NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Allen MC, Donohue P, Gilmore M, et al. Inhaled Nitric Oxide in Preterm Infants. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Oct. (Evidence Reports/Technology Assessments, No. 195.)
This publication is provided for historical reference only and the information may be out of date.
Evidence Table 1Risk of bias in randomized controlled trials
| Author, year | Followup studies | sequence adequately generated | allocation adequately concealed | allocated intervention adequately prevented for personnel during the study(ST) | allocated intervention adequately prevented for outcome assessors during the study (LT) | allocated intervention adequately prevented for personnel during the study(LT) | allocated intervention adequately prevented for outcome assessors during the study (LT) | incomplete outcome data adequately addressed (ST) | incomplete outcome data adequately addressed (LT) | reports of the study free of suggestion of selective outcome reporting | free of other problems that could put it at a high risk of bias | RoB Score |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ballard, 20061 | HIbbs, 20072 Walsh, 20103 | + | + | + | + | + | + | + | + | + | + | good |
| Dani, 20064 | 0 | + | - | - | + | - | poor | |||||
| Fanco-Belgium, 19995 | + | + | - | - + | 0 | 0 | + | + | fair | |||
| Field, 20056 | Huddy, 20087 | - | + | - | - | - | - | - | - | - | - | poor |
| Hascoet, 20058 | Hamon, 20059 | + | + | 0 | 0 | 0 | 0 | + | + | 0 | + | fair |
| Kinsella, 199910 | + | + | + | + | + | + | + | + | + | + | good | |
| KinsellaM, 200611 | Watson, 200912 | + | + | + | + | + | + | + | good | |||
| Mercier, 2010{#122 62} | + | + | + | + | + | + | + | 0 | + | fair | ||
| Schreiber, 200313 | Mestan, 200514 | + | + | + | + | + | + | + | good | |||
| Srisuparp, 200215 | + | 0 | 0 | 0 | 0 | 0 | - | + | - | - | poor | |
| Su, 200816 | + | 0 | - | 0 | - | 0 | - | 0 | + | 0 | poor | |
| Subhedar, 199717 | Bennett, 200118 | + | 0 | - | - | 0 | 0 | + | 0 | 0 | - | poor |
| Van Meurs, 200519 | Chock, 200920 Hintz, 200721 | + | + | + | + | + | + | + | good | |||
| Van Meurs, 200722 | Chock20 | + | + | + | + | + | + | + | + | + | + | good |
| KEY | ||||
|---|---|---|---|---|
| Category | Question | Yes | No | Unclear |
| Sequence generation: | Was the allocation sequence adequately generated? | + | - | 0 |
| Allocation concealment: | Was the allocation adequately concealed | + | - | 0 |
| Blinding of personnel (short-term outcomes) | Was knowledge of the allocation intervention adequately prevented for personnel during the study? | + | - | 0 |
| Blinding of outcome assessors (short-term outcomes) | Was knowledge of the allocated intervention adequately preventes for outcome assessors during the study? | + | - | 0 |
| Blinding of personnel long-term outcomes) | Was knowledge of the allocation intervention adequately prevented for personnel during the study? | + | - | 0 |
| Blinding of outcome assessors Long-term outcomes) | Was knowledge of the allocated intervention adequately preventes for outcome assessors during the study? | + | - | 0 |
| Incomplete outcome data (short-term) | Were incomplete data adequately addressed? | + | - | 0 |
| Incomplete outcome data (short-term) | Were incomplete data adequately addressed? | + | - | 0 |
| Selective outcome reporting | Are reports of the study free of suggestion of selective outcome reporting? | + | - | 0 |
| Other sources of bias | Was the study apparently free of other problems that could put it at high risk of bias? | + | - | 0 |
| good = all criteria were present "yes" |
| fair = greater than or equal to 50% of criteria are present |
| poor = less than 50% of criteria are present or unclear |
Evidence Table 2Risk of bias in observational studies
| Author, year | Representativeness of the treated cohort | Selection of the control cohort | Selection of treated patients | Demonstration that outcome of interest was present at start of study | Comparability of cohorts on the basis of the design or analysis | Assessment of outcome | Was followup long enough for outcomes to occur? | Were incomplete outcome data adequately addressed? | RoB score |
|---|---|---|---|---|---|---|---|---|---|
| Banks, 19991 | + | 0 | + | 0 | 0 | + | fair | ||
| Cheung, 19982 | - | - | - | 0 | - | - | poor | ||
| Clark 20023 | 0 | + | + | 0 | + | - | fair | ||
| Dewhurst, 20104 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | poor | |
| Kumar, 20075 | + | - | + | + | + | 0 | 0 | + | fair |
| Uga, 20046 | 0 | + | 0 | + | 0 | 0 | + | + | fair |
| Tanaka, 20077 | + | + | + | + | 0 | 0 | + | 0 | fair |
| Yadav, , 19998 | - | + | + | 0 | 0 | - | poor |
| KEY | ||||||
|---|---|---|---|---|---|---|
| Category | Question | Score | ||||
| Selection | Representativeness of treated cohort | Truly representative | Somewhat representative | No description | ||
| + | - | 0 | ||||
| Selection of control cohort | Same NICU or group of NICUs | Different source | No description | |||
| + | - | 0 | ||||
| Selection of treated patients | Medical record | other | no description | |||
| + | - | 0 | ||||
| Demonstration that outcoems of interest was not present at start of study | Yes | No | Unclear | |||
| + | - | 0 | ||||
| Comparability | Comparability of cohorts on the basis of the design or analysis | Yes | No | Unclear | ||
| + | - | 0 | ||||
| Outcome | Assessment of outcome | Independent blind assessment | record linkage | parent report | teacher report | not description |
| + | + | - | - | 0 | ||
| Was follow-up long enough four outcomes to occur? | Yes | Yes for at least 1 outcome of interest | No | Unclear | ||
| + | + | - | 0 | |||
| Were incomplete outcome data adequately addressed | Yes | No | unclear | |||
| + | - | 0 |
| good = all criteria were present "yes" |
| fair = greater than or equal to 50% of criteria are present |
| poor = less than 50% of criteria are present or unclear |
Evidence Table 3Study characteristics
| Author, Year | Study Design | Study site-Study location | Recruitment date | Planned length of follow-up | Inclusion criteria | Exclusion criteria | Risk of Bias |
|---|---|---|---|---|---|---|---|
| Ballard, 20061 | RCT | Multi-Center - North America | Start date: May-2000 – End date: Apr-2005 | 60 Weeks PMA | Age: 7-21 days GA:<= 32 weeks BW: 500-1250 Vent support: "undergoing mechanical ventilation" between 7-21 days of age Other: NCPAP for those with BW 500-799g | Congen: complex anomalies IVH: bilateral grade IV Other: previous iNO exposure | Good |
| Follow-up of Ballard, 20061 Hibbs, 20072 | RCT | Multi-Center - North America | 12 Months | Age: 7-21 days of age BW: 500-1250 grams Vent support: required vent support via CPAP or tracheal intubation | Good | ||
| Follow-up of Ballard 20061 Walsh, 20103 | RCT | Multi-Center - North America | Age: 7-21 days from birth BW: <1250 g Vent support: intubated and on mechanical ventilation | Good | |||
| Banks, 19994 | Phase II open label, non-controlled pilot study | Single Center - North America | Start date: Oct-1995 – End date: Aug-1997 | Age: >4 weeks chronologic age FiO2: >/=45% MAP: >/=10mmHg BPD: vent dependent Other: No improvement in resp. status in previous 3 days with optimal use of all standard BPD therapy: glucocorticoids, bronchodilators, diuretics per attending physician | Congen: congenital heart disease | Fair | |
| Cheung, 19985 | Prospective cohort | Single Center - North America | Start date: Dec-1993 – End date: Oct-1997 | Early childhood | GA:24-30 weeks BW: </=1500 grams Hypoxemia: hypoxemia with FiO2 > 90%, and MAP 15+/- 2 | Congen: "congenital anomalies" | Poor |
| Clark, 20026 | Multi-Center - North America | Start date: Jun-97 – End date: Jun-99 | 44 wks PMA | Age: < 30 days but > 10 days; BW: <1250; FiO2: > 40% w/o fluctuations of > 25% in the preceding 24 hours; Oligho: clinical and radiographic finding consistent with CLD | Bleeding: Plts<100,000; Congen: CHD, and lethal anomalies; iBetaAnt: if given within preceding 48 hours; IVH: progressive IVH; Corticostrds: initiation of drug within preceding 48 hours; Sepsis: 2 blood cultures yielding single organism in preceding 48 hours | ||
| Dani, 20067 | RCT | Single Center - Europe | Start date: Jan-2001 – End date: Jun-2004 | Age: <=7 days GA:< 30 wks; Inborn RDS: Classic symptoms (need for O2, tachypnea, retractions, and grunting) and typical Xray findings (reduced air content, reticulogranular pattern of lungs and air bronchograms) FiO2: FIO2>0.5 (50%) and arterial-alveolar oxygen ratio <0.15 Surfactant Vent support | Bleeding: Plateletcount <50,000/mm3 and bleeding tendency (hematuria; blood from ETT; gastric aspirate or stools; oozing from puncture sites) Congen: major congenital malformations Hydrops | Fair | |
| Dewhurst, 2010 8 | Retrospecti ve Cohort | Multi-Center - Europe | Start date: Jan-2006 End date: Dec-2007 | Age: <10 days GA: <31 weeks | |||
| Field, 20059 | RCT | Multi-Center - Europe | Start date: Feb-1997 – End date: Dec-2001 | 1 year Corrected age | Age: <28 days GA:<34 weeks Surfactant: treatment if appropriate | Bleeding: Plts <50,000 and PTT>72 sec IVH: Grade 4 IVH Other: severe anomalies; lethal chromosomal anomaly | Poor |
| Follow-up of Field 20059 Huddy, 200810 | RCT | Multi-Center - Europe | Start date: Feb-1997 – End date: Dec-2001 | 4-5 Years | Age: <28 days GA:<34 wks Respfail: severe Vent support: intubation and mechanical ventilation | Poor | |
| Franco-Belgium Collaborative NO Trial Group, 199911 | RCT | Multi-Center - Europe | Start date: Apr-1995 – End date: Jun-1997 | Until hospital discharge | Age: <7 days of age GA:<33 weeks OI: 12.5-30 | OI: > the upper limits requiring inhaled nitric oxide; according to the French Drug Agency recommendations Congen: fatal anomalies; cardiac anomalies Dshunting: PDA with severe left to right shunting Hypoxemia: Other forms of pulmonary hypoplasia IVH: grade 3 or 4 Pulmonary hypoplasia: raised pulmonary blood flow Refractory septic shock Other: abnormal neuro exam due to birth asphyxia or grade 3-4 IVH | Fair |
| Hascoet, 200512 | RCT | Multi-Center - Europe | Start date: Jul-1999 – End date: Feb-2001 | 28 Days | GA:<32 weeks | Bleeding: platelets <50,000/mm3 Congen: major fetal abnormality Hypoxemia: refractory hypoxemia (PO2<50 mmHg & PCO2 <50mmHg on FiO2 100% prior to 6 hours of age) | Fair |
| Follow-up of Hascoet 200512 Hamon, 200513 | RCT | Single Center - Europe | Start date: Jul-1999 – End date: Feb-2001 | 28 Days | Age: < 48 hours GA:< 32 wks FiO2: > 0.40 Other: aAO2 < 0.22 | Bleeding: Plts < 50,000 Congen: major abnormality Refractory hypoxemia | Fair |
| Kinsella, 199914 | RCT | Multi-Center - North America | Hospital discharge | Age: =< 7 days chronological age GA: 34 weeks or less Hypoxemia: Arterial/alveolar oxygen ratio <0.1 on 2 sequential ABGs despite mechanical vent and surfactant Vent Support: mechanical ventilation | Congen: fatal congenital anomaly; congenital heart disease (except ASD; VSD) | Good | |
| Kinsella, 200615 | RCT | Multi-Center - North America | Start date: Mar-2001 — End date: Jun-2005 | Age: <48 hours GA:<=34 wks BW: 500-1250g Respfail: requiring intubation and mechanical vent Vent Support: intubation & mechanical ventilation | Congen: lethal, congenital heart disease except atrial septal defect <= 1 cm or ventricular septal defect <=2 mm) Pneumothorax: unevaluated Pulmhem: active Vent Support:expected duration of mechanical ventilation of <48 hours | Good | |
| Follow-up of Kinsella 2006 15 Watson, 2009 16 | RCT | Multi-Center - North America | Start date: Mar 2001 — End date: Jun-2005 | 1 Year | Age: <48 hours GA:<=34 weeks BW: 500-1250g Vent Support: mechanical ventilation | Congen: lethal anomalies, CHD Pneumothorax: unevacuated Pulmhem: active hemorrhage Vent Support: expected mechanical ventilation for < 48 hours | Good |
| Mercier, 201017 | RCT | Multi-center - Europe | Start date: May-2005 End date: May-2008 | 1, 2 and 7 years | GA: <34 weeks | ||
| Schreiber, 200318 | RCT | Single Center - North America | Start date: Oct-1998 — End date: Oct-2001 | Age: <72 hours GA:<34 weeks BW: <2000 g RDS: clinical diagnosis Surfactant: Must be treated with surfactant Vent support: Require intubation and mechanical ventilation | Congen: Major congenital malformations Hydrops | Good | |
| Follow-up of Schreiber, 200318 Mestan, 200519 | RCT | Single Center - North America | Start date: Oct-1998 – End date : Oct-2001 | Two years of age | Good | ||
| Srisuparp, 200220 | RCT | Single Center - North America | Start date: Jul-1997 – End date: Jan-1998 | Neonatal period, to 28 days of age | Age: < 72 hours BW: <2000g OI: >=4 if birthweight (BW) <= 1000g; >=6 if BW 1001-1250g; >= 8 of BW 1251-1500g; >= 10 if BW 1501-1750 g; >=12 if BW 1751-2000g ArtrCath RDS Vent Support: mechanical ventilation | Congen: major anomalies Hydrops | Poor |
| Su, 200821 | RCT | Single center - Asia | Start date: Jul-2000 – End date: Jul-2006 | GA:</= 31 weeks BW: </= 1500g RDS: severe RDS - clinical signs (IC rtxs, flaring, grunting) or CXR findings severe diffuse reticulogranular infiltrates w/low lung volumes Respfail: OI >/=25 Vent Support: mechanical ventilation | Bleeding: uncorrectable Congen: severe congenital abnormalities IVH: Severe III or IV Other: lethal chromosomal anomalies | Fair | |
| Subhedar, 199722 | RCT | Single Center - Europe | Start date: Aug-1995 – End date: Sep-1996 | Not specified in article | Age: 96 hours of age GA:<32 weeks RDS: requiring mechanical ventilation Surfactant Vent Support: mechanically ventilated since birth Other: high risk for CLD by prediction score | Bleeding: Plts< 50 Congen: major anomalies; structual cardiac anomalies Dshunting:significant IVH: with parenchymal involvement Pulmhem Sepsis: Culture positive Other: GI bleed | Poor |
| Follow-up of Subhedar, 199722 Bennett, 2001 23 | RCT | Single Center - Europe | 30 Months corrected age | GA:<32 weeks | Intrprncyml: parenchymal involvement at trial entry | Poor | |
| Tanaka, 200724 | Retrospecti ve cohort | Single Center - Asia | Start date: Jan-1988 – End date: Dec-1999 | 3 Years | GA:< 34 weeks Shuting: Rt-to-L shunt at PDA or R-to-L at arterial level Hypoxemia: due to PPHN PPHN: Clinical: >5% difference in Pre- & Post-ductal SaO2, or recurrent desats <85% over 12hours despite optimal treatment of lung disease, AND Echo evidence (w/o structural heart disease): peak systolic PAP >35mmHg or >2/3 systemic systolic pressure - indicated by R-to-L shunting at PDA or arterial level | Multiple birth: Singleton only Congen: No structural heart disease | Fair |
| Uga, 200425 | Retrospective cohort | Single Center - Asia | Start date: Jan-1999 End date: NS | NS | BW: <1500 grams FiO2: 100% MAP: >8 Oligho: >5 days with PROM PPHN: defined by no response to surfactant, oligohydramnios/PROM>5 days, refractory hypoxemia PROM: >5 days Respfail: insufficient arterial oxygenation on 100% FiO2, MAP >8cmH20 Surfactant: with no response | ||
| Van Meurs, 200526 | RCT | Multi-Center -North America | Start date: Jan-2001 – End date: Sep-03 | Age: 4 to 120 hours after birth GA:< 34 weeks BW: 401-1500g OI: at least 10 on 2 ABGs between 30 min and 12 hours apart; revised to OI of at least 5.0 followed within 30 min to 12 hours of OI of at least 7.5 ArtrCath: eligible from 4 to 120 hours after birth Congen: Ventricular Septal Defect, patent ductus arteriosus and atrial level shunt permitted PPHN: idiopathic Pneumonia Pulmonary hypoplasia: suspected RDS Sepsis Surfactant: at least 4 hours before Vent Support: required assisted ventilation Other: Aspiration | Bleeding: Bleeding diathesis or platelet count at or below 50,000 per cu. mm. (thrombocytopenia) Congen: Congenital Heart Disease, major congenital anomaly involving respiratory system | Good | |
| Sub analysis of Van Meurs, 200526
Chock, 200927 | RCT | Multi-Center – North America | Start date: Jan-2001 – End date: Sep-2003 | 18 to 22 Months | GA:<34 wks; <34 wks BW: 401-1500g (iNO trial); some >1500g (larger Preemie Pilot study) Oligho: documented on U/S 5+ days prior to delivery Pulmhyp: interpretation of CXR w/small, hypoplastic appearing lungs Respfail: 4 hours following surfactant | ||
| Follow-up of Van Meurs, 200526 Hintz, 200728 | RCT | Multi-Center - North America | Start date: Jan-2001 – End date: Sep-03 | 18 - 22 Months corrected age | GA:< 34 wks BW: 401 - 1500 g OI: >/=10 on 2 consecutive blood gases 30 min to 12 h apart; revised to OI >/=5 followed by OI>/=7.5 w/in 30 min to 24 hours Respfail: severe (defined in original iNO trial) Surfactant:x1 dose at least 4hr before meeting OI criteria Vent support: Mechanical | Good | |
| Van Meurs, 200729 | RCT | Multicenter - North America | Start date: Jan-2001 – End date: Sep-2003 | 18-22 Months | GA:<34 wks BW: >1500 g OI: OI >/=15 ×2 ABGs 30 min-12 hrs apart; OI >/=10 then OI>/=12.5 within 30 min-24 hrs PPHN: idiopathic Pneumonia Pulmonary hypoplasia Sepsis RDS Surfactant: at least 1 dose >4hrs prior Vent Support: mechanical ventilation Other: Aspiration syndromes | Bleeding: Platelets <50,000; or bleeding diathesis Congen heart disease Other: decision not to provide full treatment | Good |
