Population pharmacokinetics of fentanyl in healthy volunteers.

The authors compared the population pharmacokinetics of fentanyl using a standard individualized modeling (SIM) approach versus that of a nonparametric expectation maximization (NPEM) approach. The pharmacokinetic properties of fentanyl administered as a single 5 ug/kg intravenous infusion were evaluated in 18 healthy volunteers by use of SIM as well as with NPEM. NPEM-derived parameters were a total body clearance of 2.12 +/- 0.28 L/kg/h, distributional clearance of 8.43 +/- 4.58 L/kg/h, central volume of distribution of 1.22 +/- 0.21 L/kg, and peripheral volume of distribution of 1.81 +/- 1.47 L/kg. Identified parameter values from the modeling methods resulted in virtually identical simulated profiles; this finding was confirmed when median values noted were not statistically significantly different between modeling methods (SIM or NPEM). However, the NPEM algorithm uniquely identified a greater distributional clearance in the elderly population and also illustrated a profile with at least 10% of the study population having a very high clearance of fentanyl. This finding may affect the therapeutic use of fentanyl. NPEM allows for a more informative global representation of a drug's pharmacokinetics.

Safety and efficacy of fast track in patients undergoing coronary artery bypass surgery.

BACKGROUND: The incidence of coronary artery bypass surgery has been increasing annually with increasing pressure on the health care system. Fast track has been proposed as a means to increase efficiency and volume, without an increase in hospital resources. To date this approach has not been critically assessed in Canada. METHODS: We examined 617 consecutive patients undergoing isolated CABG surgery. The patients were divided into (1) fast track (FT) recovery (n = 219), without admission to an ICU, and (2) non-fast track (NFT) recovery (n = 398) with direct admission to the ICU. There were no differences in age, gender, timing of surgery, left main stenosis, preoperative myocardial infarction, renal failure, diabetes, peripheral vascular disease, or in the incidence of chronic obstructive pulmonary disease between the two groups. The NFT group had a higher proportion of patients with NYHA Class III/IV symptoms preoperatively (65.7% vs. 57.3%, p = 0.048), in patients with an ejection fraction < 40% (42.5% vs. 30.6%, p = 0.004), or in the number of individuals with an IABP inserted before surgery (13 vs. 1, p < 0.001). RESULTS: In the FT group the average period of aortic occlusion (40.7 +/- 15.2 min vs. 71.8 +/- 26.5 min, p < 0.001) and perfusion time (67.8 +/- 24.5 min vs. 117.5 +/- 40.2 min, p < 0.001) were significantly less than in the NFT group. The number of grafts per patient was 3.3 +/- 1.0 vs. 3.2 +/- 1.0, respectively (p = 0.38). Operative mortality was 0.9% in the FT group and 1.3% in the NFT group (p = 1.0). Significant differences were seen in the proportion of patients that suffered from postoperative ventilatory failure (3.2% in FT vs. 12.1% in NFT, p < 0.001), and the proportion of patients that suffered any postoperative complication was significantly higher in the NFT group (21.4%) than in the FT group (9.1%, p < 0.001). The differences in postoperative complications resulted in a shorter length of stay (LOS) in FT patients (5.6 +/- 4.1 days vs. 9.7 +/- 9.4 days NFT, p < 0.001). Only 4.1% of patients that entered the FT group failed and required admission to the ICU. Multivariate stepwise logistic regression analysis identified non-fast track recovery as an independent predictor of morbidity in CABG surgery patients. CONCLUSIONS: The data indicate it is possible to perform isolated CABG surgery, in a large proportion of the population, without the need for admission to an ICU for postoperative care.

Oral clonidine premedication attenuates the haemodynamic effects associated with ketamine anaesthetic induction in humans.

Induction of anaesthesia is often associated with undesirable variations in blood pressure and heart rate. Clonidine has been demonstrated to attenuate many of these undesirable effects when used as a premedicant. Other alpha 2 adrenergic agonists have been used to ameliorate the cardiostimulatory effects of ketamine in animals but there are few data on the use of this combination in humans. The effect of oral clonidine premedication, 5 micrograms.kg-1 on the haemodynamic changes induced by i.v. ketamine was studied in 42 patients volunteers. Ninety minutes before surgery, patients randomly received clonidine (C), diazepam (D), or a placebo (P) in a double-blinded fashion. Anaesthesia was induced with a ketamine infusion of 1 mg.kg-1 x min-1 until loss of consciousness. Heart rate and phasic blood pressure were measured noninvasively prior to induction, before and up to seven minutes after tracheal intubation. There were no differences in demographics or baseline vital signs among the three groups. With ketamine administration, increases in heart rate and blood pressure were less in those patients given C preoperatively than in those who received either D or P. The peak increase in mean blood pressure was 39% (C) versus 70% (D) and 55% (P) (P < 0.01). Heart rate increased by a maximum of 20% (C) versus 41% (D) and 46% (P) (P < 0.01). We conclude that oral clonidine attenuates the hyperdynamic effects of anaesthetic induction with i.v. ketamine.

