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The Cochrane Database of Systematic... Jan 2008Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be... (Review)
Review
BACKGROUND
Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or treatment with indomethacin, has not been well established.
OBJECTIVES
To compare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA.
SEARCH STRATEGY
The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - July 2007), CINAHL (1982 - July 2007), EMBASE (1980 - July 2007); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002) or on line from May 2002 -July 2007. No language restrictions were applied.
SELECTION CRITERIA
All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA.
DATA COLLECTION AND ANALYSIS
Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data.
MAIN RESULTS
Only one study, trial B in the report of Gersony 1983, was found eligible. No additional studies were identified in the literature searches performed in July 2007. The trial compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity stage III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)].
AUTHORS' CONCLUSIONS
The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants. It should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care.
Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Ligation; Randomized Controlled Trials as Topic
PubMed: 18254035
DOI: 10.1002/14651858.CD003951.pub2 -
The Cochrane Database of Systematic... Jan 2008A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gastrointestinal tract. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin, with fewer side effects.
OBJECTIVES
To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants. To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants.
SEARCH STRATEGY
Randomized or quasi-randomized controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1996 - August 2007), CINAHL (1982 - August 2007), EMBASE (1980 - August 2007), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - April 2005) or on their website (to August 2007). No language restrictions were applied.
SELECTION CRITERIA
1) DESIGN: Randomized or quasi-randomized controlled trials2) POPULATION: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) with a clinically or echocardiographically diagnosed PDA3) INTERVENTION: Administration of ibuprofen (orally or intravenously) for the closure of PDA4) OUTCOMES: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ductal ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), chronic lung disease (CLD), sepsis, pulmonary hemorrhage, pulmonary hypertension, duration of supplementary oxygen, duration of mechanical ventilation, duration of hospital stay, and serum creatinine levels following treatment.
DATA COLLECTION AND ANALYSIS
At least two review authors worked independently at each step of the original review, then compared results and resolved differences. The current update was conducted by one review author (AO). Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of follow up. Weighted treatment effects, calculated using RevMan 4.2.10, included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared test (I(2)) were performed to assess the appropriateness of pooling the data.
MAIN RESULTS
No studies using mefenamic acid were identified. Sixteen studies enrolling 876 infants were identified. Four additional trials were identified for this update and two studies published as abstracts were now available as full articles. One study compared ibuprofen to placebo, but the results were not reported unblinded to intervention group. Fifteen studies including 740 infants compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.99 (95% CI 0.78, 1.27); typical RD 0.00 (95% CI -0.06, 0.06)]. There were no statistically significant differences in mortality, reopening of the ductus, need for surgical duct ligation, duration of ventilator support, duration of supplementary oxygen, pulmonary hemorrhage, pulmonary hypertension, CLD, IVH, PVL, NEC, intestinal perforation, gastrointestinal bleed, time to full enteral feeds, time to regain birth weight, ROP, sepsis, duration of hospitalization. Ibuprofen treatment was associated with statistically significantly lower serum creatinine levels after treatment (6 trials, 336 infants; WMD - 8.2 (95% CI -13.3, -3.2) mmol/L and lower incidence of 'decreased urine output' [3 trials, 336 infants; typical RR; 0.22 (95% CI 0.09, 0.51); typical RD -0.12 (95% CI -0.18, -0.06); NNT 8 (95% CI 6,17)]. There was moderate heterogeneity of treatment effect for the outcomes 'time to regain birth weight' and 'decreased urine output". Heterogeneity was not noted for other outcomes. For several of these outcomes, the sample size was small and the estimates imprecise. There are not enough data available regarding the effectiveness of oral ibuprofen compared with indomethacin to close a PDA [3 trials, 69 infants; typical RR 1.41 (95% CI 0.68, 2.93); typical RD 0.10 (95% CI -0.10, 0.30)]. Pulmonary hypertension was noted in one infant receiving ibuprofen to close a PDA enrolled in a trial in this review and an additional report of such a case was identified from the literature.
AUTHORS' CONCLUSIONS
No statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing a PDA was found. Ibuprofen compared with indomethacin reduces the risk of oliguria and is associated with lower serum creatinine levels following treatment. Pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen and one infant receiving ibuprofen for treatment in this review developed pulmonary hypertension. One additional case of pulmonary hypertension following treatment with ibuprofen to close a PDA was identified from the literature. The available data support the use of either drug for the treatment of a PDA. As both drugs are equally effective in closing a PDA, the clinician needs to weigh the potential side effects of one drug vs. the other when making a decision which drug to use. The most urgent research question to be answered is whether ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age and at the age of school entry.
Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Ibuprofen; Indomethacin; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic
PubMed: 18254020
DOI: 10.1002/14651858.CD003481.pub3 -
Nefrologia : Publicacion Oficial de La... 2007To estimate whether continuous veno-venous hemodiafiltration (CVVHDF) is superior to intermittent hemodialysis (IHD) in terms of survival of adult patients with acute... (Comparative Study)
Comparative Study Review
OBJECTIVE
To estimate whether continuous veno-venous hemodiafiltration (CVVHDF) is superior to intermittent hemodialysis (IHD) in terms of survival of adult patients with acute renal failure (ARF) admitted to the Intensive Care Unit.
SELECTION OF STUDIES
Controlled clinical trials (CCT) and systematic reviews comparing CWHDF and IHD for managing ARF in adult patients (age > 19 years). Observational and case series were excluded. SEARCH SOURCES: The basic syntax <
> was used to search Pub Med and Ovid System databases. A manual search was done by reviewing the references in the corresponding topic of UpToDate. ANALYSIS
Data were extracted by two author and their methodological quality was assessed according to the Cochrane Renal Group recommendations that include the procedure for assigning, blinding, intention to treat analysis, and follow-up. OUTCOMES VARIABLES: All data relating to mortality were extracted, specifying the time of collection, time and circumstances (mortality in the ICU or hospitalization). Values gathered are expressed as mortality rates in both the experimental group (CVVHDF) and the control group (IHD), indicating the absolute risk reduction (ARR) and its 95% confidence interval. OUTCOMES AGGREGATION: Studies meeting clinical and methodological homogeneity criteria were combined with the fix effect model by using the Review Manager tool from Cochrane Collaboration. Methodological heterogeneity was analyzed by using the chi-squared test for n-1 freedom degrees, with an alpha value of 0.05. A sensitivity analysis was done adjusting for methodological quality to confirm the results obtained.
RESULTS
Seven clinical trials directly comparing the survival of severe ARF patients in a prospective, randomized, and controlled way were identifiec. Almost all published estudies have quality problems because of being too small to study survival rates, treatment allocation problems and high numbers of loss to follow-up, differences in initial severity levels, or to premature study closure. When combining the results, it was observed that mortality was 64% for IHD and 65% for CVVHDF, with a relative risk of 0.98 (95% CI 0.89-1.07), p = 0.65, with no statistically significant heterogeneity between studies included. When excluding from the analysis the most questionable study due to selection bias, high loss to follow-up (21%), and baseline differences in co-variables influencing the study outcomes, the results are not changed, the observed mortality was 67% for extra-renal intermittent depurative techniques versus 65% for continous ones, with a relative risk of 1.03 (95% CI 0.94-1.14), p = 0.54, again with no statistically significant heterogeneity between studies included.
CONCLUSION
CVVHDF does not offer any benefit as compared to IHD in terms of survival and according to available data from the literature. However, continuous techniques bring other potential benefits such as hemodynamic stability, better tolerability of ultrafiltration, and depuration of solutes, which merit a systematic review to estimate and quantify their magnitude, and which would allow for better defining their place in the therapeutic armamentarium available for this high-mortality condition.
Topics: Acute Kidney Injury; Hemodiafiltration; Humans; Renal Dialysis; Veins
PubMed: 17763635
DOI: No ID Found -
The Cochrane Database of Systematic... Apr 2007Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority of cases, it is ineffective in up to 40% of patients. Furthermore, the ductus will re-open in up to 35% of infants who initially respond to the drug. Prolonging the course of indomethacin has the potential to achieve higher rates of ductal closure.
OBJECTIVES
To determine the effect of a prolonged course of indomethacin (compared to a short course) on the rate of treatment failure without unwanted side-effects in preterm infants with PDA.
SEARCH STRATEGY
The search included review of personal files, abstracts of conferences, and the following electronic databases: MEDLINE (1966 to December 2006), EMBASE (1974 to December 2006), and Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2006). No language restrictions were applied.
