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Eren Ozek


Late-onset sepsis, carboxyhemoglobin, preterm neonates, biomarker



Background: To evaluate carboxyhemoglobin (COHb) levels in diagnosing late-onset sepsis (LOS) in preterm neonates.

Methods: The records of culture-positive LOS in preterm neonates hospitalized in NICU from January 2017 to July 2022 were reviewed.COHb levels, C-reactive protein, procalcitonin, and neutrophil to lymphocyte ratio of septic preterm infants were compared to controls. Serial COHb levels measured within six hours before or 24h after blood culture sampling, three to seven days prior, and three to five days after starting antimicrobial therapy were retrieved from patient records.

Results: The study included 77 blood-culture-positive preterm infants and 77 non-septic controls. During the LOS episode, the COHb values were found to be significantly increased (median: 1.8, IQR: 1.4-2.5) when compared to the control group (median: 1.2, IQR: 0.8-1.6) (p < 0.001). ROC analysis yielded an AUC of 0.714 for COHb (95% CI: 0.631-0.796, p<0.001). At an optimal cut-off of >1.5%, the test’s sensitivity was 64.94%, the specificity was 72.73%, the positive predictive value was 70.42%, and the negative predictive value was 67.47%.LOS led to a dramatic rise followed by a decrease after the initiation of the antimicrobial therapy [1.8 (1.4-2.5) ] vs. [1.45 (0.2-4)] p<0.001.

Conclusion: COHb levels increased at the beginning of LOS, decreasing in response to antibiotics. When used in conjunction with other sepsis biomarkers, the variation of COHb can be important in evaluating a LOS episode in preterm infants. COHb can be utilized as a quick, bedside approach for detecting LOS in preterm neonates in NICUs.


