Treatment of patent ductus arteriosus in very preterm infants in China / 中华儿科杂志

Objective: To describe the current status and trends in the treatment of patent ductus arteriosus (PDA) among very preterm infants (VPI) admitted to the neonatal intensive care units (NICU) of the Chinese Neonatal Network (CHNN) from 2019 to 2021, and to compare the differences in PDA treatment among these units. Methods: This was a cross-sectional study based on the CHNN VPI cohort, all of 22 525 VPI (gestational age<32 weeks) admitted to 79 tertiary NICU within 3 days of age from 2019 to 2021 were included. The overall PDA treatment rates were calculated, as well as the rates of infants with different gestational ages (≤26, 27-28, 29-31 weeks), and pharmacological and surgical treatments were described. PDA was defined as those diagnosed by echocardiography during hospitalization. The PDA treatment rate was defined as the number of VPI who had received medication treatment and (or) surgical ligation of PDA divided by the number of all VPI. Logistic regression was used to investigate the changes in PDA treatment rates over the 3 years and the differences between gestational age groups. A multivariate Logistic regression model was constructed to compute the standardized ratio (SR) of PDA treatment across different units, to compare the rates after adjusting for population characteristics. Results: A total of 22 525 VPI were included in the study, with a gestational age of 30.0 (28.6, 31.0) weeks and birth weight of 1 310 (1 100, 1 540) g; 56.0% (12 615) of them were male. PDA was diagnosed by echocardiography in 49.7% (11 186/22 525) of all VPI, and the overall PDA treatment rate was 16.8% (3 795/22 525). Of 3 762 VPI who received medication treatment, the main first-line medication used was ibuprofen (93.4% (3 515/3 762)) and the postnatal day of first medication treatment was 6 (4, 10) days of age; 59.3% (2 231/3 762) of the VPI had been weaned from invasive respiratory support during the first medication treatment, and 82.2% (3 092/3 762) of the infants received only one course of medication treatment. A total of 143 VPI underwent surgery, which was conducted on 32 (22, 46) days of age. Over the 3 years from 2019 to 2021, there was no significant change in the PDA treatment rate in these VPI (P=0.650). The PDA treatment rate decreased with increasing gestational age (P<0.001). The PDA treatment rates for VPI with gestational age ≤26, 27-28, and 29-31 weeks were 39.6% (688/1 737), 25.9% (1 319/5 098), and 11.4% (1 788/15 690), respectively. There were 61 units having a total number of VPI≥100 cases, and their rates of PDA treatment were 0 (0/116)-47.4% (376/793). After adjusting for population characteristics, the range of standardized ratios for PDA treatment in the 61 units was 0 (95%CI 0-0.3) to 3.4 (95%CI 3.1-3.8). Conclusions: From 2019 to 2021, compared to the peers in developed countries, VPI in CHNN NICU had a different PDA treatment rate; specifically, the VPI with small birth gestational age had a lower treatment rate, while the VPI with large birth gestational age had a higher rate. There are significant differences in PDA treatment rates among different units.

Qual Deve Ser o Tratamento de Primeira Linha para o Fechamento de Persistência de Canal Arterial Hemodinamicamente Significativo em Bebês Prematuros? / What Should be the First-line Treatment for the Closure of Hemodynamically Significant Patent Ductus Arteriosus in Premature Infants?

