Pharmacokinetics of theophylline and its metabolites during acute renal failure. A case report.

After unsuccessful therapy with salbutamol syrup and inhaled terbutaline a 3-year-old boy with an acute exacerbation of asthma was treated with nebulised salbutamol (albuterol), intravenous aminophylline and hydrocortisone. His condition continued to deteriorate and he required artificial ventilation. Subsequently, he became anuric, with liver dysfunction, nonspecific encephalopathy and limb tremor. Peritoneal dialysis was started. Plasma theophylline concentrations were monitored and maintained in the therapeutic or subtherapeutic range. Despite this, he was hyper-reflexic with limb tremor. Excessively high plasma concentrations of the principal theophylline metabolite, 1,3-dimethyluric acid, were found [maximum 92 mg/L (470 mumol/L)], which cleared only with the return of normal renal function. Plasma concentration monitoring of drugs other than theophylline was not performed. After the patient recovered, a pharmacokinetic study demonstrated that normal methylxanthine metabolism was re-established. Pharmacokinetic analysis indicated that the undue accumulation of the metabolites was a result of an inability to clear these compounds. Thus, pharmacologically and toxicologically active metabolites of theophylline may accumulate in anuric patients on peritoneal dialysis, producing clinical symptoms of toxicity. However, in the present case the possible role of metabolites of other drugs cannot be definitely excluded.

AIDS in an infant causing severe failure to thrive.

A nine-month-old female Jamaican infant presented with a history of severe failure to thrive, recurrent pneumonia and developmental delay. She was found to have hepatosplenomegaly, generalised lymphadenopathy and hypotonia. Investigations revealed polyclonal hypergammaglobulinaemia, cytomegalovirus in her urine, and patchy lung infiltrates on her chest radiographs. Three separate tests were positive for human immunodeficiency virus in both the infant and her mother, suggesting vertical transmission, and confirming AIDS as the cause of the severe failure to thrive.

Tuberculosis presenting as laryngeal stridor in a child.

A three and a half-year-old boy developed stridor after insertion of grommets for bilateral secretory otitis media. Despite treatment with steroids systemically and locally, antibiotics and an antihistamine, the stridor worsened. Microlaryngotracheobronchoscopy (MLB) demonstrated laryngeal granulations, in which, by auramine and Ziehl-Neelsen staining, acid-fast bacilli were seen, and from which subsequently Mycobacterium tuberculosis grew in culture. Following the MLB the child became comatosed and a clinical diagnosis of tuberculosis involving the central nervous system was made. Despite quadruple antituberculous chemotherapy he died 8 days later. A Mantoux test was negative and a chest radiograph was normal. Acid-fast bacilli were not demonstrated on repeated examinations of cerebrospinal fluid, nor were they grown ante mortem or post mortem from samples of cerebrospinal fluid.

Triple antibiotic spray application to umbilical cords.

A trial in 402 newborns demonstrated that application of 'Tribiotic' spray either as a single dose at birth or repeated daily resulted in a significant reduction of umbilical cord infections compared with no antibiotic application. 'Tribiotic' spray was well tolerated but led to delayed cord separation.

The efficacy of oral theophylline in ventilated premature infants.

40 ventilated premature infants, with gestational ages of 24-34 weeks and a mean birthweight of 1422 g, were entered into a randomised controlled trial. 20 of the infants received orally 5 mg/ml anhydrous theophylline dissolved in 20% pure alcohol, with a loading dose of 5 mg/kg and then 1.25 mg/kg every 6 h. Plasma samples were assayed via an emit enzyme immunoassay, demonstrating satisfactory serum levels in all infants at 54 h after the loading dose. Possible side-effects were seen only in two infants, in one a tachycardia (220 beats/min) and the other became agitated during treatment.

The implications of the David Glass case for future clinical practice in the UK.

A recent decision of the European Court of Human Rights (ECtHR) raises issues of considerable importance to medical practitioners and paediatricians in particular. The case concerns the parental right to withhold consent to medical intervention that doctors believe to be necessary in a child's best interests. The dramatic facts of this case (in which a boy's family felt they had to fight for his life) has significant repercussions for clinical practice. This is discussed in the light of previous and recent cases that have involved babies, infants and children. The worrying trend to use the Courts to resolve these difficult clinical cases is discussed.

Infra-diaphragmatic total anomalous pulmonary venous drainage presenting with rectal bleeding.

A boy aged 1 month presented with profuse rectal bleeding. Chest x-ray film showed pulmonary oedema and at cardiac catheterisation infradiaphragmatic total anomalous pulmonary venous drainage to a dilated portal venous system was found. Ulcerated oesophageal varices were identified at necropsy after unsuccessful cardiac surgery. The late and unique presentation of this case is emphasised.

Factors influencing plasma renin and renin substrate in premature infants.

Concentrations of plasma renin (PRC) and plasma renin substrate (PRS) were measured during the first week of life in 52 infants born at less than 37 weeks' gestation (mean (SEM) gestation 30 (0.4) weeks, mean (SEM) birth weight 1.35 (0.08) kg). Both PRC (median 35, interquartiles 16.3, 94.5 ng/ml/hour) and PRS (median 2.3, interquartiles 1.3, 5.0 micrograms/ml) were raised compared with adults. The proportional rise in PRC was much greater than that in PRS, suggesting that PRS may be rate limiting in the generation of angiotensin I. Log10 PRC was inversely proportional to gestational age and a high urinary sodium loss was associated with a significantly raised log10 PRC. In hypoxaemic infants, there was a strong correlation between log10 PRS and haemoglobin concentration; this is a new observation in human infants but consistent with data available from other species.

Management and outcome of severe head injuries in the Trent region 1985-90.

