LOW-DOSE NITRIC OXIDE THERAPY FOR PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN
`
`LOW-DOSE NITRIC OXIDE THERAPY FOR PERSISTENT PULMONARY
`HYPERTENSION OF THE NEWBORN
`
`R
`EESE
`
` S
`, M.D., W. M
` W. W
`, M.D., M
` J. K
`, M.D., T
` H. C
`OUTHGATE
`ICHAEL
`ALKER
`ARSHALL
`UESER
`HOMAS
`LARK
`J
` L. H
`, R.R.T., J
` A. P
`, M.D., B
` J. R
`, M.D., M
` K
`, M.D.,
`ARTIN
`EREZ
`OSE
`UCKABY
`ERYL
`EVERLY
`OY
`ESZLER
` J
` P. K
`, M.D.,
`
` C
` I
` N
` O
` R
` G
`*
`AND
`OHN
`INSELLA
`FOR
`THE
`LINICAL
`NHALED
`ITRIC
`XIDE
`ESEARCH
`ROUP
`
`, M.D.,
`
`A
`BSTRACT
`Background
`Inhaled nitric oxide improves gas
`exchange in neonates, but the efficacy of low-dose
`inhaled nitric oxide in reducing the need for extra-
`corporeal membrane oxygenation has not been es-
`tablished.
`Methods
`We conducted a clinical trial to determine
`whether low-dose inhaled nitric oxide would reduce
`the use of extracorporeal membrane oxygenation in
`neonates with pulmonary hypertension who were
`born after 34 weeks’ gestation, were 4 days old or
`younger, required assisted ventilation, and had hy-
`poxemic respiratory failure as defined by an oxygen-
`ation index of 25 or higher. The neonates who re-
`ceived nitric oxide were treated with 20 ppm for a
`maximum of 24 hours, followed by 5 ppm for no more
`than 96 hours. The primary end point of the study
`was the use of extracorporeal membrane oxygenation.
`Results
`Of 248 neonates enrolled, 126 were ran-
`domly assigned to the nitric oxide group and 122 to
`the control group. Extracorporeal membrane oxygen-
`ation was used in 78 neonates in the control group (64
`percent) and in 48 neonates in the nitric oxide group
`(38 percent) (P=0.001). The 30-day mortality rate in
`the two groups was similar (8 percent in the control
`group and 7 percent in the nitric oxide group). Chron-
`ic lung disease developed less often in neonates treat-
`ed with nitric oxide than in those in the control group
`(7 percent vs. 20 percent, P=0.02). The efficacy of ni-
`tric oxide was independent of the base-line oxygena-
`tion index and the primary pulmonary diagnosis.
`Conclusions
`Inhaled nitric oxide reduces the ex-
`tent to which extracorporeal membrane oxygenation
`is needed in neonates with hypoxemic respiratory
`failure and pulmonary hypertension. (N Engl J Med
`2000;342:469-74.)
`©2000, Massachusetts Medical Society.
`
`P
`
`ERSISTENT pulmonary hypertension is
`common in neonates with respiratory fail-
` It is characterized by pulmonary hy-
`ure.
`1,2
`pertension and extrapulmonary right-to-left
`shunting across the foramen ovale and ductus arte-
`riosus. In many cases, the disease progressively wor-
`sens, becoming refractory to treatment.
`3-5
`When other therapies fail, neonates are treated with
` This ther-
`extracorporeal membrane oxygenation.
`3-5
`apy improves survival in neonates with respiratory
`failure,
` but its administration is labor-intensive and
`6-8
`costly and necessitates large amounts of blood prod-
`
`ucts. The mortality rate in neonates treated with extra-
`corporeal membrane oxygenation is 15 to 20 percent,
`and 10 to 20 percent of the neonates who survive
`have substantial developmental delay.
`7-12
`Nitric oxide is produced in vascular endothelial cells
`and plays an important part in increasing blood flow
`to the lungs after birth.
` Exogenously adminis-
`13-17
`tered nitric oxide causes selective pulmonary vasodil-
`atation in newborn lambs,
` and the administration
`13
`of low doses of nitric oxide causes sustained improve-
`ment in gas exchange in neonates.
` However, the ef-
`18
`ficacy of low-dose inhaled nitric oxide in reducing
`the use of extracorporeal membrane oxygenation has
`not been established. This study was undertaken to
`determine whether low-dose inhaled nitric oxide re-
`duces the use of extracorporeal membrane oxygena-
`tion in neonates with pulmonary hypertension.
