ADAPTATION OF A SINGLE INJECTION CLEARANCE METHOD TO PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL FACTS A Review of Data Obtained in Infancy and Childhood

Abstract. A retrospective analysis of 395 ⁵¹Chromium-ethylenediaminotetraacetate single injection clearances performed in infants and children is presented. In 61% of infants and 30% of the children the clearance values were calculated on the basis of a plasma disappearance half time of the reference substance, which was longer than the standard study, i.e. on the basis of extrapolated data. Plasma creatinine and urea levels were found to be appropriate indicators for predicting the plasma disappearance half time of the marker substance. 14 additional patients were studied prospectively with a duration of the study predicted by means of the plasma creatinine and urea levels. In these patients, separate determinations of the clearances using either the data obtained during the standard time of procedure only, or the data of the entire study, clearly demonstrated that the clearances obtained by means of the standard procedure overestimated glomerular filtration rate. The analysis of the data in infants show that the plasma urea level is a reasonably good indicator for predicting the time schedule of the study whereas plasma creatinine should not be used. Additionally the retrospective data indicate that a prolongation of the study should be recommended in all infants. This study demonstrates the necessity and offers means of adapting the time schedule of isotope single injection clearances to physiological and pathophysiological facts.     

Assessment of glomerular filtration rate in infants. Comparison of three methods used in clinical practice

Glomerular filtration rate was assessed in 66 infants less than 1 year of age. Results obtained by 3 different routine methods were compared to those obtained by the standard inulin clearance (GFR): 1. clearance values calculated from plasma creatinine concentration (mg/dl) and height (cm), using a k value of 0.55 derived from inulin clearance did not reliably reflect GFR (Y = 37.5 + 0.51 Cin, r = 0.82); 2. creatinine clearance values calculated over 3 h overestimated standard inulin clearance at all levels of GFR below 100 ml/min.1.73m2 (Y = 25.1 + 0.75 Cin, r = 0.77). 3. Clearance values calculated as the sum of twice the creatinine clearance plus the urea clearance, divided by 3, overestimated the standard inulin clearance at low levels of GFR and underestimated it at high GFR (Y = 20.6 + 0.66 Cin, r = 0.82). The study of several techniques for estimating GFR in infants demonstrates that there is no ideal substitute for the traditional inulin clearance when precise measurement of glomerular filtration rate is needed, and that simple 3 h creatinine clearances represent a satisfactory and rational estimate of GFR in clinical practice.     

Pharmacokinetics of injectable phenobarbital in the premature infant. Study of a new lyophilized form

A lyophilized preparation of phenobarbital was studied in newborns without cerebral palsy. Plasma levels were determined using gas chromatograph fitted with thermo ionic probe after either an intra-muscular (IM) injection in premature infants or an intravenous (IV) injection over single dose of phenobarbital 10 mg/kg within 6 hours after birth. Five term babies were included in the study as controls and received an IM injection. The results showed rapid increase in plasma concentration after IM injection in 10 of 13 subjects with a peak concentration reached 60 minutes after injection. The mean ratio (maximal concentration/dose) was 1.25 and 1.10 for term infants and preterm infants respectively. In all cases, the drug was well tolerated. In 15 preterm infants (n: 7 IM and n: 8 IV) the plasma concentrations were followed over a period of 15 days. The disappearance curve was biphasic; it varied the first 7 days, then remained constant for the following week (apparent half life 106 hours).     

Comparison of solute clearance in three modes of continuous renal replacement therapy.

