Early nitric oxide is not associated with improved outcomes in congenital diaphragmatic hernia.
Journal
Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
received:
30
06
2022
accepted:
30
12
2022
revised:
07
11
2022
medline:
3
7
2023
pubmed:
2
2
2023
entrez:
1
2
2023
Statut:
ppublish
Résumé
Inhaled nitric oxide (iNO) is widely used for the management of infants with congenital diaphragmatic hernia (CDH); however, evidence of benefit is limited. This is a multicenter cohort study using data from the Congenital Diaphragmatic Hernia Study Group between 2015 and 2020. The impact of early iNO use in the first 3 days of life prior to ECLS use on mortality or ECLS use was explored using multivariate logistic regression models and subgroup analyses. Of the 1777 infants, 863 (48.6%) infants received early iNO treatment. Infants receiving iNO had lower birth weight, larger defect size, more severe pulmonary hypertension, and abnormal ventricular size and function. After controlling for these factors, early iNO use was associated with increased mortality (aOR 2.06, 95% CI 1.05-4.03, P = 0.03) and increased ECLS use (aOR 3.44, 95% CI 2.11-5.60, P < 0.001). Subgroup analyses after stratification by echocardiographic characteristics and defect size revealed no subgroup with a reduction in mortality or ECLS use. Use of iNO in the first 3 days of life prior to ECLS was not associated with a reduction in mortality or ECLS use in either the regression models or the subgroup analyses. The widespread use of iNO in this vulnerable population requires reconsideration. Evidence to support widespread use of iNO for infants with congenital diaphragmatic hernia is limited. The use of iNO in the first 3 days of life was associated with significantly increased mortality and ECLS use. Stratification by echocardiographic characteristics and defect size did not reveal a subgroup that benefited from iNO. Even the subset of patients with R-to-L shunts at both ductal and atrial levels, a surrogate for elevated pulmonary arterial pressures in the absence of significantly decreased LV compliance, did not benefit from early iNO use. Early iNO therapy was of no benefit in the management of acute pulmonary hypertension in infants with congenital diaphragmatic hernia, supporting reconsideration of its use in this population.
Sections du résumé
BACKGROUND
BACKGROUND
Inhaled nitric oxide (iNO) is widely used for the management of infants with congenital diaphragmatic hernia (CDH); however, evidence of benefit is limited.
METHODS
METHODS
This is a multicenter cohort study using data from the Congenital Diaphragmatic Hernia Study Group between 2015 and 2020. The impact of early iNO use in the first 3 days of life prior to ECLS use on mortality or ECLS use was explored using multivariate logistic regression models and subgroup analyses.
RESULTS
RESULTS
Of the 1777 infants, 863 (48.6%) infants received early iNO treatment. Infants receiving iNO had lower birth weight, larger defect size, more severe pulmonary hypertension, and abnormal ventricular size and function. After controlling for these factors, early iNO use was associated with increased mortality (aOR 2.06, 95% CI 1.05-4.03, P = 0.03) and increased ECLS use (aOR 3.44, 95% CI 2.11-5.60, P < 0.001). Subgroup analyses after stratification by echocardiographic characteristics and defect size revealed no subgroup with a reduction in mortality or ECLS use.
CONCLUSIONS
CONCLUSIONS
Use of iNO in the first 3 days of life prior to ECLS was not associated with a reduction in mortality or ECLS use in either the regression models or the subgroup analyses. The widespread use of iNO in this vulnerable population requires reconsideration.
IMPACT
CONCLUSIONS
Evidence to support widespread use of iNO for infants with congenital diaphragmatic hernia is limited. The use of iNO in the first 3 days of life was associated with significantly increased mortality and ECLS use. Stratification by echocardiographic characteristics and defect size did not reveal a subgroup that benefited from iNO. Even the subset of patients with R-to-L shunts at both ductal and atrial levels, a surrogate for elevated pulmonary arterial pressures in the absence of significantly decreased LV compliance, did not benefit from early iNO use. Early iNO therapy was of no benefit in the management of acute pulmonary hypertension in infants with congenital diaphragmatic hernia, supporting reconsideration of its use in this population.
