Nebulized Pentoxifylline for Reducing the Duration of Oxygen Supplementation in Extremely Preterm Neonates Sven M. Schulzke, MD, MSc, FRACP1,2, Mangesh Deshmukh, FRACP1,3, Elizabeth A. Nathan, BSc4, Dorota A. Doherty, PhD4, and Sanjay K. Patole, FRACP, DrPH1,3 Objective To evaluate the efficacy and safety of nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates at high risk of bronchopulmonary dysplasia (BPD).
Study design Single-center, randomized, double-blind, placebo-controlled trial was conducted. Infants of 230 to 276 weeks’ gestational age requiring mechanical ventilation or $30% supplemental oxygen on continuous positive airway pressure at 72-168 hours were randomized to receive 20 mg/kg (1 mL/kg) nebulized pentoxifylline or an equal volume of normal saline placebo every 6 hours for 10 consecutive days via a vibrating mesh nebulizer. The primary outcome was the duration of oxygen supplementation at 40 weeks’ postmenstrual age. We used Cox proportional hazards regression modeling to analyze outcomes. Results All infants had adequate data for analysis of the primary outcome. Intention-to-treat analysis revealed no differences in duration of oxygen supplementation at 40 weeks’ postmenstrual age between pentoxifylline (n = 41) and placebo (n = 40) groups (median 2262 vs 2160 hours, adjusted hazard ratio: 1.14, 95% CI 0.72-1.80, P = .63). There was no difference in mortality and further secondary outcomes. No adverse effects were noted. Conclusions Nebulized pentoxifylline is safe but did not reduce the duration of oxygen supplementation in extremely preterm infants at high risk of BPD. Dose-ranging studies and large, well-designed clinical trials are required to determine whether the use of nebulized or systemic pentoxifylline as a prophylactic therapy offers small but relevant benefits for prevention of BPD. (J Pediatr 2015;-:---). Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12611000145909.
B
ronchopulmonary dysplasia (BPD) is a common complication in extremely preterm neonates born below 28 weeks’ gestational age (GA). Recent data from the National Institute of Child Health and Human Development Neonatal Research Network suggest that despite advances in perinatal care, the incidence of BPD in this population remains greater than 40%.1 Preterm neonates with a diagnosis of BPD have greater postdischarge mortality and morbidity such as reduced long-term cardiorespiratory function, increased risk of rehospitalization, and poor neurodevelopmental outcome.2-7 In many infants with BPD, a pulmonary inflammatory reaction occurs shortly after birth and, subsequently, proinflammatory cytokines such as interleukin-6, interleukin-8, and tumor necrosis factor-alpha (TNF-a) can be found in tracheal aspirate.8-10 Pharmacologic prophylaxis of BPD with corticosteroids is an attractive strategy because of their strong antiinflammatory properties. Although the use of systemic corticosteroids within the first week of life is effective in reducing the incidence of BPD, this intervention may cause numerous short- and long-term adverse effects.11 In contrast, published randomized trials on inhaled corticosteroids for prevention of BPD suggested no significant benefits or harms associated with inhaled treatment.12 Pentoxifylline, a methylxanthine derivative with unique immunomodulatory properties, down-regulates the production of powerful inflammatory cytokines such as interleukin-6, TNF-a, and interferon gamma.13 In vitro and animal studies revealed that pentoxifylline inhibits TNF-a production from human alveolar macrophages and prevents TNF-a–induced lung injury.14,15 Pentoxifylline stimulates the function of neonatal mouse neutrophils at low-to-moderate concentrations (0.1100 mg/mL) but suppresses neutrophil chemotaxis at greater concentrations (1000 mg/mL).16 There is very little information on pharmacokinetics and pharmacodynamics of nebulized pentoxifylline in neonates; Lauterbach and Szymura-Oleksiak reported plasma pentoxifylline concentrations (mean, 0.2 mg/mL) in preterm neonates receiving nebulized pentoxifylline (20 mg/kg and 10 mg/kg 6 hourly for 3 days if spontaneously breathing and mechanically ventilated, respectively)
BPD CPAP GA HR PMA TNF-a
