PEDIATRICS Vol. 106 No. 6 December 2000, pp. 1339-1343

Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO): How New Treatment Modalities Have Affected ECMO Utilization

Susan R. Hintz, MD^*, Denise M. Suttner, MD, Arlene M. Sheehan, MS, NNP^*, William D. Rhine, MD^*, and Krisa P. Van Meurs, MD^*

From the ^* Department of Pediatrics, Division of Neonatal Medicine, Stanford University, Stanford, California; and  Division of Neonatology, San Diego Children's Hospital, San Diego, California.

	ABSTRACT

Top Abstract Methods Results Discussion References

Objective:  Over the last decade, several new therapies, including high-frequency oscillatory ventilation (HFOV), exogenous surfactant therapy, and inhaled nitric oxide (iNO), have become available for the treatment of neonatal hypoxemic respiratory failure. The purpose of this retrospective study was to ascertain to what extent these modalities have impacted the use of neonatal extracorporeal membrane oxygenation (ECMO) at our institution.

Methods.  Patients from 2 time periods were evaluated: May 1, 1993 to November 1, 1994 (group 1) and May 1, 1996 to November 1, 1997 (group 2). During the first time period (group 1), HFOV was not consistently used; beractant (Survanta) use for meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), and pneumonia was under investigation; and iNO was not yet available. During the second time period (group 2), HFOV and beractant treatment were considered to be standard therapies, and iNO was available to patients with oxygenation index (OI) 25 × 2 at least 30 minutes apart, or on compassionate use basis. Patients were included in the data collection if they met the following entry criteria: 1) OI >15 × 1 within the first 72 hours of admission; 2) EGA 35 weeks; 3) diagnosis of MAS, PPHN or sepsis/pneumonia; 4) <5 days of age on admission; and 5) no congenital heart disease, diaphragmatic hernia, or lethal congenital anomaly.

Results.  Of the 49 patient in group 1, 21 (42.8%) required ECMO therapy. Of these ECMO patients, 14 (66.6%) had received diagnoses of MAS or PPHN. Only 3 of the patients that went on to ECMO received beractant before the initiation of bypass (14.3%). All ECMO patients in group 1 would have met criteria for iNO had it been available. Of all patients in group 1, 18 (36.7%) were treated with HFOV, and 13 (26.5%) received beractant. Of the 47 patients in group 2, only 13 (27.7%) required ECMO therapy (compared with group 1). Of these ECMO patients, only 5 (38.5%) had diagnoses of MAS or PPHN, with the majority of patients (61.5%) requiring ECMO for sepsis/pneumonia, with significant cardiovascular compromise. Only 5 of these ECMO patients, all outborn, did not receive iNO before cannulation because of the severity of their clinical status on admission. Of all patients in group 2, 41 (87.2%) were treated with HFOV (compared with group 1), 42 (89.3%) received beractant (compared with group 1), and 18 (44.7%) received iNO.

Conclusions.  The results indicate that ECMO was used less frequently when HFOV, beractant and iNO was more commonly used. The differences in treatment modalities used and subsequent use of ECMO were statistically significant. We speculate that, in this patient population, the diagnostic composition of neonatal ECMO patients has changed over time.  Key words:  high-frequency oscillatory ventilation, exogenous surfactact therapy, inhaled nitric oxide, extracorporeal membrane oxygenation.

Respiratory failure remains a major cause of morbidity and mortality in the neonatal population. Following the 1982 report by Bartlett et al¹ that infants with hypoxemic respiratory failure had an increased survival with extracorporeal membrane oxygenation (ECMO), the use of this therapeutic modality increased dramatically. Meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), and pneumonia/sepsis are still important noncardiac diagnoses associated with initiation of ECMO in the neonate (Extracorporeal Life Support Organization [ELSO] Registry, July 1999). Other treatment options previously were limited to inotropic support, conventional ventilatory management, respiratory alkalosis, paralysis and intravenous vasodilators that caused significant systemic effects. Additional adjuvant therapies for profound neonatal respiratory failure, however, have become available in recent years and include high-frequency oscillatory ventilation (HFOV), surfactant, and inhaled nitric oxide (iNO). HFOV has been advocated for use to improve lung inflation while potentially decreasing lung injury through volutrauma.² Some clinical studies suggest that this ventilatory strategy is more effective for the treatment of severe neonatal respiratory failure,^3,4 and others report enhanced efficacy when combined with iNO in certain diagnostic categories.^5,6 Subsequent to studies reporting surfactant deficiency or inactivation may contribute to neonatal respiratory failure,^7,8 exogenous surfactant therapy has been implemented with apparent success. Recent studies have shown clinical improvement, including a reduction in the need for ECMO, with institution of exogenous surfactant therapy.^9-11 From the time that iNO was reported to cause pulmonary vascular relaxation without systemic hypotension in animal models,^12,13 it has been the subject of intense clinical research. Recent studies have shown that iNO therapy in the neonate with hypoxemic respiratory failure can result in improved oxygenation and decreased need for ECMO.^14-16 HFOV, surfactant and iNO are now widely available both in neonatal ECMO centers, and in other neonatal intensive care units (NICU). Interestingly, total annual neonatal ECMO cases for respiratory failure have decreased from a peak of 1510 cases in 1992, to 786 cases in 1998.¹⁷ Therefore, examination of changing treatment practices and subsequent ECMO use in the neonatal population is of importance.

