Inhaled Nitric Oxide in Preterm Infants

Inhaled Nitric Oxide in Preterm Infants
Full Title: National Institutes of Health (NIH) State-of-the-Science Conference: Inhaled Nitric Oxide in Preterm Infants
Evidence-based Practice Center Systematic Review Protocol

Expected Release Date: late 2010

Contents
Background and Objectives for the Systematic Review
Key Questions
Analytic Framework
Methods
References
Definition of Terms
Summary of Protocol Amendments

Background and Objectives for the Systematic Review
The Agency for Healthcare Research and Quality (AHRQ) requested an evidence report on the use of "Inhaled Nitric Oxide in Preterm Infants," based on a comprehensive and systematic review of the scientific literature, other appropriate analyses, and extensive peer review of the draft protocol. Work for this report includes systematically searching, abstracting, reviewing and analyzing the scientific evidence for each key question regarding the use of inhaled nitric oxide in preterm infants, and evaluating variance, if any, of the evidence according to age, gender, race/ethnicity, birthweight and gestational age at birth.

Neonatal lung disease is the most common complication of preterm delivery, and results in significant morbidity and mortality.1 A systematic review of randomized clinical trials of fullterm infant and late preterm infants (i.e., born at 34 to 36 weeks gestation) with hypoxemic respiratory failure demonstrated that inhaled nitric oxide improved oxygenation and reduced the need for extracorporeal membrane oxygenation (ECMO).2 In 2000, the Food and Drug Administration approved inhaled nitric oxide for use in fullterm and late preterm infants with hypoxemic respiratory failure.

Since then, a number of studies have been conducted on the use of inhaled nitric oxide in clinically diverse populations of preterm infants.3-13 These studies demonstrate significant variability in their clinical indications for the use of inhaled nitric oxide, from its prophylactic use in preterm infants with mild acute respiratory distress to prevent Bronchopulmonary Dysplasia (BPD, chronic lung disease), to its use as a late rescue therapy for preterm infants with severe BPD, with resulting wide variations in inclusion and exclusion criteria for study samples. There has been considerable variation in dosage and timing of inhaled nitric oxide among studies. Differing findings regarding pulmonary effects and effects on the most common primary outcome variable, death or BPD, raises concerns about gaps in our understanding of physiological effects of inhaled nitric oxide in the rapidly developing preterm lung. Differences in the direction of effect on the developing preterm brain raises serious questions as to whether treatment of preterm infants with inhaled nitric oxide increases or decreases the incidence of brain injury.

This controversy has resulted in wide variations in clinical practice, as reports of the longer term pulmonary and neurodevelopmental outcomes at 2 to 6 years are just emerging. There has been increasing interest in the application of inhaled nitric oxide in a preterm population, in both the scientific and professional literature. This situation argues for an updated comprehensive and systematic review of the literature, thoughtful analyses of currently available and emerging data, extensive peer review of the draft report, and further discussion at an NIH State-of-the-Science Conference in October 2010.



