Larry D. Gruenke

Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation.

To determine the effect of end-stage renal disease on the pharmacokinetics of reocuronium bromide (ORG 9426), a new nondepolarizing monoquaternary steroidal neuromuscular blocking drug, the authors administered 600 micrograms/kg rocuronium (2 x ED95) intravenously to ten patients undergoing cadaver renal transplantation and ten healthy patients undergoing elective minor surgery (controls). All patients were anesthetized with nitrous oxide (50-70% in oxygen) and isoflurane (end-tidal concentrations of 1.2 +/- 0.5% and 0.8 +/- 0.2%, mean +/- SD, for control and transplant groups, respectively). Plasma concentrations of rocuronium were determined by capillary gas chromatography. A population-based pharmacokinetic analysis (NONMEM) was used to determine typical values, standard errors, and interindividual variability for the pharmacokinetic parameters and to determine whether these values differed between control and renal transplant patients. Total plasma clearance (2.89 +/- 0.25 ml.kg-1.min-1, mean +/- SE) and volume of the central compartment (76.9 +/- 10.6 ml/kg) did not differ between control and renal transplant patients, whereas volume of distribution at steady state was greater in renal transplant patients (264 +/- 19 ml/kg) than in control patients (207 +/- 14 ml/kg). This resulted in a longer elimination half life in renal transplant patients (97.2 +/- 17.3 min) compared to controls (70.9 +/- 4.7 min). The authors conclude that renal failure and renal transplantation alter the distribution but not the clearance of rocuronium.

The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients with liver disease

To determine the effect of liver disease on the pharmacokinetics of rocuronium, the authors administered 0.6 mg/kg (twice the ED95) to 10 patients with liver disease and compared these results to values in 10 healthy surgical patients. Anesthesia was induced with thiopental and maintained with isoflurane (0.9%-1.1% end-tidal concentration) and nitrous oxide (60%). Venous blood samples were obtained for 6 h after rocuronium injection and plasma concentrations were measured using gas chromatography. Pharmacokinetic differences between groups were determined using a population-based pharmacokinetic analysis (NONMEM). Hepatic impairment did not alter the plasma clearance of rocuronium (217 +/- 21.8 mL/min, mean +/- SE, for both groups), but did increase the volume of the central compartment (5.96 +/- 1.01 L for controls, 7.87 +/- 1.33 L for patients with liver disease) and volume of distribution at steady state (16.4 L for controls, 23.4 L for patients with liver disease). In turn, elimination half-life was longer in patients with liver disease (111 min) compared to controls (75.4 min). The authors conclude that liver disease alters the pharmacokinetics of rocuronium by increasing its volume of distribution. The longer elimination half-life might result in a longer duration of action of rocuronium in patients with liver disease, particularly after prolonged administration. (Anesth Analg 1995;80:754-9)

FLUORIDE METABOLITES AFTER PROLONGED EXPOSURE OF VOLUNTEERS AND PATIENTS TO DESFLURANE

We examined the metabolism of desflurane in 13 healthy volunteers given 7.35 +/- 0.81 MAC-hours (mean +/- SD) of desflurane and 26 surgical patients given 3.08 +/- 1.84 MAC-hours (mean +/- SD). Markers of desflurane metabolism included fluoride ion measured via an ion-specific electrode, nonvolatile organic fluoride measured after sodium fusion of urine samples, and trifluoroacetic acid determined by a gas chromatographic-mass spectrometric method. In both volunteer and patient groups, postanesthesia serum fluoride ion concentrations did not differ from background fluoride ion concentrations. Similarly, postanesthesia urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthesia excretion rates. However, small but significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. A peak serum concentration of 0.38 +/- 0.17 mumol/L of trifluoroacetic acid and a peak urinary excretion rate of 0.169 +/- 0.107 mumol/h were detected in volunteers at 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Thus, desflurane strongly resists biodegradation, but a small amount is metabolized in humans.

