PDF herunterladen
Am J Perinatol 2021; 38(12): 1313-1319
DOI: 10.1055/s-0040-1712951
Original Article

Intermittent Hypoxemia in Preterm Infants: A Potential Proinflammatory Process

Elie G. Abu Jawdeh
1   Division of Neonatology, Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky
,
Hong Huang
1   Division of Neonatology, Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky
,
Philip M. Westgate
2   Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, Kentucky
,
Abhijit Patwardhan
3   Department of Biomedical Engineering, College of Engineering, University of Kentucky, Lexington, Kentucky
,
Henrietta Bada
1   Division of Neonatology, Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky
,
John A. Bauer
1   Division of Neonatology, Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky
,
Peter Giannone
1   Division of Neonatology, Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, Kentucky
› Institutsangaben Funding This study was funded in part by: (1) The Gerber Foundation, (2) Kentucky Children's Hospital, Children's Miracle Network Research Fund (E.A., P.I.), (3) NIH grant R01-HD070792 (J.B. and P.G., M.P.I.), and (4) University of Kentucky's National Center for Advancing Translational Sciences, under grant UL1RR033173.
› Weitere Informationen
    Lizenzen und Reprints

Abstract

Objective A major consequence of prematurity is intermittent hypoxemia (IH). Data from both adult studies and neonatal animal models suggest that IH is proinflammatory; however, there is limited data in preterm infants. Here, we assess the relationship between IH and systemic inflammation, namely, serum C-reactive protein (CRP) in preterm infants.

Study Design Serum CRP was measured at 30 days of life, at the time of peak IH frequency. IH measures (e.g., per cent time in hypoxemia, frequency, duration) were calculated the week prior to CRP collection. Statistical analyses were based on Spearman's correlation.

Results A total of 26 infants were included. Median gestational age and birth weight were 274/7 weeks and 980 g, respectively. There were positive correlations between primary IH measures and CRP levels, especially for events longer than 1-minute duration (r range: 0.56–0.74, all p < 0.01).

Conclusion We demonstrate that IH is associated with increased CRP for the first time in preterm infants. Our findings are consistent with studies from adults and neonatal animal models suggesting that IH is a proinflammatory process.

Key Points

  • IH events are common.

  • IH is associated with elevated C-reactive protein.

  • Longer IH events (>1 min) are of most significance.

Keywords

intermittent hypoxemia - C-reactive protein - inflammation - preterm infants - apnea of prematurity


Publikationsverlauf

Eingereicht: 24. Januar 2020

Angenommen: 27. April 2020

Artikel online veröffentlicht:
08. Juni 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.

 