Bronchopulmonary dysplasia Continuous positive airway pressure Gestational age Hazard ratio Postmenstrual age Tumor necrosis factor-alpha
From the 1Centre for Neonatal Research and Education, The University of Western Australia, Crawley, Australia; 2 University Children’s Hospital Basel (UKBB), Basel, Switzerland; 3Neonatal Clinical Care Unit, King Edward Memorial Hospital for Women; and 4Women and Infants Research Foundation, Subiaco, Australia Supported by Neonatal Clinical Care Unit, King Edward Memorial Hospital, Perth, Western Australia. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.01.040
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
to be approximately 20-fold lower than those in neonates receiving the drug intravenously (60 mg/kg/day) over 6 days for sepsis.17 A systematic review suggested that intravenous pentoxifylline at a dose of 30-60 mg/kg/day as an adjunct to antibiotics decreases mortality in preterm neonates with blood culture-positive sepsis without significant adverse effects.18 A pilot randomized trial of nebulized pentoxifylline vs placebo for the prevention of BPD in preterm neonates indicated a reduced proportion of infants developing BPD in the pentoxifylline group.19 Unfortunately, the methodologic quality of the latter trial was compromised by a lack of blinding strategies and incomplete reporting of outcomes. We tested the efficacy and safety of nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates at high risk of BPD in a randomized, double-blind, placebo-controlled trial.
Methods We recruited infants for this single-center trial from the neonatal clinical care unit at King Edward Memorial Hospital for Women, Perth, Western Australia. The study was approved by the Women and Newborn Health Service Ethics Committee, and written informed consent was obtained from a parent or guardian of every study infant. No external funding sources were used. Infants of 230 to 276 weeks’ GA were eligible for study if they required mechanical ventilation or $30% supplemental oxygen on bubble continuous positive airway pressure (CPAP) of 5-8 cmH2O at 72-168 hours of life. Infants were excluded if they had a known congenital malformation potentially affecting breathing. All infants had been intubated because of clinical signs of respiratory distress syndrome; all had received surfactant within the first hour after birth (200 mg/kg Curosurf; Chiesi Farmaceutici, Parma, Italy) and caffeine citrate from day one of life. Standard of care in intubated infants further included the use of volume-targeted ventilation using Draeger Babylog 8000plus ventilators (tidal volume target, 4-6 mL/kg; Draeger AG & Co, L€ ubeck, Germany). Oxygen saturation targets were based on clinical standard operating procedures and were as follows: GA or postmenstrual age (PMA) 180 beats/min, bradycardia 15 seconds, tachypnea >60/min starting during nebulization, flow sensor alarms deemed to be related to nebulization, and any other significant adverse event). Statistical Analyses Aiming at a statistical power of 80% on the 5% significance level and assuming a loss to follow-up of 20%, we planned to recruit 90 infants to analyze data from at least 76 patients. The sample size for this pilot trial allowed us to detect a 50% reduction in the primary outcome “duration of supplemental oxygen at 40 weeks’ PMA or discharge” using Cox proportional hazards regression modeling. Descriptive statistics for demographic data were based on frequency distributions and medians, IQRs, and ranges for categorical and continuous data, respectively. Univariate analysis included c2 and Fisher exact tests for categorical comparisons, and Mann-Whitney U and t tests for continuous outcomes. Duration of supplemental oxygen, mechanical ventilation, CPAP, respiratory support, and hospital stay were estimated by the use of Kaplan-Meier probability estimates. Deaths were censored and neonates who continued on oxygen supplementation after 40 weeks’ PMA or discharge (whichever occurred first) were censored for the primary outcome. Multivariable analysis was conducted using Cox proportional hazards regression modeling to investigate the simultaneous effect of pentoxifylline and other factors that potentially influence neonatal outcome. Covariate effects were summarized using hazard ratios (HRs) and their 95% CIs. Statistical analysis was conducted using Stata 10 (Stata Statistical Software; StataCorp LP, College Station, Texas). Schulzke et al
