Randomized, Controlled Trial of Low-dose Inhaled Nitric Oxide in the
`Treatment of Term and Near-term Infants With Respiratory Failure and
`Pulmonary Hypertension
`
`David N. Cornfield, MD*; Roy C. Maynard, MD‡§; Raye-Ann O. deRegnier, MD‡§;
`Sixto F. Guiang III, MD‡; Joel E. Barbato, MD*; and Carlos E. Milla, MD*
`
`ABSTRACT. Recent reports indicate that inhaled nitric
`oxide (iNO) causes selective pulmonary vasodilation, in-
`creases arterial oxygen tension, and may decrease the use
`of extracorporeal membrane oxygenation (ECMO) in in-
`fants with persistent pulmonary hypertension of the
`newborn (PPHN). Despite these reports, the optimal dose
`and timing of iNO administration in PPHN remains un-
`clear.
`Objectives. To test the hypotheses that in PPHN 1)
`iNO at 2 parts per million (ppm) is effective at acutely
`increasing oxygenation as measured by oxygenation in-
`dex (OI); 2) early use of 2 ppm of iNO is more effective
`than control (0 ppm) in preventing clinical deterioration
`and need for iNO at 20 ppm; and 3) for those infants who
`fail the initial treatment protocol (0 or 2 ppm) iNO at 20
`ppm is effective at acutely decreasing OI.
`Study Design. A randomized, controlled trial of iNO
`in 3 nurseries in a single metropolitan area. Thirty-eight
`children, average gestational age of 37.3 weeks and aver-
`age age <1 day were enrolled. Thirty-five of 38 infants
`had echocardiographic evidence of pulmonary hyperten-
`sion. On enrollment, median OI in the control group,
`iNO at 0 ppm, (n ⴝ 23) was 33.1, compared with 36.9 in
`the 2-ppm iNO group (n ⴝ 15).
`Results.
`Initial treatment with iNO at 2 ppm for an
`average of 1 hour was not associated with a significant
`decrease in OI. Twenty of 23 (87%) control patients and
`14 of 15 (92%) of the low-dose iNO group demonstrated
`clinical deterioration and were treated with iNO at 20
`ppm. In the control group, treatment with iNO at 20 ppm
`decreased the median OI from 42.6 to 23.8, whereas in the
`2-ppm iNO group with a change in iNO from 2 to 20
`ppm, the median OI did not change (42.6 to 42.0). Five of
`15 patients in the low-dose nitric oxide group required
`ECMO and 2 died, compared with 7 of 23 requiring
`ECMO and 5 deaths in the control group.
`Conclusion.
`In infants with PPHN, iNO 1): at 2 ppm
`does not acutely improve oxygenation or prevent clinical
`deterioration, but does attenuate the rate of clinical de-
`terioration; and 2) at 20 ppm acutely improves oxygen-
`ation in infants initially treated with 0 ppm, but not in
`
`From the Divisions of *Pulmonary and Critical Care Medicine and ‡Neo-
`natology, Department of Pediatrics, University of Minnesota, Minneapolis,
`Minnesota; and §Children’s Hospitals and Clinics, Minneapolis, Minnesota.
`This work was presented in abstract form at the Society for Pediatric
`Research Meeting; May 2–6, 1997; Washington, DC.
`Received for publication Nov 23, 1998; accepted Apr 9, 1999.
`Address correspondence to David N. Cornfield, MD, Box 742, Division of
`Pediatric Pulmonology and Critical Care, University of Minnesota Medical
`School, 420 Delaware St SE, Minneapolis, MN 55455. E-mail: cornf001@
`maroon.tc.umn.edu
`PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad-
`emy of Pediatrics.
`
`infants previously treated with iNO at 2 ppm. Initial
`treatment with a subtherapeutic dose of iNO may dimin-
`ish the clinical response to 20 ppm of iNO and have
`adverse clinical sequelae. Pediatrics 1999;104:1089–1094;
`persistent pulmonary hypertension of the newborn, extra-
`corporeal membrane oxygenation, hypoxemia, respiratory
`failure, pulmonary vascular reactivity.
