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Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials.

Sood BG, Keszler M, Garg M, Klein JM, Ohls R, Ambalavanan N, Cotten CM, Malian M, Sanchez PJ, Lakshminrusimha S, Nelin LD, Van Meurs KP, Bara R, Saha S, Das A, Wallace D, Higgins RD, Shankaran S, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Netwo - Trials (2014)

Bottom Line: Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators.No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.These two pilot RCTs failed to recruit adequate eligible newborns with NHRF.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. bsood@med.wayne.edu.

ABSTRACT

Background: Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.

Methods: Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.

Results: No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.

Conclusions: These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.

Trial registration: CLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.

No MeSH data available.


Related in: MedlinePlus

Diagram of nebulizer setup in neonatal ventilator circuit. Figure legend: ETT, endotracheal tube; INO, inhaled nitric oxide; CMV, conventional mechanical ventilation; HFV, high frequency ventilation; IPGE1, inhaled PGE1 (Pfizer, New York, NY, USA).
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Fig1: Diagram of nebulizer setup in neonatal ventilator circuit. Figure legend: ETT, endotracheal tube; INO, inhaled nitric oxide; CMV, conventional mechanical ventilation; HFV, high frequency ventilation; IPGE1, inhaled PGE1 (Pfizer, New York, NY, USA).

Mentions: PGE1 solution for aerosolization was prepared from synthetic PGE1 (Prostin VR (Alprostadil) 500 μg/ml in 1 ml dehydrated ethanol, Pfizer, New York, NY, USA) by dilution in sterile 0.9% saline (Sodium Chloride 0.9% Injection USP, Hospira Inc., Lake Forest, IL, USA). Fresh solutions were prepared every 24 hours. Aerosol administration began with a PGE1 dosage of either 300 or 150 ng/kg/min diluted in 4 ml preservative-free sterile normal saline/hr in study patients, and 4 ml sterile normal saline/hr in control patients. The study medication was delivered using a syringe pump into the nebulizer chamber of the MiniHeart low flow jet nebulizer (WestMed Inc., Tucson, Arizona, United States) (Figure 1). The nebulizer was placed approximately 50 cm from the endotracheal tube for CNV, and approximately 35 cm from the endotracheal tube in HFOV, based on bench studies to determine the emitted dose [26]. The nebulizer chamber was primed with 2 ml of study medication at study aerosol initiation. For weaning purposes, normal saline was administered using a second syringe pump with a Y-connection into the nebulizer chamber with increasing dose as the study drug aerosol dose was decreased, such that the total volume delivered was always 4 ml/hour. During aerosol administration, FiO2 delivered in the gas flow through the nebulizer was matched to that delivered in the ventilator circuit.Figure 1


Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials.

Sood BG, Keszler M, Garg M, Klein JM, Ohls R, Ambalavanan N, Cotten CM, Malian M, Sanchez PJ, Lakshminrusimha S, Nelin LD, Van Meurs KP, Bara R, Saha S, Das A, Wallace D, Higgins RD, Shankaran S, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Netwo - Trials (2014)

Diagram of nebulizer setup in neonatal ventilator circuit. Figure legend: ETT, endotracheal tube; INO, inhaled nitric oxide; CMV, conventional mechanical ventilation; HFV, high frequency ventilation; IPGE1, inhaled PGE1 (Pfizer, New York, NY, USA).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4414424&req=5

Fig1: Diagram of nebulizer setup in neonatal ventilator circuit. Figure legend: ETT, endotracheal tube; INO, inhaled nitric oxide; CMV, conventional mechanical ventilation; HFV, high frequency ventilation; IPGE1, inhaled PGE1 (Pfizer, New York, NY, USA).
Mentions: PGE1 solution for aerosolization was prepared from synthetic PGE1 (Prostin VR (Alprostadil) 500 μg/ml in 1 ml dehydrated ethanol, Pfizer, New York, NY, USA) by dilution in sterile 0.9% saline (Sodium Chloride 0.9% Injection USP, Hospira Inc., Lake Forest, IL, USA). Fresh solutions were prepared every 24 hours. Aerosol administration began with a PGE1 dosage of either 300 or 150 ng/kg/min diluted in 4 ml preservative-free sterile normal saline/hr in study patients, and 4 ml sterile normal saline/hr in control patients. The study medication was delivered using a syringe pump into the nebulizer chamber of the MiniHeart low flow jet nebulizer (WestMed Inc., Tucson, Arizona, United States) (Figure 1). The nebulizer was placed approximately 50 cm from the endotracheal tube for CNV, and approximately 35 cm from the endotracheal tube in HFOV, based on bench studies to determine the emitted dose [26]. The nebulizer chamber was primed with 2 ml of study medication at study aerosol initiation. For weaning purposes, normal saline was administered using a second syringe pump with a Y-connection into the nebulizer chamber with increasing dose as the study drug aerosol dose was decreased, such that the total volume delivered was always 4 ml/hour. During aerosol administration, FiO2 delivered in the gas flow through the nebulizer was matched to that delivered in the ventilator circuit.Figure 1

Bottom Line: Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators.No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.These two pilot RCTs failed to recruit adequate eligible newborns with NHRF.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. bsood@med.wayne.edu.

ABSTRACT

Background: Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.

Methods: Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.

Results: No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.

Conclusions: These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.

Trial registration: CLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.

No MeSH data available.


Related in: MedlinePlus