SELECTION CRITERIA
Randomized or quasi-randomized controlled trials including preterm infants with PDA, diagnosed on clinical and/or echocardiographic examination that evaluated indomethacin treatment by any route given as a long course (four or more doses) vs. a short course (three or fewer doses) were included in the review. Trials needed to report on at least one of the following outcomes: failure of PDA to close, need for re-treatment, PDA re-opening, PDA ligation, mortality, duration of assisted ventilation, chronic lung disease (CLD), duration of supplemental oxygen dependence, intraventricular hemorrhage (IVH) (all and severe), diminished urine output, increased serum creatinine, necrotizing enterocolitis (NEC), bleeding diathesis, retinopathy of prematurity (ROP), and duration of hospital stay.
DATA COLLECTION AND ANALYSIS
The three review authors independently abstracted data from each study. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effect model for meta-analysis are reported. When a statistically significant RD was found, the number needed to treat (NNT) or number needed to harm (NNH) was also calculated with 95% CIs. The I squared statistic was used to test for heterogeneity of results among included trials.
MAIN RESULTS
Five trials met inclusion criteria and included 431 infants. Prolonged indomethacin treatment when compared to the short course did not result in a statistically significant difference in PDA closure, re-treatment, re-opening, or ligation rates. The prolonged course was associated with an increased risk of NEC [typical RR 1.87 (95% CI 1.07, 3.27); typical RD 0.08 (95% CI 0.01, 0.15); NNH 13 (7, 100)] and a decreased incidence of renal function impairment, as evidenced by a lower proportion of infants having diminished urine output [typical RR 0.27 (95% CI 0.13, 0.6); typical RD -0.19 (95% CI -0.28, -0.09); NNT 5 (4, 11)] and increased serum creatinine level [typical RR 0.51 (95% CI 0.33, 0.77); typical RD -0.14 (95% CI -0.23, -0.06); NNT 7 (4, 16)].
AUTHORS' CONCLUSIONS
Implications for practiceProlonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants. Implications for researchThere is a paucity of data on optimal dosing and duration of indomethacin therapy for the treatment of PDA, in particular for extremely low birth weight infants (ELBW) premature infants. It is likely that a single standard indomethacin regime is not the ideal for every premature infant. Therefore, individual patient response should be considered and evaluated, in particular in ELBW infants. Future randomized clinical trials should include this high risk population and investigate the effect of tailoring dose and duration of therapy to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes, including long-term neurodevelopmental outcomes. In addition, factors that may influence treatment effect, such as birth weight, gestational age, age at the time of randomization, total fluid intake, feeding practice, and severity of PDA, need to be taken into account when designing such studies.
Topics: Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prostaglandin Antagonists; Randomized Controlled Trials as Topic
PubMed: 17443527
DOI: 10.1002/14651858.CD003480.pub3 -
Seminars in Perinatology Jun 2006Ibuprofen, a nonsteroidal antiinflammatory drug, widely used as antipyretic, antiinflammatory, and analgesic agent and for therapy of arthritis, exerts a dose-dependent... (Comparative Study)
Comparative Study Review
Ibuprofen, a nonsteroidal antiinflammatory drug, widely used as antipyretic, antiinflammatory, and analgesic agent and for therapy of arthritis, exerts a dose-dependent constriction of the ductus arteriosus in newborn lambs. Two intravenous preparations, namely ibuprofen lysine and ibuprofen-THAM, have been studied in preterm newborns with patent ductus arteriosus. Clinical trials have compared IV ibuprofen to placebo, or to indomethacin. Pharmacodynamic effects of this drug before and after its administration have also been evaluated. Compared with placebo, IV ibuprofen effectively closed PDA with minimal effect on renal function. One study using intravenous ibuprofen-THAM showed decreased renal function and increased risk of NEC and PPHN. Compared with indomethacin, IV ibuprofen lysine exerted similar efficacy (75% to 93% closure). However, indomethacin increased abnormal renal function and decreased mesenteric and cerebral blood flow and bio-energetics. Two clinical trials showed that ibuprofen did not reduce the incidence of intraventricular hemorrhage compared with placebo. The drug has prolonged elimination (plasma half-life = ca 23 hours), suggesting that once daily dosing is appropriate. Dose finding studies indicate that a starting dose of 10 mg/kg followed by 5 mg/kg/d for 2 more days provides optimal efficacy with the least adverse effects. Neonatal data on ibuprofen and indomethacin indicate that, on the first day of life when IVH prevention is desired, indomethacin and not ibuprofen should be used since ibuprofen has no effect on IVH risk. On or after the second day of postnatal life, when early or therapeutic PDA closure is needed, ibuprofen and not indomethacin is probably the first choice due to its better adverse event profile.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Ductus Arteriosus, Patent; Female; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intravenous; Male; Randomized Controlled Trials as Topic
PubMed: 16813969
DOI: 10.1053/j.semperi.2006.04.003 -
The Annals of Pharmacotherapy May 2006Nonsteroidal antiinflammatory drugs (NSAIDs) are increasingly being used during pregnancy to treat a variety of conditions. An evaluation of the risk of premature... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nonsteroidal antiinflammatory drugs (NSAIDs) are increasingly being used during pregnancy to treat a variety of conditions. An evaluation of the risk of premature closure of the ductus arteriosus is useful in determining the safety of NSAIDs at different stages of pregnancy.
