Characteristics and incidence of transfusion-associated necrotizing enterocolitis in the UK.

Background and aims: The etiology of necrotizing enterocolitis (NEC) is unclear and postulated as being multifactorial. It has been suggested that one causative factor is the transfusion of packed red blood cells (PRBCs) leading to the disease entity commonly referred to as transfusion-associated NEC (TANEC). TANEC has been reported in North America but its incidence has not been formally investigated in the UK. Our aims were to identify the incidence of NEC and TANEC in tertiary-level UK neonatal units and to describe characteristics of TANEC cases.Materials and methods: Using strict case definitions for NEC and TANEC, we undertook a retrospective review to estimate the incidence of TANEC cases occurring in four UK tertiary-level centers during a 38-month period.Results: Of 8007 consecutive neonatal admissions of all gestations to the four centers, 68 babies went on to develop NEC and all affected infants were of very low birth weight (VLBW); 34 of these had previously received a transfusion of PRBCs but did not fit the diagnostic criteria for TANEC, whereas 15 (22%) of the 68 babies with NEC qualified as TANEC cases. UK cases occurred at an earlier postnatal age than cases reported in multiple large North American series and were of a lower birth weight.Conclusions: We have confirmed the presence of TANEC in the UK VLBW neonatal population. Its incidence lies within the wide range described in previous reports of this phenomenon globally, though with some local variation in characteristics. Further work is needed to clarify causation, pathophysiology, and possible mechanisms of prevention of TANEC.

A neonatal piglet model of intraventricular hemorrhage and posthemorrhagic ventricular dilation.

OBJECT: The combination of intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation (PHVD) remains an important cause of disability in children surviving prematurity. Currently, there is no clear agreement on the management of neonatal IVH, apart from the eventual insertion of a shunt to control PHVD. Cerebrospinal fluid (CSF) shunts are associated with a relatively high complication rate in this population. The development of new treatment options requires greater understanding of the pathophysiological mechanisms of IVH and PHVD, as well as an opportunity to monitor closely their effects on the immature brain. The authors have developed a neonatal large animal model of IVH with long-term survival, allowing the full development of PHVD. METHODS: Fourteen piglets that were 3 to 24 hours old were randomized to receive slow injections of autologous blood, autologous blood with elevated hematocrit, or artificial CSF after induction of general anesthesia. A fourth group served as controls. All animals underwent surgery to form an artificial fontanelle at the bregma. Physiological parameters, including intracranial pressure and electroencephalography, were monitored during injection. RESULTS: Serial cranial ultrasonography studies performed during the 23- to 44-day survival period demonstrated progressive ventricular dilation in the animals injected with blood. Ventricular volumes, measured with image analysis software, confirmed the highest dilation after injection of blood with an elevated hematocrit. Histological evaluation showed fibrosis in the basal subarachnoid space of hydrocephalic piglets. CONCLUSIONS: This piglet model closely replicates human neonatal IVH and PHVD. It allows detailed physiological and ultrasonographic monitoring over a prolonged survival period. It is suitable for evaluation of noninvasive as well as surgical options in the management of IVH and PHVD.

Brain development and susceptibility to damage; ion levels and movements.

Responses of immature brains to physiological and pathological stimuli often differ from those in the adult. Because CNS function critically depends on ion movements, this chapter evaluates ion levels and gradients during ontogeny and their alterations in response to adverse conditions. Total brain Na(+) and Cl(-) content decreases during development, but K(+) content rises, reflecting shrinkage of the extracellular and increase in the intracellular water spaces and a reduction in total brain water volume. Unexpectedly, [K(+)](i) seems to fall during the first postnatal week, which should reduce [K(+)](i)/ [K(+)](e) and result in a lower V(m), consistent with experimental observations. Neuronal [Cl(-)](i) is high during early postnatal development, hence the opening of Cl(-) conduction pathways may lead to plasma membrane depolarization. Equivalent loss of K(+)(i) into a relatively large extracellular space leads to a smaller increase in [K(+)](e) in immature animals, while the larger reservoir of Ca(2+)(e) may result in a greater [Ca(2+)](i) rise. In vivo and in vitro studies show that compared with adult, developing brains are more resistant to hypoxic/ischemic ion leakage: increases in [K(+)](e) and decreases in [Ca(2+)](e) are slower and smaller, consistent with the known low level of energy utilization and better maintenance of [ATP]. Severe hypoxia/ischemia may, however, lead to large Ca(2+)(i) overload. Rises in [K(+)](e) during epileptogenesis in vivo are smaller and take longer to manifest themselves in immature brains, although the rate of K(+) clearance is slower. By contrast, in vitro studies suggest the existence of a period of enhanced vulnerability sometime during the developmental period. This chapter concludes that there is a great need for more information on ion changes during ontogeny and poses the question whether the rat is the most appropriate model for investigation of mechanisms of pathological changes in human neonates.

The pathogenesis of neonatal post-hemorrhagic hydrocephalus.

