Antimicrobial drug use in hospitalised paediatric patients: a cross-national comparison between Germany and Croatia.

PURPOSE: To compare the utilisation of systemic antimicrobials at the paediatric units of the university hospitals in Marburg (Germany) and Rijeka (Croatia). METHODS: A prospective, observational analysis of hospital records from 300 incident users of antimicrobials in each study centre that were younger than 19 years. Antimicrobial utilisation was analysed in six gender-specific age groups with respect to drug choice, duration of treatment and hospital stay, indication and route of administration. The extent of antimicrobial drug use was assessed by the number of treatment courses. RESULTS: In each hospital, more than 1/3 of the patients were younger than 1 year. The duration of hospital stay was about two-fold longer in Rijeka (18.5 +/- 5.8 days) than in Marburg (8.6 +/- 3.8 days). Pneumonia and other respiratory tract infections were the most common indications in Marburg (38.6%) and Rijeka (58.7%). The cumulative percentage of patients treated with an equal number of different antimicrobials was lower in Rijeka than in Marburg. The most commonly used antimicrobials were ampicillin (40.3%) and cefuroxim (35.9%) in Marburg, but ceftriaxone (43.3%) and cefotaxim (14.0%) in Rijeka. CONCLUSIONS: A shorter treatment duration, less variation in the prescribing pattern and a greater adherence to the use of recommended antimicrobials argue for a more rational antimicrobial drug use in Marburg than in Rijeka. However, a further identification of drug choice determinants is warranted.

Pharmacotyping of hypokalaemic salt-losing tubular disorders.

UNLABELLED: Long standing confusion exists in the terminology of hypokalaemic salt-losing tubulopathies (SLTs). SLTs are autosomal recessively transmitted and characterized by normotensive secondary hyperreninism/hyperaldosteronism with hypokalaemic metabolic alkalosis. Historically, four phenotypical variants have been described: (1) the (classic) Bartter syndrome (cBS), (2) the hypomagnesaemic hypocalciuric Gitelman syndrome (GS), (3) the hypercalciuric hyperprostaglandin-E-syndrome (HPS) or antenatal Bartter syndrome (aBS) and (4) the hyperprostaglandin-E-syndrome with sensorineural deafness (HPS + SND). The latter two syndromes are the most severe variants with antenatal manifestation with polyhydramnios and life-threatening course of salt- and water-loss. Defects in five renal membrane proteins involved in electrolyte reabsorption have been identified: In HPS-patients mutations in (1) either the furosemide-sensitive sodium-potassium-chloride cotransporter NKCC2, or (2) in the potassium channel ROMK have been identified, and (3) HPS + SND is caused by mutations in the beta-subunit of the chloride channels ClC-Kb and -Ka (named barttin), all mimicking the major pharmacological effects of furosemide with minor potassium-wasting in ROMK-patients as seen in patients treated with simultaneous furosemide and amiloride, and minor calcium-wasting in Barttin-patients resembling the combination of furosemide and thiazides. (4) cBS is caused by mutations in the chloride channel ClC-Kb with similar clinical characteristics as seen under combination of thiazides and furosemide, (5) GS is caused by mutations in the thiazide-sensitive sodium-chloride cotransporter NCCT resembling the effect of long-term thiazide administration. CONCLUSION: The combination of pharmacology and genetics suggests a new terminology for the above described SLTs: Furosemide-like-SLT for HPS caused by NKCC2-mutations, furosemide/amiloride-like-SLT for HPS caused by ROMK-mutations, furosemide/thiazide-like-SLT for HPS + SND, thiazide/furosemide-like-SLT for cBS, and thiazide-like-SLT for GS.

Pathogenetic role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome: therapeutic use of the cyclooxygenase-2 inhibitor nimesulide.

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E(2), thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase-2 (COX-2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E(2) formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B(2) synthesis resulting from platelet COX-1 activity and complete inhibition of urinary 6-keto-prostaglandin F(1alpha), reflecting endothelial COX-2 activity, indicate preferential inhibition of COX-2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX-2 may play an important pathogenetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX-2-derived prostaglandin E(2) is an important mediator for stimulation of the renin-angiotensin-aldosterone system in the kidney.

