Intravenous fentanyl kinetics.

Fentanyl is considered to be a short-acting narcotic analgesic but prolonged and recurrent ventilatory depression has been reported. We examined fentanyl kinetics and excretion in 7 healthy male subjects who were given a 3.2- or 6.4-micrograms/kg dose of 3H-fentanyl intravenously. Arterial blood and urine samples were analyzed for unchanged fentanyl and total radioactivity. Fentanyl concentrations fell rapidly and 98.6% of the dose was eliminated from plasma in 60 min but the terminal elimination phase of fentanyl from the body was slow (t1/2 beta = 219 min) due to the slow return of the unchanged drug from a peripheral compartment to the central compartment where elimination occurred primarily by biotransformation. Eighty-five percent of the dose was recovered in urine and feces in 72 hr; less than 8% was recovered as unchanged fentanyl. There were fluctuations in plasma fentanyl levels during the elimination phase in all cases. The long t1/2 beta and fluctuations in plasma levels may contribute to prolonged and recurrent ventilatory effects of fentanyl.

Rectal and intravenous propranolol infusion to steady state: kinetics and beta-receptor blockade.

The effects of intravenous propranolol infusion for 24 hr was compared with those of zero-order rectal administration by an osmotic delivery system in six healthy subjects. In plasma and urine, levels of propranolol, 4-OH-propranolol (4-OH-P), and conjugates were determined just before and at 6 hr and at 20 hr during drug administration. With the rectally applied osmotic delivery system providing zero-order release, fairly constant steady-state levels of propranolol in plasma were produced within 12 to 15 hr (four to five times elimination t1/2). The mean steady-state levels were 25 ng/ml after 1.1 micrograms/min/kg rectally and 60 ng/ml after 0.8 micrograms/min/kg IV. The mean rectal systemic availability was 33%; the elimination t1/2s for the two routes did not differ. The results of analysis of plasma for metabolites indicate that after rectal propranolol different metabolic pathways are followed and that there is partial avoidance of first-pass elimination. The isoproterenol challenge resulted in a reproducible assessment of beta-receptor blockade that was closely related to the propranolol concentration in plasma in all subjects and for both routes of administration. With rate-controlled release of propranolol from an osmotic delivery device, the rectal route provides an alternative to intravenous infusion to achieve constant steady-state propranolol concentrations. This may be useful for research purposes or during the perioperative period in surgical patients.

Opioids: clinical use as anesthetic agents.

Opioids (narcotic analgesics) are widely used in the practice of anesthesia for preanesthetic medication, systemic and spinal analgesia, supplementation of general anesthetic agents, and as primary anesthetics. The last use is particularly widespread for major surgical operations, especially those involving patients with cardiovascular disease. The use of opioids in anesthetic doses is based on the absence of cardiac depression by the opioids. As with all anesthetic drugs, the opioids have limitations and side effects, but for the most part, these are easily managed on the basis of knowledge of their pharmacology. The key to their efficient use is careful titration of dose according to the individual patient's responses to the drug as well as to noxious stimulation. Although there is a very wide margin of safety, allowing administration of enormous doses intraoperatively when the patient's ventilation is supported mechanically, the disadvantage of using doses far in excess of the individual patient's need is a prolonged recovery from anesthesia with the risk of postoperative ventilatory depression. Titration of the dose can be facilitated by computer-controlled infusion pumps with the benefit that the recovery time from anesthetic doses can be appropriate for the individual patient and surgical procedure, and postoperative analgesia can be continued by patient-controlled analgesia, which is another example of computer-controlled opioid infusion. Although specific opioid antagonists are available, their use to antagonize residual anesthetic effects is potentially hazardous.

Development of the knowledge-based standard for the written certification examination of the American Board of Anesthesiology.

In 1988 and 1989, the American Board of Anesthesiology (ABA) developed a knowledge-based standard for its written certification examination. In brief, 13 "judges" developed a construct of a "borderline candidate," i.e., a candidate who was neither ideal nor clearly failing but rather had sufficient knowledge to just pass. In 1989, this construct was applied to 90 questions from the 1989 ABA examination to estimate candidate's score on that subset. When extended to the entire examination, the use of the construct resulted in a knowledge-based standard of 57% correct. (The 1988 exercise, also using the construct of a borderline candidate but with a totally different subset of questions, produced an identical standard). This standard resulted in higher success rates among the actual examinees taking the ABA examination (84% in 1989 and 90% in 1990) than had the normative standard used previously (80%). The authors suggest that the process they describe permits development of a reproducible criterion for success that is based entirely on mastery of a relevant body of knowledge rather than on normative considerations.

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.

New perspectives on anesthetic agents.

