The pharmacokinetics of remifentanil in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

UNLABELLED: Remifentanil is a potent opioid with a short duration of action. It has the potential for large-dose opioid anesthesia without an obligatory prolonged period of mechanical ventilation. However, because of high clearance and rapid tissue distribution, cardiopulmonary bypass (CPB) may influence its pharmacokinetics and alter drug requirements. We administered remifentanil by continuous infusion to 68 patients having coronary artery bypass graft surgery during CPB with hypothermia to describe the effects of these interventions on its pharmacokinetics. Remifentanil concentrations were measured before, during, and after CPB. Disposition was best described by a two-compartment model. The volume of distribution increased by 86% with institution of CPB and remained increased after CPB. Elimination clearance decreased by 6.37% for each degree Celsius decrease from 37 degrees C. IMPLICATIONS: Remifentanil concentrations decrease with the institution of cardiopulmonary bypass because of an increase in the volume of distribution. The decrease in elimination clearance with hypothermia results in increased total remifentanil concentrations during cardiopulmonary bypass if the infusion rate is not altered. More constant blood remifentanil levels may be obtained by reducing remifentanil infusion rate by 30% for each 5 degrees C decrease in temperature.

The pharmacokinetics of remifentanil.

Opioids decrease the sympathetic and somatic responses to noxious stimulation and can be given in high doses without negative inotropic effects, even in patients with impaired cardiac function. With currently available opioids, precise titration of dose to effect is difficult, and high doses result in drug accumulation and prolonged respiratory depression. Remifentanil is a new synthetic opioid with direct action on mu-opioid receptors. It has a rapid onset and short latency to peak effect. It is rapidly inactivated by esterases in both blood and tissues, resulting in a very short duration of action. The context-sensitive half-life remains very short (3 to 4 minutes), independent of the duration of infusion. These characteristics facilitate titration of dose to effect and also allow the use of very high doses (ED99) without prolonging recovery from its effects. The duration of action of remifentanil has been found to be short, even in patients with renal or hepatic failure, although only low doses have been used in the studies published to date. The hydrolysis of remifentanil produces a metabolite with very weak opioid receptor activity that does not contribute to the effects of remifentanil. Possible disadvantages of the drug include (1) the need to mix the lyophilized drug with a diluent, (2) administration as a continuous infusion, (3) risk of rapid loss of analgesic and anesthetic effects if the infusion is interrupted accidentally, and (4) difficulty in judging the dose of another, longer lasting opioid that will be required to control postoperative pain without producing excessive ventilatory depression. Remifentanil is likely to be more expensive than other opioids, but its use may reduce overall costs if prompt recovery from its effects results in shorter stays in the operating room and recovery units.

Anesthetic potency of remifentanil in dogs.

BACKGROUND: Remifentanil is an opioid that is rapidly inactivated by esterases in blood and tissues. This study examined the anesthetic potency and efficacy of remifentanil in terms of its reduction of enflurane minimum alveolar concentration (MAC) in dogs. METHODS: Twenty-five dogs were anesthetized with enflurane. One group received incremental infusion rates of remifentanil from 0.055 to 5.5 micrograms x kg(-1). A second group received constant rate infusions of remifentanil of 1.0 micrograms x kg(-1) x min(-1) for 6-8 h. Enflurane MAC was measured before, hourly during remifentanil infusion, and at the end of the experiment after naloxone administration. A third group received alternating infusions of 0.5 and 1.0 micrograms x kg(-1) x min(-1) with MAC determinations made 30 min after each change in the infusion rate. Heart rate, mean arterial pressure, and remifentanil blood concentrations were measured during MAC determinations. RESULTS: Enflurane MAC was reduced up to a maximum of 63 +/- 10.4% (mean +/- SD) in a dose-dependent manner by remifentanil infusion. The dose producing a 50% reduction in the enflurane MAC was calculated as 0.72 micrograms x kg(-1)x min(-1) and the corresponding blood concentration was calculated as 9.2 ng/ml. Enflurane MAC reduction remained stable during continuous, constant rate infusions for periods of 6-8 h without any signs of tolerance. Recovery of enflurane MAC to baseline occurred in 30 min (earliest measurement) after stopping the remifentanil infusion. CONCLUSIONS: Remifentanil is equally efficacious and about half as potent as fentanyl, judging from the blood concentrations causing equivalent reductions in enflurane MAC in the dog. The characteristics of MAC reduction are similar to those of other opioids, including the ceiling effect. Recovery from remifentanil anesthesia is much more rapid than for any other opioid studied to date, especially after continuous infusions maintained for 6 or more h.

