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Biomedical subjects

D M Fisher

Publications and source records attributed to D M Fisher.

At least 73 records · Page 4Linked to original sources
PubMed1995

Effect of increased intra-abdominal pressure on hepatic extraction and clearance of fentanyl in neonatal lambs.

Fentanyl, an opioid metabolized by hepatic mixed function oxidases, is commonly administered as the primary anesthetic for neonates undergoing surgery. Pharmacokinetic studies have suggested that abdominal surgery in neonates decreases fentanyl clearance, contending that this results from increases in intra-abdominal pressure (IAP) decreasing hepatic blood flow. To examine the effects of IAP on hepatic blood flow and fentanyl clearance, we infused fentanyl to eight neonatal lambs, measured regional blood flows by using the radionuclide-labeled microsphere technique and determined hepatic fentanyl extraction and clearance and hepatic oxygen extraction and consumption at three levels of IAP: 0, 12 and 18 mm Hg. Increased IAP did not affect portal or hepatic blood flow or ductus venosus shunt. Fentanyl extraction was 16.5 +/- 3.0% (mean +/- S.E.) at 0 mm Hg of IAP. Increased IAP decreased hepatic extraction of fentanyl, thereby decreasing fentanyl clearance. Increased IAP did not affect hepatic oxygen extraction or consumption. In two additional animals in which serial measurements of hepatic blood flow were obtained, increased IAP (15 mm Hg) transiently decreased hepatic blood flow with recovery to control values at 2 hr. The authors conclude that fentanyl is poorly extracted by neonatal livers, in contrast to its large extraction ratio in adults. The decrease in fentanyl clearance with increased IAP is consistent with pharmacokinetic studies demonstrating decreased clearance in neonates undergoing abdominal surgery. However, the present study suggests that the mechanism of decreased clearance is decreased hepatic function (decreased fentanyl extraction) rather than decreased hepatic blood flow.

Abdomen↗
PubMed1994

Acidic fibroblast growth factor: evaluation of topical formulations in a diabetic mouse wound healing model.

The efficacy of topical formulations of acidic fibroblast growth factor (aFGF) in healing of full-thickness wounds has been studied in a diabetic db+/db+ mouse model. The effect of several formulation variables, dose, and application frequency was examined. It was found that wound healing in diabetic animals treated with aFGF or placebo was slower than in their nondiabetic littermates. The availability of aFGF from the viscous vehicle employed in this study (1% hydroxyethyl cellulose) was demonstrated in vitro using diffusion cells. The viscous formulation of aFGF was equally effective in wound healing as a nonviscous formulation in phosphate-buffered saline. A formulation containing heparin (necessary for full biological and conformational stability of aFGF) at a mass ratio of 3:1 to aFGF was more efficacious than formulations with lower heparin: aFGF ratios. Wounds treated with three doses of 3.0 micrograms/cm2 aFGF healed faster than those treated with a single dose of 3.0 micrograms/cm2 aFGF. Three applications of 3.0 or 0.6 microgram/cm2 a FGF were equally effective in accelerating wound healing.

Administration, Topical↗
PubMed1994

Comparison of twitch depression of the adductor pollicis and the respiratory muscles. Pharmacodynamic modeling without plasma concentrations.

BACKGROUND: Although the respiratory muscles (the diaphragm and the laryngeal adductors) recover from paralysis more rapidly than does the adductor pollicis, patients can develop complete paralysis of the respiratory muscles, but not of the adductor pollicis, after bolus administration of vecuronium. The authors used a pharmacodynamic model not requiring muscle relaxant plasma concentrations to reconcile these findings. METHODS: The pharmacodynamic model is based on the traditional model, in which: (1) vecuronium concentration at the neuromuscular junction (C(effect)) is a function of the plasma concentration versus time curve and a rate constant for equilibration between plasma and the neuromuscular junction (k(eo)); and (2) effect is a function of C(effect), the steady-state plasma concentration that produces 50% effect (C50), and a factor to explain the sigmoid relationship between concentration and effect. In the absence of vecuronium plasma concentrations, an empiric model (rather than the usual effect compartment model) can be used to mimic the time delay (proportional, but not identical, to 1/k(eo)) between dose and effect. The model can be used to estimate the steady-state infusion rate that produces 50% effect (IR50), equal to the product of C50 and vecuronium plasma clearance; IR50 for different muscle groups then can be compared to assess relative sensitivity. The authors applied this model to published effect data for subjects given 40-70 micrograms/kg vecuronium in whom paralysis of three muscle groups was measured during opioid/propofol anesthesia. RESULTS: For IR50, the ratio of values for the larynx:diaphragm:adductor pollicis was 1.4:1.2:1; for the equilibration constant (inversely proportional to the time delay), the ratio for the respiratory muscles to the adductor pollicis was 2.5:1. CONCLUSIONS: Vecuronium concentrations peak earlier at the respiratory muscles than at the adductor pollicis, possibly the result of greater perfusion to these organs, leading to earlier onset of paralysis. The observation that bolus injection of vecuronium produces greater paralysis of the respiratory muscles than of the adductor pollicis, despite greater resistance of the respiratory muscles, can be explained by differential rates of equilibration between plasma and various muscles.