Resumo Fundamento É importante saber qual medicamento usar como tratamento de primeira linha para fechar o duto. Objetivos O objetivo deste estudo é comparar a eficácia e os efeitos colaterais das formas intravenosas (IV) de ibuprofeno e paracetamol e contribuir para a literatura investigando o primeiro medicamento selecionado no tratamento clínico da persistência do canal arterial (PCA). Métodos Nosso estudo foi realizado entre janeiro de 2017 e dezembro de 2019. Foram incluídos no estudo bebês prematuros com peso ao nascer (PN) ≤1500 g e idade gestacional (IG) ≤32 semanas. No período do estudo, todos os bebês com persistência do canal arterial hemodinamicamente significativa (hsPCA) receberam ibuprofeno intravenoso (IV) como resgate como tratamento clínico primário ou tratamento com paracetamol IV se houvesse contraindicações para o ibuprofeno. Os pacientes foram divididos em dois grupos: pacientes que receberam ibuprofeno IV e pacientes que receberam paracetamol IV. Resultados Desses pacientes, 101 receberam paracetamol IV e 169 receberam ibuprofeno IV. A taxa de sucesso do fechamento da PCA com o primeiro curso do tratamento foi de 74,3% no grupo de paracetamol IV e 72,8% no grupo de ibuprofeno IV (p=0,212). Conclusões Nossos resultados mostram que o paracetamol IV é tão eficaz quanto o ibuprofeno IV no tratamento de primeira linha de hsPCA, podendo se tornar o tratamento preferencial para o controle de hsPCA.

Abstract Background It is important which medicine to use as a first-line treatment to close the duct. Objectives The aim of this study is to compare the effectiveness and side effects of intravenous (IV) forms of ibuprofen and paracetamol and to contribute to the literature investigating the first drug selected in the medical treatment of patent ductus arteriosus (PDA). Methods Our study was conducted between January 2017 and December 2019. Premature infants with birth weight (BW) ≤1500 g and gestational age (GA) ≤32 weeks were included in the study. In the study period, all infants with hemodynamically significant patent ductus arteriosus (hsPDA) were given rescue intravenous (IV) ibuprofen as a primary medical treatment or IV paracetamol treatment if there were contraindications for ibuprofen. The patients were divided into two groups: patients receiving IV ibuprofen and patients receiving IV paracetamol. Results Of these patients, 101 were given IV paracetamol and 169 were given IV ibuprofen. The success rate of PDA closure with first-course treatment was 74.3% in the IV paracetamol group and 72.8% in the IV ibuprofen group (p=0.212). Conclusions Our results show that IV paracetamol is as effective as IV ibuprofen in the first-line treatment of hsPDA, and can become the preferred treatment for the management of hsPDA.

Patent ductus arteriosus closure: experience from a tertiary referral center / Experiência de uma maternidade terciária no fechamento do canal arterial patente

ABSTRACT Objective: To characterize the number and methods of closure of Persistent Ductus Arteriosus (PDA) over a span of 16 years in a third level maternity hospital. Methods: Retrospective study of neonates born between January 2003 and Deccember 2018, who underwent ductus arteriosus closure by pharmacological, surgical and/or transcatheter methods. Gestational age, birth weight, number and methods of closures per year were evaluated. The success rate of the pharmacologic method was calculated, as well as the mortality rate. The association between mortality and birthweight, treatment used and treatment failure was explored. Results: There were 47,198 births, 5,156 were preterm, 325 presented PDA and 106 were eligible for closure (median gestational age - 27 weeks, birthweight <1000 g - 61%). Frequency of PDA closure decreased during the study period, especially starting in 2010. Success rate with pharmacologic treatment was 62% after the first cycle and 74% after the second. After drug failure, 12 underwent surgical ligation and two underwent transcatheter closure. Exclusive surgical ligation was indicated in four infants. Ibuprofen replaced indomethacin in 2010, and acetaminophen was used in three infants. Among the 106 infants, hospital mortality was 12% and it was associated with birthweight <1000 g (13/65 <1000 vs. 0/41 >1000 g; p=0.002) and with failure in the first pharmacologic treatment cycle (13/27 with failure, vs. 0/75 without failure; p<0.001). Conclusions: The national consensus published in 2010 for the diagnosis and treatment of PDA in preterm infants led to a decrease in the indication for closure. Pharmacological closure was the method of choice, followed by surgical ligation. Birthweight <1000 g and first cycle of pharmacologic treatment failure were associated with higher mortality.