| Yadav, 199930 | Retrospective cohort | Single Center - Europe | Start year: 1993 – End year: 1997 | Hospital discharge | GA: "preterm" Hypoxemia: "severe hypoxemia despite max therapy | Congen: major malformation; | Poor |
ArtrCath: Arterial catheter, BPD: Bronchopulmonary dysplasia , BW: Birth weight, Congen: Congenital anomaly/malformation, Dshunting: Ductal Shunting, FiO2: Fraction of Inspired Oxygen, g:grams, GA: Gestational age, iNO: inhaled Nitric Oxide, intrprncyml:Intraparenchymal lesion, IVH: Intraventricular Hemorrhage, MAP: Mean airway pressure, OI: Oxygenation Index, Oligho : Oligohydramnios, PMA: post menstrual age, PPHN: Persistent Pulmonary Hypertension of the Newborn, Pulmhyp: Pulmonary hypoplasia, RDS: Respiratory distress syndrome, Respfail: Respiratory failure , Vent Support: Ventilation Support
Evidence Table 4Participant Characteristics
| Author, year | Control Interventions | N at baseline | Gestational age (weeks) | Birth weight (grams) | Race n(%) | Mode of Ventilation, n(%) | Participant age at enrollment | Oxygenation Index | iNO Dose | iNO Duration |
|---|---|---|---|---|---|---|---|---|---|---|
| Ballard, 20061 | Placebo | 288 | Mean: 26 SD: 1.5 | Mean: 759 SD: 155 | W: 145 (50.3) B: 90 (31.3) H: 43 (14.9) Other: 10 (3.) | HFV: 74 (25.7) CMV: 191 (66.3) CPAP: 23 (8) | Median:16 Range:13-19 IQR Units: Days | NA | ||
| iNO | 294 | Mean: 26 SD: 1.5 | Mean: 766 SD: 161 | W: 170 (57.8) B: 76 (25.9) H: 32 (10.9) Other: 16 (5.4) | HFV: 65 (22.1) CMV: 202 (68.7) CPAP: 27 (9.2) | Median:16 Range:12-19 IQR Units: Days | NA | 20ppm ×48-96hours: titrate every 7days for a minimum of 2 days exposure | ||
| Follow-up of Ballard, 20061 Hibbs, 20072 | Placebo | 225 | Mean: 25.7 SD: 1.5 | Mean: 762 SD: 150 | W: 121 (53.8) B: 64 (28.4) H: 31 (13.8) Other: 9 (4) | NA | NA | NA | ||
| iNO | 230 | Mean: 25.8 SD: 1.4 | Mean: 769 SD: 163 | W: 141 (61.3) B: 56 (24.2) H: 22 (9.5) Other:: 11 (4.8) | NA | NA | NA | 20ppm: weaned over at least 24days | ||
| Follow-up of Ballard 20061 Walsh, 20103 | Placebo gas | 234 | Mean: 25.7 SD:1.5 | Mean: 764 SD: 153 | W: 124(53) Other: 110(47) | NA | Median: 16 Range: 13-20 IQR Unit: days | NA | ||
| iNO | 243 | Mean:25.8 SD: 1.4 | Mean: 765 SD: 163 | W: 151(62) Other: 92(38) | NA | Median: 17 Range: 13-19 IQR Unit: days | NA | 20ppm ×24hours: decrease to 10ppm ×1week decrease to 5ppm ×1week decrease to 2ppm ×1week | ||
| Banks, 19994 | iNO | 16 | Median: 25.5 Range: 24-29 | Median: 787 Range: 448-1790 | NA | HFV: 5 (31.25) CMV :11 (68.75) | Median: 2.5 Range: 1-7 Units: Months | NA | 20ppm ×72hours: responders weaned by 20% every 3day | |
| Cheung, 19985 | iNO treated cohort | 24 | Median: 25 Range: 24-27 (25% and 75 %) | Median: 860 Range: 668-1068 (25% and 75 %) | NA | CMV : 24 (100) | NA | Median:32 Range: 28-52 (25% and 75 %) | 20ppm: decrease by 5ppm within 2hours s/p initial dose decrease by 5ppm q15-30min to lowest dose w/+ response | |
| Clark, 20026 | iNO | 33 | Mean: 25.3; Range: 23-29 | Mean: 736 Range: 509-1250 | W: 11 (33) B: 21 (64) H: 1 (3) | Mean: 19 Range: 9-29 Units: Days | 20ppm ×36hours: decrease to 15ppm and decrease by 2-3ppm every1 2hours; discontinued by 7 days. | |||
| Dani, 20067 | Control | 20 | Mean: 26.7 SD: 1.9 | Mean: 825 SD: 299 | NA | HFV: 11 (55) | NA | Mean: 15.1 SD: 4.9 | ||
| iNO | 20 | Mean: 26.3 SD: 2.6 | Mean: 937 SD: 298 | NA | HFV: 10 (50) | NA | Mean:16.4 SD: 5.1 | 5ppm: Increase by 5ppm every 30min to max 15ppm | ||
| No responders | 6 | Mean: 25.4 SD: 2.6 | Mean: 748 SD: 321.4 | NA | CPAP: 4 (67) | NA | Mean:18.1 SD: 4.2 | 5ppm: Increase by 5ppm every 30min to max 15ppm | ||
| Responders | 14 | Mean: 26.7 SD: 1.9 | Mean: 1022.7 SD: 243.1 | NA | CPAP: 13 (93) | NA | Mean:14.7 SD: 3.9 | 5ppm: Increase by 5ppm every 30min to max 15ppm | ||
| Dewhurst, 20108 | Responders | 26 | Median: 26 Range: 25-29 | Median: 920 Range: 655-1538 | NA | Median: 53 Range: 37-217 Units: Hours | Median: 47 Range: 30-78 | 10ppm: titrated | ||
| Non-responders | 8 | Median: 29 Range: 27-30 | Median: 915 Range: 723-183 | NA | Median: 75 Range: 20-183 Units: Hours | Median: 23 Range: 8-54 | 20ppm: titrated | |||
| Field, 20059 | Control | 53 | Mean: 26.3 SD: 2.4 | Mean: 890 SD: 343 | NA | HFV: 39 (74%) | Median: 1 Range: 1-5 IQR Units: Days | Median:31.9 Range: 17.4-51.8 IQR | ||
| iNO | 55 | Mean: 27.4 SD: 2.6 | Mean: 1006 SD: 395 | NA | HFC: 33 (60) | Median: 1 Range: 0-6 IQR Units: Days | Median: 32.9 Range: 22.2-49.8 IQR, | 5ppm: double dose every 15min to max 40ppm | ||
| Follow-up of Field 20059 Huddy, 200810 | Control | 16 | Mean: 28.2 SD: 2.7 | Mean: 1142 SD: 440 | NA | NA | Median: 1 Range: IQR 1.5 Units: Days | Median: 25.9 Range: IQR 41.3 | ||
| iNO | 22 | Mean: 28.5 SD: 2.4 | Mean: 1191 SD: 403 | NA | NA | Median: 1 Range: IQR 3 Units: Days | Median: 30.1 Range: IQR 20.5 | 5ppm: double dose every 15min until PaO2 increases >22.5mmHg to max 40ppm | ||
| Franco-Belgium Collaborativ e NO Trial Group, 199911 | Control | 45 | Median: 29 Range: 3.1 IQR | Median: 1150 Range: 520 IQR | NA | HFV: 34 (76) CMV : 11 (24) | Median:1 Range: 1 IQR Units: Days | Median: 18 Range: 7.4 IQR | ||
| iNO | 40 | Median: 29.6 Range: 2.6 IQR | Median: 1200 Range: 570 IQR | NA | HFV: 30 (75) CMV : 10 (25) | Range: 1.5 Units: Days | Median:20.2 Range: 8.3 IQR | 10ppm ×2-3hours: decreased to 5ppm then slowly wean off if deteriorating condition, increased dose to 20ppm | ||
| Hascoet, 200512 | Control with hypoxemic respiratory failure | 84 | NA | BW<750: 19 (22) BW 750-999: 17 (20), BW 1000-1500: 32 (39) BW >1500: 16 (19) | NA | NA | NA | Mean:12 SD: 5.6 | ||
| iNO with hypoxemic respiratory failure | 61 | NA | BW <750g: 10 (16.5) BW 750-999g: 14 (23) BW 1000-1500g: 27 (44) BW >1500g: 10 (16.5) | NA | NA | NA | OI Mean:14.6 SD: 8.9 | 5ppm: if aAO2 increase >0.22 decrease iNO to 2ppm if aAO2 increase <0.22 but >25% iNO remains at 5ppm if aAO2 unchanged increase iNO to 10ppm | ||
| Follow-up of Hascoet 200512 Hamon, 200513 | Hypoxemic respiratory failure, no iNO | 39 | Mean: 27.9 SD: 0.4 | Mean: 1102 SD: 54 | NA | NA | Mean:15.9 SD: 1.8 Units: Hours | NA | ||
| iNO treated hypoxemic respiratory failure | 37 | Mean: 27.3 SD: 0.4 | Mean: 1083 SD: 58 | NA | NA | Mean:14.1 SD:1.4 Units: Hours | NA | 5ppm: aAO2 increase >0.22 decrease iNO to 2ppm aAO2 increase <0.22 but >25% iNO remains at 5ppm aAO2 unchanged increase iNO to 10ppm | Median: 35.1 hours | |
| Kinsella, 199914 | Control | 32 | Mean: 26.8 SD: 2.5 | Mean: 988 SD: 387 | NA | NA | Mean: 27 SD:37 Units: Hours | NA | ||
| iNO | 48 | Mean: 27.1 SD: 2.5 | Mean: 1040 SD: 461 | NA | NA | Mean:30 SD: 38 Units: Hours | NA | 5ppm × 7days: if OI increase >15%, iNO restarted | ||
| Kinsella, 200615 | Placebo gas, Total sample | 395 | Mean: 25.6 SD: 1.8 | Mean: 788 SD: 185 | W: 234 of 394 (59.4) B: 98 of 394 (24.9) H: 48 of 394 (12.2) Other: 14 of 394 (3.6) | HFV: 113 of389 (29) CMV : 276 of 389 (71) | Mean:30.1 SD:13.2 Units: Hours | Mean:5.8, SD:6.7 | ||
| iNO, Total sample | 398 | Mean: 25.6 SD: 1.7 | Mean: 796 SD: 190 | W: 249 of 397(62.7) B: 94 of 397(23.7) H: 41 of 397(10.3) Other: 13 of 397 (3.3) | HFV: 113 of 393 (28.8) CMV : 280 of 393 (71.2) | Mean:30.5 SD:13.4 Units: Hours | Mean:5.4 SD: 5.2 | 5ppm × 21days | Median: 14 days | |
| Follow-up of Kinsella 200615 Watson, 200916 | Control-detailed outcome cohort | 320 | Mean: 25.7 SD: 1.9 | Mean: 791 SD: 186 | W: 192 (60) B: 71 (22.2) H: 44 (13.8) Asian/Other: 13 (4.1) | NA | NA | Median:4.1 Range: 2.7-6.4 IQR | ||
| iNO-detailed outcome cohort | 332 | Mean: 25.6 SD: 1.7 | Mean: 797 SD: 190 | W: 205 (61.8) B: 76 (22.9) H: 38 (11,5) Asian/Other: 13 (3.9) | NA | NA | Median:4.1 Range: 2.8-6.2 IQR | 5ppm ×21days or until extubated | ||
| Mercier, 201017 | Control | 401 | Mean: 26.6 SD: 1.3 | Mean: 864 SD: 192 | W: 328 (82) B: 48 (12) A: 2 (<1) Other: 23 (6) | CPAP: 42 (10) | NA | Mean: 8.6 SD: 12.7 | 5ppm | |
| iNO | 399 | Mean: 26.4 SD: 1.3 | Mean: 851 SD: 207 | W: 329 (82) B: 39 (10) A: 4 (1) Other: 27 (7) | CPAP: 41 (10) | NA | Mean: 8.0 SD: 10.7 | 5ppm | ||
| Schreiber, 200318 | Placebo | 102 | Mean: 27 SD: 2.8 | Mean: 949 SD: 387 | W: 12 (11.8) B: 74 (72.6) Other: 16 (15.7) | HFV: 48 (47) CMV: 54 (52.9) | Median:114 Range: IQR 7.6-28.5 | Median:6.8 Range: 4.4-12.7 IQR | ||
| iNO | 105 | Mean: 27.4 SD: 2.5 | Mean: 1017 SD: 369 | W: 18 (17.1) B: 71 (67.6) Other: 16 (15.2) | HFV: 54 (51.4) CMV: 51 (48.6) | Median: 12.9 Range: IQR 7.0-25.2 | Median:7.3 Range: IQR 4.1-12.3 | 10ppm ×12-24hours: decrease to 5ppm and hold 6day or 1 hour before extubation if Pa02 decrease by 15%, restart NO and decrease by 1 ppm every 6hours | ||
| Follow-up of Schreiber, 200318 Mestan, 200519 | Control | 68 | Mean: 27.2 SD: 2.6 | Mean: 958 SD: 356 | W: 8 (12) B: 52 (76) Other:: 8 (12) | NA | SD: 8.4 Units: Months | Median: 7.2 Range: IQR 4.5-14.3 | ||
| iNO | 70 | Mean: 27.5 SD: 2.4 | Mean: 1026 SD: 366 | W: 14 (20) B: 44 (63), Other:: 12 (17) | NA | Mean: 24.9 SD: 7.9 Units: Months | Median: 6.6 Range: IQR 4-11.5 | 10ppm ×24hours: decrease to 5ppm and hold 6d or 1 hours before extubation | ||
| Srisuparp, 200220 | Control | 18 | Mean: 27.2 SD: 0.5 | Mean: 901 SD: 73 | B: 16 (89) | HFV: 7 (38.9) | NA | Mean:11.9 SD: 2.2 | ||
| iNO | 16 | Mean: 26.8 SD: 0.5 | Mean: 874 SD: 70 | B: 16 (100) | HFV: 7 (43.8) | NA | Mean:10.8 SD: 1.5 | 20ppm ×6-12hours: decrease to 10ppm ×12hours decrease to 5ppm ×12hours decrease by 1ppm every 12hours | ||
| Su, 200821 | Received inhaled oxygen placebo only | 33 | Mean: 27.9 SD: 1.8 | Mean: 1050 SD: 210 | NA | NA | Mean:2.5 SD: 1.8 Units: Days | Mean: 30.5 SD: 4.7 | ||
| iNO | 32 | Mean: 27.4 SD: 2.3 | Mean: 1020 SD: 230 | NA | CMV : 32(100) | Mean: 2.45 SD: 1.7 Units: Days | Mean:30.3 SD: 3.5 | 5ppm ×6hours: if + response, decrease 1ppm every 6hours to min 1ppm if – response, increase 5ppm every 6hours to max. 20ppm | Mean: 4.9 SD: 2.3 Unit: days | |
| Subhedar, 199722 | Dexamethasone and standard of care | 22 | Median: 27 Range: 22-31 | Median: 750 Range: 520-1400 | NA | NA | Median: 104 Range: 96-120 Units: Hours | Median: 3.9 Range: 1.2-11.5 | ||
| iNO + iNO and dexamethasone) | 20 | Median: 27 Range: 24-30 | Median: 882 Range: 416-1354 | NA | NA | Median: 99 Range: 96-113 IQR Units: Hours | Median: 7.9 Range: 1.6-46.7 | 20ppm: iNo started at 20ppm, given for 2 hours, if responsive weaned by 5 ppm every 15 minutes until 5ppm then continued for 72 hours, then discontinued. | ||
| Dexamethasone alone AND dex + iNO) | 21 | Median: 27 Range: 22-31 | Median: 870 Range: 530-1400 | NA | NA | Median: 104 Range: 96-120 Units: Hours | Median: 7.9 Range: 1.2-46.7 | 20ppm: iNo started at 20ppm, given for 2 hours, if responsive weaned by 5 ppm every 15 minutes until 5ppm then continued for 72 hours, then discontinued. | ||
| iNO AND standard of care | 21 | Median: 27 Range: 22-31 | Median: 818 Range: 520-1222 | NA | NA | Median: 98 Range: 96-114 Units: Hours | Median: 4.1 Range: 1.4-28 | 20ppm: iNo started at 20ppm, given for 2 hours, if responsive weaned by 5 ppm every 15 minutes until 5ppm then continued for 72 hours, then discontinued. | ` | |
| Follow-up of Subhedar, 199722 Bennett, 200123 | Control | 22 | NA | NA | NA | CMV :22 (100) | Mean: 96 Units: Hours | NA | ||
| iNO | 20 | NA | NA | NA | CMV :20 (100) | Mean: 96 Units: Hours | NA | 5-20ppm iNO × 72hours or until extubated | ||
| Tanaka, 200724 | Control | 15 | Median: 26 Range: 24-30 | Median: 818 Range: 720-1400 IQR | NA | HFV: 9 (60) | NA | Median: 23.3 Range: 16-45 | ||
| iNO | 16 | Median: 25.5 Range: 25-28.8 | Median: 838 Range: 628-1144 IQR | NA | HFV: 14 (87.5) | NA | Median: 23.3 Range: 16-45 IQR | 10ppm: Increase 10ppm every 30min to max 30ppm | ||
| Uga, 200425 | Control | 10 | Mean: 25.8 SD: 2.4 Range: 24-30 | Mean: 809 SD: 316 Range: 426-1453 | NA | NA | NA | Mean: 13.9 SD: 10.2 | ||
| iNO | 8 | Mean: 27.2 SD: 2.2 Range: 24-30 | Mean: 996 SD: 294 Range: 570-1317 | NA | NA | NA | Mean: 28.8 SD: 18.3 | 30-40ppm | ||
| Van Meurs, 200526 | Control | 210 | Mean: 26 SD: 2 | Mean: 837 SD: 260 | W: 96 (46) B: 78 (37) H: 32 (15) Other: 4 (2) | HFV: 124 (59) CMV: 86 (41) | Mean:28 SD: 22 Units: Hours | Mean:22 SD:17 | ||
| iNO | 210 | Mean: 26 SD: 2 | Mean: 840 SD: 264 | W: 95 (45) B: 69 (33) H: 36 (17) Other: 10 (5) | HFV: 125 (59) CMV : 85 (40) | Mean:26 SD: 23 Units: Hours | Mean:23 SD:17 | 5ppm: Hold if PaO2 increases >=20mmHg or increase to 10ppm | Mean: 76 SD: 73 Unit: hours | |
| Sub analysis of Van Meurs, 200526 Chock, 200927 | Control | 6 | Mean: 29 SD: 3 | Mean: 1179 SD: 369 | W: 4 (67) B: 1 (17) H: 0 (0) Other: 1 (17) | HFV: 6 (100) | Mean:11 SD: 4 Units: Hours | Mean:44 SD: 30 Median:39 Range:10-100 | ||
| iNO | 6 | Mean: 27 SD: 2 | Mean: 1039 SD: 355 | W: 2 (33) B: 1 (17) H: 2 (33) Other: 1 (17) | HFV: 6 (100) | Mean:12 SD: 8 Units: Hours | Mean:20 SD:27 Median: 19 Range: 11-64 | 5ppm ×30min: increase 5ppm if PaO2 did not increase >20mmHg | Mean: 1 SD: 0.2 Unit: hours | |
| Follow-up of Van Meurs, 200526 Hintz, 200728 | Placebo | 102 | Mean: 26.2 SD: 2.2 | Mean: 864 SD: 271 | W: 46 (45) B: 35 (34) H: 18 (18) Other: 1 (1) | HFV: 57 (56) | NA | Mean: 18.1 SD:1 1.3 Median: 149 Range:.5 - 21.6 | Median: 2 Range: 1-75 IQR Unit: hours | |
| iNO Follow-up of group | 91 | Mean: 26.8 SD: 2.3 | Mean: 958 SD: 276 | W: 43 (47) B: 27 (30) H: 17 (19) | HFV: 61 (67) | NA | Mean: 20 SD:12.9 Median: 16.3 Range: 12-24 | 5ppm titrated | Median:72 Range: 42-115IQR | |
| Van Meurs, 200729 | Control | 15 | Mean: 31.4 SD: 1.1 | Mean: 2168 SD: 441 | W: 5 (33) B: 4 (27) H: 6 (40) | HFV: 11 (73) CMV : 2(13) HFFI: 2 (13) | NA | Mean: 28.2 SD:17.3 | ||
| iNO | 14 | Mean: 31.1 SD: 1.2 | Mean: 1970 SD: 391 | W: 7 (50) B: 5 (36) H: 1 (7) Other:1 (7) | HFV: 6 (43) CMV : 8 (57) HFFI 0 (0) | NA | Mean:25.1 SD:19.4 | 5ppm ×30min: Increase to 10ppm | ||
| Yadav, 199930 | iNO | 41 | Mean:27 SD:2.6 | Mean: 1000 SD: 46 | NA | NA | NA | Mean: 40 SD: 17 | 10ppm |
B:Non-hispanic black; H:Hispanic; W:non-hispanic white; HFV: High-frequency ventilation; CMV: Conventional mechanical ventilation; CPAP: Continuous Positive Airway Pressure; HFFI: High-frequency flow interruption; mmHg: millimeters of mercury; ppm: parts per million; iNO: inhaled nitric oxide
Evidence Table 5Death and survival outcomes for KQ1
| Author, Year | Outcome | Time of outcome measure | Arm Description | N (Number of Participants Measured) | Participants with Outcome n (%) | Relative Effect (95% CI) OR (95% CI) | Adjusted Relative Effect (95% CI) Adjusted OR (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Ballard, 20061 | Death | 36 weeks PMA | Control | 288 | 18 (6.3) | |||
| iNO | 294 | 16 (5.4) | ||||||
| 40 weeks PMA | Control | 288 | 19 (6.6) | |||||
| iNO | 294 | 19 (6.5) | ||||||
| 44 wks PMA | Control | 288 | 20 (6.9) | |||||
| iNO | 294 | 20 (6.8) | ||||||
| Dani, 20062 | NICU | Control | 20 | 6 (30) | P-value: 0.494 | birth weight | ||
| iNO | 20 | 4 (20) | ||||||
| Nonresponders | 6 | 4 (66) | P-value: 0.078 | |||||
| Responders | 14 | 3 (21) | ||||||
| Field, 20053 | 1 year | Control | 53 | 34 (64) | ||||
| iNO | 55 | 30 (55) | ||||||
| Franco-Belgium Collaborative NO Trial Group, 19994 | in NICU | Control | 45 | 16 (35) | P-value: Not significant | |||
| iNO | 40 | 11 (27) | ||||||
| Hascoet, 20055 | 7 days of life | Control with HRF | 84 | 14 (17) | P-value: 0.58 | 1 | ||
| iNO with HRF | 61 | 8 (13) | ||||||
| 28 days of life | Control with HRF | 84 | 26 (31) | P-value: Not significant | ||||
| iNO with HRF | 61 | 25 (41) | ||||||
| Kinsella, 19996 | Discharge | Control | 32 | 17 (53) | P-value: 0.65 RR: 1.11(0.7-1.8) | |||
| iNO | 48 | 23 (48) | ||||||
| Kinsella, 20067 | 36 wks PMA | Control | 392 | 98 (25) | P-value: 0.08 RR: 0.79 (0.61-1.03) | randomization strata, study sight | ||
| iNO, Total sample) | 394 | 78 (19.8) | ||||||
| Mercier, 20108 | 24-28 weeks | Control | 401 | 42 (10.5) | ||||
| iNO | 399 | 56 (14) | ||||||
| Schreiber, 20039 | NICU | Control | 102 | 23 (22.5) | P-value: 0.18 RR: 0.68 (0.38-1.20) | RR: 0.68 (0.38-1.20) | type of ventilation | |
| iNO | 105 | 16 (15.2) | ||||||
| Srisuparp, 200210 | 7 days | Control | 22 | 2 (11.1) | P-value: 1 | |||
| iNO | 16 | 2 (12.5) | ||||||
| Su, 200811 | During Study (9 death within 96 hours) | Control | 33 | 10 (30.3) | ||||
| iNO | 32 | 6 (18.8) | ||||||
| groups 1&3; iNO + iNO and dexamethasone) | 20 | 10 (50) | ||||||
| Van Meurs, 200513 | death before discharge to home or within 365 | Control | 208 | 93 (45) | P-value: 0.11 RR: 1.16 (0.96-1.39) | Birthweight, study center, OI | ||
| iNO) | 210 | 109 (52) | ||||||
| Van Meurs, 200714 | Death before discharge to home or within 365 | Control | 15 | 4 (27) | P-value: 0.7 RR: 1.34 (0.45-4.0) | p-value: 0.65 RR: 1.26 (0.47-3.41) | OI Stratum | |