The automated interview versus the personal interview. Do patient responses to preoperative health questions differ?

Laboratory testing of presurgical patients has been shown to be excessive, thereby increasing costs, reducing resources for other health care uses, and increasing risks to both patients and physicians. As one step toward reducing the number of unnecessary preoperative tests ordered, we used an automated method to aid preoperative assessment of 239 patients in Chicago and in Winnipeg. The "HealthQuiz," a small hand-held device containing a computer chip and video screen, uses a decision tree to ask a minimum of 60 health-related questions (the patient's response to certain questions determines the number of questions presented). The device then generates a summary printout of patient answers, the health areas needing further attention, and the laboratory tests most likely to uncover clinically important abnormalities in that patient. HealthQuiz responses are intended to aid the physician and not to replace the personal interview. As an aid, the automated interview highlights possible problem areas for in-depth pursuit by the physician. The need for nonselective batteries of tests is eliminated because recommendations for tests are based on specific elements of a patient's history. To be effective, responses to the HealthQuiz should be the same as responses to similar questions asked by a physician. We tested that premise in this study. Patient's answers to the HealthQuiz were compared with their responses to a randomly selected set of the same questions in a personal interview. Ninety-seven percent of the response pairs were identical, and most of the 3% that differed involved changes from "not sure" replies to the HealthQuiz. Laboratory tests suggested by responses to the two methods of questioning did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Seizures during opioid anesthetic induction--are they opioid-induced rigidity?

The tape recorded EEGs of 127 patients anesthetized with large doses of opioids were retrospectively analyzed for evidence of opioid-induced seizures, and in particular, correlated with movements that occurred during induction and could be clinically interpreted as seizures. Bilateral EEG leads in patients receiving fentanyl (20), sufentanil (20), or alfentanil (87) were recorded. Forty-six of these patients from all opioid groups manifested intense rigidity, as assessed both clinically and by EMGs recorded from eight muscles in 69 of the patients receiving alfentanil. This intense rigidity often resembled seizures, in that the phenomenon entailed severe stiffness of both limbs and trunk, with an explosive onset of myoclonic limb movements, and associated vertical nystagmus. Electroencephalographic observations were extensive, entailing 69 h of paper recordings played back from the tapes, at paper speeds of 30 or 60 mm/s, with detailed annotations from the voice track. These paper recordings were examined in detail independently by three of the investigators, who were unaware of the clinical phenomena that had occurred. The only observed EEG activity that could have been interpreted as epileptiform consisted of small sharp waves related to muscle activity or other artifact. The EEG never indicated seizure activity during these drug-induced movements and rigidity. Reports of opioid-induced seizures are reviewed and a set of criteria is offered to help achieve future consistency and credibility in evaluating this phenomenon. The available evidence does not support the existence of opioid-induced seizures in the clinical setting.

Aging and alfentanil disposition in healthy volunteers and surgical patients.

We studied the pharmacokinetic disposition of alfentanil in 20 volunteers and in 15 surgical patients 20-72 years old. Pharmacokinetic disposition was first order and was well described by a two-compartment open model. Central-compartment volume of distribution was 0.131 +/- 0.087 L.kg-1 (mean +/- SD) in young healthy volunteers and decreased modestly with increasing age (r = -0.32, P less than 0.05). However, apparent volume of distribution at steady-state, 0.404 +/- 0.205 L.kg-1 for the whole study cohort, was not age-related. Plasma clearance of alfentanil in young healthy subjects, 9.3 +/- 6.3 ml.kg-1.min-1, also showed an inverse relationship with age (r = -0.54, P less than 0.001), and was not affected by surgical stress in subjects older than 60 years. Cigarette smoking and sex of the subjects did not contribute to interindividual differences in the kinetic disposition of this drug. Our finding that interindividual differences in disposition of alfentanil were the least in older subjects suggests that its pharmacological effects related to pharmacokinetic disposition should be most predictable in the elderly.

Kinetic disposition of morphine in young males after intravenous loading and maintenance infusions.