`
`METHODS
`
`Study Subjects
`We studied 248 neonates who were born after 34 weeks’ ges-
`tation, were 4 days old or younger, required assisted ventilation,
`and had an oxygenation index of 25 or higher. The oxygenation
`index was calculated as the mean airway pressure times the frac-
`tion of inspired oxygen times 100, divided by the partial pressure
`of arterial oxygen. The neonates had clinical or echocardiographic
`evidence of pulmonary hypertension without structural heart dis-
`ease. Clinical evidence of pulmonary hypertension was defined as
`a difference of 5 percent between preductal and postductal oxy-
`gen saturation or recurrent (more than two) decreases in arterial
`oxygen saturation (to less than 85 percent) in a period of 12 hours
`despite optimal treatment of lung disease. Echocardiographic ev-
`idence of pulmonary hypertension was defined as an estimated peak
`systolic pulmonary-artery pressure that was higher than 35 mm Hg
`or more than two thirds of the systemic systolic pressure as indi-
`cated by a tricuspid regurgitant jet, a right-to-left ductus arterio-
`sus shunt, or a right-to-left atrial-level shunt. In addition, we con-
`sidered as study candidates neonates in whom extreme alkalosis
`(a pH higher than 7.55) was required to maintain a partial pres-
`sure of arterial oxygen of more than 60 mm Hg.
`
`From the Department of Pediatrics, Duke University, Durham, N.C.
`(R.H.C.); the Division of Neonatology, Carolinas Medical Center, Char-
`lotte, N.C. (T.J.K.); the Department of Neonatology, Greenville Hospital
`System, Greenville, S.C. (M.W.W.); Medical University of South Carolina,
`Charleston (W.M.S.); Egleston Children’s Hospital, Atlanta (J.L.H.); Ar-
`nold Palmer Hospital, Orlando, Fla. (J.A.P.); the Department of Pediatrics,
`Emory University, Atlanta (B.J.R.); the Division of Neonatology, George-
`town University Hospital, Washington, D.C. (M.K.); and the University of
`Colorado School of Medicine, Denver (J.P.K.). Address reprint requests to
`Dr. Clark at Pediatrix Medical Group, 1301 Concord Terr., Sunrise, FL
`33323, or at reese_clark@mail.pediatrix.com.
`*The members of the Clinical Inhaled Nitric Oxide Research Group are
`listed in the Appendix.
`
`Volume 342 Number 7
`
`·
`
`469
`
`The New England Journal of Medicine
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`Downloaded from nejm.org at REPRINTS DESK INC on October 22, 2015. For personal use only. No other uses without permission.
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` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Ex. 2031-0001
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`The New England Journal of Medicine
`
`Pre-enrollment treatment with high-frequency ventilation (model
`3100A, SensorMedics, Yorba Linda, Calif.) or surfactant was en-
`couraged. Neonates were not eligible for the study if extracorpo-
`real membrane oxygenation was urgently needed for refractory
`hypotension (a mean blood pressure lower than 35 mm Hg) or
`profound hypoxemia (a partial pressure of arterial oxygen lower
`than 30 mm Hg) or if they had a lethal congenital anomaly, a
`substantial bleeding diathesis, active seizures, or a history of severe
`asphyxia. The study was approved by the institutional review board
`at each study site, and written informed consent was obtained
`from a parent or guardian.
`
`Randomization
`To balance the distribution of pulmonary-disease diagnoses in
`the two treatment groups, each neonate was assigned to one of
`five diagnostic categories and then randomly assigned to treatment.
`The diagnostic categories were the meconium aspiration syndrome,
`which was diagnosed on the basis of a history of meconium-stained
`amniotic fluid and abnormal results on chest radiography; pneu-
`monia, with two or more risk factors for sepsis and no history that
`suggested lung immaturity (the risk factors for sepsis were maternal
`chorioamnionitis, maternal fever, positive vaginal culture for group
`B streptococcus, a white-cell count of more than 30,000 cells per
`cubic millimeter or less than 5000 cells per cubic millimeter, a ratio
`of immature to total neutrophils of more than 0.2, a serum C-reac-
`tive protein concentration of more than 2 µg per milliliter, hypo-
`tension that required vasopressor support, and coagulopathy); the
`respiratory distress syndrome, with fewer than two risk factors for
`sepsis, a history that suggested lung immaturity, and a chest radio-
`graph that had a reticulogranular appearance; lung hypoplasia syn-
`dromes, which were diagnosed on the basis of the presence of a
`congenital diaphragmatic hernia, a history of prolonged oligohy-
`dramnios, or hydrops fetalis; and idiopathic persistent pulmonary
`hypertension, which required a clinical diagnosis of pulmonary hy-
`pertension and a chest radiograph showing little or no lung disease.
