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Randomized Controlled Trial
. 2012 Oct;32(10):1888-96.
doi: 10.1038/jcbfm.2012.83. Epub 2012 Jul 18.

Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy

Dorothea D Jenkins  1 , Laura Grace Rollins, Jessica K Perkel, Carol L Wagner, Lakshmi P Katikaneni, W Thomas Bass, David A Kaufman, Michael J Horgan, Sheela Languani, Lawrence Givelichian, Koravangattu Sankaran, Jerome Y Yager, Renee H Martin
Affiliations
Randomized Controlled Trial

Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy

Dorothea D Jenkins et al. J Cereb Blood Flow Metab. 2012 Oct.

Abstract

Inflammatory cytokines may mediate hypoxic-ischemic (HI) injury and offer insights into the severity of injury and the timing of recovery. In our randomized, multicenter trial of hypothermia, we analyzed the temporal relationship of serum cytokine levels in neonates with hypoxic-ischemic encephalopathy (HIE) with neurodevelopmental outcome at 12 months. Serum cytokines were measured every 12 hours for 4 days in 28 hypothermic (H) and 22 normothermic (N) neonates with HIE. Monocyte chemotactic protein-1 (MCP-1) and interleukins (IL)-6, IL-8, and IL-10 were significantly higher in the H group. Elevated IL-6 and MCP-1 within 9 hours after birth and low macrophage inflammatory protein 1a (MIP-1a) at 60 to 70 hours of age were associated with death or severely abnormal neurodevelopment at 12 months of age. However, IL-6, IL-8, and MCP-1 showed a biphasic pattern in the H group, with early and delayed peaks. In H neonates with better outcomes, uniform down modulation of IL-6, IL-8, and IL-10 from their peak levels at 24 hours to their nadir at 36 hours was observed. Modulation of serum cytokines after HI injury may be another mechanism of improved outcomes in neonates treated with induced hypothermia.

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Figures

Figure 1
Figure 1
Median serum interleukin (IL)-8, IL-6, monocyte chemotactic protein-1 (MCP-1), IL-10 concentrations over time by treatment group, with median (pg/mL) and P values for each time point noted. *indicates P values <0.05.
Figure 2
Figure 2
Box plot of medians and interquartile ranges of serum interleukin (IL)-6, and monocyte chemotactic protein (MCP)-1 concentrations at enrollment by survival regardless of treatment group (IL-6, P=0.0023, MCP-1 P=0.0063).
Figure 3
Figure 3
Median serum interleukin (IL)-6, IL-8, and IL-10 concentrations over time in the hypothermia (H) treatment group by death or severe disability at 12 months (*IL-6 and IL-8, P=0.05, *IL-10 P=0.056).
Figure 4
Figure 4
Individual patient serum concentrations of IL-6, IL-8, and IL-10 over time in the hypothermia treatment group with a favorable outcome.
Figure 5
Figure 5
Median serum macrophage inflammatory protein 1a (MIP-1a) and interleukin (IL)-12 concentrations over time by outcome, regardless of treatment. Median MIP-1a at 60 hours in all patients with better outcomes was 26.4 pg/mL (interquartile range (IQR) 10.7 to 56.3 pg/mL, n=20), compared with 12.7 pg/mL in those with worse outcomes (IQR 7.5 to 17.3 pg/mL, n=12) (*P=0.0507). Median IL-12 concentration at 48 hours for those patients with better outcomes was 0.85 pg/mL (IQR 0.57 to 3.18 pg/mL, n=16) compared with those with adverse outcomes, 3.72 pg/mL (IQR 0.55 to 6.06, n=20, *P=0.0507). At 72 hours, median IL-12 was 0.67 pg/mL (IQR 0.51 to 0.91, n=12) for those patients with better outcomes versus 4.03 pg/mL (IQR 0.83 to 7.79, n=17, *P=0.027) for those with adverse outcomes.
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