Loading and maintenance infusions of morphine sulfate were administered to 5 young male patients 23-34-yr-old prior to elective surgery. Apparent steady-state plasma concentrations were achieved 30 minutes after the start of the drug infusion. The volume of distribution at steady-state (2.43 +/- 0.48 L X kg-1), beta elimination rate constant (0.700 +/- 0.162/h) and plasma clearance (1.66 +/- 0.33 L X kg-1 X h-1) were similar to values previously determined in young healthy subjects receiving a single bolus infusion. These data confirm our findings concerning morphine disposition in healthy young subjects and demonstrate the feasibility of achieving predictable plasma concentrations of morphine for future assessment of pharmacodynamic/pharmacokinetic relationships for this drug.

Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation.

The effects of clonidine, a centrally acting alpha 2-adrenergic receptor agonist, on depth of fentanyl anesthesia and on cardiovascular response to laryngoscopy and intubation were studied. Twenty-four patients undergoing aortocoronary bypass surgery (ACBS) with a history of arterial hypertension, coronary artery disease (NYHA class 3-4), and well-preserved left ventricular function were assigned randomly to either Group 1 (n = 12), who received standard premedication, or Group 2 (n = 12), who received clonidine 5 micrograms X kg-1 po in addition to standard premedication 90 min before estimated induction time. Depth of anesthesia was assessed by on-line aperiodic computerized analysis of the electroencephalogram (Lifescan EEG Monitor). Fentanyl was administered in 250-micrograms increments to shift the EEG to the 0.5-3-Hz frequency range (delta activity) in all subjects. In both groups, the anesthetic regimen effectively prevented hyperdynamic cardiovascular responses to laryngoscopy and intubation. No significant differences in measured or derived hemodynamic variables were observed between the two groups during the awake control period, except for stroke volume index (SVI), which was significantly greater in Group 1, 44 +/- 9 ml X beat-1 X m-2 compared with Group 2, 35 +/- 3.3 ml X beat-1 X m-2 (P less than 0.05). By contrast, fentanyl requirements in Group 2 were significantly reduced by 45% when compared with Group 1, i.e., from 110 +/- 23 to 61 +/- 19 micrograms X kg-1 (P less than 0.001). The authors conclude that at a similar anesthetic depth, as assessed by the EEG shift into the lower frequency range (0.5-3 Hz), a markedly reduced fentanyl dose effectively prevented the hyperdynamic cardiovascular response to laryngoscopy and intubation in the group of patients premedicated with clonidine. This is likely explained by the known synergistic inhibitory action of opiates and alpha 2-adrenoceptor agonists on central sympathetic outflow.

Age-related morphine kinetics.

The kinetic disposition of morphine was compared in 13 young and 7 older healthy subjects after a single intravenous dose of 10 mg/70 kg morphine. The apparent volume of distribution at steady state in elderly subjects was only half of that in young subjects. This difference was derived from reductions in both central and peripheral kinetic compartment volumes in the older subjects. The beta elimination phase for morphine was more rapid, but its plasma clearance was reduced in older subjects. Calculation of the peripheral compartment morphine concentration for these subjects indicated that drug concentration in this kinetic space was higher in older subjects for 1.5 hr after dosing.

The effect of acute elevation of blood pressure on myocardial performance during enflurane and enflurane with nitrous oxide anaesthesia in man.

Myocardial performance was assessed by a noninvasive method, when arterial pressure was raised acutely in eleven healthy subjects, awake and anaesthetized with equipotent (1 MAC) doses of either enflurane (Group 1) or enflurane with nitrous oxide 70 per cent. (Group 2). With anaesthesia, there was a significant and equal decrease in the indices of myocardial performance (p less than 0.05) in both groups with pressure elevation when compared to awake controls. The results are similar to those observed in subjects with depressed myocardial function due to either ischaemic heart disease or halothane anaesthesia.

The effect of halothane with nitrous oxide on baroreflex control of heart rate in man.

The assess the effect of halothane with 70 per cent nitrous oxide on the human baroreflex, we observed the heart rate response to pharmacological elevation of blood pressure in subjects anaesthetized to the 1 MAC and 1.25 MAC levels. We observed, in comparison to the awake control, that at 1 MAC halothane with 70 per cent nitrous oxide and oxygen, the baroreflex was depressed and this became more significant at 1.25 MAC anaesthesia. In comparison to previous similar studies on the effect of halothane-oxygen anaesthesia, there was significantly less baroreflex depression at equianaesthetic doses with halothane with 70 per cent nitrous oxide.