`Cards on which treatment assignments were written were ran-
`domly ordered (shuffled by hand three times) at Emory University
`in Atlanta and placed in sequentially numbered opaque envelopes
`in blocks of eight for diagnostic-category strata 1, 2, and 3 and in
`blocks of four for strata 4 and 5; the number in each block reflected
`the anticipated frequencies of diagnoses. Notebooks in which the
`numbered envelopes were stored were sent to each study site.
`After the attending physician obtained consent, a respiratory
`therapist was told the neonate’s diagnostic stratum and identified
`the appropriate sequentially ordered envelope. The therapist then
`set up the system of treatment delivery, completed the basic in-
`formation on the randomization card, and mailed the card to the
`center that coordinated the study. The study coordinator at the
`coordinating center monitored the order in which the treatment
`cards were used.
`Neither the physicians nor the nurses were told the treatment
`assignments. Respiratory therapists directed treatment and made
`adjustments to keep the concentration of nitric oxide within the
`prescribed range (±10 percent of the target dose). In the first 36
`neonates enrolled, the delivery systems for the two treatment
`groups were identical. The neonates assigned to the control group
`were treated by continuing the flow of oxygen without initiating
`the administration of nitric oxide. In the remaining 212 neonates,
`nitrogen (delivered through the INO Delivery System, Ohmeda,
`Madison, Wis.) was used as the control to improve the masking
`of the treatment assignment. The gas tank and monitor readouts
`were covered so that the tank and the monitored values for nitric
`oxide and nitrogen dioxide could not be seen.
`
`Treatment Guidelines and Delivery of Gas
`In the first 18 neonates in the treatment group, nitric oxide gas
`(Scott Medical Products, Plumstead, Pa.) was delivered from a
`450-ppm cylinder. Nitric oxide was introduced into the afferent
`limb of the ventilator circuit near the endotracheal tube, thus mix-
`ing with the fixed flow of gas in the ventilator circuit. The flow
`
`470
`
`·
`
`Febr uar y 17, 2000
`
`was adjusted to yield the assigned concentrations of nitric oxide.
`Nitric oxide and nitrogen dioxide were measured with electrochem-
`ical monitors (Pac II nitric oxide monitor and model 190 nitrogen
`dioxide monitor, Drager, Chantilly, Va.). For the 108 remaining ne-
`onates in the nitric oxide group, nitric oxide gas (INO Therapeu-
`tics, Port Allen, La.) was delivered from an 800-ppm cylinder. The
`control subjects received 100 percent nitrogen (Ohmeda, BOC
`Gases, Murray Hill, N.J.). The study gas (nitrogen or nitric oxide)
`was delivered (with the INO Delivery System) into the inspirato-
`ry flow of the ventilator circuit. The device measured the flow of
`gas in the ventilator circuit, and a mass-flow controller added study
`gas to the ventilator circuit to create the desired concentration. The
`device continuously sampled gas from the endotracheal side-port
`adapter and measured oxygen, nitric oxide, and nitrogen dioxide
`with electrochemical monitors. Inhaled nitric oxide and nitrogen
`had a similar effect on the fraction of inspired oxygen (reducing
`the value to 0.98).
`19
`The administration of the study gas (nitrogen or nitric oxide)
`was started at 20 ppm, and this amount was continued for four
`hours. At four hours, arterial-blood gases and methemoglobin were
`measured. The dose was decreased to 5 ppm if the neonate’s con-
`dition was stable, the partial pressure of arterial oxygen was at least
`60 mm Hg, and the pH was 7.55 or lower. If these criteria were
`not met, the administration of study gas was maintained at 20 ppm,
`and the neonate was evaluated every 4 hours until the criteria were
`met or the neonate had been treated for 24 hours. During the
`first 24 hours, the dose of study gas could be returned to 20 ppm
`if the neonate’s partial pressure of arterial oxygen fell below 60
`mm Hg when the fraction of inspired oxygen was 1.0. After 24
`hours of treatment, the dose was decreased to 5 ppm. Treatment
`was continued at 5 ppm until the fraction of inspired oxygen was
`less than 0.7, the neonate had been treated for 96 hours, or the
`neonate was seven days old, whichever came first.
`If the neonate did not tolerate the decreased dose at 24 hours
`or if at 96 hours the study gas could not be discontinued, the
`treatment was considered a failure. If a clinical decision was made
`to proceed with extracorporeal membrane oxygenation, the study
`gas was continued until it was started.
