JOURNAL CLUB

F1. Wariphan Wirayannawat

F2. Natthapicha Najmuangchan

INTRODUCTION

• Persistent patency of the ductus arteriosus is common in extremely preterm infants
• Medical treatment or surgical ligation, have not been consistently shown to improve respiratory outcomes.
• High spontaneous closure rate of PDA, lack of consistent definition of hemodynamically significant PDA, low efficacy, and significant side effects of PDA treatment are other impediments to achieving a consensus on PDA management.

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INTRODUCTION

• A randomized double-blind controlled trial was conducted in very preterm infants between January 2008 and August 2010 : early treatment of PDA with ibuprofen or expectant management would improve respiratory outcome 🡪 no difference in mortality, respiratory outcome, and other morbidities
• As a result of this trial and others suggesting lack of benefit of early PDA closure in preventing bronchopulmonary dysplasia (BPD) 🡪 considerable change in approach to PDA diagnosis and management 🡪 early diagnosis and treatment of PDA to more conservative expectant management.

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INTRODUCTION

• The objective of the present study was to evaluate the impact of changes in PDA management strategies on the respiratory outcome in extremely premature infants.

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METHODS

• Prospective data were collected and analyzed from all preterm infants of 23-30 weeks of gestational age with PDA confirmed by echocardiogram
• Admit at neonatal intensive care unit at Holtz Children’s Hospital of the University of Miami/Jackson Memorial Medical Center
• Epoch 1 : January 1, 2005 to December 31, 2007
• Epoch 2 : January 1, 2011 to December 31, 2015

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• Collected data for PDA : Postnatal age of first echo diagnosis, direction of shunt and size of PDA by echocardiography (graded as small, moderate, or large), timing of initial PDA treatment, treatment administered, incidence of PDA ligation.
• Demographic data : Gestational age (determined by the best obstetric estimate using the last menstrual period or early ultrasound examination), birth weight, small for gestational age, defined as birth weight
• Respiratory and other comorbidity data : severe respiratory distress syndrome (RDS, defined as receiving fraction of inspired oxygen 0.3 for 12 hours on day 1), receiving mechanical ventilation on day 1, blood culture positive sepsis, and postnatal steroid treatment for respiratory purposes.

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• Outcomes :
• BPD🡪 receiving supplemental oxygen at 36 weeks postmenstrual age (PMA)
• Severe BPD 🡪 receiving at least 30% inspired oxygen at 36 weeks PMA.
• The composite endpoints of BPD or death and severe BPD or death
• All data were analyzed to adjust for the occurrence of death before 36 weeks of PMA.
• Other morbidities compared : necrotizing enterocolitis (NEC) defined as Bell stage 2 and severe intraventricular hemorrhage (IVH) defined as grade III or higher

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preterm infants of 23-30 weeks of gestational age

with PDA confirmed by echocardiogram

Epoch 1 : January 1, 2005 to December 31, 2007

Collected data for PDA

Demographic data

Epoch 2 : January 1, 2011 to December 31, 2015

Respiratory and other comorbidity data

Outcome measures included BPD,

severe BPD,

The composite endpoints of BPD or death

severe BPD or death

Other morbidities.

STATISTICAL ANALYSIS

• Student t test for normality in their distributions.
• Univariate analysis of proportions was conducted by χ2.
• Mantel-Haenszel was used for stratified analysis of proportions.
• Reported P values for multiple variables were not adjusted for multiplicity.
• Multivariable analysis was conducted to model the association between epoch and BPD, severe BPD, BPD or death, severe BPD or death, death before 36 weeks, and treatment with postnatal steroids.

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STATISTICAL ANALYSIS

• A set of independent confounding variables that were considered to be risk factors for BPD including
• gestational age, race, sex, chorioamnionitis,
• 5-minute Apgar score <5, preeclampsia, multiple gestation,
• severe RDS, use of antenatal steroids, small for gestational age,
• sepsis, and the need for mechanical ventilation on day 1
• The Hosmer-Lemeshow statistic was used to evaluate goodness of fit.

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RESULTS

• 527 and 726 preterm infants of 23-30 weeks of gestation admitted to the neonatal intensive care unit at this center during epochs 1 and 2
• 710 infants met the study criteria
• 309 infants in epoch 1 and 401 in epoch 2

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RESULTS

• There was a higher proportion of male infants and infants with 5-minute Apgar <5 in epoch 2, potentially increasing their risk of poor respiratory outcome
• Lower proportion of infants with severe RDS and sepsis in epoch 2 than epoch 1
• The mean age of diagnosis of PDA by echo was significantly later in epoch 2 when compared with epoch 1.
• Infants in epoch 2 were also treated later compared with epoch 1.
• There was a significant reduction in the number of infants treated for PDA in epoch 2.
• This difference was consistent across PDA of different sizes diagnosed by echo.

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RESULTS

• With univariate analysis only, there were no significant differences in the proportion of infants with BPD, severe BPD, BPD or death, or death before 36 weeks between epoch 2 vs epoch 1
• However, when multiple confounding variables were included in multivariable logistic regression 🡪 infants in epoch 2, with later and less aggressive PDA treatment, had greater odds of poorer respiratory outcome, including BPD and BPD or death and treatment with postnatal steroids, compared with the earlier and more aggressive PDA treatment in epoch 1
• The rates of severe IVH (grade 3) or NEC did not change between epochs (severe IVH: 16.8% and 14.7% and NEC: 10.4% and 10.2% in epochs 1 and 2, respectively).

