Renal tubular interactions of digoxin.
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Animals↗
Biomedical subjects
G Koren
Publications and source records attributed to G Koren.
Sequestration of fentanyl by the cardiopulmonary bypass (CPBP).
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)
Adolescent↗
Difficulty in achieving therapeutic serum concentrations of salicylate in Kawasaki disease.
We investigated 49 children (33 boys), mean (+/- SD) age 2.6 +/- 1.8 years (range 8 months to 8 years), who had Kawasaki disease treated with acetylsalicylic acid (ASA) 30 to 180 mg/kg. There was good correlation between salicylate doses and serum concentrations (r = 0.69, P less than 0.01); however, large variability existed. With doses less than 80 mg/kg/day there was not a single therapeutic salicylate serum concentration (greater than 20 mg/dl). In children receiving 100 to 110 mg/kg/day 55% of the serum concentrations were subtherapeutic. The same pattern persisted with doses greater than 120 mg/kg/day; however, 28% of levels were in the toxic range (greater than 30 mg/dl). There was no evidence of salicylate poisoning in the group; three children receiving greater than 100 mg/kg/day had aspirin-induced gastritis. An additional four children, studied prospectively, received ASA 80 to 180 mg/kg/day. The fraction absorbed was 14% to 60%, which may be compared to a normal 85% to 90% absorption. Salicylate renal clearance in these children (7.3 to 21 ml/kg/hr) was lower than in hyperthermic children. Their steady-state serum salicylate concentrations were subtherapeutic (7 to 11.5 mg/dl). 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.
Aspirin↗
Digoxin and indomethacin in preterm infants with PDA.
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Digoxin↗
Digoxin toxicity associated with amiodarone therapy in children.
The addition of amiodarone to digoxin therapy in nine children caused a sharp increase in digoxin serum concentrations (68% to 800%) in the presence of preserved serum creatinine and BUN concentrations. Digoxin half-life was prolonged. Digoxin accumulation could be attributed in part to the decrease in the renal clearance of digoxin resulting from inhibited tubular secretion of the drug and to the reduction in the distribution volume of digoxin caused by amiodarone. Creatinine clearance was not affected by amiodarone. This interaction appears to be more acute in children than in adults, presumably because of the more important role of the renal tubular secretion of digoxin in children. Whenever digoxin and amiodarone therapy are combined, the digoxin serum concentration should be monitored carefully, with appropriate reduction of the digoxin dose.
Adolescent↗
Significance of the endogenous digoxin-like substance in infants and mothers.
Digoxin serum concentrations were measured by a routine radioimmunoassay in 30 neonates not receiving digoxin; nonetheless, digoxin levels were between 0.17 nM and 1.64nM (means = 0.64nM +/- 0.27 nM). There was a negative correlation between gestational age and concentration of an endogenous digoxin-like substance (EDLS). Neonates less than or equal to 32 wk gestational age had higher levels of EDLS than neonates greater than 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 Na+-K+-adenosinetriphosphatase activity by measurement of 86Rb uptake in erythrocytes exposed to sera samples from 30 infants in the study. EDLS levels greater than 0.6 ng/ml were associated with lesser 86Rb uptake. Simulation kinetics suggest that the presence of 0.6nM EDLS would lengthen the digoxin t1/2 by 64%, reduce the volume of distribution by 23%, and lower clearance by 53% if the peak "true" digoxin level were 2 ng/ml. EDLS concentrations of 1.5 ng/ml would increase the t1/2 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.
Birth Weight↗
Ischemic colitis in chronic intermittent peritoneal dialysis.
A 6-year and 8-month-old boy on chronic intermittent peritoneal dialysis for end stage kidney disease presented with severe diarrhea, abdominal distension, cramps, tenesmus and vomiting. Barium enema showed rigidity and irregularity of the mucosa of the sigmoid and distal descending colon, with 'thumb print like' appearance, findings compatible with ischemic colitis. The institution of hemodialysis and discontinuation of the peritoneal dialysis resulted in a marked clinical and radiological improvement. Kidney transplantation performed a month later was associated with a complete cure of his intestinal disease.
Child↗
Maturation of renal tubular transport of gentamicin.
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).
Animals↗
Epileptics refractory to anticonvulsants.
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Anticonvulsants↗
Pharmacokinetics of fentanyl in children with renal disease.
Two cases of fentanyl anesthesia in children with renal diseases are described. In a case of end stage renal failure, the pharmacokinetic parameters during cardiac surgery were similar to 18 children from the same age group with normal renal function. In a case of Wilm's tumor, there was an unusually prolonged elimination half-life of fentanyl and smaller distribution volume as compared to pediatric parameters during fentanyl anesthesia.
Anesthesia, Intravenous↗
Characteristics of the digoxin-quinidine and digoxin-verapamil interactions in the rat kidney.
