`
`Inhaled Nitric Oxide for the Early Treatment of Persistent Pulmonary
`Hypertension of the Term Newborn: A Randomized, Double-Masked,
`Placebo-Controlled, Dose-Response, Multicenter Study
`Dennis Davidson, Elaine S. Barefield, John Kattwinkel, Golde Dudell, Michael
`Study
`Damask, Richard Straube, Jared Rhines, Cheng-Tao Chang and the I-NO/PPHN
`Group
`
` 1998;101;325Pediatrics
`
`
`The online version of this article, along with updated information and services, is
`located on the World Wide Web at:
`http://pediatrics.aappublications.org/content/101/3/325.full.html
`
`
`PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
`publication, it has been published continuously since 1948. PEDIATRICS is owned,
`published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
`Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1998 by the American Academy
`of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
`
`
`
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`PEDIATRICS
`䡠䡠䡠䡠䡠䡠䡠䡠䡠䡠䡠䡠䡠䡠
`
`Mar 1998
`VOL. 101
`NO. 3
`
`Inhaled Nitric Oxide for the Early Treatment of Persistent Pulmonary
`Hypertension of the Term Newborn: A Randomized, Double-Masked,
`Placebo-Controlled, Dose-Response, Multicenter Study
`
`Dennis Davidson, MD*§; Elaine S. Barefield, MD*‡; John Kattwinkel, MD*¶; Golde Dudell, MD*†;
`Michael Damask, MD#; Richard Straube, MD#; Jared Rhines, BA#; Cheng-Tao Chang, PhD#; and
`the I-NO/PPHN Study Group
`
`ABSTRACT. Objectives. To assess the dose-related
`effects of inhaled nitric oxide (I-NO) as a specific adjunct
`to early conventional therapy for term infants with per-
`sistent pulmonary hypertension (PPHN), with regard to
`neonatal outcome, oxygenation, and safety.
`Methods. Randomized, placebo-controlled, double-
`masked, dose-response, clinical trial at 25 tertiary centers
`from April 1994 to June 1996. The primary endpoint was
`the PPHN Major Sequelae Index ([MSI], including the
`incidence of death, extracorporeal membrane oxygen-
`ation (ECMO), neurologic injury, or bronchopulmonary
`dysplasia [BPD]). Patients required a fraction of inspired
`oxygen [FIO2] of 1.0, a mean airway pressure >10 cm H2O
`on a conventional ventilator, and echocardiographic evi-
`dence of PPHN. Exogenous surfactant, concomitant high-
`frequency ventilation, and lung hypoplasia were exclu-
`sion factors. Control (0 ppm) or nitric oxide (NO) (5, 20, or
`80 ppm) treatments were administered until success or
`failure criteria were met. Due to slowing recruitment, the
`trial was stopped at N ⴝ 155 (320 planned).
`Results. The baseline oxygenation index (OI) was
`24 ⴞ 9 at 25 ⴞ 17 hours old (mean ⴞ SD). Efficacy results
`were similar among NO doses. By 30 minutes (no venti-
`lator changes) the PaO2 for only the NO groups increased
`significantly from 64 ⴞ 39 to 109 ⴞ 78 Torr (pooled) and
`systemic arterial pressure remained unchanged. The
`baseline adjusted time-weighted OI was also signifi-
`cantly reduced in the NO groups (-5 ⴞ 8) for the first 24
`
`From the Departments of *Pediatrics, §Schneider Children’s Hospital, Long
`Island Jewish Medical Center, Long Island Campus for the Albert Einstein
`College of Medicine, New Hyde Park, New York; the ‡University of Ala-
`bama, Birmingham, Alabama; the ¶University of Virginia, Charlottesville,
`Virginia; †San Diego Children’s Hospital, San Diego, California; and #Ohm-
`eda, PPD, Liberty Corner, New Jersey.
`Members of the I-NO/PPHN Study Group are listed in the Appendix.
`Received for publication Oct 8, 1997; accepted Dec 11, 1997.
`Reprint requests to (D.D.) Division of Neonatal-Perinatal Medicine, Schnei-
`der Children’s Hospital, Long Island Jewish Medical Center, New Hyde
`Park, NY 11040.
`PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Acad-
`emy of Pediatrics.
`
`hours of treatment. The MSI rate was 59% for the control
`and 50% for the NO doses (P ⴝ .36). The ECMO rate was
`34% for control and 22% for the NO doses (P ⴝ .12).