`Methemoglobin was measured at base line and at 4, 24, and 96
`hours while the neonate was receiving the study gas. The concen-
`tration of study gas was reduced by half if the neonate had a met-
`hemoglobin value of more than 4 percent or a nitrogen dioxide
`concentration of more than 5 ppm, and the administration of the
`study gas was discontinued if these values did not become normal.
`We aimed to achieve the following blood gas values in the ne-
`onates: a partial pressure of arterial oxygen of 60 to 100 mm Hg;
`a partial pressure of arterial carbon dioxide of 25 to 30 mm Hg and
`a pH of 7.40 to 7.55 in neonates with a response to alkalosis; and a
`partial pressure of arterial carbon dioxide of 35 to 45 mm Hg and
`a pH of 7.35 to 7.45 in neonates with no response to alkalosis.
`The target mean blood pressure was 45 to 60 mm Hg.
`
`Criteria for Discontinuing Treatment in the Study
`Treatment was discontinued if the neonate was successfully
`weaned from the study gas, met the criteria for treatment failure,
`or met the criteria for extracorporeal membrane oxygenation.
`Neonates who met the criteria for treatment failure were not au-
`tomatically treated with extracorporeal membrane oxygenation.
`The criteria for the use of extracorporeal membrane oxygenation
`were an oxygenation index of more than 40 on three of five meas-
`urements performed at least 30 minutes apart; a partial pressure
`of arterial oxygen lower than 40 mm Hg for 2 hours; or progres-
`sive hemodynamic deterioration (a mean blood pressure below
`35 mm Hg). The decision to use extracorporeal membrane oxy-
`genation was made by the attending physician and by the consult-
`ing team for extracorporeal membrane oxygenation.
`
`Study End Points
`Our primary hypothesis was that the use of extracorporeal mem-
`brane oxygenation would be the same in neonates treated with
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`The New England Journal of Medicine
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`Downloaded from nejm.org at REPRINTS DESK INC on October 22, 2015. For personal use only. No other uses without permission.
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` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
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`Ex. 2031-0002
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`LOW-DOSE NITRIC OXIDE THERAPY FOR PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN
`
`nitric oxide and those not treated with nitric oxide. Our second-
`ary hypotheses were that the two groups would have the same im-
`provement in the ratio of arterial oxygen to alveolar oxygen, the
`same incidence of short-term complications (hypotension, methe-
`moglobinemia, and deterioration in gas exchange), the same inci-
`dence of long-term complications (chronic lung disease and neu-
`rologic handicaps), and the same incidence of death. The results
`presented here are for follow-up at 30 days; the results of follow-
`up at 1 year are being collected now.
`
`Statistical Analysis
`We evaluated categorical variables using two-tailed chi-square and
`Fisher’s exact tests. Continuous variables were compared with use
`of a two-tailed t-test or the Kruskal–Wallis test. Ranked data were
`assessed with the two-tailed Kruskal–Wallis test. We compared
`changes over time in the two groups of neonates with regard to gas
`exchange, methemoglobin values, and nitrogen dioxide concentra-
`tions, using analysis of variance for repeated measures. We used a
`multivariate logistic-regression analysis to evaluate the independent
`effects of the following covariates on the use of extracorporeal
`membrane oxygenation and the occurrence of chronic lung disease:
`treatment group, sex, surfactant treatment, support with high-fre-
`quency ventilation, air leak (pneumothorax, pulmonary interstitial
`emphysema, or pneumomediastinum) at study entry, age at study
`entry, primary pulmonary diagnosis, and oxygenation index.
`
`RESULTS
`Base-Line Characteristics
`Two hundred forty-eight neonates were enrolled
`in the study; 126 were assigned to the nitric oxide
`group, and 122 to the control group. The base-line
`characteristics of the two treatment groups were sim-
`ilar, with the exception of prenatal care before the
`third trimester and the presence of an air leak before
`enrollment (Table 1). However, there were no differ-
`ences in obstetrical complications, and all air leaks
`were stabilized before enrollment.
`As compared with the nitric oxide group, the con-
`trol group had a higher mean (±SD) blood pressure
`(55±12 mm Hg vs. 51±11 mm Hg, P=0.02) and
`a lower partial pressure of arterial oxygen (58±42
`mm Hg vs. 72±64 mm Hg, P=0.05) (Table 2).
`However, the mean level of pressor support and the
`severity of hypoxemia, assessed by the oxygenation
`index, were similar in the two groups (Tables 1 and 2).