Recently quinidine and verapamil have been reported to cause toxic accumulation of digoxin due to mainly decrease in the renal secretion of the cardiac glycoside. Because these drugs do not alter GFR, it was assumed that the renal tubular secretion of digoxin is inhibited by them. We studied the characteristics of the renal cortical specific binding for digoxin in the rat kidney, and the antagonistic effects of quinidine and verapamil on digoxin uptake by the kidney slices. Specific binding of digoxin was documented in the renal slices with B max of 42.34 pmol/gr and Kd of 7.6 pmol/gr. The addition of quinidine in therapeutic concentrations (6.7 microM) caused a mean 23% reduction of digoxin uptake by the kidney slice (p less than 0.01). When quinidine concentrations were elevated above the therapeutic range there was additional reduction in digoxin uptake; 84 mM quinidine caused a mean 61% reduction (p less than 0.0001). A similar interaction was documented with verapamil; therapeutic concentrations (550 mM) of the drug caused 15% reduction in digoxin uptake. Further increase in verapamil concentration resulted in additional reduction in digoxin uptake; the maximal concentration used (42 microM) caused 60% decrease in uptake (p less than 0.0001). The inhibition of the renal uptake of digoxin caused by quinidine and verapamil in conjunction with the pharmacokinetic studies, which have shown that both drugs decrease the renal clearance of digoxin without changing GFR, support the suggestion that they inhibit the renal tubular secretion of digoxin.
Animals↗
The chest radiograph in the diagnosis of atypical nephritis due to infectious mononucleosis.
A four-year-old boy developed oliguria, proteinuria and hypocomplementemia, without hematuria, in the course of proven infectious mononucleosis. A chest radiograph revealed a mild cardiomegaly, prominent pulmonary vasculature and pleural fluid. These abnormalities were compatible with acute glomerulonephritis and were in support of this clinical diagnosis in spite of the absence of hematuria.
Acute Disease↗
Influence of bioavailability on the calculated Michaelis-Menten parameters of phenytoin in children.
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 (12.21 and 9.28 mg/kg/day, respectively) (p less than 0.05). 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 = 0.97, p less than 0.01). 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.
Absorption↗
Pediatric fentanyl dosing based on pharmacokinetics during cardiac surgery.
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)
Cardiopulmonary Bypass↗
Effects of indomethacin on digoxin pharmacokinetics in preterm infants.
Indomethacin is commonly coadministered with digoxin for the treatment of patent ductus arteriosus (PDA) in preterm infants. The combination of digoxin that is eliminated almost exclusively by the kidney and indomethacin, which tends to reduce renal function, has potential hazards. We report 11 preterm infants (gestational age 25-33 week) treated with digoxin for PDA in whom a standard indomethacin therapy (mean of total dose = 0.32 mg/kg) resulted in a significant elevation of serum digoxin to potentially toxic levels (from 2.2 +/- 0.7 ng/ml to 3.2 +/- 0.7) (P less than 0.001). This phenomenon correlated well with decreased urine output (from 86 +/- 34 ml to 43 +/- 24 per 24 hour) (P less than 0.001) following indomethacin. No significant change was found in serum creatinine concentration pre- and post-indomethacin. Digoxin half-life was significantly prolonged (mean 97 +/- 17 hour) following indomethacin therapy as compared with an age matched control group (mean half-life 43 +/- 19 hour) (P less than 0.05). Our data suggest that when indomethacin is added to digoxin therapy, the digoxin dosage should be reduced by 50% until urine output and digoxin serum levels can be better assessed.
Digoxin↗
Kinetics of intravenous phenytoin in children.
Single-dose intravenous phenytoin (9.4-21.3 mg/kg) effectively eradicated seizures within 3 minutes in 12 out of 13 patients in status epilepticus. Eleven additional patients were treated prophylactically. No adverse effects were observed and neurological status was unaltered in all 24 cases. Phenytoin volume of distribution was found to decline significantly with age from 1.6 L/kg at 1 year to 0.6 at 10 years (P less than 0.01). Estimates of Vmax, the maximal rate of phenytoin metabolism, were obtainable in 8/24 patients and were in the expected range (10.6 +/- 4.2 mg/kg/day) for their age (6.6 +/- 2.8 years). Therapeutic serum concentrations (initial post distribution values 17.9 +/- 9.0 micrograms/ml) were maintained for more than 10 hours in 15/24 patients. Single-dose intravenous phenytoin is both effective and safe in the treatment and prevention of epileptic seizures in pediatric patients.
Adolescent↗
Errors in computing drug doses.
The 85 members of the pediatric and neonatal divisions of a medical centre were tested for their ability to calculate the appropriate volumes of drugs commonly administered to pediatric patients. Of a total of 680 computations 43 (6.3%) were wrong. Half the errors would have led to either a 10-fold overdose or a dose a 10th of that prescribed. Significantly more of the errors (p less than 0.01) were made by the nurses in the neonatal division (11.5%) than by those in the pediatric division (3.4%). A deficiency in the in-service training of the nurses in the neonatal division appeared to contribute to the higher proportion of errors in this group. There was also a trend towards a greater chance of error as the length of professional experience increased. All medical personnel involved in the ordering and administration of drugs should be taught computing skills and be evaluated routinely.
Humans↗
Corticosteroid treatment of laryngotracheitis v spasmodic croup in children.
We compared the efficacy of high-dose dexamethasone sodium phosphate (0.6 mg/kg) in laryngotracheitis (LT) v spasmodic croup (SC) in 72 children (age range, 8 months to 8 years) using a double-blind randomized protocol that measured the individual change in respirations as an objective variable to evaluate the outcome. Administration of dexamethasone did not change the respirations in the patients with LT and significantly decreased the respirations in the patients with SC, compared with the placebo group. Since, in most cases, the pediatrician will be able to differentiate between LT and SC at admission by history and clinical signs, it seems that steroid treatment should be avoided in cases of LT and may be of benefit in some cases of SC.
Acute Disease↗