Baroreflex control of heart rate in man awake and during enflurane and enflurane--nitrous oxide anesthesia.

Baroreflex control of heart rate was assessed by means of a pressor test in two groups of subjects while awake and at two levels of anesthesia with enflurane (Group I) and enflurane-nitrous oxide (Group II). In the awake control situation, calculated mean slopes (+/- SD) were 23 +/- 8 (Group I) and 25 +/- 11 (Group II). There was no significant difference between the groups. During enflurane anesthesia (Group I) mean slopes were significantly depressed to 5 +/- 5 at 1 MAC and 6 +/- 6 at 0.8 MAC. During enflurane-nitrous oxide anesthesia (Group II), slopes were significantly depressed to 5 +/- 3 at 1 MAC and 6 +/- 4 at 0.9 MAC. There was no significant difference between the extents of depression in the two groups. It is concluded that both enflurane anesthesia and enflurane-nitrous oxide anesthesia at 1 MAC produce significant depression of baroreflex control of heart rate in man.

The effect of morphine on human neuromuscular transmission.

By utilizing high frequency nerve stimulation, we observed the effects of morphine sulphate, 0.5 mg.kg-1 on human neuromuscular transmission. Tetanic fade at 50, 100 and 200 hz did not change during the one hour period after infusion of morphine. Post-tetanic depression (PTD) of single twitch response increased progressively with time over the one-hour study period. This was most marked with the 100 and 200 hz tetanic frequencies. In contrast, control subjects displayed either no change, or a slight increase (post-tetanic facilitation; PTF), over a similar one-hour test period. We believe these results are best explained by a presynaptic action of morphine, whereby intraterminal mobilization of acetylcholine is impaired by the opiate narcotic drug.

Halothane depresses baroreflex control of heart rate in man.

Baroreflex control of heart rate was determined during three awake control situations and during two depths of halothane anesthesia in man. Baroreflex function was quantiated by calculating the pressor test slope from the R-R interval change on the ECG produced by a pharmacologically induced pressor response. During the three awake control situations the subjects breathed room air or 100 per cent O2 spontaneously or 100 per cent O2 with ventilation controlled. Mean (+/- SD) slopes obtained were 15.1 +/- 4.5, 15.6 +/- 6.8 and 18.4 +/- 9.9, respectively. No significant difference in baroreflex function slope was observed. During light halothane anesthesia (0.7 per cent endtidal) baroreflex function was significantly depressed (mean slope = 2.5 +/- 1.5), and it was abolished at 1.1 per cent end-tidal halothane (mean slope = 0.03 +/- 0.04). It is concluded that halothane anesthesia produces depression of baroreflex control of heart rate in man.

The effects of age on baroreceptor reflex function in man.

The relationship of age to baroreceptor reflex activity was determined in 35 healthy volunteers ranging in age from 19 to 65 years. Intra-arterial catheters were placed and blood pressure and pulse rate responses of each subject were observed during a Valsalva maneuver (31 subjects) and during the Pressor Test (33 subjects). The Valsalva maneuver consisted of a forced expiration sufficient to raise a column of mercury 40 torr for 10 seconds. This resulted in a reduction in pulse pressure (Baroreceptor stimulus) during the maneuver followed by a transient overshoot in diatolic pressure (response) following its termination. In comparison to younger subjects, older subjects had a greater reduction in pulse pressure but similar overshoot in diastolic pressure. The pressor test consisted of observing the effect of increasing systolic blood pressure (stimulus) on pulse duration (response) following the intravenous administration of phynylephrine. By relating each systolic pressure to the immediately succeeding R-R interval, a linear relationship was found. Its slope expressed in milliseconds of R-R interval change per torr increase in systolic pressure is an index of baroreflex function. Older subjects have less cardiac slowing compared to younger subjects and a hyperbolic relationship exists between age and slope (r = 0.84, p less than 0.05). These tests indicate that baroreceptor reflex function decreases with aging.

The myocardial effects of pancuronium.

The effect of pancuronium on myocardial contractility was studied in three different animal preparations. Pancuronium produced no change in isometric contraction of rabbit atrial or cat papillary muscle but displaced the acetylcholine dose-response curve to the right in the papillary muscle preparations, verifying a muscarinic blocking effect of this drug. In atropinized dogs in vivo pancuronium produced no significant change in the cardiovascular parameters studied. These studies show that pancuronium exerts its cardiovascular effects primarily by blocking muscarinic receptors in the heart.