Effects of prostacyclin on the early inflammatory response in patients with traumatic brain injury-a randomised clinical study

Abstract

Objective and design: A prospective, randomised, double-blinded, clinical trial was performed at a level 1 trauma centre to determine if a prostacyclin analogue, epoprostenol (Flolan®), could attenuate systemic inflammatory response in patients with severe traumatic brain injury (TBI).

Subjects: 46 patients with severe TBI, randomised to epoprostenol (n = 23) or placebo (n = 23).

Treatment: Epoprostenol, 0.5 ng · kg(-1) · min(-1), or placebo (saline) was given intravenously for 72 hours and then tapered off over the next 24 hours.

Methods: Interleukin-6 (IL-6), interleukin-8 (IL-8), soluble intracellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and asymmetric dimethylarginine (ADMA) levels were measured over five days. Measurements were made at 24 h intervals ≤24 h after TBI to 97-120 h after TBI.

Results: A significantly lower CRP level was detected in the epoprostenol group compared to the placebo group within 73-96 h (p = 0.04) and within 97-120 h (p = 0.008) after trauma. IL-6 within 73-96 h after TBI was significantly lower in the epoprostenol group compared to the placebo group (p = 0.04). ADMA was significantly increased within 49-72 h and remained elevated, but there was no effect of epoprostenol on ADMA levels. No significant differences between the epoprostenol and placebo groups were detected for IL-8 or sICAM-1.

Conclusions: Administration of the prostacyclin analogue epoprostenol significantly decreased CRP and, to some extent, IL-6 levels in patients with severe TBI compared to placebo. These findings indicate an interesting option for treatment of TBI and warrants future larger studies.

Trial registration: ClinicalTrials.gov Identifier, NCT01363583.

Keywords: Asymmetric dimethylarginine; Cytokines; Epoprostenol; Systemic inflammatory response; Traumatic brain injury.

Figures

Figure 1

IL-6 in pg/mL in patients treated with epoprostenol or placebo. IL-6, IL-8, sICAM-1, CRP, and ADMA were measured ≤24 h, 25–48 h, 49–72 h, 73–96 h, and 97–120 h after trauma. These time ranges are denoted as 24, 48, 72, 96, and 120, respectively, in the figures. Values ≤24 hours were all sampled before the start of epoprostenol (E) or placebo (P) infusion. The numbers of patients at each time point are indicated in parentheses. Data are presented as Box plots. The horizontal line within the box indicates the median, the 25th to 75th percentiles are within the box, and the minimum and maximum values are shown with error bars. Dotted line = 43 pg/mL (reference value for IL-6 according to the manufacturer). *Statistically significant difference between the epoprostenol and the placebo group within 73–96 hours after trauma (p = 0.04, Mann-Whitney’s test).

Figure 2

IL-8 in pg/mL in patients treated with epoprostenol or placebo. Dotted line = 8.6 pg/mL (reference value according to the manufacturer). For details see legend to Figure  1.

Figure 3

sICAM-1 in ng/mL in patients treated with epoprostenol or placebo. Dotted line = 230 ng/mL (reference value according to the manufacturer). For details see legend to Figure  1.

Figure 4

CRP in mg/L in patients treated with epoprostenol or placebo. Dotted line = 10 mg/L (the reference value at the accredited laboratory at Umeå University Hospital is <10 mg/L). *Statistically significant difference between the epoprostenol and the placebo group within 73–96 h (p = 0.04, Mann-Whitney’s test) and 97–120 h after trauma (p = 0.008, Mann-Whitney’s test). For details see legend to Figure  1.

Figure 5

ADMA in μmol/L in patients treated with epoprostenol or placebo. No statistically significant differences were seen between the groups. ADMA levels in both groups were significantly higher 72 h, 96 h, and 120 h after trauma compared to the 24 h sample (p < 0.001, Kruskal-Wallis test). Dotted line = 0.25 ± 0.12 μmol/L (the mean ADMA level in a reference material of healthy subjects). For details see legend to Figure  1.