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Am J Perinatol 2024; 41(S 01): e1435-e1444
DOI: 10.1055/s-0043-1764385
Original Article

Pulmonary Hypertension and Necrotizing Enterocolitis in Neonates Treated with Diazoxide

Mounya Duggal   *
1   Division of Neonatology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
,
Shiran S. Moore   *
1   Division of Neonatology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
,
Jessica Simoneau
1   Division of Neonatology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
,
Gabrielle Girard
2   Department of Pharmacy, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
,
Irène B. Gernet
2   Department of Pharmacy, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
,
Julia E. Von Oettingen
3   Division of Endocrinology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
,
Guilherme Sant'Anna
1   Division of Neonatology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
,
Gabriel Altit 
1   Division of Neonatology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
› Author Affiliations Funding This work was supported by Just for Kids Foundation and the Summer Research Bursary Program at McGill University. The funder/sponsor did not participate in the work.
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Abstract

Objective This study aimed to evaluate the prevalence of adverse outcomes, specifically pulmonary hypertension (PH) and suspected or confirmed necrotizing enterocolitis (NEC), and their associated risk factors, in neonates treated with diazoxide.

Study Design A retrospective study in infants born ≥ 316/7 weeks and admitted between January 2014 and June 2020. Combined adverse outcomes possibly associated to diazoxide were PH (systolic pulmonary pressure of ≥40 mm Hg or an eccentricity index ≥1.3) and suspected or confirmed NEC (suspected: stop feeds and antibiotics and confirmed: modified Bell stage ≥2). Echocardiography data extractors were masked to infants' characteristics.

Results A total of 63 infants were included; 7 (11%) with suspected and 1 (2%) with confirmed NEC. Of the 36 infants with an available echocardiography after initiation of diazoxide treatment, 12 (33%) had PH. All infants with suspected or confirmed NEC were males (p = 0.01), whereas PH occurred mostly in females (75%, p = 0.02). The combined adverse outcome occurred in 14/26 (54%) infants exposed to >10 mg/kg/day, compared to 6/37 (16%) exposed to ≤10 mg/kg/day (p = 0.006). This association remained significant after adjustment for sex, small for gestational age status, and gestational age at birth (odds ratio: 6.1, 95% confidence interval: 1.7–21.7, p = 0.005). Left ventricular dysfunction was found in 19 infants (30%) but was not discriminative for the combined outcome.

Conclusion PH and suspected or confirmed NEC were identified frequently in neonates treated with diazoxide. A total dose >10 mg/kg/day was associated with an increased occurrence of these complications.

Key Points

  • PH and suspected or confirmed NEC were frequently found in neonates treated with diazoxide.

  • A total dose >10 mg/kg/day was associated with an increased occurrence of these complications.

  • Echocardiography screening should be considered in neonates exposed to diazoxide.

Keywords

diazoxide - hypoglycemia - necrotizing enterocolitis - pulmonary hypertension - neonates

* These authors contributed equally to this publication.


Ethical Approval and Patient Consent

The study was performed in accordance with the Declaration of Helsinki and was approved by the McGill University Health Centre research ethics boards.


Authors' Contributions

M.D. participated in conceptualizing and design of the study, collected the data, analyzed the data, drafted the manuscript, and adjusted the manuscript according to the comments of co-authors. S.S.M. collected the data, critically appraised the analysis of the data, and adjusted and revised the final manuscript. J.S. reviewed the data. J.E.vonO. critically appraised the analysis of the data and reviewed and revised the manuscript. G.G. provided the list of patients from the pharmacy registry, critically appraised the analysis of the data, reviewed, and revised the manuscript. I.G. provided the list of patients from the pharmacy registry, critically appraised the analysis of the data, reviewed, and revised the manuscript. G.S. critically appraised the analysis of the data, reviewed, and revised the manuscript. G.A. conceptualized and designed the study, supervised data collection, critically appraised the analysis of the data, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.