`Elevated methemoglobin (>7%) and nitrogen dioxide
`(NO2) (>3 ppm) were observed only in the 80 ppm NO
`group, otherwise no adverse events could be attributed to
`I-NO, including BPD.
`Conclusion. For term infants with PPHN, early I-NO
`as the sole adjunct to conventional management pro-
`duced an acute and sustained improvement in oxygen-
`ation for 24 hours without short-term side effects (5 and
`20 ppm doses), and the suggestion that ECMO use may
`be reduced. Pediatrics 1998;101:325–334; extracorporeal
`membrane oxygenation, bronchopulmonary dysplasia,
`neonatal outcome, methemoglobinemia, nitrogen dioxide.
`
`ABBREVIATIONS. PPHN, persistent pulmonary hypertension of
`the newborn; ECMO, extracorporeal membrane oxygenation;
`I-NO, inhaled nitric oxide; BPD, bronchopulmonary dysplasia;
`NO2, nitrogen dioxide; ppm, parts per million; MSI, Major Se-
`quelae Index; RAD, reactive airway disease; Fio2, fraction of in-
`spired oxygen; NO, nitric oxide; TWOI, time-weighted oxygen-
`ation index; OI, oxygenation index.
`
`Persistent pulmonary hypertension of the new-
`
`born (PPHN) is a syndrome of acute respira-
`tory failure, characterized by systemic hypox-
`emia associated with extrapulmonary shunting of
`venous blood and evidence of elevated levels of pul-
`monary artery pressure in the absence of congenital
`heart disease. This syndrome is seen more commonly
`in term infants who have underlying diseases such as
`meconium aspiration, respiratory distress syndrome,
`sepsis, or lung hypoplasia, or it may be idiopathic
`PPHN.1,2 In the United States, approximately 10 000
`newborns per year suffer from PPHN.3,4 The diagno-
`sis of PPHN is usually made by 24 hours after birth
`and most patients are born at hospitals without ex-
`tracorporeal membrane oxygenation (ECMO).4
`
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`The standard therapy for PPHN typically includes
`conventional mechanical ventilation, oxygen, seda-
`tion, paralysis, alkalosis, inotropic support, intrave-
`nous vasodilators, and antibiotics.4,5 In 1994, the ef-
`ficacy and safety of surfactant and high-frequency
`ventilation for PPHN were unproven, and the use of
`these therapies was becoming more widespread, be-
`fore resorting to ECMO.4–7 However, previous case
`series indicated that inhaled nitric oxide (I-NO) im-
`proved oxygenation acutely by selective pulmonary
`vasodilation.8,9 Therefore, the overall hypothesis for
`the present study was that early use of I-NO could
`reduce inspired oxygen and conventional ventilator
`requirements. This, in turn, might lead to less sec-
`ondary lung injury due to the inflammatory effects of
`hyperoxia and barotrauma, a process that begins
`within 24 hours10,11 and may be deleterious to out-
`come. Accordingly, the first objective of this trial was
`to determine if early I-NO therapy would reduce the
`overall incidence of death, need for ECMO, neuro-
`logic sequelae, and bronchopulmonary dysplasia
`(BPD).
`At the start of this study, data from animal and
`human studies had not indicated what was the most
`safe and effective dose of prolonged I-NO for
`PPHN.12–15 The secondary objective of this trial was
`to determine if there was dose-related efficacy, met-
`hemoglobinemia, inspired nitrogen dioxide (NO2)
`levels, intracranial hemorrhage, or unsuspected ad-
`verse effects of I-NO in the neonatal period.16 There-
`fore, eligibility requirements were defined narrowly
`and potentially confounding, and investigational res-
`cue treatments, such as high-frequency ventilation
`and surfactant, were prohibited.
`
`METHODS
`This clinical trial was a randomized, double-masked, placebo-
`controlled, dose-response study. Twenty-five neonatal intensive
`care units enrolled patients; fifteen of the sites were ECMO cen-
`ters. The protocol, protocol amendments and each institution’s
`Informed Consent forms were approved by the local Institutional
`Review Board before patient enrollment. Written informed con-
`sent was obtained for each patient before enrollment. Equipment,
`treatment gases and funding based on patient recruitment at each
`site was provided by Ohmeda, PPD (Liberty Corner, NJ).