OBJECTIVE
To determine whether NSAID use during the third trimester of pregnancy is associated with an increased risk of premature constriction of the ductus arteriosus.
METHODS
A systematic review was conducted of MEDLINE (1966-2004), Embase (1980-2004), and the Cochrane Database of Systematic Reviews (1991-2004). Summary estimates of the odds ratios, comparing ductal outcomes in exposed and unexposed fetuses, and their 95% confidence intervals were calculated assuming a random effects model.
RESULTS
Based on 217 patients exposed to indomethacin and 221 to placebo, the risk of ductal closure was 15-fold higher in the group of women exposed to NSAIDs compared with those receiving either placebo or other NSAIDs (8 studies; OR = 15.04, 95% CI 3.29 to 68.68). There was no significant increased risk of ductal closure in the infants of women treated with indomethacin compared with those receiving other drugs (4 studies; OR = 2.12, 95% CI 0.48 to 9.25). Similar results were found when calculating rate differences.
CONCLUSIONS
Short-term use of NSAIDs in late pregnancy is associated with a significant increase in the risk of premature ductal closure.
Topics: Abnormalities, Drug-Induced; Anti-Inflammatory Agents, Non-Steroidal; Ductus Arteriosus; Female; Humans; Indomethacin; Pregnancy; Pregnancy Trimester, Third; Randomized Controlled Trials as Topic; Sulindac
PubMed: 16638921
DOI: 10.1345/aph.1G428 -
Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.The Cochrane Database of Systematic... Jan 2006A patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants and increases the risk of intraventricular hemorrhage (IVH), necrotizing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants and increases the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD) and death. The standard treatment to close a PDA is indomethacin. Its use is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has been shown to be effective in closing a PDA without reducing blood flow velocity to the brain, gut or kidneys.
OBJECTIVES
To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) in the prevention of PDA in preterm infants.
SEARCH STRATEGY
Randomized controlled trials comparing prophylactic ibuprofen use with placebo/no intervention/indomethacin were identified by searching the Cochrane Central Register of Controlled Trial (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (1966-July 2005), CINAHL (1982-July 2005), EMBASE (1980-July 2005), reference lists of published trials and abstracts published in Pediatric Research (1990-July 2005). No language restrictions were applied.
SELECTION CRITERIA
Randomized or quasi-randomized controlled trials comparing use of ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) for the prevention of PDA in preterm and/or low birth weight infants.
DATA COLLECTION AND ANALYSIS
Data regarding the clinical outcomes including presence of PDA on day three and day seven, need for surgical ligation, need for rescue treatment with cyclo-oxygenase inhibitors, IVH, mortality, renal and gastrointestinal complications were extracted. Meta-analyses were performed using RevMan 4.2 and treatment estimates were reported as weighted mean difference (WMD), typical relative risk (RR), typical risk difference (RD) and, if statistically significant, number needed to treat (NNT) or number needed to harm (NNH), along with their 95% confidence intervals (CI).
MAIN RESULTS
Four trials (n = 672) were included in the review. There was a statistically significant decrease in the incidence of PDA on day three in the ibuprofen group [typical RR 0.37 (95% CI 0.29, 0.49); typical RD -0.29 (95% CI -0.35, -0.22); NNT 3 (95% CI 3, 5); 4 trials, n = 672], in the need for rescue treatment with cyclo-oxygenase inhibitors [typical RR 0.17 (95% CI 0.11, 0.27), typical RD -0.27 (95% CI -0.35, -0.22); NNT 4 (95%CI 3, 5), and in the need for surgical ligation [typical RR 0.34 (95% CI 0.14, 0.81), typical RD -0.04 (95% CI -0.07, -0.01); NNT 25 (95% CI 14, 100). The PDA had closed spontaneously by day three in 60% of the neonates in the control group. There was a significant increase in the serum creatinine levels in the ibuprofen group [WMD 0.13 mg/dl (95% CI 0.08, 0.17); 2 trials, n = 495]. Ibuprofen reduces urine output. There were no statistically significant differences in mortality, grade 3/4 intraventricular hemorrhage, chronic lung disease at 28 days or 36 weeks, necrotizing enterocolitis , gastrointestinal hemorrhage, intestinal perforation or time to reach full feeds. One trial (Gournay 2002) (n = 135) reported on three infants in the ibuprofen group who developed pulmonary hypertension responsive to nitric oxide treatment.
