Early Indomethacin Research Articles

Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome

Objective: To compare efficacy and side effects of early versus late indomethacin treatment for patent ductus arteriosus (PDA) in premature infants. Methods: One hundred twenty-seven neonates receiving ventilatory assistance (gestational age: 26-31 weeks) with PDA confirmed by echocardiography were randomly assigned in a prospective multicenter trial to either early (day 3, n = 64) or late (day 7, n = 63) intravenous indomethacin treatment (3 × 0.2 mg/kg every 12 hours). Treatment history and side effects were registered. Results: The PDA closure rate was higher in the early treatment group at both 6 (73% vs 44%, P =.0008) and 9 days of age (91% vs 78%, P =.047). However, there was no significant difference in PDA ligation. Urine output was significantly lower (P <.0001), serum creatinine level was higher (P =.016), and more indomethacin courses were administered in the early treatment group (70 vs 26). Respiratory support, number of deaths, and intraventricular hemorrhages were similar in both groups. However, on the whole, major adverse events (death, necrotizing enterocolitis, and/or localized perforation, extension of hemorrhage, or cystic leukomalacia) occurred more frequently in the early treatment group (P =.017). Conclusion: Early indomethacin treatment improves PDA closure but is associated with increased renal side effects and more severe complications and has no respiratory advantage over late indomethacin administration in ventilated, surfactant-treated, preterm infants <32 weeks’ gestational age. (J Pediatr 2001;138:205-11)

Is Indomethacin Harmful in Spinal Cord Injury Treatment?

This study was designed to analyze the effect of early indomethacin on the lipid peroxidation after spinal cord injury in rats. The use of anti-inflammatory drugs to affect delayed and secondary injury after trauma to the spinal cord has now become a matter of standard clinical practice. However, spinal cord injury remains an enormous clinical problem and research that may lead to improved treatment is to be encouraged and commended. Three experimental groups consisting of 40 rats each were formed. Using microsurgical technique, total laminectomy between T5 and T10 was performed. Spinal cord injury was achieved with an epidural aneurysm clip, and pharmacological treatment immediate after the injury was performed by injecting indomethacin intraperitoneally (i.p.) at a dose of 3 mg/kg to indomethacin-treated group. The three main groups were divided into subgroups of 8 rats each. It was planned to stop the biochemical reactions at a different time in each of these subgroups, by the application of liquid nitrogen to the spinal cord and paravertebral structures at the end of the 1st, 15th, 30th, 60th, and 90th minutes. All the spinal cords were removed and protected from further reactions by immersing in the liquid nitrogen tank. The lipid peroxidation levels were assessed by determining thiobarbituric acid reactive substances formation. The results of the study showed that the administration of 3 mg/kg indomethacin immediately after spinal cord injury induces lipid peroxidation to a significant degree (p < 0.05 one-way ANOVA and Tukey HSD tests) when compared to the saline-treated group. This result suggests that early posttraumatic indomethacin treatment may be harmful in spinal cord injury.

Focal reduction of villous blood flow in early indomethacin enteropathy: a dynamic vascular study in the rat

Background—Oral indomethacin causes villous shortening, microvascular damage, and distortion, which might induce mucosal ischaemia and necrosis.Aims—In order to determine the early events in indomethacin induced jejunal injury we examined the...

Vascular anatomy defines sites of indomethacin induced jejunal ulceration along the mesenteric margin

Background—Indomethacin induces ulceration in the rat jejunum with sparing of the ileum. The ulcers localise between vasa recta along the mesenteric margin of the bowel, observations that have not been...

Evidence for tumor necrosis factor α as a mediator of the toxicity of a cyclooxygenase inhibitor in Gram-negative sepsis

To investigate the effect of cyclooxygenase inhibition in experimental Gram-negative sepsis, indomethacin was administered to mice at different times (1 or 5 days, or 1 h) before sublethal infection with an intravenous inoculum of Pseudomonas aeruginosa. Early indomethacin exposure did not alter the outcome of infection, yet treatment at the time of bacterial challenge resulted in a high mortality rate. Polymerase chain reaction-assisted mRNA amplification in the spleens of infected mice revealed that tumor necrosis factor α (TNF-α) messenger was selectively expressed by the drug-treated and infected mice during the 24 h preceding death. Higher TNF-α levels were found in sera from these mice, whose macrophages produced increased levels of nitric oxide in vitro. Both pentoxifylline, an inhibitor of TNF-α synthesis, and an inhibitor of nitric oxide production improved survival in the indomethacin-treated and infected mice, although no such effect followed the administration of TNF-neutralizing antibodies. These data support the notion that cyclooxygenase inhibitors may exert both positive and negative effects in Gram-negative sepsis, the latter presumably involving overproduction of TNF-α.