`There were no differences between the two groups
`in the incidence of echocardiographic evidence of
`pulmonary hypertension.
`
`Deviations from the Protocol
`Two neonates assigned to the control group were
`treated with nitric oxide; both were included in the
`control group in an intention-to-treat analysis. There
`were 21 deviations from the protocol. In 12 neonates,
`an oxygenation index higher than 25 at base line was
`not documented adequately. Three neonates had par-
`tial pressures of arterial oxygen that were lower than
`30 mm Hg at base line and thus fulfilled the criteria
`for exclusion because of their urgent need for extra-
`corporeal membrane oxygenation. Two neonates did
`not have pulmonary hypertension. Four other neo-
`nates should not have been enrolled in the study, be-
`
`T
`
`ABLE
`
` 1.
`
`B
`
`ASE
`
`-L
`
`INE
`
` C
`
`HARACTERISTICS
`
`
`
`OF
`
`
`
`THE
`
` S
`TUDY
`
` S
`
`UBJECTS
`
`.*
`
`C
`HARACTERISTIC
`
`Prenatal care before third trimester —
`no. (%)
`Birth weight — kg
`Male sex — no. (%)
`Referred from another hospital —
`no. (%)
`Race or ethnic group — no. (%)
`Non-Hispanic black
`Hispanic
`Non-Hispanic white
`Primary pulmonary diagnosis — no. (%)
`Meconium aspiration syndrome
`Pneumonia
`Idiopathic pulmonary hypertension
`Respiratory distress syndrome
`Congenital diaphragmatic hernia
`Pulmonary hypoplasia
`Lung disease — no. (%)†
`None
`Mild
`Moderate
`Severe
`Air leak before enrollment — no. (%)
`Drugs used before enrollment —
`no. (%)
`Surfactant
`Sodium bicarbonate
`Vasopressors (dopamine, dobutamine,
`and epinephrine)
`Age at enrollment — hr
`
`C
`ONTROL
`G
`ROUP
`(N=122)
`
`N
` O
`XIDE
`ITRIC
`G
`ROUP
`(N=126)
`
`P
`V
`ALUE
`
`101 (83)
`
`116 (92)
`
`0.02
`
`3.3±0.6
`73 (60)
`83 (68)
`
`3.3±0.5
`60 (48)
`92 (73)
`
`41 (34)
`14 (11)
`67 (55)
`
`42 (34)
`26 (21)
`25 (20)
`11 (9)
`18 (15)
`0
`
`10 (8)
`31 (25)
`57 (47)
`24 (20)
`29 (24)
`
`49 (39)
`10 (8)
`67 (53)
`
`43 (34)
`26 (21)
`32 (25)
`11 (9)
`13 (10)
`1 (1)
`
`16 (13)
`33 (26)
`51 (40)
`26 (21)
`16 (13)
`
`52 (43)
`89 (73)
`109 (89)
`
`43 (34)
`97 (77)
`110 (87)
`
`0.59
`0.06
`0.38
`
`0.38
`
`0.80
`
`0.50
`
`0.03
`
`0.19
`0.47
`0.86
`
`28±17
`
`28±20
`
`0.77
`
`*Plus–minus values are means ±SD.
`†The severity of lung disease was determined on the basis of chest radi-
`ography. None indicates no radiographic signs of lung disease; mild indi-
`cates minimal streaky infiltrates or reticulogranular changes with easily vis-
`ualized borders of the heart and diaphragm; moderate indicates diffuse
`infiltrates or reticulogranular changes with obscure but visible borders of
`the heart and diaphragm; and severe indicates diffuse infiltrates with bor-
`ders of the heart and diaphragm that were difficult to visualize.
`
`cause they had congenital heart disease, seizures, an
`estimated gestational age of less than 34 weeks, or a
`lethal anomaly (an inoperable cystic hygroma).
`
`Primary Outcome
`The use of extracorporeal membrane oxygenation
`was less common in the nitric oxide group than in the
`control group (38 percent vs. 64 percent, P=0.001)
`(Table 3). This was true in all pulmonary diagnostic
`groups except neonates with congenital diaphrag-
`matic hernia (Table 4). In the neonates treated with
`extracorporeal membrane oxygenation, the median
`time from the start of treatment to the start of ex-
`tracorporeal membrane oxygenation was similar in the
`two groups (5 hours in the control group [range, 1 to
`86] and 9 hours in the nitric oxide group [range, 2 to
`150]). Eight neonates (three in the control group and
`
`Volume 342 Number 7
`
`·
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`471
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`The New England Journal of Medicine
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`Downloaded from nejm.org at REPRINTS DESK INC on October 22, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Ex. 2031-0003
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`The New England Journal of Medicine
`
`T
`
`ABLE
`
` 2.
