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Biomedical subjects

D M Fisher

Publications and source records attributed to D M Fisher.

At least 19 recordsLinked to original sources
PubMed1998

Human cardiovascular and metabolic response to acute, severe isovolemic anemia.

CONTEXT: Although concern over the risks of red blood cell transfusion has resulted in several practice guidelines for transfusion, lack of data regarding the physiological effects of anemia in humans has caused uncertainty regarding the blood hemoglobin (Hb) concentration requiring treatment. OBJECTIVE: To test the hypothesis that acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport. DESIGN: Before and after interventional study. SETTING: Academic tertiary care medical center. PARTICIPANTS: Conscious healthy patients (n =11) prior to anesthesia and surgery and volunteers not undergoing surgery (n=21). INTERVENTIONS: Aliquots of blood (450-900 mL) were removed to reduce blood Hb concentration from 131 (2) g/L to 50 (1) g/L [mean (SE)]. Isovolemia was maintained with 5% human albumin and/or autologous plasma. Cardiovascular parameters, arterial and mixed venous oxygen content, oxyhemoglobin saturation, and arterial blood lactate were measured before and after removal of each aliquot of blood. Electrocardiogram and, in a subset, Holter monitor were monitored continuously. MAIN OUTCOME MEASURES: "Critical" oxygen delivery (TO2) as assessed by oxygen consumption (VO2), plasma lactate concentration, and ST changes on electrocardiogram. RESULTS: Acute, isovolemic reduction of Hb concentration decreased systemic vascular resistance and TO2 and increased heart rate, stroke volume, and cardiac index (each P<.001). We did not find evidence of inadequate oxygenation: VO2 increased slightly from a mean (SD) of 3.07 (0.44) mL of oxygen per kilogram per minute (mL O2 x kg(-1) x min[-1]) to 3.42 (0.54) mL O2 x kg(-1) x min(-1) (P<.001) and plasma lactate concentration did not change (0.81 [0.11] mmol/L to 0.62 [0.19] mmol/L; P=.09). Two subjects developed significant ST changes on Holter monitor: one apparently related to body position or activity, the other to an increase in heart rate (at an Hb concentration of 46-53 g/L); both occurred in young women and resolved without sequelae. CONCLUSIONS: Acute isovolemic reduction of blood Hb concentration to 50 g/L in conscious healthy resting humans does not produce evidence of inadequate systemic TO2, as assessed by lack of change of VO2 and plasma lactate concentration. Analysis of Holter readings suggests that at this Hb concentration in this resting healthy population, myocardial ischemia would occur infrequently.

Adult↗
PubMed1998

Can bioavailability of low-variance drugs be estimated with an unpaired, sparse sampling design?

OBJECTIVE: Bioavailability (F) with nonintravenous administration is traditionally estimated by comparison of the area under the plasma concentration versus time curve (AUC) after drug administration by each of the nonintravenous and intravenous routes in the same individual. This paired approach may not always be possible. We simulated whether F and the absorption rate constant (ka) could be estimated accurately for a drug with low variance using different patients for nonintravenous and intravenous routes and whether sparse sampling permitted accurate estimates. METHODS: Using pharmacokinetic parameters for cisatracurium besylate (INN, cisatracurium besilate), we simulated data sets representing 20 administrations (10 intravenous and 10 nonintravenous) with either three (sparse) or 16 (extensive) samples per administration. Simulations were performed twice, with ka values of 0.1 (slow absorption) or 0.3 (rapid absorption) min-1. With use of NONMEM, we estimated F and ka for each data set using both two-stage and mixed-effects modeling approaches and paired and unpaired designs to determine the percentage of estimates that deviated > 25% from the simulated value. RESULTS: Estimates of F with extensive data were satisfactory for all approaches. With sparse sampling, two-stage analysis of unpaired data were not possible, two-stage analysis of paired data yielded erroneous estimates, and mixed-effects modeling gave satisfactory estimates. Estimates of ka were sometimes erroneous with all approaches except for paired analysis of extensive data with slow absorption; sparse data and two-stage analysis increased the likelihood of errors compared with extensive data and mixed-effects modeling. CONCLUSIONS: Mixed-effects modeling facilitates estimation of F and ka for low-variance drugs in situations in which traditional paired extensive data designs are not possible.

Administration, Oral↗
PubMed1998

The pharmacokinetics and steady state pharmacodynamics of mivacurium in children.

