Ethamsylate in the prevention of periventricular-intraventricular hemorrhage in premature infants. Multicentre trial of ethamsylate for prevention of periventricular haemorrhage in very low birthweight infants. Role of ethamsylate in preventing periventricular-intraventricular hemorrhage in premature infants below 34 weeks of gestation. Ethamsylate reduces the incidence of periventricular haemorrhage in very low birth-weight babies. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. The effect of ethamsylate on neonatal mortality in preterm infants. International randomised controlled trial of acetazolamide and furosemide in posthaemorrhagic ventricular dilatation in infancy. International PHVD Drug Trial Group. A randomized, controlled trial of oral and intramuscular dexamethasone in the prevention of neonatal respiratory distress syndrome. Antenatal phenobarbital for the prevention of periventricular and intraventricular hemorrhage: a double-blind, randomized, placebo-controlled, multihospital trial.
A random and controlled trial was conducted to evaluate the efficacy and safety of ethamsylate in the prevention of periventricular-intraventricular hemorrhage (PIVH) in premature infants. Between January 1990 and July 1992, 171 premature infants with a birth weight of < 1,751 g who displayed no PIVH on initial cranial ultrasound scan, performed within an hour of delivery, were randomly divided into two groups. Group 1 consisted of 86 premature infants with a mean birth weight of 1.4 +/- 0.5 kg and a mean gestational age of 30.1 +/- 2.4 weeks. The first dose of ethamsylate 12.5 mg/kg (0.1 mL/kg from 250 mg/2mL ampoules) was given to group 1 intravenously within an hour of delivery and was followed by doses at six-hourly intervals for four days (total dose 200 mg/kg). Group 2 consisted of 85 premature infants with mean birth weight of 1.4 +/- 0.3 kg and mean gestational age of 30.4 +/- 2.2 weeks. Group 2 received 0.1 mL/kg normal saline intravenously in a similar fashion as the ethamsylate-treated group. Cranial ultrasound examinations were performed on postnatal days one, two, three, five, seven and 14. The incidence of PIVH in the ethamsylate-treated group was 24/86 (27.9%) and 39/85 (45.9%) in the control group (p < 0.02). In addition, the incidence of severe PIVH in the ethamsylate-treated group was 9/86 (10.5%) and 20/85 (23.5%) in the control group (p < 0.05). No adverse effects were attributed to ethamsylate therapy in this study. The effectiveness of ethamsylate in the prevention of periventricular haemorrhage (PVH) in very low birthweight infants was evaluated by means of a multicentre, placebo-controlled, double-blind trial. In 330 infants without evidence of PVH on initial cranial ultrasound examination there was little difference between ethamsylate and placebo groups with respect to subependymal haemorrhage, but intraventricular and parenchymal haemorrhages developed in 30/162 infants (18.5%) in the treated group, compared with 50/168 (29.8%) in the control group (p less than 0.02). The incidence of intraventricular and parenchymal haemorrhage in survivors was 20/137 (14.6%) in the ethamsylate group and 37/146 (25.3%) in the controls (p less than 0.05). In 30 infants with evidence of PVH on the initial scan, ethamsylate treatment seemed to limit parenchymal extension. Analysis of the total cohort of 360 infants showed that the proportion of infants in whom an increase of two or more grades of severity of PVH was recorded during the trial was lower in the treated than in the placebo group (p less than 0.01). No adverse effects were attributed to ethamsylate therapy. The reported incidence of patent ductus arterious was lower in the treated than in the placebo group (p less than 0.02). Mortality was similar in the two groups. To determine the role of ethamsylate in prevention of PVH-IVH in premature infants <34 weeks gestational age.
                Prospective, randomized, controlled study.
                Infants less than 34 weeks gestational age were included in the trial. Neonates with congenital malformations, family history of bleeding disorders and with Apgar scores <5 at 5 minutes were excluded. Subjects were randomized into two groups--Group A infants received intravenous ethamsylate (12.5 mg/kg) six hourly for four days and Group B infants served as a control group. Regular cranial ultrasounds to detect the presence of PVH-IVH were done between days 3-5, 10-14 and 28-30 of post natal age, and before hospital discharge in all infants and weekly in infants detected to have PVH-IVH on earlier scans. Various antenatal and postnatal factors known to affect the incidence of PVH-IVH were recorded.