  • References

  • 1 Di Fiore JM, Martin RJ, Gauda EB. Apnea of prematurity--perfect storm. Respir Physiol Neurobiol 2013; 189 (02) 213-222
    CrossrefPubMedGoogle Scholar
  • 2 Martin RJ, Di Fiore JM, Walsh MC. Hypoxic episodes in bronchopulmonary dysplasia. Clin Perinatol 2015; 42 (04) 825-838
    CrossrefPubMedGoogle Scholar
  • 3 Abu Jawdeh EG, Martin RJ, Dick TE, Walsh MC, Di Fiore JM. The effect of red blood cell transfusion on intermittent hypoxemia in ELBW infants. J Perinatol 2014; 34 (12) 921-925
    CrossrefPubMedGoogle Scholar
  • 4 Di Fiore JM, Bloom JN, Orge F. et al. A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity. J Pediatr 2010; 157 (01) 69-73
    CrossrefPubMedGoogle Scholar
  • 5 Abu Jawdeh EG. Intermittent hypoxemia in preterm infants: etiology and clinical relevance. Neoreviews 2017; 18 (11) e637-e646
    CrossrefPubMedGoogle Scholar
  • 6 Abu Jawdeh EG, Westgate PM, Pant A. et al. Prenatal opioid exposure and intermittent hypoxemia in preterm infants: a retrospective assessment. Front Pediatr 2017; 5 (253) 253
    CrossrefPubMedGoogle Scholar
  • 7 Hofstetter AO, Saha S, Siljehav V, Jakobsson PJ, Herlenius E. The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates. Proc Natl Acad Sci U S A 2007; 104 (23) 9894-9899
    CrossrefPubMedGoogle Scholar
  • 8 Sullivan BA, Fairchild KD. Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock. Semin Fetal Neonatal Med 2015; 20 (04) 255-261
    CrossrefPubMedGoogle Scholar
  • 9 Fairchild KD, Lake DE, Kattwinkel J. et al. Vital signs and their cross-correlation in sepsis and NEC: a study of 1,065 very-low-birth-weight infants in two NICUs. Pediatr Res 2017; 81 (02) 315-321
    CrossrefPubMedGoogle Scholar
  • 10 Pillekamp F, Hermann C, Keller T, von Gontard A, Kribs A, Roth B. Factors influencing apnea and bradycardia of prematurity - implications for neurodevelopment. Neonatology 2007; 91 (03) 155-161
    CrossrefPubMedGoogle Scholar
  • 11 Poets CF, Roberts RS, Schmidt B. et al; Canadian Oxygen Trial Investigators. Association between intermittent hypoxemia or bradycardia and late death or disability in extremely preterm infants. JAMA 2015; 314 (06) 595-603
    CrossrefPubMedGoogle Scholar
  • 12 Poets CF. Intermittent hypoxemia/bradycardia and the developing brain: how much is too much? Commentary on M.B. Schmid et al.: Cerebral oxygenation during intermittent hypoxemia and bradycardia in preterm infants (Neonatology 2015;107:137-146). Neonatology 2015; 107 (02) 147-149
    CrossrefPubMedGoogle Scholar
  • 13 Di Fiore JM, Poets CF, Gauda E, Martin RJ, MacFarlane P. Cardiorespiratory events in preterm infants: interventions and consequences. J Perinatol 2016; 36 (04) 251-258
    CrossrefPubMedGoogle Scholar
  • 14 Marcus CL, Meltzer LJ, Roberts RS. et al; Caffeine for Apnea of Prematurity–Sleep Study. Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age. Am J Respir Crit Care Med 2014; 190 (07) 791-799
    CrossrefPubMedGoogle Scholar
  • 15 Di Fiore JM, Martin RJ, Li H. et al; SUPPORT Study Group of the Eunice Kennedy Shriver National Institute of Child Health, and Human Development Neonatal Research Network. Patterns of oxygenation, mortality, and growth status in the surfactant positive pressure and oxygen trial cohort. J Pediatr 2017; 186: 49-56.e1
    CrossrefPubMedGoogle Scholar
  • 16 Sands SA, Edwards BA, Kelly VJ, Davidson MR, Wilkinson MH, Berger PJ. A model analysis of arterial oxygen desaturation during apnea in preterm infants. PLOS Comput Biol 2009; 5 (12) e1000588
    CrossrefPubMedGoogle Scholar
  • 17 Raffay TM, Dylag AM, Sattar A. et al. Neonatal intermittent hypoxemia events are associated with diagnosis of bronchopulmonary dysplasia at 36 weeks postmenstrual age. Pediatr Res 2019; 85 (03) 318-323
    CrossrefPubMedGoogle Scholar
  • 18 Gautier-Veyret E, Arnaud C, Bäck M. et al. Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis. Eur Respir J 2013; 42 (02) 404-413
    CrossrefPubMedGoogle Scholar
  • 19 Li K, Wei P, Qin Y, Wei Y. Is C-reactive protein a marker of obstructive sleep apnea?: A meta-analysis. Medicine (Baltimore) 2017; 96 (19) e6850
    CrossrefPubMedGoogle Scholar
  • 20 Nadeem R, Molnar J, Madbouly EM. et al. Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med 2013; 9 (10) 1003-1012
    CrossrefPubMedGoogle Scholar
  • 21 Wang J, Yu W, Gao M. et al. Impact of obstructive sleep apnea syndrome on endothelial function, arterial stiffening, and serum inflammatory markers: an updated meta-analysis and metaregression of 18 studies. J Am Heart Assoc 2015; 4 (11) e002454
    CrossrefPubMedGoogle Scholar