Histamine concentrations and hemodynamic responses after remifentanil.

Remifentanil is a new potent opioid analgesic that undergoes rapid esterase metabolism. The purpose of this study was to investigate hemodynamic responses to 2-30 micrograms/kg remifentanil (escalating doses) injected as a bolus over 1 min during general anesthesia. After general anesthesia with endotracheal intubation, placement of a radial artery catheter, and pretreatment with glycopyrrolate, remifentanil 2, 5, 15, or 30 micrograms/kg (six patients, three male and three female per group) was administered over 1 min. Arterial blood pressure and heart rate were measured noninvasively before drug administration, after drug administration, and then every minute for 5 min. Arterial blood was taken for histamine determinations before drug administration and then at 1, 3, and 5 min after drug administration. Administration of remifentanil was associated with a reduction in systolic blood pressure from 134 +/- 18 to 91 +/- 16 mm Hg and heart rate from 99 +/- 20 to 69 +/- 21 bpm and was not associated with alterations in histamine concentration.

A demonstration of validity for certification by the American Board of Anesthesiology.

PURPOSE: To investigate the validity of the certification process of the American Board of Anesthesiology. Specifically, does board certification in anesthesiology identify physicians judged to be clinically superior by evaluators who are not part of the certification process? METHOD: All 154 U.S. anesthesiology program directors (or faculty members they chose to represent them), unaware of the study's intent, were asked whether they would permit each of their residents completing training in 1991 to administer three increasingly complex anesthetic regimens to the directors themselves. This clinical skills rating was compared with the residents' performances in the certification process in 1992. A list of personal characteristics was also provided to the directors so they could identify reasons for less-than-optimal clinical skills ratings. A total of 1,310 residents participated in the certification process in 1992. RESULTS: A total of 146 programs responded. The directors would have accepted anesthetic care for all three increasingly complex operations from 828 (63.2%) of their own residents; for only the two less complex procedures, from 262 (20%); and for only the least complex procedure, from 127 (9.7%). In addition, 93 residents (7.1%) would not have been accepted to administer anesthesia to their directors for any of these operations. Certification success rates for these groups were 74.6%, 53.8%, 44.9%, and 49%, respectively (p < .00001). The personal characteristics believed important to the practice of anesthesiology were strongly linked to the clinical skills ratings; these included motivation, adaptability, clinical judgment, manual dexterity, several work habits, response to criticism, and handling of stressful situations. CONCLUSION: These data support validity for certification in anesthesiology and identify characteristics considered necessary for high-quality practice of the specialty.

Pharmacokinetics of intravenous milrinone in patients undergoing cardiac surgery.

BACKGROUND: Milrinone is a phosphodiesterase inhibitor with positive inotropic and vasodilator effects that are useful in the treatment of ventricular dysfunction after cardiac surgery. However, the pharmacokinetics of the drug have been investigated only in healthy volunteers and in patients with chronic congestive heart failure. This study investigates the pharmacokinetics of milrinone in adult cardiac surgical patients after cardiopulmonary bypass. METHODS: Milrinone was administered to 25 patients just before or immediately after separation from cardiopulmonary bypass. Arterial blood was sampled over the next 16 h and milrinone plasma concentrations were determined by high-performance liquid chromatography. Data were analyzed by extended nonlinear least-squares regression. The relation between milrinone plasma concentration and hemodynamic effect was examined in an additional 11 patients who had cardiac indices less than 2.5 l.min-1.m-2 immediately after separation from cardiopulmonary bypass. Milrinone was administered and plasma concentrations were related to changes in cardiac index during the next 10 min. RESULTS: A milrinone dose of 50 micrograms/kg in conjunction with an infusion of 0.5 micrograms.kg-1.min-1 consistently maintained plasma concentrations in excess of 100 ng/ml. A triexponential equation describing the plasma concentration as a function of time was used to describe the data. Central-compartment volume was 102 ml/kg, volume of distribution was 1,698 ml/kg, and elimination clearance was 1.88 ml.kg-1.min-1. Pharmacokinetic parameters were independent of dose. The relation between plasma concentration and percentage increase in cardiac index could be described by a sigmoidal curve with the plasma concentration associated with a 50% increase in cardiac index equal to 167 ng/ml. CONCLUSIONS: A milrinone dose of 50 micrograms/kg with an infusion at 0.5 micrograms.kg-1.min-1 maintains plasma concentrations at or above the threshold of therapeutic effects.