| iNO | 14 | 5 (36) | ||||||
| Ballard, 20061 | Survival without BPD | 36 weeks PMA | Control | 288 | 105 (36.5) | p-value:0.04 RR: 1.26 (1.02-1.55) | RR: 1.45 (1.03-2.04) | cluster (multiples) using GEE; from the letter to the editor correction |
| iNO | 294 | 129 (43.9) | ||||||
| Hascoet, 20055 | 28 days | Control with HRF | 84 | 18 (21.4) | p-value:NS | |||
| iNO with HRF | 61 | 14 (23) | p-value:NS | |||||
| Schreiber, 20039 | Survived NICU | iNO | 89 | 54 (60.7) | ||||
| Control | 79 | 37 (46.8) | ||||||
| Schreiber, 20039 | Survival with BPD | Survived NICU | Control | 102 | 42 (53.2) | p-value:0.07 RR:0.74 (0.53-1.03) | ||
| iNO | 105 | 35 (39.3) | ||||||
| Subhedar, 199712 | Not Specified | Control dexamethasone and standard of care | 22 | 14 (64) | RR: 1.07 (0.71-1.37) RR: 0.92 (0.67-1.28) | |||
| Groups 1&3; iNO + iNO and dexamethasone | 10 | 10 (100) | ||||||
| Dexamethasone alone AND dex + iNO | 21 | 11 (52) | ||||||
| iNO AND standard of care | 21 | 13 (62) | ||||||
| Schreiber, 20039 | Survival, BPD not specific | Survived NICU | Control | 102 | 79 (77.5) | |||
| iNO | 105 | 89 (84.8) |
BPD: Bronchopulmonary Dysplasia, CI: Confidence Interval, GEE: Generalized estimating equation, HRF: Hypoxemic Respiratory Failure , iNO: Inhaled nitric oxide, NICU: Neonatal intensive care unit, NS: Not significant, OI: Oxygenation Index, OR: Odds ratio, PMA: Post-menstrual age , RR: Relative risk
Evidence Table 6BPD for KQ1
| Author, Year | Time of outcome measure | Study Arm | N (number of participants measured) | Participants with Outcome—n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments | Duration (days) | Difference in Duration (p-value) |
|---|---|---|---|---|---|---|---|---|---|
| Ballard, 20061 | 36 weeks PMA | Control | 288 | 164 (56.9) | |||||
| iNO | 294 | 149 (50.7) | |||||||
| Dani, 20062 | 36 weeks PMA | Control | 20 | 12 (60) | P-value: 0.067 | Mean: 69.4 SD: 30.2 | 0.054 | ||
| iNO | 20 | 6 (30) | Mean: 47.3 SD: 39.4 | ||||||
| Nonresponders | 6 | 2 (33) | Mean: 19.8 SD: 11.5 | 0.084 | |||||
| Responders | 14 | 7 (50) | Mean: 48.6 SD: 37.3 | ||||||
| Field, 20053 | 36 weeks PMA | Control | 55 | 15 (27) | Mean: 6 IQR:1.0-17.0 | ||||
| iNO | 53 | 26 (49) | Mean: 15 IQR:2-71 | ||||||
| Franco-Belgium Collabor ative NO Trial Group, 19994 | during hospitalization | Control | 29 | 8 (29) | p-value: NS | Median: 23 IQR:41 | 0.38 | ||
| iNO | 29 | 7 (24) | p-value: NS OR: 0.95 (0.44–2.04) | Median: 14 IQR:43 | |||||
| Kinsella, 20065 | 36 weeks PMA | Control | 309 | 210 (68) | P-value: 0.43 | RR:0.96 (0.86–1.09) | randomizati on strata, study sight | ||
| iNO | 326 | 212 (65) | |||||||
| Kinsella, 19996 | 36 weeks PMA | Control | 15 | 12 (80) | p-value: 0.3 RR: 0.75(0.5-1.13) | ||||
| iNO | 25 | 15(60) | |||||||
| Mercier, 20107 | 24-28 weeks | Control | 358 | 96 (27) | |||||
| iNO | 339 | 81(24) | |||||||
| Schreiber, 20038 | 36 weeks PMA | Control | 102 | 42 (53.2) | P-value: 0.07 RR: 0.74 (0.53–1.03) | type of ventilation | |||
| iNO | 105 | 35 (39.3) | |||||||
| Su, 20089 | 36 weeks PMA | Control | 33 | 11 (33.3) | |||||
| iNO | 32 | 10 (31.3) | |||||||
| Subhedar, 199710 | 36 weeks PMA | Dexamethas one and standard of care | 22 | 14 (64) | |||||
| Groups 1&3; iNO + iNO and dexamethas one | 20 | 10 (50) | |||||||
| Dexamethas one alone AND dex + iNO | 21 | 11 (52) | |||||||
| iNO AND standard of care | 21 | 13 (62) | |||||||
| Van Meurs, 200711 | 36 weeks PMA | Control | 11 | 5 (45) | p-value: 0.66 RR: 0.66 (0.21-2.08) | p-value: 0.21 RR: 0.40 (0.09-1.71) | OI stratum | Mean: 32 SD: 23 | 0.45 |
| iNO | 10 | 3 (30) | Mean: 23.8 SD: 24.4 | ||||||
| Van Meurs, 200512 | 36 weeks PMA | Control | 127 | 86 (68) | P-value: 0.26 | RR: 0.90 (0.75–1.08) | |||
| iNO | 109 | 65 (60) | |||||||
| Ballard, 20061 | 40 weeks PMA | Control | 288 | 84 (29.2) | |||||
| iNO | 294 | 66 (22.4) | |||||||
| 44 weeks PMA | Control | 288 | 35 (12.2) | ||||||
| iNO | 294 | 27 (9.2) | |||||||
| Dani, 20062 | Duration of supplemental oxygen | Control | 20 | 69.4 days* | |||||
| iNO | 20 | 47.3 days* | |||||||
| Nonresponders | 6 | 19.8 days* | |||||||
| Responders | 14 | 48.6 days* | |||||||
| Field, 20053 | 1 year corrected age | Control | 18 survivors | 1 (6) | |||||
| iNO | 20 survivors | 3 (15) | |||||||
| At term (EDC) | Control | 53 | 12 (23) | Median: 81 IQR:14-100 | |||||
| iNO | 55 | 16 (29) | Median: 59 IQR:30-78 | ||||||
| Franco-Belgium Collaborative NO Trial Group, 19994 | 28 days | Control | 29 | 14 (48) | p-value: NS | ||||
| iNO | 29 | 13 (45) | |||||||
| Kinsella, 19996 | Hospital discharge | Control | 15 | 12 (80) | p-value: 0. 1 | ||||
| RR: 0.65 (0.41-1.02) | |||||||||
| iNO | 25 | 13 (54) | p-value: 0.1 1.02) | ||||||
| RR: 0.65(0.41- | |||||||||
| Kinsella, 20065 | Post-natal corticosteroids | Control | 365 | 204 (56) | p-value: 0.24 | ||||
| iNO | 369 | 222 (60) | |||||||
| Schreiber, 20038 | Duration of Mechanical Ventilation | Control | 102 | 28.5 days* | |||||
| iNO | 105 | 16 days | |||||||
| Su, 20089 | Duration of Mechanical Ventilation | Control | 33 | 14.2 days* | |||||
| iNO | 32 | 12.8 days * | |||||||
| Van Meurs, 200512 | Days on Mechanical Ventilation | Control | 210 | 47 days* | |||||
| iNO | 210 | 39 days* | |||||||
| Van Meurs, 200711 | Physiologic BPD as per Walsh criteria | Control | 10 | 4 (40) | p-value: 1 RR: 0.91 (0.31-2.70) | p-value: 0.61 RR: 0.74 (0.26-2.09) | |||
| iNO | 11 | 4 (36) | |||||||
| Ballard, 20061 | 40 weeks PMA, severe | Control | 288 | 30 (10.4) | |||||
| iNO | 294 | 18 (6.1) | |||||||
| 44 weeks PMA, severe | Control | 288 | 12 (4.2) | ||||||
| iNO | 294 | 6 (2) | |||||||
| Dani, 20062 | In NICU, severe | Control | 20 | 20 (100) | 14.9 (Mean) 18.1 (SD) | ||||
| iNO | 20 | 20 (100) | 1 | 12.5 (Mean) 10.1 (SD) | 0.608 | ||||
| Nonresponders | 6 | 6 (100) | 19 (Mean) 12.7 (SD) | ||||||
| Responders | 14 | 14 (100) | 1 | 15.8 (Mean) 17.3 (SD) | 0.69 | ||||
| Field, 20053 | During hospitalization, severe | Control | 53 | 4 (Mean) 1.0-9.0 IQR | |||||
| iNO | 55 | 7 (Median) 2-26 IQR | |||||||
| Hascoet , 200513 | 48 hours of life, severe | Control with HRF | 84 | 30 (35.7) | 0.024 | ||||
| iNO with HRF | 61 | 49 (80.3) | 0.024 | ||||||
| Franco-Belgium, 19994 | during hospitalizati on, severe | Control | 29 | 16 (Median) 14 IQR | ns | ||||
| iNO | 29 | 12 (Median) 32 IQR | 0.78 | ||||||
| Schreiber, 20038 | Before Discharge, severe | Control | 79 survivors | 28.5 (Median) IQR 8-48 | |||||
| iNO | 89 survivors | 16 (Median) IQR 8-37 | 0.19 | ||||||
| Subhedar, 199710 | Before Discharge, severe | Dexamethas one and standard of care | 22 | 19 (Median) 5-39 range | |||||
| Groups 1&3; iNO + iNO and dexamethas one | 20 | 11 (Median) 5-44 range | |||||||
| Dexamethas one alone AND dex + iNO | 21 | 23 (Median) 6-44 range | |||||||
| iNO AND standard of care | 21 | 13 (Median) 5-39 range | |||||||
| Time to extubation, severe | Dexamethas one and standard of care | 22 | 11 (Median) range 5-35 | ||||||
| Groups 1&3; iNO + iNO and dexamethas one | 20 | 6.5 (Median) range 5-28 | |||||||
| Dexamethas one alone AND dex + iNO | 21 | 8.5 (Median) 5-35 range | |||||||
| iNO AND standard of care | 21 | 11 (Median) 5-28 range | |||||||
| Van Meurs, 200512 | NICU, severe | Control | 117 | Mean:47 SD: 53 | |||||
| iNO | 101 | Mean:39 SD:45 | 0.56 |
* Measure given in days, not number of participants
BPD: Bronchopulmonary Dysplasia, EDC: Estimated date of confinement, HFOV: High-frequency oscillatory ventilation, HRF: Hypoxemic respiratory failure, iNO: Inhaled Nitric Oxide, IQR: Inter-quartile range, NICU: Neonatal Intensive Care Unit, NS: Not significant, PMA: Post-menstrual age, SD: Standard Deviation
Evidence Table 7Death of BPD outcomes for KQ1
| Author, Year | Time of outcome measure | Arm Description | N (Number of Participants Measured) | Participants with Outcome n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|
| OR (95% CI) | Adjusted OR (95% CI) | ||||||
| Ballard, 20061 | 36 weeks PMA | Control | 288 | 182 (63.2) | |||
| iNO | 294 | 165 (56.1) | |||||
| Dani, 20062 | NICU | Control | 20 | 18 (90) | P-value: 0.016 OR: 0.111 (0.02-0.610) | ||
| iNO | 20 | 10 (50) | |||||
| Nonresponders | 6 | 6 (100) | P-value: 0.035 | ||||
| Responders | 14 | 10 (71) | |||||
| Field, 20053 | 36 weeks PMA | Control | 53 | 48 (91) | |||
| iNO | 55 | 49 (89) | |||||
| Franco-Belgium Collaborative NO Trial Group, 19994 | In NICU | Control | 45 | 24 (53) | |||
| iNO | 40 | 18 (45) | |||||
| Kinsella, 19995 | Discharge | Control | 32 | 29 (91) | P-value: 0.14 RR: 0.85(0.7-1.03) | ||
| iNO | 48 | 37 (77) | |||||
| Kinsella, 20066 | 36 wks PMA | Control | 392 | 295 (75.3) | P-value: 0.24 RR: 0.95 (0.87-1.03) | Study sight, randomization strata | |
| iNO | 394 | 282 (71.6) | |||||
| Mercier, 20107 | 24-28 weeks | Control | 400 | 138 (35) | |||
| iNO | 395 | 137 (35) | |||||
| Schreiber, 20038 | NICU | Control | 102 | 65 (63.7) | P-value: 0.03 RR: 0.76 (0.60-0.97) | RR: 0.77 (0.60-0.98) | type of ventilation |
| iNO | 105 | 51 (48.6) | |||||
| Su, 20089 | 36 weeks PMA | Control | 33 | 21 (64) | |||
| iNO | 32 | 16 (50) | |||||
| Subhedar, 199710 | Before Discharge | Control | 22 | 21 (95) | RR = 1.05 (0.84-1.25) | ||
| iNO | 20 | 20 (100) | |||||
| Van Meurs, 200711 | Death before discharge to home or within 365 | Control | 15 | 9 (60) | P-value: 0.87 RR: 0.83 (0.43-1.62) | p-value: 0.5 RR: 0.80 (0.43-1.48) | OI Stratum |
| iNO | 14 | 7 (50) | |||||
| Van Meurs, 200512 | before discharge to home or within 365 days among hospitalized infants | Control | 208 | 170 (82) | P-value: 0.52 RR: 0.97 (0.86-1.06) | Birth weight, study site, Oxygenation index | |
| iNO | 210 | 167 (80) |
BPD: Bronchopulmonary Dysplasia, iNO: Inhaled nitric oxide, NICU: Neonatal intensive care unit, OI: Oxygenation Index, OR: Odds ratio, PMA: Post-menstrual age , RR: Relative risk
Evidence Table 8Brain injury outcomes for KQ2
| Author, Year | Outcomes | Time of outcome measure | Arm Description | N (number of participants measured) | Participants with outcome—n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Dani, 20061 | Brain injury, any IVH | before discharge | Control | 20 | 4 (20) | P-value:0.725 | ||
| iNO | 20 | 5 (25) | ||||||
| Hascoet, 20052 | 28 days | Control | 84 | 6 (7) | P-value: NS | |||
| iNO | 61 | 4 (6) | ||||||
| Kinsella, 19993 | 7 days or 36 weeks postconception al age | iNO | 32 | 18 (56) | P-value: NS | |||
| Control | 17 | 10 (59) | ||||||
| Su, 20084 | Not specified | Control | 33 | 12 (36.3) | ||||
| iNO | 32 | 8 (25) | ||||||
| Dani, 20061 | Brain injury, IVH grades 3 and 4 | Before discharge | Control | 20 | 2 (10) | P-value: 1 | ||
| iNO | 20 | 2 (10) | ||||||
| Nonresponders | 6 | 3 (50) | P-value: 0.225 | |||||
| Responders | 14 | 3 (21) | ||||||
| Kinsella, 19993 | 7 days | Control | 43 | 16 (37) | ||||
| iNO | 26 | 10 (40) | ||||||
| Kinsella, 20065 | 7 to 14 days of age and / or at more than 30 days of age | Control | 394 | 63 (16) | p-value 0.14 RR: 0.77 (0.54-1.09) | study sight, randomization strata | ||
| iNO | 398 | 49 (12.3) | ||||||
| Mercier, 20106 | 24-28 weeks | Control | 397 | 32 (8) | ||||
| iNO | 395 | 24 (6.1) | ||||||
| Srisuparp, 20027 | 72 hours | Control | 18 | 5 (27.8) | ||||
| iNO | 16 | 4 (25.1) | ||||||
| Su, 20084 | Not specified | Control | 33 | 8 (24.2) | ||||
| iNO | 32 | 4 (12.5) | ||||||
| Ballard, 20068 | Brain Injury, IVH Grades 3 or 4 and / or PVL | after study entry | Control | 288 | 10 (4.1) | P-value: 0.67 RR:1.21(0.53-2.76) | ||
| iNO | 294 | 13 (5) | ||||||
| Franco-Belgium Collaborativ e NO Trial Group, 19999 | during hospitalization | Control | 45 | 12 (27) | P-value: NS | |||
| iNO | 40 | 13 (32) | ||||||
| Kinsella, 20065 | 21 days until extubation | Control | 364 | 87 (24) | ||||
| iNO | 366 | 64 (17) | ||||||
| Schreiber, 200310 | NICU | Control | 102 | 24 (23.5) | P-value: 0.04 RR: 0.53 (0.28-0.98) | |||
| iNO | 105 | 13 (12.4) | ||||||
| Van Meurs, 200711 | 28 +/- 3 days | Control | 9 (HUS available) | 2 (22) | P-value: 0.47 | |||
| iNO | 9 | 0 (0) | ||||||
| Van Meurs, 200512 | Not specified | Control | 155 | 50 (32) | P-value: 0. 11 RR: 1.25 (0.95-1.66) | |||
| iNO | 170 | 69 (39) | ||||||
| Dani, 20061 | Brain Injury, PVL | Before discharge | Control | 20 | 1 (5) | P-value: 0.5 | ||
| iNO | 20 | 0 (0) | ||||||
| Nonresponders | 6 | 0 (0) | P-value: 1 | |||||
| Responders | 14 | 0 (0) | ||||||
| Kinsella, 20065 | 7 to 14 days of age and / or at more than 30 days of age | Control | 356 | 32 (9) | P-value: 0.048 RR: 0.58 (0.33-1.00) | study site, randomization strata | ||
| iNO | 365 | 19 (5.2) | ||||||
| Kinsella, 19993 | 7 days or 36 weeks postconception al age | Control | 15 | 2 (13) | P-value: 0.62 | |||
| iNO | 25 | 2 (8) | ||||||
| Mercier, 20106 | 24-28 weeks | Control | 397 | 1 (0.2) | ||||
| iNO | 395 | 7 (1.7) | ||||||
| Su, 20084 | Not specified | Control | 33 | 4 (12.1) | ||||
| iNO | 32 | 3 (9.4) |
CI: Confidence Interval, iNO: Inhaled nitric oxide, IVH: Intraventricular hemorrhage, NS: Not significant, PVL: Periventricular leukomalacia, RR: Relative risk
Evidence Table 9Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and methemoglobinemia
| Author, Year | Outcomes | Time of outcome measure | Arm Description | N (number of participants measured) | Participants with outcome—n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Ballard, 20061 | Cardiac Outcomes, PDA Requiring Medical or Surgical Treatment | after study entry | Control | 288 | 55 (19.1) | P-value: 0.85 RR: 0.96 (0.68-1.35) | ||
| iNO | 294 | 54 (18.4) | ||||||
| Field, 20052 | during hospitalization | Control | 53 | 13 (25) | ||||
| iNO | 55 | 9 (16) | ||||||
| Schreiber, 20033 | Before discharge | Control | 102 | 26 (25.5) | P-value: 0.27 RR: 0.75 (0.45-1.25) | |||
| iNO | 105 | 20 (19) | ||||||
| Kinsella, 20064 | Cardiac Outcomes, PDA Requiring Medical Treatment | Before discharge | Control | 395 | 212 (53.7) | P-value: 0.92 | study sight, randomization strata | |
| iNO | 398 | 215 (54) | ||||||
| Srisuparp, 20025 | Before discharge | Control | 18 | 1 (5.6) | P-value: 1 | |||
| iNO | 16 | 0 (0) | ||||||
| Su, 20086 | Before discharge | Control | 33 | 8 (24.2) | ||||
| iNO | 32 | 9 (28.1) | ||||||
| Subhedar, 19977 | Before discharge | Control dexamethasone and standard of care | 22 | 1 (5) | ||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 3 (15) | ||||||
| Dexamethasone alone AND dex + iNO | 21 | 1 (5) | ||||||
| iNO AND standard of care | 21 | 2 (10) | ||||||
| Kinsella, 20064 | Cardiac Outcomes, PDA requiring surgical treatment | Before discharge | Control | 395 | 86 (21.8) | P-value: 0.96 | study sight, randomization strata | |
| iNO | 398 | 86 (21.6) | ||||||
| Mercier, 20108 | 24-28 weeks | Control | 397 | 45 (11.3) | ||||
| iNO | 395 | 59 (14.9) | ||||||
| Srisuparp, 20025 | Before discharge | Control | 18 | 0 (0) | P-value: 0.47 | |||
| iNO | 16 | 1 (6.3) | ||||||
| Subhedar, 19977 | Before discharge | Control dexamethasone and standard of care | 22 | 2 (10) | ||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 1 (5) | ||||||
| Dexamethasone alone AND dex + iNO | 21 | 2 (10) | ||||||
| iNO AND standard of care | 21 | 2 (10) | ||||||
| Dani, 20069 | Cardiac Outcomes, Incidence of PDA | Before discharge | Control | 20 | 18 (90) | P-value: 0.421 | ||
| iNO | 20 | 16 (80) | ||||||
| Nonresponders | 6 | 5 (60) | P-value: 0.657 | |||||
| Responders | 14 | 11 (80) | ||||||
| Kinsella, 199910 | Cardiac Outcomes, Symptomatic PDA | Before discharge | Control | Unclear | Unclear (19) | P-value: NS | ||
| iNO | Unclear (21) | |||||||
| Subhedar, 19977 | Before discharge | Control dexamethasone and standard of care | 22 | 3 (15) | ||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 4 (20) | ||||||
| Dexamethasone alone AND dex + iNO | 21 | 3 (14) | ||||||
| iNO AND standard of care | 21 | 4 (19) | ||||||
| Hascoet, 200511 | Cardiac Outcomes, Undefined PDA | 28 days | Control with Hypoxemic Respiratory Failure | 84 | 31 (37) | P-value: NS | ||
| iNO with Hypoxemic Respiratory Failure | 61 | 20.74 (34) | ||||||
| Dani, 20069 | Sepsis Defined by Positive Culture | before discharge | Control | 20 | 10 (50) | |||
| iNO | 20 | 8 (40) | 0.751 | |||||
| Responders | 6 | 2 (33) | ||||||
| Nonresponders | 14 | 6 (43) | 0.545 | |||||
| Field, 20052 | during hospitalization | Control | 53 | 21 (40) | ||||
| iNO | 55 | 23 (42) | ||||||
| Srisuparp, 20025 | Unspecified | Control | 18 | 7 (38.9) | 1 | |||
| iNO | 16 | 7 (43.8) | 1 | |||||
| Field, 20052 | Sepsis Defined by Clinician | during hospitalization | Control | 53 | ||||
| iNO | 55 | 12 (22) | ||||||
| Su, 2008 {#200) | Undefined Sepsis | Unspecified | Control | 33 | 2 (6.1) | |||
| iNO | 32 | 3 (9.4) | ||||||
| Kinsella, 20064 | Unspecified | Control | 369 | 118 (32) | ||||
| iNO | 381 | 139 (0.365) | 0.19 | randomization strata, study sight | ||||