BACKGROUND: The authors previously showed that children require larger infusion rates of mivacurium than adults to maintain target twitch depression. Here, they determined whether there are differences between children and adults in mivacurium's pharmacokinetic and pharmacodynamic properties. METHODS: Twenty-seven patients aged 1-58 yr were anesthetized with nitrous oxide and isoflurane. Cholinesterase activity and adductor pollicis twitch tension in response to train-of-four stimuli were measured. Mivacurium was infused, targeting 90% twitch depression. When twitch was stably depressed 85%-95% for 10 min with no change in infusion rate for 15 min, plasma was sampled to determine concentrations of mivacurium's stereoisomers. Clearance of the trans-trans (Cl(trans-trans)) and cis-trans (Cl(cis-trans)) isomers was determined as the mivacurium infusion rate (adjusted for isomer composition) divided by the concentration of that isomer. Using the Hill equation, assuming equipotency of the trans-trans and cis-trans isomers, and ignoring the contribution of the nonpotent cis-cis isomer, the authors estimated the steady state plasma concentration yielding 90% twitch depression, C90. The effect of age on cholinesterase activity, the infusion rate depressing twitch tension by 90% (IR90), C90, Cl(trans-trans), and Cl(cis-trans) was determined using linear regression. RESULTS: Cholinesterase activity, IR90, and C90 did not vary with age. Both Cl(trans-trans) (r2 = 0.19, P = 0.01) and Cl(cis-trans) (r2 = 0.19, P = 0.02) decreased with age. CONCLUSION: Clearance of mivacurium's potent isomers is larger in younger patients, consistent with the larger mivacurium infusion requirement in children than in adults reported previously.

Adolescent↗
PubMed1998

A model for the cleft lip nasal deformity.

The underlying pathology of the cleft lip nasal deformity has yet to be fully realized, and cleft lip rhinoplasty continues to challenge the reconstructive surgeon. A new model is proposed, which is composed of elements that represent known anatomical structures of the nose. These structures are considered elemental to the mechanism of the primary cleft lip nasal deformity. The lobule is reduced to four arches. Five points on the skull provide foundations for these arches, which react interdependently to extrinsic forces and positional change. When certain changes are imposed on the model, predictable alterations in the configuration of the model imitate the observed deformities in the spectrum of the cleft lip nasal deformity, unilateral and bilateral, mild through severe. The model is described with illustrations, anatomic dissection, physical models, and selected clinical cases. A better understanding of the mechanisms of the cleft nasal deformities can be obtained through analysis of the model.

Cadaver↗
PubMed1998

Opioid-induced analgesia in neonatal dogs: pharmacodynamic differences between morphine and fentanyl.

Whether the analgesic effects of opioids change as a neonate matures is not well understood. To address this issue, we determined the pharmacokinetics and pharmacodynamics of analgesic effects of morphine and fentanyl in 35 dogs aged 1 to 34 days. Opioids were infused to produce analgesia, response times to a noxious thermal stimulus were measured and plasma opioid concentrations were determined. An effect compartment pharmacodynamic model was fit to the values for time to response to determine the rate constant for equilibration (Keo) between plasma and effect-site (Ce) concentrations and analgesic effect (increase in time to response to a noxious stimulus) above baseline per microgram/ml of Ce (delta). A time-to-event data analysis (modeled with a Weibull function) was used to account for censored time to response values. For both opioids, values for Keo did not vary with age. Values for delta decreased with age (i.e., decreasing sensitivity with increasing age), and the magnitude of the change during the first month of life was similar for the two opioids. In the context of our previous study concerning ventilatory depressant effects of these opioids (that sensitivity to morphine, but not to fentanyl, decreased markedly during the first month of life), these results in dogs suggest that fentanyl has greater utility than morphine in neonates during spontaneous ventilation.

Analgesia↗
PubMed1997

Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine.