AUTHORS' CONCLUSIONS
Prophylactic use of ibuprofen reduces the incidence of PDA, the need for rescue treatment with cyclo-oxygenase inhibitors and surgical closure. However, in the control group, the PDA had closed spontaneously by day three in 60% of the neonates. Prophylactic treatment therefore exposes a large proportion of infants unnecessarily to a drug that has important side effects (mainly involving the kidneys) without conferring any important short term benefits. Prophylactic treatment with ibuprofen is not recommended. Until long-term follow-up results are published from the trials included in this review, no further trials of prophylactic ibuprofen are recommended.
Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Enzyme Inhibitors; Humans; Ibuprofen; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic
PubMed: 16437478
DOI: 10.1002/14651858.CD004213.pub2 -
The Cochrane Database of Systematic... Oct 2005A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gut. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective with fewer side effects.
OBJECTIVES
To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants. To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants.
SEARCH STRATEGY
Randomized or quasi-randomized controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2005), MEDLINE (1996 - July 2005), CINAHL (1982 - July 2005), EMBASE (1980 - July 2005), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - April 2005). No language restrictions were applied.
SELECTION CRITERIA
1) DESIGN: Randomized or quasi-randomized controlled trials 2) POPULATION: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 grams) with a clinically or echocardiographically diagnosed PDA 3) INTERVENTION: Administration of ibuprofen for the closure of PDA 4) OUTCOMES: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), chronic lung disease (CLD), sepsis, days on supplementary oxygen.
DATA COLLECTION AND ANALYSIS
At least two authors worked independently at each step of the original review, then compared results and resolved differences. The current update was conducted by one author (AO). Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of follow up. Weighted treatment effects, calculated using RevMan 4.2, included typical relative risk (RR), typical risk difference (RD), number needed to treat (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including I(2 )were performed to assess the appropriateness of pooling the data.
MAIN RESULTS
No study using mefenamic acid was identified. One study compared ibuprofen to placebo but results were not reported unblinded to group. Eleven studies including 620 patients compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. There was no statistically significant heterogeneity of treatment effect for any of the outcomes. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.96 (95% CI 0.74, 1.25)]. There were no statistically significant differences in mortality, surgical duct ligation, duration of ventilator support, IVH, PVL, NEC, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed. For many of these outcomes the sample size was small and the estimates imprecise. The incidence of decreased urine output (< 1cc/kg/hr) was lower in the ibuprofen group as compared to the indomethacin group [NNT 9 (95% CI 5-14)]. This was the only statistically significant clinical finding favouring ibuprofen. CLD defined as oxygen requirement at 28 days post-natally was statistically significantly more likely to occur in the ibuprofen group [typical RR 1.37 (95% CI 1.01, 1.86); NNH 7 (95% CI 3 - 100)]. There was a similar trend for CLD at 36 weeks corrected gestational age.
AUTHORS' CONCLUSIONS
We found no statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing the PDA. Ibuprofen reduces the risk of oliguria. However, ibuprofen may increase the risk for CLD, and pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen. Based on currently available information ibuprofen does not appear to confer a net benefit over indomethacin for the treatment of a PDA. We conclude that indomethacin should remain the drug of choice for the treatment of a PDA. The most urgent research question to be answered is weather ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age.
Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Enzyme Inhibitors; Humans; Ibuprofen; Indomethacin; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic
PubMed: 16235321
DOI: 10.1002/14651858.CD003481.pub2 -
The Cochrane Database of Systematic... 2004Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority of cases, it is ineffective in up to 40% of patients. Furthermore, the ductus will re-open in up to 35% of infants who initially respond to the drug. A more prolonged course of indomethacin has been studied regarding the potential to achieve higher rates of ductal closure.
OBJECTIVES
To determine if a prolonged course of indomethacin (compared to a short course) reduces the rate of treatment failure in preterm infants with PDA without unwanted side-effects.