Factors associated with obtaining nipple aspirate fluid: Analysis of 1428 women and literature review

SummaryStudies of cytologic and biochemical constituents of nipple aspirates of breast fluid have contributed to understanding the natural history of benign and malignant breast disease. We conducted multivariate analyses using 1428 women from a recent case-control study of breast disease to determine which factors were independently associated with the ability to obtain breast fluid from nonlactating women. We then compared results from these analyses to the results from five previous studies that also used the aspiration technique of Sartorius. Four factors were consistently associated across studies with increased ability to obtain breast fluid: 1) age up to 35 to 50 years; 2) earlier age at menarche; 3) non-Asian compared to Asian ethnicity; and 4) history of lactation. Exogenous estrogen use, endogenous estrogen concentrations, phase of menstrual cycle, family history of breast cancer, type of menopause, and less than full-term pregnancy consistently did not influence ability to obtain fluid.New findings from this study shed light on some apparently contradictory findings from the previous studies. In particular, this study showed that the effects of age on ability to obtain fluid appeared to be independent of the effects of menopause. Furthermore, discrepancies in previous findings on the effects of parity on ability to obtain fluid may be explained by our finding that the increased ability to obtain fluid from parous compared to nulliparous women applied only to parous women who had breastfed.

Dual carbon-labeled isotope experiments using D-[6-14C] glucose and L-[1,2,3-13C3] lactate: A new approach for investigating human myocardial metabolism during ischemia

Simultaneous lactate production and extraction have been previously demonstrated in the myocardium in patients with coronary artery disease. To quantitate this lactate production and determine its source, dual carbon-labeled isotope experiments were performed. L-[1,2,3-13C3] lactate and D-[6-14C] glucose were infused in 10 patients with significant coronary artery disease. Metabolic samples were obtained at rest and during atrial pacing. Despite net chemical myocardial lactate extraction in the 10 patients at rest and no evidence of clinical ischemia, the L-[1,2,3-13C3] lactate analysis demonstrated that lactate was being released by the myocardium. During atrial pacing, seven patients did not develop clinical symptoms of ischemia, and the chemical lactate analysis showed net lactate extraction. However, tracer analysis demonstrated that there was a significant increase in the lactate released during atrial pacing (from 6.9 +/- 2.3 to 16.2 +/- 10.1 mumol/min) (p less than 0.05). In these seven patients, circulating glucose was the source of 23 +/- 15% of the lactate released at rest, and there was no significant change during pacing. The remaining three patients had mild chest pain and net chemical lactate production during pacing. Lactate release detected by the tracer increased from 5.7 +/- 3.0 mumol/min at rest to 50.9 +/- 16.8 mumol/min during pacing (p less than 0.01). In these patients, the contribution of glucose to lactate production increased significantly during pacing-induced clinical ischemia from 25 +/- 22 to 67 +/- 14% (p less than 0.005). Thus, dual carbon-labeled isotopic experiments are powerful tools for investigating myocardial metabolic pathways.(ABSTRACT TRUNCATED AT 250 WORDS)

Mild intraoperative hypothermia does not change the pharmacodynamics (concentration-effect relationship) of vecuronium in humans

To investigate the effect of mild hypothermia on the neuromuscular junction sensitivity to vecuronium, we determined the pharmacodynamics (concentration-effect relationship) of vecuronium in 10 patients (ASA physical class I or II; age range, 21–46 yr; weight range, 54–104 kg), during isoflurane-nitrous oxide-fentanyl anesthesia. Five were cooled to a mean temperature of 34.4°C and five were maintained normothermic at a mean temperature of 36.8°C. Neuromuscular function was monitored by measuring the evoked mechanical response of the adductor pollicis muscle after supra-maximal train-of-four stimulation of the ulnar nerve at the wrist. Vecuronium, 3 μg·kg−1.min−1, was infused for 10 min, venous blood sampled for 60 min, and twitch tension and plasma concentration data were used to determine pharmacodynamic variables in each patient. Results for the hypothermic and normothermic groups were compared by Mann-Whitney U-test. There were no differences in any pharmacodynamic variable between the hypothermic and normothermic patients. For the hypothermic and normothermic patients, respectively, steady-state plasma concentrations of vecuronium producing 50% neuromuscular block (CSS50) were 73 ± 13 ng/mL (mean ± SD) and 79 ± 31 ng/mL; the rate constants for equilibration of vecuronium between the plasma and the neuromuscular junction (Keo) were 0.27 ± 0.14 per min−1 and 0.26 ± 0.11 per min, and the power functions representing the slope of the concentration-effect relationship (γ) were 5.7 ± 1.9 and 4.4 ± 1.8. We conclude that the pharmacodynamics (concentration-effect relationship) of vecuronium are similar at 34.4 and 36.8°C and that pharmacodynamic factors do not explain the prolongation of action of vecuronium previously observed during mild hypothermia.