The practices of anesthesiology are changing to meet the needs of an older and sicker patient population, to adapt to advances in medical technology and operating techniques, and to provide better postoperative conditions for patients and those caring for them. There is a large spectrum of anesthetics and a variety of anesthetic techniques that allow anesthetic onset and recovery to be rapid, vital functions to be maintained within normal limits, and operating conditions to be adapted to the needs of both patients and surgeons. Nevertheless, all anesthetic drugs and techniques have inherent risks as well as benefits, and despite expertise and caution in their use, a satisfactory outcome for the patient cannot be guaranteed.

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.

The anesthesiologist's response to a low-output state after cardiopulmonary bypass: etiologies and remedies.

Artifacts or mechanical problems may cause data which suggest poor myocardial performance during emergence from cardiopulmonary bypass (CPB). Transducer and monitoring equipment malfunctions, damping of the arterial blood pressure tracing, effects of drugs, hypercarbia, inordinately high intrathoracic pressure, cardiac tamponade, and others are all possible culprits. It is important to have a systematic plan for evaluating and interpreting the signs and data that are evident. Causes of hypotension after CPB include low hematocrit, hypercarbia, sympathetic inhibition, vasodilator action, anaphylaxis or anaphylactoid reactions, protamine reactions, and impaired myocardial performance. Impaired myocardial performance can be attributable to rate and rhythm disturbances, inadequate ventricular preload, inappropriately elevated right and left ventricular afterload, and decreased myocardial contractility. Common causes of hypoxemia include a malfunctioning ventilator system, pulmonary problems such as atelectasis and shunt, anemia, and inordinately high utilization of oxygen.

Making a choice of inotropes and vasodilators in clinical situations.

There are five variables affecting cardiac output: heart rate and rhythm; contractility; ventricular preload; and ventricular afterload. The choice of specific drugs to augment myocardial performance is based on the spectra of their effects on these variables. In order to use inotropes and vasodilators efficiently in clinical situations, it is important to recognize the dose-response relationship, to consider route and rate of administration, and to take into account the presence of other drugs as well as the abnormal pathophysiology of the patient. The safe and effective use of inotropes and vasodilators in critically ill patients is most readily achieved when there is a systematic plan for introducing the drug, evaluating its effects, and adjusting those hemodynamic variables that can be controlled.

Use of cardiopulmonary bypass in studies of the circulation.

In summary, CPB provides a complex set of physiological circumstances during which the patient is subjected to severe physiological alterations with surprisingly few adverse sequelae. Our ultimate goal in performing medical research is to provide scientific insights that improve patient care. Results of studies of animal models may not always be applicable to man. Although CPB possesses faults inherent to any experimental model, it nonetheless provides a unique opportunity to study safely and effectively a variety of physiological and pharmacological variables that affect cardiovascular functions in man.

Plasma concentrations of alfentanil required to supplement nitrous oxide anaesthesia for lower abdominal surgery.

In 15 patients about to undergo lower abdominal surgery, anaesthesia was induced with alfentanil 150 micrograms kg-1 i.v. and 66% nitrous oxide in oxygen. Thereafter, nitrous oxide anaesthesia was supplemented with a continuous infusion of alfentanil at a rate which varied between 25 and 150 micrograms kg-1, as indicated by the patient's responses to the stimulation of surgery. Small bolus doses of alfentanil 7 micrograms kg-1 were administered to suppress precisely defined somatic, haemodynamic and other responses to stimulation. With one exception, all responses were rapidly controlled by increments of alfentanil. By measuring the arterial plasma concentrations of alfentanil at times with and without a response, we were able to estimate the alfentanil concentrations required (with nitrous oxide) to suppress responses to different stimuli during surgery. The results demonstrate the feasibility of continuous infusion of alfentanil in anaesthesia.

The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC.

Infusion rates for fentanyl were calculated to produce stable plasma concentrations at which the ability of fentanyl to reduce enflurane MAC could be studied utilizing the tail clamp method and measurement of end-tidal enflurane. Following the determination of control enflurane MAC in each animal, an infusion of fentanyl was begun. Group 1 received continuous successive infusion rates of 0.05, 0.1, and 0.2 micrograms . kg-1 . min-1 with respective loading doses (given over 20 min) of 15, 15, and 30 micrograms/kg; Group 2 received infusions of 0.2, 0.8, and 3.2 micrograms . kg-1 . min-1 with loading doses of 30, 90, and 270 micrograms/kg, respectively. Group 3 was studied in the same manner except that fentanyl was omitted from the infusion solution. Enflurane MAC was determined at each infusion level and blood samples were analyzed for the concentration of fentanyl. Fentanyl concentrations in plasma were proportional to the infusion rate. Enflurane MAC was decreased significantly in proportion to fentanyl plasma concentrations up to 30 ng/ml where a reduction of MAC by 65% was evident. A threefold higher concentration produced a minimal further reduction. In Group 3 dogs, no change in enflurane MAC was seen. It was concluded that predictable, stable levels of fentanyl in plasma can be achieved, that there is a close relationship between the concentration of fentanyl in plasma and its enflurane sparing effect, and that there is a ceiling to this concentration-response relationship.