RESUMO Objetivo: Caraterizar o número e métodos de fechamento de canal arterial durante 16 anos numa maternidade de nível terciário. Métodos: Estudo retrospetivo de nascidos entre 01 de janeiro de 2003 a 31 de dezembro de 2018 submetidos a fechamento do canal arterial por métodos farmacológico, cirúrgico e/ou percutâneo. Avaliaram-se idade gestacional, sexo, peso ao nascimento, número de fechamentos por ano e método utilizado. Aferiram-se as taxas de sucesso de método farmacológico e de mortalidade e sua associação com peso ao nascer, fármaco utilizado e insucesso do fechamento. Resultados: Verificaram-se 47.198 recém-nascidos, 5.156 prematuros, dos quais 325 com canal arterial patente, sendo 106 com indicação para fechamento (idade gestacional mediana 27 semanas, peso <1000 g em 61%). Verificou-se diminuição do número de fechamentos ao longo dos anos, sobretudo a partir de 2010. O fechamento ocorreu em 62% após primeiro ciclo de tratamento farmacológico e em 74% após segundo. Após insucesso farmacológico, 12 realizaram ligadura cirúrgica e dois, fechamento percutâneo. Houve indicação de ligadura cirúrgica exclusiva em quatro. O ibuprofeno substituiu a indometacina em 2010. O acetaminofen foi usado em três doentes. A mortalidade nos 106 pacientes foi de 12%, associando-se ao peso ao nascer (13/65 <1000 vs. 0/41 >1000 g; p=0,002) e à falha do primeiro ciclo de tratamento farmacológico (13/27 com falha vs. 0/75 com sucesso; p<0,001). Conclusões: Consenso nacional de 2010 para diagnóstico e tratamento do canal arterial nos prematuros levou à diminuição do número de fechamentos desse canal. O fechamento farmacológico foi o método mais utilizado, seguido da ligadura cirúrgica. Peso <1000 g e falha no primeiro ciclo de fechamento farmacológico se associaram à maior mortalidade.

Complicaciones digestivas y renales por indometacina e ibuprofeno en prematuros extremos con ductus arterioso permeable / Digestive and Kidney Complications by indomethacin and ibuprofen in extreme preterm infants with patent ductus arteriosus

El ductus arterioso permeable sintomático (DAPs) es frecuente en prematuros extremos (PE), siendo importante su cierre para disminuir la repercusión hemodinámica. Para ello se usa indometacina o ibuprofeno con los riesgos subyacentes. OBJETIVO: Caracterizar las complicaciones digestivas y renales en PE tratados por DAPs. PACIENTES Y MÉTODO: Estudio retrospectivo en PE nacidos entre enero de 2004 y diciembre de 2013. Según diagnóstico se distribuyeron en 3 grupos: sin DAPs, con DAPs tratados con indometacina y con ibuprofeno. Se excluyeron PE con otras complicaciones graves. Se evaluaron complicaciones digestivas y renales graves. Se usó significación estadistica con p ≤ 0,05. RESULTADOS: Se enrolaron 599 PE; 33,1% recibió tratamiento por DAPs, 66,9% no lo requirió. Hubo asociación estadística entre DAPs y menor edad gestacional, depresión neonatal y distrés respiratorio. Del grupo no tratado, el 5% presentó enterocolitis y el 0,25% falla renal; entre los tratados el 2,5% presentó enterocolitis y el 1,0% falla renal. No hubo diferencias estadísticas significativas considerando ambas complicaciones (p = 0,17), sólo enterocolitis (p = 0,11) o sólo falla renal (p = 0,33) entre tratados y no tratados; tampoco las hubo al comparar complicaciones entre tratados con indometacina o ibuprofeno. CONCLUSIONES: Los resultados en nuestra población demuestran que el tratamiento médico del DAPs, en ausencia de otras complicaciones clínicas, no representa un mayor riesgo de complicaciones graves digestivas o renales. No se demostraron ventajas entre la indometacina e ibuprofeno.