                A total of 192 infants underwent the trial, 93 in Group A and 99 in Group B. Antenatal corticosteroids (1 or 2 doses) were administered to 32 ( 34.4%) and 36 (36.3%) women in Group A and Group B, respectively. None of the mothers received phenobarbitone, vitamin K or indomethacin antenatally and none of the infants received phenobarbitone, vitamin E or indomethacin postnatally during the study period. PVH-IVH was seen in 26 infants in Group A, of which Grade I IVH occurred in 9, Grade II in 14, Grade III in 2 and Grade IV in one infant. Twenty-nine infants had PVH-IVH in Group B of which 11 had Grade I, 15 Grade II and 3 Grade III. None of the differences were statistically significant.
                Postnatal administration of ethamsylate did not decrease the incidence of PVH-IVH in the study infants. nan Preterm neonates are exposed to multiple painful procedures after birth and exhibit acute physiological responses to pain. Occurrence of early intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intraventricular hemorrhage and periventricular leukomalacia. We proposed that such neurologic outcomes in preterm neonates who require ventilatory support may be reduced by morphine analgesia or midazolam sedation compared with a placebo.
                To define the incidence of clinical outcomes in the target study population, to estimate the effect size and adverse effects associated with analgesia and sedation, and to calculate the sample size for a definitive test of this hypothesis.
                Sixty-seven preterm neonates were randomized in a pilot clinical trial from 9 centers. Neonates of 24 to 32 weeks gestation were eligible if they had been intubated and required ventilatory support for less than 8 hours and if they were enrolled within 72 hours after birth. Exclusion criteria included major congenital anomalies, severe intrapartum asphyxia, and participation in other research studies. Severity of illness was assessed by the Clinical Risk Index for Babies, and neonates were randomized to receive continuous infusions of morphine sulfate, midazolam hydrochloride, or 10% dextrose (placebo). Masked study medications were continued as long as clinically necessary, then weaned and stopped according to predefined criteria. Levels of sedation (COMFORT scores) and responses to pain (Premature Infant Pain Profile scores) were measured before, during, and 12 hours after discontinuation of drug infusion. Cranial ultrasound examinations were performed as part of routine practice, and poor neurologic outcomes were defined as neonatal death, severe intraventricular hemorrhage (grade III or IV), or periventricular leukomalacia.
                No significant differences occurred in the demographic, clinical, and socioeconomic variables related to mothers and neonates in the 3 groups or in the severity of illness at birth as measured by Clinical Risk Index for Babies scores. Two neonates in the placebo group and 1 neonate in the midazolam group died; no deaths occurred in the morphine group. Poor neurologic outcomes occurred in 24% of neonates in the placebo group, 32% in the midazolam group, and 4% in the morphine group (likelihood ratio chi2 = 7.04, P = .03). Secondary clinical outcomes and neurobehavioral outcomes at 36 weeks' postconceptional age were similar in the 3 groups. Responses elicited by endotracheal tube suction (Premature Infant Pain Profile scores) were significantly reduced during the morphine (P<.001) and midazolam (P = .002) infusions compared with the placebo group.
                This pilot trial suggests that preemptive analgesia given by continuous low-dose morphine infusion may reduce the incidence of poor neurologic outcomes in preterm neonates who require ventilatory support. Limitations in the sample size of this pilot study suggest that these results should be confirmed in a large multicenter randomized trial. nan Furosemide and acetazolamide are widely used in the treatment of posthaemorrhagic ventricular dilatation (PHVD) in the hope of avoiding the need for surgical management, but this approach has not been evaluated in a controlled trial. This multicentre randomised controlled trial tested the hypothesis that these drugs would reduce the rate of shunt placement and increase disability-free survival at 1 year of age.
                Between 1992 and 1996, 177 infants aged less than 3 months past term, and with ventricular width more than 4 mm above 97th centile after intraventricular haemorrhage, were randomly assigned standard therapy alone or standard therapy plus treatment with acetazolamide (100 mg/kg daily) and furosemide (1 mg/kg daily). A minimisation algorithm ensured balance between groups with respect to both referral centre and the presence of a cerebral parenchymal lesion on cerebral ultrasonography at enrolment. The trial was stopped in September, 1996, because the data showed a clear advantage with standard therapy.