`
`Hypotheses
`The primary hypothesis was that a fixed dose of I-NO at either
`5, 20, or 80 parts per million (ppm), delivered to term infants with
`PPHN, would reduce the PPHN Major Sequelae Index (MSI) by
`30%. This composite endpoint included the incidence of death,
`ECMO, neurologic sequelae in the neonatal period, or broncho-
`pulmonary dysplasia/reactive airway disease (BPD/RAD). Neu-
`rologic sequelae in the neonatal period were defined as clinical or
`electroencephalogram-proven seizures or an abnormal cranial im-
`aging study (demonstrating either hemorrhage, infarct, or other
`diagnoses) during the neonatal hospitalization. BPD was defined
`as the need for supplemental oxygen at 28 days after birth with a
`concurrent abnormal chest x-ray. RAD was defined as the need for
`bronchodilator therapy at discharge from the nursery.
`Secondary hypotheses were that I-NO would: 1) produce a
`sustained improvement in oxygenation during the first 24 hours of
`treatment, 2) reduce the incidence of treatment failures due to
`hypoxemia and/or hypotension leading to institution of other
`forms of rescue therapy, and 3) reduce days on the ventilator, on
`supplemental oxygen, and length of hospital stay.
`It was also hypothesized that there would be no increase in
`adverse events experienced by the neonates receiving I-NO as
`measured by methemoglobin levels, inspired NO2 levels, worsen-
`
`ing of primary or secondary efficacy outcome measures, delay in
`initiating rescue therapy, adverse events described by the inves-
`tigators, or abnormalities in clinical hematologic and biochemical
`blood studies. A separate comprehensive 1-year follow-up study
`was designed to examine the general pediatric, neurodevelopmen-
`tal, and audiologic outcomes.
`
`Patient Entry Criteria
`Term infants (ⱖ37 weeks gestation) with birth weights of
`ⱖ2500 g requiring mechanical ventilation having a fraction of
`inspired oxygen (Fio2) of 1.0 were eligible within 72 hours of birth.
`Small for gestational age infants with birth weights of ⱖ2000 g
`were included if the gestational age was assessed to be ⱖ39 weeks.
`On study entry, an Infant Star conventional ventilator (Infrasonics,
`Inc, San Diego, CA) was used, with a continuous flow rate be-
`tween 10 and 15 L/min. Intermittent mandatory ventilator rates
`⬎100 breaths/minute and inverse inspiratory to expiratory ratios
`were not permitted. For study entry, patients required an arterial
`blood gas with a Pao2 of ⱖ40 and ⱕ100 Torr drawn from an
`indwelling postductal arterial catheter when the mean airway
`pressure was ⱖ10 cm H2O and the Fio2 was 1.0. They also required
`a color Doppler echocardiogram with evidence of PPHN or a
`preductal versus postductal transcutaneous O2 saturation gradient
`of ⱖ10%. The following were considered echocardiographic evi-
`dence of PPHN: 1) a right-to-left or bidirectional ductal shunt, or
`2) if the ductus was closed, a right-to-left or bidirectional foramen
`ovale shunt with either a tricuspid insufficiency jet with an esti-
`mated systolic pulmonary artery pressure ⱖ75% of systolic aortic
`pressure or posterior systolic bowing of the interventricular sep-
`tum. Before starting the treatment gas, the patient had to have a
`chest x-ray within 12 hours and a head ultrasound within 24
`hours. A standardized history and physical examination were
`required. Preductal and postductal transcutaneous O2 saturations
`were obtained with all arterial blood gas samples.
`Exclusion criteria were lung hypoplasia syndromes, congenital
`heart disease (other than a small, hemodynamically insignificant
`ventricular septal defect) as determined by echocardiography,
`intracranial hemorrhage ⱖgrade 2, uncorrected polycythemia (he-
`matocrit ⱖ70%), mean systemic arterial pressure ⬍35 Torr, a lethal
`syndrome, a suspected or confirmed chromosomal abnormality,
`use of intravenous vasodilators after entry criteria were met at the
`study site, uncontrollable coagulopathy or serious bleeding, and
`enrollment in any other investigational drug or interventional
`study. Patients were excluded if they had received previous or
`concomitant surfactant therapy. Patients who received a trial of
`high-frequency ventilation within 6 hours before starting the treat-
`ment gas were also ineligible.
`
`Masking Procedures and Randomization
`Strict masking procedures and personnel designations were
`approved by the steering committee before a site enrollment.
`Clinical investigators remained masked to the group assignment
`through the 1-year follow-up for all patients in the study. The
`clinical investigator managed patient care, assured compliance to
`the protocol, and assigned adverse events.