Anesthetic and hemodynamic interactions of dexmedetomidine and fentanyl in dogs.

BACKGROUND: Anesthetic doses of dexmedetomidine (DMED), a highly selective alpha 2 agonist, are not well tolerated hemodynamically. The combination of an opioid with DMED might reduce the dosage requirements for each drug and thereby allow the same anesthetic depth to be achieved with lesser degrees of their individual side effects. METHODS: Dogs were anesthetized with enflurane. One group (n = 5) received intravenous doses of DMED from 0.1 to 10 micrograms/kg. Two other groups of five dogs each received fentanyl 15 micrograms/kg plus 0.05 microgram.kg-1.min-1 or fentanyl 45 micrograms/kg plus 0.2 micrograms.kg-1.min-1. Thereafter, they received DMED doses of 0.03-3 micrograms/kg. After the effects of the last DMED dose were measured, atipamezole 0.3 mg/kg was infused intravenously and all measurements were repeated. Then, naloxone (1 mg/kg) was injected intravenously and a final set of measurements obtained. Anesthetic effects were assessed by determining enflurane minimum alveolar concentration (MAC). Hemodynamics and plasma fentanyl concentrations were measured at each determination of MAC. RESULTS: DMED and fentanyl individually produced dose-related reductions of enflurane MAC. During the lower rate infusion of fentanyl (plasma fentanyl concentration 1.0 +/- 0.3 ng/ml), DMED reduced enflurane MAC more than could be attributed to a simple additive interaction. During the higher rate infusion of fentanyl (plasma fentanyl concentration 4.4 +/- 0.7 ng/ml), DMED reduced enflurane MAC to greater degrees than were achievable by fentanyl alone. DMED caused a dose-dependent increase in arterial pressure concomitantly with a decrease in cardiac output, and these changes were not modified by fentanyl. The bradycardia following DMED was augmented by fentanyl. CONCLUSIONS: There was a positive interaction, additive or synergistic, between DMED and fentanyl with respect to their enflurane-sparing effects. The interaction allowed the same depth of anesthesia to be achieved by lower doses of all three drugs, potentially limiting the intensity of their individual side effects. However, the presence of fentanyl increased the degree of bradycardia induced by DMED.

Alfentanil pharmacokinetics in cardiac surgical patients.

There is growing interest in early tracheal extubation and intensive care unit. (ICU) discharge of cardiac surgical patients. Among the opioids currently available, alfentanil seems to be particularly suited to these goals because of its pharmacokinetic and pharmacodynamic characteristics. However, the pharmacokinetics of alfentanil after cardiopulmonary bypass (CPB) have not been fully characterized. Eight patients undergoing coronary artery bypass grafting (CABG) with hypothermic CPB received alfentanil 125 micrograms/kg intravenously (IV) at the induction of anesthesia and again 5 h later after the completion of CPB. Arterial blood samples were analyzed for alfentanil (n = 8) and for plasma proteins (n = 3). Arterial blood samples were obtained from another six patients for measurements of the concentrations of plasma proteins at various stages of the perioperative period. Compared to the pre-CPB period as well as to patients not exposed to CPB, CABG patients after CPB exhibited an increased elimination half-time (t1/2 beta = 180 +/- 55 min SD), central distribution volume (Vc = 0.25 +/- 0.07 L/kg), and total volume of distribution (Vdss 0.63 +/- 0.08 L/kg; Vd area 0.92 +/- 0.23 L/kg) which reflected a 33%-50% decrease in alpha 1-acid glycoprotein, the principal plasma protein to which alfentanil is bound. There was no substantial change in the concentration of free alfentanil at the start of CPB. The clearance of total alfentanil was not affected significantly by CPB. We conclude: 1) Alfentanil pharmacokinetics in CABG patients before CPB are similar to those found in noncardiac surgical patients and volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery.