                We report outcomes for 151 infants whose expected date of delivery was before the end of 1995, with complete information at 1 year for 129 infants. The median gestational age was 28 weeks, mean birthweight 1299 g, and mean postnatal age at enrolment 25 days. 44% had a parenchymal lesion at randomisation. Death or shunt placement occurred in 49 of 75 infants allocated drugs plus standard therapy, compared with 35 of 76 allocated to standard therapy alone. The relative risk was 1.42 (95% CI 1.06-1.90; p=0.026), which is equivalent to one extra death or shunt placement for every five infants allocated drug therapy. 84% (52/62) of infants assigned drug therapy had died or were disabled or impaired at 1 year, compared with 60% (40/67) of those assigned standard therapy (relative risk 1.40 [1.12-1.76]; p=0.012).
                These preliminary results suggest that the use of acetazolamide and furosemide in preterm infants with PHVD is associated with a higher rate of shunt placement and increased neurological morbidity, and so cannot be recommended. The study's objective was to compare the efficacies of oral and intramuscular antenatal administration of dexamethasone in reducing neonatal respiratory distress syndrome.
                Subjects at high risk for preterm delivery between 24 and 33 weeks' gestation were prospectively randomly assigned to receive either 6 mg intramuscular dexamethasone or 8 mg oral dexamethasone every 12 hours for 4 doses. The regimen was repeated weekly until 34 weeks' gestation if delivery had not yet occurred. A blinded data review was performed. The primary outcome of the trial was respiratory distress syndrome. Data were analyzed in an intent to treat fashion. Comparisons were made with an unpaired t test, chi2 or Fisher exact test, and survival analysis. P <.05 was considered significant.
                The study was discontinued at 39% enrollment after a blinded review of available outcomes. A total of 170 women with 188 fetuses were randomly assigned. The oral and intramuscular groups had similar mean gestational ages at enrollment (29.9 weeks vs 29.2 weeks) and similar median latencies (9.5 vs 10 days). No difference in the frequency of respiratory distress syndrome was found between the oral and intramuscular groups, (34.3% vs 29.8%). Neonatal sepsis (10.1% vs 1.2%, P =.01) and intraventricular hemorrhage (10.1% vs 2. 4%, P =.04) were significantly higher in the oral group. There were no statistical differences in the frequencies of necrotizing enterocolitis or neonatal death. A subgroup analysis of 112 patients who were delivered at <34 weeks' gestation revealed no statistical difference in respiratory distress syndrome between the groups; however, oral dexamethasone was associated with a significant increase in sepsis (15.9% vs 1.6%, P =.009) and intraventricular hemorrhage (15.9% vs 3.3%, P =.03).
                Oral administration increases neonatal morbidity without demonstrable benefit and should not at this time be used clinically for induction of fetal pulmonary maturation. To determine whether the neuroprotective properties of phenobarbital would alter the incidence and severity of intracranial hemorrhage in premature infants, we randomly assigned 110 women at less than 31 weeks of gestation to receive 10 mg/kg phenobarbital or placebo in a blinded fashion before delivery. Infants were examined postnatally with real-time ultrasonography for evidence of intracranial hemorrhage. Maternal demographics, pregnancy complications, antenatal management, and route of delivery did not differ between the phenobarbital group (n = 50) and the placebo group (n = 60). The total incidence of periventricular-intraventricular hemorrhage did not differ between the phenobarbital-treated (n = 54) and the placebo-treated (n = 67) infants. However, the frequency of grade 3 and grade 4 hemorrhages was 15% (10 infants) in the placebo group and 3.7% (2 infants) in the phenobarbital group (p less than 0.05). There were no differences in the severity of associated conditions in the babies to explain the difference in the incidence of severe hemorrhage between the study groups. We conclude that antenatal administration of phenobarbital appears to be effective in decreasing the severity of periventricular-intraventricular hemorrhage in infants delivered at less than 31 weeks of gestation.
Preterm infants treated with ethamsylate showed no reductions in mortality or neurodevelopmental impairment despite the reduction in any grade of intraventricular haemorrhage seen in infants < 35 weeks gestation.