Neonatal Intraventricular Hemorrhage Research Articles

Prevention of Intraventricular Hemorrhage With Phenobarbital Therapy: Now What?

In the April issue of Pediatrics, Kuban and colleagues1 report on what is now the largest trial of phenobarbital administration to prevent neonatal intraventricular hemorrhage. They randomized 280 ventilator-dependent preterm infants weighing less than 1,751 g at birth. Three affiliated intensive care nurseries collaborated during a 3-year period to enroll a sample size determined by a prospective statistical analysis to test a predicted reduction of intraventricular hemorrhage by 50% in treated patients. Infants were entered into the trial only if they were receiving assisted ventilation before 12 hours of age and had no evidence of intraventricular hemorrhage by sonographic examination. This clinical trial was well designed and carefully run.

Status at two years in 121 very low birth weight survivors related to neonatal intraventricular haemorrhage and mode of delivery.

All 121 infants with birthweight less than or equal to 1500 g (VLBW) discharged from our department through an 18-month period were followed up at two years of age. All but 10 infants were examined by cranial ultrasound scanning in the neonatal period. Six had died after discharge; and of these two had severe brain damage following neonatal intraventricular haemorrhage. Twelve children had definite neuromotor abnormality; of these, the nine children with spastic types of cerebral palsy had all been delivered vaginally. Of the remaining children, one half had at least one neurodevelopmental symptom suggesting perinatal brain damage. Outcome was associated to neonatal intraventricular/subependymal haemorrhage when complicated by ventricular dilatation. Outcome in children with simple haemorrhage was similar to that in children without haemorrhage. The association between outcome and haemorrhage was considerably reduced by simultaneously considering the associations of gestational age at birth and the use of mechanical ventilation in the neonatal period. Head circumference at follow-up was greatest in those children with haemorrhage complicated by ventricular dilatation, when adjusted for actual body weight, birth weight, and gestational age at birth.

Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants

We admitted 48 preterm neonates (600 to 1250 gm birth weight, normal 6-hour echoencephalograms) to a randomized prospective indomethacin or placebo trial for the prevention of neonatal intraventricular hemorrhage. Beginning at 6 postnatal hours, indomethacin or placebo was administered intravenously every 12 hours for a total of five doses. Cardiac ultrasound studies to assess the status of the ductus arteriosus were performed at 6 postnatal hours and on day 5. Urinary output, serum electrolytes, and renal and clotting functions were monitored. No differences in birth weight, gestational age, Apgar scores, or ventilatory needs were noted between the two groups. Six infants given indomethacin had intraventricular hemorrhage, compared to 14 control infants (P = 0.02). The indomethacin-treated group had significant decreases in serum prostaglandin values 30 hours after the initiation of therapy. The overall incidence of patent ductus arteriosus was 82% at 6 postnatal hours; 84% of the indomethacin-treated infants experienced closure of the ductus, compared to 60% of the placebo-treated patients. Closure of the ductus was not related to incidence of intraventricular hemorrhage. We speculate that indomethacin may provide some protection against neonatal intraventricular hemorrhage by acting on the cerebral microvasculature.

Evoked potential synchrony patterns in young children with learning disabilities

Objectives: To determine whether magnesium sulfate (MgSO4) exposure is associated with a reduced risk for neonatal intraventricular hemorrhage (IVH). Study design: In a randomized, controlled trial, women in preterm labor were randomly assigned to receive MgSO4, “other” tocolytic, or saline control. At delivery, we collected maternal antecubital and umbilical cord blood for determination of serum ionized magnesium levels. Neonatal IVH was diagnosed by cranial ultrasonogram. Results: Among 144 infants, 24 were diagnosed with IVH. Using crude intention-to-treat analysis, we found that 18% (13/74) of survivors exposed after birth to MgSO4 had IVH compared with 16% (11/70) of babies who were not exposed. Infants who had IVH were more likely to have been delivered by mothers with higher serum ionized magnesium (Mg) levels (0.75 vs 0.56 mmol/L) (P =.01). Using multivariable logistic regression, we confirmed that higher Mg levels are a significant predictor of neonatal IVH (adjusted odds ratio, 15.8; 95% CI, 1.4-175.0) even when adjusted for birth weight, gestational age, antenatal hemorrhage, and neonatal glucocorticoid exposure. Conclusions: In mothers with preterm labor, our data indicate that antenatal MgSO4 exposure may be associated with an increased risk for IVH among their newborns. (J Pediatr 2002;140:540-6)