`
`ABBREVIATIONS. PPHN, persistent pulmonary hypertension of
`the newborn; iNO, inhaled nitric oxide; ECMO, extracorporeal
`membrane oxygenation; OI, oxygenation index; P/F, arterial par-
`tial pressure of oxygen/fraction of inspired oxygen; a/A, arterial/
`alveolar ratio; NO, nitric oxide; NO2, nitrogen dioxide.
`
`At birth, the pulmonary circulation changes
`
`dramatically. Pulmonary blood flow in-
`creases 8- to 10-fold and pulmonary arterial
`blood pressure decreases to less than half systemic
`levels in the first 24 hours of life.1 Although increased
`oxygenation, ventilation,2 establishment of an air-
`liquid interface,3 and elaboration of vasoactive me-
`diators4–6 have been shown to play a central role in
`modulating the transition of the pulmonary circula-
`tion, endothelium-derived nitric oxide (NO) produc-
`tion is necessary for the successful transition of the
`pulmonary circulation.7,8 If postnatal adaptation of
`the pulmonary circulation does not occur, a clinical
`syndrome, persistent pulmonary hypertension of the
`newborn (PPHN), results. PPHN is characterized by
`extrapulmonary shunting of blood and severe central
`hypoxemia that is not responsive to high concentra-
`tions of inspired oxygen.9 PPHN is often complicated
`by parenchymal lung injury, such as meconium as-
`piration, pneumonia, and surfactant deficiency, fur-
`ther compromising efforts to improve oxygenation.
`Effective treatment has been limited by the ab-
`sence of a selective pulmonary vasodilator. Intrave-
`nous vasodilator agents can cause nonselective vaso-
`dilation, resulting in worsening of intrapulmonary
`shunting10 or systemic hypotension. Recent studies
`have demonstrated that inhaled nitric oxide (iNO)
`causes selective and sustained pulmonary vasodila-
`tion in infants with PPHN. In 1992, 2 groups of
`investigators independently reported improved oxy-
`genation in infants with PPHN.11,12 Further studies
`have demonstrated that in infants with PPHN, iNO
`can decrease the need for more invasive and costly
`support modalities such as extracorporeal membrane
`oxygenation (ECMO).13,14
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`Although the use of iNO may contribute to the
`successful treatment of patients with severe PPHN,
`the optimal dose and timing of iNO administration
`has yet to be established. Experimental data supports
`the notion that the minimally effective dose of iNO
`should be used. For example, at high concentrations
`iNO can react with oxygen to form ONOO, which
`has been shown in vitro to cause surfactant destruc-
`tion.15 Exposure of NO to high concentrations of
`inspired oxygen can yield peroxynitrite, a potent
`oxidant
`that
`is capable of causing tissue injury
`through lipid peroxidation16 and potentiating lung
`injury.
`To determine the effects of low-dose iNO in the
`treatment of near-term infants with neonatal respira-
`tory failure compounded by pulmonary hyperten-
`sion, we conducted a randomized, controlled trial
`comparing iNO at 2 parts per million (ppm) with
`iNO at 0 ppm. We hypothesized that an acute im-
`provement in oxygenation would result with iNO
`treatment at 1) 2 ppm; and 2) 20 ppm. To test these
`hypotheses, we randomly assigned 38 infants with
`respiratory failure and pulmonary hypertension to
`receive iNO at 2 ppm or 0 ppm. Infants who did not
`improve with the initial assignment were subse-
`quently treated with iNO at 20 ppm.
`
`METHODS
`Organization and Eligibility Criteria
`Three clinical centers with experience in treating infants with
`PPHN participated in this trial. The study was approved by the
`institutional review board at each center. Criteria for enrollment
`included the following: infants ⱖ34 week’s gestation; ⬍7 days of
`age at the time of enrollment; severe respiratory failure requiring
`mechanical ventilation with an oxygenation index (OI) ⱖ25 on 2
`consecutive blood gases 60 minutes apart; (OI is calculated as
`follows: mean airway pressure ⫻ fraction of inspired oxygen ⫻
`100 ⫼ (divided by) the arterial partial pressure of oxygen, mea-
`sured from a postductal blood gas sample); echocardiographic
`evidence of pulmonary arterial hypertension (defined as right-to-
`left or bidirectional shunting at the ductus arteriosus or foramen
`ovale, or pulmonary artery pressure more than two thirds of
`systemic pressure as estimated Doppler measurement of the tri-
`cuspid regurgitation jet). Exclusion criteria included: the presence
`of lethal congenital anomalies; head ultrasound demonstrating
`grade III or IV intraventricular hemorrhage; neonates who present
`to the neonatal intensive care unit with hemodynamic collapse
`and require ECMO emergently; or major structural cardiac defect.