Key Questions
1. Does inhaled nitric oxide (iNO) therapy increase survival and/or reduce the occurrence or severity of bronchopulmonary dysplasia (BPD) among premature infants who receive respiratory support? [Occurrence = incidence; respiratory support includes mechanical ventilation, CPAP, or supplemental oxygen alone]
2. Are there short-term risks of iNO therapy among premature infants who receive respiratory support? [Short-term = initial hospital course]
3. Are there effects of iNO therapy on long-term pulmonary and/or neurodevelopmental outcomes among premature infants who receive respiratory support? [Time frame/Long-term = initial hospital discharge home to school age]
4. Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary across subpopulations of premature infants? Subpopulations include:
4.1. Exposure to antenatal steroids, gestational age, small for gestational age (SGA), gender, race, birthweight, chorioamnionitis, socioeconomic status (SES), multiple birth.
4.2. Severity of respiratory illness (oxygen requirements, type and mode of ventilation, oxygenation index).
4.3. Causes of respiratory failure: respiratory distress syndrome (RDS), sepsis, pneumonia, premature prolonged rupture of membranes (PPROM) with possible pulmonary hypoplasia, pulmonary hypertension.
5. Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary by timing of initiation, mode of delivery, dose and duration, or concurrent (prostacyclin, phosphodiesterase inhibitors, ductal inhibitors, systemic steroids, surfactant, and vitamin A) therapies?
5.1. Postnatal age at initiation of therapy includes less than 72 hours, less than 7 days, and greater than or equal to 7 days.
5.2. Mode of drug delivery includes mechanical ventilation (conventional and high frequency ventilation, jet and oscillator), low-flow or high-flow nasal cannula, continuous positive airway pressure (CPAP), and heated, humidified, nasal cannula.
5.3. Dose, as parts per million (5, 10, 20) and cumulative dose.
5.4. Duration (up to 1 week, up to 1 month, greater than 1 month).
5.5. Concurrent therapy (systemic steroids, surfactant, vitamin A, indomethacin).

Population(s):
The target population will include preterm infants born before 34 weeks gestation who require respiratory support. We will impose no other age limitations and we will impose no sex, birthweight, or geographic limitations.

Interventions:
The only intervention to be studied is treatment with inhaled nitric oxide. No study of inhaled nitric oxide in preterm infants will be excluded because of dosage, timing, or duration of treatment.

Comparators:
Key Questions 1 to 5 address comparisons of preterm infants treated with inhaled nitric oxide with preterm infants who did not receive inhaled nitric oxide.

Outcomes for each question:

1. Outcomes for Key Questions 1, 4, and 5:

. BPD: receipt of supplemental oxygen at 36 weeks postmenstrual age.
.. Severe BPD: receiving oxygen and ventilatory support at 36 weeks postmenstrual age (including mechanical ventilation, CPAP and high flow nasal cannula at 2 lpm and higher); duration of ventilator support.
... Survival: to initial hospital discharge.


2. Outcomes for Key Question 2:

. Cardiopulmonary risk includes patent ductus arteriosus (PDA, requiring medical and/or surgical treatment); pulmonary hemorrhage; air leak; pulmonary hypertension (right heart failure); methemoglobinemia; bleeding.
.. Infectious risk includes sepsis, necrotizing enterocolitis (NEC).
... Neurological risk includes intraventricular hemorrhage (IVH, all grades and severe IVH); periventricular leukomalacia (PVL); other signs of white matter injury (WMI); retinopathy of prematurity (ROP requiring treatment); hydrocephalus requiring surgical drainage; ventriculomegaly.


3. Outcomes for Key Question 3:

. Pulmonary outcomes: rehospitalization for all causes and for respiratory disease; respiratory symptoms; need for respiratory medications (steroids, bronchodilators, diuretics); need for supplemental oxygen; poor pulmonary function assessments; presence of pulmonary hypertension (right heart disease).
.. Neurodevelopment outcomes: cognitive and motor delay (e.g., Bayley Scale of Infant Development Mental Developmental Index and Psychomotor Developmental Index); cerebral palsy (CP); visual impairment and blindness; hearing impairment and deafness; seizures; hydrocephalus requiring surgical interventions (e.g., VP shunts); school readiness and behavioral impairment; behavioral problems; social and emotional problems.
... Growth (height, weight, head circumference).
.... Chronic medical diseases and conditions, of the lungs and/or brain if any.
..... Survival: to childhood.


Timing:
We will focus our review on any published articles.

Settings:
No restrictions as to setting of study will be applied including country where study was located.



Analytic Framework
Select for the analytic framework (36 KB).
http://www.ahrq.gov/clinic/tp/inofig1.htm



We will use a toxicology framework for infants and children as we consider iNO and the physiology of the developing preterm lung and brain.14-16 Neurodevelopmental disabilities and functional outcomes of children exposed to iNO as preterm infants will be used to assess neurodevelopment.