The purpose of this retrospective study was to evaluate changes in treatment modalities, and to ascertain whether the diagnostic composition of neonatal ECMO patients has changed concomitantly. We compared the usage of neonatal ECMO for MAS, PPHN, and pneumonia/sepsis at our institution during 2 time periods, May 1, 1993 to November 1, 1994 (group 1) and May 1, 1996 to November 1, 1997 (group 2), as well as the treatment interventions used for management during those periods. We also attempted to uncover any changes in ECMO patient diagnostic categories between the time periods, and the severity of illness within those populations.

	METHODS

Top Abstract Methods Results Discussion References

Patient Selection

Data were collected by retrospective chart review. Patients from 2 time periods were evaluated: May 1, 1993 to November 1, 1994 (group 1) and May 1, 1996 to November 1, 1997 (group 2). Patients were included in the study groups provided that they met the following criteria:

1. Oxygenation index (OI) >15 at least once during the first 72 hours of admission;
2. gestational age 36 weeks;
3. diagnosed with MAS, PPHN, or pneumonia/sepsis;
4. <5 days of age on admission to our institution; and
5. absence of congenital heart disease, diaphragmatic hernia, or lethal congenital anomaly.

During the first time period (group 1), HFOV was not consistently used at our center; the use of beractant for MAS, PPHN and pneumonia was under study at our institution and others as part of a multi-center trial; and iNO was not yet available. During the second time period (group 2), HFOV and beractant treatment were considered to be standard therapies for the above diagnoses, and iNO was available to patients with OI 25 × 2 at least 30 minutes apart.

Ventilatory Management

For all patients reviewed, management involved maintaining optimal PaO₂ while minimizing barotrauma and fraction of inspired oxygen (FIO₂). Initial ventilatory management was usually undertaken with conventional mechanical ventilators with conversion to HFOV (SensorMedics) if tidal expansion, gas exchange or oxygenation could not be achieved. The ultimate goal of this type of ventilation was to optimize lung inflation to 9 to 10 ribs, subsequently documented by serial chest radiographs. Other types of high frequency ventilation, specifically jet ventilation or high-frequency flow interruption, were not implemented.

Beractant Treatment

Use of beractant (Survanta) therapy in the treatment of MAS, PPHN, and sepsis/pneumonia was under investigation at our institution as part of a double-blinded, randomized, multi-center trial beginning November 23, 1992; the study was in progress during the group 1 study period, but was closed by the beginning of the group 2 study period. However, use of beractant for these disease entities was undertaken outside of the beractant study parameters during the group 1 study period at the neonatologist's discretion. At the time of our retrospective chart review, beractant treatment from group 1 patients had been unmasked, and therefore data regarding treatment of these patients could be collected. Beractant therapy was used routinely in our institution for the treatment of neonatal respiratory failure after the completion of the multicenter trial demonstrating a reduction in the need for ECMO in the surfactant-treated infant.⁹

iNO Protocol

Open label iNO became available at our institution on May 1, 1996 after results of a previous randomized trial of iNO in infants with hypoxemic respiratory failure revealed a reduction in the need for ECMO.¹⁴ Inhaled NO was administered through the granting of an IND Protocol (#45 264) from the Food and Drug Administration, and by approval of this protocol by the Institutional Review Board of Stanford University. Criteria for initiation of iNO for pulmonary hypertension at that time included: 1) signed informed consent; 2) echocardiogram performed before initiation; 3) OI 25 × 2 at least 30 minutes apart (OI = mean airway pressure × FIO₂ × 100/PaO₂), with initiation of NO within 15 minutes of second arterial blood gas; and 4) gestational age 34 weeks. Nitric oxide was then administered by a protocol that required initiation of iNO at 20 parts per million (ppm), then increasing to 80 ppm or remaining at 20 ppm depending on response to the gas. Weaning from iNO was also undertaken by a protocol defining specific parameters.