Supplementary Material



Publication History

Received: 12 July 2022

Accepted: 03 February 2023

Article published online:
07 March 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Gϋemes M, Rahman SA, Kapoor RR. et al. Hyperinsulinemic hypoglycemia in children and adolescents: recent advances in understanding of pathophysiology and management. Rev Endocr Metab Disord 2020; 21 (04) 577-597
    CrossrefPubMedSearch in Google Scholar
  • 2 Katzung BG, Masters SB, Trevor AJ. . Basic & Clinical Pharmacology. New York, NY: McGraw-Hill Medical; 2012
    PubMed
  • 3 Steinhorn RH. Neonatal pulmonary hypertension. Pediatr Crit Care Med 2010; 11 (02) , Suppl): S79-S84
    CrossrefPubMedSearch in Google Scholar
  • 4 Thompson AM, Bizzarro MJ. Necrotizing enterocolitis in newborns: pathogenesis, prevention and management. Drugs 2008; 68 (09) 1227-1238
    CrossrefPubMedSearch in Google Scholar
  • 5 Stark J, Simma B, Blassnig-Ezeh A. Incidence of hypoglycemia in newborn infants identified as at risk. J Matern Fetal Neonatal Med 2020; 33 (18) 3091-3096
    CrossrefPubMedSearch in Google Scholar
  • 6 Farris FF. . Diazoxide. In: Wexler P, ed. Encyclopedia of Toxicology. 3rd ed. Cambridge, MA: Academic Press; 2014:60–61
  • 7 Gray KD, Dudash K, Escobar C. et al; Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee. Prevalence and safety of diazoxide in the neonatal intensive care unit. J Perinatol 2018; 38 (11) 1496-1502
    CrossrefPubMedSearch in Google Scholar
  • 8 Theodorou CM, Hirose S. Necrotizing enterocolitis following diazoxide therapy for persistent neonatal hypoglycemia. J Pediatr Surg Case Rep 2020; 52: 101356
    CrossrefPubMedSearch in Google Scholar
  • 9 FDA.. FDA Drug Safety Communication: FDA warns about a serious lung condition in infants and newborns treated with Proglycem (diazoxide). Published online September 2, 2019. Accessed March 25, 2022 at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-lung-condition-infants-and-newborns-treated
    PubMed
  • 10 Timlin MR, Black AB, Delaney HM, Matos RI, Percival CS. Development of pulmonary hypertension during treatment with diazoxide: a case series and literature review. Pediatr Cardiol 2017; 38 (06) 1247-1250
    CrossrefPubMedSearch in Google Scholar
  • 11 Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013; 13 (01) 59
    CrossrefPubMedSearch in Google Scholar
  • 12 Thornton PS, Stanley CA, De Leon DD. et al; Pediatric Endocrine Society. Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr 2015; 167 (02) 238-245
    CrossrefPubMedSearch in Google Scholar
  • 13 Narvey MR, Marks SD. The screening and management of newborns at risk for low blood glucose. Paediatr Child Health 2019; 24 (08) 536-554
    CrossrefPubMedSearch in Google Scholar
  • 14 Altit G, Bonifacio SL, Guimaraes CV. et al. Cardiac dysfunction in neonatal HIE is associated with increased mortality and brain injury by MRI. Am J Perinatol 2021; (e-pub ahead of print).
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Altit G, Bhombal S, Van Meurs K, Tacy TA. Diminished cardiac performance and left ventricular dimensions in neonates with congenital diaphragmatic hernia. Pediatr Cardiol 2018; 39 (05) 993-1000
    CrossrefPubMedSearch in Google Scholar
  • 16 Altit G, Bhombal S, Feinstein J, Hopper RK, Tacy TA. Diminished right ventricular function at diagnosis of pulmonary hypertension is associated with mortality in bronchopulmonary dysplasia. Pulm Circ 2019; 9 (03) 2045894019878598