RESULTS

• Expectant PDA treatment failed to show superiority with aggressive PDA management.
• The PDA-TOLERATE randomized control trial showed similar results, with no improvement in respiratory outcome with early vs conservative PDA management.
• In addition, a randomized placebo-controlled trial of PDA non intervention vs oral ibuprofen did not result in a reduction in BPD or death.

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DISCUSSION

• Infants of 23-30 weeks of gestation diagnosed with PDA, adoption of a more expectant PDA management approach increased the risk of worse respiratory outcome in comparison with the earlier epoch that use of pharmacologic and surgical closure of the PDA.
• Randomized control trials including those performed by Van Overmeire, Kluckow, and this study, examined respiratory outcomes following early diagnosis and treatment of PDA vs delayed, expectant PDA treatment, and failed to show superiority with aggressive PDA management.

DISCUSSION

• The PDA-TOLERATE randomized control trial showed similar result
• In addition, a randomized placebo-controlled trial of PDA nonintervention vs oral ibuprofen did not result in a reduction in BPD or death

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DISCUSSION

• Factor that influenced PDA management
• The lack of efficacy of early and aggressive PDA management in numerous clinical trials,
• the potential for spontaneous PDA closure,
• Considerable rates of crossover from placebo to open label treatment in some trials,
• High failure rate of medical PDA treatments and their potential side effects,
• The lack of consensus in defining a hemodynamically significant PDA

DISCUSSION

• The results clearly demonstrated a change in PDA management
• with fewer infants receiving PDA treatment (54% vs 90%, P < .001) in the later time period of analysis (2011-2015), compared with the earlier time period (2005-2007).
• Multivariable regression analysis demonstrated significantly increased risk of BPD, composite of BPD or death and postnatal steroid administration

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DISCUSSION

• In conclusion, our single center cohort study showed that changes in PDA treatment strategy to a more expectant approach resulted in poorer respiratory outcome in spite of more favorable presentation and lower rates of confounding risk factors.
• These findings underline the importance of a more targeted approach to treat a PDA of well-defined hemodynamic significance and at the most appropriate time.

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CRITICAL APPRAISAL��COHORT STUDY

SECTION A�ARE THE RESULTS OF THE STUDY VALID?

• Population:
• All preterm infants GA 23-30 weeks with PDA confirmed by echo
• Admit NICU at Holtz Children’s Hospital of the University of Miami/Jackson Memorial Medical Center
• During January 1, 2005 to December 31, 2007 (epoch1), and January 1, 2011 to December 31, 2015 (epoch2)

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✔

• Risk factors:
• Postnatal age of first echo diagnosis
• Direction of shunt and size of PDA by echo (graded of PDA)
• Timing of initial PDA tx, tx administered, and incidence of PDA ligation
• Demographic data: GA, BW, SGA, race, sex, multiple pregnancy, preeclampsia, chorioamnionitis, antenatal steroid, Apgar score at 5 min
• Co-morbid: RDS, receiving mechanical ventilation on day 1, blood culture positive sepsis, and postnatal steroid for respiratory purposes

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• Try to detect beneficial or harmful effect:
• Decreased BPD?
• Use of postnatal steroid?
• Severe BPD or death?
• Other co-morbid?

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• Outcome:
• BPD
• Severe BPD
• Composite endpoints of BPD or death and severe BPD or death
• Other morbidities compared between epochs
• NEC (Bell stage 2 or higher) and severe IVH (grade III or higher)

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• Population:
• All preterm infants GA 23-30 weeks with PDA confirmed by echo
• Admit NICU at Holtz Children’s Hospital of the University of Miami/Jackson Memorial Medical Center
• During January 1, 2005 to December 31, 2007 (epoch1), and January 1, 2011 to December 31, 2015 (epoch2)

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• It is possible that additional practice changes that could impact respiratory outcomes between epochs
• Target range of arterial oxygen saturation differed minimally from 88%-96% to 90%-95% from epoch 1 to epoch 2

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• Objective outcome
• Definition
• BPD: receiving supplemental oxygen at 36 weeks PMA
• Severe BPD: receiving at least 30% inspired oxygen at 36 weeks PMA
• Composite endpoints of BPD or death and severe BPD or death: analyzed to adjust for the occurrence of death before 36 weeks PMA
• NEC: Bell stage 2 or higher
• Severe IVH: grade III or higher

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✔

A set of independent confounding variables that were considered to be risk factors for BPD including GA, race, sex, chorioamnionitis, 5-minute Apgar score <5, preeclampsia, multiple gestation, severe RDS, use of antenatal steroids, SGA, sepsis, and the need for MV on day 1 were initially included in the multivariable model.

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SECTION B�WHAT ARE THE RESULTS?

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SECTION C�WILL THE RESULTS HELP LOCALLY?

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• These findings underline the importance of a more targeted approach to treat a PDA of well-defined hemodynamic significance and at the most appropriate time
• This approach 🡪 avoid the progression of hemodynamic impact and the consequent worse respiratory outcome, while avoiding exposure to treatments and side effects in cases where the PDA poses little harm

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Thank you