The symptomatic patent ductus arteriosus (sPDA) is common in extremely premature infants (EPI). In order to decrease the hemodynamic repercussion and avoid complications it is necessary to close it. Indomethacin or ibuprofen are used for this purpose with its associated risks. OBJECTIVE: Characterize digestive and renal complications in EPI who received indomethacin or ibuprofen as sPDA treatment. PATIENTS AND METHOD: Retrospective study on EPI between January-2004 and December-2013. Three groups were compared: treated with indomethacin or ibuprofen and a non-treated group. EPI with other serious complications were excluded. The primary outcomes on each group were digestive and/or renal complications. Statistical significance was p < 0.05. RESULTS: 599 EPI were included, 33.1% with PDA received treatment and 66.9% did not need it. A statistical association was found between sPDA and lower gestational ages, neonatal depression and respiratory distress. In the non-treated group, 5% presented enterocolitis and 0.25% renal failure; on the treated group, 2.5% presented enterocolitis and 1.0% renal failure. No significant differences were found between the treated and non-treated groups in relation to complications considering enterocolitis (p = 0.11) or renal failure (p = 0.33) alone, or combined (p = 0.17). No difference were detected either between those treated with indomethacin or ibuprofen. CONCLUSIONS: The results show that in absence of other clinical complication, medical treatment of sPDA with indomethacin or ibuprofen, do not increase the risk of serious digestive or renal disorders. There were no advantages of using indomethacin or ibuprofen over the other.

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns / Comparação de dois esquemas posológicos de ibuprofeno para o fechamento do canal arterial em recém-nascidos pré-termo

Abstract Objective: To compare the efficacy of intravenous ibuprofen at high (20-10-10 mg/kg/dose) and low doses (10-5-5 mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. Methods: A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Results: Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p > 0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p > 0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p = 0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p > 0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p = 0.86). Conclusions: There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens.

Resumo Objetivo: Comparar a eficácia do ibuprofeno endovenoso em doses altas (20, 10 e 10 mg/kg/dose) e em doses baixas (10, 5 e 5 mg/kg/dose) para o fechamento do canal arterial em recém-nascidos pré-termo. Métodos: Estudo de coorte com controle histórico que pesquisou recém-nascidos que receberam ibuprofeno endovenoso, de 2010 a 2013, na unidade de internação neonatal, em doses altas e baixas para o fechamento do canal arterial, documentado por ecocardiograma. Como desfechos secundários foram avaliados o número de ciclos de ibuprofeno feitos, a incidência de displasia broncopulmonar, enterocolite necrosante, alteração de função renal e óbito. Resultados: Receberam três doses de ibuprofeno para tratamento do canal arterial 77 pacientes, 33 dose alta e 44 dose baixa; 25 (56,8%) dos que receberam dose baixa fecharam o canal após o 1° ciclo e 17 (51,5%) fecharam após receberem dose alta (p > 0,99); 16 pacientes receberam o 2° ciclo e 50% fecharam o canal após uso de dose baixa e 60% após o uso de dose alta (p > 0.99); sete pacientes foram à cirurgia para fechamento do canal, 13,6% do grupo que recebeu dose baixa e 3% dose alta (p = 0,22); 39 pacientes desenvolveram displasia broncopulmonar, 50% do grupo de dose baixa e 51,5% do grupo de dose alta (p > 0,99); 22 (50%) dos pacientes do grupo dose baixa evoluíram a óbito versus 15 (45,5%) dos pacientes do grupo de dose alta (p = 0,86). Conclusão: Não encontramos diferença em relação ao fechamento do canal arterial, assim como ocorrência de efeitos adversos, quando comparamos os dois esquemas posológicos.

Medication error in an extremely low birth weight infant: paracetamol overdose / Medication error in an extremely low birth weight infant: paracetamol overdose.