`The site’s unmasked laboratory investigator randomized pa-
`tients to a placebo or nitric oxide (NO) dose group from a scratch
`off card. The randomization was blocked for each site in a block
`size of four patients allocated to one of the four treatment gases.
`The laboratory investigator set up, calibrated, and operated the
`I-NO delivery device and measured methemoglobin. All sites
`used Ciba-Corning 270 Co-oximeters (Ciba Corning Diagnostics
`Corporation, Medford, MA) for methemoglobin levels.
`
`Baseline Procedures
`As soon as the patient was randomized, baseline hemody-
`namic, ventilator, and blood gas analyses were obtained at three
`time points 15 to 30 minutes apart. A baseline methemoglobin
`level was also obtained. If the patient met entry criteria at the first
`two time points, the Fio2 was reduced to 0.95, and the third
`baseline measurement was obtained. If the Pao2 remained ⱖ40
`and ⱕ100 Torr, treatment gas was begun immediately. A patient
`who failed baseline criteria was allowed one additional opportu-
`nity to meet baseline oxygen criteria if deemed stable by the
`clinical investigator.
`The following laboratory studies were also obtained before
`
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`starting the treatment gas: a complete blood count, serum creati-
`nine, blood urea nitrogen, total protein, albumin, total bilirubin,
`alkaline phosphatase, lactic acid dehydrogenase, serum glutamic-
`oxaloacetic transaminase, total calcium, inorganic phosphorous,
`uric acid, and glucose.
`
`I-NO Delivery
`The I-NO delivery system (Ohmeda, PPD, Madison, WI) was
`designed expressly to deliver NO mixed with nitrogen, or nitro-
`gen alone (BOC Specialty Gases, Port Allen, LA) into the inspira-
`tory limb of the ventilator circuit using a mass flow controller. A
`sample gas catheter was attached to the inspiratory limb of the
`ventilator immediately before the patient connection. Electro-
`chemical detectors attached to the delivery device provided a
`continuous measurement of NO and NO2 (model EC90 NO mon-
`itor and model EC40 NO2 monitor, Bedfont Scientific Ltd, Kent,
`England). The accuracy of NO measurement for values between 0
`to 5 ppm was ⫾ 0.5 ppm and for 5 to 80 ppm, was ⫾ 2 ppm,
`regardless of the Fio2.17 Validation was performed by using a
`known standard, blended by mass flow controllers and verified by
`chemiluminescence (error of ⫾ 1%). Electrochemical cell analyzers
`for NO2 have been shown to over estimate NO2 levels, due to the
`formation of NO2 in the sampling circuit.18 In the presence of
`oxygen, the NO2 monitor overestimates by 1.2 ppm at 80 ppm of
`NO, 0.3 ppm at 40 ppm of NO, and 0.1 ppm at 20 ppm of NO.
`Verification was performed using a selective NO2 ultraviolet ab-
`the NO2 analyzers was
`sorbance analyzer. The linearity of
`within ⫾ 3%.
`On randomization, the laboratory investigator calibrated the
`delivery device with standard concentrations of NO (112 ppm) in
`nitrogen and NO2 (7.2 ppm) in nitrogen. The I-NO delivery device
`mixed the NO source gas 1:20 with ventilator gas. To deliver NO
`at doses of 0, 5, 20, and 80 ppm, source tanks of 0, 100, 400, and
`1600 ppm of NO, balance N2, were used. Because delivery of any
`treatment gas diluted the ventilator gas by 5%, the maximal Fio2
`delivered to the patient was 0.95. Therefore, patients were placed
`on an Fio2 setting of 0.95 before starting treatment gas. The ven-
`tilator Fio2 setting was increased to 1.0 when the treatment gas
`was started. As a result, an Fio2 of 0.95 was delivered on initiation
`of the treatment gas for all groups.
`
`Protocol for Management During Treatment Gas
`Administration
`No Fio2 or ventilator changes were to be made over the first
`half hour of treatment gas. High-frequency jet and oscillatory
`ventilation were not permitted. Ventilator settings, heart rate,
`blood pressure, and postductal arterial blood gases, preductal and
`postductal transcutaneous oxygen saturations, inspired gas levels,
`and methemoglobin levels were obtained at 0.5, 1, 2, 3, 4, and then
`every 4 hours or as needed while on 100% treatment gas. Patients
`were not permitted to receive treatment gas for ⬎14 days.