    CrossrefPubMedSearch in Google Scholar
  • 17 Altit G, Bhombal S, Chock VY, Tacy TA. Immediate postnatal ventricular performance is associated with mortality in hypoplastic left heart syndrome. Pediatr Cardiol 2019; 40 (01) 168-176
    CrossrefPubMedSearch in Google Scholar
  • 18 Altit G, Bhombal S, Van Meurs K, Tacy TA. Ventricular performance is associated with need for extracorporeal membrane oxygenation in newborns with congenital diaphragmatic hernia. J Pediatr 2017; 191: 28.e1-34.e1
    CrossrefPubMedSearch in Google Scholar
  • 19 Hansmann G, Koestenberger M, Alastalo TP. et al. 2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: the European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT. J Heart Lung Transplant 2019; 38 (09) 879-901
    CrossrefPubMedSearch in Google Scholar
  • 20 Mourani PM, Sontag MK, Younoszai A. et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 2015; 191 (01) 87-95
    CrossrefPubMedSearch in Google Scholar
  • 21 Abraham S, Weismann CG. Left ventricular end-systolic eccentricity index for assessment of pulmonary hypertension in infants. Echocardiography 2016; 33 (06) 910-915
    CrossrefPubMedSearch in Google Scholar
  • 22 de Carvalho Nunes G, Wutthigate P, Simoneau J. et al. The biventricular contribution to chronic pulmonary hypertension of the extremely premature infant. J Perinatol 2023; 43 (02) 174-180
    CrossrefPubMedSearch in Google Scholar
  • 23 Carlton EF, Sontag MK, Younoszai A. et al. Reliability of echocardiographic indicators of pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. J Pediatr 2017; 186: 29-33
    CrossrefPubMedSearch in Google Scholar
  • 24 Krishnan U, Feinstein JA, Adatia I. et al; Pediatric Pulmonary Hypertension Network (PPHNet). Evaluation and management of pulmonary hypertension in children with bronchopulmonary dysplasia. J Pediatr 2017; 188: 24-34.e1
    CrossrefPubMedSearch in Google Scholar
  • 25 Singh Y. Echocardiographic evaluation of hemodynamics in neonates and children. Front Pediatr 2017; 5: 201
    CrossrefPubMedSearch in Google Scholar
  • 26 Altit G, Dancea A, Renaud C, Perreault T, Lands LC, Sant'Anna G. Pathophysiology, screening and diagnosis of pulmonary hypertension in infants with bronchopulmonary dysplasia - a review of the literature. Paediatr Respir Rev 2017; 23: 16-26
    PubMedSearch in Google Scholar
  • 27 Koestenberger M, Ravekes W, Everett AD. et al. Right ventricular function in infants, children and adolescents: reference values of the tricuspid annular plane systolic excursion (TAPSE) in 640 healthy patients and calculation of z score values. J Am Soc Echocardiogr 2009; 22 (06) 715-719
    CrossrefPubMedSearch in Google Scholar
  • 28 UpToDate.. Modified Bell staging NEC. Accessed March 25, 2022 at: https://www.uptodate.com/contents/image?imageKey=PEDS%2F54166&topicKey=PEDS%2F5019&source=outline_link
    PubMed
  • 29 Shu LP, Zhang RH, Cai YH, Zhou JB, Yang JK, Qi L. Maternal diabetes mellitus and persistent pulmonary hypertension of the newborn: accumulated evidence from observational studies. Can J Diabetes 2020; 44 (04) 327.e3-334.e3
    PubMedSearch in Google Scholar
  • 30 Grandi C, Tapia JL, Cardoso VC. Impact of maternal diabetes mellitus on mortality and morbidity of very low birth weight infants: a multicenter Latin America study. J Pediatr (Rio J) 2015; 91 (03) 234-241