ECMO Eligibility

Eligibility criteria guidelines for neonatal ECMO included: 1) weight >2000 g; 2) gestational age 34 weeks; 3) absence of intraventricular hemorrhage grade II; 4) absence of uncorrectable coagulopathy; 5) decision made to provide full intensive care support; 6) absence of cyanotic heart disease; and 7) failure of maximal medical intervention. It is important to note that individual clinical situations were considered when making a decision regarding ECMO cannulation.

Patient Data and Statistical Analysis

Gestational age, age at admission, demographic, clinical, therapeutic, and outcome data were collected on all patients. Comparison of interval parameters between groups 1 and 2 was made by 2-tailed Student's t test. Differences in ordinal therapeutic interventions and clinical outcomes were analyzed using the ² test or Fisher's exact test. Differences were considered statistically significant at P < .05.

	RESULTS

Top Abstract Methods Results Discussion References

In group 1 (May 1993 to November 1994), 49 patients were identified by chart review who met criteria for inclusion in this study. In group 2 (May 1996 to November 1997), 47 patients met inclusion criteria. Several demographic and diagnostic descriptors were evaluated to assess whether these groups were statistically similar (Table 1). Age at admission to our NICU was the same (0.84 ± 0.92 in group 1 vs 0.82 ± 1.02 in group 2), as was gender distribution (31 males in group 1 vs 30 in group 2). Gestational age was statistically similar (39.42 ± 1.65 weeks in group 1 vs 38.94 ± 2.02 weeks in group 2) and diagnostic distribution was also approximately the same (with 35% of infants diagnosed with pneumonia/sepsis in group 1 vs 45% in group 2).

Overall ECMO use decreased significantly in this particular patient population between the time periods defined by groups 1 and 2 (Table 2). In group 1, 21 of the 49 patients required ECMO therapy (42.8%) whereas in group 2, only 13 of the 47 patients required ECMO (27.6%) (P < .001 compared with group 1). Concomitantly, there was a significant difference seen in the treatment modalities employed between the 2 groups. Of all patients in group 1, 18 (36.7%) were treated with HFOV, and 13 (26.5%) received beractant. Of all patients in group 2, 41 (87.2%) were treated with HFOV (P < .001 compared with group 1) and 42 (89.3%) received beractant (P < .001 compared with group 1). Eighteen of the 47 patients in group 2 (44.7%) received iNO. Death rates were virtually identical between groups 1 and 2, with a total of 4 deaths in each group (Table 2). In group 1, 1 death was in an infant who did not receive ECMO, but had suffered significant ischemic hypoxic injury; the remaining 3 (2 with pneumonia/sepsis and 1 with PPHN) had been placed emergently on ECMO, then were found to have sustained severe ischemic hypoxic insult leading to significant neurological findings or multisystem organ failure. In group 2, 3 of the deaths were in infants who did not receive ECMO; 1 in an infant whose parents refused the procedure, and the other 2 in infants who had been diagnosed with severe encephalopathy by clinical and electroencephalographic findings. The remaining death in group 2 was in an infant who had been placed emergently on ECMO, then was later found to have severe and irreversible multisystem organ failure.

Within group 1, all patients who went on to ECMO (21 patients, or 42.8% of group 1) would have qualified for iNO by the criteria used during 1996-1997. Three patients were placed on ECMO directly after transport from outside hospitals with cardiopulmonary resuscitation in progress. OI calculations for these patients were therefore based on bag ventilation pressures. Of the ECMO patients within group 2, all 13 (27.7%) would have qualified for iNO therapy; however, 5 did not receive iNO before cannulation because of overwhelming shock or rapidly worsening respiratory failure that was judged to be imminently life-threatening, requiring immediate placement on bypass.

Nineteen of the 28 patients (67.9%) who did not require ECMO in group 1 would have qualified for iNO therapy by the 1996-1997 criteria. Of those 34 patients in group 2 who did not require ECMO, only 13 (38.2%) qualified for and received iNO therapy (P < .025 compared with iNO-qualified, non-ECMO patients in group 1).