The analytic framework illustrates the patient population, preterm infants <34 weeks gestation treated with inhaled nitric oxide (iNO); subgroups of interest; treatment characteristics, such as dose of iNO; and short and long-term infant outcomes. Short-term outcomes measure adverse events and clinical outcomes associated with iNO treatment that occur during the initial hospitalization after birth. Long-term outcomes reflect the effects of iNO treatment on infant health and functional outcome in early childhood and include measures of chronic pulmonary disease, growth, developmental delay and disability, and survival.



Methods
A. Criteria for Inclusion/Exclusion of Studies in the Review

- We will only include randomized controlled trials (RCTs) on the use of inhaled nitric oxide for Key Questions 1 and 2. Studies addressing Key Question 3, 4 or 5 will not be limited by study design.

- We are interested in studies evaluating both short-term (hospital outcomes including mortality) and long-term risks and outcomes (pulmonary and neurological function in childhood). Studies will be selected if they address either short or long-term outcomes.

- Currently, we do not plan on restricting study inclusion by sample size. Articles will not be excluded if they are written in a language other than English, however, we will include only studies written in English for data abstraction. We will track the number of articles that apply to our key questions that are published in other languages. We will only include studies conducted on humans.

B. Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions

We will conduct searches of the following databases:

.MEDLINE® (via PubMed).
.EMBASE.
.The Cochrane Library (including the Cochrane CENTRAL Register of Controlled Trials).
.PsycINFO.

Comprehensive search strategies will be developed through an analysis of studies known to be eligible for this review and related systematic reviews. These strategies will combine controlled vocabulary terms (i.e., MeSH, EMTREE terms) with free-text terms. As an example, our preliminary search strategies are provided in Appendix 1 [http://www.ahrq.gov/clinic/tp/inoap1.htm]. We will scan the reference lists of all eligible articles by January 1, 2010.

As information on long-term outcome of infants treated with iNO is just emerging, we also intend to consider for our review the relevant data from proceedings of the Pediatric Academic Societies Meeting in 2009.17-21 Researchers presenting data in this forum that has not yet been published will be contacted and asked to share results for specific outcomes from their studies. For example, investigators from France presented, in abstract form, clinical, respiratory, and neurodevelopmental outcomes at 7 years of age for preterm infant with respiratory failure randomized to iNO or placebo within 48 hours after birth.19-21 In addition, we will search ClinicalTrials.gov for ongoing or completed trials and seek information from the investigators registered. Schreiber et al. recently completed (March 2009) school aged outcomes (ages 4-7 years) of preterm infants enrolled in the NOVA trial of iNO (ClinicalTrials.gov identifier NCT00152542). Outcomes include school-readiness and health status as measured by a neurodevelopmental examination. Functional Independence Measure for Children (WeeFIM) survey, hearing and visual screening exams, and parent and teacher surveys; these data have not yet been published. Inclusion of these data should result in the most current information available.

C. Data Abstraction and Data Management

The Johns Hopkins University (JHU) EPC will be using the new system, DistillerSR, to manage the screening and review process. It manages all levels of the review process. All applicable citations identified by the search strategies are uploaded to the system and managed in the following manner:

i. Abstract screening: Each title and abstract is reviewed by 2 independent reviewers. Both reviewers must agree on whether or not an abstract is eligible. If there is disagreement between the 2 reviewers, the following protocol will be followed:
a. The reviewer who indicated that the article is eligible for the next level of review will first re-evaluate his/her answer. If he/she agrees it should be excluded, he/she will change the answer in the SRS system and the conflict is resolved.
b. If the first reviewer (above) believes that the article is eligible for the next level of review he/she will contact the second reviewer with the rationale for inclusion. The second reviewer will re-evaluate his/her answer. If he/she agrees with reviewer 1 he/she will change the answer in the SRS system.
c. If the first and second reviewers (above) cannot come to an agreement, the abstract will be discussed at a meeting of investigators.
ii. Full-text article screening: The review protocol for this level is the same as for the abstract inclusion/exclusion level.
iii. Data abstraction: Eligible articles will be sent to data abstraction. Forms to abstract details about the study design and conduct, the population, intervention(s) and outcomes will be designed to answer the key questions.