BACKGROUND: Remifentanil is a highly potent opioid with a rapid onset and a short duration of action due to its rapid hydrolysis by esterases in blood and tissues. The major metabolite of remifentanil, GI90291, is much less potent than remifentanil. METHODS: The pharmacokinetics of remifentanil and its major metabolite, GI90291, were determined in 24 patients undergoing elective inpatient surgery. Remifentanil was administered as a 1-min infusion (2, 5, 15, and 30 micrograms/kg) after the induction of anesthesia and tracheal intubation. Serial arterial blood samples were collected over 6 h and assayed for remifentanil and GI90291. RESULTS: The pharmacokinetics of remifentanil were described using a three-compartment model. Total clearance (250-300 l/h) of remifentanil was independent of dose and was approximately three to four times greater than the normal hepatic blood flow. Volume of distribution at steady state (25-40 l) also was independent of dose. The terminal half-life of remifentanil ranged from 10 to 21 min. Covariate analysis of remifentanil clearance and patient demographics showed that patient body weight, age, and gender did not influence total clearance. This suggests that remifentanil may not need to be dosed according to body weight in adult patients. A simulation was conducted to determine the time required for a 50% reduction in effect site concentration after an infusion designed to maintain a constant effect site concentration. The time required for a 50% reduction in the effect site concentration of remifentanil (3.65 min) was considerably less than that for sufentanil (33.9 min), alfentanil (58.5 min), and fentanyl (262 min). The pharmacokinetics of the major metabolite, GI90291, were independent of the dose of remifentanil. The mean terminal half-life of GI90291 ranged from 88 to 137 min. CONCLUSIONS: The pharmacokinetics of remifentanil are consistent with its rapid elimination by blood and tissue esterases; its major metabolite is eliminated more slowly but is not likely to make any significant contribution to the total effect because of its much lower potency. The rapid onset and short duration of action of remifentanil make it well suited for titration of dose (infusion rate) to the desired degree of effect.

The initial clinical experience of 1819 physicians in maintaining anesthesia with propofol: characteristics associated with prolonged time to awakening.

In October 1989, propofol underwent Phase IV Food and Drug Administration testing that involved 25,981 patients, 1722 institutions, and 1819 anesthesiologists. Participants were 18-80 yr of age and ASA physical status I-III; they could not have a continuing pregnancy or prior adverse anesthetic experience. Anesthesiologists completed detailed forms to describe their use of propofol in this three-step study: propofol for induction only (Step 1), for induction and then maintenance by intermittent bolus injection (Step 2), or for continuous infusion (Step 3). In early 1992, our group of anesthesiologists and epidemiologists analyzed the resulting data base. We evaluated data from 14,882 patients (8095 given bolus injections and 6787 given continuous infusion) to determine factors predicting prolonged time (> 15 min after cessation of all anesthesia) to awakening, one measure of recovery from anesthesia. The incidence of prolonged awakening was 6.8% (1016 patients); the median and mean (+/- SD) times to awakening were, respectively, 5 min and 7.2 +/- 7.3 min. The following variables were associated (P < 0.05) with prolonged awakening from propofol maintenance anesthesia: a total dose of propofol > 8 mg/kg, male gender, endotracheal intubation, age > 65 yr, abdominal surgery, continuous infusion of propofol, and concomitant use of isoflurane or benzodiazepines. These results support the clinical impression that recovery from propofol anesthesia is remarkably rapid; although the vast majority of physicians participating in this study were using propofol for maintenance for the first time, only 6.8% of patients had awakening times exceeding 15 min.

Effects on recovery when isoflurane is used to supplement propofol-nitrous oxide anesthesia.