The Magnitude and Time Course of Vecuronium Potentiation by Desflurane Versus Isoflurane

BACKGROUND Preliminary studies suggest that desflurane and isoflurane potentiate the action of muscle relaxants equally. However, variability between subjects may confound these comparisons. A crossover study was performed in volunteers on the ability of desflurane and isoflurane to potentiate the neuromuscular effect of vecuronium, to influence its duration of action, and on the magnitude and time course of reversal of potentiation when anesthesia was withdrawn. METHODS Adductor pollicis twitch tension was monitored in 16 volunteers given 1.25 MAC desflurane on one occasion, and 1.25 MAC isoflurane on another. In eight subjects, vecuronium bolus dose potency was determined using a two-dose dose-response technique; the vecuronium infusion dose requirement to achieve 85% twitch depression also was determined. Also in these subjects, the magnitude and time course of spontaneous neuromuscular recovery were determined when the anesthetic was withdrawn while maintaining a constant vecuronium infusion. In the other eight subjects, the time course of action of 100 micrograms/kg vecuronium was determined. RESULTS Vecuroniums ED50 and infusion requirement to maintain 85% twitch depression were 20% less during desflurane, compared to isoflurane, anesthesia; vecuronium plasma clearance was similar during the two anesthetics. After 100 micrograms/kg vecuronium, onset was faster and recovery was longer during desflurane anesthesia. When the end-tidal anesthetic concentration was abruptly reduced from 1.25 to 0.75 MAC, twitch tension increased similarly (approximately 15% of control), and time for the twitch tension to reach 90% of the final change was similar (approximately 30 min) with both anesthetics. Decreasing anesthetic concentration from 0.75 to 0.25 MAC increased twitch tension by 46 +/- 10% and 25 +/- 7% of control (mean +/- SD, P < 0.001) with desflurane and isoflurane, respectively; 90% response times for these changes were 31 +/- 10 min and 18 +/- 7 min (P < 0.05), respectively. CONCLUSIONS Desflurane potentiates the effect of vecuronium approximately 20% more than does an equipotent dose of isoflurane.

Cumulative characteristics of atracurium and vecuronium. A simultaneous clinical and pharmacokinetic study.