1519 ANTENATAL PHENOBARBITAL FOR PREVENTION OF NEONATAL IANTRAVENTRICULAR HEMORRHAGE

A prospective randomized controlled study was performed evaluating the effects of antenatal phenobarbital (PB) on neonatal intraventricular hemorrhage (IVH). Forty-six pregnant women in labor <35 wks gestation were assigned to control (n=22) or treatment groups (n=24); the treatment group received 500 mg PB by slow intravenous infusion prior to delivery. Echoencephalograms were performed on all infants. The time between dose of PB and delivery was 5.6 ± 4.6 hrs (all values mean ± SD). Maternal PB levels at delivery were 8.72 ± 2.01 μg/mL and cord serum PB levels were 8.85 ± 1.57 μg/mL. The infants in the control group and those in the PB treated group did not differ regarding delivery route, presentation, Apgar scores, ventilatory support, episodes of acidosis, hypoxemia, hypercarbia, hypotension and fluid therapy in the first 3 days. The results indicate a significant decrease in mortality and occurrence of moderate and severe IVH in the PB treated group as compared to the control group.

Beagle puppy model of intraventricular hemorrhage. Effect of superoxide dismutase on cerebral blood flow and prostaglandins.

Intraventricular hemorrhage (IVH) represents a major problem for preterm neonates and is thought to occur secondary to alterations in cerebral blood flow (CBF) to damaged germinal matrix tissues. Many investigators believe that both local CBF and changes in capillary morphology and permeability may be partially controlled by prostaglandins. To evaluate this hypothesis, the authors have studied the effects of superoxide dismutase (SOD), a known free-radical scavenger, on newborn beagle pups that were randomly assigned by computer to four groups consisting of either SOD- or saline-pretreated animals that underwent either insult by hemorrhagic hypotension/volume reexpansion or no insult. Prostaglandin levels were determined prior to and 60 minutes following the administration of the solutions, and carbon-14 iodoantipyrine autoradiography was performed for determination of CBF. It was demonstrated that, although SOD significantly decreased the incidence of IVH in this model (p less than 0.05), it caused no alterations in baseline CBF or prostaglandin levels. In addition, SOD did not prevent either the systemic blood pressure changes or the alterations in CBF found in response to a hemorrhagic hypotensive insult. The authors propose that neonatal IVH results from a combination of factors, one of which is prostaglandin-mediated alterations in CBF to a damaged capillary matrix.

Cranial ultrasound and clinical studies in preterm infants

Serial ultrasound imaging of the brain was used to determine the ventricular index (VI), and the ratio (VR) of the VI to the cranial hemidiameter during the nursery course and first year post-term in preterm infants of less than 33 weeks gestation. Twenty-nine of the infant survivors with no intracranial hemorrhage or major medical complication during their nursery course composed group 1. Twenty-two survivors with intracranial hemorrhage unassociated with early ventricular dilation composed group 2. Group 3 was comprised of 10 other survivors who had neonatal intraventricular hemorrhage with early ventriculomegaly; all 10 infants had at least one major medical complication during their neonatal course. In groups 1 and 2 the VR decreased and the VI increased significantly with age post-conception. Infants in group 3, compared with those in groups 1 or 2, had decreased occipitofrontal growth during the early postnatal period and increased VR and VI during the neonatal period and first year post-term. These results suggest that the ventriculomegaly associated with neonatal intracranial hemorrhage cannot be explained by posthemorrhagic hydrocephalus alone and may also be related to cerebral atrophy or decreased brain growth or both. Neurodevelopmental assessments at 20 to 30 months of age disclosed significantly lower Bayley Motor Development scores in group 3 compared with groups 1 or 2. Four infants in group 3, but none in groups 1 or 2, had cerebral palsy. The neurodevelopmental deficits in group 3 infants may reflect the complex pathogenesis of the ventriculomegaly as well as the effects of the intraventricular hemorrhage and posthemorrhagic hydrocephalus.

Perinatal cerebral infarction.

