Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus

doi:10.1016/S0022-3476(97)70060-X

The Journal of Pediatrics

Volume 131, Issue 4, October 1997, Pages 549-554

https://doi.org/10.1016/S0022-3476(97)70060-X Get rights and content

Abstract

Objective: To compare the effects on cerebral perfusion and oxygenation of intravenous ibuprofen and indomethacin as treatment for patent ductus arteriosus in preterm infants.

Study design: Sixteen infants receiving mechanical ventilation (< 31 weeks gestation) with patent ductus arteriosus received either 0.2 mg/kg indomethacin ( n = 8) or 10 mg/kg ibuprofen ( n = 8) infused over 1 minute. Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidized cytochrome oxidase concentration. Cerebral blood flow velocity in the pericallosal artery was measured using Doppler ultrasonography.

Results: Indomethacin caused a significant reduction of CBV (maximal changes in cerebral blood volume: −320 ± 171 μL/100 gm) and, in four of eight patients, a fall in oxidized cytochrome oxidase concentration (maximal change in oxidized cytochrome oxidase concentration in the eight patients: −0.68 ± 0.98 μmol/L, NS). Cerebral blood flow velocity fell significantly. Ibuprofen caused no significant reduction of cerebral blood volume, oxidized cytochrome oxidase concentration, or cerebral blood flow velocity, whereas a significant increase of cerebral blood volume (+207 ± 200 μL/100 gm) was observed after 60 minutes. Ductus closure was seen in six of eight infants after the first dose of indomethacin and in five of eight infants after the first dose of ibuprofen. The therapeutic cycle involved administration of a second and third dose, provided no side effects occurred. Treatment was effective in all infants.

Conclusion: Compared with indomethacin, treatment with ibuprofen does not significantly reduce cerebral perfusion and oxygen availability; the observed increase in cerebral blood volume requires further investigation. ( J Pediatr 1997;131:549-54)

Section snippets

Patients

We included preterm infants of gestational age less than 32 weeks, who were mechanically ventilated for respiratory distress syndrome, had echocardiographic evidence of hemodynamically significant PDA (left atrium/aortic root diameter ratio >1.4), ²⁶ and had normal renal echographic appearance in the study. The presence of congenital malformations, intraventricular hemorrhage of grade 2 or higher according to the classification of Papile et al., ²⁷ or platelet count less than 50,000/mm ³ were

Patients

Sixteen preterm infants were studied. Eight patients (five male and three female) of gestational age 28 weeks (range, 25 to 30), birth weight 820 gm (range, 600 to 1390), and postnatal age 29 hours (range, 5 to 120) were treated with indomethacin; eight infants of 29 weeks gestational age (range, 27 to 31), 855 gm birth weight (range, 620 to 1620), 24 hours postnatal age (range, 10 to 53), four males and four females, were treated with ibuprofen. No significant differences in gestational age,

Discussion

The results of our study support the hypothesis that pharmacologic closure of the ductus arteriosus with ibuprofen does not significantly reduce cerebral perfusion in contrast to indomethacin. Doppler sonographic results of our study agree with previous findings, 12, 13, 14, 15 indicating a reduction of CBF velocity after rapid indomethacin administration in preterm infants with PDA, ranging from 25% to 60% and lasting at least 120 minutes. The concordance of the results of a clinical ¹³³ Xenon