`
`Study Design
`At time of enrollment, all patients were ventilated with either a
`time-cycled, pressure limited neonatal ventilator or high fre-
`quency oscillatory ventilator. No attempt was made to control the
`mode of ventilation. However, no changes in mode of ventilation
`were permitted from 1 hour before study enrollment until a min-
`imum of 4 hours after enrollment in the study. Eligible patients
`with an OI ⱖ 25 were randomized in a nonblinded manner to
`receive either 2 parts per million ([ppm]; 2-ppm group) of NO or
`no NO (0-ppm group). Patients were randomized through a com-
`puter generated random-number table. The minimum period of
`time in this initial assignment was 1 hour. Patients with an OI ⱖ
`35 for⬎1 hour after enrollment were considered treatment failures
`and were treated with iNO at 20 ppm. Figure 1 is a schematic
`representation of the study design. Patients who presented with
`cardiovascular collapse were not enrolled in the study and were
`emergently treated with ECMO as determined by the attending
`physician.
`Arterial blood gas tensions and systemic arterial blood pres-
`sures were recorded at baseline, 30, and 60 minutes, at 2, 4, 6, 8, 12,
`and 24 hours, and every 12 hours for the duration of treatment in
`
`Fig 1. Schematic representation of the experimental design. Pa-
`tients with an oxygenation index ⬎25 were eligible. After enroll-
`ment, patients were randomized to receive either 0 or 2 ppm
`inhaled nitric oxide. Patients with an oxygenation index ⬎35 for
`⬎1 hour after being enrolled in the study were eligible to receive
`inhaled nitric oxide at 20 ppm and were considered treatment
`failures.
`
`all patients. The same measurements were obtained 1 hour after
`the initiation of iNO at 20 ppm. Methemoglobin levels were ob-
`tained at every 6 hours on the first day of the study and at least
`twice daily for the duration of the study.
`
`Sample Size and Data Analysis
`Sample size estimates and outcomes within each treatment
`category were based on pilot studies. It was estimated that 60
`patients would be required to provide an 80% power to detect at
`the 0.05 level a 60% difference in the failure rates between the
`treatment groups. As part of study monitoring, interim blinded
`analysis was planned to be performed on recruitment of two
`thirds of the projected sample size. The interim analysis was
`performed blindly by the investigator in charge of the data anal-
`ysis and trial monitoring (C.E.M.). This investigator had no in-
`volvement in the care of the patients. Based on this analysis, a
`decision was made to terminate the study early because significant
`differences were detected for response to 20 ppm of iNO depend-
`ing on the initial assignment. Secondary analyses of differences
`between the treatment groups were performed after study termi-
`nation.
`Data are presented as mean ⫾ SD for normally distributed
`variables and as median (rank) for those variables not normally
`distributed. To test for differences in characteristics at baseline
`between the treatment groups (0 ppm and 2 ppm), either the t test
`(normally distributed variables) or the Wilcoxon test (nonnor-
`mally distributed variables or ordinal variables) were used. Be-
`cause the main outcomes of interest (OI, arterial partial pressure of
`oxygen/fraction of inspired oxygen [P/F], and arterial to alveolar
`oxygen gradient (a/A ratio), were not normally distributed, re-
`sponses within each of the treatment groups were performed by
`the nonparametric sign test. For comparisons between the treat-
`ment groups in the responses seen, the data were analyzed by
`rank analysis of covariance, so as to control for the value of each
`variable of interest at baseline. To evaluate for differences between
`the treatment groups in time-to-event for different events consid-
`ered of importance, the log-rank test was used and Kaplan-Meier
`plots were generated. A significance level of 0.05 was used for all
`analyses.