Humans↗
PubMed1994

Is intramuscular mivacurium an alternative to intramuscular succinylcholine?

BACKGROUND: Mivacurium's rapid onset and short duration of action in children suggests that intramuscular administration might treat laryngospasm and facilitate tracheal intubation without producing prolonged paralysis. Accordingly, the authors measured the neuromuscular effects of intramuscular mivacurium in anesthetized infants and children. METHODS: Twenty unpremedicated infants and children (3 months to 5 yr of age) were anesthetized with nitrous oxide and halothane and permitted to breathe spontaneously. When anesthetic conditions were stable, mivacurium was injected into the quadriceps or deltoid muscle. Minute ventilation and adductor pollicis twitch tension were measured. The initial mivacurium dose was 250 micrograms/kg and was increased (to a maximum of 800 micrograms/kg, at which dose the trial was ended) or decreased according to the response of the previous patient, the goal being to bracket the dose producing 80-90% twitch depression within 5 min of drug administration. RESULTS: No patient achieved > 80% twitch depression within 5 min of mivacurium administration. Peak twitch depression was 90 +/- 13% (mean +/- SD) for infants and 88 +/- 15% for children at 15.0 +/- 4.6 min and 18.4 +/- 6.4 min, respectively. Ventilatory depression (a 50% decrease in minute ventilation or a 10-mmHg increase in end-tidal carbon dioxide tension) occurred at 9.0 +/- 4.4 min in nine infants and 13.6 +/- 7.5 min in 10 children; ventilatory depression did not develop in one infant given a dose of 350 micrograms/kg. Time to peak twitch depression or ventilatory depression was not faster with larger doses. CONCLUSIONS: Although ventilatory depression preceded twitch depression, both occurred later with intramuscular mivacurium than would be expected after intravenous mivacurium or intramuscular succinylcholine. The authors speculate that the onset of intramuscular mivacurium is too slow to treat laryngospasm or to facilitate routine tracheal intubation in infants or children, despite administration of large doses.

Anesthesia, Inhalation↗
PubMed1994

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

BACKGROUND: Cumulative effects (increased 25-75% recovery time with increasing dose) are evident with vecuronium but not with atracurium. Pharmacokinetic simulations suggest that vecuronium's cumulation occurs as recovery shifts from distribution to elimination whereas atracurium's recovery always occurs during elimination. The purpose of this study was to examine this pharmacokinetic explanation. METHODS: We assigned 12 volunteers to receive atracurium of 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. RESULTS: Atracurium's 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). Atracurium's recovery phase half-life was 14.6 +/- 1.7 and 20.1 +/- 2.3 min with the small and large doses (P < 0.05); vecuronium's recovery phase half-life increased similarly from 13.5 +/- 2.3 to 18.5 +/- 5.0 min (P < 0.05). At 75% recovery, vecuronium's 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 vecuronium's metabolite, 3-desacetylvecuronium. CONCLUSIONS: Although 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-desacetylvecuronium contributes to vecuronium's cumulative effect, even after usual clinical doses.

Adult↗
PubMed1994

The pharmacodynamics and pharmacokinetics of the metabolite 3-desacetylvecuronium (ORG 7268) and its parent compound, vecuronium, in human volunteers.

The pharmacology of 3-desacetylvecuronium, the principal metabolite of vecuronium, was investigated. We studied 12 healthy volunteers, each on two occasions. First they received 3-desacetylvecuronium alone and then, on a later occasion, vecuronium. Six subjects received a large dose of each drug (pharmacokinetic study), the remaining six received a small dose (pharmacodynamic study). Drug concentrations in plasma and urine were measured using capillary gas chromatography. Neuromuscular block was assessed by measuring force of contraction of the adductor pollicis. Drug plasma concentration vs. time and neuromuscular effect data were analyzed by nonlinear mixed-effects modeling. 3-Desacetylvecuronium, compared with vecuronium (median, range in parentheses), had a smaller plasma clearance, 3.51 (2.11-6.57) vs. 5.39 (5.04-7.19) ml.kg-1.min-1; a larger steady-state distribution volume, 254 (215-410) vs. 152 (111-170) ml.kg-1; a longer terminal elimination half-life 116 (44-672) vs. 34 (25-61) min and a longer mean residence time, 67 (42-145) vs. 26 (18-32) min (P < .05). Renal clearances of 3-desacetylvecuronium and vecuronium were 0.85 (0.15-1.24) and 0.58 (0.16-0.66) ml.kg-1.min-1, respectively (P < .05). Conversion to 3-desacetylvecuronium accounted for 12% of vecuronium's clearance. Concentrations of 3-desacetylvecuronium and vecuronium that produced 50% neuromuscular block were 123 (109-154) and 102 (71-123) ng.ml-1, respectively (P < .05). 3-Desacetylvecuronium is a potent neuromuscular blocking drug and may be responsible for episodes of prolonged paralysis after long-term administration of vecuronium to patients in intensive care units.