Evaluation of long-term treatment with indomethacin in hereditary hypokalemic salt-losing tubulopathies.

OBJECTIVE: Evaluation of the benefit/risk ratio of long-term treatment with indomethacin in salt-losing tubulopathies with special attention to renal function. STUDY DESIGN: Twelve patients (median age, 14.9 years) had received indomethacin for a median of 13 years (median cumulative dose, 10.7 g/kg). Creatinine clearance, serum electrolyte levels, endocrine status, and excretion of prostaglandins and electrolytes were examined during indomethacin therapy and after its withdrawal. All patients underwent ultrasound-guided renal biopsy. For statistical evaluation, the Wilcoxon test and Pearson correlation coefficient were used. RESULTS: After indomethacin withdrawal, the biochemical features of the tubulopathy reappeared. The median creatinine clearance rose from 67.4 to 96.5 mL/min/1.73 m(2) (P <.05) but remained subnormal in 4 patients. Ultrasonography elucidated medullary nephrocalcinosis in 8 patients. Renal tissue showed slight/moderate focal tubular atrophy and interstitial fibrosis in 8 patients. Comparison with biopsy specimens, obtained 11 to 14 years before study participation from 5 patients, revealed no progression. A correlation between fractional sodium and magnesium excretion and percentage of altered tubulointerstitial compartment was found (P <.001). The 4 patients with mutations in the gene of the inwardly rectifying adenosine triphosphate-regulated potassium channel (ROMK) had almost normal renal histologic findings and normal renal function. CONCLUSION: Renal function and histology are unaffected by long-term indomethacin treatment.

Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness.

OBJECTIVE: To characterize a rare inherited hypokalemic salt-losing tubulopathy with linkage to chromosome 1p31. METHODS: We conducted a retrospective analysis of the clinical data for 7 patients in whom cosegregation of the disease with chromosome 1p31 had been demonstrated. In addition, in 1 kindred, prenatal diagnosis in the second child was established, allowing a prospective clinical evaluation. RESULTS: Clinical presentation of the patients was homogeneous and included premature birth attributable to polyhydramnios, severe renal salt loss, normotensive hyperreninemia, hypokalemic alkalosis, and excessive hyperprostaglandin E-uria, which suggested the diagnosis of hyperprostaglandin E syndrome/antenatal Bartter syndrome. However, the response to indomethacin was only poor, accounting for a more severe variant of the disease. The patients invariably developed chronic renal failure. The majority had extreme growth retardation, and motor development was markedly delayed. In addition, all patients turned out to be deaf. CONCLUSION: The hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness represents not only genetically but also clinically a disease entity distinct from hyperprostaglandin E syndrome/antenatal Bartter syndrome. A pleiotropic effect of a single gene defect is most likely causative for syndromic hearing loss.

Determination of free and glucuronide conjugated 20-hydroxyarachidonic acid (20-HETE) in urine by gas chromatography/negative ion chemical ionization mass spectrometry.

20-Hydroxy-arachidonic acid (20-HETE) was determined in urine by an isotope dilution assay using gas chromatography/mass spectrometry (GC/MS). After addition of 18O2-internal standard, 20-HETE was extracted from urine with hexane either directly or after treatment with glucuronidase. 20-HETE was derivatized to the pentafluorobenzylester and the sample was applied to thin layer chromatography with iso-octane/iso-propanol 9:1 (v/v) as the developing solvent. The corresponding zone was extracted and 20-HETE was hydrogenated. After derivatization to the trimethylsilylether, 20-HETE was determined by GC/MS using the [M-pentafluorobenzyl]- -ion in the negative ion chemical ionization mode. Excretion rates of free and glucuronide conjugated 20-HETE was determined in healthy children and in children with hyperprostaglandin-E-syndrome/antenatal Bartter syndrome (HPS/aBS) with or without indomethacin treatment. Compared to the controls, the HPS/aBS children showed higher excretion rates of 20-HETE, which were suppressed to normal values under indomethacin medication. Free and glucuronide conjugated 20-HETE do not correlate with PGE2 excluding any participation in HPS/aBS.