Errors are part of human nature and are usually present in our actions. Medical errors occur quite often and can be serious. Medication errors are among the most frequent, especially in newborn infants because of the multiple steps that occur during the process of prescribing and administering drugs and because most drugs are not licensed for being used in newborn infants (off-label). The aim of this report is to describe a medication error in prescribing paracetamol for closing a patent ductus arteriosus in a preterm infant and to analyze its causes. A preterm female infant born at 27 weeks of gestational age with a birth weight of 750 g received paracetamol at 9 days old at a dose 20 times greater than required. The initial plasma level was 480 Ag/mL. N-acetylcysteine was administered and her clinical outcome was satisfactory. Parents were notified of the event, which was recorded in the medical record and in the electronic error reporting system of the Hospital Italiano de Buenos Aires. We consider this report as an example that we are exposed to making mistakes and should maximize precautions to improve patient safety in neonatal units.

Comparação de ibuprofeno via oral e indometacina intravenosa no tratamento da persistência do canal arterial em neonatos com extremo baixo peso ao nascer / Comparison of oral ibuprofen and intravenous indomethacin for the treatment of patent ductus arteriosus in extremely low birth weight infants

OBJETIVO: Existem poucos relatórios publicados com relação à eficácia do ibuprofeno via oral no tratamento da persistência do canal arterial (PCA) em neonatos com extremo baixo peso ao nascer (EBPN). Comparamos o ibuprofeno via oral à indometacina intravenosa no que diz respeito à eficácia e segurança no tratamento de PCA em neonatos com peso inferior a 1.000 g ao nascer. MÉTODO: Este foi um estudo retrospectivo em um único centro. Coletamos dados de neonatos com EBPN que tiveram PCA ecocardiograficamente confirmada. Os neonatos foram tratados tanto com indometacina intravenosa quanto com ibuprofeno via oral. A taxa de fechamento do canal, a necessidade de tratamentos adicionais, os efeitos colaterais ou as complicações relacionadas ao medicamento e a mortalidade foram comparados entre os dois grupos de tratamento. RESULTADO: Examinamos 26 neonatos que receberam indometacina e 22 que receberam ibuprofeno. A taxa geral de fechamento do canal foi semelhante nos dois tratamentos: o fechamento do canal ocorreu em 23 dos 26 neonatos (88,5%) no grupo indometacina, e em 18 dos 22 neonatos (81,8%) no grupo ibuprofeno (p = 0,40). A taxa de ligadura cirúrgica (11,5% em comparação a 18,2%; p = 0,40) não diferiu de forma significativa entre os dois grupos de tratamento. Após o tratamento, não foi encontrada nenhuma diferença significativa nas concentrações de creatinina sérica entre os dois grupos. Não houve diferenças significativas com relação a efeitos colaterais ou complicações adicionais. CONCLUSÃO: Em neonatos com EBPN, o ibuprofeno via oral é tão eficaz quanto a indometacina intravenosa no tratamento da PCA. Não há diferenças entre os medicamentos no que diz respeito à segurança. O ibuprofeno via oral poderia ser usado como um agente alternativo no tratamento da PCA em neonatos com EBPN.

OBJECTIVE: There are few published reports concerning the efficacy of oral ibuprofen for the treatment of patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Oral ibuprofen was compared to intravenous indomethacin regarding efficacy and safety in the treatment of PDA in infants weighting less than 1,000 g at birth. METHOD: This was a retrospective study in a single center. Data on ELBW infants who had an echocardiographically confirmed PDA were collected. The infants were treated with either intravenous indomethacin or oral ibuprofen. Rate of ductal closure, need for additional treatment, drug-related side effects or complications, and mortality were compared between the two treatment groups. RESULT: 26 infants who received indomethacin and 22 infants who received ibuprofen were studied. The overall rate of ductal closure was similar between the two treatments: it occurred in 23 of 26 infants (88.5%) treated with indomethacin, and in 18 of 22 infants (81.8%) treated with ibuprofen (p = 0.40). The rate of surgical ligation (11.5% versus 18.2%; p = 0.40) did not differ significantly between the two treatment groups. No significant difference was found in post-treatment serum creatinine concentrations between the two groups. There were no significant differences regarding additional side effects or complications. CONCLUSION: In ELBW infants, oral ibuprofen is as efficacious as intravenous indomethacin for the treatment of PDA. There were no differences between the two drugs with respect to safety. Oral ibuprofen could be used as an alternative agent for the treatment of PDA in ELBW infants.

