Serum nitric oxide and pediatric sepsis outcomes

Main Article Content

Ronald Chandra
Jose M. Mandei
Jeanette I. Ch. Manoppo
Rocky Wilar
Ari L. Runtunuwu
Phey Liana


Background Sepsis is the complex pathophysiologic responses
of the host against systemic infection. Sepsis can cause severe
conditions such as septic shock and multiple organ failure.
Although we have a better understanding of the molecular basis
of sepsis as well as aggressive therapy, the mortality rate remains
high, between 20-80%. Nitric oxide (NO) is one of the mediators
associated with cardiovascular failure, apoptosis and organ
dysfunction in sepsis.
Objective To evaluate for a possible correlation between NO
levels and outcomes in pediatric sepsis.
Methods A prospective cohort study was conducted at the
pediatric intensive care unit (PICU) of Prof. Dr. R.D. Kandou
General Hospital in Manado, from June to November 2012. Forty
children aged one month to five year old, fulfilled the International
Pediatrics Sepsis Consensus Conference 2 005 criteria were recruited.
Nitrite oxide metabolites (nitrite and nitrate) levels were measured
using a calorimetric assay kit (Cayman®, Catalog No.780001)
from venous blood specimens collected at admission. All patients
received antibiotics empirically within an hour of the diagnosis.
Outcomes of patients recorded were survivor or died, and length
of stay in PICU.
Results Mann-Whitney U test revealed a significant difference
between median serum NO levels ins urvivors and those who died
(18.60 vs. 36.50 fLM/L, respectively; P= 0.016).
Conclusion Serum NO concentration is higher in those who
died than in survivors of pediatric sepsis. Specific NO inhibition
may be beneficial in decreasing morbidity and mortality in this

Article Details

How to Cite
Chandra R, Mandei J, Manoppo J, Wilar R, Runtunuwu A, Liana P. Serum nitric oxide and pediatric sepsis outcomes. PI [Internet]. 31Aug.2014 [cited 20Sep.2020];54(4):213-. Available from:
Received 2016-09-16
Accepted 2016-09-16
Published 2014-08-31