  • 22 Wang Y, Chai Y, He X. et al. Intermittent hypoxia simulating obstructive sleep apnea causes pulmonary inflammation and activates the Nrf2/HO-1 pathway. Exp Ther Med 2017; 14 (04) 3463-3470
    CrossrefPubMedGoogle Scholar
  • 23 Turnbull CD. Intermittent hypoxia, cardiovascular disease and obstructive sleep apnoea. J Thorac Dis 2018; 10 (Suppl. 01) S33-S39
    CrossrefPubMedGoogle Scholar
  • 24 Garvey JF, Taylor CT, McNicholas WT. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. Eur Respir J 2009; 33 (05) 1195-1205
    CrossrefPubMedGoogle Scholar
  • 25 Darnall RA, Chen X, Nemani KV. et al. Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism. Pediatr Res 2017; 82 (01) 164-172
    CrossrefPubMedGoogle Scholar
  • 26 Gauda EB, Shirahata M, Mason A, Pichard LE, Kostuk EW, Chavez-Valdez R. Inflammation in the carotid body during development and its contribution to apnea of prematurity. Respir Physiol Neurobiol 2013; 185 (01) 120-131
    CrossrefPubMedGoogle Scholar
  • 27 Julien CA, Joseph V, Bairam A. Alteration of carotid body chemoreflexes after neonatal intermittent hypoxia and caffeine treatment in rat pups. Respir Physiol Neurobiol 2011; 177 (03) 301-312
    CrossrefPubMedGoogle Scholar
  • 28 Gauda EB, Carroll JL, Donnelly DF. Developmental maturation of chemosensitivity to hypoxia of peripheral arterial chemoreceptors--invited article. Adv Exp Med Biol 2009; 648: 243-255
    CrossrefPubMedGoogle Scholar
  • 29 Liu X, He L, Stensaas L, Dinger B, Fidone S. Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. Am J Physiol Lung Cell Mol Physiol 2009; 296 (02) L158-L166
    CrossrefPubMedGoogle Scholar
  • 30 Rhein LM, Dobson NR, Darnall RA. et al; Caffeine Pilot Study Group. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr 2014; 168 (03) 250-257
    CrossrefPubMedGoogle Scholar
  • 31 Leviton A, Allred EN, Fichorova RN, Kuban KC, Michael O'Shea T, Dammann O. ; ELGAN study investigators. Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation. Early Hum Dev 2016; 93: 25-32
    CrossrefPubMedGoogle Scholar
  • 32 Di Fiore JM, Walsh M, Wrage L. et al; SUPPORT Study Group of Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Low oxygen saturation target range is associated with increased incidence of intermittent hypoxemia. J Pediatr 2012; 161 (06) 1047-1052
    CrossrefPubMedGoogle Scholar
  • 33 Walsh MC, Di Fiore JM, Martin RJ, Gantz M, Carlo WA, Finer N. Association of oxygen target and growth status with increased mortality in small for gestational age infants: further analysis of the surfactant, positive pressure and pulse oximetry randomized trial. JAMA Pediatr 2016; 170 (03) 292-294
    CrossrefPubMedGoogle Scholar
  • 34 Kushner I, Samols D, Magrey M. A unifying biologic explanation for “high-sensitivity” C-reactive protein and “low-grade” inflammation. Arthritis Care Res (Hoboken) 2010; 62 (04) 442-446
    CrossrefPubMedGoogle Scholar
  • 35 Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454 (7203): 428-435
    CrossrefPubMedGoogle Scholar
  • 36 Pourcyrous M, Korones SB, Arheart KL, Bada HS. Primary immunization of premature infants with gestational age <35 weeks: cardiorespiratory complications and C-reactive protein responses associated with administration of single and multiple separate vaccines simultaneously. J Pediatr 2007; 151 (02) 167-172
    CrossrefPubMedGoogle Scholar
  • 37 Pourcyrous M, Korones SB, Yang W, Boulden TF, Bada HS. C-reactive protein in the diagnosis, management, and prognosis of neonatal necrotizing enterocolitis. Pediatrics 2005; 116 (05) 1064-1069
    CrossrefPubMedGoogle Scholar
  • 38 Pourcyrous M, Bada HS, Korones SB, Baselski V, Wong SP. Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics 1993; 92 (03) 431-435
    CrossrefPubMedGoogle Scholar
  • 39 Posen R, deLemos RA. C-reactive protein levels in the extremely premature infant: case studies and literature review. J Perinatol 1998; 18 (02) 138-141
    PubMedGoogle Scholar
  • 40 Kervinen H, Palosuo T, Manninen V, Tenkanen L, Vaarala O, Mänttäri M. Joint effects of C-reactive protein and other risk factors on acute coronary events. Am Heart J 2001; 141 (04) 580-585
    CrossrefPubMedGoogle Scholar
  • 41 Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103 (13) 1813-1818
    CrossrefPubMedGoogle Scholar
  • 42 Koenig W, Löwel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany. Circulation 2004; 109 (11) 1349-1353
    CrossrefPubMedGoogle Scholar
  • 43 Chiesa C, Natale F, Pascone R. et al. C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period. Clin Chim Acta 2011; 412 (11-12): 1053-1059
    CrossrefPubMedGoogle Scholar