Supplementary Material for: A pilot, single-blinded, randomized cross-over trial of cramp reduction with angiotensin II in maintenance patients on hemodialysis (The CRAMP-HD study)

Introduction: Angiotensin II may reduce muscle ischemia during intermittent hemodialysis and thereby decrease the incidence and/or intensity of intradialytic muscle cramps. We aimed to test whether angiotensin II infusion during intermittent hemodialysis is safe, feasible, and effective in the attenuation of muscle cramps. Methods: We performed a pilot, single-blinded, randomized crossover trial of patients receiving intermittent hemodialysis who frequently experience intradialytic muscle cramps. Patients were randomly allocated to receive either intravenous angiotensin II or placebo for the duration of their first dialysis session of the week. They crossed over to the alternate arm each week for four weeks. The primary outcome was safety. Secondary outcomes included cramp-related symptoms, hemodynamic parameters, dialysis prescription alterations, and biomarkers. Results: We studied 24 sessions in 6 patients. Intradialytic hypertension (systolic blood pressure >180mmHg) occurred more often with angiotensin II than with placebo (33% vs 17% sessions, P=0.64). There were no other adverse events. Compared with placebo, muscle cramps were less frequent (33% vs. 92% sessions, P=0.009) and of lower intensity with angiotensin II (median Brief Pain Inventory score 1.4 vs. 5.3; P<0.001; maximal Brief Pain Inventory score 1.2 vs. 6.0; P<0.001). Fluid bolus administration for cramps was less common during angiotensin II infusion than placebo (0% vs. 42% sessions, P=0.037). Conclusion: Angiotensin II increased blood pressure and heart rate but not cardiac output or levels of troponin, creatine kinase or renin. In conclusion, angiotensin II infusion during intermittent hemodialysis appears safe and effective at reducing intradialytic muscle cramps. These observations justify further investigation in larger controlled studies.