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.
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
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.