UNLABELLED: Dexmedetomidine is a selective alpha2-adrenoceptor agonist with centrally mediated sympatholytic, sedative, and analgesic effects. This study evaluated: 1) pharmacokinetics of dexmedetomidine in plasma and cerebrospinal fluid (CSF) in surgical patients; 2) precision of a computer-controlled infusion protocol (CCIP) for dexmedetomidine during the immediate postoperative period; and 3) dexmedetomidine's sympatholytic effects during that period. Dexmedetomidine was infused postoperatively by CCIP for 60 min to eight women, targeting a plasma concentration (Cp) of 600 pg/mL. Before, during, and after infusion, blood was sampled to determine plasma concentrations of norepinephrine, epinephrine, and dexmedetomidine, and CSF was sampled to determine dexmedetomidine concentrations (C[CSF]). Heart rate and arterial blood pressure were measured continuously from 5 min before until 3 h after the end of infusion. During the infusion, Cp values generally exceeded the target value: median percent error averaged 21% and ranged from -2% to 74%; median absolute percent error averaged 23% and ranged from 4% to 74%. After infusion, C(CSF) was 4% +/- 1% of Cp. Because C(CSF) barely exceeded the assay's limit of quantitation, CSF pharmacokinetics were not determined. During the infusion, norepinephrine decreased from 2.1 +/- 0.8 to 0.7 +/- 0.3 nmol/L; epinephrine decreased from 0.7 +/- 0.5 to 0.2 +/- 0.2 nmol/L; heart rate decreased from 76 +/- 15 to 64 +/- 11 bpm; and systolic blood pressure decreased from 158 +/- 23 to 140 +/- 23 mm Hg. We conclude that infusion of dexmedetomidine by CCIP using published pharmacokinetic parameters overshoots target dexmedetomidine concentrations during the early postoperative period. Hemodynamic and catecholamine results suggest that dexmedetomidine attenuates sympathetic activity during the immediate postoperative period. IMPLICATIONS: We studied the pharmacokinetic and sympatholytic effects of dexmedetomidine during the immediate postoperative period and found that during this period, the published pharmacokinetic data slightly overshoot target plasma dexmedetomidine concentrations. We also found that heart rate, blood pressure, and plasma catecholamine concentrations decrease during dexmedetomidine infusion.

Adrenergic alpha-Agonists↗
PubMed1997

Improving the design of muscle relaxant studies. Stabilization period and tetanic recruitment.

BACKGROUND: The results from studies of muscle relaxants show wide variations among institutions. The authors hypothesized that some of this variability could be explained by differences in duration of nerve stimulation before drug administration (stabilization period). METHODS: Train-of-four stimulation was applied every 12 s to both ulnar nerves and adductor pollicis twitch tension was measured in anesthetized participants given 30 micrograms/kg vecuronium. In phase 1, the stabilization period was > 30 min for both extremities. In phase 2-4, stabilization period was 20 min for one extremity and 2 min for the other. In addition, in phase 3, a 2-s 50-Hz tetanus initiated the 2-min stimulation period; in phase 4, duration of tetanus was 5 s. Twitch recovery was recorded until stable for more than 15 min. Time to 25% recovery (clinical duration) was calculated based on two indices: predrug and final (recovery) twitch tension. Values for onset and clinical duration were compared by paired parametric and nonparametric tests. RESULTS: In phase 1, predrug and recovery twitch tension were similar in each extremity, and onset and clinical duration did not differ between extremities, permitting paired comparisons in remaining studies. In phase 2, onset was more rapid with 20-min of prestimulation. With 20-min prestimulation, predrug and recovery twitch tension were similar; with 2-min prestimulation, recovery twitch tension exceeded predrug values. When referenced to predrug twitch tension, clinical duration was shorter with 2-min, that with 20-min prestimulation. Initiating stimulation with 2-s or 5-s 50-Hz tetani (phases 3, 4) abolished differences between extremities in onset and recovery. CONCLUSIONS: With only train-of-four stimulation (no tetani), onset and clinical duration vary with duration of prestimulation, suggesting that a brief period of predrug stimulation is inadequate. However, lengthy prestimulation may be impractical in clinical studies. Tetanic stimulation for 2 or 5 s obviates the need for prolonged stabilization during studies of muscle relaxants.

Adult↗
PubMed1997

Pharmacodynamic modeling of vecuronium-induced twitch depression. Rapid plasma-effect site equilibration explains faster onset at resistant laryngeal muscles than at the adductor pollicis.

BACKGROUND: After bolus doses of nondepolarizing muscle relaxants, the adductor pollicis recovers from paralysis more slowly than the diaphragm and the laryngeal adductors, suggesting that the adductor pollicis is more sensitive than the respiratory muscles to effects of those drugs. In contrast, during onset, the respiratory muscles are paralyzed more rapidly than the adductor pollicis, suggesting that the respiratory muscles are more sensitive than the adductor pollicis. To reconcile these apparently conflicting findings, we determined vecuronium's pharmacokinetics and its pharmacodynamics at both the adductor pollicis and the laryngeal adductors. METHODS: Six volunteers were studied on two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Vecuronium (15-60 micrograms/kg) was given and arterial plasma samples were obtained from 0.5-60 min. Vecuronium doses differed by twofold on the two occasions. A pharmacokinetic model accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine relative sensitivities and rates of equilibration between plasma and effect site concentrations. RESULTS: The steady-state plasma concentration depressing laryngeal adductor twitch tension by 50% was approximately 1.5 times larger than that for the adductor pollicis. The equilibration rate constant between plasma and laryngeal adductor concentrations was about 1.5 faster than that between plasma and adductor pollicis concentrations. The Hill factor (gamma) that describes the steepness of the laryngeal adductor concentration-effect relation was approximately 0.6 times that of the adductor pollicis. CONCLUSIONS: More rapid equilibration between plasma and laryngeal adductor vecuronium concentrations explains why onset is more rapid at the laryngeal adductors than at the adductor pollicis. During recovery, both rapid equilibration and lesser sensitivity of the laryngeal adductors contribute to earlier recovery.