| Ballard, 20061 | after study entry | Control | 288 | 118 (41) | 0.91 | |||
| 0.98(0.80-1.20) | ||||||||
| iNO | 294 | 121 (41.2) | 0.91 | |||||
| 0.98(0.80-1.20) | ||||||||
| Schreiber, 20033 | After 24 hours of age | Control | 102 | 50 (49) | ||||
| iNO | 105 | 54 (51.5) | 0.73 | |||||
| 1.05 (0.80-1.38) | ||||||||
| Ballard, 20061 | Cardiac Outcomes, NEC requiring surgical treatment | after study entry | Control | 288 | 19 (6.6) | P-value: 0.63 RR: 1.17(0.64-2.13) | ||
| iNO | 294 | 23 (7.8) | ||||||
| Ballard, 20061 | Cardiac Outcomes, NEC requiring medical treatment | after study entry | Control | 288 | 8 (2.8) | P-value: 0.84 RR:1.20(0.46-3.13) | ||
| iNO | 294 | 10 (3.4) | ||||||
| Dani, 20069 | Cardiac Outcomes, NEC diagnosed by clinical criteria | Before discharge | Control | 20 | 0 (0) | P-value: 0.5 | ||
| iNO | 20 | 1 (5) | ||||||
| Before discharge | Nonresponders | 6 | 0 (0) | P-value: 0.7 | ||||
| Responders | 14 | 1 (7) | ||||||
| Hascoet, 200511 | Cardiac Outcomes, NEC undefined | 28 days of life | Control with Hypoxemic Respiratory Failure | 84 | (6) | NS | ||
| iNO with Hypoxemic Respiratory Failure | 61 | (8) | ||||||
| Kinsella, 20064 | Before discharge | Control | 369 | 46 (12.5) | 0.54 | study site, randomization strata | ||
| iNO | 379 | 53 (14) | ||||||
| Mercier, 20108 | Before discharge | Control | 397 | 7 (1.8) | ||||
| iNO | 395 | 11 (2.8) | ||||||
| Schreiber, 20033 | before discharge | Control | 102 | 6 (5.9) | P-value: 0.11 RR: 2.10 (0.83-5.32) | |||
| iNO | 105 | 13 (12.4) | ||||||
| Su, 20086 | Before discharge | Control | 33 | 2 (6.1) | ||||
| iNO | 32 | 2 (6.3) | ||||||
| Subhedar, 19977 | before discharge | Control dexamethasone and standard of care | 22 | 2 (10) | ||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 1 (5) | ||||||
| Dexamethasone alone AND dex + iNO | 21 | 2 (10) | ||||||
| iNO AND standard of care | 21 | 1 (5) | ||||||
| Ballard, 20061 | ROP requiring treatment by cryo or laser | After study entry | Control | 288 | 68 (23.6) | p-value: 0.95 RR = 0.97 (0.72-1.31) | ||
| iNO | 294 | 72 (24.5) | ||||||
| Field, 20052 | Before hospital discharge | Control | 49 | 4 (8) | ||||
| iNO | 50 | 8 (16) | ||||||
| Kinsella, 199910 | Before hospital discharge | Control | 15 | 3 (20) | P-value: 0.1 | |||
| iNO | 25 | 1 (4) | ||||||
| Kinsella, 20064 | Before Discharge | Control | 395 | 60 (15.2) | P-value: 0.59 | |||
| iNO | 398 | 66 (16.6) | ||||||
| Schreiber, 20033 | Before hospital discharge | Control | 102 | 10 (9.8) | P-value: 0.27 | |||
| iNO | 105 | 6 (5.7) | ||||||
| Subhedar, 19977 | Before Hospital Discharge | Control dexamethasone and standard of care | 22 | 0 (0) | ||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 2 (10) | ||||||
| Dexamethasone alone AND dex + iNO | 21 | 2 (10) | ||||||
| iNO AND standard of care | 21 | 0 (0) | ||||||
| Van Meurs, 200712 | Before Discharge | Control | 5 | 2 (40) | P-value: 0.44 | |||
| iNO | 5 | 0 (0) | ||||||
| Van Meurs, 200513 | before hospital discharge | Control | 112 | 36 (32) | P-value: 0.42 | Study center, Oxygenation index, birth weight | ||
| iNO | 98 | 29 (30) | ||||||
| Field, 20052 | Pulmonary Hemorrhage | Hospital discharge | Control | 53 | 5 (9) | |||
| iNO | 55 | 4 (7) | ||||||
| Kinsella, 20064 | Before discharge | Control | 395 | 26 (6.6) | 0.75 | study sight, randomization strata | ||
| iNO | 398 | 24 (6) | ||||||
| Mercier, 20108 | Discharge | Control | 397 | 14 (3.5) | ||||
| iNO | 395 | 12 (3) | ||||||
| Schreiber, 20033 | Before discharge | Control | 102 | 4 (3.8) | P-value: 0.37 RR:0.56 (0.17-1.84) | |||
| iNO | 105 | 7 (6.9) | ||||||
| Su, 20086 | Before discharge | Control | 33 | 2 (6.1) | ||||
| iNO | 32 | 3 (9.4) | ||||||
| Field, 20052 | Air Leak | Hospital discharge | Control | 53 | 20 (38) | |||
| iNO | 55 | 20 (36) | ||||||
| Kinsella, 199910 | ||||||||
| Kinsella, 20064 | Before discharge | Control | 395 | 24 (6.1) | P-value: 0.94 | study sight, randomization strata | ||
| iNO, Total sample) | 398 | 25 (6.3) | ||||||
| Mercier, 20108 | 24-28 weeks | Control | 397 | 13(3) | ||||
| iNO | 395 | 12 (2) | ||||||
| Schreiber, 20033 | Before discharge | Control | 102 | 16 (15.7) | P-value: 0.27 RR: 0.67 (0.33-1.37) | |||
| iNO | 105 | 11 (10.5) | ||||||
| Before discharge | Control | 102 | Pulmonary interstitial emphysema 35 (34.3) | P-value: 0.23 RR: 0.78 (0.51-1.18) | ||||
| iNO | 105 | Pulmonary interstitial emphysema 28 (26.7) | ||||||
| Srisuparp, 20025 | 72 hours | Control | 18 | 1 (5.6) | p-value: 0.59 | |||
| iNO | 16 | 2 (12.5) | ||||||
| Su, 20086 | Before discharge | Control | 33 | 2 (6.1) | ||||
| iNO | 32 | 2 (6.3) | ||||||
| Subhedar, 19977 | Before discharge | Control dexamethasone and standard of care | 22 | 1 (5) | ||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 3 (15) | ||||||
| Dexamethasone alone AND dex + iNO | 21 | 3 (14) | ||||||
| iNO AND standard of care | 21 | 1 (5) | ||||||
| Van Meurs, 200513 | Before discharge | Control | 117 | 37 (32) | P-value: 0.55 RR: 1.12 (0.78-1.61) | center, Oxygenation index, birth weight | ||
| iNO | 101 | 35 (35) | ||||||
| Van Meurs, 200712 | discharge | Control | 11 | 2 (18) | P-value:0.48 | |||
| iNO | 9 | 0 (0) | ||||||
| Schreiber, 20033 | Cardiac Outcomes, Methemoglobi nemia >4% | Before discharge | Control | 102 | 0 (0) | |||
| iNO | 105 | 3 (2.9) | ||||||
| Van Meurs, 200712 | Before discharge | Control | 14 | 0 (0) | ||||
| iNO | 14 | 0 (0) | ||||||
| Van Meurs, 200513 | Before discharge | Control | 210 | 2 (1) | center, Oxygenation index | |||
| iNO | 210 | 2 (1) | ||||||
| Schreiber, 20033 | Cardiac Outcomes, Methemoglobi nemia >8% | Before discharge | Control | 102 | 0 (0) | |||
| iNO | 105 | 0 (0) | ||||||
| Van Meurs, 200513 | Before discharge | Control | 210 | 0 (0) | P-value: 0.99 | center, Oxygenation index |
CI: Confidence Interval; HRF: Hypoxemic respiratory failure; iNO: Inhaled nitric oxide; NEC: Necrotizing enterocolitis; NS: Not significant,: Relative risk; PDA: Patent Ductus Arteriosis; ROP: Retinopathy of Prematurity; RR: Relative risk;
Evidence Table 10Death and survival beyond the NICU for KQ3
| Study, year | Outcomes | Time of outcome measure | Study Arm | N (Participant Measured) | Participants with Outcome—n (%) | Relative Effect (95% CI) | Adjusted. Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Bennett, 20011 | Death | 30 months corrected age | Control | 22 | 7 (32) | P-value: 0.13 RR: 1.65 (0.87–3.3) | ||
| iNO | 20 | 10 (50) | ||||||
| Hintz, 20072 | 18-22 months | Control | 98 | 210 (47) | ||||
| iNO | 109 | 210 (52) | ||||||
| Huddy, 20083 | 4-5 years, median 4.52 (IQR 0.9) | Control | 19 | 0 (0) | ||||
| 4-5 years, median 4.63, IQR 0.84) | iNO | 25 | 1 (4) | |||||
| Walsh, 20104 | 2 years | Control | 288 | 23 (8) | RR: 1.02 (0.59-1.77) | |||
| iNO | 294 | 24 (8.2) | ||||||
| Watson, 20095 | 1 year corrected age | Control | 384 | 98 (25.5) | P-value: 0.12 | |||
| iNO | 385 | 80 (20.8) | ||||||
| Mestan KK, 20056 | Survival | 25.2+/-8.4 months corrected age | Control | 102 | 79 (0.775) | |||
| 24.9 +/-7.9 months corrected age | iNO | 105 | 89 (84.8) |
CP: Cerebral palsy, iNO: Inhaled nitric oxide, IQR: Inter-quartile range, MDI: Mental developmental index, NDI: Neurodevelopmental impairment, NS: Not significant,OI: Oxygenation index, PDI: Physical developmental index
Evidence Table 11Cerebral palsy outcomes in KQ3
| Refid | Outcome | Time of Outcome Measure | Study Arm | N (Participants Measured) | Number of Participants with Outcome—n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Bennett, 20011 | Moderate / Severe CP | 18 to 22 months | Control | 14 | 2 (14.3) | |||
| iNO | 7 | 0 (0) | ||||||
| Hintz SR, 20072 | Moderate / Severe CP | 3 years | Control | 102 | 11 (11) | P-value; 0.11 RR: 1.85 (0.93-3.71) | P-value: Model #1: 0.0453; Model #2: 0.048 RR: Model #1: 2.01 (1.01-3.98); Model #2 2.41 (1.01-5.75) | Model #1: adjusted for BWt, center, sex, and OI entry criterion, birth weight, Model #2: adjusted for BWt, center, OI entry criterion, sex, BPD, IVH gr 3 or 4 or PVL, length of iNO exposure, postnatal steroids |
| iNO | 90 | 18 (20) | ||||||
| Huddy, 20083 | Mild CP | 4-5 years | iNO | 16 | 4 (25) | |||
| Control | 22 | 6 (27.3) | ||||||
| Moderate / Severe CP | 4-5 years | Control | 16 | 2 (12.5) | ||||
| iNO | 22 | 3 (13.6) | ||||||
| Mestan KK, 20054 | Any CP | 25.2+/-8.4 months corrected age 24.9+/-7.9 months corrected age | Control | 68 | 7 (10) | P-value: 0.78 | ||
| iNO | 70 | 6 (9) | ||||||
| Tanaka, 20075 | Any CP | 3 years | Control | 15 | 7 (46.7) | |||
| iNO | 16 | 2 (12.5) | ||||||
| Van Meurs, 20076 | Moderate/Severe CP | 18-22 months | Control | 0 | 8 (0) | |||
| iNO | 0 | 9 (0) | ||||||
| Walsh, 20107 | Moderate / Severe CP | 2 years | Control | 234 | 12 (5.1) | RR: 1.23 (0.59-2.55) | ||
| 24.9+/-7.9 months corrected age | iNO | 243 | 15 (6.2) |
CI: Confidence Interval, CP: Cerebral Palsy, iNO: Inhaled Nitric Oxide, OI: Oxygenation Index, RR: Risk Ratio
Evidence Table 12Cognitive outcomes for KQ3
| Author, year | Outcome | Time of Outcome Measure | Study Arm | N (Participants Measured) | Number of Participants with Outcome—n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Hintz, 20071 | NDI: any of the following: mod-severe CP, blind, deaf, MDI<70 or PDI<70 | 18-22 months | Control | 102 | 48 (47) | P-value:0.74 RR: 1.07 (0.80 - 1.44) | Model #1: BW, center, OI entry criterion strata, sex, Model #2: same as model #1 + BPD, IVH gr 3 or 4 or PVL, length of iNO exposure, postnatal steroids | |
| iNO | 89 | 45 (51) | ||||||
| Isolated delay = MDI<70 or PDI<70 in absence of mod-severe CP, deafness or blindness | Control | 102 | 35 (34) | P-value:0.37 RR:0.79 (0.51-1.23) | P-value: Model #1: 0.78: Model #2 0.37 RR: Model #1: 1.04 (0.79-1.36); Model #2: 1.19 (0.81-1.73) | Model #1: BW, center, OI entry criterion strata, sex | ||
| iNO | 88 | 24 (27) | ||||||
| Huddy, 20082 | Any cognitive disability (GCAS<85) | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 9 (56.2) | |||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 11 (50) | |||||
| Moderate or severe cognitive disability (GCAS<70) | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 6 (37.5) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 6 (27.3) | |||||
| Severe cognitive disability (GCAS <50) | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 3 (18.7) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 3 (13.6) | |||||
| GCAS>84 | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 7 (43.7) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 11 (50) | |||||
| Overall outcome: severe disability | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 3 (18.7) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 3 (13.6) | |||||
| Overall outcome: Moderate disability | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 4 (25) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 5 (22.7) | |||||
| Overall outcome: Normal | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 3 (18.7) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 5 (22.7) | |||||
| Overall outcome: mild disability | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 4 (25) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 6 (27.3) | |||||
| Mestan, 20053 | Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/- 8.4 months corrected age 24.9 +/- 7.9 months corrected age | Control | 67 | 31 (46) | P-value:0.01 RR: 0.53 (0.33-0.87) | P-value: Model #1: 0.50: Model #2: 0.79 RR: Model #1: 0.85 (0.54-1.35); Model #2: 0.91 (0.46-1.81) | |
| iNO | 70 | 17 (24) | ||||||
| Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) | 25.2+/- 8.4 months corrected age | Control | 67 | birth weight | ||||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 67 | P-value:0.002 RR:0.57(0.35-0.93 | sex | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 67 | P-value:0.006 RR:0.52 (0.32-0.82) | Mother graduation fromhigh school | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 67 | P-value:0.007 RR:0.48 (0.28-0.82) | household without employed person | |||
| 24.9 +/-7.9months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/- 8.4 Months corrected age | Control | 67 | P-value:0.006 RR:0.49 (0.29-0.82) | type of ventilation | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 67 | P-value:0.01 RR:0.53 (0.33-0.87) | chronic lung disease and severe IVH or PVL | |||
| 24.9 +/- 7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) | 25.2+/- 8.4 months corrected age | Control | 67 | P-value:0.03 RR:0.6 (0.38-0.96) | prolonged postnatal exposure to corticosteroids | |||
| 24.9 +/- 7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 67 | P-value:0.01 RR:0.53 (0.33-0.87) | birth weight and sex | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) | 25.2+/- 8.4 months corrected age | Control | 67 | P-value:0.01 RR:0.55 (0.35-0.99) | severe intraventricular hemorrhage or periventricular leukomalacia | |||
| 24.9 +/- 7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) | 25.2+/- 8.4 months corrected age | Control | 67 | P-value:0.01 RR:0.55 (0.34-0.89) | chronic lung disease | |||
| 24.9 +/- 7.9 months corrected age | iNO | 70 | ||||||
| Delay without disability | 25.2+/- 8.4 months corrected age | Control | 67 | 23 (34) | P-value:0.03 RR:0.55 (0.36-0.95) | |||
| 24.9 +/- 7.9 months corrected age | iNO | 69 | 11 (16) | |||||
| Disability (CP, bilateral blindness or bilateral hearing loss) | 25.2+/- 8.4 months corrected age | Control | 68 | 8 (12) | ||||
| 24.9 +/- 7.9 months corrected age | iNO | 67 | 6 (9) | |||||
| MDI or PDI < 70 | 25.2+/- 8.4 months corrected age | Control | 67 | 28 (42) | P-value: 0.03 | |||
| 24.9 +/- 7.9 months corrected age | iNO | 69 | 16 (23) | |||||
| MDI and PDI < 70 | 25.2+/- 8.4 months corrected age | Control | 67 | 8 (12) | P-value: 0.58 | |||
| 24.9 +/- 7.9 months corrected age | iNO | 69 | 6 (9) | |||||
| Van Meurs, 20074 | NDI = any one of the following: moderate to severe CP, blind, deaf, MDI <70, or PDI <70 | 18 to 22 months | Control | 8 | 2 (25) | P-value:0.58 RR: 0.44 (0.05-4,02) | OI stratum | |
| iNO | 9 | 1 (11) | ||||||
| Walsh, 20105 | MDI>85 | 2 years | Control | 214 | 83 (35) | |||
| 24.9 +/- 7.9 months corrected age | iNO | 210 | 95 (45.2) | |||||
| PDI>85 | 2 years | Control | 212 | 73 (31) | ||||
| iNO | 207 | 75 (36.2) | ||||||
| NDI in subset with complete evaluations | 2 years | Control | 212 | (51) | RR:0.93 (0.76-1.14) | |||
| iNO | 207 | (48) | ||||||
| Neurodevelopme ntal Impairment (NDI = MDI<70, PDI<70, unable to crawl or walk (GMFCS>=2), bilateral blindness, or bilateral deafness requiring amplification). | 2 years | Control | 234 | 114 (49) | RR: 0.92 (0.75-1.12) | |||
| iNO | 243 | 109 (44.8) |
BSID: Bayley Scale of Infant Development, BW: Birth weight, CP: Cerebral Palsy, GCAS: General conceptual ability score, GMFCS: Gross Motor Function Classification System, iNO: Inhaled Nitric Oxide, IQR: Inter-quartile range, IVH: Intravascular hemorrhage, MDI: Mental Development Index, NDI: Neurodevelopmental Impairment, OI: Oxygenation Index, PDI: Psychomotor Development Index, PVL: Periventricular leukomalacia, RR: Relative Risk
Evidence Table 13Sensory impairment for KQ3
| Author, year | Outcome | Time of Outcome Measure | Study Arm | N (Participants Measured) | Number of Participants with Outcome—n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Bennett, 20011 | Sensorineural Impairment | Control | 22 | 1 (5) | ||||
| iNO | 20 | 0 (0) | ||||||
| Field, 20052 | Visual Impairment | 1 year corrected age | Control | 53 | 0 (0) | |||
| iNO | 55 | 1 (2) | ||||||
| Hearing Impairment | Control | 53 | 0 (0) | |||||
| iNO | 55 | 3 (5) | ||||||
| Huddy, 20083 | Visual Impairment | 4-5 years | Control | 16 | 7 (43.7) | |||
| iNO | 22 | 13 (59.1) | ||||||
| Hearing Impairment | 4-5 years | Control | 16 | 0 (0) | ||||
| iNO | 22 | 2 (9.1) | ||||||
| Mestan KK, 20054 | Hearing Aid | 25.2+/-8.4 months corrected age 24.9+/-7.9 months corrected age | Control | 68 | 1 (1) | P-value: 0.49 | ||
| iNO | 70 | 0 (0) | ||||||
| Blindness | 25.2+/-8.4 months corrected age 24.9+/-7.9 | Control | 68 | 2 (3) | P-value: 0.24 | |||
| iNO | 70 | 0 (0) | ||||||
| Van Meurs, 20075 | Deafness | 4-5 years | Control | 16 | 0 (0) | |||
| iNO | 22 | 1 (4.5) | ||||||
| No recognizable speech | 4-5 years | Control | 16 | 0 (0) | ||||
| iNO | 22 | 3 (13.6) | ||||||
| Any disability of hearing or communication | 4-5 years | Control | 16 | 3 (18.7) | ||||
| iNO | 22 | 3 (13.6) | ||||||
| Deafness | 18 to 22 months | Control | 8 | 0 (0) | ||||
| iNO | 9 | 0 (0) | ||||||
| Walsh, 20106 | Deafness | 2 years | Control | 234 | 3 (1) | RR: 2.56 (0.68-9.52) | ||
| 24.9+/-7.9 months corrected age | iNO | 243 | 8 (3.2) | |||||
| Blindness | 2 years | Control | 234 | 9 (4) | RR: 0.97 (0.40-2.40) | |||
| 24.9+/-7.9 | iNO | 243 | 9 (3.7) | |||||
| Watson, 2009 7 | Sensory impairment included in NDI but not individually. | |||||||