`
`B
`
`ASE
`
`-L
`
`INE
`
` V
`
` S
`ENTILATORY
`S
`.*
`UBJECTS
`
`TATUS
`
`
`
`OF
`
`
`
`THE
`
` S
`
`TUDY
`
`
`
`N
` O
`XIDE
`ITRIC
`G
`ROUP
`(N=126)
`
`P
`V
`ALUE
`
`severe chronic lung disease. The other two neonates
`who died had contraindications to treatment with
`extracorporeal membrane oxygenation: one had un-
`controlled bleeding, and the other had an inopera-
`ble cystic hygroma.
`
`V
`ARIABLE
`
`Receiving high-frequency oscillation —
`no. (%)
`Receiving conventional mechanical
`ventilation — no. (%)
`
`FiO
`2
`Neonates assessed — no. (%)
`Mean value
`Peak pressure†
`Neonates assessed — no. (%)
`Mean value — cm of water
`Pressure amplitude‡
`Neonates assessed — no. (%)
`Mean value — cm of water
`Rate for high-frequency oscillation
`Neonates assessed — no. (%)
`Mean value — Hz
`Rate for conventional mechanical
`ventilation
`Neonates assessed — no. (%)
`Mean value — breaths/min
`Mean airway pressure
`High-frequency oscillation
`Neonates assessed — no. (%)
`Mean value — cm of water
`Conventional mechanical ventilation
`Neonates assessed — no. (%)
`Mean value — cm of water
`Arterial-blood gas values
`pH
`Neonates assessed — no. (%)
`Mean value
`PaO
`2
`Neonates assessed — no. (%)
`Mean value — mm Hg
`PaCO
`2
`Neonates assessed — no. (%)
`Mean value — mm Hg
`Oxygenation index§
`Neonates assessed — no. (%)
`Mean value
`
`C
`ONTROL
`G
`ROUP
`(N=122)
`
`72 (59)
`
`62 (49)
`
`46 (38)
`
`59 (47)
`
`118 (97)
`1.0±0.03
`
`125 (99)
`1.0±0.03
`
`46 (38)
`33±7
`
`69 (57)
`42±11
`
`70 (57)
`10±1
`
`59 (47)
`33±7
`
`62 (49)
`42±11
`
`62 (49)
`10±2
`
`0.10
`
`0.10
`
`0.64
`
`0.64
`
`0.94
`
`0.27
`
`46 (38)
`57±13
`
`59 (47)
`58±14
`
`0.63
`
`69 (57)
`20±4
`
`43 (35)
`16±3
`
`62 (49)
`20±4
`
`55 (44)
`15±4
`
`114 (93)
`7.44±0.1
`
`119 (94)
`7.45±0.1
`
`113 (93)
`58±42
`
`113 (93)
`36±12
`
`107 (88)
`41±21
`
`119 (94)
`72±64
`
`119 (94)
`35±13
`
`111 (88)
`37±24
`
`0.72
`
`0.21
`
`0.35
`
`0.05
`
`0.68
`
`0.17
`
`*Values are not included for neonates who were receiving manual venti-
`lation at base line or for whom blood gas values were obtained after the
` denotes fraction of inspired oxygen, PaO
` partial
`start of treatment. FiO
`2
`2
`pressure of arterial oxygen, and PaCO
` partial pressure of arterial carbon
`2
`dioxide. Plus–minus values are means ±SD.
`†These values are for neonates who were receiving conventional venti-
`lation.
`‡These values are for neonates who were receiving high-frequency oscil-
`lation.
`§The oxygenation index was calculated as the mean airway pressure
`times the fraction of inspired oxygen times 100, divided by the partial pres-
`sure of arterial oxygen.
`
`five in the nitric oxide group) met the criteria for ex-
`tracorporeal membrane oxygenation but did not re-
`ceive it. All survived to discharge, and chronic lung
`disease did not develop in any of them. Four neo-
`nates who were not treated with extracorporeal mem-
`brane oxygenation died. Two died after prolonged
`assisted ventilation; one of these neonates had ade-
`noviral bronchiolitis obliterans, and the other had
`
`472
`
`·
`
`Febr uar y 17, 2000
`
`Secondary Outcomes
`Twenty-three neonates died before discharge: 13
`in the control group and 10 in the nitric oxide group
`(P=0.82). There were no differences between the
`two groups in terms of the cause of death.