`
`Monitoring
`The level of NO and nitrogen dioxide (NO2) delivered to the
`patient was monitored using either a chemiluminescent or an
`electrochemical analyzer and a microcomputer. The gas was sam-
`pled from the inspiratory limb of the ventilator circuit. Approxi-
`mately 150 mL/min of gas was drawn into the analyzer. A mi-
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`croprocessor monitored the function of the analyzer and triggered
`an alarm in the event of analyzer malfunction or if the levels of NO
`or NO2 were out of specified ranges. The computer recorded the
`levels of NO and NO2. On initiation of the study, continuous
`on-line monitoring was in place.
`
`RESULTS
`Comparability of Treatment Groups Based on Initial
`Assignment
`Data were analyzed from a total of 38 newborn
`infants enrolled in this trial. Clinical characteristics at
`enrollment for the study groups did not differ in
`terms of age, weight, severity of illness, duration of
`mechanical ventilation (Table 1), or diagnosis (Table
`2). There were no significant differences between the
`group randomized to treatment with 0 ppm of iNO
`(n ⫽ 23) and the group randomized to treatment
`with 2 ppm iNO (n ⫽ 15) in any of their baseline
`characteristics (all P ⬎ .1), an indication that the
`randomization procedure produced comparable
`treatment groups.
`
`Response to Initial Assignment
`After randomization, the OI, P/F, or a/A ratio did
`not change from baseline in either of the treatment
`groups (Fig 2). There was no significant difference
`between the treatment groups in the responses seen.
`Thus, treatment with iNO at 2 ppm did not induce
`any detectable acute effects. Of the 23 infants treated
`with 0 ppm of gas, 20 were considered treatment
`failures and progressed to treatment with 20 ppm of
`iNO. Of the 15 infants treated with 2 ppm of iNO, 13
`were considered treatment failures and progressed
`to treatment with 20 ppm of iNO. There was no
`statistically significant difference in the failure rate
`between the treatment groups. However, there was a
`marked difference between the treatment groups in
`the time elapsed to treatment failure (Fig 3), with all
`but 1 of the failures occurring before the second hour
`of treatment in the group treated with 0 ppm. The
`median time to treatment failure in the 0-ppm group
`was 1 hour compared with 2 hours in the 2 ppm
`group (P ⬍ .01).
`
`2 ppm NO
`(n ⫽ 15)
`15.6 (1–87)
`38.46 ⫾ 2.50
`10⬊5
`6 (1–8)
`8 (1–9)
`36.9 (25–91)
`0.068 (0.03–0.23)
`
`Characteristics of the Study Participants at the
`TABLE 1.
`Time of Enrollment Into the Study*
`0 ppm NO
`(n ⫽ 23)
`15.0 (1.8–113.3)
`37.57 ⫾ 2.39
`16⬊7
`6 (1–9)
`7 (1–10)
`33.9 (25–114)
`0.075 (0.04–0.13)
`
`Age (h)
`Gestational age (wk)
`Male⬊female
`1-minute Apgar
`5-minute Apgar
`Oxygenation index
`Arterial/alveolar
`oxygen ratio
`46 (21–151)
`48 (25–81)
`P/F
`9.0 (1–92)
`8.8 (1–77)
`Duration of ventilation (h)
`46%
`59%
`Surfactant treatment
`Abbreviation: P/F, arterial partial pressure of oxygen/fraction of
`inspired oxygen.
`* Values are expressed as the mean ⫾ SD or as the median (range).
`There was no difference between these groups in any of the
`measured parameters.
`
`TABLE 2.
`Study
`
`Diagnosis of Study Participants Enrolled Into the
`
`2 ppm NO
`0 ppm NO
`(n ⫽ 15)
`(n ⫽ 23)
`4
`4
`Respiratory distress syndrome
`3
`5
`Meconium aspiration syndrome
`1
`3
`Pneumonia
`2
`4
`Sepsis
`4
`5
`Congenital diaphragmatic hernia
`1
`2
`Idiopathic (PPHN)
`Abbreviation: PPHN, persistent pulmonary hypertension of the
`newborn.
