Multicentric Study on Combined Verticalization and Mobilization in Patients With Severe Acquired Brain Injury: A Randomized Controlled Trial

Background Italian Consensus on rehabilitation of patients with severe acquired brain injury (sABI) and recent American Academy of Neurology guidelines on patients with sABI and prolonged disorder of consciousness (pDoC) provided recommendations for admission of such complex disabled patients to inpatient specialized rehabilitation units with high expertise on multidisciplinary care.

In such dedicated settings (in Italy named as high specialty rehabilitation for sABI, Cod 75) a comprehensive standard rehabilitation programme includes positioning, prolonged passive range of motion exercises, and splinting protocols to prevent or remediate neuromuscular complications (contractures, spasticity, and heterotopic ossifications). Simultaneously, basic multi-sensory stimulation or targeted cognitive training should be implemented for facilitating cognitive functioning recovery. In the rehabilitation project for patients with sABI, it is essential to include exercises that facilitate the recovery of the upright position (or verticalization), in order to prevent secondary complications from immobility (e.g., stasis pneumonias, deep vein thrombosis), to facilitate the stabilization of the haemodynamic balance (known to be altered in this population after the acute event), to promote the improvement of cognitive performance (especially vigilance and attention), and to improve the muscular-cutaneous trophism. Verticalization with traditional tilt-table training can show several adverse events: no leg movements during tilt-table verticalization lead to limited musculoskeletal and cardiovascular response; 2. pooling of blood in the lower extremities which can lead to a drop of the central blood and hypotension; 3. It requires substantial modification of cardiovascular therapy due to presyncope symptoms.

More recently, tilt-table equipped with the robot-assisted lower limbs cyclic mobilization has been proposed as a safe and suitable device for accelerating the adaptation to vertical posture in bedridden patients with brain-injury since the acute phase. However, contrasting, and inconclusive effects of controlled verticalization on functionality, gait/balance and level of consciousness in patients with sABI have been found, likely because of the limited methodological quality of the available clinical trials. All studies present some concerns such as small cohorts or heterogeneous cohorts of patients with sABI (e.g., chronic patients with sequelae of sABI) or the randomization process is not described.

The present multicentre study aims at overcoming these limitations evaluating the effectiveness of robotic assisted verticalization versus traditional verticalization (TV) in a large cohort of patients with sABI. Standardized and validated clinical tools will be used for evaluating effect on patient's motor, cognitive and functional performances. Additional markers will be used as outcome measures for investigating possible brain plasticity. Neurophysiological findings (e.g., EEG background activity and reactivity and quantitative EEG metrics) and blood biomarkers have been correlated to cognitive performance and assist prognostication in patients with sABI and pDoC34,. Brain-derived neurotrophic factor, BDNF, a neurotrophin involved in neurogenesis and synaptic plasticity can be upregulated by physical exercise. However, a recent study showed that BDNF serum levels do not change after robotic assisted verticalization in patients with pDoC. Neurofilament light chain, NF-L, a marker of primary and secondary neurodegeneration in sABI was linked to long-term axonal degeneration and poor outcome. Glial fibrillary acid protein, GFAP, a filament protein is related to brain function recovery.

Methods 118 patients will be randomized to receive either VEM or TV at the same period of the day throughout the experiment. In the week before starting study protocol, the VEM and TV groups will undergo a preliminary "tolerance session test" of gradual verticalization (starting from 10 min and then progression toward 30 min).