Temporal Relationship between Serum Levels of Interleukin-6 and C-Reactive Protein in Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

Abstract

Objective C-reactive protein (CRP) is a useful marker of neonatal infection. Recent studies have shown that neonatal therapeutic hypothermia delays an elevation of CRP in infants with hypoxic-ischemic encephalopathy (HIE). This study investigated the time difference of peak levels of serum CRP and other inflammatory responses during therapeutic hypothermia.

Study design We prospectively studied the serial serum data of CRP, interleukin-6 (IL-6), procalcitonin (PCT), and complete blood counts during the first week of life in HIE infants receiving therapeutic hypothermia.

Results We identified 22 infants who received therapeutic hypothermia between August 2013 and July 2015. No infants developed clinically overt infections. The peak of serum levels of IL-6, PCT, and CRP were postnatal days 1, 2, and 4, respectively. White blood cells, neutrophils, and platelet counts gradually decreased from days 1 to 7. Early postnatal serum levels of IL-6 correlated with CRP on day 4 (IL-6 on day 2; r = 0.78, p < 0.001).

Conclusion The peak value of CRP on day 4 might reflect the early production and secretion of IL-6 rather than an actual infection. Serial measurement of IL-6 might help avoid invasive sepsis workup and unnecessary change of antibiotics in infants.

Keywords

C-reactive protein - infants - interleukin-6 - procalcitonin - sepsis

• References

• 1 Azzopardi DV, Strohm B, Edwards AD , et al; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361 (14) 1349-1358
• 2 Shankaran S, Pappas A, McDonald SA , et al; Eunice Kennedy Shriver NICHD Neonatal Research Network. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012; 366 (22) 2085-2092
• 3 Guillet R, Edwards AD, Thoresen M , et al; CoolCap Trial Group. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012; 71 (2) 205-209
• 4 Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med 2012; 166 (6) 558-566
• 5 van Oss CJ, Absolom DR, Moore LL, Park BH, Humbert JR. Effect of temperature on the chemotaxis, phagocytic engulfment, digestion and O2 consumption of human polymorphonuclear leukocytes. J Reticuloendothel Soc 1980; 27 (6) 561-565
• 6 Akriotis V, Biggar WD. The effects of hypothermia on neutrophil function in vitro. J Leukoc Biol 1985; 37 (1) 51-61
• 7 Biggar WD, Bohn D, Kent G. Neutrophil circulation and release from bone marrow during hypothermia. Infect Immun 1983; 40 (2) 708-712
• 8 Venkatesh M, Flores A, Luna RA, Versalovic J. Molecular microbiological methods in the diagnosis of neonatal sepsis. Expert Rev Anti Infect Ther 2010; 8 (9) 1037-1048
• 9 McWilliam S, Riordan A. How to use: C-reactive protein. Arch Dis Child Educ Pract Ed 2010; 95 (2) 55-58
• 10 Hofer N, Zacharias E, Müller W, Resch B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012; 102 (1) 25-36
• 11 Pourcyrous M, Bada HS, Korones SB, Baselski V, Wong SP. Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics 1993; 92 (3) 431-435
• 12 Kawamura M, Nishida H. The usefulness of serial C-reactive protein measurement in managing neonatal infection. Acta Paediatr 1995; 84 (1) 10-13
• 13 Nuntnarumit P, Pinkaew O, Kitiwanwanich S. Predictive values of serial C-reactive protein in neonatal sepsis. J Med Assoc Thai 2002; 85 (Suppl. 04) S1151-S1158
• 14 Rath S, Narasimhan R, Lumsden C. C-reactive protein (CRP) responses in neonates with hypoxic ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2014; 99 (2) F172
• 15 Chakkarapani E, Davis J, Thoresen M. Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed 2014; 99 (6) F458-F463
• 16 Okumuş N, Beken S, Aydın B , et al. Effect of therapeutic hypothermia on C-reactive protein levels in patients with perinatal asphyxia. Am J Perinatol 2015; 32 (7) 667-674
• 17 Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1: CD003311
• 18 Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998; 102 (4) E41
• 19 Schuetz P, Affolter B, Hunziker S , et al. Serum procalcitonin, C-reactive protein and white blood cell levels following hypothermia after cardiac arrest: a retrospective cohort study. Eur J Clin Invest 2010; 40 (4) 376-381
• 20 Hofer N, Müller W, Resch B. Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life. Clin Chem Lab Med 2011; 49 (2) 297-302
• 21 Ainbender E, Cabatu EE, Guzman DM, Sweet AY. Serum C-reactive protein and problems of newborn infants. J Pediatr 1982; 101 (3) 438-440
• 22 Forest JC, Larivière F, Dolcé P, Masson M, Nadeau L. C-reactive protein as biochemical indicator of bacterial infection in neonates. Clin Biochem 1986; 19 (3) 192-194
• 23 Kääpä P, Koistinen E. Maternal and neonatal C-reactive protein after interventions during delivery. Acta Obstet Gynecol Scand 1993; 72 (7) 543-546
• 24 Berger C, Uehlinger J, Ghelfi D, Blau N, Fanconi S. Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia. Eur J Pediatr 1995; 154 (2) 138-144
• 25 Chiesa C, Signore F, Assumma M , et al. Serial measurements of C-reactive protein and interleukin-6 in the immediate postnatal period: reference intervals and analysis of maternal and perinatal confounders. Clin Chem 2001; 47 (6) 1016-1022
• 26 Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J 1997; 16 (8) 735-746 , quiz 746–747
• 27 Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111 (12) 1805-1812
• 28 Jenkins DD, Rollins LG, Perkel JK , et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab 2012; 32 (10) 1888-1896
• 29 Fries M, Stoppe C, Brücken D, Rossaint R, Kuhlen R. Influence of mild therapeutic hypothermia on the inflammatory response after successful resuscitation from cardiac arrest. J Crit Care 2009; 24 (3) 453-457
• 30 Chalak LF, Sánchez PJ, Adams-Huet B, Laptook AR, Heyne RJ, Rosenfeld CR. Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J Pediatr 2014; 164 (3) 468-74.e1
• 31 Schuchat A, Zywicki SS, Dinsmoor MJ , et al. Risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case-control study. Pediatrics 2000; 105 (1 Pt 1) 21-26