`
`Response to 20 ppm After Failure of Initial Assignment
`The group initially treated with 0 ppm demon-
`strated a significant improvement in OI, P/F, and
`a/A ratio after the start of iNO at 20 ppm. In con-
`trast, oxygenation did not improve in the group ini-
`tially treated with 2 ppm (Fig 4). There was no acute
`improvement in oxygenation as assessed by OI, P/F,
`and a/A ratio. In the control group, treatment with
`iNO at 20 ppm resulted in a decrease of the median
`OI from 42.6 to 23.8 (P ⬍ .01), whereas in the 2-ppm
`iNO group with a change in iNO concentration from
`2 to 20 ppm, OI did not change (42.6 to 42.0; P ⫽ NS).
`The differences in the responses between the treat-
`ment groups were statistically significant for the 3
`variables measured (P ⫽ .01 for OI, P ⫽ .049 for P/F,
`P ⫽ .049 for a/A). Despite the initial response to iNO
`at 20 ppm in the 0-ppm iNO group, 5 infants pro-
`gressed to ECMO and 7 died. Of the infants initially
`treated with 2 ppm of iNO, 5 progressed to ECMO,
`and 2 died. There was no difference between the 2
`treatment groups with respect to the rate of progres-
`sion to ECMO or death (Fig 5). In addition, initial
`treatment with iNO at 2 ppm did not decrease the
`total duration of mechanical ventilation, the total
`number of hours on iNO at 20 ppm, or the total
`exposure to NO in dose-hours (all P ⬎ .1, compared
`with the control group).
`
`Adverse Events
`No acute adverse events were associated with iNO
`treatment. Methemoglobin levels were 0.8 ⫾.3% on
`enrollment, 0.9 ⫾ 0.4% after 1 hour, 1.3 ⫾ 0.5% at 6
`hours, and 1.3 ⫾ 0.4% at 24 hours. Methemoglobin
`levels were not different between study groups. In
`no patient was the study discontinued as the result of
`an elevated methemoglobin level. Chronic lung dis-
`ease (defined as oxygen requirement at 28 days of
`age) was 11% for the entire study group. There was
`no difference between study groups.
`
`DISCUSSION
`We report that in term and near term infants with
`respiratory failure and pulmonary hypertension,
`treatment with iNO at 2 ppm did not cause an acute
`improvement in oxygenation. iNO at 2 ppm had no
`acute effect on oxygenation and did not prevent clin-
`ical deterioration, but did attenuate the rate of clini-
`cal deterioration in these infants. The observation
`that iNO at 20 ppm caused an acute improvement in
`oxygenation is consistent with other reports in the
`literature.11–14 However, infants that had been ran-
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`Fig 2. Responses in oxygenation index seen in the treat-
`ment groups after randomization. After 1 hour of treat-
`ment, no significant changes in the median oxygenation
`index (bar) were seen in both groups, with no significant
`differences seen in the responses between the treatment
`groups (P ⬎ .1).
`
`Fig 3. Kaplan-Meier plot of the time to
`treatment failure for both the 0- and
`2-ppm treatment groups. There was a
`significant difference (P ⬍ .02) between
`the groups in their rate of clinical dete-
`rioration, with all but 1 of the patients
`initially treated with 0 ppm failing be-
`fore the second hour of treatment.
`
`domized to receive 2 ppm of iNO had no improve-
`ment in oxygenation after an increase in iNO to 20
`ppm. This observation is significant because it im-
`plies that administration of a subtherapeutic dose of
`iNO may adversely affect the clinical response to a
`therapeutic dose of iNO.
`Recent studies have demonstrated that iNO causes
`a significant improvement in oxygenation in some
`neonates with severe PPHN. Previous investigators
`have shown acute improvement in oxygenation us-
`ing iNO in doses ranging from 5 to 80 ppm.11,17,18 This
`is the first study to evaluate the effect of iNO at 2
`ppm. We chose to evaluate iNO at 2 ppm because
`there is data to suggest that the naturally occurring
`level of NO is in the parts per billion range.19 More-
`over, work in animal models of acute lung injury
`suggest that iNO at 2 ppm is sufficient to cause
`significant pulmonary vasodilation.20,21 Given the in
`vitro data that NO can cause surfactant destruction15
`and evidence that iNO can combine with oxygen to
`form molecules that can damage pulmonary epithe-
`lium,16,22 we attempted to determine the minimally
`effective dose of iNO.