- 2015
ORIGINAL ARTICLES
All hypothesis tests were 2-sided, and a P value of
Study design Single-center, randomized, double-blind, placebo-controlled trial was conducted. Infants of 230 to 276 weeks’ gestational age requiring mechanical ventilation or $30% supplemental oxygen on continuous positive airway pressure at 72-168 hours were randomized to receive 20 mg/kg (1 mL/kg) nebulized pentoxifylline or an equal volume of normal saline placebo every 6 hours for 10 consecutive days via a vibrating mesh nebulizer. The primary outcome was the duration of oxygen supplementation at 40 weeks’ postmenstrual age. We used Cox proportional hazards regression modeling to analyze outcomes. Results All infants had adequate data for analysis of the primary outcome. Intention-to-treat analysis revealed no differences in duration of oxygen supplementation at 40 weeks’ postmenstrual age between pentoxifylline (n = 41) and placebo (n = 40) groups (median 2262 vs 2160 hours, adjusted hazard ratio: 1.14, 95% CI 0.72-1.80, P = .63). There was no difference in mortality and further secondary outcomes. No adverse effects were noted. Conclusions Nebulized pentoxifylline is safe but did not reduce the duration of oxygen supplementation in extremely preterm infants at high risk of BPD. Dose-ranging studies and large, well-designed clinical trials are required to determine whether the use of nebulized or systemic pentoxifylline as a prophylactic therapy offers small but relevant benefits for prevention of BPD. (J Pediatr 2015;-:---). Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12611000145909.
B
ronchopulmonary dysplasia (BPD) is a common complication in extremely preterm neonates born below 28 weeks’ gestational age (GA). Recent data from the National Institute of Child Health and Human Development Neonatal Research Network suggest that despite advances in perinatal care, the incidence of BPD in this population remains greater than 40%.1 Preterm neonates with a diagnosis of BPD have greater postdischarge mortality and morbidity such as reduced long-term cardiorespiratory function, increased risk of rehospitalization, and poor neurodevelopmental outcome.2-7 In many infants with BPD, a pulmonary inflammatory reaction occurs shortly after birth and, subsequently, proinflammatory cytokines such as interleukin-6, interleukin-8, and tumor necrosis factor-alpha (TNF-a) can be found in tracheal aspirate.8-10 Pharmacologic prophylaxis of BPD with corticosteroids is an attractive strategy because of their strong antiinflammatory properties. Although the use of systemic corticosteroids within the first week of life is effective in reducing the incidence of BPD, this intervention may cause numerous short- and long-term adverse effects.11 In contrast, published randomized trials on inhaled corticosteroids for prevention of BPD suggested no significant benefits or harms associated with inhaled treatment.12 Pentoxifylline, a methylxanthine derivative with unique immunomodulatory properties, down-regulates the production of powerful inflammatory cytokines such as interleukin-6, TNF-a, and interferon gamma.13 In vitro and animal studies revealed that pentoxifylline inhibits TNF-a production from human alveolar macrophages and prevents TNF-a–induced lung injury.14,15 Pentoxifylline stimulates the function of neonatal mouse neutrophils at low-to-moderate concentrations (0.1100 mg/mL) but suppresses neutrophil chemotaxis at greater concentrations (1000 mg/mL).16 There is very little information on pharmacokinetics and pharmacodynamics of nebulized pentoxifylline in neonates; Lauterbach and Szymura-Oleksiak reported plasma pentoxifylline concentrations (mean, 0.2 mg/mL) in preterm neonates receiving nebulized pentoxifylline (20 mg/kg and 10 mg/kg 6 hourly for 3 days if spontaneously breathing and mechanically ventilated, respectively)
BPD CPAP GA HR PMA TNF-a
Bronchopulmonary dysplasia Continuous positive airway pressure Gestational age Hazard ratio Postmenstrual age Tumor necrosis factor-alpha