CI: Confidence Interval, iNO: Inhaled nitric oxide, NDI: Neurodevelopmental Impairment, RR: Relative Risk
Evidence Table 14NDI and death or NDI outcomes for KQ3
| Author, year | Outcome | Time of Outcome Measure | Study Arm | N (Participants Measured) | Number of Participants with Outcome—n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Bennett, 20011 | Severe neurodisability - one or more of: moderate or severe developmental delay; CP; sensorineural impairment (hearing loss requiring hearing aids and blindness) | 30 months corrected age | Control | 14 | 5 (36) | P-value: 0.12 | ||
| iNO | 7 | 0 (0) | ||||||
| Hintz SR, 20072 | NDI: any of the following: mod-severe CP, blind, deaf, MDI<70 or PDI<70 | 18-22 months | Control | 102 | 48(47) | P-value:0.74 RR: 1.07 (0.80 - 1.44) | Model #1: BWt,center, OI entry <criterion strata, sex, Model #2: same as model #1 + BPD, IVH gr 3 or 4 or PVL, length of iNO exposure, postnatal steroids | |
| iNO | 89 | 45 (51) | ||||||
| Isolated delay = MDI<70 or PDI<70 n absence of mod-severe CP, deafness or blindness | Control | 102 | 35 (34) | P-value:0.37 RR:0.79 (0.51-1.23) | P-value: Model #1: 0.78: Model #2 0.37 RR: Model #1: 1.04 (0.79-1.36); Model #2: 1.19 (0.81-1.73) | Model #1: BWt, center, OI entry criterion strata, sex | ||
| iNO | 88 | 24 (27) | ||||||
| Unimpaired = MDI & PDI>85, no mod-severe CP, and not blind or deaf | Control | 102 | 26 (25) | P-value:0.86 RR:0.92 (0.56-1.51) | P-value: Model #1: 0.10; Model #2 0.43 RR: Model #1: 0.72 (0.48-1.07); Model #2: 0.79 (0.44-1.42) | Model #1: BWt, center, OI entry criterion strata, sex | ||
| Huddy, 20083 | Overall outcome: severe disability | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 3 (18.7) | |||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 3 (13.6) | |||||
| Overall outcome: Moderate disability | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 4 (25) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 5 (22.7) | |||||
| Overall outcome: Normal | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 3 (18.7) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 5 (22.7) | |||||
| Overall outcome: mild disability | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 4 (25) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 6 (27.3) | |||||
| Mestan, 20054 | Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age 24.9 +/-7.9 months corrected age | Control | 68 | 31 (46) | P-value:0.01 RR: 0.53 (0.33-0.87) | P-value: Model #1: 0.50: Model #2 0.79 RR: Model #1: 0.85 (0.54-1.35); Model #2: 0.91 (0.46-1.81)) | |
| iNO | 70 | 17 (24) | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | birth weight | ||||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.002 RR:0.57(0.35-0.93 | sex | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.006 RR:0.52 (0.32-0.82) | Mother graduation from high school | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.007 RR:0.48 (0.28-0.82) | household without employed person | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.006 RR:0.49 (0.29-0.82) | type of ventilation | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.01 RR:0.53 (0.33-0.87) | chronic lung disease and severe IVH or PVL | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.03 RR:0.6 (0.38-0.96) | prolonged postnatal exposure to corticosteroids | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.01 RR:0.53 (0.33-0.87) | birth weight and sex | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.01 RR:0.55 (0.35-0.99) | severe intraventricular hemorrhage or periventricular leukomalacia | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Abnormal neurodevelopmental outcome (any disability or any BSID II score <70) | 25.2+/-8.4 months corrected age | Control | 68 | P-value:0.01 RR:0.55 (0.34-0.89) | chronic lung disease | |||
| 24.9 +/-7.9 months corrected age | iNO | 70 | ||||||
| Van Meurs, 20075 | NDI = any one of the following: moderate to severe CP, blind, deaf, MDI <70, or PDI <70 | 18 to 22 months | Control | 8 | 2 (25) | P-value:0.58 RR: 0.44 (0.05-4.02) | OI stratum | |
| iNO | 9 | 1 (11) | ||||||
| Walsh, 20106 | NDI in subset with complete evaluations | 2 years | Control | 212 | (51) | RR:0.93 (0.76-1.14) | ||
| 24.9 +/-7.9 months corrected age | iNO | 207 | (48) | |||||
| Neuro development al Impairment (NDI = MDI<70, PDI<70, unable to crawl or walk (GMFCS>=2), bilateral blindness, or bilateral deafness requiring amplification). | 2 years | Control | 234 | 114 (49) | RR: 0.92 (0.75-1.12) | |||
| iNO | 243 | 109 (44.8) | ||||||
| Watson, 20097 | NDI (CP, severe hearing loss, MDI or PDI< 70,or blindness) | 1 year corrected age | Control | 218 | 73 (33.5) | P-value: 0.66 | ||
| iNO | 237 | 84 (35.4) | ||||||
| Van Meurs, 20075 | Death or NDI, Death and/or NDI | 18 to 22 months | Control | 12 | 6 (50) | P-value: 1 RR: 0.86 (0.37-1.96) | P-value: 0.8 RR: 0.90 (0.40-2.02) | OI Strata |
| iNO | 14 | 6 (43) | ||||||
| Van Meurs, 20075 | Death or NDI, Death and/or moderate to severe CP | 18 to 22 months | Control | 12 | 4 (33) | P-value: 1 RR: 1.07 (0.37-3.11) | P-value: 0.88 RR: 1.08 (0.39-3.03) | OI Strata |
| iNO | 14 | 5 (36) | ||||||
| Bennett, 20011 | Death or NDI, Death or severe neurodisability | 30 months corrected age | Control | 22 | 13 (59) | P-value: 0.79 RR: 1.1 (0.57-2.3) | ||
| iNO | 19 | 12 (63) | ||||||
| Watson, 20097 | Death or NDI, Death or NDI (CP, severe hearing loss, MDI or PDI< 70,or blindness) | 1 year corrected age | Control | 384 | 171 (44.5) | P-value: 0.55 | ||
| iNO | 387 | 164 (42.4) | ||||||
| Watson, 20097 | Death or NDI, Death, on oxygen, or NDI (CP, severe hearing loss, MDI or PDI< 70,or blindness) | 1 year corrected age | Control | 384 | 175 (45.6) | P-value: 0.65 | ||
| iNO | 387 | 170 (43.9) | ||||||
| Hintz SR, 20072 | Death or NDI, Death or NDI:any of the following: mod-severe CP, blind, deaf, MDI<70 or PDI<70 | 18-22 months | Control | 200 | 146 (73) | P-value: 0.32 RR:1.07 (0.95-1.19) | P-value: 0.3 RR: Model #1:1.06 (0.95-1.17) | Model #1: BWt, center, OI entry criterion strata, sex |
| iNO | 198 | 154 (78) | ||||||
| Hintz SR, 20072 | Death or NDI, Death or moderate to severe CP | 18-22 months | Control | 200 | 109 (54) | P-value: 0.07 RR: 1.17 (0.99-1.38) | P-value: 0.07 RR: Model #1: 1.15 (0.99-1.34) | Model #1: BWt, center, OI entry criterion strata, sex |
| iNO | 199 | 127 (64) |
CI: Confidence Interval; CP: Cerebral Palsy; GMFCS: Gross motor function classification system; iNO: Inhaled nitric oxide; IQR: Inter-quartile range; MDI: Mental developmental index; NDI: Neurodevelopmental impairment; NS: Not significant,OI: Oxygenation index; OI: Oxygenation Index; PDI: Physical developmental index;
Evidence Table 15Other long term outcomes included in KQ3 including seizures, growth, oral feeding, pulmonary outcomes
| Refid | Outcome | Time of Outcome Measure | Study Arm | N (Participants Measured) | Number of Participants with Outcome—n (%) | Z-score | Measurement | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) |
|---|---|---|---|---|---|---|---|---|---|
| Field, 20051 | Seizures | 1 year corrected age | Control | 18 | 0 (0) | ||||
| iNO | 25 | 3 (12) | |||||||
| Huddy, 20082 | Seizures | 4-5 years | Control | 16 | 2 (9.1) | ||||
| iNO | 22 | 3 (13.6) | |||||||
| Field, 20051 | Oral feeding | 1 year corrected | Control | 53 | 20 (38) | ||||
| iNO | 55 | 28 (51) | |||||||
| Huddy, 20082 | Steroids, Inhaled | 4-5 years | Control | 16 | 3 (18.8) | ||||
| iNO | 22 | 4 (18.2) | |||||||
| Field, 20051 | Steroids, Unspecified | 1 year corrected age | Control | 18 | 5 (28) | ||||
| iNO | 25 | 5 (20) | |||||||
| Hibbs, 20073 | 12 +/- 3 months | Control | 225 | (17.7) | OR: 0.5 (0.32-0.77) | ||||
| iNO | 230 | (11) | |||||||
| 12 +/- 3 months | Control | 225 | (32.4) | OR: 0.56 (0.32-0.97) | |||||
| iNO | 230 | (19.8) | |||||||
| Cheung, 19984 | Bronchodilators | iNO | 10 | 1 (10) | |||||
| Field, 20051 | 1 year corrected age | Control | 18 | 7 (39) | |||||
| 1 year corrected age | iNO | 25 | 10 (40) | ||||||
| Hibbs, 20073 | 12 +/- 3 months | Control | 225 | (54.1) | OR:0.53(0.36-0.78) | ||||
| iNO | 230 | (40.1) | |||||||
| Huddy, 20082 | 4-5 years | Control | 16 | 4 (25) | |||||
| iNO | 22 | 7 (31.8) | |||||||
| Hibbs AM, 20073 | Diuretics | 12 +/- 3 months | Control | 225 | (28.4) | OR: 0.54 (0.34-0.85) | |||
| iNO | 230 | (18.6) | |||||||
| Huddy 20082 | Long-Term Pulmonary Outcomes, Asthma | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 4 (25) | ||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 9 (40.9) | ||||||
| Huddy, 20082 | Long-Term Pulmonary Outcomes, Respiratory Disability | 4-5 yrs | Control | 16 | 1 (6.2) | ||||
| iNO | 22 | 2 (9.1) | |||||||
| Field, 20051 | Long-Term Pulmonary Outcomes, Feeding tube | 1 year corrected age | Control | 18 | 1 (6) | ||||
| iNO | 25 | 1 (4) | |||||||
| Cheung, 19984 | Long-Term Pulmonary Outcomes, Wheezing | > 1 year corrected age | iNO | 10 | 4 (40) | ||||
| Field, 20051 | 1 year corrected age | Control | 18 | 5 (28) | |||||
| iNO | 25 | 13 (52) | |||||||
| Hibbs, 20073 | 12 +/- 3 months | Control | 225 | (56.4) | OR: 0.7 (0.48-1.03) | ||||
| iNO | 230 | (49.6) | |||||||
| Huddy, 20082 | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 6 (50) | |||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 9 (40.9) | ||||||
| Cheung, 1998 4 | Long-Term Pulmonary Outcomes, Recurrent Aspiration Pneumonia | > 1 year corrected age | iNO | 10 | 1 (10) | ||||
| Clark, 20025 | Long-Term Pulmonary Outcomes, Supplemental Oxygen | 6 months PCA | iNO | 25 | 10 (40) | ||||
| Field, 2005 1 | 1 year corrected age | Control | 18 | 1 (6) | |||||
| iNO | 25 | 3 (12) | |||||||
| Hibbs, 20073 | Any Home | Control | 225 | (49.5) | |||||
| Oxygen Use | iNO | 230 | (38.4) | ||||||
| Persistent oxygen use at time of followup | Control | 225 | (9.4) | ||||||
| iNO | 230 | (3) | |||||||
| Huddy, 20082 | 4-5 years (Oxygen discontinued prior to follow-up) | Control | 16 | 4 (25) | |||||
| iNO | 22 | 4 (18) | |||||||
| Watson, 20096 | 1 year corrected age 500-749g | Control | 192 | 3 (2) | |||||
| iNO | 192 | 13 (7) | |||||||
| 1 year corrected age 750-999g | Control | 139 | 5 (4) | ||||||
| iNO | 141 | 4 (3) | |||||||
| 1 year corrected age 1000-1250g | Control | 64 | 3 (5) | ||||||
| iNO | 65 | 0 (0) | |||||||
| Huddy, 20082 | Height | 4-5 years | Control | 16 | -0.68 | ||||
| iNO | 22 | -0.9 | |||||||
| Mestan KK, 20057 | 2 years | Control | 79 | 68 (86) | -0.59 (IQR -1.25 to 0.41) | Median:83.9 cm IQR 81-88.3 cm | 0.55 | 0.32 | |
| iNO | 138 | 70 (51) | -0.23 (IQR -0.83 to 0.36) | Median:84.5 cm IQR 81.2-88.5 | |||||
| Walsh, 20108 | 2 Years | Control | 234 | Mean: 85.3 cm SD:6 cm | |||||
| iNO | 243 | Mean: 85.2 cm SD:5.2 cm | |||||||
| Hintz SR, 20079 | Weight | 2 Years | Control | 102 | Mean 10.6 kg SD:1.7 kg | 0.72 | |||
| iNO | 91 | Mean:10.6 kg SD: 1.4 kg | |||||||
| Huddy, 20082 | 4-5 years | Control | 16 | -1.02 | |||||
| iNO | 22 | -0.86 | |||||||
| Mestan KK, 20057 | 2 years | Control | 79 | 68 (.86) | -1.07 (IQR -2.25 to -0.38) | Median:10.8 kg IQR 9.5-1 2.2 kg | 0.04 | 0.02 | |
| iNO | 138 | 70 () | -0.49 (IQR -1.51 to 0.61 | Median:1.17 kg IQR 1.05-1.35 kg | |||||
| Walsh, 20108 | 2 Years | Control | 234 | Mean: 11.5 kg SD:1.7 kg | |||||
| iNO | 243 | Mean: 11.4 kg SD: 1.7 | |||||||
| 513 Field, 20051 | Head Circumferance | 1 year | Control | 18 | 15 (83) | Mean:45.2 cm SD:1.6 cm | |||
| iNO | 25 | 23 (92) | 45.5 SD:1.8 cm | ||||||
| Hintz SR, 20079 | 18-22 Months | Control | 102 | Mean:46.7 cm SD:1.9 cm | 0.64 | ||||
| iNO | 91 | Mean:46.8 cm SD:1.7 cm | |||||||
| 160 Huddy, 20082 | 4-5 years | Control | 16 | -1.53 | |||||
| iNO | 22 | -1.48 | |||||||
| Walsh, 20108 | 2 Years | Control | 234 | Mean:47.8 cm SD:1.9 cm | |||||
| iNO | 243 | Mean:47.6 cm SD:2.1 cm | |||||||
| Cheung, 1998 4 | Slow Weight, Height or Head Circumference Development | 1 year | iNO | 10 | 4 |
CI: Confidence Interval; CP: Cerebral Palsy; iNO: Inhaled Nitric Oxide; IQR: Inter-quartile range; OI: Oxygenation Index; RR: Risk Ratio
Evidence Table 16All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or BPD, Survival without BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy
| Author, Year | Outcomes | Time of outcome measure | Study Arm | N (number of participants measured) | Participants with Outcome— n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments |
|---|---|---|---|---|---|---|---|---|
| Chock, 20091 | BPD at 36 weeks | 36 weeks PMA | Control | 2 | 2 (100) | P-value: 0.43 | ||
| iNO | 5 | 2 (40) | ||||||
| Field, 20052 | 36 weeks PMA | Control | 55 | 15 (27) | ||||
| iNO | 53 | 26 (49) | ||||||
| Kinsella, 20063 | 36 weeks PMA | Control | 309 | 210 (68) | P-value: 0.43 | RR:0.96 (0.86–1.09) | randomization strata, study sight | |
| iNO | 326 | 212(65) | ||||||
| 36 weeks PMA | Control Birth weight of 500–749 g | 189 | 66 (34.9) | P-value: 0.20 RR: 0.82 (0.61-1.11) | randomization strata, study sight | |||
| iNO Birth weight of 500–749 g | 191 | 55 (28.8) | ||||||
| 36 weeks PMA | Control Birth weight of 750–999 g | 139 | 24 (17.3) | P-value: 0.19 RR: 0.63 (0.35-1.15) | randomization strata, study sight | |||
| iNO Birth weight of 750–999 g | 138 | 15 (10.9) | ||||||
| 36 weeks PMA | Control Birth weight of 1000–1250 g | 64 | 8 (12.5) | P-value: 0.97 RR: 0.98 (0.39-2.46) | randomization strata, study sight | |||
| iNO Birth weight of 1000–1250 g | 65 | 8 (12.3) | ||||||
| Schreiber, 20034 | 36 weeks PMA | Control | 102 | 42 (53.2) | P-value: 0.07 RR: 0.74 (0.53–1.03) | type of ventilation | ||
| iNO | 105 | 35 (39.3) | ||||||
| Van Meurs, 20055 | 36 weeks PMA | Control | 127 | 86 (68) | P-value: 0.26 | RR: 0.90 (0.75–1.08) | center, birth-weight group, and oxygenation-index stratum | |
| iNO | 109 | 65 (60) | ||||||
| Control BW<=1000g | 88 | 64 (73) | P-value: 0.84 | RR: 1.02 (0.85–1.23) | center, birth-weight group, and oxygenation-index stratum | |||
| Arm B BW<=1000 g | 67 | 49 (73) | ||||||
| Control BW>1000 g | 37 | 21( 57) | P-value: 0.08 | RR: 0.68 (0.45–1.05) | center, birth-weight group, and oxygenation-index stratum | |||
| iNO BW> 1000g | 42 | 16 (38) | ||||||
| Control OI<=17 | 76 | 50 (66) | P-value: 0.12 | RR: 0.80 (0.61–1.06) | center, birth-weight group, and oxygenation-index stratum | |||
| iNO OI<=17 | 59 | 30 (51) | ||||||
| Control OI>17 | 49 | 36 (72) | P-value: 0.85 | RR: 0.98 (0.77–1.24) | center, birth-weight group, and oxygenation-index stratum | |||
| iNO OI>17 | 50 | 35 (70) | ||||||
| Ballard, 20066 | Survival without BPD | 36 weeks PMA | Control | 288 | 105 (36.5) | P-value: 0.04 RR: 1.45 (1.03-2.04) | ||
| iNO | 294 | 129 (43.9) | ||||||
| 36 weeks PMA | Control 500-799 g) | 197 | 74 (37.6) | P-value: 0.07 RR: 1.20 (0.94–1.54) | ||||
| iNO 500-799 g | 197 | 85 (43.1) | ||||||
| 36 weeks PMA | Control 800-1250 grams birth weight) | 91 | 32 (35.2) | P-value: 0.14 RR: 1.30 (0.91-1.87) | ||||
| iNO 800-1250 grams birth weight | 97 | 44 (45.4) | ||||||
| 36 weeks PMA | Control OI at study entry < 3.5 | 149 | 68 (45.6) | RR: 1.28(1.02-1.61) | ||||
| iNO OI at study entry < 3.5 | 162 | 92 (56.8) | ||||||
| 36 weeks PMA | Control OI at study entry >= 3.5) | 139 | 37 (26.6) | RR: 1.11(0.74-1.66) | ||||
| iNO OI at study entry>= 3.5 | 132 | 37 (28) | ||||||
| Schreiber, 20034 | Survived NICU | Control | 79 | 37 (46.8) | ||||
| iNO | 89 | 54 (60.7) | ||||||
| Survived NICU | Control BW<=750 g | 40 | 4 (10) | |||||
| iNO BW<=750 g | 32 | 7 (21.9) | ||||||
| Survived NICU | iNO BW 751-1000 g | 28 | 14 (50) | |||||
| Control BW 751-1000 g | 29 | 11 (37.9) | ||||||
| Survived NICU | Control BW 1001-1500 g | 21 | 12 (57.1) | |||||
| iNO BW 1001-1500 g | 30 | 18 (60) | ||||||
| Survived NICU | Control BW >1500 g | 12 | 10 (83.3) | |||||
| iNO BW 1500 g | 15 | 15 (100) | ||||||
| Survived NICU | Control OI<6.94 (median) | 49 | 16 (32.7) | |||||
| iNO OI<6.94 (median) | 50 | 32 (64) | ||||||
| Survived NICU | Control OI>=6.94 (median) | 48 | 20 (41.7) | |||||
| iNO 0I>=6.94 (median)) | 51 | 21 (41.2) | ||||||
| Schreiber, 20034 | Survival with BPD | Survived NICU | Control | 102 | 42 (53.2) | p-value = 0.07 RR = 0.74 (0.53-1.03) | 0.75 (0.54-1.05) | |
| iNO | 105 | 35 (39.3) | ||||||
| Banks, 19997 | Death | 3-24 months from enrollment | iNO | 16 | 7 (44) | |||
| iNO responders | 11 | 4 (36) | ||||||
| iNO non-responders | 5 | 3 (60) | ||||||
| Chock, 20091 | Death prior to discharge home or within 365 days | Control | 6 | 4 (67) | P-value: 0.57 | |||
| iNO | 6 | 2 (33) | ||||||
| Field, 20052 | 36 weeks | Control | 53 | 34 (64) | ||||
| iNO | 55 | 30 (55) | ||||||
| Hintz SR, 20078 | 18-22 months | Control Birth weight</= 1 000g, F/U cohort | 152 | 79 (52) | P-value: 0.04 | RR: 1.22 (1.10- | OI criterion, birth weight, study center, sex | |
| iNO tx, Birth weight </=1000gm | 152 | 98 (64) | ||||||
| Control Birth weight >1000g, F/U Cohort | 48 | 19 (40) | P-value: 0.08-1.46) | RR: 0.58 (0.31-1.07) | OI criterion, birth weight, study center, sex | |||
