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Revista Brasileira de Terapia Intensiva

versión impresa ISSN 0103-507X

Rev. bras. ter. intensiva vol.24 no.1 São Paulo enero/mar. 2012 



Immunoinflammatory prognostic markers of early-onset neonatal sepsis in critically ill preterm newborns



Rita de Cassia Silveira; Renato Soibelmann Procianoy

Department of Pediatrics, Universidade Federal do Rio Grande do Sul - UFRGS - Porto Alegre (RS), Brazil and Division of Neonatology, Hospital de Clínicas de Porto Alegre - Porto Alegre (RS), Brazil

Corresponding author



It is challenging to determine the relationship between inflammatory and oxidative markers and the severity of sepsis in preterm neonates. This is especially true considering the high mortality caused either directly or indirectly by the pathogen and the classical immunoinflammatory multiorganic response, which causes significant delays in the neurodevelopment outcomes. The complications of neonatal sepsis include severe intraventricular hemorrhage (grades III and IV) with or without post-hemorrhagic dilation and periventricular leukomalacia.(1-3) TNF-α is an early neonatal sepsis marker, and its relationship with septic shock and diffuse tissue damage is well-defined in neonatology.(4) Cytokines, especially interleukin-6, are produced by a number of cells and are highly sensitive markers of early-onset neonatal sepsis in association with other immune-inflammatory markers, such as TNF-α, interleukin-8, procalcitonin and C-reactive protein.(5)

However, several peripartum conditions promote a balance of proinflammatory and anti-inflammatory events, affecting the cytokine levels in both: blood and cord blood samples. The multiple-hits theory describes perinatal inflammation as a cause and/or consequence of future impairment and poor prognosis in critically ill patients.(6) Fetal inflammatory response is a frequent causes of preterm delivery; indeed, it is estimated that 40% of preterm deliveries are associated with intra-uterine infection.(7) Additionally, preterm delivery is associated with immunological immaturity, rendering the preterm infant particularly vulnerable to early neonatal sepsis.(8)

In this issue of the Brazilian Journal of Intensive Care, Valerio et al. conclude that thiobarbituric acid reactive substances (TBARS) and IL-6 have a mild to moderate correlation with the SNAPPE-II severity scores but not mortality. The authors suggest that these molecules may represent early diagnostic markers of neonatal sepsis but they aren't good prognostic markers or good predictors of infection as a direct cause of death.(9) The data published by Valerio et al. are interesting and deserve further investigation in the future.(9) Several studies indicate that fetal inflammatory response preceding early delivery and increased fetal circulating cytokines are related to an increased risk of neonatal morbidities that diminish the short- and long-term prognosis of neonates, such as perinatal asphyxia, retinopathy of prematurity, bronchopulmonary dysplasia, white matter injury and cerebral palsy.(10-13)

Recently, we investigated the association between increased cytokine levels and retinopathy in seventy-four very low birth weight preterm infants with clinical criteria consistent with early infection; cytokines were assessed within the first three days of life. IL-6 > 357 pg/mL, IL-8 >216 pg/mL and TNF-α > 245 pg/mL were significantly associated with the development of retinopathy of prematurity.(14) Maternal chorioamnionitis, even when controlled for gestational age, gender, birth weight and maternal use of steroids and antibiotics, increases the risk of cerebral hemorrhage and retinopathy of prematurity.(15) In a two-year cohort follow-up of very low birth weight preterm newborns, we found that the severity of early-life inflammatory response, as measured by the levels of proinflammatory cytokines, was associated with poorer neurodevelopment outcome at two years corrected age.(16)

It is fundamental to understand the immune-inflammatory response secondary to neonatal sepsis and to describe a set of markers that can predict impairments. These markers should be assessed in future multicenter trials. It is currently unclear whether inflammatory response that begins in utero is the major factor responsible for the unfavorable events that are common in preterm infants.



1. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, Higgins RD; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292(19): 2357-65.         [ Links ]

2. Klinger G, Levy I, Sirota L, Boyko V, Lerner-Geva L, Reichman B; in collaboration with the Israel Neonatal Network. Outcome of early-onset sepsis in a national cohort of very low birth weight infants. Pediatrics. 2010; 125(4):e736-40.         [ Links ]

3. Procianoy RS, Silveira RC. Association between high cytokine levels with white matter injury in preterm infants with sepsis. Pediatr Crit Care Med. 2012;13(2):183-7.         [ Links ]

4. Silveira RC, Procianoy RS. Evaluation of interleukin-6, tumour necrosis factor-alpha and interleukin-1beta for early diagnosis of neonatal sepsis. Acta Paediatr. 1999;88(6):647-50.         [ Links ]

5. Lam HS, Ng PC. Biochemical markers of neonatal sepsis. Pathology. 2008;40(2):141-8.         [ Links ]

6. Dammann O, O'Shea TM. Cytokines and perinatal brain damage. Clin Perinatol. 2008;35(4):643-63, v. Erratum in Clin Perinatol. 2009;36(1):xvii.         [ Links ]

7. Lamont RF. Infection in the prediction and antibiotics in the prevention of spontaneous preterm labour and preterm birth. BJOG. 2003;110 Suppl 20:71-5. Review.         [ Links ]

8. Agrawal V, Hirsch E. Intrauterine infection and preterm labor. Semin Fetal Neonatal Med. 2012;17(1):12-9.         [ Links ]

9. Valerio TA, Cancelier AC, Constantino L, Petronilho F, Riiter C, Dal-Pizzol F. Marcadores inflamatórios e oxidativos em sangue de cordão umbilical como preditores de gravidade em sepse neonatal. Rev Bras Ter Intensiva. 2012;24(1):30-4.         [ Links ]

10. Silveira RC, Procianoy RS, Dill JC, da Costa CS. Periventricular leukomalacia in very low birth weight preterm neonates with high risk for neonatal sepsis. J Pediatr (Rio J). 2008;84(3):211-6.         [ Links ]

11. Paananen R, Husa AK, Vuolteenaho R, Herva R, Kaukola T, Hallman M. Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia. J Pediatr. 2009;154(1):39-43.e3.         [ Links ]

12. Jobe AH. Antenatal factors and the development of bronchopulmonary dysplasia. Semin Neonatol. 2003;8(1):9-17.         [ Links ]

13. Ambalavanan N, Carlo WA, D'Angio CT, McDonald SA, Das A, Schendel D, Thorsen P, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics. 2009;123(4):1132-41.         [ Links ]

14. Silveira RC, Fortes Filho JB, Procianoy RS. Assessment of the contribution of cytokine plasma levels to detect retinopathy of prematurity in very low birth weight infants. Invest Ophthalmol Vis Sci. 2011;52(3):1297-301.         [ Links ]

15. Polam S, Koons A, Anwar M, Shen-Schwarz S, Hegyi T. Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch Pediatr Adolesc Med. 2005;159(11):1032-5.         [ Links ]

16. Silveira RC, Procianoy RS. High plasma cytokine levels, white matter injury and neurodevelopment of high risk preterm infants: assessment at two years. Early Hum Dev. 2011; 87(6):433-7.         [ Links ]



Corresponding author:
Rita de Cássia Silveira
Rua Silva Jardim, 1155 - apto 701
Zip Code: 90450-071 - Porto Alegre (RS), Brazil

Conflicts of interest: None.

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