Low Frequency Ventilation During Cardiopulmonary Bypass to Protect Postoperative Lung Function in Cardiac Valvular Surgery: The PROTECTION Phase II Randomized Trial

Abstract

Background: Cardiac surgery with cardiopulmonary bypass (CPB) triggers pulmonary injury. In this trial we assessed the feasibility, safety, and efficacy of low frequency ventilation (LFV) during CPB in patients undergoing valvular surgery.

Methods and results: Patients with severe mitral or aortic valve disease were randomized to either LFV or usual care. Primary outcomes included release of generic inflammatory and vascular biomarkers and the lung-specific biomarker sRAGE (soluble receptor for advance glycation end products) up to 24 hours postsurgery. Secondary outcomes included pulmonary function tests and 6-minute walking test up to 8 weeks postdischarge. Sixty-three patients were randomized (33 LFV versus 30 usual care). Mean age was 66.8 years and 30% were female. LFV was associated with changes of sRAGE (soluble receptor for advance glycation end products) levels (geometric mean ratio, 3.05; [95% CI, 1.13-8.24] 10 minutes post CPB, and 1.07 [95% CI, 0.64-1.79], 0.84 [95% CI, 0.55-1.27], 0.67 [95% CI, 0.42-1.07], and 0.62 [95% CI, 0.45-0.85] at 2, 6, 12, and 24 hours post CPB respectively). No changes were observed for any of the generic biomarkers. Respiratory index soon after surgery (mean difference, -0.61 [95% CI, -1.24 to 0.015] 10 minutes post end of CPB), forced expiratory volume after 1 second/forced vital capacity ratio (0.050 [95% CI, 0.007-0.093] at 6 to 8 weeks pos-surgery), Forced vital capacity alone (95% CI, -0.191 L [-0.394 to 0.012]) and 6-minute walking test score at discharge (63.2 m [95% CI, 12.9-113.6]) were better preserved in the LFV group. No other differences were noted.

Conclusions: The use of LFV during CPB in patients undergoing valvular surgery was feasible and safe and was associated with changes in sRAGE levels along with better preserved lung function and walking performance. These observations warrant further investigation in larger future studies.

Registration: URL: https://www.isrctn.com; Unique Identifier: ISRCTN75795633.

Keywords: cardiopulmonary bypass; low frequency ventilation; lung protection; pulmonary function tests; sRAGE; valvular surgery.

Figure 1. CONSORT flow chart.

CONSORT flow chart illustrating the allocation of patients between groups, exclusions, withdrawals overtime and follow‐up. CONSORT indicates Consolidated Standards of Reporting Trials; and CPB, cardiopulmonary bypass.

Figure 2. Effect of LFV on primary biomarkers outcome.

Forest plot illustrating the treatment effect for each biomarker. All the biomarkers shown, with the exception of S1P, were reported in pg/mL. The mean difference for tPAI‐1 was MD=81.5, 95% CI (−431.8 to 594.8) and is not presented in the figure. S1P was reported in μg/L. CPB indicates cardiopulmonary bypass; GMR, geometric mean ratio; IL, interleukin; LFV, low frequency ventilation; MD, mean difference; TNFα, tumor necrosis factor alpha; tPAI‐1, plasminogen activator inhibitor‐1; S1P, sphingosine‐1‐phosphate; sICAM‐1, soluble intercellular adhesion molecules‐1; sRAGE, soluble receptor for advance glycation end products; and sVCAM‐1, soluble vascular cell adhesion molecules‐1.