D. Assessment of Risk of Bias of Individual Studies

The review of eligible studies to assess the risk of bias or methodological quality is very important. The elements of critical appraisal will be designed by both methodologists and clinicians since study design features and relevant clinical measurements may influence the risk of bias. Our approach is to involve both methodologists and clinicians in construction of explicit criteria and in the appraisal of studies.

We will assess the risk of bias for individual studies at the inclusion/exclusion stage such as through the inclusion of stronger study designs, including only randomized controlled trials or quasi-randomized controlled trials for Key Questions 1 and 2. During the review of individual studies, we will complete critical appraisal. Instruments designed for specific study designs will be used along with quality tools previously used by this EPC.

We will assess the risk of bias and appropriateness of all studies that meet our eligibility criteria, following the guidance contained in the EPC Program's methods guide (available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=318, Chapter 6). We will use a limited number of key criteria that are most appropriate for each study design and that are most important for determining the validity of the studies. We will add criteria, if necessary, to assess unique aspects of the design and conduct of studies on a given topic. Individual study quality will be classified as "good", "fair," or "poor" based on the degree to which they adhere to the defined criteria. We will also assess other elements of study design that affect the applicability of the studies. Generally, a "good" study at least partially fulfills all criteria. A "fair" study does not meet at least one important criterion, or generally meets most criteria but has a major flaw. A "poor" study does not meet most criteria, or has a fatal flaw. For randomized controlled trials, important criteria include randomization method, allocation concealment, blinding or masking, dropouts and withdrawals, and method of statistical analysis (intention to treat).

We will seek advice from our advisors and technical experts regarding the need for additional study appraisal criteria. The additional criteria may include, but are not limited to, comparability of groups assembled at baseline, and reliability and validity of outcome measures. The evidence report will include a description and listing of each study's strengths and weaknesses.

E. Data Synthesis

Based on preliminary literature searches, we believe the studies will support a meta-analysis.

F. Grading the Evidence for Each Key Question

We will assess/rate the strength of the body of evidence according to predetermined criteria, such as by using the GRADE system (www.bmj.com, June 19, 2004). At a minimum, we will assess the overall strength of the evidence on each question, taking into consideration: study design, overall internal validity of studies, direction and magnitude of associations, consistency of findings, directness of the evidence, and overall external validity.



References
1. Behrman RE, Butler AS, Institute of Medicine (U.S.). Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Preterm birth: causes, consequences, and prevention. Washington, D.C.: National Academies Press; 2007.

2. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006:CD000399.

3. Hintz SR, Van Meurs KP, Perritt R, et al. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr 2007;151:16-22.

4. Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2007:CD000509.

5. Hoehn T, Krause MF, Buhrer C. Meta-analysis of inhaled nitric oxide in premature infants: an update. Klin Padiatr 2006;218:57-61.

6. Steinhorn RH, Porta NF. Use of inhaled nitric oxide in the preterm infant. Curr Opin Pediatr 2007;19:137-41.

7. Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. NEJM 2006;355:343-53.

8. Huddy CL, Bennett CC, Hardy P, et al. The INNOVO multicentre randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008;93:F430-5.

9. Hoo AF, Beardsmore CS, Castle RA, et al. Respiratory function during infancy in survivors of the INNOVO trial. Pediatr Pulmonol 2009;44:155-61.

10. Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. NEJM 2006;355:354-64.

