Showing papers by "Gideon Koren published in 1984"
TL;DR: The data suggest that children with intracardiac shunts undergoing surgery under F anesthesia require an F bolus 30 μg·kg−1 combined with a 0.min−1 continuous infusion throughout the operation, and this regimen has been shown to be effective in an additional 9 children.
Abstract: The pharmacokinetics of fentanyl (F) were studied in 10 children, age 5 months-4.5 yr (mean 19 months) undergoing cardiac surgery with cardiopulmonary bypass ( CPBP ). They suffered from transposition of the great arteries (6), tetralogy of Fallot (2), and atrio-ventricular (A-V) canal (2). Induction of anesthesia included a bolus of 50 micrograms X kg-1 X min-1 F followed by a continuous F infusion of either 0.15 micrograms X kg-1 X min-1 (4 patients) or 0.3 micrograms X kg-1 X min-1 (6 patients). The F infusion was discontinued when cardiopulmonary bypass was started, 81-141 min (mean 112 min) along with deep hypothermia. Blood was collected throughout surgery from an indwelling radial arterial catheter and plasma concentration of F was assayed by GLC. F plasma concentrations after 30 min were 2-3-fold higher than reported with the same regimen in adults. The calculated values for t1/2 alpha (12 +/- 9 min) (mean +/- SD), t1/2 beta (141 +/- 98 min) and total body clearance (12.8 +/- 7.3 ml X min-1 X kg-1) were similar to adult values. The significantly lower steady-state volume of distribution observed in children with intracardiac shunts (1385 +/- 875 ml X kg-1) compared to reported values for adults (3200-6000 ml X kg-1) explains the higher F plasma concentrations achieved in these children. Cardiopulmonary bypass produced a mean 70% (range, 56-89%) decrease in plasma F, significantly higher than would be expected from hemodilution alone. Studies of F disposition in the CPBP demonstrated that F is bound to the pump.(ABSTRACT TRUNCATED AT 250 WORDS)
72 citations
TL;DR: In order to study the possibility that fentanyl is sequestered by the bypass, levels of the primed drug in the bypass were assessed before connecting the pump to the children and a steep fall from 20 ng/ml to zero was shown before initiation of bypass.
Abstract: Immediately following the connection of pediatric patients to cardiopulmonary bypass we have consistently observed a steep decrease in fentanyl plasma concentration (74 +/- 8.7%) (mean +/- SD), much greater than would have been expected from hemodilution alone (50.6% +/- 12.0%) (p less than 0.0001). Priming of the pump with 20 ng/ml of fentanyl before connection to the patients did not prevent this phenomenon. In order to study the possibility that fentanyl is sequestered by the bypass, levels of the primed drug in the bypass were assessed before connecting the pump to the children and a steep fall from 20 ng/ml to zero was shown before initiation of bypass. Pharmacokinetic assessment of fentanyl in a closed pump circuit showed that levels of 120 ng/ml fall to 2 ng/ml within 3 min and remain stable at the lower concentration for at least 30 min. Further studies have identified the membrane oxygenator as the major site of fentanyl sequestration. Concentrations across the membrane fall from 120 ng/ml to 10 ng/ml. The attached siliconized tubing is associated with a minor binding effect sufficient to reduce concentrations from 110 to 84 ng/ml. The pvc tubing, aluminium heat exchanger and plastic reservoir had no binding effect on fentanyl. The possibility that a decrease in fentanyl protein binding caused the fall in serum concentration was checked in 5 patients undergoing open heart surgery. After initiation of the cardiopulmonary bypass, there was a significant decrease in albumin serum concentrations from 32.0 +/- 2.3 mM to 15.0 +/- 1.6 mM (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
68 citations
TL;DR: serious doubts are cast on the validity of currently accepted digoxin kinetics and dosing in preterm infants and the presence of an endogenous digoxin‐like substance EDLS.
Abstract: Digoxin serum concentrations were measured by a routine radioimmunoassay in 30 neonates not receiving digoxin; nonetheless, digoxin levels were between 0.17nM and 1.64nM (2 = 0.64nM * 0.27nM). There was a negative correlation between gestational age and concentration of an endogenous digoxin-like substance (EDLS). Neonates 32 wk gestational age had higher levels of EDLS than neonates >32 wk old. EDLS concentrations were compared in 22 mothers and their 24 offspring and were higher in all newborn infants (0.34nM * 0.09nM and 0.15nM * 0.08nM). EDLS was shown to inhibit Nuf-K+-adenosinetriphosphatase activity by measurement of S6Rb uptake in erythrocytes exposed to sera samples from 30 infants in the study. EDLS levels >0.6 nglml were associated with lesser 88Rb uptake. Simulation kinetics suggest that the presence of 0.6nM EDLS would lengthen the digoxin t% by 64%, reduce the volume of distribution by 23%, and lower clearance by 53% if the peak "true" digoxin level were 2 ngiml. EDLS concentrations of 1.5 ngiml would increase the t'/z by 207% while reducing the volume of distribution by 43% and clearance by 81 %. These considerations cast serious doubts on the validity of currently accepted digoxin kinetics and dosing in preterm infants.
33 citations
TL;DR: The addition of amiodarone to digoxin therapy in nine children caused a sharp increase in digoxin serum concentrations in the presence of preserved serum creatinine and BUN concentrations, and digoxin half-life was prolonged.
31 citations
27 citations
TL;DR: The high ASA dose needed to overcome the impaired absorption should be accompanied by frequent monitoring of levels because of the unpredictable changes in absorption.
