Download PDF
Am J Perinatol 2022; 39(09): 0944-0950
DOI: 10.1055/s-0040-1718879
Original Article

The Relationship between Serum Total Bilirubin and Severity of Hypoxic Injury in Neonatal Hypoxic–Ischemic Encephalopathy

Mitsuhiro Haga 
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
2   Department of Pediatrics, Saitama Medical Center, Kawagoe, Saitama, Japan
,
Ken Kawabata
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
,
Wakako Sumiya
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
,
Saori Kurita
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
,
Toshiyuki Imanishi
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
,
Chika Kanno
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
,
Masayuki Kanno
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
,
Masami Kanno
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
,
Masaki Shimizu
1   Department of Neonatology, Saitama Children's Medical Center, Saitama, Saitama, Japan
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Introduction Bilirubin has been found to be a natural antioxidant protecting the body from oxidative stress. This study aims to investigate the severity of neonatal hypoxic injury on bilirubin levels to clarify the physiological role of bilirubin.

Study Design Using lactate as a biomarker for the severity of hypoxic injury, we retrospectively analyzed the association of admission lactate levels on serum total bilirubin (TB) levels following birth in neonates with hypoxic–ischemic encephalopathy (HIE). We created a univariate linear regression model to predict TB using the admission lactate level as a predictor. We also performed a multivariate linear regression analysis to predict TB with admission lactate levels that included phenobarbital cumulative dosage, admission hematocrit, and subgaleal hemorrhage as predictor variables.

Results A total of 86 patients were studied. Admission lactate levels had a significant negative effect on TB from admission to 3 days of life. The standardized regression coefficient for admission lactate on TB was −0.37 (admission), −0.42 (day 1), −0.32 (day 2), and −0.28 (day 3). A similar negative effect of admission lactate on TB levels was also observed in the multivariate linear regression model even after controlling for the other variables.

Conclusion These results are consistent with the hypothesis that bilirubin functions as an antioxidant in vivo, and is consumed by scavenging free radicals in proportion to the severity of hypoxic injury.

Key Points

  • Lactate levels have a negative effect on serum TB levels in patients with neonatal HIE.

  • Bilirubin might work as a natural antioxidant to protect the body from oxidative stress.

  • Serum TB might be a marker for the severity of hypoxic injury.