`This study provides evidence that treatment with
`iNO at 2 ppm: 1) does not cause an acute improve-
`
`ment in oxygenation; and 2) may compromise the
`response to iNO at 20 ppm. Interestingly, although
`iNO at 2 ppm did not acutely improve oxygenation,
`it did attenuate the rate of clinical deterioration. This
`suggests that even in the absence of an acute effect on
`oxygenation, iNO at 2 ppm likely had a biological
`effect that was not directly demonstrated by the out-
`comes measured in this trial. iNO at 2 ppm might
`sufficiently stimulate
`the pulmonary vascular
`smooth muscle to prevent further pulmonary vaso-
`constriction, but insufficient to cause vasorelaxation.
`Although several previous studies have demon-
`strated that iNO at ⬎5 ppm acutely increases oxy-
`genation,26 this is the first to suggest that exposure to
`a subtherapeutic dose of iNO might diminish the
`efficacy of iNO at ⬎5 ppm. The observation that iNO
`at 20 ppm had no acute effect on oxygenation in the
`group initially randomized to receive iNO at 2 ppm;
`whereas the group of infants initially randomized to
`receive iNO at 0 ppm had a marked improvement in
`oxygenation may have significant clinical implica-
`tions. First, this data suggests that optimal iNO treat-
`ment in this patient population includes administra-
`tion of iNO at a dose that exceeds 2 ppm. Although
`further study is necessary to establish a minimum
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`Fig 4. Responses seen in the treatment failures in
`both groups after the administration of inhaled
`nitric oxide (iNO) at a dose of 20 ppm. A signifi-
`cant decrease in median oxygenation index (bars)
`occurred in the group initially treated with 0 ppm
`of iNO (P ⫽ .001), but not in the group initially
`treated with iNO at 2 ppm. The difference in the
`response between groups was significant (P ⬍
`.01).
`
`phate breakdown and diminished pulmonary vaso-
`dilation.24,25
`There was no difference in terms of outcome asso-
`ciated with the 2 treatment groups. The rate of fail-
`ure, defined as neonates having an OI ⬍35 1 hour
`after enrollment, was the same. There was no differ-
`ence between the 2 groups in terms of infants going
`on to ECMO or death. Whereas treatment with iNO
`at 2 ppm attenuated the acute response to iNO at 20
`ppm, it is not possible, based on the data presented
`in this study, to determine the degree, if any, that the
`biologic response to iNO was attenuated. It is impor-
`tant to note that this study was not designed to
`address the questions surrounding the efficacy of
`iNO relative to placebo. Another limitation of this
`study is that the clinicians caring for these children
`were aware of the initial assignment to the 0- or 2-
`ppm groups. To mitigate against this potential bias, a
`change in the mode of ventilation was not allowed
`during the initial 4 hours of the study. Interestingly,
`the conclusions of this study are unchanged even if
`infants with congenital diaphragmatic hernia are ex-
`cluded from the data analysis. This fact increases the
`likelihood that the present conclusions are biologi-
`cally relevant, as opposed to being the result of
`studying a nonrepresentative population.
`
`CONCLUSION
`In summary, this study provides evidence that
`iNO at 20 ppm causes an acute improvement in
`oxygenation in infants with PPHN. Although iNO at
`2 ppm may attenuate the rate of clinical deteriora-
`tion, it does not cause an acute improvement in
`oxygenation. Interestingly, infants receiving iNO at 2
`ppm have an attenuated response to the subsequent
`administration of iNO at 20 ppm. Although the rea-
`sons for the diminished response to iNO remain
`incompletely understood, this observation has im-
`portant implications for the treatment strategies used
`in the clinical treatment of infants with PPHN. Fur-
`ther studies are necessary to establish the minimal
`effective treatment dose of iNO in infants with
`PPHN and the physiologic alterations that underlie
`the attenuated response to iNO at 20 ppm in infants
`previously treated with iNO at 2 ppm.