Of the ECMO patients in group 1, 33.3% had diagnoses of sepsis/pneumonia, whereas of the ECMO patients in group 2, 61.5% had diagnoses of sepsis/pneumonia, although the actual number of patients with this diagnosis was the same in each group (7 vs 7) (Table 3). Thus, there seemed to be a difference in the diagnostic composition of ECMO patients in group 1 compared with group 2, indicating a trend toward fewer MAS and PPHN patients (66.6% vs 38.5%) over time. However, power analysis revealed that 64 members in each group would have been required to have a 90% chance of detecting a difference between these 2 numbers with a P < .05. The worst OI attained by each patient in the ECMO groups was also calculated (Table 3), and was found to be statistically similar (P = .1, NS), suggesting that the use of iNO did not delay the initiation of ECMO.

	DISCUSSION

Top Abstract Methods Results Discussion References

The central finding of this retrospective study examining therapeutic and outcome variables in infants >36 weeks EGA with diagnoses of MAS, PPHN or pneumonia and OI  15, was that ECMO was required significantly less frequently in the more recent time period when HFOV, beractant and iNO were consistently used therapies (42.7% vs 27.7%). These findings are similar to those of Kennaugh et al, who also found decreased neonatal ECMO use over time.¹⁸ As a corollary, we found that differences in treatment modalities used, specifically HFOV and beractant, were also statistically significant between the 2 retrospective study groups, with iNO not available at all during the first time period. These findings are important in determining the probable reasons for the changing use and composition of the neonatal ECMO population,¹⁹ but not surprising, given the findings of previous randomized control studies that have examined the effects of each of these therapeutic modalities on oxygenation or ECMO use.^3,9,20 Although prospective analysis, with only 1 independent variable or treatment modality, is ideal in scientific investigation, it is not possible in most clinical situations. The study by Davidson et al,²⁰ which attempted to independently assess the effect of iNO as the only adjuvant therapy in the management of PPHN, was successful in demonstrating acute and improved oxygenation, yet it was necessary to halt the study earlier than expected resulting from rapidly decreasing enrollment. Because of the increased use of adjuvant therapies, it is likely that any further randomized, control studies that strive to tease out the best of these treatments, or to what extent each contributes to improved oxygenation, will also suffer from extremely low enrollment, thereby leading to an inability to make meaningful conclusions. Given the current widespread use and apparent benefit of combined adjuvant therapies for neonatal respiratory failure, a randomized, control trial of each treatment modality would be neither advisable nor possible.

We further attempted to define changes during these time periods by ascertaining which group 1 patients would have qualified for iNO therapy by criteria used for group 2. We found that of the group 1 infants who went on to require ECMO, all would have been eligible for iNO. This finding, of course, does not suggest that all of these patients would have been spared ECMO if iNO had been available. In 3 cases in group 1, for example, the infants were in extremis, and ECMO was emergently implemented. In fact, clinical scenarios such as cardiovascular collapse in patients in group 2, when iNO was available, led to ECMO cannulation without use of iNO. Interestingly, when analyzing patients who did not require ECMO during the 2 time periods, those in group 2 qualified for iNO significantly less frequently than did those in group 1. We speculate that the increased use of HFOV and beractant during the group 2 period was responsible for an improvement in oxygenation parameters in this non-ECMO group over time. This study was not designed to answer subsequent questions, and patient numbers in these subgroups were small, however this finding suggests further investigations. It is not known, for example, whether these non-ECMO patients who qualified for, but did not receive iNO, would be different from later non-ECMO patients who had the benefit of iNO in terms of baro- or volutrauma, potential oxygen toxicity, or days to discharge.¹⁹ An alternative view, considering the complex biochemical properties of which nitric oxide is apparently capable, would be that iNO therapy, particularly in combination with high FIO₂ could lead to significant tissue injury.^20-22 Further long-term comparative studies are warranted to discover to what extent iNO therapy affects eventual patient outcome.²³

It has been reported that ECMO duration and rates of complications have increased in recent years, leading to speculation that use, or misuse, of alternate treatment modalities may be in part to blame.¹⁹ Further, it has been suggested that adjuvant therapies such as HFOV, exogenous surfactant therapy and iNO may cause a delay to ECMO for some patients. This concern does not seem to be substantiated by the present study. Although patient numbers were small, worst oxygenation indices in the ECMO patients in both groups 1 and 2 were analyzed and compared. In this retrospective analysis, we found that the worst OIs in the ECMO group 1, when HFOV and beractant were used less frequently and iNO was not available, were statistically similar to the worst OIs in ECMO group 2, when these treatment modalities were available and frequently used. This would lead to the conclusion that infants of similar severity of illness were placed on ECMO, regardless of other therapies available.