The diagnosis of perinatal cerebral infarction, although frequently suggested clinically, has been made most commonly at postmortem examination; few infants surviving stroke are reported in the literature. We evaluated 18 infants with perinatal cerebral infarction in a recent twelve-month interval. Seven were preterm neonates, 6 of whom had experienced neonatal intraventricular hemorrhage. Three full-term infants were thought to have experienced cerebral infarction in utero and had evidence of well-defined strokes on computed tomographic scans performed shortly after birth. Eight infants developed stroke at term. The most common cause of cerebral infarction in our series was perinatal asphyxia. Fourteen of the infants were seen with neonatal seizures. Fourteen of the 18 have died or are faring poorly at 4 to 12 months of age (corrected).

Concepts in Pediatric Neurosurgery

Pediatric neurosurgery has emerged as a distinct subspecialty in the field of neurosurgery. This volume contains the scientific presentations of the sixth annual meeting of the American Society for Pediatric Neurosurgery and reflects some of the latest research and clinical thoughts of these ultraspecialized persons. A uniquely valuable feature of this book is the editorial comment by Humphreys that follows each paper; although succinct, these editorial comments serve to review the subject matter in general and place the presentation in proper perspective. There are 26 chapters, each an original contribution by a well-known pediatric neurosurgeon. The first chapter by Vries details a comprehensive computerized information management system for a pediatric neurosurgical practice; this establishes the current and vital nature of the remaining articles. Although not divided into specific sections, the first 14 chapters primarily deal with developmental abnormalities. They range from an excellent investigational study of neonatal intraventricular hemorrhage in

PROSTAGLANDIN-MEDIATED CONTROL OF NEONATAL CEREBRAL BLOOD FLOW

Intraventricular hemorrhage (IVH) represents a major problem of preterm neonates & is believed to be secondary to alterations in cerebral blood flow (CBF). The newborn beagle pup provides an excellent model for the study of this problem as well as for the study of neonatal CBF. We have studied the alterations in CBF in the newborn beagle pup exposed to hemorrhagic hypotension followed by volume re-expansion for IVH & the effects of the PG-system inhibitors, indomethacin (INDO), ethamsylate (ETHAM) & superoxide dismutase (SOD) in this model system. INDO, believed to inhibit the cyclo-oxygenase pathway, prevented IVH (8% incidence), blunted the BP changes found in saline pretreated pups (IVH rate 75%) & prevented the cortical & germinal matrix CBF changes found in that group as well. ETHAM thought to inhibit the PG-specific synthetic enzymes, lowered baseline CBF, but prevented IVH less well than INDO (30%). ETHAM only somewhat blunted CBF changes & did not prevent the BP changes found in this model. SOD, a free-radical scavenger, prevented IVH (10%) but had no effect on CBF or BP. INDO & ETHAM inhibited the synthesis of TXB2 & 6-keto PGF1α, the breakdown products of TXA2 & PGI2 respectively (baseline controls: TXB2 700 pg/ml, 6-keto PGF1α 650 pg/ml; after INDO 289, 250 respectively; after ETHAM 132, 247 respectively). SOD had no effect on the synthesis of either PG. We hypothesize that neonatal IVH may be secondary to both alterations in CBF & free radical mediated germinal matrix capillary changes.

Beagle puppy model of intraventricular hemorrhage. Effect of indomethacin on local cerebral glucose utilization.

The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). A study was designed to determine if indomethacin can prevent IVH, and if indomethacin would produce changes in local cerebral glucose utilization (LCGU). By computerized random design, newborn beagle puppies were pretreated with either indomethacin (a known inhibitor of prostaglandin synthetase) or saline, and then assigned either to receive a hemorrhagic hypotension/volume reexpansion insult or to receive no insult. Pretreatment with indomethacin produced a marked drop in the incidence of IVH as well as significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult. Carbon-14 autoradiography was used to determine LCGU: no alterations were demonstrated in cerebral metabolism in uninjured pups pretreated with indomethacin compared to saline-pretreated animals. In addition, although the hemorrhagic hypotension/volume reexpansion insult produced marked alterations in LCGU in both groups of traumatized pups, indomethacin prevented the changes in LCGU in the germinal matrix and white matter that were found in the saline-pretreated animals.

Neurodevelopmental outcome of survivors with posthemorrhagic hydrocephalus following Grade II neonatal intraventricular hemorrhage.