Adolescent↗
PubMed1992

MAC of desflurane in 60% nitrous oxide in infants and children.

Desflurane, an inhaled anesthetic, may be useful for outpatient procedures in pediatric patients because its blood solubility (similar to that of nitrous oxide and less than that of commercially available potent inhaled anesthetics) may facilitate emergence and recovery from anesthesia. Although the MAC of desflurane without nitrous oxide has been determined in pediatric patients, it is likely that clinicians will administer desflurane with nitrous oxide. To determine the potency of desflurane administered with 60% nitrous oxide in pediatric patients, the authors determined the minimum alveolar concentration that prevents movement in 50% of subjects (MAC) in 12 infants aged 17 weeks-12 months and 12 children aged 1-5 yr. Anesthesia was induced with desflurane in oxygen; nitrous oxide was not administered during induction of anesthesia to minimize the likelihood of hypoxia if laryngospasm occurred. Following tracheal intubation, nitrous oxide and desflurane were administered and maintained at target concentrations for a minimum of 10 min before surgical incision. No additional anesthetic, sedative/hypnotic, or analgesic drugs were administered prior to incision. Following surgical incision, anesthesia was maintained with nitrous oxide, desflurane, and fentanyl, 4 +/- 1 micrograms/kg (mean +/- SD). MAC, determined using a modification of Dixon's "up-and-down" technique, was 7.5 +/- 0.1% (mean +/- SE) for infants and 6.4 +/- 0.2% for children; similar values were obtained using logistic regression (7.5 +/- 0.01% and 6.3 +/- 0.03%, respectively). Time from discontinuation of anesthesia to eye-opening and tracheal extubation was 5.4 +/- 3.6 min (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1992

Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children.

To determine the induction and maintenance characteristics of desflurane in pediatric patients, the authors anesthetized 206 infants and children aged 1 month to 12 yr with nitrous oxide plus desflurane and/or halothane in oxygen. Patients were assigned to one of four groups: anesthesia was 1) induced and maintained with desflurane after premedication with an oral combination of meperidine, diazepam, and atropine; 2) induced and maintained with desflurane; 3) induced with halothane and maintained with desflurane; or 4) induced and maintained with halothane. An unblinded observer recorded time to loss of consciousness (lid reflex), time to intubation, and clinical characteristics of the induction and maintenance of anesthesia. Moderate-to-severe laryngospasm (49%) and moderate-to-severe coughing (58%) occurred frequently during induction of anesthesia with desflurane; the incidence of these was not altered by premedication. In contrast, laryngospasm and coughing were rare during induction of anesthesia with halothane. In unpremedicated patients, time to loss of lid reflex (mean +/- SD) was similar for desflurane (2.4 +/- 1.2 min) and halothane (2.1 +/- 0.8 min). During induction of anesthesia, before laryngoscopy and intubation, mean arterial pressure less than 80% of baseline was more common with halothane; heart rate and mean arterial pressure greater than 120% of baseline were more common with desflurane. Intraoperatively, heart rate greater than 120% of baseline was more common with desflurane; blood pressures were similar for the two anesthetics. The authors conclude that the high incidence of airway complications during induction of anesthesia with desflurane limits its utility for inhalation induction in pediatric patients. Anesthesia can be safely maintained with desflurane if induced with a different anesthetic.

Anesthesia, Inhalation↗
PubMed1992

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.

Adult↗
PubMed1991

The "educated hand". Can anesthesiologists assess changes in neonatal pulmonary compliance manually?

To determine whether anesthesiologists can manually detect significant changes in pulmonary compliance in neonates using an "educated hand," the authors tested whether clinicians could detect clamping of an endotracheal tube connecting a neonatal lung model to one of three anesthesia breathing circuits. The test lungs corresponded to the lung of a full-term neonate (large lung) or a premature neonate (small lung), and the circuits were a disposable Mapleson D and a disposable pediatric circle system with and without a humidifier. Clinicians having four levels of expertise (inexperienced anesthesia residents, experienced anesthesia residents, faculty not specializing in pediatric anesthesia, and specialized pediatric anesthesia faculty) were permitted to choose fresh gas flows, ventilatory pattern, and rate. After an acclimation period, the endotracheal tube connecting the test lung to the circuit was occluded once for 30 s. Clinicians were credited with a successful detection if they reported the occlusion within 15 s and had fewer than one false positive per minute. With the large lung model, only 4 of 24 clinicians detected occlusion with the Mapleson D circuit; similar results were obtained with the other circuits. With the small lung model, the only successful detection occurred with the Mapleson D circuit. Success at detecting occlusion was similarly low for clinicians with different levels of expertise. The authors conclude that the commonly held belief that the "educated hand" permits clinicians to detect subtle changes in pulmonary compliance in neonates during anesthesia (necessitating manual rather than mechanical ventilation) is not true.

Anesthesiology↗