`Study patients received a fixed dose of either 0, 5, 20, or 80 ppm
`of NO until one of four events occurred: 1) a treatment success was
`achieved, based on improved oxygenation (Pao2 ⱖ60 Torr, Fio2
`⬍0.6, and mean airway pressure ⬍10 cm H2O); 2) a treatment
`failure resulted, based on a decrease of Pao2 ⬍40 Torr for 30
`minutes in the absence of a reversible mechanical problem, a mean
`systemic arterial pressure ⬍35 Torr, the patient reached the site’s
`ECMO criteria, 14 days of treatment gas had elapsed, or if remain-
`ing in the study was not in the best interest due to cardiopulmo-
`nary instability or local ECMO criteria that was not covered by the
`study’s failure criteria; 3) inspired NO2 levels were ⬎3 ppm for 30
`minutes19; or 4) a methemoglobin level that exceeded 7%. All
`patients, whether treatment successes or failures, were included in
`the data analyses.
`For treatment successes and failures, the protocol permitted
`sequential 20% decrements in treatment gas at a minimum of 30
`minutes and maximum of 4 hours. Ventilator settings, an arterial
`blood gas, preductal and postductal transcutaneous saturations,
`inspiratory gas levels, and vital signs were required immediately
`before and 30 minutes after a 20% reduction. During this half hour
`period, it was requested that no ventilator change be made unless
`the Pao2 became ⬍40 Torr. If this level of hypoxemia occurred on
`a reduction, the treatment gas could be increased 20%. The wean-
`ing process would begin again when the criteria for success were
`met or in the case of a treatment failure, the treatment gas would
`have to be discontinued before other rescue therapy was begun.
`
`Treatment gas could not be re-instituted and no other investiga-
`tional drug or intervention was permitted. I-NO for treatment
`failures was not permitted.
`For patients with elevated methemoglobin and inspired NO2
`levels based on the protocol definitions, treatment gas could be
`continued at a lower level (one of the 20% decrements) if the
`methemoglobin or NO2 levels dropped below threshold levels.
`
`Posttreatment Gas Data
`A methemoglobin level was obtained 2 hours after the treat-
`ment gas was discontinued. The baseline complete blood count
`and blood chemistries were repeated within 12 hours of discon-
`tinuing the treatment gas. A repeat head ultrasound, computer-
`ized axial tomography, or magnetic resonance imaging was re-
`quired before discharge. A bilateral evoked response hearing
`screen was obtained before discharge. A chest x-ray was per-
`formed on day 28 if the patient still required supplemental oxygen.
`
`Safety Monitoring
`An independent data safety and monitoring board was com-
`posed of statisticians and pediatric specialists. An interim, blinded
`safety analysis was performed after data from 100 patients were
`obtained.
`
`Sample Size and Statistics
`We estimated the incidence of PPHN major sequelae before the
`start of this trial by a retrospective survey of seven sites. Data were
`obtained on 107 patients who would have been eligible for the
`present study. The incidences of the major sequelae were: death,
`8%; ECMO, 36%; neonatal neurologic sequelae 20%; and BPD, 5%.
`To determine if NO could reduce PPHN major sequelae by 30% (␣
`level ⫽ 0.05, ␤ level ⫽ 0.2), a total of 320 patients (80 in each of 4
`groups) were required. The Cochran-Mantel-Haenszel ␹2 test was
`used for discrete or categorical data, such as PPHN major sequelae
`(death, ECMO, neurologic sequelae, BPD, or composite), treat-
`ment failures due to cardiopulmonary instability, and adverse
`events by organ systems. Fisher’s exact test was used if the fre-
`quencies were small.
`The Wilcoxon rank sum test was used to analyze continuous
`variables (eg, the time-weighted oxygenation index [TWOI], du-
`ration of supplemental oxygen, acute change in Pao2, or methe-
`moglobin levels). For ventilatory and hemodynamic data, baseline
`was considered as the third qualifying time point (Fio2 ⫽ 0.95)
`immediately before starting the treatment gas. A two-tailed t test
`was used only for the change from baseline for the clinical hema-
`tologic and biochemical variables. The significance level for all
`tests was set at 0.05. There was no ␣level adjustment for pairwise
`comparisons performed in the study. The incidence of adverse
`events was tabulated using the COSTART body system classifica-
`tion.20
`One of the major secondary endpoints of this study was to
`determine whether I-NO produced a sustained improvement in
`oxygenation. Therefore, we prospectively defined the TWOI as the
`change in oxygenation index (OI) from the individual’s baseline
`OI over time, divided by the duration on treatment gas up to 24
`hours. This method adjusts for attrition from treatment failure or
`success. If the patient worsened from his/her own baseline, the
`TWOI would be a positive number. If the patient improved, the
`index would be a negative number as shown in Fig 1.