During propofol-nitrous oxide (N2O) anesthesia, volatile anesthetics are frequently administered to treat signs of inadequate anesthesia and to decrease the possibility of intraoperative awareness. Because the clinical effects of this combination have not been examined rigorously, we used data from the 1989-90 Phase IV clinical trial with propofol to evaluate recovery from propofol-N2O anesthesia with and without supplementation with isoflurane. In this study involving 15,806 patients at 1722 institutions, propofol was administered for induction and maintenance of anesthesia with N2O for procedures lasting less than 60 min. At the discretion of the anesthesiologist, volatile anesthetics were administered as needed during maintenance of anesthesia (the incidence of use of inhaled anesthetics was 14.7% for isoflurane, 2.2% for enflurane, and 0.2% for halothane). Other intraoperative medications included opioid analgesics, muscle relaxants, and anticholinergic drugs. The present study concerns the subset of 7796 patients given propofol-N2O maintenance anesthesia (intermittent bolus or continuous infusion) with or without isoflurane supplementation for procedures lasting less than 60 min. Isoflurane was used more frequently for procedures lasting 30-60 min than for those less than 30 min. Nevertheless, the maintenance dose of propofol was significantly (P < 0.05) less with isoflurane (178 vs 235 mg). Adjunctive use of isoflurane prolonged the time to awakening and to becoming oriented, but discharge times were similar for the two groups. The incidence of postoperative nausea, vomiting, recall, and excitement did not differ between the two groups. We conclude that the addition of isoflurane to a propofol-N2O anesthetic does not alter recovery from anesthesia.

Hemodynamic effects of propofol: data from over 25,000 patients.

To investigate clinically important hypotension and bradycardia after induction of anesthesia with propofol, we analyzed data from a Phase IV stepwise study involving 25,981 patients, 1722 institutions, and 1819 anesthesiologists. In Step 1, propofol was used for induction only. In Step 2, propofol was used for induction and then maintenance by intermittent injection. In Step 3, an induction dose was followed by a maintenance infusion. Participants were to be 18-80 yr of age and ASA physical status I-III; they could not have a continuing pregnancy or prior adverse anesthetic experience. Detailed data on demographic, perioperative, and outcome variables were recorded on data collection forms. The overall incidence of hypotension (systolic blood pressure < 90 mm Hg) was 15.7%; 77% of the episodes were recorded within 10 min of induction of anesthesia with propofol. Bradycardia (heart rate < 50 beats/min) occurred in 4.8% of patients, with 42% of the episodes in the first 10 min. Only 1.3% of patients had both hypotension and bradycardia. The incidence of hypotension was significantly higher for the elderly, females, Caucasians, those undergoing abdominal and integumentary procedures, and those given propofol with opioids, benzodiazepines, or propranolol. Bradycardia was significantly more common when propofol was combined with opioids or chronically taken beta-adrenergic receptor-blocking drugs. Bradycardia and hypotension were not commonly associated. Giving this new drug by protocol, even inexperienced anesthesiologists incurred few adverse hemodynamic changes. Hemodynamic changes were transient and rarely (< 0.2%) required drug therapy. Cardiovascular changes and drug interactions were predictable and manageable based on knowledge of the pharmacology of propofol.

Adverse events in a multicenter phase IV study of propofol: evaluation by anesthesiologists and postanesthesia care unit nurses.

Phase II and III studies are tightly controlled trials investigating adverse effects before government approval of a new drug. However, because postapproval Phase IV studies involve a much larger and more complex population, the true nature of adverse effects can be seen. We analyzed Phase IV data for the new drug propofol with regard to the incidence of adverse events, and evaluations of such events by anesthesiologists versus postanesthesia care unit (PACU) nurses. Data pertained to 25,981 patients, 1722 institutions, and 1819 anesthesiologists giving propofol in three anesthetic regimens. Inclusion criteria were liberal: age, 18-80 yr; ASA physical status I-III; no continuing pregnancy; and no prior adverse anesthetic experience. Anesthesiologists and PACU nurses used data collection forms to record demographic, perioperative, and outcome variables; to evaluate recovery (excellent, good, or poor); and to describe adverse events. Adverse events were reported for 2813 patients (10.8%); the most common events were pain on injection (5.2%), hypotension (1.1%), nausea/vomiting (1.9%), and excitement (1.3%). The incidences of pain on injection and nausea/vomiting were approximately one-half and one-fifth, respectively, the values reported in earlier studies. Six hundred thirty-three patients (2.4%) had a "poor" recovery according to one or both of the evaluators (the anesthesiologist or PACU nurse). The PACU nurse was more influenced by nausea, vomiting, or postoperative pain; and the anesthesiologist was more influenced by postoperative confusion or delayed emergence from anesthesia. For only 0.6% of patients did both evaluators rate recovery as poor. Anesthesiologists gave more weight to intraoperative adverse events, and nurses to postoperative events.(ABSTRACT TRUNCATED AT 250 WORDS)

How do anesthesiologists select patients when introducing a new drug into practice?