Adult↗
PubMed1997

Are plasma concentration values necessary for pharmacodynamic modeling of muscle relaxants?

BACKGROUND: The traditional approach to pharmacokinetic/ pharmacodynamic modeling of muscle relaxants requires sampling of plasma to determine drug concentrations. The authors recently proposed that certain pharmacodynamic characteristics (IR50, the steady-state infusion rate to maintain 50% twitch depression; keo, the rate constant for equilibration between plasma concentration and effect; and gamma, the Hill factor describing sigmoidicity of the concentration-effect relation) could be estimated without plasma concentration data. Here estimates for IR50, keo, and gamma determined with and without plasma concentration data are compared. METHODS: Six volunteers were given 15-60 micrograms/kg vecuronium on each of two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Various pharmacokinetic models accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine IR50 keo, and gamma for each effect. One model related dose to effect without plasma concentration data. RESULTS: Values for IR50(adductor pollicis), IR50(laryngeal adductors), gamma (adductor pollicis), and gamma (laryngeal adductors) were similar when determined with and without plasma concentration values. Values for keo (adductor pollicis) and keo (laryngeal adductors) were larger when determined without plasma concentration values compared with those determined with these values; however, the ratio of keo (adductor pollicis) to keo(laryngeal adductors) was similar when determined with and without plasma concentration values. CONCLUSIONS: Certain pharmacodynamic parameters were estimated accurately in the absence of plasma concentration values. This suggests limited utility for plasma concentration data under conditions similar to those of the present study.

Body Fluid Compartments↗
PubMed1997

Pharmacokinetics of rocuronium during the three stages of liver transplantation.

BACKGROUND: Little is known about the influence of liver transplantation on the pharmacokinetics of most anesthetic drugs. The authors determined the pharmacokinetics of rocuronium during liver transplantation and examined whether variability in pharmacokinetics could explain variability in recovery of neuromuscular function. METHODS: Twenty patients undergoing liver transplantation were given rocuronium, 600 microg/kg, after induction of anesthesia and again after perfusion of the transplanted liver. Plasma was sampled to determine rocuronium concentrations. Pharmacokinetic models were fit to rocuronium concentrations versus time data using a mixed-effects population approach. Various models permitted changes in clearance (Cl) or central compartment volume to account for changes in hepatic function and circulatory status during the paleohepatic, anhepatic, and neohepatic periods. Time to initial recovery of four twitches of the orbicularis oculi was determined. RESULTS: During the paleohepatic and anhepatic periods, the typical value of Cl was 2.47 ml x kg(-1) x min(-1) and was not influenced by the magnitude of preexisting liver disease (as evidenced by prothrombin time, bilirubin, serum albumin, alanine transaminase [ALT], and aspartate transaminase [AST]). During the neohepatic period, the typical value of Cl varied as a function of the duration of warm ischemia of the hepatic allograft and was 2.72 ml x kg(-1) x min(-1) for a patient with an average 60-min period of warm ischemia; time to neuromuscular recovery varied as a function of Cl. CONCLUSIONS: Despite prolonged hypothermic ischemia, the newly transplanted liver eliminates rocuronium as well as the diseased native liver (and comparably with historical control values). However, some patients had decreased rocuronium Cl during the neohepatic period, apparently a result of prolonged graft warm ischemia. The authors' finding of preservation of hepatic drug elimination in the hepatic allograft is consistent with limited data for other drugs evaluated during anesthesia.

Adult↗
PubMed1997

Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations.