Furthermore, death rates between the 2 groups were comparable, although again, the present study is a single institution retrospective analysis. Of the infants who did expire but were not placed on ECMO before death, it is likely that none would have had a favorable long-term outcome; ECMO therapy could not have reversed or ameliorated the underlying clinical situation; and the decision not to provide ECMO was therefore well considered (see "Results"). Similarly, a trend in the diagnostic composition of the neonatal ECMO population in our institution seems to have changed over time, with fewer MAS and PPHN patients, likely attributable to the concentration of the most severely affected infants who did not respond to other therapies. This is not an unexpected finding, as treatment modalities such as HFOV and iNO, alone or in combination, may be disease-specific in the extent to which they improve oxygenation.^6,26 It is likely, therefore, that infants with respiratory failure in specific diagnostic categories more amenable to pre-ECMO therapies will be managed by ECMO increasingly less frequently.

With new therapies, however, come new responsibilities. Risks and benefits of each new treatment must be investigated and weighed, and appropriate implementation of each therapy must be required. It is likely that earlier use of some of these adjuvant therapies is indicated, particularly for certain disease processes.^6,26 Exogenous surfactant therapy in the term infant with respiratory failure may be most efficacious in less severely ill patients,⁹ thus early treatment may be a key component to its ultimate benefit. Similarly, it has been suggested that iNO may be more successful if implemented earlier in the clinical process,²⁷ and a multicenter randomized control trial is underway to test this hypothesis. Therapies in combination could exponentially improve the benefit afforded by 1 therapy alone,^28,29 and further investigations into appropriate application of these combined therapies is warranted. Despite the excitement created by therapies that may improve patient outcomes, caution is required in their usage. Recent studies have focused further attention on the mechanism of action of iNO even in patients thought to be treatment failures, raising questions regarding the safety of initiation of this therapy in a center where ECMO cannot be offered, and of transport to an ECMO facility if iNO cannot be continued en route.³⁰ The danger exists that complacency as to the effectiveness of these relatively new therapies will lead to poorly controlled, widespread promulgation of these therapies. Even under the most skilled care, therapies such as HFOV, surfactant and iNO may not improve a rapidly failing critically ill infant; if that infant happens to be at a distant, non-ECMO site, a potentially life-saving therapy may come too late.

	FOOTNOTES

Received for publication Oct 26 1999; accepted Mar 21 2000.

Reprint requests to (S.R.H.) Division of Neonatal and Developmental Medicine, Stanford University, 750 Welch Rd, Suite 315, Palo Alto, CA 94304.

	ABBREVIATIONS

ECMO, extracorporeal membrane oxygenation; MAS, meconium aspiration syndrome; PPHN, persistent pulmonary hypertension of the newborn; ELSO, Extracorporeal Life Support Organization; HFOV, high-frequency oscillatory ventilation; iNO, inhaled nitric oxide; NICU, neonatal intensive care unit; OI, oxygenation index; FIO₂, fraction of inspired oxygen; ppm, parts per million.