The enflurane sparing effect of morphine, butorphanol, and nalbuphine.

The potencies of morphine and of the narcotic analgesic agonist-antagonists butorphanol and nalbuphine in terms of their ability to decrease enflurane MAC were studied. Following the determination of control MAC for enflurane in each dog, an intravenous bolus dose of either butorphanol tartrate, nalbuphine hydrochloride, morphine, or placebo was administered and enflurane MAC was redetermined. A higher dose of the same drug was then administered and enflurane MAC was redetermined up to a total of four doses in each animal. The successive doses for morphine and nalbuphine were 0.5, 1.5, 5.0, and 20.0 mg/kg; for butorphanol, 0.1, 0.3, 1.0, and 4.0 mg/kg; lactated Ringer's solution was used as a placebo. Both butorphanol and nalbuphine produced significant reductions of enflurane MAC (11 and 8%, respectively) at their lowest doses. No further reductions were produced by three- to forty-fold larger doses of either agonist-antagonist. Morphine produced a 17% reduction of enflurane MAC at the lowest dose with progressive decreases of enflurane MAC up to 63% at a dose of 5 mg/kg morphine. A fourfold increase in the morphine dose did not further decrease MAC. No change in enflurane MAC occurred in the animals given placebo. It was concluded that there is a "ceiling" to the potency of butorphanol and nalbuphine as anesthetic supplements. There is also a limit to the anesthetic sparing effect of morphine, but it is considerably greater than that of the agonist-antagonist narcotic analgesics.

Tissue redistribution of fentanyl and termination of its effects in rats.

The kinetics of fentanyl elimination from plasma suggest its rapid and extensive uptake by tissues. The authors determined the relationships between tissue and plasma concentrations of fentanyl. Six rats injected iv with 3H-fentanyl citrate (50 micrograms/kg) were sacrificed at each of the following times: 1.5, 5, 15, 30, 60, 120, and 240 min after injection. Tissues were analyzed for unchanged 3H-fentanyl citrate and for total 3H-radioactivity. Fentanyl effects were evident 10 s after injection; recovery began at 5 min and was complete within 60 min. Fentanyl concentrations in brain, heart, and lung equilibrated with that in plasma before 1.5 min and declined at the same rate (t 1/2 alpha = 8 min, t 1/2 beta = 45 min). Fentanyl uptake by muscle and fat was slower and equilibration with plasma occurred by 120 min. Muscle accumulated 56 per cent of the dose within 5 min by which time brain fentanyl levels had declined by 90 per cent. Only 6 per cent of the dose was in fat at 5 min but this increased to a maximum of 17 per cent at 30 min. Fentanyl was extensively metabolized; metabolites represented 25 per cent of body 3H-radioactivity at 15 min, and 80 per cent at 4 h. The authors conclude that the short duration of fentanyl effect is due to its rapid redistribution from sites of action in the brain to sites of storage (muscle and fat) and biotransformation (liver). The elimination of fentanyl from the body is governed by its reuptake from storage sites and its metabolism in the liver. Most of the dose is ultimately excreted in the form of fentanyl metabolites in urine.

Pharmacokinetics of intravenous morphine in patients anesthetized with enflurane-nitrous oxide.

Morphine is used as an anesthetic supplement. Its disposition in surgical patients under enflurane-nitrous oxide anesthesia has not been determined. Available data on morphine concentrations in plasma after equivalent intravenous doses are conflicting, possibly as a result of varying degrees of specificity of the analytical methods for the unchanged, pharmacologically active form of the drug. This study determined the pharmacokinetics of morphine (0.05, 0.1, 0.14, or 0.2 mg/kg) injected intravenously in 10 surgical patients anesthetized with enflurane-N2O-O2. Arterial plasma was analyzed for unchanged morphine and conjugated morphine. Specificity of the analytical procedure for unchanged morphine was achieved by the combination of solvent extraction and radioimmunoassay techniques. Kinetic indices were derived by nonlinear least-squares analysis of log concentration (ng/ml) vs. time relationships. Morphine disposition was independent of dose in this fourfold range and was best described by a three-compartment model with a mean elimination half-time (t1/2 beta) of 104 +/- 5 min. The apparent volumes of distribution (Vd) and of the central compartment (V1) were 3.4 +/- 0.2 and 0.13 +/- 0.02 l/kg, respectively, while the clearance (ClB) was 23 +/- 1 ml x min-1 x kg-1. Extraction of morphine by the liver appeared to be complete. Conjugated morphine was eliminated from plasma with a t1/2 beta of 169 +/- 15 min. The ultimate elimination of morphine from the body was dependent upon its uptake from slowly perfused peripheral tissues, K10 greater than k31(P less than .001).