OBJECTIVES: To compare the clearances of low molecular weight molecules using three modalities of continuous renal replacement therapy (CRRT) at the low blood flow rates typically used in pediatric patients. DESIGN: A controlled, in vitro laboratory study. SETTING: Research laboratory of a health sciences university. SUBJECTS: AN69 dialysis hemofilter. INTERVENTIONS: CRRT was performed using a 0.6 m(2) AN69 hemofilter. Human whole blood and plasma were combined to achieve a hematocrit of approximately 30%. Urea and creatinine were added to obtain concentrations of approximately 54 mmol/L of blood urea nitrogen and 1770 micromol/L of creatinine. Clearance data for urea and creatinine at a blood flow rate of 60 mL/min were generated using predilution continuous venovenous hemofiltration (CVVH), postdilution CVVH, and continuous venovenous hemodialysis (CVVHD). MEASUREMENTS AND MAIN RESULTS: Clearance of all three modalities was compared at a replacement solution (CVVH) or dialysate (CVVHD) flow rate of 16.7% of the blood flow rate. Both postdilution CVVH and CVVHD had a urea clearance of 11.3 mL/min, which was 15% greater than the 9.8 mL/min urea clearance of predilution CVVH (p <.005). Creatinine clearance with postdilution CVVH (10.7 mL/min) was 15% greater than the 9.0 mL/min clearance produced by predilution CVVH (p < 0.01). Predilution CVVH and CVVHD were compared at a flow rate of either replacement solution (CVVH) or dialysate (CVVHD) of 33% and 50% of the blood flow rate. Postdilution CVVH was not performed at high ultrafiltration rates due to the potential problem of hemoconcentration. CVVHD clearances of urea and creatinine were statistically superior to predilution CVVH at both flow rates. CONCLUSIONS: CVVHD was superior to predilution CVVH for clearance of urea and creatinine. Postdilution CVVH and CVVHD gave nearly equivalent clearances. At the low blood flow rates used in pediatric patients, which raise concerns about high ultrafiltration during postdilution CVVH causing excessive hemoconcentration and filter clotting, CVVHD appears to be the optimal modality for maximizing clearance of small solutes during CRRT.     

Plasma concentrations of urea and creatinine in primary school children in Ujung Pandang.

A study of plasma concentrations of urea creatinine in 202 primary school children aged between 6 to 15 years was carried out in Ujung Pandang from November 1, 1988 through February 28, 1989. Sampling was done using multi-stage random sampling method. Plasma urea concentrations were not affected by sex, age and nutritional status. Normal distribution of plasma urea concentrations in P2.5 and P97.5 were 8.13 mg/dl and 24.09 mg/dl respectively (95% confidence level). There was no difference of creatinine concentration between the two sexes. The overall mean creatinine concentrations was significantly higher in the well-nourished group (0.73 +/- 0.081) mg/dl) as compared to PEM group (0.63 +/- 0.066 mg/dl). This study revealed a correlation between age and plasma creatinine concentrations in the well-nourished (r = 0.46, p less than 0.01) as well as in PEM (r = 0.37, p less than 0.01) group. Hence, normal distribution of plasma creatinine concentrations should be base on values in each age group. This study showed no correlation between plasma urea and creatinine concentrations.     

Validity of endogenous creatinine clearance in low birthweight infants

Despite methodologic problems, endogenous creatinine clearance is commonly used as an estimation of glomerular filtration rate (GFR). Inulin clearance was compared to endogenous creatinine clearance in a group of low birthweight infants to establish the validity of the latter. Thirty-three low birthweight infants (birthweight mean = 1600 g, gestational age mean = 33 wk) were studied between 10 hr and 10 days of age to simultaneously measure GFR by inulin and endogenous creatinine clearances. Inulin and creatinine clearances correlated directly (r = 0.738, P greater than 0.001). The slope of the regression line suggested an overestimation of GFR (inulin clearance) by creatinine clearance at the low GFR range and an underestimation at the high GFR range. The data were divided into two groups by the median inulin clearance (12.5 ml/min/1.73m2). The ratio of creatinine to inulin clearance was significantly higher in the low GFR group (1.28 +/- 0.16 vs. 0.89 +/- 0.04 SEM, n = 19, P less than 0.05). There was no difference between the two groups in plasma creatinine, birthweight, gestational age, incidence of respiratory distress, or oxygen requirements at the time of the studies. Endogenous creatinine clearance represents a good estimation of GFR (inulin clearance) in low birthweight infants. However, at the low GFR range, it represents an overestimation and at the high GFR range, an underestimation.     