Identifiants
pubmed: 36725908
doi: 10.1038/s41390-023-02491-8
pii: 10.1038/s41390-023-02491-8
doi:
Substances chimiques
Nitric Oxide
31C4KY9ESH
Types de publication
Multicenter Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1899-1906Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.
Références
Gupta, V. S. & Harting, M. T. Congenital diaphragmatic hernia-associated pulmonary hypertension. Semin. Perinatol. 44, 151–167 (2020).
doi: 10.1053/j.semperi.2019.07.006
Levin, D. L. Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J. Pediatr. 92, 805–809 (1978).
pubmed: 641633
doi: 10.1016/S0022-3476(78)80162-0
Lath, N. R. et al. Defective pulmonary innervation and autonomic imbalance in congenital diaphragmatic hernia. Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L390–L398 (2012).
pubmed: 22114150
doi: 10.1152/ajplung.00275.2011
Irish, M. S. et al. Contractile properties of intralobar pulmonary arteries and veins in the fetal lamb model of congenital diaphragmatic hernia. J. Pediatr. Surg. 33, 921–928 (1998).
pubmed: 9660230
doi: 10.1016/S0022-3468(98)90675-3
Patel, N. et al. Ventricular dysfunction is a critical determinant of mortality in congenital diaphragmatic hernia. Am. J. Respir. Crit. Care Med. 200, 1522–1530 (2019).
pubmed: 31409095
doi: 10.1164/rccm.201904-0731OC
Heiss, K. et al. Reversal of mortality for congenital diaphragmatic hernia with ECMO. Ann. Surg. 209, 225–230 (1989).
pubmed: 2644900
pmcid: 1493900
doi: 10.1097/00000658-198902000-00014
Schumacher, R. E., Roloff, D. W., Chapman, R., Snedecor, S. & Bartlett, R. H. Extracorporeal membrane oxygenation in term newborns. ASAIO J. 39, 873–879 (1993).
pubmed: 8123920
doi: 10.1097/00002480-199339040-00010
UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 348, 75–82 (1996).
doi: 10.1016/S0140-6736(96)04100-1
Congenital Diaphragmatic Hernia Study Group. Does extracorporeal membrane oxygenation improve survival in neonates with congenital diaphragmatic hernia? J. Pediatr. Surg. 34, 720–725 (1999).
doi: 10.1016/S0022-3468(99)90363-9
Kays, D. W. ECMO in CDH: is there a role? Semin. Pediatr. Surg. 26, 166–170 (2017).
pubmed: 28641755
doi: 10.1053/j.sempedsurg.2017.04.006
Langham, M. R. et al. Twenty years of progress in congenital diaphragmatic hernia at the University of Florida. Am. Surg. 69, 45–52 (2003).
pubmed: 12575780
doi: 10.1177/000313480306900110
Moyer, V. A. et al. Late versus early surgical correction for congenital diaphragmatic hernia in newborn infants. Cochrane Database Syst. Rev. 2000, CD001695 (2000).
pmcid: 8406654
Jancelewicz, T. et al. Survival benefit associated with the use of extracorporeal life support for neonates with congenital diaphragmatic hernia. Ann. Surg. 275, e256–e263 (2022).
pubmed: 33060376
doi: 10.1097/SLA.0000000000003928
Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N. Engl. J. Med. 336, 597–604 (1997).
doi: 10.1056/NEJM199702273360901
Clark, R. H. et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N. Engl. J. Med. 342, 469–474 (2000).
pubmed: 10675427
doi: 10.1056/NEJM200002173420704
Barrington, K. J., Finer, N., Pennaforte, T. & Altit, G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst. Rev. 2017, CD000399 (2017).
pmcid: 6464941
Campbell, B. T. et al. Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia. Pediatrics 134, e420–e426 (2014).
pubmed: 25022736
doi: 10.1542/peds.2013-2644
Putnam, L. R. et al. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatr. 170, 1188 (2016).
