a t1/2ke0 (a parameter used to characterise the delay between peak blood drug concentration and peak pharmacodynamic effect utilising a theoretical effect compartment) of approximately 1 to 2 minutes. Remifentanil is likely to be a welcome addition to the anaesthesia drug formulary. Anaesthetists have long recognised the need for a short-acting opioid with a predictable pharmacokinetic profile.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Acute compartment syndrome following a minor athletic injury.

An athletic young male presented with right calf pain following a twisting injury during a soccer game. Other than apparently severe calf pain, no symptoms or signs of compartment syndrome were noted. The patient later returned with lateral and anterior compartment syndrome, and suffered partial loss of peroneal nerve and muscle function despite fasciotomy. Although rare, acute compartment syndrome resulting from seemingly minor injury or exertion has been reported. Pain out of proportion to the apparent injury and a history of chronic leg pain with exertion may be helpful in identifying these patients prior to development of more obvious signs and symptoms. The diagnosis of acute compartment syndrome may be confirmed by compartmental pressure measurement. Prompt intervention is indicated once the diagnosis is established.

The use of remifentanil infusion to facilitate epidural catheter placement in a parturient: a case report with pharmacokinetic simulations.

We present a case in which remifentanil infusion was used to provide analgesia during epidural catheter placement in a parturient who was experiencing great difficulty staying motionless because of extremely painful uterine contractions. Remifentanil may provide certain advantages in this setting, including improved analgesia during the procedure, briefer residual maternal and fetal (or newborn) drug effects after the procedure, and greater technical ease of catheter placement because of decreased movement induced by pain. Pharmacokinetic simulation of the dose administered suggests that analgesic effect-site concentrations can be rapidly produced, and that these concentrations decline rapidly to clinically insignificant levels after the infusion.

Perioperative smoking cessation and anesthesia: a review.

Perioperative smoking causes acute changes in cardiopulmonary function that can have unfavorable implications for patients undergoing anesthesia. These cardiopulmonary effects are carbon monoxide and nicotine mediated changes in oxygen (O2) delivery and myocardial O2 balance. Smokers also are at increased risk for postoperative pulmonary complications that are secondary to chronic changes in lung function. Smoking-induced acute changes in cardiopulmonary function can be largely avoided by a brief period of preoperative smoking abstinence. Bringing about a decrease in postoperative pulmonary complications requires a much longer period of preoperative abstinence. Because the perioperative period is in many ways an ideal time to abandon the smoking habit permanently, anesthesiologists, in cooperation with other health professionals, can perhaps play a more active role in facilitating this process.

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 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.

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.

Predicting difficult laryngoscopy for tracheal intubation: an approach to airway assessment.

Tracheal intubation by direct laryngoscopy is an essential skill for physicians working in the operating room, emergency room or intensive care unit settings. While tracheal intubation can usually be accomplished with ease by direct laryngoscopy, it is sometimes difficult or impossible because of coexisting disease or abnormal physical features. When recognized before attempts at tracheal intubation, virtually all difficult airways can be secured by the selected use of specialized tracheal intubation techniques, although many of these methods require special training, experience, assistance and equipment. When a difficult airway is unrecognized before attempts at intubation the results can be catastrophic because the personnel and equipment necessary for utilizing the specialized tracheal intubation techniques may not be immediately available and the patient's spontaneous respiratory efforts may have been eliminated by anesthetics or muscle relaxants. Thus, identifying patients who are likely to harbor an airway that cannot reliably be secured by simple direct laryngoscopy is an important skill for all acute or critical care physicians. There is an extensive research data base describing historical information, physical examination findings and radiographic features that are associated with the difficult airway. Reviewed collectively, one of the most important underlying concepts suggested by this body of research literature is that the difficult airway is a product of many anatomic and pathologic variables. A surprisingly wide variety of historical, physical examination and radiographic features associated with difficult direct laryngoscopy have been described. A rational approach to airway assessment, therefore, naturally includes a detailed history, a careful physical examination and inspection of relevant x-rays whenever time permits. As outlined in Table 5, there are specific questions to address that may warn the physician about possible airway difficulty. A number of airway assessment schemes based on physical examination findings have been proposed and tested. These schemes vary in their complexity and their clinical convenience. The simpler schemes fail to address the multifactorial nature of the problem, while the more complex systems are clinically impractical. Schemes combining the distance of the thyromental space and the visibility of the oropharyngeal structures, such as that proposed by Frerk, are perhaps the most practical and reliable of the methods proposed to date. Clearly, no one scheme is ideal. At present, preintubation airway evaluation remains a poorly quantified gestalt estimate of the chances for difficulty based on a complex juxtaposition of historical information and physical findings.(ABSTRACT TRUNCATED AT 400 WORDS)

Defining the concentration-effect relationship of volatile anesthetics in vessels using an in vitro nonsteady-state technique.

We compared traditional steady-state experiments with nonsteady-state experiments in defining the vasodilating potency of isoflurane in isolated cerebral vessels. The effects of volatile anesthetics on isolated arterial vessel wall tension are typically examined by means of steady-state methodology. This requires the prolonged administration of the agent under study until a stable wall tension is achieved. An alternative, non-steady-state approach to such experiments is proposed as an adjunct technique to help simplify and in some cases evaluate more fully vascular response. Cylindrical segments of the rabbit basilar artery were placed into a perfused tissue bath, stretched to a resting tension of approximately 2000 dynes and then constricted with 30 nM K+. Thirty minutes later, 2.0 MAC of isoflurane was introduced into the fluid reservoir supplying the chamber. This administration was continued for 10 min, at which time isoflurane was discontinued and vessel tension was monitored for another 10 min. During this 20-min washin-washout period, samples of bath fluid were obtained q 1 min and isoflurane concentrations were subsequently determined by gas chromatography. After completion of these "nonsteady-state" measurements, another 30-min waiting period was allowed, after which vessels were exposed to stable concentrations of 0.5, 1.0, 1.5 and 2.0 MAC of isoflurane in varied order. Each exposure was for 15 min, with a 30-min agent-free rest period between exposures. An effect compartment model was selected for analysis of the nonsteady-state data. Ke0, a first order rate constant linking the concentrations in the bath to a theoretical effect compartment, was estimated by using a hysteresis minimization technique.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Pharmacokinetic/dynamic assessment in drug development: application to the investigational opioid mirfentanil.

The safety, pharmacokinetics, and pharmacodynamics of the investigational partial opioid agonist, mirfentanil, were determined in a dose-escalating, Phase 1 study in healthy male volunteers. Hemodynamic, central nervous system, and respiratory monitoring were used for safety assessment. The electroencephalogram (EEG) was evaluated as a surrogate measure of drug effect. Butorphanol was chosen as the control drug. In the mirfentanil group (n = 8) the dose was increased in sequential subjects from 25 micrograms.kg-1.min-1 for 30 min to 450 micrograms.kg-1.min-1 for 15 min, and in the butorphanol group (n = 10) from 2 micrograms.kg-1.min-1 for 30 min to 25 micrograms.kg-1.min-1 for 15 min. In the mirfentanil group, serious side effects were observed at plasma concentrations more than 2000 ng/mL: heart rates exceeded 130 bpm (n = 2), epileptiform EEG potentials (n = 2), and a convulsion (n = 1). The clearance of mirfentanil was high (5.8-7.2 L/min), and the volume of distribution large (247-348 L). The EEG of the subjects receiving mirfentanil showed no changes typical for opioids. Butorphanol however, caused intermittent slowing in the delta and theta ranges. The results of our study define the upper limit of safe plasma concentrations in future mirfentanil studies.