As part of the marketing strategy for the anesthetic drug propofol (Diprivan), Stuart Pharmaceuticals began a Phase IV postmarketing study soon after the drug received Food and Drug Administration approval in 1989. We used data from this study to test the hypothesis that anesthesiologists would initially use propofol for young, relatively healthy patients and then, with experience, for older, sicker patients. The Phase IV study involved 1722 institutions, 1819 anesthesiologists, and 25,981 patients. The study incorporated three sequential steps, each to be tested in five patients. In Step 1, propofol was used for induction only; in Step 2, for induction and maintenance of anesthesia by intermittent injection; and, in Step 3, for induction and maintenance by continuous infusion. Inclusion criteria were age 18-80 yr and ASA physical status I-III. Exclusion criteria were continuing pregnancy and a previous adverse anesthetic experience. Physicians used standardized data collection forms to voluntarily compile detailed demographic, perioperative, and outcome variables for patients. Data were then evaluated by an independent, multicenter team of seven anesthesiologists and three epidemiologists to determine whether the first two patients selected to participate in each step (Patients 1 and 2, 6 and 7, and 11 and 12) were less sick, younger, or undergoing less invasive or shorter procedures than patients enrolled later in the same steps (Patients 4 and 5, 9 and 10, and 14 and 15). Physicians gave propofol first to patients with fewer concurrent diseases than are found in the general population (10% were hypertensive versus 16%; 3% were diabetic versus 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Phase IV study of propofol: validation of the data set.

In 1989-1990, Stuart Pharmaceuticals conducted a Phase IV study of propofol on over 26,000 patients, later making the large data base available to a team of epidemiologists and anesthesiologists for analysis. We now describe the process of verifying the data to provide a sound basis for further analyses. Original data were collected by 1819 physicians at 1761 hospitals. In that study, anesthesia was induced by bolus injection of propofol and was maintained by inhaled drug and N2O-O2 (Step 1), or by propofol (either intermittent bolus injection [Step 2] or continuous infusion [Step 3]) and N2O-O2. Forty-six recorded variables described history, physical examination, course and quality of anesthesia and recovery, and adverse events. Data were scrutinized for inaccuracy or bias regarding adverse events, completeness of data, data entry, and violations of the study protocol. The initial data set pertained to 26,841 patients (10,698, Step 1; 8886, Step 2; and 7257, Step 3). Because we excluded data if 25% of the items were missing from the data set, 3.2% of the case reports were eliminated: the final data set used for subsequent analyses contained 25,981 patients (10,184, Step 1; 8672, Step 2; and 7125, Step 3). Inaccuracy of data entry was not excessive, and violations of study protocol were less frequent than in similar studies. The nature and frequency of adverse events were similar to those reported in Phase II and III clinical trials of propofol. Analysis showed that missing data occurred randomly and did not introduce obvious bias. We conclude that the data set was valid and most likely represents perioperative events occurring in similar patients; that Phase IV studies can be valuable because of the range of patients studied and the ability to detect even rare events; and that future Phase IV studies could be improved by more efficient design of data collection forms for both hypotheses to be tested and the entry of data onto forms.

The role of pharmacoepidemiology research in postmarketing surveillance and anesthesia practice/critical care medicine.

Despite tremendous efforts to ensure the safety and effectiveness of newly marketed medications, a number of these have had significant problems after introduction of the drug to the market. Such problems highlight the practical limitations of clinical trials performed to obtain FDA approval for marketing. Pharmacoepidemiology research methodologies provide a powerful mechanism for exploring the determinants of drug safety and effectiveness in broad-based populations and can serve as a scientific foundation for outcome research. Using these methodologies, largescale postmarketing surveillance studies similar to the type described in the accompanying articles would constitute an important way of confirming and identifying the determinants of drug safety and effectiveness in large, diverse patient populations.