`After one hour of treatment, the ratio of arterial
`to alveolar oxygen increased more in the nitric oxide
`group than in the control group (by 0.10±0.14 vs.
`0.05±0.13, P=0.02). There was no difference be-
`tween the two groups with regard to ventilator set-
`tings, heart rate, mean blood pressure, or level of
`dopamine support during the first four hours of
`treatment.
`Thirty neonates had chronic lung disease (as de-
`termined by the need for supplemental oxygen at 30
`days). Nineteen neonates died before 30 days of age.
`In the group of 224 survivors for whom data were
`available, the incidence of chronic lung disease was
`lower in the neonates treated with nitric oxide than
`in the neonates in the control group (7 percent vs.
`20 percent, P=0.02).
`Among the survivors, there was no difference be-
`tween the two treatment groups with regard to age
`at discharge, age at extubation, or duration of extra-
`corporeal membrane oxygenation. Neurologic abnor-
`malities occurred at the same rate in the two groups
`(Table 3).
`The use of nitric oxide independently affected both
`the use of extracorporeal membrane oxygenation and
`the occurrence of chronic lung disease. A high oxy-
`genation index, assignment to the control group, and
`a diagnosis of congenital diaphragmatic hernia were
`all associated with the use of extracorporeal mem-
`brane oxygenation. The most important factor that
`affected the development of chronic lung disease was
`the diagnosis of congenital diaphragmatic hernia. The
`oxygenation index and the presence of an air leak
`before enrollment in the study were not independ-
`ent predictors of chronic lung disease.
`
`DISCUSSION
`We found that the administration of low doses of
`nitric oxide reduced the use of extracorporeal mem-
`brane oxygenation and decreased the need for sup-
`plemental oxygen at 30 days in neonates with hy-
`poxemic respiratory failure and persistent pulmonary
`hypertension. We stratified the neonates in both
`groups according to the diagnosis in order to assess
`the relative efficacy of treatment across diagnostic
`groups and to minimize the effect of underlying dis-
`ease as a confounding variable. Our results confirm
`the findings of the Neonatal Inhaled Nitric Oxide
`
`The New England Journal of Medicine
`
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`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Ex. 2031-0004
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`
`LOW-DOSE NITRIC OXIDE THERAPY FOR PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN
`
`TABLE 3. OUTCOME ANALYSIS.*
`
`T
`
`ABLE
`
` M
` E
`
` R
` R
` 4.
`EMBRANE
`XTRACORPOREAL
`OF
`ISK
`ELATIVE
`O
` A
`
` D
`.
`CCORDING
`XYGENATION
`TO
`IAGNOSIS
`
`
`
`CONTROL
`GROUP
`(N=122)
`
`NITRIC OXIDE
`GROUP
`(N=126)
`
`P
`VALUE
`
`D
`IAGNOSIS
`
`OUTCOME
`
`Received extracorporeal membrane
`oxygenation
`Intention-to-treat analysis —
`no./total no. (%)
`Neonates with no protocol
`violations — no./total no. (%)
`Died before 30 days of age — no. (%)
`Died before discharge — no. (%)
`Died before discharge or received
`extracorporeal membrane
`oxygenation — no. (%)
`Length of stay in the hospital for
`survivors
`Neonates assessed — no. (%)
`Mean no. of days
`Duration of assisted ventilation for
`survivors
`Neonates assessed — no. (%)
`Mean no. of days
`Pulmonary outcome in survivors
`Were receiving supplemental oxygen
`at 30 days — no./total no. (%)†
`Received supplemental oxygen
`after discharge — no./total
`no. (%)†
`Intraventricular hemorrhages (more
`than two) or infarct — no. (%)
`Seizures — no. (%)
`
`78/122 (64)
`
`48/126 (38)
`
`0.001
`
`74/116 (64)
`
`43/111 (39)
`
`0.001
`
`10 (8)
`13 (11)
`80 (66)
`
`9 (7)
`10 (8)
`50 (40)
`
`0.40
`0.82
`0.001
`
`104 (85)
`29±23
`
`113 (90)
`25±15
`
`0.09
`
`109 (89)
`12±10
`
`116 (92)
`11±7
`
`0.40
`
`22/110 (20)
`
`8/114 (7)
`
`0.02
`
`12/107 (11)
`
`6/113 (5)
`
`0.14
`
`8 (7)
`
`1 (1)
`
`4 (3)
`
`1 (1)
`
`0.34
`
`0.49
`
`*Plus–minus values are means ±SD.