| iNO Tx, Birth weight > 1000g | 48 | 11 (23) | ||||||
| Control Placebo, Birth weight 401-750grams | 99 | 55 (56) | P-value: 0.01 | OI criterion, birth weight, study center, sex | ||||
| iNO tx, Birth weight 401-750grams | 94 / 400 (for analysis cohort) | 69 (73) | ||||||
| Control Placebo, Birth weight 751-1000grams | 53 | 24 (45) | P-value: 0.63 | OI criterion, birth weight, study center, sex | ||||
| iNO tx, Birth weight 751-1000grams) | 58 / 400 (analysis cohort) | 29 (50) | ||||||
| Control Placebo, Birth weight 1001-1500 grams | 48 / 400 (analysis cohort) | 19 (40) | P-value: 0.07 | OI criterion, birth weight, study center, sex | ||||
| iNO tx. Birth eight 1001-1500grams | 48 / 400 (analysis cohort) | 11 (23) | ||||||
| Kinsella, 20063 | 36 wks PMA | Control | 392 | 98 (25) | P-value: 0.08 RR: 0.79 (0.61-1.03) | randomization strata, study sight | ||
| iNO | 394 | 78 (19.8) | ||||||
| 36 wks PMA | Control BW 500-749 g; mean 639, SD 71 | 189 | 66 (34.9) | P-value:0.2 RR: 0.82 (0.61-1.11) | randomization strata, study sight | |||
| iNO BW 500-749 g; mean 642, SD 76 | 191 | 55 (28.8) | ||||||
| 36 wks PMA | Control BW 750-999 g; mean 843, SD 71 | 139 | 24 (17.3) | P-value: 0.13 RR: 0.63 (0.35-1.15) | randomization strata, study sight | |||
| iNO BW 750-999 g; mean 851, SD 71 | 138 | 15 (10.9) | ||||||
| 36 wks PMA | Control BW 1000-1250 g; mean 1113 g, SD 77g | 64 | 8 (12.5) | P-value: 0.97 RR: 0.98 (0.39-2.46) | randomization strata, study sight | |||
| iNO BW 1000-1250 g; mean 1129 g, SD 68g | 65 | 8 (12.3) | ||||||
| Kumar, 20079 | Control | |||||||
| iNO | 23 | |||||||
| Schreiber, 20034 | NICU | Control | 102 | 23 (22.5) | P-value: 0.18 RR: 0.68 (0.38-1.20) | type of ventilation | ||
| iNO | 105 | 16 (15.2) | ||||||
| Van Meurs, 20055 | Death before discharge to home or within 365 days among hospitalized infants | Control | 208 | 93 (44) | P-value: 0. 11 RR: 1.16 (0.96-1.39) | birth weight, study center, Oxygenation index | ||
| iNO | 210 | 109 (52) | ||||||
| Death before discharge to home or within 3 65 days among hospitalized infants | Control BW<=1000g | 158 | 76 (48) | P-value: 0.01 RR: 1.28 (1.06-1.54) | birth weight, study center, Oxygenation index | |||
| iNO BW<=1000 g | 158 | 98 (62) | ||||||
| Death before discharge to home or within 365 days among hospitalized infants | Control BW>1000 g) | 52 | 17 (33) | P-value: 0.16 RR: 0.65 (0.36-1.18) | birth weight, study center,Oxygenation index | |||
| iNO BW>1000g | 52 | 11 (21) | ||||||
| Death before discharge to home or within 365 days among hospitalized infants | Control OI<=17 | 110 | 40 (36) | P-value: 0.09 RR: 1.27 (0.96-1.68) | birth weight, study center, Oxygenation index | |||
| iNO OI<=17 | 100 | 45 (45) | ||||||
| Death before discharge to home or within 365 days among hospitalized infants | Control OI>17 | 100 | 53 (53) | P-value: 0.39 RR: 1.11 (0.88-1.4) | birth weight, study center, Oxygenation index | |||
| iNO OI>17 | 110 | 64 (58) | ||||||
| Yadav, 199910 | Prior to hospital discharge | iNO | 41 | 25 (61) | ||||
| iNO responders to iNO based on decrease in IO by 10 in first 60 minutes of treatment | 26 | 11 (42) | ||||||
| iNO noesponders based on failure to decrease OI by 10 in 60 minutes of treatment | 15 | 14 (93) | ||||||
| Chock, 20091 | Death or BPD | Death prior to discharge home or within 365 days | Control | 6 | 6 (100) | P-value: 0.18 | ||
| iNO | 6 | 3 (50) | ||||||
| Field, 20052 | 36 weeks PMA | Control | 53 | 48 (91) | Diagnosis, OI severity | |||
| iNO | 55 | 49(89) | ||||||
| 36 weeks PMA | Control acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) | 36 | 32 (89) | RR: 0.98(0.87-1.11) | Diagnosis, OI severity | |||
| iNO acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) | 35 | 30 (86) | ||||||
| 36 weeks PMA | Control chronic diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) | 9 | 9 (100) | Diagnosis, OI severity | ||||
| iNO chronic diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) | 10 | 10 (100) | ||||||
| 36 weeks PMA | Control other diagnosis (developed lung disease after initial recovery from respiratory problems) | 8 | 7 (88) | RR: 0.98(0.87-1.12) | Diagnosis, OI severity | |||
| iNO other diagnosis (developed lung disease after initial recovery fromrespiratory problems) | 10 | 9 (10) | ||||||
| 36 weeks PMA | Control OI<=30 at study entry | 25 | 22 (88) | Diagnosis, OI severity | ||||
| iNO OI<=30 at study entry | 25 | 22 (88) | ||||||
| 36 weeks PMA | Control OI>30 at study entry | 28 | 26 (93) | RR: 0.98(0.87-1.12) | Diagnosis, OI severity | |||
| iNO OI>30 at study entry | 30 | 27 (90) | ||||||
| Term EDC | Control acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) | 36 | 29 (81) | |||||
| iNO acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) | 35 | 22 (63) | ||||||
| Term EDC | Control chronic diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days) | 9 | 9 (100) | |||||
| iNO chronic diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days) | 10 | 10 (100) | ||||||
| Term EDC | Control other diagnosis (developed lung disease after initial recovery from respiratory problems) | 8 | 7 (88) | |||||
| iNO other diagnosis (developed lung disease after initial recovery from respiratory problems) | 10 | 7 (70) | ||||||
| Term EDC | Control OI<=30 at study entry | 25 | 20 (80) | |||||
| iNO OI<=30 at study entry | 25 | 17 (68) | ||||||
| Control OI>30 at study entry | 28 | 25 (89) | ||||||
| iNO OI>30 at study entry | 30 | 22 (73) | ||||||
| Kinsella, 20063 | 36 wks PMA | Control | 392 | 295 (75.3) | P-value: 0.24 RR: 0.95 (0.87-1.03) | study sight, randomization strata | ||
| iNO | 394 | 282 (71.6) | ||||||
| 36 wks PMA | Control BW 500-749 g; mean 639, SD 71) | 189 | 159 (84.1) | P-value: 0.85 RR: 1.01 (0.92-1.1) | study sight, randomization strata | |||
| iNO BW 500-749 g; mean 642, SD 76 | 191 | 162 (84.8) | ||||||
| 36 wks PMA | Control BW 750-999 g; mean 843, SD 71 | 139 | 95 (68.3) | P-value: 0.93 RR: 1.01 (0.86-1.18) | study sight, randomization strata | |||
| iNO BW 750-999 g; mean 851, SD 71 | 138 | 95 (68.8) | ||||||
| 36 wks PMA | Control BW 1000-1250 g; mean 1113 g, SD 77 g) | 64 | 41 (64.1) | P-value: 0.004 RR: 0.6 (0.42-0.86) | study sight, randomization strata | |||
| BW 1000-1250 g; mean 1129 g, SD 68g | 65 | 25 (38.5) | ||||||
| Schreiber, 20034 | Survived NICU | Control | 102 | 51 (48.6) | p = 0.03 RR = 0.76 (0.60-0.97) | 0.77 (0.60-0.98) | ||
| iNO | 105 | 65 (63.7) | ||||||
| Van Meurs, 200711 | Death before discharge to home or within 365 | Control | 15 | 9 (60) | P-value: 0.87 RR: 0.83 (0.43-1.62) | p-value: 0.5 RR: 0.80 (0.43-1.48) | OI Stratum | |
| iNO | 14 | 7 (50) | ||||||
| Van Meurs, 20055 | Before discharge to home or within 365 days among hospitalized infants | Control | 208 | 170 (82) | P-value: 0.52 RR: 0.97 (0.86-1.06) | Birth weight , study site, Oxygenation index | ||
| iNO | 210 | 167 (80) | ||||||
| Before discharge to home or within 365 days among hospitalized infants | Control BW<=1000 g | 158 | 133 (85) | P-value: 0.29 RR: 1.04 (0.96-1.13) | Birth weight , study site, Oxygenation index | |||
| iNO BW<=1000 g | 158 | 141 (89) | ||||||
| Before discharge to home or within 365 days among hospitalized infants | Control BW<=1000g | 52 | 35 (69) | P-value: 0.03 RR: 0.72 (0.54-0.96) | Birth weight , study site, Oxygenation index | |||
| iNO BW>1000 g | 52 | 26 (50) | ||||||
| Before discharge to home or within 365 days among hospitalized infants | Control OI<=17 | 110 | 83 (75) | P-value: 0.37 RR: 0.93 (0.81-1.08) | Birth weight , study site, Oxygenation index | |||
| iNO OI<=17 | 100 | 71 (71) | ||||||
| Before discharge to home or within 365 days among hospitalized infants | Control OI>17 | 100 | 85 (86) | P-value: 0.75 RR: 1.02 (0.92-1.12) | Birth weight , study site, Oxygenation index | |||
| iNO OI>17 | 110 | 96 (87) | ||||||
| Watson, 200912 | 1 year corrected age | Control | 383 | 110 (28.7) | P-value: 0.29 | |||
| iNO | 384 | 97 (25.3) | ||||||
| 1 year corrected age | Control birth weight 500-749 g | 187 | 70 (37.4) | P-value: 0.99 | ||||
| iNO birth weight 500-749 g | 187 | 70 (37.4) | ||||||
| 1 year corrected age | Control birth weight 750-999 g | 133 | 29 (21.8) | P-value: 0.08 | ||||
| iNO birth weight 750-999 g | 139 | 19 (13.7) | ||||||
| 1 year corrected age | Controlbirth weight 1000-1250 g | 64 | 11 (17.2) | P-value: 0.61 | ||||
| iNO birth weight 1000-1250 g | 58 | 8 (13.8) | ||||||
| Van Meurs, 20055 | Brain Injury, Severe IVH (grades 3-4) or PVL | 36 weeks | Control | 210 | 50 (32) | p-value = 0.11 RR= 1.25 (0.95-1.66) | ||
| iNO | 210 | 69 (39) | ||||||
| Kinsella, 20063 | Death or Brain Injury, Death or grade 3 or 4 ICH or PVL | 30 days | Control | 391 | 151 (38.6) | P-value: 0.02 RR: 0.79 (0.65-0.96) | study site, randomization | |
| iNO | 392 | 120 (30.6) | ||||||
| 30 days | Control BW 500-749 g; mean 639, SD 71 | 189 | 89 (47.1) | P-value: 0.18 RR: 0.86 (0.68-1.08) | study site, randomization | |||
| iNO BW 500-749 g; mean 642, SD 76 | 191 | 77 (40.3) | ||||||
| 30 days | Control BW 750-999 g; mean 843, SD 71 | 139 | 47 (33.8) | P-value: 0.02 RR: 0.63 (0.42-0.93) | study site, randomization | |||
| iNO BW 750-999 g; mean 851, SD 71) | 137 | 29 (21.2) | ||||||
| 30 days | Control BW 1000-1250 g; mean 1113 g, SD 77 g | 63 | 15 (23.8) | P-value: 0.8 RR: 0.92 (0.48-1.74) | study site, randomization | |||
| iNO BW1000-1250 g; mean 1129 g, SD 68 g) | 64 | 14 (21.9) | ||||||
| Field, 20052 | Death or NDI | 1 year corrected | Control acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) | 36 | 24 (67) | RR: 0.99(0.76-1.28) | diagnosis, OI severity | |
| iNO acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) | 35 | 23 (66) | ||||||
| 1 year corrected | Control chronic diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) | 9 | 7 (78) | diagnosis, OI severity | ||||
| iNO chronic diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) | 10 | 8 (10) | ||||||
| 1 year corrected | Control other diagnosis (developed lung disease after initial recovery from respiratory problems) | 8 | 5 (63) | diagnosis, OI severity | ||||
| iNO other diagnosis (developed lung disease after initial recovery from respiratory problems) | 10 | 6 (60) | ||||||
| 1 year corrected | Control OI<=30 at study entry | 25 | 15 (60) | RR: 0.99(0.76-1.28) | diagnosis, OI severity | |||
| iNO OI<=30 at study entry | 25 | 16 (64) | ||||||
| 1 year corrected | Control OI>30 at study entry | 28 | 21 (75) | |||||
| iNO OI>30 at study entry | 30 | 21 (70) | ||||||
| iNO | 387 | 164 (42.4) | ||||||
| Hintz SR, 20078 | 18-22 months | Control | 196 | 146 (73) | P-value: 0.32 RR: 1.07(0.95-1.19) | P-value: 0.3 RR: Model #1:1.06 (0.95-1.17) | Model #1: Birth weight, center, OI entry criterion strata, sex | |
| iNO | 198 | 154 (78) | ||||||
| 18-22 months | Control Birth weight </=1000g, F/U cohort | 152 | 120 (79) | P-value: 0.12 RR: 1.08 (0.98-1.20) | OI criterion, center, and sex | |||
| iNO tx, Birth weight </= 1000gm | 151 | 131 (87) | ||||||
| 18-22 months | Control Birth weight >1000g, F/U Cohort | 48 | 26 (54) | P-value: 0.63 RR: 0.91 (0.63-1.33) | OI criterion, center, and sex | |||
| iNO Tx, Birth weight >1000g | 47 | 23 (49) | ||||||
| 18-22 months | Control Placebo, Birth weight 401-750grams | 99 / 400 (analysis cohort) | 81 (82) | P-value 0.051 | OI criterion, center, and sex Birth weight, center, OI entry criterion strata, sex | |||
| iNO tx, Birth weight 401-750grams | 94 / 400 (for analysis cohort) | 86 (91) | ||||||
| 18-22 months | Control Placebo, Birth weight 751-1000grams | 53 | 39 (74) | P-value: 0.51 | OI criterion, center, and sex Birth weight, center, OI entry criterion strata, sex | |||
| iNO tx, Birth weight 751-1000grams | 58 / 400 (analysis cohort) | 45 / 57 (79) | ||||||
| 18-22 months | Control Placebo, Birth weight 1001-1500 grams | 48 / 400 (analysis group) | 26 (54) | P-value: 0.54 | OI criterion, center, and sex Birth weight, center, OI entrycriterion strata, sex | |||
| iNO tx. Birth weight 1001-1500grams | 48 / 400 (analysis group) | 23 / 47 (49) | ||||||
| 18-22 months | Control | 200 | 109 (54) | P-value: 0.07 1.17 RR:(0.99-1.38) | P-value: 0.07 RR: Model #1:1.15 (0.99-1.34) | OI criterion, center, and sex Birth weight, center, OI entry criterion strata, sex | ||
| iNO | 199 | 127 (64) | ||||||
| 18-22 months | Control Birth weight </= 1000g, F/U cohort | 152 | 89 (59) | P-value: 0.01 | RR: 1.22 (1.05-1.43) | OI criterion, center, and sex Birth weight, center, OI entry criterion strata, sex | ||
| iNO tx, Birth weight </= 1000gm | 152 | 111/151 (74) | ||||||
| 18-22 months | Control Birth weight >1000g, F/U Cohort | 48 | 20 (42) | P-value: 0.39 | RR: 0.80 (0.48-1.33) | OI criterion, center, and sex Birth weight, center, OI entry criterion strata, sex | ||
| iNO Tx, Birth weight >1000g | 48 | 16 (33) | ||||||
| 18-22 months | Control Placebo, Birth weight 401-750grams | 99 / 400 (analysis cohort) | 61 (62) | Center, and sex | ||||
| iNO tx, Birth weight 401-750grams | 94 / 400 (for analysis cohort) | 75 / 93 (81) | ||||||
| 18-22 months | Control Placebo, Birth weight 751-1000grams | 53 | 28 (53) | Center, and sex | ||||
| iNO tx, Birth weight 751-1000grams) | 58 / 400 (analysis cohort) | 36 (62) | ||||||
| 18-22 months | Control Placebo, Birth weight 1001-1500 grams) | 48 / 400 (analysis group) | 20 (42) | Center, and sex | ||||
| iNO tx. Birth weight 1001-1500grams) | 48 / 400 (analysis group) | 16 (33) | ||||||
| Watson, 200912 | 1 year corrected age | Control birth weight 500-749 g | 187 | 96 (51.3) | P-value: 0.57 | |||
| iNO birth weight 500-749 g | 188 | 102 (54.3) | ||||||
| 1 year corrected age | Control birth weight 750-999 g | 133 | 59 (44.4) | P-value: 0.04 | ||||
| iNO birth weight 750-999 g) | 140 | 45 (32.1) | ||||||
| 1 year corrected age | Control birth weight 1000-1250 g | 64 | 16 (25) | P-value: 0.63 | ||||
| iNO birth weight 1000-1250 g | 59 | 17 (28.8) | ||||||
| 1 year corrected age | Control | 384 | 171 (44.5) | P-value: 0.55 | ||||
| iNO | 387 | 164 (42.4) | ||||||
| 1 year corrected age | Control | 384 | 175 (45.6) | P-value: 0.65 | ||||
| iNO | 387 | 170 (43.9) | ||||||
| 1 year corrected age | Control birth weight 500-749 g | 187 | 98 (52.4) | P-value: 0.38 | ||||
| iNO birth weight 500-749 g | 188 | 107 (56.9) | ||||||
| 1 year corrected age | Control birth weight 750-999 g | 133 | 60 (45.1) | P-value: 0.04 | ||||
| iNO birth weight 750-999 g | 140 | 46 (32.9) | ||||||
| 1 year corrected age | Control birth weight 1000-1250 g | 64 | 17 (26.6) | P-value: 0.78 | ||||
| iNO birth weight 1000-1250 g) | 59 | 17 (28.8) | ||||||
| Uga, 200413 | Survival | 28 days | Control | 5 | 10 (50) | |||
| iNO | 8 | 8 (100) | ||||||
| Field, 20052 | Severe Disability | 1 year | Control | 53 | 2 (4) | |||
| iNO | 55 | 7 (13) | ||||||
| Yadav, 199910 | Survival to Discharge | 27 weeks | Responders | 15 | 26 | |||
| Non-responders | 1 | 15 | ||||||
| Hintz, 20078 | Death or Moderate to severe CP | 18-22 months | Control | 109 (54) | P = 0.07 RR = 1.17 (0.99-1.38) | |||
| iNO | 199 | 127 (64) | ||||||
| Watson, 200912 | Death/Oxygen/NDI | 1 year | Control | 175 (45.6) | P = 0.65 | |||
| iNO | 170 (43.9) | |||||||
| BW: 500-749g | Control | 98 (52.4) | ||||||
| iNO | 107 (56.9) | |||||||
| BW: 750-999g | Control | 60 (45.1) | ||||||
| iNO | 46 (32.9) | |||||||
| BW: 1000-1250g | Control | 17 (26.6) | ||||||
| iNO | 17 (28.8) |
BPD: Bronchopulmonary Dysplasia; BPD: Bronchopulmonary Dysplasia; BSID: Bayley scale of infant development; BW: Birth weight; CI: Confidence Interval; CP: Cerebral palsy; DQ: Developmental quotient; EDC: Estimated date of confinement; F/U: Follow: up; GEE: Generalized estimated equations; HFOV: High-frequency oscillatory ventilation; HFV: High-frequency ventilation; HRF: Hypoxemic respiratory failure; ICH: Intracranial Hemorrhage; iNO: Inhaled nitric oxide; IQR: Inter-quartile range; IVH: Intraventricular hemorrhage ; MDI: Mental developmental scale; NDI: Neurodevelopmental impairment; NICU: Neonatal intensive care unit; NS: Not significant; OI: Oxygenation index; PMA: Postmenstrual age; PVL: Periventricular leukomalacia; RR: Relative risk; SD: Standard deviation; tx: treatment;
Evidence Table 17All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI
| Author, Year | Outcome | Time of outcome measure | Study Arm | N (number of participants measured) | Participants with Outcome— n (%) | Relative Effect (95% CI) | Adjusted Relative Effect (95% CI) | Adjustments | Duration | Difference in Duration (p-value) |
|---|---|---|---|---|---|---|---|---|---|---|
| Ballard, 20061 | BPD | 36 weeks PMA | Control | 288 | 164 (56.9) | |||||
| iNO | 294 | 149 (50.7) | ||||||||
| Dani, 20062 | 36 weeks PMA | Control | 20 | 12 (60) | P-value: 0.067 | Mean: 69.4 SD: 30.2 | 0.054 | |||
| iNO | 20 | 6 (30) | Mean: 47.3 SD: 39.4 | |||||||
