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RATIONALE Diaphragm dysfunction is frequently observed in critically ill patients with difficult weaning from mechanical ventilation. OBJECTIVES To evaluate the effects of temporary transvenous diaphragm neurostimulation on weaning outcome and maximal inspiratory pressure. METHODS Multicentre, open-label, randomised, controlled study. Patients aged ≥18 years on invasive mechanical ventilation for ≥4 days and having failed ≥2 weaning attempts received temporary transvenous diaphragm neurostimulation using a multi-electrode stimulating central venous catheter (bilateral phrenic stimulation) and standard of care (treatment) (N=57) or standard of care (control) (N=55). In 7 patients, the catheter could not be inserted and in 7 pacing therapy could not be delivered, consequently data were available for 43 patients. The primary outcome was the proportion of patients successfully weaned. Other endpoints were mechanical ventilation duration, 30-day survival, maximal inspiratory pressure, diaphragm thickening fraction, adverse events, and stimulation-related pain. MEASUREMENTS AND MAIN RESULTS The incidence of successful weaning was 82% (treatment) and 74% (control) (absolute difference [95% CI]: 7% [-10,25], P=0.59). Mechanical ventilation duration (mean±standard deviation) was 12.7±9.9 days and 14.1±10.8 days (P=0.50); maximal inspiratory pressure increased by 16.6 cmH2O and 4.8 cmH2O (difference [95% CI] 11.8 [5, 19] P=0.001); right hemidiaphragm thickening fraction during unassisted spontaneous breathing was +17% and -14% (P=0.006), without correlation with changes in maximal inspiratory pressure. Serious adverse event frequency was similar in both groups. Median stimulation-related pain in the treatment group was 0 (no pain). CONCLUSIONS Temporary transvenous diaphragm neurostimulation did not increase the proportion of successful weaning from mechanical ventilation. It was associated with a significant increase in maximal inspiratory pressure suggesting reversal of the course of diaphragm dysfunction. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03096639.