26 citations
9 citations
Journal Article•
TL;DR: The data suggest that Michaelis-Menten kinetics can be used to predict phenytoin levels even when impaired bioavailability exists, providing that the fraction of absorption is constant.
Abstract: In spite of the fact that therapeutic and toxic ranges of phenytoin are well defined, it is still often difficult to calculate an optimal dosage regimen because of the nonlinear saturable kinetics of the drug Predictions are much more complicated when impaired bioavailability exists We estimated individual Michaelis-Menten pharmacokinetic parameters from two reliable steady-state serum concentrations of phenytoin following two different drug dosages in 13 epileptic children treated with a preparation that has been shown to be poorly absorbed Their calculated average Vmax (the maximal rate of elimination) was significantly higher than the average for their age (1221 and 928 mg/kg/day, respectively) (p less than 005) The impaired bioavailability did not affect the values of Km In the six children who needed a third adjustment of dosage, the observed steady-state serum levels of phenytoin with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with the predicted levels (r = 097, p less than 001) Our data suggest that Michaelis-Menten kinetics can be used to predict phenytoin levels even when impaired bioavailability exists, providing that the fraction of absorption is constant
3 citations
2 citations
TL;DR: The data suggest an optimal pediatric F dose of 30 mcg/kg given as a bolus combined with an infusion of 0.3 mcG/kg/min throughout surgery.
Abstract: F is a useful anesthetic in cardiac surgery; however, an optimal F dosage for children has not been defined on the basis of pharmacokinetic analysis. We studied 19 patients (5 mo-16 yr) at cardiac surgery with cardiopulmonary bypass (CPB). An F bolus of 50 or 30 mcg/kg was given over 30 sec. with concomitant initiation of F continuous infusion at a rate of .15 or .3 mcg/kg/ min. F plasma concentrations of 30 minutes were up to 3-fold higher than reported with similar regimens in adults. The calculated mean values for T½ α (10.2 min); T½ β (102 min); and TBC (13.3 ml/kg/min) were close to adult whereas the mean Vdss (1.2 L/kg) was significantly lower. There was a positive correlation between age and Vdss (r=0.85; p<0.01), and a negative correlation between age and TBC (r=-0.73, p<0.05. Following the commencement of CPB there was a 74% mean decrease in F levels, much greater than would have been expected from hemodilution alone. Sequestration of F by the CPB with binding to both the membrane oxygenator (major) and to the siliconized tubing (minor) accounts for much of the steep decrease in F levels. During CPB and hypothermia F concentrations remained low but stable probably reflecting a significant reduction in hepatic metabolism of F. Our data suggest an optimal pediatric F dose of 30 mcg/kg given as a bolus combined with an infusion of 0.3 mcg/kg/min throughout surgery.
TL;DR: There was a significant age-related increment in gentamicin uptake and gentamicIn uptake of their renal cortical slices at 6 weeks of age was similar to that observed in the parallel age group of the nonstimulated rats.
Abstract: Previous data have suggested an age-related increase in renal clearance of gentamicin. This phenomenon could be the result of an increase in glomerular filtration rate (GFR) and/or of an augmentation in its transtubular influx. To investigate this question, four groups of rats, 2, 4, 6 and 8 weeks old, were sacrificed. 125I-labeled gentamicin uptake was measured in renal cortical slices as the cpm/mg wet tissue slice/medium (S/M) ratio. There was a significant age-related increment in gentamicin uptake. S/M ratios at 2, 4, 6 and 8 weeks were 3.49 +/- 0.46 (n = 7), 3.52 +/- 0.37 (n = 10), 4.23 +/- 0.42 (n = 10), 4.81 +/- 0.45 (n = 17), respectively (mean +/- SD; r = 0.78; p less than 0.01). Intraperitoneal injections of gentamicin were administered to another group of rats for 10 consecutive days from age 2 weeks and more. Gentamicin uptake of their renal cortical slices at 6 weeks of age was similar to that observed in the parallel age group of the nonstimulated rats (S/M ratio 4.18 +/- 0.41).
TL;DR: It is believed that respiratory rates in an awakened child represent also his emotional state and not only the severity of his disease, and more than a few pediatricians tend to treat it with corticosteroids.
Abstract: In Reply.—In our study,1all admitted cases of croup were assessed. Naturally these included severe, moderate, and mild cases. In referring to the respiratory rates presented, one should remember that these were measured during sleep, which was induced by chloral hydrate. All these children had had much higher respiratory rates while they were awake; however, as stated, we believe that respiratory rates in an awakened child represent also his emotional state and not only the severity of his disease.2The mean respiratory rates are comparable with other studies of children with croup from the same age group.3 I agree with Drs Orr and Caplan that mild croup is usualy a self-limited disease. Yet, more than a few pediatricians tend to treat it with corticosteroids since, in many cases, one cannot predict the course of the croup attack, and a mild disease at the time of diagnosis
TL;DR: My colleagues and I have stated that one should be careful in extrapolating the six-hour data into the full course of the croup attack, and it is shown that the patients with SC who received placebo did improve well.
Abstract: In Reply.—I agree with Lacroix and Massicotte that there are various differences in the design of the study by Massicotte and Tetreault1as compared with ours.2By including only severe cases, I believe that many of their patients with SC were excluded. This may explain the different results in the patients with SC as compared with our patients. However, unlike the interpretation of Lacroix and Massicotte, we have clearly shown that the patients with SC who received placebo did improve well. Therateof improvement was more favorable in the corticosteroid-treated group. My colleagues and I have stated that one should be careful in extrapolating the six-hour data into the full course of the croup attack. However, we believe that in studying a disease that, in most cases, has a short course, one should try to achieve accurate information on the first critical hours, when most variables