BACKGROUND: Although bilirubin is a proven antioxidant substance and a protective factor against the development of various diseases, in emergency medicine, its increased concentration is considered solely a marker of organ damage and negative prognosis. However, clinical data on the role of bilirubin in cardiac arrest (CA) and reperfusion injury, are sparse. The presented study investigates the protective effects of increased serum bilirubin concentrations and genetic determinants (UGT1A1 promoter variations) on the outcomes of patients with refractory out-of-hospital CA (r-OHCA) in a randomized population. METHODS: Between March 1, 2013, and October 25, 2020, 256 randomized Prague OHCA patients with r-OHCA were evaluated for inclusion and categorized as having increased (>10 µmol/l) or low/normal serum bilirubin concentrations on hospital arrival and present or absent genetic variations for mild hyperbilirubinemia. The primary outcome was survival with a good neurological outcome (defined as cerebral performance category 1-2) 180 days after randomization. RESULTS: Finally, 164 patients were included in the bilirubin concentration analysis. Favorable neurological survival after 180 days occurred in 50 of 99 patients (50.5 %) in the group with higher initial serum bilirubin concentrations and 18 of 65 patients (27.7 %) in the low-bilirubin group (absolute difference 22.8 [8.1-37.5]; P = 0.006). The effect persisted also in multivariable analysis (OR for favorable outcome = 3.02 [95 % CI = 1.16-7.84]; P = 0.023). Genetic predisposition for mild hyperbilirubinemia was not associated with any patient outcomes. CONCLUSIONS: A higher initial serum bilirubin concentration predicts better outcomes in patients with refractory OHCA regardless of the treatment used. UGT1A1 gene promotor variations are not associated with refractory OHCA patient outcomes.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague U Nemocnice 2 Praha 2 128 00 Czech Republic

3rd Faculty of Medicine Charles University Ruská 2411 Vinohrady 100 00 Czech Republic

4th Department of Internal Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague U Nemocnice 2 Praha 2 128 00 Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Na Bojišti 3 Praha 2 120 00 Czech Republic

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Yannopoulos D., Bartos J., Raveendran G., et al. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial. Lancet. 2020;396:1807–1816. PubMed PMC

Belohlavek J., Smalcova J., Rob D., et al. Effect of intra-arrest transport, extracorporeal cardiopulmonary resuscitation, and immediate invasive assessment and treatment on functional neurologic outcome in refractory out-of-hospital cardiac arrest: a randomized clinical trial. JAMA. 2022;327:737–747. PubMed PMC

Suverein M.M., Delnoij T.S.R., Lorusso R., et al. Early extracorporeal CPR for refractory out-of-hospital cardiac arrest. N Engl J Med. 2023;388:299–309. PubMed

Sekhon M.S., Ainslie P.N., Griesdale D.E. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model. Crit Care. 2017;21:90. PubMed PMC

Sandroni C., Cronberg T., Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med. 2021;47:1393–1414. PubMed PMC

Mathru M., Dries D.J., Barnes L., Tonino P., Sukhani R., Rooney M.W. Tourniquet-induced exsanguination in patients requiring lower limb surgery. An ischemia-reperfusion model of oxidant and antioxidant metabolism. Anesthesiology. 1996;84:14–22. PubMed

Orban J.C., Garrel C., Deroche D., et al. Assessment of oxidative stress after out-of-hospital cardiac arrest. Am J Emerg Med. 2016;34:1561–1566. PubMed

Vitek L., Hinds T.D., Jr., Stec D.E., Tiribelli C. The physiology of bilirubin: health and disease equilibrium. Trends Mol Med. 2023;29:315–328. PubMed PMC

Vitek L. Bilirubin as a signaling molecule. Med Res Rev. 2020;40:1335–1351. PubMed

Vitek L., Tiribelli C. Bilirubin: the yellow hormone? J Hepatol. 2021;75:1485–1490. PubMed

Vitek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol. 2012;3:55. PubMed PMC

Vitek L. Bilirubin and atherosclerotic diseases. Physiol Res. 2017;66:S11–S20. PubMed

Vitek L., Hubacek J.A., Pajak A., et al. Association between plasma bilirubin and mortality. Ann Hepatol. 2019;18:379–385. PubMed

Bosma P.J., Chowdhury J.R., Bakker C., et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333:1171–1175. PubMed

Vitek L., Tiribelli C. Gilbert's syndrome revisited. J Hepatol. 2023;79:1049–1055. PubMed

Vincent J.L., Moreno R., Takala J., et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–710. PubMed

Keegan M.T., Gajic O., Afessa B. Comparison of APACHE III, APACHE IV, SAPS 3, and MPM0III and influence of resuscitation status on model performance. Chest. 2012;142:851–858. PubMed PMC

Lee S.H., Cho Y., Oh J., et al. Total cholesterol and bilirubin levels are associated with neurologic outcomes in patients with out-of-hospital cardiac arrest. Intern Emerg Med. 2024 doi: 10.1007/s11739-024-03742-0. Epub ahead of print. PMID: 39516448. PubMed DOI

Belohlavek J., Kucera K., Jarkovsky J., et al. Hyperinvasive approach to out-of hospital cardiac arrest using mechanical chest compression device, prehospital intraarrest cooling, extracorporeal life support and early invasive assessment compared to standard of care. A randomized parallel groups comparative study proposal. “Prague OHCA study”. J Transl Med. 2012;10:163. PubMed PMC

Jennett B., Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480–484. PubMed

Woronyczova J., Novákova M., Lenicek M., et al. Serum bilirubin concentrations and the prevalence of Gilbert syndrome in elite athletes. Sports Med Open. 2022:1–10. PubMed PMC

Eremiasova L., Hubacek J.A., Danzig V., et al. Serum bilirubin in the Czech population – relationship to the risk of myocardial infarction in males. Circ J. 2020;84:1779–1785. PubMed

Wagner K.H., Wallner M., Molzer C., et al. Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. Clin Sci (Lond) 2015;129:1–25. PubMed

Zheng Z., Chang Z., Chen Y., et al. Total bilirubin is associated with all-cause mortality in patients with acute respiratory distress syndrome: a retrospective study. Ann Transl Med. 2022;10:1160. PubMed PMC

Bunte S., Walz R., Merkel J., et al. Bilirubin – a possible prognostic mortality marker for patients with ECLS. J Clin Med. 2020;9 PubMed PMC

Ferreira F.L., Bota D.P., Bross A., Melot C., Vincent J.L. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286:1754–1758. PubMed

Laimoud M., Alanazi M. The validity of SOFA score to predict mortality in adult patients with cardiogenic shock on venoarterial extracorporeal membrane oxygenation. Crit Care Res Pract. 2020;2020 PubMed PMC

Roedl K., Spiel A.O., Nurnberger A., et al. Hypoxic liver injury after in- and out-of-hospital cardiac arrest: risk factors and neurological outcome. Resuscitation. 2019;137:175–182. PubMed

Sedlak T.W., Snyder S.H. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics. 2004;113:1776–1782. PubMed

Lin J.P., Vitek L., Schwertner H.A. Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease. Clin Chem. 2010;56:1535–1543. PubMed

Gazzin S., Masutti F., Vitek L., Tiribelli C. The molecular basis of jaundice: an old symptom revisited. Liver Int. 2017;37:1094–1102. PubMed

Nagar H., Piao S., Kim C.S. Role of mitochondrial oxidative stress in sepsis. Acute Crit Care. 2018;33:65–72. PubMed PMC