Randomized Clinical Study of Temporary Transvenous Phrenic Nerve Stimulation in Difficult-to-Wean Patients

Abstract

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: Multicenter, open-label, randomized, controlled study. Patients aged ⩾18 years on invasive mechanical ventilation for ⩾4 days and having failed at least two weaning attempts received temporary transvenous diaphragm neurostimulation using a multielectrode stimulating central venous catheter (bilateral phrenic stimulation) and standard of care (treatment) (n = 57) or standard of care (control) (n = 55). In seven patients, the catheter could not be inserted, and in seven others, 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 incidences of successful weaning were 82% (treatment) and 74% (control) (absolute difference [95% confidence interval (CI)], 7% [-10 to 25]), P = 0.59. Mechanical ventilation duration (mean ± SD) was 12.7 ± 9.9 days and 14.1 ± 10.8 days, respectively, P = 0.50; maximal inspiratory pressure increased by 16.6 cm H₂O and 4.8 cm H₂O, respectively (difference [95% CI], 11.8 [5 to 19]), P = 0.001; and right hemidiaphragm thickening fraction during unassisted spontaneous breathing was +17% and -14%, respectively, 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 registered with www.clinicaltrials.gov (NCT03096639) and the European Database on Medical Devices (CIV-17-06-020004).

Keywords: diaphragm weakness; mechanical ventilation; ventilator-induced diaphragmatic dysfunction; weaning.

Figure 1.

Study flow chart. Of the 127 eligible patients who consented to the study, 12 were not randomized and therefore were not included in the study. They were part of a “roll-in” process intended to familiarize the investigators with the technology. As such, for these patients, the catheter was inserted, and the therapy was delivered for training purposes, but they were not included in the study. Fifty-five patients were randomized to the control group, and 57 to the treatment group. All patients who were randomized to the control group qualified for the modified intent-to-treat (mITT) population; 45 of these patients completed the 30-day follow-up, 8 died before the 30-day follow-up, and 2 did not complete the study for other reasons (one patient was a screening failure, and the other patient was transferred to another hospital and withdrew from the study upon transfer). Treatment = temporary transvenous diaphragm neurostimulation. *Of the 57 patients of the treatment group, the therapy could not be achieved in 14 patients; therefore, these patients did not qualify for the mITT population. The reasons for not achieving therapy were the following: 1) The catheter was inserted and correctly positioned, but the diaphragm could not be stimulated (n = 7); 2) the catheter was not inserted in 4 patients (guidewire could not be passed [n = 2], presence of different catheter already in place [n = 1], or vessel damage because of radiotherapy [n = 1]); 3) no attempt (patient withdrew consent [n = 1] or screening failure due to a body mass index of >40 [n = 1]); and 4) the catheter was inserted but removed on the same day because of resistance and thrombus in the vessel (n = 1). These patients were followed for adverse events 48 hours after the initial attempt to place the catheter or last contact with the catheter. The remaining 43 patients were evaluable for the primary effectiveness analysis (mITT), 38 completed the Day 30 follow-up, 3 died before the 30th day, and 2 did not complete the study for other reasons (one patient was withdrawn by the investigator and the second chose to withdraw from the study due to pain associated with stimulation).

Figure 2.

Time course of maximal inspiratory pressure (MIP). Control = standard of care for difficult and prolonged mechanical ventilation weaning. Treatment = temporary transvenous diaphragm neurostimulation. Top: change in MIP with last observation carried forward. For independent variables, randomized group P < 0.001; study day P = 0.071; and randomized group × study day interaction P = 0.089. Bottom: change in MIP with last observation carried forward. For independent variables, randomized group P = 0.019, study day P = 0.069, baseline MIP P = 0.0006, baseline BMI P = 0.562, and randomized group × study day interaction P = 0.0881. BMI = body mass index; CI = confidence interval; mITT = modified intent to treat.

Figure 3.

Dose relationship between stimulation “dose” and maximal inspiratory pressure (MIP). For study group with treatment divided into two groups on the basis of the median proportion of protocol required stimulations received, P < 0.001, study day P = 0.025, and study group × study interaction P = 0.108. CI = confidence interval.