pubmed: 27723858
doi: 10.1001/jamapediatrics.2016.2023
Kinsella, J. P., Neish, S. R., Ivy, D. D., Shaffer, E. & Abman, S. H. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J. Pediatr. 123, 103–108 (1993).
pubmed: 8320602
doi: 10.1016/S0022-3476(05)81551-3
Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 99, 838–845 (1997).
doi: 10.1542/peds.99.6.838
Lawrence, K. M. et al. Inhaled nitric oxide is associated with improved oxygenation in a subpopulation of infants with congenital diaphragmatic hernia and pulmonary hypertension. J. Pediatr. 219, 167–172 (2019).
pubmed: 31706636
doi: 10.1016/j.jpeds.2019.09.052
Ferguson, D. M. et al. Early, postnatal pulmonary hypertension severity predicts inpatient outcomes in congenital diaphragmatic hernia. Neonatology 118, 147–154 (2021).
pubmed: 33849011
doi: 10.1159/000512966
Byrne, F. A. et al. Severe left diaphragmatic hernia limits size of fetal left heart more than does right diaphragmatic hernia. Ultrasound Obstet. Gynecol. 46, 688–694 (2015).
pubmed: 25597867
doi: 10.1002/uog.14790
Kailin, J. A. et al. Fetal left‐sided cardiac structural dimensions in left‐sided congenital diaphragmatic hernia – association with severity and impact on postnatal outcomes. Prenat. Diagn. 37, 502–509 (2017).
pubmed: 28370263
doi: 10.1002/pd.5045
Massolo, A. C. et al. Fetal cardiac dimensions in congenital diaphragmatic hernia: relationship with gestational age and postnatal outcomes. J. Perinatol. 41, 1651–1659 (2021).
pubmed: 33649439
doi: 10.1038/s41372-021-00986-y
Nair, J. & Lakshminrusimha, S. Update on PPHN: mechanisms and treatment. Semin. Perinatol. 38, 78–91 (2014).
pubmed: 24580763
pmcid: 3942674
doi: 10.1053/j.semperi.2013.11.004
Gien, J. & Kinsella, J. P. Management of pulmonary hypertension in infants with congenital diaphragmatic hernia. J. Perinatol. 36, S28–S31 (2016).
pubmed: 27225962
doi: 10.1038/jp.2016.46
Wehrmann, M. et al. Implications of atrial-level shunting by echocardiography in newborns with congenital diaphragmatic hernia. J. Pediatr. 219, 43–47 (2020).
pubmed: 32014282
doi: 10.1016/j.jpeds.2019.12.037
Tsao, K. & Lally, K. P. The Congenital Diaphragmatic Hernia Study Group: a voluntary international registry. Semin. Pediatr. Surg. 17, 90–97 (2008).
pubmed: 18395658
doi: 10.1053/j.sempedsurg.2008.02.004
Harting, M. T. & Lally, K. P. The Congenital Diaphragmatic Hernia Study Group registry update. Semin. Fetal Neonatal Med. 19, 370–375 (2014).
pubmed: 25306471
doi: 10.1016/j.siny.2014.09.004
CDHSG Data Collection Form v4. https://med.uth.edu/pediatricsurgery/wp-content/uploads/sites/3/2020/08/CDH_Data_Form_V4_2020.docx (2020).
Van Meurs, K. P. et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N. Engl. J. Med. 353, 13–22 (2005).
pubmed: 16000352
doi: 10.1056/NEJMoa043927
Mercier, J.-C. et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet 376, 346–354 (2010).
pubmed: 20655106
doi: 10.1016/S0140-6736(10)60664-2
Kinsella, J. P. et al. The left ventricle in congenital diaphragmatic hernia: implications for the management of pulmonary hypertension. J. Pediatr. 197, 17–22 (2018).
pubmed: 29628412
doi: 10.1016/j.jpeds.2018.02.040
Lally, K. P. et al. Standardized reporting for congenital diaphragmatic hernia – an international consensus. J. Pediatr. Surg. 48, 2408–2415 (2013).