Keywords

bilirubin - hypoxic–ischemic encephalopathy - oxidative stress - lactate

Supplementary Material



Publication History

Received: 26 May 2020

Accepted: 16 September 2020

Article published online:
22 October 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Maisels MJWJ. Jaundice. In: MacDonald MG, Seshia MMK. , eds. Avery's Nonatology: Pathophysiology & Management of the Newborn. 7th ed.. Philadelphia, PA: Wolters Kluwer; 2016: 587-645
    Search in Google Scholar
  • 2 Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 2004; 113 (06) 1776-1782
    CrossrefPubMedSearch in Google Scholar
  • 3 Bin-Nun A, Mimouni FB, Kasirer Y. , et al. Might bilirubin serve as a natural antioxidant in response to neonatal encephalopathy?. Am J Perinatol 2018; 35 (11) 1107-1112
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Harrison Jr. H, Coen RW. Bilirubinemia in asphyxiated term infants. A clinical observation. Alaska Med 1996; 38 (03) 98-100
    PubMedSearch in Google Scholar
  • 5 Taniguchi K, Sugihara S, Koga M. , et al. Clinical consideration of serum bilirubin in neonatal axphyxi. J Jpn Pediatr Soc. 2007; 111 (06) 746-749
    PubMedSearch in Google Scholar
  • 6 Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992; 20 (01) 80-93
    CrossrefPubMedSearch in Google Scholar
  • 7 Okorie ON, Dellinger P. Lactate: biomarker and potential therapeutic target. Crit Care Clin 2011; 27 (02) 299-326
    CrossrefPubMedSearch in Google Scholar
  • 8 Shah S, Tracy M, Smyth J. Postnatal lactate as an early predictor of short-term outcome after intrapartum asphyxia. J Perinatol 2004; 24 (01) 16-20
    CrossrefPubMedSearch in Google Scholar
  • 9 Takenouchi T, Iwata O, Nabetani M, Tamura M. Therapeutic hypothermia for neonatal encephalopathy: JSPNM & MHLW Japan Working Group Practice Guidelines Consensus Statement from the Working Group on Therapeutic Hypothermia for Neonatal Encephalopathy, Ministry of Health, Labor and Welfare (MHLW), Japan, and Japan Society for Perinatal and Neonatal Medicine (JSPNM). Brain Dev 2012; 34 (02) 165-170
    PubMedSearch in Google Scholar
  • 10 Perlman JM, Wyllie J, Kattwinkel J. et al. Neonatal Resuscitation Chapter Collaborators. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010; 122 (16, Supp 02): S516-S538
    CrossrefPubMedSearch in Google Scholar
  • 11 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33 (10) 696-705
    CrossrefPubMedSearch in Google Scholar
  • 12 Nakamura H, Yonetani M, Uetani Y, Funato M, Lee Y. Determination of serum unbound bilirubin for prediction of kernicterus in low birthweight infants. Acta Paediatr Jpn 1992; 34 (06) 642-647
    CrossrefPubMedSearch in Google Scholar
  • 13 McDonagh AF. Is bilirubin good for you?. Clin Perinatol 1990; 17 (02) 359-369
    CrossrefPubMedSearch in Google Scholar
  • 14 Yamaguchi T, Sugiyama A. Anit-oxidant effects of bilirbuin as a low molecular antioxidant. J Anal Bio-Sci. 2009; 32 (04) 281-288
    PubMedSearch in Google Scholar
  • 15 Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci U S A 1987; 84 (16) 5918-5922
    CrossrefPubMedSearch in Google Scholar
  • 16 Stocker R, Peterhans E. Antioxidant properties of conjugated bilirubin and biliverdin: biologically relevant scavenging of hypochlorous acid. Free Radic Res Commun 1989; 6 (01) 57-66
    CrossrefPubMedSearch in Google Scholar
  • 17 Stocker R, McDonagh AF, Glazer AN, Ames BN. Antioxidant activities of bile pigments: biliverdin and bilirubin. Methods Enzymol 1990; 186: 301-309
    CrossrefPubMedSearch in Google Scholar
  • 18 Gazzin S, Vitek L, Watchko J, Shapiro SM, Tiribelli C. A novel perspective on the biology of bilirubin in health and disease. Trends Mol Med 2016; 22 (09) 758-768
    CrossrefPubMedSearch in Google Scholar
  • 19 Kunutsor SK, Bakker SJ, Gansevoort RT, Chowdhury R, Dullaart RP. Circulating total bilirubin and risk of incident cardiovascular disease in the general population. Arterioscler Thromb Vasc Biol 2015; 35 (03) 716-724
    CrossrefPubMedSearch in Google Scholar
  • 20 Schwertner HA, Vítek L. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin. Atherosclerosis 2008; 198 (01) 1-11
    CrossrefPubMedSearch in Google Scholar
  • 21 Yamaguchi T, Shioji I, Sugimoto A, Komoda Y, Nakajima H. Chemical structure of a new family of bile pigments from human urine. J Biochem 1994; 116 (02) 298-303
    CrossrefPubMedSearch in Google Scholar
  • 22 Yamaguchi T, Shioji I, Sugimoto A, Yamaoka M. Psychological stress increases bilirubin metabolites in human urine. Biochem Biophys Res Commun 2002; 293 (01) 517-520
    CrossrefPubMedSearch in Google Scholar
  • 23 Shimizu M. Neonatal hypoxic ischemic encephalopathy and free radical scavengers. Shusanki-igaku. 2009; 39 (12) 1691-1695
    PubMedSearch in Google Scholar
  • 24 Brierley CH, Senafi SB, Clarke D, Hsu MH, Johnson EF, Burchell B. Regulation of the human bilirubin UDP-glucuronosyltransferase gene. Adv Enzyme Regul 1996; 36: 85-97
    CrossrefPubMedSearch in Google Scholar