`
`RESULTS
`Enrollment began in April 1994. One hundred
`fifty-five patients were enrolled. The trial was halted
`in June 1996 because of slow recruitment. The accrual
`goal was 320 patients.
`
`Patients Screened and Patients Enrolled
`A total of 1282 patients were screened. The most
`common conditions preventing enrollment were: ox-
`ygenation outside the eligible range (26%) and lack
`of echocardiographic evidence of PPHN (19%). Sur-
`factant
`therapy (12%), high-frequency ventilation
`(9%), prematurity (8%), lung hypoplasia syndromes
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`TABLE 2.
`
`Baseline Ventilatory Status
`Variable
`Control Group
`(n ⫽ 41)
`
`0.95 ⫾ 0
`14 ⫾ 4
`
`59 ⫾ 16
`25 ⫾ 10
`
`Nitric Oxide
`Groups
`(n ⫽ 114)
`0.95 ⫾ 0
`14 ⫾ 3
`
`64 ⫾ 39
`24 ⫾ 9
`
`Fio2
`Mean airway pressure
`(cm H2O)
`Pao2 (Torr)
`Oxygenation index
`(cm H2O/Torr)
`Arterial/alveolar Po2
`ratio
`pH
`Paco2 (Torr)
`Intermittent mandatory
`ventilation (breaths/min)
`Peak inspiratory pressure
`(cm H2O)
`Positive end expiratory
`pressure (cm H2O)
`Values are mean ⫾ SD at 25 ⫾ 17 hours after birth.
`
`the time-weighted oxygenation index
`Fig 1. Calculation of
`(TWOI) as a measure of the change in oxygenation over time by a
`treatment gas (control or NO) in term infants with PPHN. The
`black area is the change in the OI from the baseline OI over the
`duration of the treatment gas or 24 hours, whichever came first.
`The area is divided (weighted) by time. In this theoretical exam-
`ple, the patient had a negative TWOI indicating an improvement
`in oxygenation over time.
`
`(8%), and age ⬎72 hours (5%) were the other condi-
`tions preventing enrollment.
`A total of 8 patients, 2 in the control group and 6 in
`the NO groups were erroneously enrolled. All pa-
`tients were included in the efficacy and safety anal-
`yses. Of the 155 randomized patients, the number of
`patients who received treatment in each group (0, 5,
`20, and 80 ppm) were 41, 41, 36, and 37 respectively.
`
`Baseline Patient Profile
`Baseline variables were similar among treatment
`groups. Baseline data are presented (Tables 1 and 2)
`for the control group (N ⫽ 41) and the pooled I-NO
`group (N ⫽ 114). The majority of patients were de-
`livered by cesarean section (62%) and at hospitals
`other than the study site (over 90%). Most infants
`(77%) received conventional mechanical ventilation
`and 5% received high-frequency jet or oscillatory
`ventilation before admission to the study site. Un-
`derlying conditions associated with PPHN were also
`well-balanced among treatment groups with a ma-
`jority of patients diagnosed with meconium aspira-
`
`TABLE 1.
`
`Patient Profile
`Trait
`
`Control
`Group
`(n ⫽ 41)
`3.4 ⫾ 0.5
`39.7 ⫾ 1.8
`7 ⫾ 2
`26 ⫾ 18
`27 (66)
`
`Birth weight, kg*
`Gestational age, wk*
`5-Min Apgar Score, no. *‡
`Age, start 嗱 gas, h*
`Male sex, no. (%)
`Race, no. (%)
`Black
`Hispanic
`White
`Other
`Cesarean section, no. (%)†
`Inborn, no. (%)
`Primary diagnosis, no. (%)
`Meconium aspiration syndrome
`Sepsis
`Idiopathic PPHN
`Respiratory distress syndrome
`Other
`* Values are mean ⫾ SD.
`† One patient has missing information.
`‡ Two patients have missing information.