Phenobarbital prophylaxis for hyperbilirubinemia in preterm infants. A controlled study of bilirubin disappearance and infant behavior

Phenobarbital (PB) has been used at several pediatric centers for prophylaxis against neonatal hyperbilirubinemia. However, few attempts have been made to evaluate this procedure quantitatively, and a variety of dose schedules has been proposed. Therefore, a randomized, controlled clinical trial was performed in which the effects on bilirubin disposition and on neonatal behavior was quantitated. Forty-three preterm infants were randomized into one of four dose groups and given 0, 4, 8, or 12 mg of PB per kg in a single dose within the first few hours after birth (mean 2.2 h). The total serum bilirubin disappearance rate was found to be significantly increased (p less than 0.01) only in the 12 mg/kg group. This effect was not evident until postnatal day 7. The 4 and 8 mg/kg groups were not significantly different from the control group at any time. Infant behavior was monitored by a non-invasive time-lapse filming technique. The time spent in quiet sleep was found to be proportional to the plasma PB concentration at one day of age (r = 0.61). The infants in the 12 mg group spent a larger proportion of time in quiet sleep than the other groups (p less than 0.05). The plasma half-lives, plasma clearances and volumes of distribution of PB were similar in the three dose groups. No correlation was found between the pharmacokinetics and the gestational age of the infant. It is concluded that in order to enhance the bilirubin disappearance rate, PB has to be administered in doses that will affect behavior.     

DETERMINATION OF GLOMERULAR FILTRATION RATE IN THE NEWBORN Comparison between Results Obtained by the Single Injection Technique without Collection of Urine and the Standard Clearance Technique

Determination of glomerular filtration rate was performed in fifteen infants by both the single injection technique and the standard inu-lin clearance technique. Eleven infants were fasted for four hours before the study. In those patients there was a good accordance between the two methods for determination of glomerular filtration rate. Four infants received breast milk or formula within 1 hour before the single injection procedure was started. In those infants there was a considerable over-estimation of glomerular filtration rate with the single injection technique. The error of the method introduced by recent feeding is discussed.     

CONCENTRATIONS OF DIGOXIN IN PLASMA AND URINE IN NEONATES, INFANTS, AND CHILDREN WITH HEART DISEASE

ABSTRACT. Wettrell, G., Andersson, K.-E., Bertler, Å. and Lundström, N. R. (Departments of Paediatrics and Clinical Pharmacology, University Hospital, Lund, Sweden). Concentrations of digoxin in plasma and urine in neonates, infants, and children with heart disease. Acta Paediatr Scand, 63: 705, 1974.—By means of radioimmunoassay and ⁸⁶Rb-uptake inhibition assay, concentrations of digoxin in plasma and urine have been determined in different paediatric age groups. On equal daily maintenance doses (0.012–0.013 mg digoxin/kg b.w./day) a higher mean plasma digoxin level was found in full term neonates (3–30 days), 2.1 ng/ml, than in infants (1–12 months) and children (1–10 years), 1.2 and 1.4 ng/ml, respectively. On a maintenance dose of 0.019 mg/kg b.w./day, one group of infants had an average plasma digoxin level of 2.1 ng/ml (range 1.1–2.9 ng/ml). No signs of toxicity were found. A gradual increase in the renal clearance of digoxin during the first few months of life was demonstrated. There was a highly significant correlation between the clearances of digoxin and creatinine (r=0.87, p<0.001). It is concluded that the high mean plasma digoxin level in full-term neonates could be explained by low renal elimination of the glycoside.     

Renal toxicity of cisplatin in children

We measured renal function in 22 children receiving cisplatin as initial treatment for neuroblastoma or malignant germ cell tumors. Glomerular filtration rates were estimated from the plasma clearance of 51Cr-EDTA and were compared with measurements of plasma creatinine concentration and creatinine clearance. The degree of cisplatin-induced renal damage varied widely, and plasma creatinine measurements and creatinine clearances were not reliable guides to glomerular filtration rate. Renal function in children receiving cisplatin should be monitored by measurement of glomerular filtration rate with an isotope clearance technique.     

