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 198 patients will be randomized to receive either RV or TV at the same period of
the day throughout the experiment. In the week before starting study protocol, the RV and
TV groups will undergo a preliminary "tolerance session test" of gradual verticalization
(starting from 10 min and then progression toward 30 min).
The study protocol will involve 5 RV or 5 TV sessions per week for 4 weeks (total 20
sessions). Each daily RV or SR session last 30 minutes.
RV protocol and parameters: Erigo® gradual verticalization (from supine position up to
maximum 90°, in 3 steps), depending on the patient's vital signs compliance. The Erigo
verticalization is coupled with the rhythmic passive movement of the lower limbs ensuring
the more normal range of motion (ROM) and the alternation of loading and unloading of the
lower limbs, based on patient's osteo-articular condition (e.g., ROM=45°; cadence=min. 24
steps per minute).
TV protocol: consists in gradual verticalization (from supine position up to maximum 90°,
in 3 steps), depending on the patient's vital signs compliance, using a traditional
standing device (i.e., non-robotic traditional tilt table) Both groups received an
additional 60 minute-comprehensive daily (60 minutes) rehabilitation programme in the 3
months of the study. This programme consists of alternate bed positioning, passive limbs
mobilization, activities to increase arousal (e.g., multisensory stimulation), language
and swallowing therapy based on patient's functional condition.
Primary endpoint Coma Recovery-Scale Revised, CRS-R (pDoC) and Level of Cognitive
Functioning, LCF (EpDoC) Secondary endpoints Modified Ashworth scale, MAS; Muscle
Research Council, MRC (EpDoC) pDoC reflex movement to nociceptive stimulation (pDoC);
Disability Rating Scale, DRS; Adverse Events Report (AER)+Agitation Behavior Scale and
Nociception Coma Scale respectively; System Usability Scale (SUS); modified Barthel Index
(mBI).
Exploratory endpoints EEG architecture (e.g., microstates, functional connectivity, and
complexity measures) Blood biomarkers (i.e., BDNF, NF-L, and GFAP); Fondazione Don
Gnocchi-Clinical Complications Scale, FDG-CCS.
Adverse Events Report (weekly from enrolment through termination of RV or TV protocol).
During VEM session Heart rate (HR), mean arterial pressure (MAP), oxygen saturation
(SaO2), agitation, and pain will be monitored. Additionally, agitation and pain will be
measured by the Agitation Behavior Scale and Nociception Coma Scale respectively.