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In full-term infants, obliteration of the ductus arteriosus (DA) takes place through a process of vasoconstriction and anatomic remodeling after birth. In contrast, preterm newborn infants frequently fail to close their DA. Factors that play a prominent role in DA regulation involve those that promote constriction of the ductus (e.g., oxygen, endothelin, Ca²⁺ channels, catecholamines, and Rho kinase), those that oppose it (e.g., intraluminal pressure, prostaglandins, nitric oxide, carbon monoxide, potassium channels, and cyclic adenosine monophosphate [AMP] and cyclic guanosine monophosphate [GMP]), and those that regulate ductus smooth muscle hypoxia, neointimal mound formation, and smooth muscle cell death. The relative importance of each of these factors depends on the intrauterine and extrauterine environment, the degree of ductus maturation, and the genetic background and species being studied. The clinical consequences of a patent ductus arteriosus (PDA) are related to the magnitude of the left-to-right shunt through the PDA, the cardiac and vascular responses to the shunt, and the associated changes in blood flow to the lungs, kidneys, intestine, and brain. Controlled clinical trials demonstrate that a moderate-to-large PDA increases the incidence of severe pulmonary hemorrhage and systemic hypotension during the first week as well as the need for higher levels of ventilator support at the end of the first week. However, controversy exists about the consequences of exposure to a persistent moderate-to-large PDA shunt for greater than 1 week. Further investigations will be needed to determine which infants are likely to benefit from early PDA treatment and which infants might best be left untreated while awaiting spontaneous ductus closure.
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Managing fluids, electrolytes, and acid–base status is arguably one of the most important skills of the neonatal clinician. First, this chapter describes the physiology and pathophysiology of fluid and electrolyte homeostasis from fetal through neonatal life, including the impact of the most relevant hormones and the changes that occur with maturation of the different organ systems. Next, the specific diagnostic approaches to assess the fluid and electrolyte status and its disturbances are discussed, followed by management guidelines. Since a number of clinical conditions are associated with fluid and electrolyte disturbances, the next section describes the relationship of fluid and electrolyte homeostasis with extreme prematurity, transient tachypnea of the newborn, respiratory distress syndrome, bronchopulmonary dysplasia, patent ductus arteriosus, the syndrome of inappropriate antidiuretic hormone, and selected surgical conditions. In the final section, the acid–base status in health and disease is discussed. Understanding the physiology of acid–base homeostasis and the changes taking place during development, particularly during the transition from fetal to neonatal life is critical. In the closing part of the final section, the different forms of acidosis and alkalosis associated with the most frequently encountered pathological conditions are reviewed and treatment guidelines are discussed.
Efficacy and safety of pharmacological treatments for patent ductus arteriosus closure: A systematic review and network meta-analysis of clinical trials and observational studies
2019, Pharmacological Research
Efficacy and safety profiles of different pharmacological interventions used to treat patent ductus arteriosus (PDA) are relatively unexplored. Integrating the findings of randomized clinical trials (RCTs) with those from observational studies may provide key evidence on this important issue.
We aimed at estimating the relative likelihood of failure to close the PDA, need for surgical closure, and occurrence of adverse events among preterm and full-term infants treated with indomethacin, ibuprofen, or acetaminophen, placebo, or no treatment including both RCTs and observational studies.
We searched PubMed, Embase, and the Register of Controlled Trials from inception to October 30, 2018. We first estimated proportions of subjects with failure to close the PDA, subjects in whom surgical closure was performed after pharmacological treatment, death, and subjects with selected adverse events (AEs). These estimates were obtained using frequentist random-effect meta-analysis of arm-specific proportions. We then compared active drugs with each other and with control (either placebo or no treatment) by summarizing results at the end of treatment reported in the papers, regardless of number of administration(s), dose, route and type of administration, and study design and quality. We also summarized primary outcome results separately at first, second and third cycles of treatment. These estimates were obtained using Bayesian random-effects network meta-analysis for mixed comparisons, and frequentist random-effect pairwise meta-analysis for direct comparisons.
We included 64 RCTs and 24 observational studies including 14,568 subjects (5339 in RCTs and 9229 in observational studies, 8292 subjects received indomethacin, 4761 ibuprofen, 574 acetaminophen, and 941 control (including placebo or no intervention).The proportion of subjects with failure to close the PDA was 0.24 (95% Confidence Interval, CI: 0.20, 0.29) for indomethacin, 0.18 (0.14, 0.22) for ibuprofen, 0.19 (0.09, 0.30) for acetaminophen, and 0.59 (0.48, 0.69) for control. At end of treatment, compared to control, we found inverse associations between all active drugs and failure to close PDA (for indomethacin Odds Ratio, OR, was 0.17 [95% Credible Interval, CrI: 0.11-0.24], ibuprofen 0.19 [0.12-0.28], and acetaminophen 0.15 [0.09-0.26]), without differences among active drugs. We showed inverse associations between effective drugs and need for surgical closure, as compared to control (for indomethacin OR was 0.28 [0.15-0.50], ibuprofen 0.30 [0.16-0.54], and acetaminophen 0.19 [0.07-0.46]), without differences among drugs. Indomethacin was directly associated with intraventricular hemorrhage (IVH) (1.27; 1.00, 1.62) compared to ibuprofen, and to oliguria as compared to ibuprofen (3.92; 1.69, 9.82) or acetaminophen (10.8; 1.86, 93.1). In conclusion, active pharmacological treatment, with indomethacin, ibuprofen, or acetaminophen, is inversely associated with failure to close the PDA compared to non-treatment. Ibuprofen should be preferred to indomethacin to avoid occurrence of IVH or oliguria, acetaminophen should be preferred to indomethacin to avoid oliguria.
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^☆: Reprint requests: Fabio Mosca, MD, Patologia Neonatale, Clinica “Mangiagalli,” via Commenda 12, 20122, Milano, Italy.

^☆☆: 9/21/80254

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Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus☆,☆☆

Abstract

Section snippets

Patients

Patients

Discussion

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Lancet

Lancet

J Pediatr

Biochem Biophys Res Comm

The vasoactivity of the fetal lamb ductus arteriosus studied in utero

Pediatr Res

Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study

J Pediatr

Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants

Pediatrics

Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial

Pediatrics

Response of the cerebral circulation in baboons to changing perfusion pressure after indomethacin

Circ Res

The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at normal and increased carbon dioxide tension

Acta Physiol Scand

Cerebral blood flow responses to indomethacin in awake newborn pigs

Pediatr Res

Effects of indomethacin on cerebral blood flow velocity of premature newborns

Biol Neonate

Cerebral blood flow velocity changes in preterm infants after a single dose of indomethacin: duration of its effects

Pediatrics

Cerebral blood flow following indomethacin administration

Dev Pharmacol Ther