Prophylaxis of symptomatic patent ductus arteriosus with oral ibuprofen in very low birth weight infants.

BACKGROUND: Patent ductus arteriosus (PDA) is a common cause of mortality and morbidity among very low birth weight infants. Oral ibuprofen suspension has been shown to have the same efficacy and safety as intravenous indomethacin in the prevention and treatment of symptomatic PDA. With lower dosage, the prevalence of side effects may decrease without changes in efficacy. OBJECTIVE: To evaluate the efficacy and side effects of low dose ibuprofen suspension for prevention of symptomatic PDA in very low birth weight infants. PATIENTS AND METHOD: A prospective, double blind, randomized controlled trial was conducted on premature neonates with gestational ages between 28-32 weeks, birth weight 1500 grams or less, at the Neonatal Unit, Queen Sirikit National Institute of Child Health (QSNICH) during October 2005 to October 2006. Only infants who had PDA on echocardiogram were included in the study. Three doses of ibuprofen suspension or placebo were randomly given at the dosage of 10, 5, 5 mg/kg every 24 hours. Daily physical examination, serial laboratory evaluation and echocardiogram were used to evaluate symptomatic PDA, complications and side effects. RESULTS: Sixty-two infants were recruited in the study and randomly assigned into the study and control group. The gestational age and birthweight of the 2 groups were similar The prevalence of symptomatic PDA was less in the ibuprofen group than in placebo group (9.86% vs. 35.48%; p = 0.015). There were no differences in the prevalence of complications and adverse effects between the two groups. CONCLUSION: Prophylactic oral ibuprofen suspension at lower dosage results in less symptomatic PDA without significant side-effects.

Oral ibuprofen prophylaxis for symptomatic patent ductus arteriosus of prematurity.

BACKGROUND: The oral suspension form of ibuprofen has been shown to have the same efficacy and safety as indomethacin in the treatment of symptomatic PDA, however its role is still questionable in the prophylaxis of symptomatic PDA. OBJECTIVES: 1. To assess the efficacy and safety of the drug in the prevention of symptomatic PDA in premature infants. 2. To study its pharmacokinetics-pharmacodynamics relationship. MATERIAL AND METHOD: A randomized, single-blinded, controlled study was performed on premature neonates with a gestational age between 28-32 weeks, birthweight < or = 1500 grams at the neonatal unit, Queen Sirikit National Institute of Child Health from July 2003 to April 2004. Three doses of ibuprofen suspension or placebo were given 24 hours apart. Clinical evaluation was performed daily until the 28th day of life. Echocardiogram was performed prior to the drug administration, on the 3rd and 7th day of life. RESULTS: There were 22 and 20 cases in the ibuprofen and control group respectively. The epidemiologic data between the groups before enrollment showed no significant differences. Prevalence of symptomatic PDA was lower in the ibuprofen than in the control group without any significant side effects (0/22 vs 5/20, p = 0.015 on day 3 and 0/22 vs 6/20, p = 0.006 on day 7). Comparing with the pharmacokinetic study in older children and adult, the present study revealed nearly the same Cmax but longer Tmax and T1/2 in premature neonates. CONCLUSION: Oral ibuprofen suspension could reduce the prevalence of symptomatic PDA without any significant side effects.

Indometacina profiláctica en el prematuro extremo / Prophylactic indomethacin in the very low birth weight infant