	REFERENCES

Top Abstract Methods Results Discussion References

1. Bartlett RH, Andrews AF, Toomasian JM, et al. Extracorporeal membrane oxygenation for newborn respiratory failure: 45 cases. Surgery. 1982; 92:425-433 [Medline]
2. Clark RH High frequency ventilation. J Pediatr. 1994; 124:661-670 [CrossRef][Medline]
3. Clark RH, Yoder BA, Sell MS Prospective, randomized comparison of high-frequency oxygenation. J Pediatr. 1994; 124:447-454 [CrossRef][Medline]
4. Varnholt V, Lasch P, Suske G High frequency oscillatory ventilation and extracorporeal membrane oxygenation in severe persistent pulmonary hypertension of the newborn. Eur J Pediatr. 1992; 151:769-774 [CrossRef][Medline]
5. Kachel W, Varnholt V, Lasch P, Muller W, Lorenz C, Wirth H High-frequency oscillatory ventilation and nitric oxide: alternative or complementary to ECMO. Int J Artif Organs. 1995; 18:589-597 [Medline]
6. Kinsella JP, Abman SH Inhaled nitric oxide and high frequency oscillatory ventilation in persistent pulmonary hypertension of the newborn. Eur J Pediatr. 1998; 157:S28-S30
7. Bae CW, Takahashi A, Chida S, Sasaki M Morphology and function of pulmonary surfactant inhibition by meconium. Pediatr Res. 1998; 44:187-191 [Medline]
8. Lotze A, Whitsett JA, Kammerman LA Surfactant protein A concentrations in tracheal aspirate fluid from infants requiring extracorporeal membrane oxygenation. J Pediatr. 1990; 116:435-440 [CrossRef][Medline]
9. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH Multicenter study of surfactant (beractant) in treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr. 1998; 132:40-47 [CrossRef][Medline]
10. Auten RL, Notter RH, Kendig JW Surfactant treatment of full-term newborns with respiratory failure. Pediatrics. 1991; 87:101-107 [Abstract/Free Full Text]
11. Marks SD, Nicholl RM The reduction in the need for ECMO by using surfactant in meconium aspiration syndrome. J Pediatr. 1999; 135:267-268 [Medline]
12. Pepke Zaba J, Higenbottam TW, Dinh Xuan AT, Stone D, Wallwork J Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet. 1991; 338:1173-1174 [CrossRef][Medline]
13. DeMarco V, Skimming J, Ellis TM, Cassin S Nitric oxide inhalation: effect of the ovine neonatal pulmonary and systemic circulations. Chest. 1994; 105:91S-2S
14. Neonatal Inhaled Nitric Oxide Study: Inhaled NO in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997;336:597-604
15. Kinsella JP, Kneish SR, Ivy DD, Shaffer E, Abman SH Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr. 1993; 123:103-108 [CrossRef][Medline]
16. Wessel DL, Adatia I, Van Marter LJ, et al. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics. 1997;100(5). URL: http://www.pediatrics.org/cgi/content/full/100/5/e7
17. ECMO Registry of the Extracorporeal Life Support Organization (ELSO). Ann Arbor, MI: ELSO; July 1999
18. Kennaugh JM, Kinsella JP, Abman SH, Hernandez JA, Moreland SG, Rosenberg AA Impact of new treatments for neonatal pulmonary hypertension on extracorporeal membrane oxygenation use and outcome. J Perinatol. 1997; 17:266-269 [Medline]
19. Wilson JM, Bower LK, Thompson JE, Fauza DA, FacklerJC: ECMO in evolution: The impact of changing patient demographics and alternative therapies on ECMO J Pediatr Surg. 1996; 31:1116-1123 [CrossRef][Medline]
20. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang C, .-T., I-NO/PPHN Study Group 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; 101:325-332 [Abstract/Free Full Text]
21. Schindler MB Strategies to prevent chronic neonatal lung disease. J Paediatr Child Health. 1996; 32:477-479 [Medline]
22. Kooy NW, Royall JA, Ye YZ Peroxynitrite is produced during human ARDS. Am J Respir Crit Care Med. 1995; 151:1250-1254 [Abstract]
23. Gordge MP How cytotoxic is nitric oxide? Exp Nephrol. 1998; 6:12-16 [CrossRef][Medline]
24. Wink DA, Mitchell JB Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Rad Biol Med. 1998; 25:434-456 [CrossRef][Medline]
25. Rosenberg AA, Kennaugh JM, Moreland SG, Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. J Pediatr. 1997; 131:70-75 [CrossRef][Medline]
26. Mercier J, .-C., Lacze T, Storme L, Roze J.-C., Tuan Dinh-Xuan A, Dehan M, the French Paediatric Study Group of Inhaled NO Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure. Eur J Pediatr. 1998; 157:747-752 [CrossRef][Medline]
27. Lonnqvist PA, Winberg P, Lundell B, Sellden H, Olsson GL Inhaled nitric oxide in neonates and children with pulmonary hypertension. Acta Pediatr. 1994; 83:1132-1136 [Medline]
28. Kinsella JP, AbmanSH: High-frequency oscillatory ventilation augments the response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn: Nitric Oxide Study Group Chest 1998; 114:100S [Free Full Text]
29. Kinsella JP, Parker TA, Galan H, Sheridan BC, Abman SH Independent and combined effects of inhaled nitric oxide, liquid perfluorochemical, and high-frequency oscillatory ventilation in premature lambs with respiratory distress syndrome. Am J Respir Crit Care Med. 1999; 159:1220-1227 [Abstract/Free Full Text]
30. Davidson D, Barefield ES, Kattwinkel J, , and the I-NO/PPHN Study Group. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics. 1999; 104:231-236 [Abstract/Free Full Text]