    CrossrefPubMedSearch in Google Scholar
  • 31 Bental Y, Reichman B, Shiff Y. et al; Collaboration With the Israel Neonatal Network. Impact of maternal diabetes mellitus on mortality and morbidity of preterm infants (24-33 weeks' gestation). Pediatrics 2011; 128 (04) e848-e855
    CrossrefPubMedSearch in Google Scholar
  • 32 Boghossian NS, Hansen NI, Bell EF. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Outcomes of extremely preterm infants born to insulin-dependent diabetic mothers. Pediatrics 2016; 137 (06) e20153424
    CrossrefPubMedSearch in Google Scholar
  • 33 Prado LA, Castro M, Weisz DE, Jain A, Belik J. Necrotising enterocolitis in newborns receiving diazoxide. Arch Dis Child Fetal Neonatal Ed 2021; 106 (03) 306-310
    CrossrefPubMedSearch in Google Scholar
  • 34 Hypertensive urgencies and emergencies. Compr Hypertens 2007; 761-774
    PubMedSearch in Google Scholar
  • 35 Pohl JEF, Thurston H, Swales JD. The dntidiuretic action of diazoxide. Clin Sci 1972; 42 (02) 145-152
    CrossrefPubMedSearch in Google Scholar
  • 36 Howell S, Dodman J. The peripheral circulation. Foundations of anesthesia. Mosby 2006; 525-536
    PubMedSearch in Google Scholar
  • 37 Leong A, Gordon A, Alshaikh B, Yusuf K, Dersch-Mills D. Osmolality of medications administered in the neonatal intensive care unit. Can J Hosp Pharm 2020; 73 (04) 288-289
    PubMedSearch in Google Scholar
  • 38 Ghosh S, Whitley CS, Haribabu B, Jala VR. Regulation of intestinal barrier function by microbial metabolites. Cell Mol Gastroenterol Hepatol 2021; 11 (05) 1463-1482
    CrossrefPubMedSearch in Google Scholar
  • 39 Silvani P, Camporesi A, Mandelli A, Wolfler A, Salvo I. A case of severe diazoxide toxicity. Paediatr Anaesth 2004; 14 (07) 607-609
    CrossrefPubMedSearch in Google Scholar
  • 40 Yoshida K, Kawai M, Marumo C. et al. High prevalence of severe circulatory complications with diazoxide in premature infants. Neonatology 2014; 105 (03) 166-171
    CrossrefPubMedSearch in Google Scholar
  • 41 Hawkes CP, Lado JJ, Givler S, De Leon DD. The effect of continuous intravenous glucagon on glucose requirements in infants with congenital hyperinsulinism. JIMD Rep 2019; 45: 45-50
    CrossrefPubMedSearch in Google Scholar
  • 42 Hawkes CP, De Leon DD, Rickels MR. Novel preparations of glucagon for the prevention and treatment of hypoglycemia. Curr Diab Rep 2019; 19 (10) 97
    CrossrefPubMedSearch in Google Scholar
  • 43 Ghouse J, Voegg O, Sillesen AS. et al. Association between maternal diabetes and cardiac left ventricular structure and function in the neonate: a study from the Copenhagen Baby Heart Study. Eur Heart J 2020; 41 (Supplement_2): ehaa946.3047
    CrossrefPubMedSearch in Google Scholar
  • 44 Thornburg KL, Drake R, Valent AM. Maternal hypertension affects heart growth in offspring. J Am Heart Assoc 2020; 9 (09) e016538
    CrossrefPubMedSearch in Google Scholar
  • 45 NeoCardio Lab.. 2D and 3D speckle tracking echocardiography. Accessed March 25, 2022 at: https://www.neocardiolab.com/2d-and-3d-speckle-tracking-echocardiography
    PubMed
  • 46 Abu-Osba YK, Manasra KB, Mathew PM. Complications of diazoxide treatment in persistent neonatal hyperinsulinism. Arch Dis Child 1989; 64 (10) 1496-1500
    CrossrefPubMedSearch in Google Scholar