Immunomodulatory Effects of Remote Ischemic Conditioning in Hemorrhagic Shock Patients in a Randomized Controlled Trial

Author(s):
Chung Ho Leung; Sandro Rizoli; Shawn Rhind; Andrew Baker; Christopher A. Caldarone; Ori Rotstein

Background:

Derangements in the immune response following hemorrhagic shock/resuscitation contribute to systemic inflammatory response syndrome and multiple organ dysfunction. We have previously reported that remote ischemic conditioning (RIC) prevented inflammation and organ injury in experimental models of hemorrhagic shock and therefore has potential to improve outcomes in humans. In the present study, we investigated the safety and immunomodulatory effects of administering RIC to trauma patients in hemorrhagic shock following arrival to our Level 1 Trauma Centre.

Hypothesis:

RIC is safe and exerts anti-inflammatory effects in trauma patients.

Methods:

A prospective phase II double blind randomized controlled trial was conducted on trauma patients admitted to a Level 1 trauma centre with blunt or penetrating injuries in hemorrhagic shock (systolic BP < 90mmHG). Patients were randomized in a 1:1 ratio to receive either Sham (0 mmHg) or RIC (5-min thigh cuff inflation at 250 mmHg followed by 5-min deflation repeated for 4 cycles). Blood samples were taken at admission (pre-intervention), one, three, and 24 hr post-intervention for evaluation of neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase (MPO) as a marker of degranulation. A panel of plasma cytokines and chemokines were evaluated by multiplex assay.

Results:

A total of 39 patients (21 Sham and 18 RIC) with a median ISS of 17 were enrolled. Hemorrhagic shock primed neutrophils for augmented PMA-stimulated oxidative burst activity and CD62L expression, but there was no difference between Sham and RIC groups. In addition, both groups had significant elevations in plasma levels of pro and anti-inflammatory cytokines and chemokines, but did not differ between groups. In a subgroup analysis of patients who received transfusion of blood products, RIC patients had significantly lower plasma MPO levels at 24 hr post-intervention (P < 0.05). In addition, RIC prevented the significant increases in Th2 chemokines TARC (CCL17) and MDC (CCL22) at 24 hr post-intervention (P < 0.05). Secondary clinical outcomes (blood products transfused, ICU and ventilator free days, nosocomial infections, adverse events, and 24 hr and 28 day mortality) were not different between groups.

Conclusions:

In our cohort of trauma patients, administration of RIC was safe and did not adversely affect clinical outcomes.  RIC appeared to prevent neutrophil degranulation and the rise in Th2 chemokines in the post resuscitation period. Further studies are warranted to study the impact of RIC in trauma patients.