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1. Shane AL, Stoll BJ. Recent developments and current issues in the epidemiology, diagnosis, and management of bacterial and fungal neonatal sepsis. Am J Perinatol. 2013;30(2):131-41.
2. Ran NC, van den Hoogen A, Hemels MAC. Gram-negative Late-onset Sepsis in Extremely Low Birth Weight Infants Is Emerging in The Netherlands Despite Quality Improvement Programs and Antibiotic Stewardship!Pediatr Infect Dis J. 2019;38(9):952-957.
3. McArdle AJ, Webbe J, Sim K, Parrish G, Hoggart C, Wang Y, Kroll JS, Godambe S, Cunnington AJ. Determinants of Carboxyhemoglobin Levels and Relationship with Sepsis in a Retrospective Cohort of Preterm Neonates. PLoS One. 2016;11(8):e0161784. doi: 10.1371/journal.pone.0161784. eCollection 2016.
4. Turgut K, Yavuz E. Comparison of non-invasive CPAP with mask use in carbon monoxide poisoning Am J Emerg Med. 2020;38(7):1454-1457.doi: 10.1016/j.ajem.2020.04.050.
5. Panda SK, Nayak MK, Rath S, Das P. The Utility of the Neutrophil-Lymphocyte Ratio as an Early Diagnostic Marker in Neonatal Sepsis. Cureus. 2021;13(1):e12891.doi: 10.7759/cureus.12891.
6. Goldberg O, Amitai N, Chodick G, Bromiker R, Scheuerman O, Ben-Zvi H, Klinger G. Can we improve early identification of neonatal late-onset sepsis? A validated prediction model. J Perinatol. 2020; 40(9):1315-1322.
7. Fukuzumi N, Osawa K, Sato I, Iwatani S, Ishino R, Hayashi N, Iijima K, Saegusa J, Morioka I. Age-specific percentile-based reference curve of serum procalcitonin concentrations in Japanese preterm infants. Sci Rep. 2016; 6: 23871.
8. Kurul Ş, Simons SHP, Ramakers CRB, De Rijke YB, Kornelisse RF, Reiss IKM, Taal HR. Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates. Crit Care. 2021;25(1):12. doi: 10.1186/s13054-020-03423-2.
9. Inder TE Perlman JM, Volpe JJ. Preterm Intraventricular Hemorrhage/Posthemorrhagic Hydrocephalus. In: Volpe JJ (Ed) Volpe’s Neurology of the Newborn 6th Ed. Philadelphia, Elsevier.2018; 637-98.
10. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001; 163:1723–9.
11. International Committee for the Classification of Retinopathy of Prematurity, The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123(7):991-9.
12. Pergialiotis V, Konstantopoulos P, Karampetsou N, Koutaki D, Gkioka E, Perrea DN, Papantoniou N. Calprotectin levels in necrotizing enterocolitis: a systematic review of the literature. Inflamm Res. 2016; 65:847-852.
13. Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet. 2017;390(10104):1770-1780.
doi: 10.1016/S0140-6736(17)31002-4.
14. Acheampong EN, Tsiase JA, Afriyie DK, Amponsah SK. Neonatal Sepsis in a Resource-Limited Setting: Causative Microorganisms and Antimicrobial Susceptibility Profile. Interdiscip Perspect Infect Dis. 2022 ;2022:7905727. doi: 10.1155/2022/7905727.
15. Goldberg O, Amitai N, Chodick G, Bromiker R, Scheuerman O, Ben-Zvi H, Klinger G. Can we improve early identification of neonatal late-onset sepsis? A validated prediction model. J Perinatol. 2020;40(9):1315-1322.doi: 10.1038/s41372-020-0649-6.
16. Eschborn S, Weitkamp JH. Procalcitonin versus C-reactive protein: review of kinetics and performance for diagnosis of neonatal sepsis. J Perinatol. 2019;39(7):893-903.doi: 10.1038/s41372-019-0363X
17. Liu Y, Zhao L, Wu Z. Accuracy of C-Reactive Protein Test for Neonatal Septicemia: A Diagnostic Meta-Analysis. Med Sci Monit. 2019; 25:4076-4081. doi: 10.12659/MSM.916968.
18. Reinhart K, Meisner M, Brunkhorst FM. Markers for sepsis diagnosis: what is useful? Crit Care Clin. 2006;22(3):503-19, ix-x.doi: 10.1016/j.ccc.2006.03.003.
19. Pontrelli G, De Crescenzo F, Buzzetti R, Jenkner A, Balduzzi S, Calò Carducci F, Amodio D, De Luca M, Chiurchiù S, Davies EH, Copponi G, Simonetti A, Ferretti E, Di Franco V, Rasi V, Della Corte M, Gramatica L, Ciabattini M, Livadiotti S, Rossi P. Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis. BMC Infect Dis. 2017; 17(1):302.
20. Alkan Ozdemir S, Arun Ozer E, Ilhan O, Sutcuoglu S. Can neutrophil to lymphocyte ratio predict late-onset sepsis in preterm infants? J Clin Lab Anal. 2018;32(4):e22338.
21. Hornik CP, Benjamin DK, Becker KC, Benjamin DK Jr, Li J, Clark RH, Cohen-Wolkowiez M, Smith PB.Use of the complete blood cell count in late-onset neonatal sepsis. Pediatr Infect Dis J. 2012; 31(8):803-7.
22. Guney Varal I, Dogan P. Serial Carboxyhemoglobin Levels and Its Relationship with Late Onset Sepsis in Preterm Infants: An Observational Cohort Study. Fetal Pediatr Pathol. 2020; 39(2):145-155.doi: 10.1080/15513815.2019.1652377.
23. McArdle AJ, Webbe J, Sim K, Parrish G, Hoggart C, Wang Y, et al. Determinants of Carboxyhemoglobin Levels and Relationship with Sepsis in a Retrospective Cohort of Preterm Neonates. PLoS One. 2016;11(8):e0161784.
24. Wagener FA, Volk HD, Willis D, Abraham NG, Soares MP, Adema GJ, Figdor CG. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev. 2003;55(3):551-71. doi: 10.1124/pr.55.3.5.
25. Kondo M, Itoh S, Kusaka T, Imai T, Isobe K, Onishi S. The ability of neonatal and maternal erythrocytes to produce reactive oxygen species in response to oxidative stress. Early Hum Dev. 2002;66(2):81-8.doi: 10.1016/s0378-3782(01)00234-1.
26. Engel RR, Rodkey FL, O'Neal JD, Collison HA. Relative affinity of human fetal hemoglobin for carbon monoxide and oxygen. Blood 1969;33(1):37-45.
27. Shi Y, Pan F, Li H, Pan J, Qin S, Jiang D, Shen C. Carbon monoxide concentrations in paediatric sepsis syndrome Arch Dis Child. 2003;88(10):889-90.doi: 10.1136/adc.88.10.889.
28. Zegdi R, Perrin D, Burdin M, Boiteau R, Tenaillon A. Increased endogenous carbon monoxide production in severe sepsis. Intensive Care Med. 2002;28(6):793-6. doi: 10.1007/s00134-002-1269-7.
29. Sharma VS, Schmidt MR, Ranney HM. Dissociation of CO from carboxyhemoglobin. J Biol Chem1976 ;251(14):4267-72.
30. Sedlacek M, Halpern NA, Uribarri J. Carboxyhemoglobin and lactate levels do not correlate in critically ill patients. Am J Ther 1999;6(5):241-4. doi: 10.1097/00045391-199909000-00003.
31. Grigorescu BL, Săplăcan I, Bordea IR, Petrisor M, Coman O, Puiac CI, Toncean A, Fodor RS. Endogenous Carboxyhemoglobin Level Variation in COVID-19 and Bacterial Sepsis: A Novel Approach? Microorganisms. 2022;10(2):305.doi: 10.3390/microorganisms10020305.
32. Zuckerbraun BS, Otterbein LE, Boyle P, Jaffe R, Upperman J, Zamora R, Ford HR. Carbon monoxide protects against the development of experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. 2005;289(3):G607-13.doi: 10.1152/ajpgi.00055.2005.