Hydrocephalus after intraventricular hemorrhage (IVH) has emerged as a major complication of preterm birth and is especially problematic to treat. The hydrocephalus is usually ascribed to fibrosing arachnoiditis, meningeal fibrosis and subependymal gliosis, which impair flow and resorption of cerebrospinal fluid (CSF). Recent experimental studies have suggested that acute parenchymal compression and ischemic damage, and increased parenchymal and perivascular deposition of extracellular matrix proteins--probably due at least partly to upregulation of transforming growth factor-beta (TGF-beta)--are further important contributors to the development of the hydrocephalus. IVH is associated with damage to periventricular white matter and the damage is exacerbated by the development of hydrocephalus; combinations of pressure, distortion, ischaemia, inflammation, and free radical-mediated injury are probably responsible. The damage to white matter accounts for the high frequency of cerebral palsy in this group of infants. The identification of mechanisms and mediators of hydrocephalus and white matter damage is leading to the development of new treatments to prevent permanent hydrocephalus and its neurological complications, and to avoid shunt dependence.

Energy metabolism in mammalian brain during development.

Production of energy for the maintenance of ionic disequilibria necessary for generation and transmission of nerve impulses is one of the primary functions of the brain. This review attempts to link the plethora of information on the maturation of the central nervous system with the ontogeny of ATP metabolism, placing special emphasis on variations that occur during development in different brain regions and across the mammalian species. It correlates morphological events and markers with biochemical changes in activities of enzymes and pathways that participate in the production of ATP. The paper also evaluates alterations in energy levels as a function of age and, based on the tenet that ATP synthesis and utilization cannot be considered in isolation, investigates maturational profiles of the key processes that utilize energy. Finally, an attempt is made to assess the relevance of currently available animal models to improvement of our understanding of the etiopathology of various disease states in the human infant. This is deemed essential for the development and testing of novel strategies for prevention and treatment of several severe neurological deficits.

Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy.

OBJECTIVE: Treatment of posthemorrhagic ventricular dilation in premature infants is fraught with failures and complications. We have piloted a new treatment aimed at removing intraventricular blood and the cytokines associated with hydrocephalus. METHODS: Twenty-four infants were enrolled with ventricular width enlarged to 4 mm over the 97th centile after a large intraventricular hemorrhage. Sixteen had parenchymal brain lesions before treatment. Median gestation was 28 weeks, and birth weight was 1150 g. At a median postnatal age of 17 days, 2 ventricular catheters (1 right frontal, 1 left occipital) were inserted with 13 infants also having a reservoir frontally. Tissue plasminogen activator 0.5 mg/kg was given intraventricularly 8 hours before the ventricles were irrigated with artificial cerebrospinal fluid at 20 mL/h for a median of 72 hours. RESULTS: Seventeen of 23 survivors (74%) did not require a ventriculoperitoneal shunt. One infant (of 23 weeks' gestation) died. Two infants developed reservoir-associated infection, and 2 infants had a second intraventricular hemorrhage. Of the 19 survivors aged >12 months postterm, 8 were normal, 7 (37%) had single disability, and 4 (21%) had multiple disabilities. CONCLUSIONS: Shunt surgery was reduced compared with historical controls with similar treatment criteria. Mortality and single and multiple disability rates all showed downward trends. Reducing pressure, free iron, and proinflammatory and profibrotic cytokines may reduce periventricular brain damage and permanent hydrocephalus. Additional advances will require a controlled trial and better knowledge of the mechanisms of hydrocephalus.

Posthemorrhagic ventricular dilation in the neonate: development and characterization of a rat model.

Intraventricular hemorrhage is a common complication of prematurity. Posthemorrhagic ventricular dilation (PHVD) has a high rate of disability and no safe and effective treatment. Its pathogenesis is poorly understood, largely because of the lack of a satisfactory animal model. We have developed a model of neonatal PHVD in the rat. Seven-day-old (P7) Wistar rat pups were given 80-microl injections of citrated rat blood or artificial cerebrospinal fluid (CSF) into alternate lateral ventricles on P7 and P8. Intracranial pressure was monitored and increased briefly by over 8-fold. Some rats received further 10-microl intraventricular injections of India ink on P21. Animals were weighed daily and simple neurologic tests performed. On P21 (or P22 if India ink had been injected), the rats were perfusion-fixed and blocks processed for paraffin histology. Sixty-five percent of pups injected with blood and 50% injected with artificial CSF developed dilated lateral ventricles, with patchy loss of ependyma, marked astrocytic gliosis, and rarefaction of periventricular white matter. India ink injection revealed slow transit of CSF from the dilated lateral ventricles but eventual passage into the subarachnoid space. Pups that had received intraventricular injections but did not develop ventricular dilation nonetheless had lighter brains than littermate controls (p < 0.001). Body weights were not significantly different from controls. Hydrocephalic animals had reduced motor performance as assessed by a grip traction test (p = 0.0002). This model is well suited to studying the pathogenesis of PHVD.