La indometacina es útil en el cierre del ductus arterioso. Durante los últimos años, se ha utilizado de manera profiláctica precoz, en la disminución de la incidencia de hemorragia intraventricular (HIV) y ductus arterioso persistente (DAP). Diferentes esquemas terapéuticos han sido publicados. Nuestro objetivo es reportar la experiencia clínica de dos protocolos profilácticos comparándolos con un grupo sin profilaxis. Se incluyó recién nacidos (RN) menores de 1 500 gramos y/o edad gestacional inferior a 32 semanas. Se utilizó un grupo histórico sin profilaxis, con RN pareados según peso y edad gestacional, nacidos en el período 1994-1996 (n = 74). Se consideró grupo I a 71 RN con estas características, nacidos entre 1997-1999 y grupo II, 83 RN del período 1999-2001. Se excluyeron en todos los grupos, aquellos con cardiopatías congénitas, asfixia severa, trastornos genéticos y malformaciones mayores. Todos los niños fueron evaluados con ecotomografía encefálica, en los días 3, 10 y 30 de vida, y con ecocardiografía el 7° día de acuerdo a normas de tratamiento similares en los tres periodos. Se registró la incidencia de complicaciones. El grupo I, recibió indometacina en dosis de 0,1 mg/kg, a las 6, 30 y 54 horas de vida; mientras que el grupo II, una dosis única a las 6 horas. En todos los pacientes se administró en infusión continua en 30 minutos. Los tres grupos resultaron comparables. En el grupo sin profilaxis, se observó DAP en 14 pacientes (18,9 por ciento) y HIV en 13 casos (17,5 por ciento). En el grupo I, 6 niños presentaron DAP (8,4 por ciento) y 7 HIV (9,8 por ciento). En el grupo II, se registró DAP en 6 RN (8,4 por ciento), mientras que HIV en 13 pacientes (15,7 por ciento). Así, la incidencia de DAP se puede disminuir utilizando una o tres dosis de indometacina (61,9 por ciento y 55,5 por ciento respectivamente, en relación al grupo sin profilaxis, p < 0,01). Sin embargo, se observó disminución significativa de HIV, sólo con el esquema de tres dosis (disminución de 44 por ciento, p < 0,01 vs 10,28 por ciento en el grupo II, NS). Conclusión: El uso precoz de Indometacina profiláctica, puede disminuir la incidencia de DAP. La dosis única puede ser tan efectiva, como el protocolo de tres. Sin embargo, en la reducción de HIV, sólo éste último demostró utilidad. De esta manera, la elección del esquema a usar debe basarse en los objetivos terapéuticos de cada centro...

A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants.

BACKGROUND: Indomethacin is widely accepted as the treatment for patent ductus arteriosus (PDA) in preterm infants but it has various side effects. Ibuprofen is the alternative treatment and believed to be less likely to induce side effects. OBJECTIVE: To compare efficacy and side effects of ibuprofen versus indomethacin treatment for symptomatic patent ductus arteriosus (PDA) in preterm infants. METHOD: The authors studied 30 infants (gestational age < or = 35 weeks, aged < or = 10 days) who were diagnosed as having symptomatic PDA confirmed by echocardiogram. The infants were randomly assigned to receive three intravenous doses of indomethacin given at 12-hour intervals or three doses of ibuprofen given at 24-hour intervals, starting within ten days of life. The demographic data, rate of clinical closure, need for additional treatment, side effects, complications and the infants' clinical course were recorded within 28 days. RESULTS: The rate of ductal closure was similar with the two treatment regimes. Ductal closure occurred in 7 of 15 infants given ibuprofen (46.67%) and 10 of 15 infants given indomethacin (66.67%). (Relative risk 0.669; 95% confidence interval, 0.328 to 1.364; p = 0.462) The number of infants who needed a second pharmacologic treatment was not significantly different between the two groups, (6 cases in the ibuprofen group, 5 cases in the indomethacin group) but surgical ligation was performed in two cases in the indomethacin group. There was a significant difference in using the diuretic drug (furosemide) in the indomethacin group (11 cases), compared to the ibuprofen group (3 cases), (p = 0.009). More cases of necrotizing enterocolitis were seen in the indomethacin group (66.67% compared to 40% in the ibuprofen group) but there was no statistically significant difference. CONCLUSION: Ibuprofen has the same efficiency as indomethacin for the treatment of symptomatic patent ductus arteriosus in preterm infants and less likely to induce necrotizing enterocolitis and renal toxicity than indomethacin.

A preliminary study on pharmacokinetics of oral indomethacin in premature infants in north India.