In a five year period, 39 children (29 boys, 10 girls) aged 2 months to 13 years (mean 7.8 years) were studied who had suffered a major head injury (29 road traffic accidents, six falls, and four non-accidental injury). The injury had been assessed clinically and by cranial computed tomography or cranial ultrasound (in a single baby of 2 months). Initial Glasgow coma scores for all subjects ranged from 3-11 (mean 5.5), intact survivors 5-11 (7.4), minor handicap 4-11 (6.1), major handicap 3-6 (4.3), fatalities 3-6 (4.1). All were treated with sedation, paralysis, hyperventilation (arterial carbon dioxide tension 3.0-3.5 kPa), intracranial pressure monitoring and moderate body surface hypothermia to 32 degrees C. Nine children died and 30 survived (nine intact, 13 minor disability, and eight major disability). The worst cerebral perfusion pressure was over 40 mm Hg in all but one survivor, and less than 40 mm Hg in seven of nine fatalities. Severe hypocapnia both in the first 24 hours and overall was correlated with poor outcomes (dead or major disability), as were bilateral contusions or diffuse axonal injury.

Whole blood assay of theophylline concentrations using immunochromatographic stick at the bedside.

Blood was collected from 77 patients for estimation of theophylline concentration by whole blood assay using an immunochromatographic stick (Acculevel, Syva UK, Maidenhead, Berkshire). Results were validated by high performance liquid chromatography (HPLC). The stick method was rapid, reliable, required no technical expertise, and produced results equivalent to those obtained from assay from HPLC.

Magnetic resonance imaging in neurological disorders.

To investigate the role of magnetic resonance imaging (MRI) in neurological disorders, 115 children were studied in two groups. Group A (78 patients) was studied by paired computed tomography and MRI cranial scans. Group B (37 patients) was studied by paired computed tomography assisted myelography (CTM) and MRI spinal scans. In group A, the scans were generally equivalent for supratentorial tumours and for investigating fits, hydrocephalus, benign intracranial hypertension, and cerebral atrophies, but MRI scanning was superior for posterior fossa tumours and cysts. In group B, MRI scans were superior for intramedullary spinal tumours, spinal dysraphic problems with tethering or syrinx, and were complementary to CTM in diastematomyelia.

The trisomy (5)(q31-qter) syndrome: study of a family with a t(5:14) translocation.

We report a child with multiple malformations caused by trisomy for the distal part of the long arm of chromosome No 5. A neonatal diagnosis of Down's syndrome had previously been made on the basis of clinical examination and the detection of an additional chromosome not unlike No 21. A subsequent clinical re-evaluation, with the cooperation of the parents who permitted further studies, led to the confirmation of the true diagnosis. The mother was the carrier of a balanced translocation between chromosome No 5 and No 14. The child had severe growth and psychomotor retardation and characteristic features: microcephaly, antimongoloid slant, epicanthus, low set ears, down-turned mouth, and long upper lip. She was hypertonic and a congenital heart disease (atrial septal defect) was present. We have compared this case with others known to be trisomic for segment 5q31-qter.

Sustained release theophylline in nocturnal asthma.

Twice daily sustained release theophylline gave satisfactory steady serum theophylline concentrations in asthmatic children aged 7 to 14 years. The children showed improvement in symptoms, less frequent waking at night, reduced use of beta agonist inhalers, and improved early morning peak flows while being treated with this preparation. There was no improvement in peak flow at other times, but the patients recorded increased use of beta agonists during the placebo period.

Morphine kinetics after diamorphine infusion in premature neonates.

1. The pharmacokinetics of morphine were studied in 26 newborn premature neonates (26-38 weeks gestational age) who were given a loading dose of 50 micrograms kg-1 of diamorphine followed by an intravenous infusion of 15 micrograms kg-1 h-1 of diamorphine. Plasma concentrations of morphine were measured during the infusion at steady-state and for 24 h after the cessation of the diamorphine infusion. 2. The mean steady-state plasma morphine concentration (+/- s.d.) for a diamorphine infusion rate of 15 micrograms kg-1 h-1 was 62.5 +/- 22.8 ng ml-1. 3. Morphine clearance was 3.6 +/- 0.9 ml min-1 kg-1, the elimination half-life was 8.9 +/- 3.3 h and the volume of distribution was 2.7 +/- 1.01 kg-1. 4. Morphine elimination kinetics were described by a mono-exponential function. 5. There was a direct relationship between the gestational age of the patients and the clearance (r2 = 0.31, P = 0.003) and half-life (r2 = 0.35, P = 0.01) of morphine, but no relationship was found between gestational age and volume of distribution. 6. The results suggest that the currently used dosing regimen of diamorphine achieves a safe and effective morphine concentration in the premature newborn but that the loading dose could be modified to achieve a more rapid onset of analgesia.

Diamorphine infusion in the preterm neonate.

The effects of diamorphine were studied in 34 premature neonates who were given a loading dose of 50 micrograms/kg of diamorphine followed by a constant rate intravenous infusion of 15 micrograms/kg/hour. Small but significant falls were noted in blood pressure (at 30 minutes) and heart rate (at 30 minutes, six hours, and 12 hours) after administration of diamorphine, but these did not appear to cause any clinical deterioration and were thought to be related to the sedative effect of the drug. A significant fall in respiration rate at 30 and 60 minutes reflected the desired intention to encourage synchronisation of the infants' breathing with the ventilator. The mean (SD) plasma concentration of morphine measured during the infusion at steady state was 62.5 (22.8) ng/ml (range 20 to 98 ng/ml). The data suggest that this dosage regimen of diamorphine is safe. It results in plasma concentrations of morphine in the premature neonate which are comparable with those that are known to provide effective analgesia in the child and adult.