BACKGROUND: Rectal acetaminophen is often administered during operation to provide supplemental analgesia or antipyresis in children. Recent studies examining current dose guidelines are limited by short sampling times. The authors extended the drug sampling period to more clearly define acetaminophen pharmacokinetics in children having surgery. METHODS: Children (n = 28) were randomized to receive a single dose of 10, 20, or 30 mg/kg rectal acetaminophen after induction of anesthesia. Venous blood samples were taken every 30 min for 4 h, every 60 min for 4 h, and every 4 h for 16 h. Data were analyzed using a mixed-effects modeling technique (using NONMEM software) to determine the volume of distribution and clearance normalized for bioavailability. Additional models accounted for suppository dissolution followed by acetaminophen absorption. RESULTS: Age, weight, estimated blood loss, volume of intravenous fluid administered, and anesthesia time were similar in the three groups. Most patients did not achieve peak or sustained serum values in the 10-20 microg/ml serum concentration range associated with antipyresis. The volume of distribution was 385 ml/kg, and clearance normalized for bioavailability, F, was 5.46 ml x kg(-1) x min(-1). Pharmacokinetic models suggest that absorption of acetaminophen is a function of zero-order dissolution of suppositories and first-order absorption from the rectum. Suppository dose size also may affect absorption characteristics. CONCLUSIONS: The current recommended rectal acetaminophen dose of 10-15 mg/kg yields peak serum concentrations less than the antipyretic serum concentration of 10-20 microg/ml. Based on the observed kinetics, the authors recommend that the initial dose should be approximately 40 mg/kg.

Acetaminophen↗
PubMed1997

Bioavailability of intramuscular rocuronium in infants and children.

BACKGROUND: Intramuscular rocuronium, in doses of 1,000 microg/kg in infants and 1,800 microg/kg in children, produces complete twitch depression in 5-6 min. To determine the rate and extent of absorption of rocuronium after intramuscular administration, blood was sampled at various intervals after rocuronium administration by both intramuscular and intravenous routes to determine plasma concentrations (Cp) of rocuronium. METHODS: Twenty-nine pediatric patients ages 3 months to 5 yr were anesthetized with N2O and halothane. The trachea was intubated, ventilation was controlled, and adductor pollicis twitch tension was measured. When anesthetic conditions were stable, rocuronium (1,000 microg/kg for infants and 1,800 microg/kg for children) was injected either intramuscularly (in the deltoid muscle) or intravenously. Four venous plasma samples were obtained from each child 2-240 min after rocuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak Cp with intramuscular administration. RESULTS: With intramuscular administration, rocuronium's bioavailability averaged 82.6% and its absorption rate constant was 0.105 min(-1). Simulation indicated that Cp peaked 13 min after rocuronium was given intramuscularly, and that 30 min after intramuscular administration, less than 4% of the administered dose remained to be absorbed from the intramuscular depot. CONCLUSIONS: After rocuronium is administered into the deltoid muscle, plasma concentrations peak at 13 min, and approximately 80% of the administered drug is absorbed systemically.

Androstanols↗
PubMed1997

Bilateral buccal flaps with double opposing Z-plasty for wider palatal clefts.

Described is a technique that has evolved from the challenges of closure of larger cleft palate defects and that we are now using in preference over other techniques to repair a wide variety of clefts. Soft-palate closure and muscular sling reconstruction are accomplished using a modified Furlow technique. An associated cleft of the hard palate and the gaps produced by posterior displacement of the reconstructed soft palate are closed by adding tissue, buccal flaps, rather than by closure under tension or leaving residual raw surfaces. Palate lengthening is achieved both by the Z-plasty effect and by the interposition of buccal flaps between the hard and soft palate. Seventy-six palates have been repaired using this procedure. There were three postoperative fistulas.

Cleft Palate↗
PubMed1996

Does age or pseudocholinesterase activity predict mivacurium infusion rate in children?

Previous studies have suggested that the mivacurium infusion rate to maintain target twitch depression is greater in children than in adults, and that there is only a limited relationship between pseudocholinesterase activity and mivacurium infusion rate in children. We therefore examined whether mivacurium infusion rates are larger in children than in adults, and whether pseudocholinesterase activity influences mivacurium infusion rate in children. In 20 children aged 1-9 yr, mechanical twitch response to ulnar nerve train-of-four stimulation was measured; concurrent data were obtained in 14 adults aged 18-58 yr. All patients were anesthetized with N2O and isoflurane, 0.75 minimum alveolar anesthetic concentration (MAC) (age-adjusted). Mivacurium was infused at constant rates for > 15 min targeting 50% and 90% twitch depression. The Hill equation was fit to the resulting values for twitch depression versus mivacurium infusion rate to predict infusion rates producing 50% and 90% twitch depression (IR50 and IR90, respectively). The relationship of IR50 and IR90 to pseudocholinesterase activity was determined by linear regression; values for children and adults were compared by analysis of covariance. For children, IR50 (r2 = 0.22, P = 0.038) but not IR90 (r2 = 0.11 P = 0.21) was related to pseudocholinesterase activity. Infusion rates were approximately twice as large in children as in adults. We confirm that mivacurium infusion rates are larger in children than in adults and demonstrate a relationship between pseudocholinesterase activity and infusion rates.

Adult↗