| Nonresponders | 6 | Mean: 19.8 SD: 11.5 | 0.084 | |||||||
| Responders | 14 | Mean: 48.6 SD: 37.3 | ||||||||
| Field, 20053 | 36 weeks PMA | Control | 49 | 15 (28) | Mean: 6 IQR:1.0-17.0 | |||||
| iNO | 50 | 26 (47) | Mean: 15 IQR:2-71 | |||||||
| Franco-Belgium Collabor ative NO Trial Group, 19994 | during hospitalization | Control | 29 | 8 (29) | p-value: NS | Median: 23 IQR:41 | 0.38 | |||
| iNO | 29 | 7 (24) | p-value: NS OR: 0.95 (0.44–2.04) | Median: 14 IQR:43 | ||||||
| Kinsella, 19995 | 36 weeks PMA | Control | 15 | 12 (80) | p-value: 0.3 RR: 0.75(0.5-1.13) | |||||
| iNO | 25 | 15 (60) | ||||||||
| Kinsella, 20066 | 36 weeks BDP at 36 weeks PMA | Control | 309 | 210 (68) | P-value: 0.43 | RR:0.96 (0.86–1.09) | randomization strata, study sight | |||
| iNO | 326 | 212 (65) | ||||||||
| Mercier, 20107 | 36 weeks PMA | Control | 358 | 96 (27) | ||||||
| iNO | 339 | 81(24) | ||||||||
| Schreiber, 20038 | 36 weeks PMA | Control | 102 | 42 (53.2) | P-value: 0.07 RR: 0.74 (0.53–1.03) | type of ventilation | ||||
| iNO | 105 | 35 (39.3) | ||||||||
| Su, 20089 | 36 weeks PMA | Control | 33 | 11 (33.3) | ||||||
| iNO | 32 | 10 (31.3) | ||||||||
| Subhedar, 199710 | 36 weeks PMA | Control dexamethasone and standard of care | 22 | 14 (64) | ||||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 10 (50) | RR: 0.79(0.44-1.33) | |||||||
| Dexamethasone alone AND dex + iNO | 21 | 11 (52) | ||||||||
| iNO AND standard of care | 21 | 13 (62) | RR: 0.85(0.48-1.44) | |||||||
| Van Meurs, 200711 | 36 weeks PMA | Control | 11 | 5 (45) | p-value: 0.66 RR: 0.66(0.21-2.08) | p-value: 0.21 RR: 0.40 (0.09-1.71) | OI stratum | Mean: 32 SD:23 | 0.45 | |
| iNO | 10 | 3 (30) | Mean: 23.8 SD: 24.4 | |||||||
| Van Meurs, 200712 | 36 weeks PMA | Control | 127 | 86 (68) | P-value: 0.26 | RR: 0.90 (0.75–1.08) | ||||
| iNO | 109 | 65 (60) | ||||||||
| Ballard, 20061 | 40 weeks PMA | Control | 288 | 84 (29.2) | ||||||
| iNO | 294 | 66 (22.4) | ||||||||
| Control | 288 | 35 (12.2) | ||||||||
| iNO | 294 | 27 (9.2) | ||||||||
| Field, 20053 | At term (EDC) | Control | 53 | 12 (23) | Median: 81 IQR:14-100 | |||||
| iNO | 55 | 16 (29) | Median: 59 IQR:30-78 | |||||||
| Field, 20053 | 1 year corrected age | Control | 18 survivors | 1 (6) | ||||||
| iNO | 20 survivors | 3 (15) | ||||||||
| Franco-Belgium Collabor ative NO Trial Group, 19994 | 28 days | Control | 29 | 14 (48) | p-value: NS | |||||
| iNO | 29 | 13 (45) | ||||||||
| Hamon, 200513 | 28 days | Control Hypoxemic Respiratory Failure, no iNO | 29 | 15 (55.6) | ||||||
| iNO treated Hypoxemic Respiratory Failure | 22 | 8 (36.4) | ||||||||
| Kinsella,19995 | Hospital discharge | Control | 15 | 12 (80) | p-value: 0.1 | |||||
| RR: 0.65 (0.41-1.02) | ||||||||||
| iNO | 25 | 13 (54) | p-value: 0.1 1.02) | |||||||
| RR: 0.65(0.41- | ||||||||||
| Van Meurs,200512 | Physiologic BPD as per Walsh criteria | Control | 115 | 69 (60) | P-value: 0.17 | RR: 0.87 (0.68–1.10) | center, birth-weight group, and oxygenation-index entry stratum | |||
| iNO | 100 | 50 (50) | ||||||||
| OR (95% CI) | Adjusted OR (95% CI) | |||||||||
| Ballard, 20061 | Death | 36 weeks PMA | Control | 288 | 18 (6.3) | |||||
| iNO | 294 | 16 (5.4) | ||||||||
| 40 weeks PMA | Control | 288 | 19 (6.6) | |||||||
| iNO | 294 | 19 (6.5) | ||||||||
| 44 wks PMA | Control | 288 | 20 (6.9) | |||||||
| iNO | 294 | 20 (6.8) | ||||||||
| 36 weeks PMA | Control 7-14 days age at study entry | 115 | 13 (11.3) | |||||||
| 7-14 days age at study entry | 112 | 12 (10.7) | ||||||||
| 36 weeks PMA | Control 15-21 days age at study entry | 173 | 10 (5.8) | |||||||
| iNO 15-21 days age at study entry | 182 | 12 (6.6) | ||||||||
| Banks, 199914 | 3-24 months from enrollment | iNO | 16 | 7 (44) | ||||||
| Bennett, 200115 | 30 months corrected age | Control | 22 | 7 (32) | P-value: 0.13 RR: 1.65 (0.87–3.3) | |||||
| iNO | 20 | 10 (50) | ||||||||
| 24.9 +/- 7.9 months corrected age | iNO | 105 | 89 (85) | |||||||
| Dani, 20026 | NICU | Control | 20 | 6(30) | P-value: 0.494 | birth weight | ||||
| iNO | 20 | 4 (20) | ||||||||
| Nonresponders | 6 | 4 (66) | P-value: 0.078 | |||||||
| Responders | 14 | 3 (21) | ||||||||
| Field, 20053 | 1 year | Control | 53 | 34 (64) | ||||||
| iNO | 55 | 30 (55) | ||||||||
| Franco-Belgium Collaborative NO Trial Group, 19994 | in NICU | Control | 45 | 16 (35) | P-value: Not significant | |||||
| iNO | 40 | 11 (27) | ||||||||
| Hascoet, 200516 | 7 days of life | Control with Hypoxemic Respiratory Failure | 84 | 14 (17) | P-value: 0.58 | 1 | ||||
| iNO with Hypoxemic Respiratory Failure | 61 | 8 (13) | ||||||||
| 28 days of life | Control with Hypoxemic Respiratory Failure | 84 | 26 (31) | P-value: Not significant | ||||||
| iNO with Hypoxemic Respiratory Failure | 61 | 25 (41) | ||||||||
| Hintz SR, 200717 | 18-22 months | Control | 210 | 98 (47) | P-value: 0.27 | birth weight category, OI strata | ||||
| iNO | 210 | 109 (52) | ||||||||
| Huddy, 200818 | 4-5 years, median 4.52 (IQR 0.9) | Control | 19 | 0 (0) | ||||||
| 4-5 years, median 4.63, IQR 0.84) | iNO | 25 | 1 (4) | |||||||
| Kinsella , 20066 | 36 wks PMA | Control | 392 | 98 (25) | P-value: 0.08 RR: 0.79 (0.61-1.03) | randomization strata, study sight | ||||
| iNO | 394 | 78 (19.8) | ||||||||
| Kinsella, 19995 | Discharge | Control | 32 | 17 (53) | P-value: 0.65 RR: 1.11(0.7-1.8) | |||||
| iNO | 48 | 23 (48) | ||||||||
| Mercier, 20107 | Control | 401 | 42 (10.5) | |||||||
| iNO | 399 | 56 (14) | ||||||||
| Schreiber, 20038 | NICU | Control | 102 | 23 (22.5) | P-value: 0.18 RR: 0.68 (0.38-1.20) | RR: 0.68 (0.38-1.20) | type of ventilation | |||
| iNO | 105 | 16 (15.2) | ||||||||
| Srisuparp, 200219 | 7 days | Control | 22 | 2 (11.1) | P-value: 1 | |||||
| iNO | 16 | 2 (12.5) | ||||||||
| Su, 20089 | During Study (9 death within 96 hours) | Control | 33 | 10 (30.3) | ||||||
| iNO | 32 | 6 (18.8) | ||||||||
| Subhedar, 199710 | 36 wks PMA | Control dexamethasone and standard of care | 22 | 7 (32) | RR: 1.57(0.76-3.38) | |||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 10 (50) | ||||||||
| Dexamethasone alone AND dex + iNO | 21 | 9 (43) | RR: 1.13 (0.54-2.36) | |||||||
| iNO AND standard of care | 21 | 8 (38) | ||||||||
| Van Meurs, 200512 | death before discharge to home or within 365 | Control | 208 | 93 (45) | P-value: 0. 11 RR:1.16 (0.96-1.39) | Birthweight study center, Oxygen ation index | ||||
| iNO | 210 | 109 (52) | ||||||||
| Van Meurs, 200711 | Death before discharge to home or within 365 | Control | 15 | 4 (27) | P-value: 0.7 RR: 1.34 (0.45-4.0) | p-value: 0.65 RR: 1.26 (0.47-3.41) | OI Stratum | |||
| iNO | 14 | 5 (36) | ||||||||
| Walsh, 201020 | 2 years | Control | 288 | 23 (8) | RR: 1.02 (0.59-1.77) | |||||
| iNO | 294 | 24 (8.2) | ||||||||
| Watson, 200921 | 1 year corrected age | Control | 384 | 98 (25.5) | P-value: 0.12 | |||||
| iNO | 385 | 80 (20.8) | ||||||||
| Ballard, 20061 | Death or BPD | 36 weeks PMA | Control | 288 | 182 (63.2) | |||||
| iNO | 294 | 165 (56.1) | ||||||||
| Dani, 20062 | NICU | Control | 20 | 18 (90) | P-value: 0.016 OR: 0.111 (0.02-0.610) | |||||
| iNO | 20 | 10 (50) | ||||||||
| Nonresponders | 6 | 6 (100) | P-value: 0.035 | |||||||
| Responders | 14 | 10 (71) | ||||||||
| Field, 20053 | 36 weeks PMA | Control | 53 | 48 (91) | ||||||
| iNO | 55 | 49 (89) | ||||||||
| 36 weeks PMA | Control trial entry <= 3 days | 37 | 32 (86) | RR: 0.98(0.87-1.11) | ||||||
| iNO trial entry <= 3 days) | 38 | 32 (84) | ||||||||
| 36 weeks PMA | Control trial entry > 3 days | 16 | 16 (100) | |||||||
| iNO trial entry > 3 days | 17 | 17 (100) | ||||||||
| Franco-Belgium Collabor ative NO Trial Group, 19994 | in NICU | Control | 45 | 24 (53) | ||||||
| iNO | 40 | 18 (45) | ||||||||
| Kinsella, 19995 | Discharge | Control | 32 | 29 (91) | P-value: 0. 14 RR: 0.85(0.7-1.03) | |||||
| iNO | 48 | 37 (77) | ||||||||
| Kinsella, 20066 | 36 wks PMA | Control | 392 | 295 (75.3) | P-value: 0.24 RR: 0.95 (0.87-1.03) | Study sight, randomization strata | ||||
| iNO | 394 | 282 (71.6) | ||||||||
| Schreiber, 20038 | NICU | Control | 102 | 65 (63.7) | P-value: 0.03 RR: 0.76 (0.60-0.97) | RR: 0.77 (0.60-0.98) | type of ventilation | |||
| iNO | 105 | 51 (48.6) | ||||||||
| Subhedar, 199710 | 36 weeks PMA | Control dexamethasone and standard of care | 22 | 21 (95) | RR: 1.05(0.84-1.25) | |||||
| Groups 1&3; iNO + iNO and dexamethasone | 20 | 20 (100) | ||||||||
| Dexamethasone alone AND dex + iNO | 21 | 20 (95) | RR: 0.95 (0.79-1.18) | |||||||
| iNO AND standard of care | 21 | 21 (100) | ||||||||
| Van Meurs, 200711 | Death before discharge to home or within 365 | Control | 15 | 9 (60) | P-value: 0.87 RR: 0.83 (0.43-1.62) | p-value: 0.5 RR: 0.80 (0.43-1.48) | OI Stratum | |||
| iNO | 14 | 7 (50) | ||||||||
| Van Meurs, 200512 | before discharge to home or within 365 days among hospitalized infants | Control | 208 | 170 (82) | P-value: 0.52 RR: 0.97 (0.86-1.06) | birth weight, study site, Oxygenation index | ||||
| iNO | 210 | 167 (80) | ||||||||
| Watson, 200921 | 1 Year corrected | Control | 385 | 110 (28.7) | P-value: 0.29 | |||||
| iNO | 384 | 97 (25.3) | ||||||||
| Hintz SR, 200717 | Death or NDI, Death or moderate to severe CP | 18-22 months | Control | 200 | 109 (54) | P-value: 0.07 RR:1.17 (0.99-1.38) | P-value: 0.07 RR: Model #1: 1.15 (0.99-1.34) | Model #1:BWt, center, OI entry criterion strata, sex | ||
| iNO Follow-Up group | 199 | 127 (64) | ||||||||
| Hintz SR, 200717 | Death or NDI Death or NDI:any of the following: mod-severe CP, blind, deaf, MDI<70 or PDI<70 | 18-22 months | Control | 200 | 146 (73) | P-value: 0.32 RR:1.07 (0.95-1.19) | P-value: 0.3 RR: Model #1: 1.06 (0.95-1.17) | Model #1: BWt, center, OI entry criterion strata, sex | ||
| iNO Follow-Up group | 198 | 154 (78) | ||||||||
| 18-22 months | Control HFV, F/U cohort | 119 | 93 (78) | P-value: 0.91 | RR: 1.01 (0.88-1.15) | OI criterion, center, and sex Birth weight, center, OI entry criterion strata, sex | ||||
| iNO tx, HFV | 115 | 90 (78) | ||||||||
| 18-22 months | Control Convention al vent, F/U cohort | 81 | 53 (65) | P-value: 0.12 | RR: 1.15(0.97-1.36) | OI criterion, center, and sex Birth weight, center, OI entry criterion strata, sex | ||||
| iNO tx, Convention al Vent | 83 | 64 (77) | ||||||||
| Field, 20053 | Death or Severe Disability | 1 year corrected | Control trial entry <= 3 days | 37 | 24 (65) | RR: 0.99(0.76-1.28) | diagnosis, OI severity | |||
| iNO trial entry <= 3 days | 38 | 25 (66) | ||||||||
| 1 year corrected | Control trial entry > 3 days | 16 | 12 (75) | diagnosis, OI severity | ||||||
| iNO trial entry > 3 days | 17 | 12 (71) | ||||||||
| Bennett, 200115 | Survival | 30 months corrected age | Control | 22 | 14 (63.6) | P-value: 0.13 RR: 1.65(0.87-3.3) | ||||
| iNO | 20 | 8(40) | ||||||||
| Hamon, 200513 | 28 days | Control Hypoxemic Respiratory Failure, no iNO | 39 | 27 (69.3) | ||||||
| iNO treated Hypoxemic Respiratory Failure | 37 | 22 (59.5) | ||||||||
| Mestan, 200522 | 25.2+/-8.4 months corrected age | Control | 102 | 79 (78) | ||||||
| Schreiber, 20038 | Survived NICU | Control | 102 | 79 (77.5) | ||||||
| iNO | 105 | 89 (84.8) | ||||||||
| Ballard, 20061 | Survival without BPD | 36 weeks PMA | Control | 288 | 105 (36.5) | p-value:0.04 RR: 1.26 (1.02-1.55) | RR: 1.45 (1.03-2.04) | cluster (multiples) using GEE; from the letter to the editor correction | ||
| iNO | 294 | 129 (43.9) | ||||||||
| Control 7-14 days age at study entry | 115 | 31 (27) | RR: 1.91 (1.31-2.78) | |||||||
| iNO 7-14 days age at study entry | 112 | 55 (49.1) | ||||||||
| Control 15-21 days age at study entry | 173 | 74 (42.8) | RR: 0.99 (0.77-1.28) | |||||||
| iNO 15-21 days age at study entry | 182 | 74 (40.7) | ||||||||
| Hamon, 200513 | 28 days | Control | 39 | 12 (31) | ||||||
| iNO | 37 | 14 (38) | ||||||||
| Bennett, 200115 | Severe neurodisability - one or more of: moderate or severe developmental delay; CP; sensorine ural impairment (hearing loss requiring hearing aids and blindness) | 30 months corrected age | Control | 14 | 5 (36) | P-value: 0.12 | ||||
| iNO | 7 | 0 (0) | ||||||||
| Field, 20053 | Severe disability defined as no /little head control or inability to sit unsupport ed or no/minimal response to visual stim (equivalent to DQ <50 age adjusted) | 1 year corrected age | Control | 18 | 2 (11) | |||||
| iNO | 25 | 7 (28) | ||||||||
| Hintz SR, 200717 | NDI: any of the following: mod-severe CP, blind, deaf, MDI<70 or PDI<70 | 18-22 months | Control | 102 | 48 (47) | P-value:0.74 RR: 1.07(0.80 - 1.44) | ||||
| iNO | 89 | 45 (51) | ||||||||
| Huddy, 200818 | Moderate or severe cognitive disability (GCAS<7 0) | 4-5 yrs, median 4.52 (IQR 0.9) | Control | 16 | 6(37.5) | |||||
| 4-5 yrs, median 4.63, IQR 0.84) | iNO | 22 | 6(27.3) | |||||||
| Moderate / Severe CP | 4-5 years | Control | 16 | 2(12.5) | ||||||
| iNO | 22 | 3(13.6) | ||||||||
| Mestan, 200522 | Abnormal neurodeve lopmental outcome (any Disability or any BSID II score <70) | 25.2+/-8.4 months corrected age 24.9+/- 7.9 months corrected age | Control | 68 | 31 (46) | P-value:0.01 RR: 0.53 (0.33-0.87) | ||||
| iNO | 70 | 17 (24) | ||||||||
| Van Meurs 200711 | NDI = any one of the following: moderate to severe CP, blind, deaf, MDI <70, or PDI <70 | 18 to 22 months | Control | 8 | 2 (25) | |||||
| iNO | 9 | 1 (11) | ||||||||
| Walsh, 201020 | NDI in subset with complete evaluations | 2 years | Control | 212 | (51) | RR:0.93 (0.76-1.14) | ||||
| iNO | 207 | (48) | ||||||||
| Neurodev elopmental Impairment (NDI = MDI<70, PDI<70, unable to crawl or walk (GMFCS> =2), bilateral blindness, or bilateral deafness requiring amplification). | 2 years | Control | 234 | 114 (49) | RR: 0.92 (0.75-1.12) | |||||
| iNO | 243 | 109 (44.8) | ||||||||
| Moderate / Severe CP | 2 years | Control | 234 | 12 (5.1) | RR: 1.23 (0.59-2.55) | |||||
| iNO | 243 | 12 (4.9) | ||||||||
| Watson, 200921 | NDI (CP, severe hearing loss, MDI or PDI< 70,or blindness) | 1 year corrected age | Control | 218 | 73 (33.5) | P-value: 0.66 | ||||
| iNO | 237 | 84 (35.4) | ||||||||
| Van Meurs, 200711 | Moderate / Severe CP | 18 to 22 months | Control | 8 | 0 (0) | |||||
| iNO | 9 | 0 (0) |
BPD: Bronchopulmonary Dysplasia; BSID: Bayley scale of infant devleopment; BW: Birth weight; CI: Confidence Interval; CP: Cerebral palsy; DQ: Developmental quotient; EDC: Estimated date of confinement; F/U: Follow: up; HFOV: High-frequency oscillatory ventilation; HFV: High-frequency ventilation; HRF: Hypoxemic respiratory failure; iNO: Inhaled nitric oxide; IQR: Inter-quartile range; IVH: Intraventricular hemorrhage ; MDI: Mental developmental scale; NDI: Neurodevelopmental impairment; NICU: Neonatal intensive care unit; NS: Not significant; OI: Oxygenation index; OR: Odds ratio; PDI: Psychomotor Development Index; PMA: Post-menstrual age; PVL: Periventricular leukomalacia; RR: Relative risk; SD: Standard Deviation; tx: Treatment;
Appendix E References
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Hibbs AM, Walsh MC, Martin RJ, et al. One Year Respiratory Outcomes of the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide (iNO). 2007. N/A.
- 3.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 4.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 5.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 6.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 7.
- 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(6):F430–5. [PubMed: 18375612]
- 8.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 9.
- Hamon I, Fresson J, Nicolas MB, Buchweiller MC, Franck P, Hascoet JM. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res. 2005;57(5 Pt 1):637–43. [PubMed: 15746261]
- 10.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomized controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 11.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 12.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 13.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 14.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 15.
- Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai. 2002;85(Suppl 2):S469–78. [PubMed: 12403222]
- 16.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 17.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 18.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 19.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 20.
- Chock VY, Van Meurs KP, Hintz SR, et al. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol. 2009;26(4):317–22. [PMC free article: PMC2676224] [PubMed: 19067285]
- 21.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 22.
- 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(6):347–52. [PubMed: 17443204]
- 1.
- Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopul monary dysplasia. Pediatrics. 1999;103(3):610–8. [PubMed: 10049965]
- 2.
- Cheung P-Y, Peliowski A, Robertson CMT. The outcome of very low birth weight neonates ((less-than or equal to) 1500 g) rescued by inhaled nitric oxide: Neurodevelopment in early childhood. J. Pediatr. 1998;133(6):735–9. [PubMed: 9842035]
