Neuropsychological outcome at adolescence of very preterm birth and its relation to brain structure.

Neuropsychological outcome at 14 to 15 years of age of a cohort of 75 participants (39 male, 36 female) born at <33 weeks' gestation was investigated. Research was conducted parallel to a recent MRI study by Stewart and colleagues which reported that 55% of this cohort had evidence of brain abnormality. One aim of the study was to compare neuropsychological function in those very preterm children with and without MRI abnormality. Compared to a control sample of term adolescents, very preterm participants had impairment only on a measure of word production. On measures of attention, memory, perceptual skill, and visuomotor and executive function, the adolescents born very preterm performed in the normal range, whether or not they had evidence of MRI abnormality. Our findings are encouraging as the neuropsychological consequences of damage to the very preterm brain, still evident on MRI at 14 to 15 years of age, appear to be minor.

Epilepsy in very preterm infants: neonatal cranial ultrasound reveals a high-risk subcategory.

The aim of this study was to investigate the association between epilepsy and perinatal brain injury in a cohort of 610 infants born preterm at <33 weeks' gestation. The prevalence of epilepsy in this cohort was 4.3% as determined by a postal questionnaire survey. Most children with epilepsy (16 of 24) had high-risk cranial ultrasound lesions including haemorrhagic parenchymal infarction (HPI), posthaemorrhagic hydrocephalus, and cystic periventricular leukomalacia (PVL). Of all the children in our cohort with high-risk brain lesions, those with epilepsy were more likely to have HPI and significantly less likely to have cystic PVL, although it is possible that PVL was not noticed in some cases. Children with epilepsy and high-risk cranial ultrasound lesions also showed more cognitive impairment than children with high-risk lesions but no epilepsy, which suggested more cortical grey-matter damage. We suggest that brain injury has occurred outside the confines of the periventricular white matter in this group of preterm infants with epilepsy.

Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years.

Cerebral oxidative metabolism was studied using phosphorus magnetic resonance spectroscopy during the first week of life and neurodevelopmental outcome was assessed at 4 years in 62 infants who had clinical and/or biochemical evidence consistent with birth asphyxia (critically impaired intrapartum gas exchange). Twenty-one died and the neurodevelopmental status of the 41 who survived was assessed by a range of tests at age 4 years. The minimum recorded values for the cerebral phosphocreatine:inorganic phosphate concentration ratio (an index of oxidative metabolism) were related to outcome. The results showed significant relations between the extent of derangement of neonatal oxidative metabolism and a range of adverse outcomes, including death, and at 4 years reduced head growth and the presence and severity of neuromotor impairments, overall neurodevelopmental impairments, and cognitive functioning. Strong correlations between the extent of derangement of neonatal oxidative metabolism and outcome at 1 and 4 years were also shown. We conclude that the severities of adverse outcomes at 1 and 4 years of age were closely related to the extent of cerebral energy derangement in the first week of life, and we also conclude that primary intrapartum hypoxic-ischaemic cerebral injury was generally responsible for the events that led to death, microcephaly, and impaired

Follow-up by questionnaire?

Recently, proposals have been made to include larger numbers of infants and reduce the cost of obtaining follow-up information pertaining to modern perinatal management. These proposals have been made in response to requests from purchasers and providers of health care as well as the obstetricians and neonatologists actively engaged in delivery of the service. These initiatives are welcome, but care must be taken to provide objective, meaningful data. In addition to standardised recording including by questionnaire, standardised data collection designed to identify relevant impairments must be the primary objective; the nature and extent of disability at particular ages can then be assigned but it is misleading to regard disability as the principle outcome measure.

Relation between neurodevelopmental status of very preterm infants at one and eight years.

The relation between neurodevelopmental status at one and eight years of age was investigated in a cohort of 207 infants born between 1979 and 1982 at < 33 weeks of gestation. The probability of a major disabling impairment at eight years was only 1 per cent among 164 children with normal neurodevelopment at one year, but 56 per cent for the 43 impaired children and 92 per cent for the 23 of these who had major disabling impairments. Close correspondence was found between the type of major impairment diagnosed at one and eight years. Neurodevelopmental status at one year also predicted the need for extra educational provision by eight years, with probabilities of 9 per cent for children without impairment at one year, 56 per cent for impaired children and 87 per cent for those with major impairments. Similarly, neurodevelopmental status predicted an IQ of more than 2 SD below the mean (< 70), with probabilities of 0, 30 per cent and 48 per cent, respectively.

Incidence of digoxin toxicity in outpatients.