Neonatal Bartter syndrome: spontaneous resolution of all signs and symptoms.

This baby boy was born after a pregnancy complicated by severe polyhydramnios at a gestational age of 28 weeks. Analysis of the amniotic fluid had shown a high chloride content, but normal concentrations of sodium, potassium, and calcium. After birth he displayed extreme polyuria, severe renal sodium and chloride loss, and marked hypercalciuria. Five weeks after birth, his sodium chloride loss turned into renal potassium loss, along with a marked decrease in urine output. All these features are characteristic of the neonatal variant of Bartter syndrome. He was discharged after 11 weeks with oral supplements of sodium chloride, potassium gluconate, and 500 ml of fluid. The follow-up for a period of 6 years showed a surprising evolution: he has no hypokalemic alkalosis, no polyuria, and no hypercalciuria; growth and development are within the normal ranges and, at the time of writing, he is a healthy boy needing no medication and with no medical problems whatsoever.

Impaired response to furosemide in hyperprostaglandin E syndrome: evidence for a tubular defect in the loop of Henle.

In hyperprostaglandin E syndrome (HPS) renal wasting of electrolytes and water is consistently associated with enhanced synthesis of prostaglandin E2. In contrast to Bartter or Gitelman syndrome (BS/GS), HPS is characterized by its severe prenatal manifestation, leading to fetal polyuria, development of polyhydramnios, and premature birth. This disorder mimics furosemide treatment with hypokalemic alkalosis, hypochloremia, isosthenuria, and impaired renal conservation of both calcium and magnesium. Therefore the thick ascending limb of the loop of Henle seems to be involved in HPS. To characterize the tubular defect we investigated the response to furosemide (2 mg/kg) in HPS (n = 8) and BS/GS (n = 3) 1 week after discontinuation of long-term indomethacin treatment. Sensitivity to furosemide was completely maintained in patients with BS/GS. The diuretic, saluretic, and hormonal responses were similar to those of a control group of healthy children (n = 13), indicating an intact function of the thick ascending limb of the loop of Henle in BS/GS. In contrast, patients with HPS had a marked resistance to this loop diuretic. Furosemide treatment increased urine output by 7.5 +/- 0.7 ml/kg per hour in healthy control subjects but only by 4.4 +/- 1.2 ml/kg per hour (p < 0.5) in children with HPS. In parallel, the latter also had a markedly impaired saluretic response (delta Cl(urine) 0.14 +/- 0.04 mmol/kg per hour vs 0.85 +/- 0.09 mmol/kg per hour, p < 0.001; delta Na(urine) 0.23 +/- 0.06 mmol/kg per hour vs 0.77 +/- 0.09 mmol/kg per hour, p < 0.001). Furosemide therapy further enhanced prostaglandin E2 excretion in patients with HPS (54 +/- 17 to 107 +/- 28 ng/hr per 1.73 m2, p < 0.05), whereas no significant effect was observed in healthy children (20 +/- 3 to 12 +/- 3 ng/hr per 1.73 m2). We conclude that a defect of electrolyte reabsorption in the thick ascending limb of the loop of Henle plays a major role in HPS.

Pre-pubertal growth in the hyperprostaglandin E syndrome.

Pre-pubertal body growth was followed in eight children with the hyperprostaglandin E syndrome (neonatal Bartter syndrome) treated with indomethacin over a period of 5-12 years. When corrected for prematurity, the general growth pattern was normal, with the exception of a child with delayed therapy. From the first observation (usually at birth) to the start of indomethacin, the mean height standard deviation score (SDS) corrected for prematurity changed from -0.2 to -2.8. During the first 2 years of therapy rapid catch-up growth occurred, followed by a slow adaptation of the growth pattern to that of healthy children born at term. At last observation the mean corrected height SDS was -0.5 (range -1.9 to +0.9) and the mean target height -0.9 SDS (range -1.8 to +0.1). Weight, body mass index and bone maturation also reached the normal range. No correlation was found between height SDS per year and serum potassium levels or calcium excretion. We conclude that under indomethacin treatment long-term skeletal growth of children with the hyperprostaglandin E syndrome is similar to that of other preterm children.