BACKGROUND & OBJECTIVES: Patent ductus arteriosus (PDA) is a frequent complication in premature infants. Intravenous indomethacin is the standard mode of medical therapy and has been shown to be efficacious in closing the ductus. In our setup, oral indomethacin is being regularly used for medical treatment of suspected or clinically diagnosed PDA. Non-availability of the parenteral preparation and lack of information regarding the pharmacokinetic disposition of indomethacin in the premature infants in north Indian population led us to conduct this pharmacokinetic study with oral indomethacin. METHODS: Twenty premature infants with gestational age 30.3 +/- 0.3 wk and birth weight, 1209.8 +/- 39.5 g; admitted to the neonatal unit of the Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh were enrolled in the study. Indomethacin was administered in a single oral dose of 0.2 mg/kg and blood samples were collected through an indwelling vascular catheter at 0 and 1, 2, 4, 8 and 12 h after administration of indomethacin. Plasma indomethacin concentrations were assayed by spectrofluorometric technique. RESULTS: Large interindividual variability was observed for peak plasma concentrations (Cmax; 137.9 +/- 14.0 ng/ml), elimination half-life (t1/2 el; 21.4 +/- 1.7 h) and area under the plasma concentrations time curve (AUC0-infinity;4172 +/- 303 ng.h/ml) in these infants. Variables like birth weight, and sex did not have any sigiificant effect on indomethacin pharmacokinetics. However, the plasma t1/2 el of indomethacin was significantly (P < 0.01) larger in older infants (gestational age > 30 wk) in comparison to younger ones (gestational age < or = 30 wk). There was a negative correlation between gestational age and elimination t1/2 (r = -0.77). INTERPRETATION & CONCLUSION: In conclusion, indomethacin pharmacokinetics showed a wide variability in premature infants. In view of these findings it can be suggested that infants of smaller gestational age are at greater risk of cumulative toxicity if more than one dose of indomethacin is given. With advancing age, metabolism as well as elimination of drug is faster that may require modification in indomethacin dose to achieve therapeutic response. These preliminary results may be of use in designing future pharmacokinetic studies of oral indomethacin in preterm neonates on a larger sample.

Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi Hospital.

BACKGROUND: Ibuprofen given intravenously to premature newborn infants is a proven treatment for patent ductus arteriosus (PDA). The efficacy of ibuprofen is comparable to indomethacin in many clinical trials with fewer renal side effects. However, the intravenous form of ibuprofen is not available in Thailand, whereas, the oral suspension form is widely used for antipyretic treatment in children. Therefore, the authors investigated the possibilities of using oral ibuprofen for the treatment of PDA in premature newborn infants. OBJECTIVE: To assess whether oral ibuprofen at 10 mg/kg/dose daily for 3 days was as effective as indomethacin to treat symptomatic PDA in premature infants and to compare the side effects of oral ibuprofen to indomethacin. SUBJECTS AND METHOD: Eighteen premature infants with gestational ages less than 34 weeks born at Ramathibodi Hospital who developed symptomatic PDA were randomly assigned to receive three doses of either indomethacin (oral or intravenous administration 0.2 mg/kg/dose for three doses given at 12 hourly intervals or oral ibuprofen (10 mg/kg/dose for three doses given at 24 hourly intervals). The rates of ductal closure, infants' clinical courses, side effects and complications were recorded. RESULTS: Birth weight, gestational age, gender, age onset and number of infants who had respiratory distress syndrome were similar in both groups, PDA was closed in 7 of 9 infants given ibuprofen (78%) and in 8 of 9 infants given indomethacin (89%) (p > 0.05). The mean plasma concentration of ibuprofen was 28.05 microg/ml at 1 hour after the third dose. Neonates in the ibuprofen group had more urine output. However, the increment of serum BUN and creatinine were not significantly different in both groups. There were no significant differences in duration of ventilator support as well as number of patients with bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis and death in both groups. CONCLUSION: Oral ibuprofen therapy is as effective as indomethacin for the treatment of PDA in premature infants and seems to have fewer renal side effects.