- 3.
- Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2002;86(1):F41–5. [PMC free article: PMC1721346] [PubMed: 11815547]
- 4.
- Dewhurst C, Ibrahim H, Gothberg S, Jonsson B, Subhedar N. Use of inhaled nitric oxide in the new born period: Results from the European inhaled nitric oxide registry. Acta Paediatr. Int. J. Paediatr. 2010;99(6):854–60. [PubMed: 20219040]
- 5.
- Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC 3rd, Wynn RJ, Ryan RM. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol. 2007;27(4):214–9. [PubMed: 17330053]
- 6.
- Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatr. Int. 2004;46(1):10–4. [PubMed: 15043657]
- 7.
- 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(6):1159–64. [PubMed: 17545384]
- 8.
- Yadav M, Emmerson AJ. Inhaled nitric oxide in premature neonates. Lancet. 1999;354(9196):2162–3. [PubMed: 10609839]
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Hibbs AM, Walsh MC, Martin RJ, et al. One Year Respiratory Outcomes of the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide (iNO). 2007. N/A.
- 3.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 4.
- Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics. 1999;103(3):610–8. [PubMed: 10049965]
- 5.
- Cheung P-Y, Peliowski A, Robertson CMT. The outcome of very low birth weight neonates ((less-than or equal to)1500 g) rescued by inhaled nitric oxide: Neurodevelopment in early childhood. J. Pediatr. 1998;133(6):735–9. [PubMed: 9842035]
- 6.
- Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2002;86(1):F41–5. [PMC free article: PMC1721346] [PubMed: 11815547]
- 7.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 8.
- Dewhurst C, Ibrahim H, Gothberg S, Jonsson B, Subhedar N. Use of inhaled nitric oxide in the new born period: Results from the European inhaled nitric oxide registry. Acta Paediatr. Int. J. Paediatr. 2010;99(6):854–60. [PubMed: 20219040]
- 9.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 10.
- 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(6):F430–5. [PubMed: 18375612]
- 11.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 12.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 13.
- Hamon I, Fresson J, Nicolas MB, Buchweiller MC, Franck P, Hascoet JM. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res. 2005;57(5 Pt 1):637–43. [PubMed: 15746261]
- 14.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 15.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 16.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 17.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 18.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 19.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 20.
- Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai. 2002;85(Suppl 2):S469–78. [PubMed: 12403222]
- 21.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 22.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 23.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 24.
- 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(6):1159–64. [PubMed: 17545384]
- 25.
- Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatr. Int. 2004;46(1):10–4. [PubMed: 15043657]
- 26.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 27.
- Chock VY, Van Meurs KP, Hintz SR, et al. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol. 2009;26(4):317–22. [PMC free article: PMC2676224] [PubMed: 19067285]
- 28.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 29.
- 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(6):347–52. [PubMed: 17443204]
- 30.
- Yadav M, Emmerson AJ. Inhaled nitric oxide in premature neonates. Lancet. 1999;354(9196):2162–3. [PubMed: 10609839]
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Hibbs AM, Walsh MC, Martin RJ, et al. One Year Respiratory Outcomes of the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide (iNO). 2007. N/A.
- 3.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 4.
- Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics. 1999;103(3):610–8. [PubMed: 10049965]
- 5.
- Cheung P-Y, Peliowski A, Robertson CMT. The outcome of very low birth weight neonates ((less-than or equal to) 1500 g) rescued by inhaled nitric oxide: Neurodevelopment in early childhood. J. Pediatr. 1998;133(6):735–9. [PubMed: 9842035]
- 6.
- Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2002;86(1):F41–5. [PMC free article: PMC1721346] [PubMed: 11815547]
- 7.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 8.
- Dewhurst C, Ibrahim H, Gothberg S, Jonsson B, Subhedar N. Use of inhaled nitric oxide in the new born period: Results from the European inhaled nitric oxide registry. Acta Paediatr. Int. J. Paediatr. 2010;99(6):854–60. [PubMed: 20219040]
- 9.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 10.
- 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(6):F430–5. [PubMed: 18375612]
- 11.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 12.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 13.
- Hamon I, Fresson J, Nicolas MB, Buchweiller MC, Franck P, Hascoet JM. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res. 2005;57(5 Pt 1):637–43. [PubMed: 15746261]
- 14.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 15.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 16.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 17.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 18.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 19.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 20.
- Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai. 2002;85(Suppl 2):S469–78. [PubMed: 12403222]
- 21.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 22.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 23.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 24.
- 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(6):1159–64. [PubMed: 17545384]
- 25.
- Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatr. Int. 2004;46(1):10–4. [PubMed: 15043657]
- 26.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 27.
- Chock VY, Van Meurs KP, Hintz SR, et al. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol. 2009;26(4):317–22. [PMC free article: PMC2676224] [PubMed: 19067285]
- 28.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 29.
- 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(6):347–52. [PubMed: 17443204]
- 30.
- Yadav M, Emmerson AJ. Inhaled nitric oxide in premature neonates. Lancet. 1999;354(9196):2162–3. [PubMed: 10609839]
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 3.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 4.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 5.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 6.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 7.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 8.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 9.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 10.
- Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai. 2002;85(Suppl 2):S469–78. [PubMed: 12403222]
- 11.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 12.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 13.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 14.
- 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(6):347–52. [PubMed: 17443204]
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 3.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 4.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 5.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 6.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 7.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 8.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 9.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 10.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 11.
- 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(6):347–52. [PubMed: 17443204]
- 12.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 13.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 3.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 4.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 5.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 6.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 7.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 8.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 9.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 10.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 11.
- 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(6):347–52. [PubMed: 17443204]
- 12.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 1.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 2.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 3.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 4.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 5.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 6.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 7.
- Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai. 2002;85(Suppl 2):S469–78. [PubMed: 12403222]
- 8.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 9.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 10.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 11.
- 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(6):347–52. [PubMed: 17443204]
- 12.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 3.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 4.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 5.
- Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai. 2002;85(Suppl 2):S469–78. [PubMed: 12403222]
- 6.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 7.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 8.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 9.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 10.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 11.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 12.
- 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(6):347–52. [PubMed: 17443204]
- 13.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 1.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 2.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 3.
- 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(6):F430–5. [PubMed: 18375612]
- 4.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 5.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 6.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 1.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 2.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 3.
- 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(6):F430–5. [PubMed: 18375612]
- 4.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 5.
- 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(6):1159–64. [PubMed: 17545384]
- 6.
- 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(6):347–52. [PubMed: 17443204]
- 7.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 1.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 2.
- 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(6):F430–5. [PubMed: 18375612]
- 3.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 4.
- 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(6):347–52. [PubMed: 17443204]
- 5.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 1.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 2.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 3.
- 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(6):F430–5. [PubMed: 18375612]
- 4.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 5.
- 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(6):347–52. [PubMed: 17443204]
- 6.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 7.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 1.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 2.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 3.
- 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(6):F430–5. [PubMed: 18375612]
- 4.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 5.
- 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(6):347–52. [PubMed: 17443204]
- 6.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 7.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 1.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 2.
- 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(6):F430–5. [PubMed: 18375612]
- 3.
- Hibbs AM, Walsh MC, Martin RJ, et al. One Year Respiratory Outcomes of the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide (iNO). 2007. N/A.
- 4.
- Cheung P-Y, Peliowski A, Robertson CMT. The outcome of very low birth weight neonates ((less-than or equal to)1500 g) rescued by inhaled nitric oxide: Neurodevelopment in early childhood. J. Pediatr. 1998;133(6):735–9. [PubMed: 9842035]
- 5.
- Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2002;86(1):F41–5. [PMC free article: PMC1721346] [PubMed: 11815547]
- 6.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 7.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]
- 8.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 9.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 1.
- Chock VY, Van Meurs KP, Hintz SR, et al. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol. 2009;26(4):317–22. [PMC free article: PMC2676224] [PubMed: 19067285]
- 2.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 3.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 4.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 5.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 6.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 7.
- Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics. 1999;103(3):610–8. [PubMed: 10049965]
- 8.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 9.
- Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC 3rd, Wynn RJ, Ryan RM. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol. 2007;27(4):214–9. [PubMed: 17330053]
- 10.
- Yadav M, Emmerson AJ. Inhaled nitric oxide in premature neonates. Lancet. 1999;354(9196):2162–3. [PubMed: 10609839]
- 11.
- 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(6):347–52. [PubMed: 17443204]
- 12.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 13.
- Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatr. Int. 2004;46(1):10–4. [PubMed: 15043657]
- 1.
- Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New Engl. J. Med. 2006;355(4):343–53. [PubMed: 16870913]
- 2.
- Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr. 2006;95(9):1116–23. [PubMed: 16938760]
- 3.
- Field D, Elbourne D, Truesdale A, et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics. 2005;115(4):926–36. [PubMed: 15805366]
- 4.
- Franco-Belgium Collaborative NO Trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet. 1999;354(9184):1066–71. [PubMed: 10509497]
- 5.
- Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet. 1999;354(9184):1061–5. [PubMed: 10509496]
- 6.
- Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64. [PubMed: 16870914]
- 7.
- Mercier JC, Hummler H, Durrmeyer X, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet. 2010 [PubMed: 20655106]
- 8.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New Engl. J. Med. 2003;349(22):2099–107. [PubMed: 14645637]
- 9.
- Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol. 2008;28(2):112–6. [PubMed: 17989696]
- 10.
- Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(3):F185–90. [PMC free article: PMC1720712] [PubMed: 9462187]
- 11.
- 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(6):347–52. [PubMed: 17443204]
- 12.
- Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13–22. [PubMed: 16000352]
- 13.
- Hamon I, Fresson J, Nicolas MB, Buchweiller MC, Franck P, Hascoet JM. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res. 2005;57(5 Pt 1):637–43. [PubMed: 15746261]
- 14.
- Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics. 1999;103(3):610–8. [PubMed: 10049965]
- 15.
- Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr. 2001;90(5):573–6. [PubMed: 11430720]
- 16.
- Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J. Pediatr. 2005;146(3):318–23. [PubMed: 15756211]
- 17.
- 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(1):16–22. 22.e1–3. [PMC free article: PMC2770191] [PubMed: 17586184]
- 18.
- 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(6):F430–5. [PubMed: 18375612]
- 19.
- Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai. 2002;85(Suppl 2):S469–78. [PubMed: 12403222]
- 20.
- Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr. 2010;156(4):556–61.e1. [PMC free article: PMC2843768] [PubMed: 20138299]
- 21.
- Watson RS, Clermont G, Kinsella JP, et al. Clinical and economic effects of iNO in premature newborns with respiratory failure at 1 year. Pediatrics. 2009;124(5):1333–43. [PubMed: 19841128]
- 22.
- Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353(1):23–32. [PubMed: 16000353]