11. Tanaka Y, Hayashi T, Kitajima H, Sumi K, Fujimura M. Inhaled nitric oxide therapy decreases the risk of cerebral palsy in preterm infants with persistent pulmonary hypertension of the newborn. Pediatrics 2007;119:1159-64.

12. Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. NEJM 2005;353:13-22.

13. Van Meurs KP, Hintz SR, Ehrenkranz RA, et al. Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure. J Perinatol 2007;27:347-52.

14. Weinberger B, Laskin DL, Heck DE, Laskin JD. The toxicology of inhaled nitric oxide. Toxicol Sci 2001;59:5-16.

15. Truog WE. Inhaled nitric oxide for the prevention of bronchopulmonary dysplasia. Expert Opin Pharmacother 2007;8:1505-13.

16. Gressens P, Rogido M, Paindaveine B, Sola A. The impact of neonatal intensive care practices on the developing brain. J Pediatr 2002;140:646-53.

17. Kinsella JP CG, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. Outcomes of premature infants enrolled in the early inhaled nitric oxide for the prevention of chronic lung disease trial. Pediaric Research 2009:E2155.6.

18. Keller RL WM, Vittinghoff E, Palermo L, Ballard PL, Ballard RA. Response to inhaled nitric oxide (iNO) and neurodevelopmental impairment (NDI) in NO CLD. Pediatric Research 2009:E2155.7.

19. Hascoet JM MF, Schweitzer C, Tankeu S, Hamon I. Respiratory outcome at 7 years of age in former sick premature infants treated with inhaled nitric oxide (iNO). Pediatric Research 2009:E3861.198.

20. Hamon I DH, Espagne S, Gaga S, Selton D, Hascoet JM. Neurodevelopmental and cognitive outcomes at school age of premature infants treated at birth with inhaled nitric oxide (iNO). Pediatric Research 2009:E4356.462.

21. Hamon I GS, Espagne S, Merdariu D, Debruille C, Hascoet JM. Clinical outcome at 7 years of age in former premature infants treated at birth with inhaled nitric oxide (iNO). Pediatric Research 2009:E3450.6.



Definition of Terms
Air leak = conditions that presumably result from alveolar rupture, including pulmonary interstitial emphysema (i.e. air dissection) and pneumothorax (i.e., accumulation of air between lung and pleura).

All IVH = all grades of severity of IVH, including germinal matrix hemorrhage, choroid plexus hemorrhage and intraparenchymal hemorrhage.

Bronchopulmonary Dysplasia = BPD = chronic lung disease = receipt of supplemental oxygen at 36 weeks postmenstrual age.

Cardiopulmonary risk includes patent ductus arteriosus, pulmonary hemorrhage, air leak and methemoglibinemia.

Continuous positive airway pressure = CPAP.

Duration of ventilator support = length of time the infant is on a mechanical ventilator.

Growth = height, weight and head circumference.

High frequency ventilation = ventilation with an oscillator or jet ventilator, which deliver gas at very high frequencies.

Hydrocephalus = increase in intracranial pressure with ventricular enlargement, requiring surgical drainage, including placement of a ventriculoperitoneal (VP) shunt.

Intraparenchymal hemorrhage = blood within the brain tissue.

Intraventricular hemorrhage = IVH = blood in the ventricles, with or without enlargement of the ventricles.

Methemoglobinemia = high amount of methemoglobin, a toxic by product of inhaled nitric oxide, in the blood.

Necrotizing enterocolitis = NEC = requiring medical or surgical treatment.

Neurodevelopmental outcomes include cognitive and motor assessments (e.g. Bayley Scale of Infant Development), cerebral palsy, visual impairment and blindness, seizures, hearing impairment and deafness, hydrocephalus requiring surgical interventions (e.g. VP shunts), and school readiness and behavioral impairments..

Neurological risks are evidence of brain injury, and include intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity requiring treatment, hydrocephalus requiring surgical drainage, ventriculomegaly.

Occurrence = incidence.