Assessment of tubular reabsorption of sodium, glucose, phosphate and amino acids based on spot urine samples

Reference values for tubular transport of sodium, phosphate, glucose and amino acids are generally based on inulin or creatinine short-term clearances, which are difficult to obtain in children. Hence, quantitative assessment of tubular transport capacities is rarely performed. For a simplified procedure, reference values for fractional sodium excretion, phosphate reabsorption related to glomerular filtration rate, percent glucose and percent amino acid reabsorption were established in 62 children from spot urine and simultaneously obtained blood samples. Sodium excretion, and glucose and amino acid reabsorption were significantly lower in infants than children, whereas phosphate reabsorption decreased during the first year of life. Results using the proposed protocol and those obtained from timed urine specimens correlated well; the phenomenon of renal adaptation during childhood could equally well be demonstrated. Renal tubular dysfunction can be diagnosed without timed urine specimens.     

Serial measurements of plasma half-lives and urinary excretion of antipyrine in low-birth-weight infants.

Antipyrine has been used previously to estimate total body water in infants. In the present study, antipyrine spaces were determined early on the first day of life and again at the end of the fourth day in 22 early mild-fed low-birth-weight babies as part of a study of serial measurements of water balance. This report deals with findings arising from analysis of disappearance rates of antipyrine in plasma used for the determination of antipyrine space (total body water estimation). Urine excretion of antipyrine was measured from 24-hour urine outputs in 9 of these babies. The data showed that: (1) wide individual variants of plasma antipyrine half-life times occurred on both the first and fourth days of life; (2) plasma half-life times in the low-birth-weight infants were usually much longer than those of adults; (3) half-life times on the first day of life were significantly longer than on the fourth day of life; (4) urine excretion of unchanged antipyrine was a significant factor in the disappearance rate of antipyrine from the body with between 7 and 36% of the dose appearing in the urine (average 21%) within 96 h of the initial injection.     

Phenobarbital Prophylaxis for Hyperbilirubinemia in Preterm Infants

Phenobarbital (PB) has been used at several pediatric centers for prophylaxis against neonatal hyperbilirubinemia. However, few attempts have been made to evaluate this procedure quantitatively, and a variety of dose schedules has been proposed. Therefore, a randomized, controlled clinical trial was performed in which the effects on bilirubin disposition and on neonatal behavior was quantitated. Forty-three preterm infants were randomized into one of four dose groups and given 0, 4, 8, or 12 mg of PB per kg in a single dose within the first few hours after birth (mean 2.2 h). The total serum bilirubin disappearance rate was found to be significantly increased ( p < 0.01) only in the 12 mg/kg group. This effect was not evident until postnatal day 7. The 4 and 8 mg/kg groups were not significantly different from the control group at any time. Infant behavior was monitored by a non-invasive time-lapse filming technique. The time spent in quiet sleep was found to be proportional to the plasma PB concentration at one day of age ( r = 0.61). The infants in the 12 mg group spent a larger proportion of time in quiet sleep than the other groups ( p < 0.05). The plasma half-lives, plasma clearances and volumes of distribution of PB were similar in the three dose groups. No correlation was found between the pharmacokinetics and the gestational age of the infant. It is concluded that in order to enhance the bilirubin disappearance rate, PB has to be administered in doses that will affect behavior.     

Estimation of Digoxin Dosage in VLBW Infants Using Serum Creatinine Concentrations