`
`Fig 5. Kaplan-Meier plot of the time to extracorporeal membrane
`oxygenation or death, whichever occurred first, as a combined
`outcome for both the 0- and 2-ppm treatment groups. There was
`no significant difference in the experience of the 2 treatment
`groups with respect to progressing to either extracorporeal mem-
`brane oxygenation or death. (P ⫽ .5).
`
`threshold for effective iNO administration, the expe-
`rience of Finer and coworkers18 suggests that iNO at
`5 ppm may represent an acceptable minimum dose.
`Consideration of the reasons that underlie the di-
`minished response to 20 ppm of iNO after treatment
`with iNO at 2 ppm may provide insight into the
`physiologic effect of iNO in infants with PPHN. First,
`administration of a subtherapeutic dose of iNO may
`allow for increased production of a pulmonary va-
`soconstrictor agent such as endothelin. Because en-
`dothelin production is increased in infants in
`PPHN,5,6 it is possible that treatment with a subthera-
`peutic dose of iNO allows for enhanced production
`of an endogenous pulmonary vasoconstrictor agent.
`Alternatively, there is evidence suggesting that en-
`dogenous vasodilator activity may be decreased after
`prolonged exposure to iNO.23 Thus, administration
`of a subtherapeutic dose of iNO may attenuate the
`response of the pulmonary circulation to endothelial-
`derived vasodilator agents such as endogenous NO
`or prostacyclin. Finally, the attenuated response may
`be the result of altered phosphodiesterase activity in
`the pulmonary vascular smooth muscle, leading to
`accelerated rate of cyclic 3⬘,5⬘-guanosine monophos-
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`ACKNOWLEDGMENTS
`This work was supported by an American Heart Association
`Clinician Scientist Award (D.N.C.), the Viking Children’s Fund
`(D.N.C.), and the University of Minnesota Children’s Foundation
`(D.N.C.).
`We gratefully acknowledge the contributions of Allan Rozen-
`berg, MS; T. Alan Williams, RRT; and Michael Boyle, RRT. Pamela
`Vavra rendered invaluable assistance in the preparation of the
`manuscript.
`
`REFERENCES
`1. Rudolph A. Distribution and regulation of blood flow in the fetal and
`neonatal lamb. Circ Res. 1985;57:811–821
`2. Cassin S, Dawes GS, Mott JC, Ross BB, Strang LB. The vascular resis-
`tance of the fetal and newly ventilated lung of the lamb. J Physiol.
`1964;171:61–79
`3. Dawes GS, Mott JC, Widdicombe JG, Wyatt DG. Changes in the lungs
`of the newborn lamb. J Physiol Lond. 1953;121:141–162
`4. Leffler CW, Hessler JR, Green RS. The onset of breathing at birth
`stimulates pulmonary vascular prostacyclin synthesis. Pediatr Res. 1984;
`18:938–942
`5. Christou H, Adatia I, Van Marter LJ, et al. Effect of inhaled nitric oxide
`on endothelin-1 and cyclic guanosine 5⬘-monophosphate plasma con-
`centrations in newborn infants with persistent pulmonary hyperten-
`sion. J Pediatr. 1997;130:603–611
`6. Kumar P, Kazzi NJ, Shankaran S. Plasma immunoreactive endothelin-1
`concentrations in infants with persistent pulmonary hypertension of the
`newborn. Am J Perinatol. 1996;13:335–341
`7. Abman SH, Chatfield BA, Hall SL, McMurtry IF. Role of endothelium-
`derived relaxing factor during transition of pulmonary circulation at
`birth. Am J Physiol. 1990;259:H1921–H1927
`8. Cornfield D, Chatfield B, McQueston J, McMurtry I, Abman S. Effects of
`birth-related stimuli on L-arginine-dependent pulmonary vasodilation
`in ovine fetus. Am J Physiol. 1992;262:H1474–H1481
`9. Stenmark K, Abman SH, Accurso FJ: Etiologic mechanisms in persistent
`pulmonary hypertension of the newborn. In: Reeves, JT, Weir, EK, eds.