1. Jaramillo-Bustamante JC, Marin-Agudelo A, Fernan dezLaverde M, Bareno-Silva J. Epidemiology of sepsis in pediatric intensive care units: first Colombian multicenter study. Pediatr Crit Care Med. 2012;13:501-8
2. Thomas NJ, Tamburro RF, Hall MW, Rajasekaran S, Venglarcik JS. Bacterial sepsis and mechanisms of microbial pathogenesis. In: Nichols DG, Ackerman AD, Argent AC, editors. Rogers' Textbook of Pediatric Intensive Care. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 1300-27.
3. Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. International pediatrics sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2-8.
4. Pavare J, Grope I, Gardovska D. Prevalence of systematic inflammatory response syndrome (SIRS) in hospitalized children: a point prevalence study. BMC Pediatr. 2009;9:25.
5. Khan MR, Maheshwari PK, Masood K, Qamar FN, Haque A Epidemiology and outcome of sepsis in a tertiary care PICU of Pakistan. Indian J Pediatr. 2012;79:1454-8.
6. Wong HR, Carcillo JA, Burckart G, Shah N, Janosky JE. Increased serum nitrite and nitrate concentrations in children with the sepsis syndrome. Crit Care Med. 1995;23:835-42.
7. von-Dessauer B, Bongain J, Molina V, Quilodran J, Castillo R, Rodrigo R. Oxidative stress as a novel target in pediatric sepsis management. J Crit Care. 2011;26:103el-7.
8. Weighardt H, Holzmann B. Role ofToll-like receptor responses for sepsis pathogenesis. Immunobiology. 2007;212:715-22.
9. Brilli RJ, Goldstein B. Pediatric sepsis definitions: Past, present and future. Pediatr Crit Care Med. 2005;6:6-8.
10. Peters K, Unger RE, Brunner J, Kirkpatrick CJ. Molecular basis of endothelial dysfunction in sepsis. Cardiovasc Res. 2003;60:49-57.
11. Azevedo LCP. Mitochondrial dysfunction during sepsis. Endocr Metab Immune Disord Drug targets. 2010;10:214-23.
12. Victor VM, Esplugues JV, Hernandez-Mijares A, Rocha M. Oxidative stress and mitochondrial dysfunction in sepsis: a potential therapy with mitoch ondria-targeted antioxidan ts. Infect Disord Drug Targets.2009;9:376-89.
13. Cena J, Chow AK, Schulz R. Nitric oxide, peroxynitrite and matrix metalloproteinases: insight into the pathogenesis of sepsis. In: Tota B, Trimmer B, editors. Nitric Oxide. 1st ed. Oxford: Elsevier; 2007. p. 367-95.
14. Victor VM, Rocha M, De la Fuente M. Immune cells: free radicals and antioxidants in sepsis. Int Immunopharmacol. 2004;4:327-47.
15. Symeonides S, Balk RA. Nitric oxide in the pathogenesis of sepsis. Infect Dis Clin North Am. 1999;13:449-63.
16. Gross SS, Wolin MS. Nitric oxide: pathophysiological mechanisms. Ann Rev Physiol. 1995;57:737-69.
17. Wearden ME. Nitric oxide synthase inhibitors for septic shock. Sem Pediatr Infect Dis. 2001;12:42-5.
18. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315-424.
19. Suchner U, Heyland DK, Peter K. Immune-modulatory actions of arginine in the critically ill. Br J Nutt. 2002;87:121-32.
20. Duke T, South M, Stewart A. Activation of L-arginine nitric oxide pathway in severe sepsis. Arch Dis Child. 1997;76:203-9.
21. Doughty L, Carcillo JA, Kaplan S, Janosky J. Plasma nitrite and nitrate concentrations and multiple organ failure in pediatric sepsis. Crit Care Med. 1998;26:157-62.
22. Barthlen W, Stadler J, Lehn NL, Miethke T, Bartels H, Siewert JR. Serum levels of end products of nitric oxide synthesis correlate positively with tumor necrosis factor alpha and negatively with body temperature in patients with postoperative abdominal sepsis. Shock. 1994;2:398-401.
23. Terregino CA, Lopez BL, Karras DJ, Killian AJ, Arnold GK. Endogenous mediators in emergency department patients with presumed sepsis: are levels associated with progression to severe sepsis and death? Ann Emerg Med. 2000;35:26-34.
24. Adamik B, Kubler-Keilb J, Golebiowska B, Gamian A, Kubler A. Effect of sepsis and cardiac surgery with cardiopulmonary bypass on plasma level of nitric oxide metabolites, neopterin, and procalcitonin: correlation with mortality and postoperative complications. Inten sive Care Med. 2000;26:1259-67.
25. Mitaka C, Hirata Y, Yokoyama K, Wakimoto H, Hirokawa M, Nosaka T, et al. Relationships of circulating nitrite/nitrate levels to severity and multiple organ dysfunction syndromes in systemic inflammatory response syndrome. Sh ock. 2003;19:305-9.
26. Baines PB, Stanford S, Bishop-Bailey D, Sills JA, Thomson APJ, Mitchell JA, Fear SC, Hart CA, Petros AJ. Nitrite oxide production in meningococcal disease is directly related to disease severity. Crit Care Med. 1999;27:1187-90.
27. Ho JT, Chapman MJ, O'Connor S, Lam S, Edwards J, Ludbrook G, Lewis JG, et al. Characteristics of plasma NOx levels in severe sepsis: high interindividual variability and correlation with illness severity, but lack of correlation with cortisol levels. Clin Endocrinol. 2010;73:413-20.
28. Wong HR, Carcillo JA, Burckart G, Kaplan SS. Nitric oxide production in critically ill patients. Arch Dis Child. 1996;74:482-9.
29. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnock JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem. 1989;126:131-8.
30. El-Gawad TAA, El-Sahrigy SAF, Abdel-Rahman AMO, Ghaffar EA, El-Rasheed EA. Plasma levels of nitric oxide and carbon monoxide in critically ill children with septic syndrome. J Med Sci. 2007;7:769-75.
31. Galley HF, Webster NR. Plasma nitrite is increased in patients who die from sepsis. Intensive Care Med. 1996;22:S327.
32. Fortin CF, McDonald PP, Fulop T, Lesur O. Sepsis, leukocytes, and nitric oxide (NO): an intricate affair. Shock. 2010;33:344-52.
33. Collaborative group for the study of sepsis in PICUs in Sanghai area. Hospital epidemiology, management and outcome of pediatric sepsis and severe sepsis in 4 PICUs in Sanghai. Zhonghua Er Ke Za Zhi. 2012;50:172-7.
34. Groeneveld PH, Kwappen berg KM, Langermans JA, Nibbering PH, Curtis L. Relation between pro- and antiinflammatory cytokines and the production of nitric oxide (NO) in severe sepsis. Cytokine. 1997;9:138-42.
35. Doughty LA, Kaplan SS, Carcillo JA. Inflammatory cytokines and nitric oxide respons es in pediatric sepsis and organ failure. Crit Care Med. 1996;24:1137-43.
36. Survillan JS, Kilpatrick L, Costarino AT Jr, Lee SC, Harris MC. Correlation of plasma cytokine elevations with mortality rate in children with sepsis. J Pediatr. 1994;124:105-111.
37. Ellis G, Adatia I, Yazdanpanah M, Makela SK. Nitrite and nitrate analyses: a clinical biochemistry perspective. Clin Biochem. 1998;31:195-220.
38. Strand OA, Leone A, Giercksky KE, Kirkeboen KA. Nitric oxide indices in human septic shock. Crit Care Med. 2000;8:2779-85.