BackgroundCumulative effects (Increased 25–75% recovery time with increasing dose) are evident with vecuronium but not with atracurium. Pharmacokinetic simulations suggest that vecuroniums cumulation occurs as recovery shifts from distribution to elimination whereas atracuriums recovery always occurs during elimination. The purpose of this study was to examine this pharmacokinetic explanation. MethodsWe assigned 12 volunteers to receive atracurium or vecuronium on three occasions during nitrous oxide-isoflurane anesthesia. Evoked adductor pollicis twitch tension was monitored. On occasion 1, the dose expected to produce 95% block (ED95) was estimated for each subject. On occasions 2 and 3, 1.2 or 3.0 multiples of ED95 were given as a bolus. Plasma was sampled for 128 min to determine muscle relaxant concentrations; pharmacodynamic modeling was used to determine effect-compartment drug concentrations (Ce). For each drug, recovery time, recovery phase half-life (rate of decrease in Ce during recovery), and Ce at 25% and 75% recovery were compared between doses. ResultsAtracuriums recovery time increased 2.4 ± 2.2 min (mean ± SD) with the larger dose, less than the Increase with vecuronium (8.2 ± 3.8 min). Atracuriums recovery phase half-life was 14.6 ± 1.7 and 20.1 ± 2.3 min with the small and large doses (P < 0.05); vecuroniums recovery phase half-life increased similarly from 13.5 ± 2.3 to 18.5 ± 5.0 min (P < 0.05). At 75% recovery, vecuroniums Ce decreased from 65 ± 18 ng/ml with the small dose to 55 ± 15 ng/ml with the large dose (P < 0.05). Assuming that neuromuscular junction sensitivity was constant, this difference could be explained by considering neuromuscular effects of vecuroniums metabolite, 3-desacetylvecuronium. ConclusionsAlthough vecuronium was cumulative (as predicted), atracurium was also slightly cumulative. Inconsistent with our hypothesis, recovery phase half-lives for both drugs Increased similarly between doses; therefore, differences In cumulation were not solely explained by pharmacokinetics of the muscle relaxant. It appears that 3-desacetyIvecuronium contributes to vecuroniums cumulative effect, even after usual clinical doses.

Edrophonium Increases Mivacurium Concentrations during Constant Mivacurium Infusion, and Large Doses Minimally Antagonize Paralysis

Background Mivacurium, a nondepolarizing muscle relaxant, is metabolized by plasma cholinesterase. Although edrophonium does not alter plasma cholinesterase activity, we have observed that doses of edrophonium that antagonize paralysis from other nondepolarizing muscle relaxants are less effective with mivacurium. We speculated that edrophonium might alter metabolism of mivacurium, thereby hindering antagonism of paralysis. Accordingly, we determined the effect of edrophonium on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion. Methods We infused mivacurium to maintain 90% depression of adductor pollicis twitch tension and then gave edrophonium in doses ranging from 125-2,000 micro gram/kg without altering the mivacurium infusion. Peak twitch tension after edrophonium was determined to estimate the dose of edrophonium antagonizing 50% of twitch depression for antagonism of mivacurium; plasma cholinesterase activity and mivacurium concentrations before and after edrophonium were measured. Additional subjects were given 500 micro gram/kg edrophonium to antagonize continuous infusions of d-tubocurarine and vecuronium. Results With mivacurium, edrophonium increased twitch tension in a dose-dependent manner: the dose of edrophonium antagonizing 50% of twitch depression was 2,810 micro gram/kg. The largest dose of edrophonium (2,000 micro gram/kg) produced only 45 plus/minus 7% antagonism. Edrophonium, 500 micro gram/kg, antagonized mivacurium markedly less than it antagonized d-tubocurarine and vecuronium. Edrophonium increased plasma concentrations of the two potent stereoisomers of mivacurium 48% and 79%, these peaking at 1-2 min; plasma cholinesterase activity was unchanged. Conclusions Edrophonium doses that antagonize d-tubocurarine and vecuronium are less effective in antagonizing the neuromuscular effects of mivacurium during constant infusion. Edrophonium increases plasma mivacurium concentrations, partly or completely explaining its limited efficacy; the mechanism by which edrophonium increases mivacurium concentrations remains unexplained. Our results demonstrate that antagonism of mivacurium by edrophonium is impaired, and therefore we question whether edrophonium should be used to antagonize mivacurium.

The determination of nicotine in biological fluids at picogram levels by selected ion recording

Using a combined gas chromatographic-mass spectrometric-selected ion recording technique it has been possible to achieve detection, identification, and quantitation of nicotine in biological fluids in amounts as low as 25 pg. Employing the deuterated variant nicotine-5′,5′-d2 both as an internal standard and as a carrier in an inverse isotope dilution method, an accurate, sensitive, and specific method for picogram level quantitation of nicotine is obtained. Careful precautions were necessary to prevent positive “blank” values at low levels due to extraneous nicotine, which were found to arise both from the solvents used in the extractions and from airborne sources.