ABSTRACT. Digoxin steady state plasma concentrations (C_ss) and the corresponding serum creatinine concentrations were studied in 17 VLBW infants. Birth weight was in the range of 760-1500 g (mean 1068 g), gestational age ranged from 26 to 32 weeks (mean 28.7 weeks). Digoxin steady state plasma concentrations were found in the range of 0.5-6.5 μg/ml (mean 1.88 μg/ ml) during maintenance therapy with 1.6-8.4 μg/kg BW/24 h (mean 4.4 μg/kg BW724 h) given in two divided doses intravenously. No digoxin-like immunoreactive substance could be detected in the plasma of 18 infants (10 patients with a birth weight <1500 g, 8 patients with a birth weight of 2100-4 730 g) that were not treated with digoxin. The calculated digoxin clearance ranged from 0.38-4.03 ml/min/kg BW. Serum creatinine concentrations were found in the range of 35-274 μmol/l (0.4-3.1 mg/100 ml). A hyperbolic correlation may be derived from the digoxin clearance and the corresponding serum creatinine concentration. A linear relationship was observed between the dose normalized digoxin concentrations (y=C_ss/dose in 24 h) and the respective creatinine concentrations x (v=0.52x-0.05; n=17; 5=0.24; r=0.86; p<0.01). According to this equation we suggest a dosing schedule for digoxin in VLBW infants with impaired renal function. Digoxin maintenance dose is derived from the digoxin target and the creatinine serum concentration. This dose recommendation proved reliable on four VLBW infants (birth weight 770-1260 g) with decreased renal function.     

A screening program for detecting children with an increased SIDS risk (sudden and unexpected infant death)

The prospective study presented conducted to prevent SIDS (sudden infant death syndrome). One of the proposed hypotheses on SIDS postulates a brainstem abnormality in the neuroregulation of cardiorespiratory processes. Therefore we characterized cardiorespiratory control mechanisms by examining the neurotransmitter substance P in plasma and polysomnographic investigations. With respect to the probable multifactorial origin of SIDS we selected children firstly anamnestically by means of an epidemiologically evaluated pre-, peri- and postnatal risk score. We reported the results of 208 polysomnographically and biochemically examined children anamnestically selected from a group of 2500 neonates. Examinations were performed on infants aged 2-4 weeks up to 1 year. To characterize respiratory control, length and frequency of apnoeas were separately estimated by means of polysomnography in the sleep states active and quiet sleep. If there were polygraphic risk factors representing a disturbance of respiratory control, the children were prophylactically treated with aminophylline 3 x 3 mg/kg b.w. for 4 weeks. We found a significant age dependence both of the mean apnoea duration in active sleep and the substance P level in plasma in the SIDS-risk group but not in the controls. High mean apnoea duration was correlated with low substance P level in the first months of age in SIDS risk infants selected anamnestically. This may reflect a delayed maturation of respiratory control mechanisms. In this way the polysomnography and the investigation of the neuropeptide substance P may be useful for a screening method indicating wether the respiratory control mechanisms are mature or not.     

Urinary oxalate and glycolate excretion and plasma oxalate concentration.

The diagnosis of primary hyperoxaluria in young children is hampered by the lack of a reliable reference range for urinary oxalate excretion, especially in infants. We present data on urinary oxalate and glycolate excretion in 137 normal children, on the plasma oxalate concentration in 33 normal children and 53 with chronic renal failure, and on amniotic fluid oxalate concentration in 63 uncomplicated pregnancies. The urinary oxalate:creatinine molar ratios were log normally distributed: mean (range) values were less than 1 year 0.061 (0.015-0.26), 1-5 years 0.036 (0.011-0.12), 5-12 years 0.030 (0.0059-0.15), and greater than 12 years 0.013 (0.0021-0.083). Geometric mean (range) plasma oxalate concentration in the normal children was 1.53 (0.78-3.02) mumols/l and was independent of age. The mean (SD) plasma oxalate: creatinine molar ratio in these normal children and 50 with chronic renal failure was 0.033 (0.013), and was independent of age and renal function. Mean (SD) amniotic fluid oxalate concentration was 19.0 (4.3) mumols/l.     

Measurement of urinary constituents and output using disposable napkins.

A procedure for estimating 24 hour urine output in infants using disposable nappies has been validated. In addition, it has been shown experimentally that the urinary concentrations, and hence 24 hour outputs of a range of constituents (sodium, potassium, nitrogen, creatinine, urea, amino acids, and deuterium oxide), may be measured accurately using samples of urine obtained from nappies. It is concluded that the urine collection procedure described has several major advantages over traditional urine bag methods, and has a wide application in clinical practice and research.     