This report describes the neurodevelopmental outcome in 12 children who developed posthemorrhagic hydrocephalus following Grade II intraventricular hemorrhage. Grade II intraventricular hemorrhage is defined as the partial filling of both lateral ventricles by intraventricular blood, documented by computed tomographic brain scan. Characteristics of the study group included a mean birth weight of 1.8 kg and a mean gestation of 32.3 weeks. Subjects were followed for three to seven years (mean, four and one-half years). Neurological evaluations were conducted prospectively. Bayley's Scales of Infant Development and McCarthy's Scales of Children's Abilities were used for the psychometric evaluations. All children were ambulatory. Only 1 had moderate spastic diplegia. Nine children (75%) had IQ scores within the normal range. The results of this prospective analysis suggest a favorable outcome for infants surviving with Grade II intraventricular hemorrhage, even with the complication of posthemorrhagic hydrocephalus.

Beagle puppy model of intraventricular hemorrhage: Ethamsylate studies

Intraventricular hemorrhage (IVH) remains a major problem of preterm neonates, and ethamsylate, an inhibitor of specific prostaglandin-synthetic enzymes has been demonstrated to prevent IVH in these patients. We have examined the effects of ethamsylate on newborn beagle pups who were, by randomized computerized design, assigned to four cells consisting of (a) either ethamsylate or saline pretreatment and (b) either insulted or not insulted with hemorrhagic hypovolemia/volume re-expansion. Prostaglandin levels were obtained prior to and thirty minutes following administration of the solutions and 14C iodoantipyrine autoradiography was performed for cerebral blood flow (CBF) determinations. Ethymsylate produced a significant decrease in the incidence of IVH in this model (p < 0.05). Following drug administration, ethamsylate-pretreated pups had significant declines in thromboxane B 2 and 6-keto PGF 1 α levels, the major breakdown products of thromboxane A 2 and prostacyclin. Although ethamsylate significantly lowered baseline CBF in all brain regions examined in insulted and non-insulted pups (p < 0.05), in the drug-treated group it did not prevent the changes seen in CBF to the germinal matrix region which were detected in the saline-pretreated pups. Nor did it significantly blunt the blood pressure changes in response to the hemorrhagic hypovolemia/volume re-expansion insult found in the latter group of animals. In addition, only ethamsylate pretreated pups had marked hypotensive responses to the reperfusion phase of the insult. Although the diminution of baseline CBF may contribute to the prevention of neonatal IVH which this drug has been demonstrated to exhibit, ethamsylate may also act as a capillary stabilizing agent.

Survival of low-birth-weight infants with neonatal intraventricular hemorrhage. Outcome in the preschool years.

Twenty-nine low-birth-weight infants who survived neonatal intraventricular hemorrhage (IVH) were followed up prospectively and were last examined at a mean age of 3 1/2 years. The mean gestational age (+/- SD) of the group was 28.9 weeks (+/- 2.4 weeks), and the mean birth weight (+/- SD) was 1,167 g (+/- 292 g). Ten patients (34%) had normal neurologic outcome, and four (14%) had minimal abnormalities. Nine children (31%) were categorized as moderately abnormal, and six (21%) had severe abnormalities on neurologic examination. Intellectual performance was normal for 14 patients (48%), mildly delayed for seven (24%), and in the retarded range for eight (28%). Twelve children (41%), at 3 years of age, had handicapping conditions severe enough to warrant admission to special education programs in the public school. The grade of IVH was related significantly to neurologic outcome; both grade of hemorrhage and birth weight were correlated significantly with need for special education. Intellectual performance was related not only to grade of hemorrhage and birth weight, but also to paternal social class.

Can obstetricians prevent neonatal intraventricular haemorrhage?

The possible influence of obstetric and early neonatal factors on the development of neonatal intraventricular haemorrhage (IVH) in very low birth-weight infants have been studied. Caesarean section was associated with a significantly lower incidence of IVH, this reduction being largely confined to infants of 25-28 weeks' gestation. Forceps delivery did not seem to influence the rate of occurrence of IVH if one allowed for differences in gestational age between infants delivered spontaneously and those with forceps. Similarly the use of an episiotomy at the time of delivery did not seem to reduce the incidence of IVH, and a similar lack of correlation was found with the other factors examined.

