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

Junichi Saito; Jun Shibasaki; Tomoyuki Shimokaze; Makoto Kishigami; Makiko Ohyama; Rikuo Hoshino; Katsuaki Toyoshima; Yasufumi Itani

doi:10.1055/s-0036-1583192

American Journal of Perinatology, Table of Contents

Am J Perinatol 2016; 33(14): 1401-1406
DOI: 10.1055/s-0036-1583192

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Junichi Saito

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

,

Jun Shibasaki

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

,

Tomoyuki Shimokaze

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

,

Makoto Kishigami

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

,

Makiko Ohyama

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

,

Rikuo Hoshino

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

,

Katsuaki Toyoshima

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

,

Yasufumi Itani

¹Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan

› Author Affiliations

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

Full Text

References

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