Plasma concentrations of phenobarbital in the treatment of seizures in newborns.

The plasma concentration of phenobarbital given as anticonvulsive treatment in the newborn period has been followed in 18 infants. With constant daily doses, the drug accummulated for at least 5 days. After intramuscular injection of a single dose, 90% of the peak concentration was reached within 4 hours in 8 of the 10 infants. The peak concentration (in mug/ml) approximately equalled 1.3 x the dose (in mg/kg). Absorption after oral administration was less reliable. In 12 of the infants the clinical course allowed attempts to evaluate the anticonvulsive effect of phenobarbital. In 4 cases the convulsions continued. In those 8 infants where phenobarbital seemed to be effective, the approximate range of phenobarbital concentration when convulsions ceased was 12-30 mug/ml. Phenobarbital half-life ranged between 59 and 182 hours. In some infants the rate of phenobarbital disappearance from the plasma varied considerably from day to day. The pathological conditions causing seizures probably influence the distribution, metabolism and excretion of the drug. For the often seriously ill infants with convulsions it is therefore difficult to construct rational maintenance dose schedules, and optimal dosage must be based on repeated determinations of the plasma concentration.     

Interpreting the 13C-urea breath test among a large population of young children from a developing country.

The 13C-urea breath test is a noninvasive tool for the diagnosis of gastric Helicobacter pylori infection. However, it has not been validated in young children from the developing world, where infection is very common. 13C urea breath tests were performed on 1532 occasions on 247 Gambian infants and children aged from 3 to 48 mo. The means and variances of the separate sub-populations of 13C enrichment results contained within the overall dataset were estimated by a Genstat procedure using the EM algorithm, thereby identifying a cut-off value to discriminate positive from negative results. To illustrate the appropriateness of this calculated cut-off value, 13C urea breath tests were performed upon a small group of 14 patients aged 6 to 28 mo undergoing diagnostic upper endoscopy. Fixed gastric antral biopsies were examined to identify H. pylori. Two subpopulations were identified within the large dataset. A cut-off value of 5.47 delta per thousand relative to Pee Dee Belemnite limestone above baseline at 30 min identified 95% of the normally distributed negative sub-population and 99.4% of the log normal distributed positive sub-population. Comparison with endoscopic data confirmed that this cut-off value was appropriate for this population, as 7/7 children without H. pylori on their gastric biopsies had negative urea breath tests, and 6/7 children with gastric H. pylori colonization had positive urea breath tests. These findings confirm the value of the urea breath test as a diagnostic tool in young children from developing countries. They also offer a way to calculate the most appropriate cut-off value for use in different populations and the likelihood that it will correctly assign any value into the appropriate sub-population, without the need for endoscopy.     

Scheduled urine collection using disposable diapers with an acoustic signal emitter

Usually, urine is collected from infants by means of a urine bag. This procedure has some disadvantages, as it can cause discomfort and may even be painful for the child if repeated application of the bags is necessary. Correct placement is difficult for parents or other untrained people and bag displacement is common especially in older mobile children. Urine collection with disposable diapers followed by urine extraction for analysis might be a simple alternative procedure especially for field studies. Urine output is measured by weighing the diapers. A moisture sensor with a sound signal indicates the moment of urination. Stool contaminated diapers must not be excluded from urine collection, if the stool is quickly removed after defecation using diaper liners. Wet diapers are sealed in plastic bags and may be stored at -20 degrees C until extraction. With a hydraulic press urine is extracted from the diapers for measuring concentrations of urinary constituents. After extracting urine after 1 hour and 10 hours contact time only the pH falls significantly. Concentrations of the other constituents tested (creatinine, urea, phosphorus, calcium, sodium, potassium, magnesium, chloride) and total osmolality are not effected. After freezing the wet diapers for storage osmolality and the concentration of creatinine tend to be slightly lower. For clinical practice these effects can be neglected. However, they must be considered using this urine collection method in research.(ABSTRACT TRUNCATED AT 250 WORDS)