Beagle puppy model of intraventricular hemorrhage. Effect of indomethacin on cerebral blood flow.

The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). A study was designed to determine if indomethacin can prevent IVH and if indomethacin would produce changes in cerebral blood flow (CBF). Newborn beagle puppies were randomized by computer into two groups: one was pretreated with indomethacin, a known inhibitor of prostaglandin synthetase, and the other was saline. The dogs in both groups were then assigned either to undergo hemorrhagic hypotension/volume reexpansion insult or to receive no insult. Twenty percent of all pups receiving indomethacin and undergoing the insult experienced IVH, compared to 71% of the pups undergoing insult that had been pretreated with saline. Significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult were noted in the former group compared to the saline-pretreated pups subjected to insult. Finally, employing carbon-14 autoradiography for the determination of CBF, it was demonstrated that indomethacin decreases resting CBF of the newborn beagle pups and, in indomethacin-pretreated animals subjected to insult, prevents the increases in CBF seen in the saline-pretreated traumatized pups.

Regional cerebral blood flow in the beagle puppy model of neonatal intraventricular hemorrhage: studies during systemic hypertension.

The newborn beagle puppy serves as an animal model for intraventricular hemorrhage (IVH) of the premature infant. Since increased systemic blood pressure has been implicated in the genesis of IVH in both babies and puppies, we studied regional cerebral blood flow in control and hypertensive puppies. Hypertension significantly increased blood flow to all structures. The largest increases occurred in gray matter, especially deep cerebral and brainstem nuclei. Blood flow also increased to deep hemispheric white matter, but the magnitude of the increase was smaller. Hypertension also increased blood flow to the subependymal germinal matrix (GM). The magnitude of the increase to most of the GM was small and similar to deep hemispheric white matter. The increase to the most rostral GM was higher and equal to the mean increase seen in gray matter. This rostral-caudal gradient of hypertension-induced hyperperfusion may explain the tendency for IVH to occur in rostral GM in premature babies. However, the failure to find a disproportionate increase in blood flow to GM during hypertension implies that additional factors besides hypertension-induced GM hyperperfusion may be involved in the pathogenesis of IVH.

The role of intracranial hypotension in neonatal intraventricular hemorrhage.

Most preterm infants develop transient intracranial hypotension, which reaches its lowest level on the 2nd day of life. This corresponds to the time when most neonatal intraventricular hemorrhage (IVH) occurs. In order to test the hypothesis that intracranial hypotension may have an etiological role in the development of IVH in premature infants, the authors induced intracranial hypotension in the preterm rabbit by the intraperitoneal injection of glycerol. The rabbit model is well suited for this study because this animal is at risk of developing spontaneous germinal matrix and ventricular hemorrhage. Compared to control littermates, the glycerol-treated animals exhibited a greater than 3.5-fold incidence of germinal matrix and intraventricular hemorrhage.

Beagle puppy model of intraventricular hemorrhage

The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). By randomized computerized design, indomethacin, a known inhibitor of prostaglandin synthetase, was administered to newborn beagle puppies, all of which underwent the experimental model of hemorrhagic hypotension followed by volume reexpansion for the production of IVH, to determine whether indomethacin can prevent intraventricular hemorrhage in this model. Nine percent of all pups receiving indomethacin experienced intraventricular hemorrhage, compared with 80% of animals who received the saline vehicle. In addition, significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult were noted in this group when compared with control animals.

Computed tomographic findings of neonatal intraventricular hemorrhage.

Intraventricular hemorrhage frequently occurs in premature new-born infants, and the prognosis is usually poor. Recently, with new methods for computed tomography (CT) and ultrasonic tomography, the size of the hematoma and the degree of ventricular dilatation can be determined allowing early therapeutic management of this disease. Papile et al. (1980) classified subependymal and intraventricular hemorrhage in premature infants into four types, and reported the prognosis, especially the incidence of hydrocephalus for each type. Since the report of Goldstein et al. (1976), early treatment with repeated lumbar punctures (RLP) have been tried at several institutions. A few reports evaluating this treatment have been published. In this paper the features of CT in eighteen surviving infants with intraventricular hemorrhage are described. Early clinical management of the hemorrhage with repeated lumbar punctures is evaluated.