`Pulmonary Vascular Physiology and Pathophysiology. New York, NY: Mar-
`cel Dekker; 1989:355–402
`10. Radermacher P, Santak P, Becker H, Falke KJ: Prostaglandin E1 and
`nitroglycerin reduce pulmonary capillary wedge pressure but worsen
`V/Q distribution in patients with adult respiratory distress syndrome.
`Anesthesiology. 1989;70:601–609
`11. Kinsella JP, Neish SR, Shaffer E, Abman SH: Low-dose inhalational
`nitric oxide in persistent pulmonary hypertension of the newborn.
`
`Lancet. 1992;340:819–820
`12. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in
`persistent pulmonary hypertension of the newborn. Lancet. 1992;340:
`818–819
`13. Roberts JJ, Fineman J, Morin FC, et al. Inhaled nitric oxide and persis-
`tent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide
`Study Group. N Engl J Med. 1997;336:605–610
`14. Kinsella JP, Truog WE, Walsh WF, et al. Randomized, multicenter trial
`of inhaled nitric oxide in severe, persistent pulmonary hypertension of
`the newborn. J Pediatr. 1997;131:55–62
`15. Haddad I, Ischiropoulos H, Holm B, Beckman J, Baker J, Matalon S.
`Mechanisms of peroxynitrite-induced injury to pulmonary surfactants.
`Am J Physiol. 1993;265:L555–L564
`16. Radi R, Beckman JS, Bush KM, Freeman B: Peroxynitrite-induced mem-
`brane lipid peroxidation. Arch Biochem Biophys. 1991;288:481–487
`17. Hoffman GM, Ross GA, Day SE, Rice TB, Nelin LD. Inhaled nitric oxide
`reduces the utilization of extracorporeal membrane oxygenation in
`persistent pulmonary hypertension of the newborn. Crit Care Med.
`1997;25:352–359
`18. Finer NN, Etches PC, Kamstra B, Tierney AJ, Peliowski A, Ryan CA.
`Inhaled nitric oxide in infants referred for extracorporeal membrane
`oxygenation: dose response. J Pediatr. 1994;124:302–308
`19. Leone AM, Gustafsson LE, Francis PL, Persson MG, Wiklund NP,
`Moncada S. Nitric oxide is present in exhaled breath in humans: direct
`GC-MS confirmation. Biochem Biophys Res Commun. 1994;201:883–887
`20. Ogura H, Cioffi WG, Jordan BS. The effect of inhaled NO on smoke
`inhalation injury in an ovine model. J Trauma. 1994;37:294–302
`21. Ogura H, Cioffi WG, Offner PJ. The effect of inhaled NO on pulmonary
`function following sepsis in an ovine model. Surgery. 1994;116:315–321
`22. Matalon S, DeMarco V, Haddad IY, Myles C, Skimming JW, Schurch
`SC. Inhaled nitric oxide injures the pulmonary surfactant system of
`lambs in vivo. Am J Physiol. 1996;270:L273–L280
`23. Oka M, Ohnishi M, Takahashi H, et al. Altered vasoreactivity in lungs
`isolated from rats exposed to nitric oxide gas. Am J Physiol. 1996;271:
`L419–L424
`24. Ziegler JW, Ivy DD, Fox JJ, Kinsella JP, Clarke WR, Abman SH: Dipy-
`ridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary va-
`sodilation in the ovine fetus. Am J Physiol. 1995;269:H473–H479
`25. Kinsella JP, Torielli F, Ziegler JW, Ivy DD, Abman SH. Dipyridamole
`augmentation of response to nitric oxide. Lancet. 1995;346:647–648.
`Letter
`26. Davidson D, Barefield ES, Kattwinkel J, et al. 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. Pediatrics. 1998;101:325–334
`
`ADAM SMITH FAILS IN ALLOCATION OF HEALTH CARE
`
`Our failure [as physicians] to seek common ground with our patients allowed
`investors and managers to take charge of the [US] health care system. There is
`simply no way for us to defend patient care, teaching, and research if we join battle
`with the entrepreneurs on their turf and on their terms. Simply put, health as a
`social good cannot be allocated effectively by the invisible hand of the market.
`
`Eisenberg L. Where is the voice of the faculty? Talk given before the American Association of University
`Professors, May 22, 1999
`
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