Oxygenation index = (FiO2 x MAP x 100) / PaO2.

Patent ductus arteriosus = PDA= failure of the ductus arteriosus to close after premature birth, requiring medical treatment (i.e., indomethacin, ibuprofen, fluid restriction) or surgical ligation.

Periventricular leukomalacia = PVL = white matter injury with resorption of brain tissue and formation of cysts.

Phosphodiesterase Inhibitors = caffeine, theophylline, milrinone, sildenafil.

Postmenstrual age = PMA = Gestational age at birth plus chronological age.

Premature infants for this project are infants born before 34 weeks gestation.

Premature prolonged rupture of membranes = PPROM = rupture of chorioamniotic membranes prior to term and greater than 24 hours before birth.

Prostocyclin = a potent vasodilator and inhibitor of platelet agregation .

Pulmonary hypertension = increased pulmonary artery pressure to at or above systemic blood pressure, due to increased pulmonary vasculature resistence, right-heart failure.

Pulmonary hypoplasia = lungs that are too small and/or immature to support extrauterine life.

Pulmonary outcomes include rehospitalizations for respiratory disease or any reason, respiratory symptoms (e.g., wheezing, recurring cough), use of respiratory medications (including steroids, bronchodilators and diuretics), use of supplemental oxygen, pulmonary functional assessments and pulmonary hypertension.

Respiratory distress syndrome = RDS = Lung disease of a premature infant.

Respiratory support includes mechanical ventilation, CPAP, or supplemental oxygen alone.

Retinopathy of Prematurity = ROP requiring treatment.

Severe BPD = receiving oxygen and ventilatory support (including CPAP, high flow nasal cannula at 2 lpm or more, or mechanical ventilation) at 36 weeks postmenstrual age.

Severe IVH includes enlarged ventricles filled with blood and intraparenchymal hemorrhage .

Short-term = during initial hospitalization.

Small for gestational age = SGA = birthweight at or below 10th percentile for gestational age at birth.

Socioeconomic status = SES = As defined by each study.

Survival = survival at 36 weeks postmenstrual age or later, if available (Short-term survival = survival to initial hospital discharge/long-term survival = survival to childhood).

Vapotherm delivers by nasal cannula gas that has been humidified.

Ventriculomegaly = any ventricular enlargement.


Summary of Protocol Amendments
In the event of protocol amendments, the date of each amendment will be accompanied by a description of the change and the rationale.

Note: The following protocol elements are standard procedures for all protocols.

Review of Key Questions

For Comparative Effectiveness reviews the key questions were posted for public comment and finalized after review of the comments. For other systematic reviews, key questions submitted by partners are reviewed and refined as needed by the EPC and the Technical Expert Panel (TEP) to assure that the questions are specific and explicit about what information is being reviewed.


Technical Expert Panel (TEP)

A TEP panel is selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicted opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design and/or methodological approaches do not necessarily represent the views of individual technical and content experts. The TEP provides information to the EPC to identify literature search strategies, review the draft report and recommend approaches to specific issues as requested by the EPC. The TEP does not do analysis of any kind nor contribute to the writing of the report.

Peer Review (Standard Language)

Approximately five experts in the field will be asked to peer review the draft report and provide comments. The peer reviewer may represent stakeholder groups such as professional or advocacy organizations with knowledge of the topic. On some specific reports such as reports requested by the Office of Medical Applications of Research, National Institutes of Health there may be other rules that apply regarding participation in the peer review process. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will, for Comparative Effectiveness Reviews (CERs) and Technical Briefs, be published three months after the publication of the Evidence Report.

It is our policy not to release the names of the peer reviewers or TEP panel members until the report is published so that they can maintain their objectivity during the review process.

Current as of February 2010
(Revised February 22, 2010)

Internet Citation:

Inhaled Nitric Oxide in Preterm Infants, Systematic Review Protocol. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/tp/inoinftp.htm