Prophylactic Indomethacin for Prevention of Intraventricular Hemorrhage in Premature Infants

The impact of early prophylactic use of intravenous indomethacin on the incidence and severity of periventricular-intraventricular hemorrhage and patent ductus arteriosus in 199 oxygen-requiring premature infants (less than or equal to 1300 g birth weight) was prospectively investigated. The trial was controlled, the infants were randomized, and the investigators were unaware of the group assignments. Patients with minimal (grade I) or no periventricular-intraventricular hemorrhage determined by prestudy echoencephalography were randomized within two birth weight subgroups (500 to 899 and 900 to 1300 g) to receive either prophylactic indomethacin (n = 99) or an equal volume of saline-vehicle placebo (n = 100). The first dose (0.2 mg/kg) was given within 12 hours of delivery and two subsequent doses (0.1 mg/kg) were administered at 12 hourly intervals. Prophylactic indomethacin significantly reduced the incidence of grades II to IV periventricular-intraventricular hemorrhage. Intraventricular hemorrhage was half as common in infants given prophylactic indomethacin as in control infants (23% v 46%, P less than .002). The reduction was manifested in both birth weight subgroups. Results of this study also confirmed a lower incidence of clinically significant patent ductus arteriosus in infants who received prophylactic indomethacin in contrast to those who received placebo (11% v 42%, P less than .001). No significant differences were found between treatment and control groups in the duration of oxygen therapy, mechanical ventilation, or hospitalization or in the incidence of pneumothorax, chronic lung disease, sepsis, necrotizing enterocolitis, retinopathy of prematurity, or death. Early prophylactic indomethacin initiated within 12 hours of delivery is effective in reducing the incidence of intraventricular hemorrhage as well as clinically significant patent ductus arteriosus in very low birth weight premature infants.

406 PROPHYLACTIC INDOMETHACIN: EFFECTS ON RENAL FUNCTION

This controlled, double-blind, study assessed the renal impact of early (< 12 hr postnatal age) indomethacin [I], for prevention of patent ductus arteriosus (PDA), in O2 dependent inborn infants with birth weights (BW)≤1300 gm. Fifty infants randomly received 3 IV doses of [I] or placebo [P] at 12 hr intervals. Dose1 (D1) was 0.2 mg/kg;D2 and D3 were 0.1 mg/kg each. Fluid balance, serum sodium (Na), potassium (K), creatinine (Cr), blood urea nitrogen (BUN) and fractional Na excretion (FENa) were evaluated pre-D1, 6-12 hr post-D1, 12-36 hr post-D3, and 1 wk post-D3. Timed urine specimens were used to derive Cr clearance (CCr) post-D3 and 1 wk post-D3. The 25 infants in each group were comparable in BW, gestational age, APGARs, pH and base excess at study entry. [I]-treated infants had reduced urine output (UO) in the 12 hr period following D1 that was no longer evident post-D3. Fluid intake, Na, K, BUN, Cr, FENa, and CCF were similar throughout the study. Renal data (x±SEM) revealed: In contrast to reports of renal dysfunction induced by indomethacin therapy for symptomatic PDA, early [I] appears to alter renal function minimally in prematures without significant PDA.

Early indomethacin in patent ductus of the very small premature.

ABSTRACT. Thirty-six babies below 1500g birth weight with patent ductus arteriosus were treated orally with indomethacin, for symptomatic reasons on 30 occasions and prophylactically on 44. Closure was significantly more frequent before 12.5 days of age and when treatment was given with 48 hours of development of clinical signs. Independently of age at treatment it was five times more successful when given within 48 hours of signs developing than when given later. Babies below 1000g birth weight responded as well as those above. Responsiveness did not appear to depend on individual idiosyncrasy. The approach described was aimed to minimise the contribution of a patent ductus to the dangerous recurrent apnoea of the very low birth weight infant. The use of indomethacin in the patent ductus arteriosus (PDA) of prematurity has been widely reported1,2. The lesion has a close relationship both to the degree of immaturity and to the presence of hyaline membrane disease (HMD)3–5. Reports in the literature deal mainly with this combination. However, it is also common in babies of very low birth weight who do not have HMD. Pharmacological treatment has been emphasised as a first line in management6,7, and evidence suggests it is more likely to succeed when given earlier rather than later after birth8. The published indications for treatment remain broadly those of deteriorating symptoms for which ligation might have otherwise been recommended. The present report compares that approach with treatment at an earlier stage.

Improved Lung Compliance following Indomethacin Therapy in Premature Infants with Persistent Ductus Arteriosus

In the course of a double-blind controlled study of intravenous indomethacin therapy in premature infants with patent ducts arteriosus (PDA), dynamic lung compliance (CL) was determined in 11 infants (six control, five indomethacin) who were not on assisted ventilation during the study period. The clinical, biochemical and laboratory data before the study were comparable between the groups. Following therapy with indomethacin there was a significant decrease in left atrial/aortic root ratio (LA/Ao), left ventricular end-diastolic dimension (LVEDD) on echocardiogram, and an increase in tidal volume (VT) and CL. In the control group, these variables did not change significantly. The improved lung compliance following early indomethacin closure of PDA may alter the clinical course and outcome of these premature infants.