Efficacy and safety of HD-tDCS and respiratory rehabilitation for critically ill patients with COVID-19 The HD-RECOVERY randomized clinical trial

Abstract

Background and purpose: Acute Respiratory Distress Syndrome (ADRS) due to coronavirus disease 2019 (COVID-19) has been associated with muscle fatigue, corticospinal pathways dysfunction, and mortality. High-Definition transcranial Direct Current Stimulation (HD-tDCS) may be used to attenuate clinical impairment in these patients. The HD-RECOVERY randomized clinical trial was conducted to evaluate the efficacy and safety of HD-tDCS with respiratory rehabilitation in patients with moderate to severe ARDS due to COVID-19.

Methods: Fifty-six critically ill patients were randomized 1:1 to active (n = 28) or sham (n = 28) HD-tDCS (twice a day, 30-min, 3-mA) plus respiratory rehabilitation for up to 10 days or until intensive care unit discharge. The primary outcome was ventilator-free days during the first 28 days, defined as the number of days free from mechanical ventilation. Furthermore, secondary outcomes such as delirium, organ failure, hospital length of stay and adverse effects were investigated.

Results: Active HD-tDCS induced more ventilator-free days compared to sham HD-tDCS. Patients in the active group vs in the sham group experienced lower organ dysfunction, delirium, and length of stay rates over time. In addition, positive clinical response was higher in the active vs sham group. There was no significant difference in the prespecified secondary outcomes at 5 days. Adverse events were similar between groups.

Conclusions: Among patients with COVID-19 and moderate to severe ARDS, use of active HD-tDCS compared with sham HD-tDCS plus respiratory rehabilitation resulted in a statistically significant increase in the number of ventilator-free days over 28 days. HD-tDCS combined with concurrent rehabilitation therapy is a safe, feasible, potentially add-on intervention, and further trials should examine HD-tDCS efficacy in a larger sample of patients with COVID-19 and severe hypoxemia.

Keywords: Acute respiratory distress syndrome; Coronavirus disease; High-definition transcranial direct current stimulation; Noninvasive brain stimulation; Respiratory rehabilitation.

Fig. 1

HD-tDCS setup and montage. A. 4x1 HD-tDCS device. B. Soterix neurostimulator delivering the current on the 5 electrodes in a 4x1 HD-tDCS montage positioned around a circle of 7.5 cm of diameter centered to the target electrode position (the left diaphragmatic motor cortex).

Fig. 2

Screening, Randomization, and Follow-up of Patients in the HD-RECOVERY trial. HD-tDCS indicates High-definition transcranial direct current stimulation.

Fig. 3

Ventilator-Free Days at 28 Days. Panels showing individual changes in ventilator-free days from baseline to treatment slopes (follow-up) are displayed with box plots for groups (mean, central line; SD, boxes) overlaid with dots for single patients.

Fig. 4

Organ Dysfunction and Delirium Rates. Distributions of the Secondary Outcomes Organ Dysfunction, SOFA score, (A) and Delirium, CAM-ICU score, (B) from baseline to endpoint. Active High-definition transcranial direct current stimulation (HD-tDCS) was superior to sham. Intention-to-treat analysis. Error bars indicate 1 SD.

Fig. 5

Clinical Response. Distributions of the Secondary Outcomes Organ Dysfunction, SOFA score, (A) and Delirium, CAM-ICU score, (B) from baseline to endpoint. Active High-definition transcranial direct current stimulation (HD-tDCS) was superior to sham. Intention-to-treat analysis. Error bars indicate 1 SD.