SEARCH STRATEGY
The search included review of personal files, abstracts of conferences, and the following electronic databases: MEDLINE (1966 to April 2003), EMBASE (1974 to April 2003), and Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2003). No language restrictions were applied.
SELECTION CRITERIA
1) DESIGN AND POPULATION: Randomized or quasi-randomized controlled trials including preterm infants with PDA diagnosed on clinical and/or echocardiographic examination.2) INTERVENTION: Indomethacin treatment by any route given as a long course (four or more doses) vs a short course (three or fewer doses). 3) OUTCOMES: Report of at least one of the following outcomes: failure of PDA to close, need for re-treatment, PDA re-opening, PDA ligation, mortality, duration of assisted ventilation, chronic lung disease (CLD), duration of supplemental oxygen dependence, intraventricular hemorrhage (IVH) (all and severe), diminished urine output, increased serum creatinine, necrotizing enterocolitis (NEC), bleeding diathesis, retinopathy of prematurity (ROP), and duration of hospital stay.
DATA COLLECTION AND ANALYSIS
The three reviewers independently abstracted data from each study. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effect model for meta-analysis are reported. When a statistically significant RD was found, the number needed to treat (NNT) or number needed to harm (NNH) was also calculated with 95% CIs. A chi-square test was used to test for heterogeneity of results among included trials.
MAIN RESULTS
Prolonged indomethacin treatment when compared to the short course resulted in a borderline statistically significant difference in PDA re-opening rate favoring the prolonged course [RR 0.54 (95% CI 0.3, 0.99); RD -0.12 (95% CI -0.24, -0.01); NNT = 8 (4, 100). There was no statistically significant treatment effect on PDA closure, re-treatment, or ligation rates. The prolonged course was associated with a decreased incidence of severe IVH [RR 0.49 (95% CI 0.25, 0.98); RD -0.12 (95% CI -0.24, -0.01); NNT 8 (4, 100)] and renal function impairment, as evidenced by a lower proportion of infants having an increased creatinine level [RR 0.52 (95% CI 0.34, 0.81); RD -0.20 (95% CI -0.33, -0.08); NNT 5 (3, 13)]. However, there was a trend for the prolonged course to increase the proportion of infants with CLD in the one trial reporting this outcome [RR 2.24 (95% CI 0.98, 5.12); RD 0.24 (95% CI 0.01, 0.47)].
IMPLICATIONS FOR PRACTICE
Prolonged as compared to short course of indomethacin for the treatment of PDA in preterm infants has a borderline effect on reducing the rate of PDA re-opening and it may be associated with an increased risk for CLD. However, prolonged course of indomethacin appears to reduce the risk of severe intracranial hemorrhage and renal impairment in this population. Definitive recommendations about the preferred duration of indomethacin therapy, i.e. prolonged versus short course, for the treatment of PDA in premature infants cannot be made based on the current findings of this review.
IMPLICATIONS FOR RESEARCH
There is a paucity of data on optimal duration of indomethacin therapy for the treatment of PDA, in particular for ELBW premature infants. Future randomized clinical trials should include this high risk population and investigate the premature infants. Future randomized clinical trials should include this high risk population and investigate the possibility of tailoring duration of therapy (prolonged versus short) to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes and potential complications associated with either strategy. In addition, factors which may influence treatment effect need to be taken into account when designing such studies.
Topics: Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prostaglandin Antagonists; Randomized Controlled Trials as Topic
PubMed: 14974018
DOI: 10.1002/14651858.CD003480.pub2 -
The Cochrane Database of Systematic... 2003Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be... (Review)
Review
BACKGROUND
Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors, or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or trial of indomethacin, has not been well established.
OBJECTIVES
To compare the effect of surgical ligation of PDA versus medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA.
SEARCH STRATEGY
The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2002), MEDLINE (1966 - December 2002), CINAHL (1982 - December 2002), EMBASE (1980 - December 2002); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002). No language restrictions were applied.
SELECTION CRITERIA
All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA.
DATA COLLECTION AND ANALYSIS
Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data.
MAIN RESULTS
Only one study, trial B in the report of Gersony 1983, was found eligible. The trial compared the effect of surgical ligation of PDA versus medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity grade III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)].
REVIEWER'S CONCLUSIONS
The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants.
Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Ligation; Randomized Controlled Trials as Topic
PubMed: 12917997
DOI: 10.1002/14651858.CD003951