From the 1Centre for Neonatal Research and Education, The University of Western Australia, Crawley, Australia; 2 University Children’s Hospital Basel (UKBB), Basel, Switzerland; 3Neonatal Clinical Care Unit, King Edward Memorial Hospital for Women; and 4Women and Infants Research Foundation, Subiaco, Australia Supported by Neonatal Clinical Care Unit, King Edward Memorial Hospital, Perth, Western Australia. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.01.040
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
to be approximately 20-fold lower than those in neonates receiving the drug intravenously (60 mg/kg/day) over 6 days for sepsis.17 A systematic review suggested that intravenous pentoxifylline at a dose of 30-60 mg/kg/day as an adjunct to antibiotics decreases mortality in preterm neonates with blood culture-positive sepsis without significant adverse effects.18 A pilot randomized trial of nebulized pentoxifylline vs placebo for the prevention of BPD in preterm neonates indicated a reduced proportion of infants developing BPD in the pentoxifylline group.19 Unfortunately, the methodologic quality of the latter trial was compromised by a lack of blinding strategies and incomplete reporting of outcomes. We tested the efficacy and safety of nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates at high risk of BPD in a randomized, double-blind, placebo-controlled trial.
Methods We recruited infants for this single-center trial from the neonatal clinical care unit at King Edward Memorial Hospital for Women, Perth, Western Australia. The study was approved by the Women and Newborn Health Service Ethics Committee, and written informed consent was obtained from a parent or guardian of every study infant. No external funding sources were used. Infants of 230 to 276 weeks’ GA were eligible for study if they required mechanical ventilation or $30% supplemental oxygen on bubble continuous positive airway pressure (CPAP) of 5-8 cmH2O at 72-168 hours of life. Infants were excluded if they had a known congenital malformation potentially affecting breathing. All infants had been intubated because of clinical signs of respiratory distress syndrome; all had received surfactant within the first hour after birth (200 mg/kg Curosurf; Chiesi Farmaceutici, Parma, Italy) and caffeine citrate from day one of life. Standard of care in intubated infants further included the use of volume-targeted ventilation using Draeger Babylog 8000plus ventilators (tidal volume target, 4-6 mL/kg; Draeger AG & Co, L€ ubeck, Germany). Oxygen saturation targets were based on clinical standard operating procedures and were as follows: GA or postmenstrual age (PMA) 180 beats/min, bradycardia 15 seconds, tachypnea >60/min starting during nebulization, flow sensor alarms deemed to be related to nebulization, and any other significant adverse event). Statistical Analyses Aiming at a statistical power of 80% on the 5% significance level and assuming a loss to follow-up of 20%, we planned to recruit 90 infants to analyze data from at least 76 patients. The sample size for this pilot trial allowed us to detect a 50% reduction in the primary outcome “duration of supplemental oxygen at 40 weeks’ PMA or discharge” using Cox proportional hazards regression modeling. Descriptive statistics for demographic data were based on frequency distributions and medians, IQRs, and ranges for categorical and continuous data, respectively. Univariate analysis included c2 and Fisher exact tests for categorical comparisons, and Mann-Whitney U and t tests for continuous outcomes. Duration of supplemental oxygen, mechanical ventilation, CPAP, respiratory support, and hospital stay were estimated by the use of Kaplan-Meier probability estimates. Deaths were censored and neonates who continued on oxygen supplementation after 40 weeks’ PMA or discharge (whichever occurred first) were censored for the primary outcome. Multivariable analysis was conducted using Cox proportional hazards regression modeling to investigate the simultaneous effect of pentoxifylline and other factors that potentially influence neonatal outcome. Covariate effects were summarized using hazard ratios (HRs) and their 95% CIs. Statistical analysis was conducted using Stata 10 (Stata Statistical Software; StataCorp LP, College Station, Texas). Schulzke et al
- 2015
ORIGINAL ARTICLES
All hypothesis tests were 2-sided, and a P value of