`
`11 (27)
`10 (24)
`20 (49)
`0 (0)
`25 (61)
`3 (7)
`
`26 (63)
`13 (32)
`5 (12)
`4 (10)
`5 (12)
`
`Nitric Oxide
`Groups
`(n ⫽ 114)
`3.4 ⫾ 0.5
`39.8 ⫾ 1.6
`7 ⫾ 2
`25 ⫾ 17
`58 (51)
`
`25 (22)
`20 (18)
`59 (52)
`10 (9)
`70 (62)
`12 (11)
`
`60 (53)
`30 (26)
`24 (21)
`13 (11)
`22 (19)
`
`0.09 ⫾ 0.02
`
`0.10 ⫾ 0.06
`
`7.48 ⫾ 0.12
`33 ⫾ 10
`59 ⫾ 15
`
`7.50 ⫾ 0.11
`30 ⫾ 9
`59 ⫾ 15
`
`33 ⫾ 6
`
`5 ⫾ 2
`
`32 ⫾ 6
`
`5 ⫾ 1
`
`tion. Although there were more patients with idio-
`pathic PPHN in the NO groups compared with
`placebo, this was not statistically significant. Seizures
`were documented in 17% of the control patients and
`20% of the patients who went on to receive NO.
`Abnormal head ultrasounds, almost all due to low-
`grade intracranial hemorrhages, were demonstrated
`in 10% of the control patients and 5% of the pooled
`NO patients.
`The baseline ventilatory (Table 2) and hemody-
`namic conditions were also very similar between
`control and NO groups. The patients required high
`levels of conventional ventilatory support. The base-
`line inspiratory Fio2 for all patients was 0.95 by pro-
`tocol. Systolic, mean, and diastolic, systemic arterial
`pressures were 67 ⫾ 13, 53 ⫾ 10, and 44 ⫾ 10 Torr,
`respectively. Dopamine and/or dobutamine (to a
`lesser extent) were used in 76% and 74% of the
`control and the pooled NO group, respectively, at the
`start of the treatment gas. Most patients had echo-
`cardiographic evidence for PPHN; only 9% were di-
`agnosed by preductal versus postductal oxygen sat-
`uration difference of ⬎10%. The mean preductal and
`postductal transcutaneous oxygen saturations were
`similar for all groups; for the control group the sat-
`urations were 93.6 ⫾ 3.0% and 93.2% ⫾ 4.1%, respec-
`tively.
`
`Acute Changes in Blood Gases, pH, and
`Hemodynamics
`The acute changes in Pao2 after the first half hour
`of treatment gas, on stable ventilator settings are
`shown in Fig 2. There was a statistically significant
`increase in Pao2 from baseline for each NO group
`compared with control. Although a higher mean
`Pao2 was observed for the 80 ppm dose, this was not
`statistically different from the other NO doses. The
`corresponding OIs at 30 minutes for each group from
`lowest to highest NO dose were 24 ⫾ 14, 20 ⫾ 11,
`21 ⫾ 13, and 15 ⫾ 10; the pooled NO value was 19 ⫾
`11 (cm H2O/Torr). There were no appreciable differ-
`ences between and within groups for pH, Paco2, or
`ventilator settings at 30 minutes compared with
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`Fig 2. Acute change in Pao2 during the first half hour of treat-
`ment gas administration (control⫽ NO at 0 ppm) to term infants
`with PPHN. During this period, there were no changes in the Fio2
`or conventional ventilator settings.
`
`baseline. At 30 minutes for control and pooled NO
`groups respectively, the pH was 7.49 ⫾ 0.11 and
`7.52 ⫾ 0.12, the Paco2 was 32 ⫾ 71 and 29 ⫾ 10 Torr,
`the peak inspiratory pressure for both groups was
`33 ⫾ 6 cm H2O, the ventilator rate was 59 ⫾ 15 and
`58 ⫾ 14 breaths/minute, and the positive end expi-
`ratory pressure was 5.1 ⫾ 1.6 and 5.0 ⫾ 1.2 cm H2O.
`Systolic, mean, and diastolic systemic arterial pres-
`sures, as well as heart rate, remained steady during
`the first half hour of treatment gas. The mean arterial
`blood pressure for the 0, 5, 20, and 80 ppm groups at
`30 minutes of treatment gas were 54 ⫾ 9, 52 ⫾ 9, 50 ⫾
`9, and 50 ⫾ 10 Torr; the value for the pooled NO
`group was 51 ⫾ 9 Torr. The corresponding heart
`rates at 30 minutes, from the lowest (control) to
`highest NO dose were 151 ⫾ 20, 151 ⫾ 24, 155 ⫾ 27,
`and 155 ⫾ 24 beats/minute; the value for the pooled
`NO group was 154 ⫾ 25 beats/minute. Blood pres-
`sure and heart rate data were similar for all groups
`during administration of the treatment gas.