pubmed: 24314179
doi: 10.1016/j.jpedsurg.2013.08.014
Altit, G., Bhombal, S., Van Meurs, K. P. & Tacy, T. A. Ventricular performance is associated with need for extracorporeal membrane oxygenation in newborns with congenital diaphragmatic hernia. J. Pediatr. 191, 28.e1–34.e1 (2017).
doi: 10.1016/j.jpeds.2017.08.060
Patel, N. et al. Early postnatal ventricular dysfunction is associated with disease severity in patients with congenital diaphragmatic hernia. J. Pediatr. 203, 400.e1–407.e1 (2018).
doi: 10.1016/j.jpeds.2018.07.062
Moenkemeyer, F. & Patel, N. Right ventricular diastolic function measured by tissue doppler imaging predicts early outcome in congenital diaphragmatic hernia. Pediatr. Crit. Care Med. 15, 49–55 (2014).
pubmed: 23925147
doi: 10.1097/PCC.0b013e31829b1e7a
Herich, K. et al. iNO therapy in patients with congenital diaphragmatic hernia – discrepancy between widespread use and therapeutic effects. Klin. Pädiatr. 231, 320–325 (2019).
pubmed: 31466085
doi: 10.1055/a-0991-0455
Kumar, V. H. S., Dadiz, R., Koumoundouros, J., Guilford, S. & Lakshminrusimha, S. Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia. Pediatr. Surg. Int. 34, 735–742 (2018).
pubmed: 29808281
doi: 10.1007/s00383-018-4286-5
Mohseni-Bod, H. & Bohn, D. Pulmonary hypertension in congenital diaphragmatic hernia. Semin. Pediatr. Surg. 16, 126–133 (2007).
pubmed: 17462565
doi: 10.1053/j.sempedsurg.2007.01.008
Shehata, S. M. K., Sharma, H. S., Mooi, W. J. & Tibboel, D. Pulmonary hypertension in human newborns with congenital diaphragmatic hernia is associated with decreased vascular expression of nitric-oxide synthase. Cell Biochem. Biophys. 44, 147–155 (2006).
pubmed: 16456243
doi: 10.1385/CBB:44:1:147
Solari, V., Piotrowska, A. P. & Puri, P. Expression of heme oxygenase-1 and endothelial nitric oxide synthase in the lung of newborns with congenital diaphragmatic hernia and persistent pulmonary hypertension. J. Pediatr. Surg. 38, 808–813 (2003).
pubmed: 12720199
doi: 10.1016/jpsu.2003.50172
Mous, D. S., Kempen, M. J. B., Wijnen, R. M. H., Tibboel, D. & Rottier, R. J. Changes in vasoactive pathways in congenital diaphragmatic hernia associated pulmonary hypertension explain unresponsiveness to pharmacotherapy. Respir. Res. 18, 187 (2017).
pubmed: 29115963
pmcid: 5688796
doi: 10.1186/s12931-017-0670-2
Coppola, C. P. & Gosche, J. R. Oxygen-induced vasodilation is blunted in pulmonary arterioles from fetal rats with nitrofen-induced congenital diaphragmatic hernia. J. Pediatr. Surg. 36, 593–597 (2001).
pubmed: 11283884
doi: 10.1053/jpsu.2001.22289
Galié, N., Manes, A. & Branzi, A. The endothelin system in pulmonary arterial hypertension. Cardiovasc. Res. 61, 227–237 (2004).
pubmed: 14736539
doi: 10.1016/j.cardiores.2003.11.026
Okazaki, T., Sharma, H. S., McCune, S. K. & Tibboel, D. Pulmonary vascular balance in congenital diaphragmatic hernia: enhanced endothelin-1 gene expression as a possible cause of pulmonary vasoconstriction. J. Pediatr. Surg. 33, 81–84 (1998).
pubmed: 9473106
doi: 10.1016/S0022-3468(98)90367-0
Keller, R. L. et al. Congenital diaphragmatic hernia: endothelin-1, pulmonary hypertension, and disease severity. Am. J. Respir. Crit. Care Med. 182, 555–561 (2010).
pubmed: 20413632
pmcid: 2937245
doi: 10.1164/rccm.200907-1126OC