The incidence of digoxin toxicity among patients in hospitals has declined in recent years. To evaluate whether a similar decline has occurred in ambulatory care, we reviewed randomly selected medical records for 183 outpatients receiving ongoing treatment with digoxin at 10 urban and rural Department of Veterans Affairs Medical Centers in the Rocky Mountain region. The prevalence of traditional risk factors for digoxin toxicity--elevated serum digoxin and serum creatinine levels, hypokalemia, and a new prescription of an interacting drug-was established from computerized laboratory and pharmacy records. Of the 183 patients, 50 (27.3%) had one or more risk factors for digoxin toxicity: serum digoxin levels were elevated in 13.6% of patients in whom a level was obtained, with hypokalemia in 14.3%, elevated creatinine levels in 17.9%, and possible drug interactions in 5.5% of patients over a 1-year period. Nevertheless, digoxin toxicity occurred in only 2 persons (1.1% or 1.4 per 100 patient-years of treatment). We conclude that digoxin toxicity was rare in this group of outpatients, even in persons presumed to be at high risk because of metabolic abnormalities, increased digoxin concentrations, or the use of interacting drugs. The low rate of digoxin toxicity in outpatients parallels the decline in the incidence of toxicity observed in hospital-based studies.

Relation between ultrasound appearance of the brain of very preterm infants and neurodevelopmental impairment at eight years.

The relation between the ultrasound appearance of the brain and neurodevelopmental outcome at eight years of age was investigated in 206 infants born between 1979 and 1982 at < 33 weeks gestation (600 to 2500g birthweights). Only 4 per cent of the 112 infants with normal scans at discharge from the neonatal unit developed major, disabling impairment. No significant adverse effect of uncomplicated periventricular haemorrhage was detected. The probability of a major impairment in infants with ventricular dilatation or hydrocephalus was 27 per cent, and 69 per cent in those with cerebral atrophy. 44 per cent of the children demonstrated significant differences in their cognitive processing skills, which appeared capable of affecting learning and may possibly have been caused by undetected hypoxic-ischaemic damage to callosal fibres.

The effect of prescription size on acquisition of maintenance medications.

OBJECTIVE: To determine whether large prescriptions (> or = 90 days' supplies) enhance the acquisition of maintenance medications by patients. DESIGN: Study 1: multisite, retrospective cohort study evaluating outpatient digoxin use. Study 2: single-site, retrospective cohort study to confirm Study 1. SETTING: Study 1: Ten Veterans Affairs Medical Centers in the Rocky Mountain region. Study 2: The only facility from Study 1 (site C) that dispensed large prescriptions of maintenance medications. PATIENTS: Randomly selected outpatients receiving two or more digoxin prescriptions (n = 176 in Study 1, n = 114 in Study 2). INTERVENTION: None. RESULTS: The main outcome measure was the proportion of prescribed doses of maintenance medications obtained. In Study 1, patients who received at least one large digoxin prescription obtained a mean of 137.2% of their prescribed digoxin doses over a mean of nine months, compared with 91.3% for patients who received only small prescriptions of < 90 days' supplies (p = 0.02). Patients receiving large prescriptions were more likely to obtain at least 100% of their prescribed amounts of digoxin (adjusted OR = 11.4, 95% CI = 1.3-96.8, p = 0.03). At site C, patients in Study 1 obtained a mean of 129.0% of all maintenance drugs given in large supplies, compared with 95.2% of drugs prescribed only in small supplies (p = 0.006). In Study 2, acquisition of digoxin increased progressively from 89.7% among individuals who received only small digoxin prescriptions to 113.0% for those who received only large supplies (p = 0.002), over a mean of 14 months. CONCLUSIONS: Large prescriptions facilitate the acquisition of maintenance medications but may lead to oversupplies, while small prescriptions impose a barrier to obtaining these drugs.

Cerebral hemodynamic effects of treatment with modified natural surfactant investigated by near infrared spectroscopy.

The purpose of this study was to investigate the effects on cerebral hemodynamics of administering modified natural surfactant (Curosurf, 200 mg.kg-1) to infants requiring mechanical ventilation for hyaline membrane disease. Observations were made using near infrared spectroscopy on 20 infants for between 26 and 109 (median 57) min before and 22 to 112 (median 46) min after surfactant instillation. Changes in cerebral oxyhemoglobin concentration and cerebral blood volume (CBV) were monitored continuously; cerebral blood flow, oxygen delivery, and the response of CBV to changes in arterial carbon dioxide tension were measured while the infants were stable shortly before and after surfactant was given. Cerebral oxyhemoglobin concentration fell transiently in all infants immediately after surfactant by a median of -0.21 (range -0.46 to 0.05) mL x 100 g-1, but quickly recovered so that the median change during the 10 min after surfactant was 0.01 (-0.46 to 0.46) mL x 100 g-1. Alterations in CBV also occurred ranging from -0.44 to 0.40 (median 0) mL x 100 g-1, which represented -12 to 16% of total CBV; these changes rapidly resolved. When the infants were stable before and after surfactant, the values for mean (SD) cerebral blood flow were 20.5 (7.5) and 23.1 (5.2) mL.100 g-1 x min-1, respectively (n = 9); for mean cerebral oxygen delivery, values were 2.71 (0.89) and 3.15 (0.73) mL x 100 g-1 x min-1 (n = 9); and for response of CBV to changes in arterial carbon dioxide tension, they were 0.14 (0.09) and 0.11 (0.11) mL x 100 g-1 x kPa-1 (n = 16); these changes were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between cerebral oxidative metabolism following birth asphyxia, and neurodevelopmental outcome and brain growth at one year.

