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.引言：血管紧张素II（angiotensin II）可在间歇性血液透析过程中减轻肌肉缺血，进而降低透析中肌肉痉挛的发生率和/或严重程度。本研究旨在验证间歇性血液透析期间输注血管紧张素II在缓解肌肉痉挛方面的安全性、可行性与有效性。方法：本研究针对频繁出现透析中肌肉痉挛的间歇性血液透析患者开展了一项先导性、单盲、随机交叉试验。患者被随机分配至接受静脉输注血管紧张素II或安慰剂组，干预周期为当周首次血液透析疗程；随后每周交叉切换至另一组别，共持续4周。主要结局指标为安全性，次要结局指标包括痉挛相关症状、血流动力学参数、透析处方调整情况及生物标志物水平。结果：本研究共纳入6名患者，完成24次透析疗程的观察。与安慰剂组相比，血管紧张素II组透析中高血压（收缩压＞180mmHg）的发生率更高（33% vs 17%，P=0.64），未观察到其他不良事件。相较于安慰剂组，肌肉痉挛发作频率更低（33% vs 92%，P=0.009），且痉挛严重程度更低：简要疼痛量表（Brief Pain Inventory）中位评分分别为1.4与5.3（P＜0.001），最大评分分别为1.2与6.0（P＜0.001）。针对痉挛的快速补液干预在血管紧张素II输注期间也更为少见（0% vs 42%，P=0.037）。结论：血管紧张素II可升高血压与心率，但对心输出量、肌钙蛋白、肌酸激酶或肾素水平无显著影响。综上，间歇性血液透析期间输注血管紧张素II在缓解透析中肌肉痉挛方面展现出良好的安全性与有效性，该研究结果支持开展更大规模的对照研究以进一步验证其临床价值。