`†Data were missing for five neonates (two in the control group and three
`in the nitric oxide group); these neonates were transported back to the re-
`ferring hospitals, so data were not available at 30 days.
`
`Study that nitric oxide is effective across a broad range
` The only exception was neonates with
`of diagnoses.
`20
`congenital diaphragmatic hernia, in whom nitric ox-
`ide did not reduce the use of extracorporeal mem-
`brane oxygenation or improve the outcome.
`21
`The most important difference between our trial
`and previous studies is that we used a low dose of in-
`haled nitric oxide for a limited amount of time (a max-
`imum of 96 hours). Other trials have used higher
`doses (80 ppm) for longer periods (as long as two
` By limiting the duration of treatment,
`weeks).
`19,20,22
`we hoped to avoid delaying extracorporeal mem-
`brane oxygenation beyond the point at which its ef-
`ficacy might be reduced. Our data, combined with
`the results of previous studies, suggest that this ap-
`proach is effective. In the Neonatal Inhaled Nitric
`Oxide Study, neonates who did not have a response
`to 20 ppm of nitric oxide rarely had a response to
`80 ppm.
` The median duration of successful treat-
`20
`ment in our study was 44 hours, and all but two ne-
`onates were weaned from nitric oxide by 96 hours.
`The potentially toxic effects of inhaled nitric oxide
`at high doses include decreased platelet aggregation,
`15
`
` R
`R
`ISK
`ELATIVE
`(95% CI)*
`
`E
`XTRACORPOREAL
` O
`M
`EMBRANE
`XYGENATION
` OXIDE
`CONTROL
`NITRIC
`GROUP
`GROUP
`=122)
`(
`(N=126)
`N
`
`no./total no. (%)
`
`Meconium aspiration syndrome 26/42 (62) 15/43 (35) 0.6 (0.3–0.9)
`Pneumonia
`18/26 (69)
`9/26 (35) 0.5 (0.3–0.9)
`Idiopathic pulmonary hyperten-
`9/25 (36)
`9/32 (28) 0.8 (0.3–1.9)
`sion
`Respiratory distress syndrome
`Congenital diaphragmatic
`hernia
`Pulmonary hypoplasia
`
`0
`
`0/1
`
`3/11 (27) 0.3 (0.1–0.9)
`9/11 (82)
`16/18 (89) 12/13 (92) 1.0 (0.8–1.2)
`
`*The relative risk is expressed as the risk of a need for extracorporeal
`membrane oxygenation in the group of neonates treated with nitric oxide
`as compared with the control group. CI denotes confidence interval.
`
`an increased risk of bleeding,
` acute lung injury
`23-25
`as a result of oxidant injury,
` and surfactant dys-
`26-29
`function.
` In our study, none of the neonates had
`30
`high concentrations of nitrogen dioxide, only two had
`high methemoglobin values, and nitric oxide was not
`associated with an increase in the occurrence of in-
`tracranial hemorrhages or chronic lung disease. In
`fact, nitric oxide was associated with a decrease in the
`occurrence of chronic lung disease.
`The strength of the association between treatment
`with nitric oxide and an improved pulmonary out-
`come is demonstrated by the fact that the associa-
`tion remained significant in multivariate and sub-
`group analyses. The reason for this improvement is
`unclear. One possibility is that inhaled nitric oxide
`reduces lung inflammation. Studies in animals sug-
`gest that inhaled nitric oxide may reduce the accu-
`mulation of neutrophils in the lung and the attend-
`ant inflammatory cascade that contributes to acute
` Another possibility is that nitric ox-
`lung injury.
`31-33
`ide reduces ventilator-induced lung injury by improv-
`ing gas exchange and reducing the intensity of re-
`quired ventilatory support.
`In conclusion, low-dose inhaled nitric oxide reduc-
`es the need for extracorporeal membrane oxygenation
`and reduces the occurrence of chronic lung disease in
`neonates with hypoxemic respiratory failure that does
`not result from congenital diaphragmatic hernia.
`
`Supported in part by a grant from INO Therapeutics.
`Dr. Clark has acted as a consultant to INO Therapeutics regarding the
`submission of data to the Food and Drug Administration. He is also the
`principal investigator for the grant that supported this study. Dr. Kinsella
`has acted as a consultant to INO Therapeutics regarding the submission of
`data to the Food and Drug Administration. Mrs. Huckaby has acted as a
`clinical research associate for INO Therapeutics in monitoring this study.
`
`Volume 342 Number 7
`
`·
`
`473
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at REPRINTS DESK INC on October 22, 2015. For personal use only. No other uses without permission