Studies of cerebral oxidative metabolism were carried out by phosphorous magnetic resonance spectroscopy during the first week of life in 52 infants with clinical and/or biochemical evidence of birth asphyxia. 15 infants died and the 37 survivors were assessed by a wide range of neurodevelopmental tests at one year of age. The minimum recorded values for cerebral phosphocreatine/inorganic phosphate concentration ratio (an index of oxidative metabolism) were related to outcome. The results showed a significant relation between the extent of derangement of oxidative metabolism and the severity of adverse outcomes, including death, neurodevelopmental impairment and reduced head growth.

Experimentally measured optical pathlengths for the adult head, calf and forearm and the head of the newborn infant as a function of inter optode spacing.

The Differential Pathlength Factor (DPF) has been measured for several different tissues. The results showed that the DPF varied with the type of tissue studied, and in the case of the adult calf with sex. However, the DPF for all tissues studied was constant once the inter optode spacing exceeded 2.5 cm. Thus, measurements can be made by NIR spectroscopy at a range of inter optode spacings, and a single DPF used in the calculation of chromophore concentration. The results also showed that the major source of error in the DPF lay in the measurement of the inter optode spacing. To improve accuracy, two options are possible. Firstly, some means of continuous measurement of inter optode spacing could be incorporated in the NIR instrumentation. The better alternative would be an instrument incorporating a method of directly measuring the optical pathlength at each wavelength. This could be done either by time of flight measurement, or if it can be validated, by phase shift measurement.

New non-invasive methods for the investigation of cerebral oxidative metabolism and haemodynamics in newborn infants.

Magnetic resonance spectroscopy and near infrared spectroscopy provide complimentary information about cerebral oxidative metabolism and haemodynamics and are valuable methods for investigating normal brain development and the pathogenesis of perinatal brain injury. Magnetic resonance spectroscopy can be used to measure in brain tissue the concentrations of important phosphorus compounds that are involved in oxidative metabolism, notably adenosine triphosphate, phosphocreatine and inorganic orthophosphate: intracellular pH can also be estimated. Abnormalities indicating impaired oxidative phosphorylation have been detected in a range of situations where hypoxic-ischaemic brain injury was known or suspected to have occurred, such as birth asphyxia and periventricular leucomalacia. Following acute cerebral injury a latent period of many hours has frequently been found before evidence of impaired oxidative phosphorylation developed, suggesting the possibility of effective early treatment. The extent of the metabolic impairment was related to long term outcome. Near infrared spectroscopy provides cotside information about cerebral oxygenation and haemodynamics. Quantitative information can be obtained about oxyhaemoglobin, deoxyhaemoglobin and the redox state of cytochrome aa3. Methods have been described for calculating cerebral blood flow, oxygen delivery, blood volume and carbon dioxide reactivity; and maturational changes are being defined. In birth-asphyxiated babies, abnormalities are detectable well before oxidative phosphorylation becomes impaired.

Quantification of concentration changes in neonatal human cerebral oxidized cytochrome oxidase.

The oxygenation of cerebral cytochrome oxidase in vivo was investigated in eight newborn preterm infants. Near-infrared spectroscopy was used to quantify changes in the concentration of oxidized cytochrome oxidase ([CytO2]) observed during alterations in arterial oxygen saturation (SaO2) in the range of 85-99% and of carbon dioxide tension (PaCO2) in the range of 4.3-9.6 kPa. No relation was found between changes in SaO2 and [CytO2]. Alterations in PaCO2 were positively related both to changes in [CytO2] and total cerebral hemoglobin concentration [( Hb]t). The changes in [CytO2] ranged from 0.09 to 0.33 (median 0.21) mumol.l-1.kPa-1. The ratio [CytO2]/[Hb]t ranged from 0.06 to 0.12 (median 0.08). The relation of delta [CytO2] to the change in cerebral blood volume (delta CBV) was calculated: delta [CytO2]/delta CBV ranged from 0.09 to 0.18 (median 0.11) mumol/ml. These results define a fraction of cerebral cytochrome oxidase in the newborn infant that is oxidized after an increase in PaCO2 but demonstrate that a change in SaO2 in the range studied was not sufficient by itself to change [CytO2]. They differ from results of studies in adults; this may reflect significant differences between adult and neonatal brain.

Effect of intervention on development of hip posture in very preterm babies.

Preterm babies are physiologically hypotonic, which causes their posture to be flattened when lying in the prone position. This flattened posture may persist beyond term. In a prospective, randomised, controlled, double blind trial of postural support carried out on 45 babies born at less than 33 weeks of gestation, we showed that infants positioned with specific hip support during the period of intensive care had significantly fewer features of flattened posture at the age equivalent to term.

Epiphyseal dysplasia of the femoral head, mild vertebral abnormality, myopia, and sensorineural deafness: report of a pedigree with autosomal dominant inheritance.

A family is presented with short stature, femoral epiphyseal dysplasia, mild vertebral changes, and sensorineural deafness inherited as an autosomal dominant trait. Myopia and retinal detachment presenting in adult life were also present in some affected members. We suggest that this disorder may be a distinct entity within the spondyloepiphyseal dysplasia group of disorders.