Rajbeer Singh Sangha, MD

Rasmussen R, Wetterslev J, Stavngaard T, Juhler M, Skjøth-Rasmussen J, Grände PO, and Olsen NV. Effects of Prostacyclin on Cerebral Blood Flow and Vasospasm After Subarachnoid Hemorrhage: Randomized, Pilot Trial. Stroke. 2014

Delayed ischemic neurologic deficit (DIND) is a serious complication of aneurysmal subarachnoid hemorrhage. Although advances in treatment have improved prognosis for these patients, long-term clinical outcomes remain disappointing and the causes of DNID still remain largely understood. In the past it was thought to be secondary to angiographic vasospasm however current research models have debunked this theory suggesting that the factors that cause DNID may be more complex. The condition may manifest itself anytime within the first two weeks but most incidences occur between Day 5 and Day 10 and a peak incidence around Day 8. Factors related to the vascular endothelium and the smooth muscle cells are believed to play an important role. Prostacyclin is an endogenous substance released from the vascular endothelium. It is a potent vasodilator and inhibitor of leukocyte activation, platelet aggregation and leukocyte-endothelial interactions, all of which have been postulated to have an impact on the development of DIND. The authors of this study conducted a randomized, placebo-controlled trial, investigating the possible pharmacodynamic effects of prostacyclin on the human brain following SAH. 

The trial was a single-center, randomized, placebo controlled, parallel group, blinded, clinical, pilot trial. The primary outcome measured was change in global CBF from baseline calculated as CBF during intervention minus CBF at baseline. Secondary outcomes included occurrence of one or more DIND during the intervention, cerebral vasospasm qualified as severe, moderate, mild, or absent on a CT angiography, change from baseline in regional blood flow in each of the six vascular territories, and Glasgow Outcome Score (GOS) at three months after SAH. 111 patients met the inclusion criteria and of these 90 patients were included. The mean change in CBF for the placebo group was -4.65 ml/100g/min (95% CI, -8.64 to -0.17). The mean change in CBF for the groups receiving prostacyclin 1 ng/kg/min and 2 ng/kg/min were -2.05 (95% CI, -5.58 to 1.47) and -0.066 (95% CI, -3.59 to 3.46), respectively. Unadjusted analysis showed no statistically significant difference between the 3 groups (P =0.20). The highest incidence of DIND was observed in the placebo group (38%) and the lowest incidence was observed in the group receiving prostacyclin 1 ng/kg/min (21%); however, the difference between the three groups was not statistically significant (P =0.28). Analysis adjusted for baseline covariates was also not statistically significant (P =0.36).

This study was the first randomized, clinical trial investigating the possible pharmacological effects of prostacyclin on the human brain after subarachnoid hemorrhage. Based on the primary outcome in this trial, global CBF, was not markedly affected by administration of prostacyclin and does not seem to increase the net perfusion of the brain after SAH. While not statistically significant, the group receiving 1 ng/kg/min only approximately half of the DIND incidences and angiographic vasospasm was observed compared with the group receiving placebo. This could mean that the study was not powered to detect a difference. Given the safety of prostacyclin that was established from this trial, future trials investigating low-dose prostacyclin in relation to SAH should consider focusing on doses around 1 ng/kg/min and should be powered to detect changes in clinical outcome. Furthermore, patient outcomes should be analyzed using more sensitive scales such as validated self reported measures of quality of life (Neuro QOL); this would allow for smaller changes in functional outcomes to be detected as opposed to the glasgow coma scale.