`
`Secondary Outcomes
`The TWOI corrected from baseline was used as a
`measure of a sustained improvement in oxygenation.
`Figure 3 demonstrates that the TWOI improved (neg-
`ative number) for all NO groups. For the control
`group, this index was not statistically improved from
`baseline. There was a highly significant reduction in
`the baseline-adjusted, TWOI for the pooled NO
`group compared with placebo.
`The incidence of any treatment failure for the con-
`trol group was 37% and for the 5, 20, and 80 ppm NO
`doses, 29%, 28%, and 59%, respectively, (the pooled
`value for NO subjects was 39%). The higher inci-
`dence of treatment gas failures in the 80 ppm group
`was related primarily to methemoglobinemia (13 of
`37, 35%) and elevated NO2 levels (7 of 37, 19%). The
`incidence of treatment failures due to cardiopulmo-
`nary instability (hypoxemia or hypotension criteria)
`
`Fig 3. The time-weighted oxygenation index (TWOI) over 24
`hours or duration of the treatment gas (control ⫽ NO at 0 ppm)
`whichever came first, for term infants with PPHN. A negative
`TWOI indicates a sustained improvement in oxygenation from the
`baseline OI of each treatment group.
`
`was reduced by NO (control 34%, the pooled value
`for NO subjects was 25%), but this result did not
`reach statistical significance (P ⫽ .29); the incidences
`of treatment failures for each group were 34%, 27%,
`25%, and 24% for 0, 5, 20, and 80 ppm NO groups,
`respectively. Hypoxemia was the principal cause of
`treatment failure due to cardiopulmonary instability.
`Only 3 patients were classified as treatment failures
`due to hypotension, 2 in the 5 ppm and 1 in the 80
`ppm NO groups. The frequency of premature dis-
`continuation of treatment gas when the investigator
`felt it was in the best interest of the patient (eg,
`immediate rescue therapy was needed) was 20% for
`the control group and 18% for the pooled NO group.
`One patient in the placebo group had the treatment
`gas discontinued because of a malfunction in the
`inspiratory gas monitor. For patients classified as
`treatment failures based on hypoxemia and/or hy-
`potension, the incidence of rescue therapy for pla-
`cebo and the pooled I-NO group, respectively, were:
`ECMO (71% and 48%), high-frequency oscillatory
`ventilation (64% and 72%), surfactant (36% and 45%),
`and vasodilator therapy (36% and 21%).
`The duration of treatment gas, mechanical ventila-
`tion, supplemental oxygen, ECMO, and hospitaliza-
`tion are shown in Table 3. These results give a de-
`scriptive view of the hospital course but are difficult
`to analyze because of the issue of dropouts in both
`the placebo and NO groups. Patients generally re-
`ceived the treatment gas for about 21⁄2 days. The
`mean durations on treatment gas for patients with
`treatment success were 107.4, 95.4, 72.2, and 65.1
`hours for the control, 5, 20, and 80 ppm groups,
`respectively. Thus, among treatment successes, it ap-
`peared that there was a dose-response trend in du-
`ration of treatment gas. Patients who became treat-
`ment failures due to cardiopulmonary instability had
`gas discontinued at similar times in the control
`group (9.9 ⫾ 11.0 h) and the NO groups (10.0 ⫾
`12.7 h). The mean TWOIs for the treatment failures
`due to cardiopulmonary instability were ⫹1.25 in the
`control group and ⫹1.49 in the NO group; this was
`not statistically different. The mean OI at the time a
`patient was declared a treatment failure due to car-
`diopulmonary instability was 52.7 ⫾ 16.3 and 43.2 ⫾
`
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`TABLE 3.
`
`Duration of Treatment*
`Treatment Gas
`
`Control Group
`(n ⫽ 41)
`
`Nitric Oxide Groups
`(n ⫽ 114)
`
`P Value㛳
`
`Treatment gas (h)
`All patients
`Until success: weaning criteria†
`Until failure: cardiopulmonary instability‡
`Time to ECMO (h)
`Duration of ECMO (h)
`Mechanical ventilation (h)
`Supplemental oxygen (h)
`All patients
`Success: weaning criteria†
`Failure: cardiopulmonary instabi