Reduction of Muscle Catabolism Through Brain Activation in Burn Patients

Critically ill patients with extensive burn injuries are at exceptionally high risk of developing profound skeletal muscle wasting and weakness as part of critical illness-related myopathy and neuropathy (CRIMYNE). This condition represents a major determinant of short- and long-term outcomes, contributing to delayed ventilator weaning, prolonged intensive care unit (ICU) and hospital length of stay, impaired rehabilitation, and persistent functional disability after discharge. In patients with large burns, muscle loss is particularly rapid and severe during the early post-injury phase, frequently exceeding 1 kg of lean body mass per day, and is accompanied by mitochondrial dysfunction, systemic inflammation, altered myokine signaling, and neurodegenerative changes affecting central, peripheral, and autonomic nervous systems.

Despite extensive research, effective preventive or therapeutic strategies to limit skeletal muscle catabolism in critically ill burn patients remain limited. Nutritional optimization, pharmacological interventions, and passive or assisted rehabilitation techniques have demonstrated minimal or inconsistent benefit. Active rehabilitation remains the only proven preventive approach; however, a substantial proportion of burn patients are unable to participate due to deep sedation, invasive mechanical ventilation, hemodynamic instability, prone positioning, unstable fractures, or the extent and severity of burn injuries. Consequently, there is a critical unmet need for rehabilitation strategies that can be applied safely and effectively during the early acute phase of critical illness.

Recent advances in neurorehabilitation suggest that activation of central motor pathways may exert anti-catabolic effects on skeletal muscle even in immobilized or unconscious patients. Functional proprioceptive stimulation (illusory movements induced by focal muscle vibration) activates cortical motor areas and has been shown to promote antidegenerative processes within the nervous system and skeletal muscle. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique capable of modulating cortical excitability and enhancing neuroplasticity, with established safety and efficacy in various neurological and movement disorders. Virtual reality (VR)-assisted rehabilitation provides immersive multisensory stimulation and may enhance motor network activation and engagement in conscious patients.

Sedation strategy is another critical determinant of neurological and functional outcomes in critically ill patients. Conventional intravenous sedatives, including propofol, dexmedetomidine, and benzodiazepines, are associated with adverse effects such as hemodynamic instability, prolonged awakening, delirium, drug accumulation, and potential neurodegenerative effects. Inhalational sedation with isoflurane represents a validated alternative that allows predictable awakening, preservation of spontaneous breathing, reduced opioid requirements, and potentially improved neurocognitive outcomes. Its use may facilitate daily sedation interruptions and early rehabilitation strategies in ICU patients.

The REMBRANT (REduction of Muscle catabolism through BRAin activation in burn patieNTs) study is a single-center, randomized, controlled, open-label clinical trial designed to evaluate whether a multimodal brain-activating rehabilitation strategy can attenuate skeletal muscle catabolism and improve functional outcomes in adult patients with extensive burn injuries. The study aims to integrate optimized sedation with innovative neurorehabilitation techniques to target the central mechanisms contributing to muscle wasting in critical illness.

A total of 30 adult patients with burns involving more than 30% of total body surface area (TBSA), admitted to the ICU and expected to require invasive mechanical ventilation and continuous sedation for at least seven days, will be enrolled. Participants will be randomized in a 1:1 ratio to either a control group receiving standard care or an intervention group receiving the Burn-Bundle Extended Rehabilitation Program. The study is conducted at a single specialized burn center to ensure standardized implementation of complex interventions and uniform data acquisition.

Both groups will receive standardized burn care and conventional rehabilitation according to institutional protocols. The control group will be sedated using standard intravenous sedatives, including propofol and/or dexmedetomidine. The intervention group will undergo inhalational sedation with isoflurane for the required duration of sedation. In addition, the intervention group will receive the Burn-Bundle Extended Rehabilitation Program, consisting of functional proprioceptive stimulation, repetitive transcranial magnetic stimulation, and virtual reality-assisted rehabilitation when consciousness allows. Functional proprioceptive stimulation will be applied twice daily during the early acute phase after burn injury, while rTMS will be administered once daily to potentiate cortical activation. Virtual reality-based interventions will be introduced in conscious patients as part of semi-active rehabilitation.

The primary objective of the study is to evaluate the effect of the intervention on skeletal muscle quantity and functional status during hospitalization and after discharge. Skeletal muscle mass and body composition will be assessed using dual-energy X-ray absorptiometry (DEXA), ultrasound measurement of the rectus femoris muscle, and anthropometric assessments. Functional status will be evaluated using standardized functional tests, including the Medical Research Council (MRC) sum score.

Secondary objectives include assessment of ICU length of stay, ventilator-free days, cognitive recovery, and quality of life. Quality of life will be evaluated using the EQ-5D-5L questionnaire at discharge and during follow-up visits at 3 and 6 months after hospital discharge. Cognitive recovery will be assessed using standardized clinical evaluations appropriate for critically ill patients.

A key mechanistic component of the study involves detailed metabolic and molecular analyses of skeletal muscle. Muscle biopsies obtained during routine surgical procedures will be used to assess mitochondrial bioenergetics using high-resolution respirometry. Parameters of mitochondrial function, including oxidative phosphorylation capacity, fatty acid oxidation, and respiratory control ratios, will be analyzed to determine the impact of the intervention on muscle energy metabolism.

In parallel, circulating and intramuscular myokine profiles will be analyzed using multiplex immunoassays. Selected myokines involved in muscle metabolism, inflammation, and neuro-muscular signaling will be measured in plasma samples and muscle biopsies at predefined time points during hospitalization. These analyses aim to elucidate the molecular mechanisms underlying muscle catabolism and recovery and to identify potential biomarkers associated with response to rehabilitation.

The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local regulatory requirements. Written informed consent will be obtained from all participants or their legally authorized representatives prior to study inclusion. The study protocol has been approved by the local Ethics Committee.

By combining optimized inhalational sedation with innovative neurorehabilitation techniques applicable during the acute phase of critical illness, the REMBRANT study aims to establish a novel therapeutic approach to limit skeletal muscle wasting in critically ill burn patients. The results of this study may provide important insights into central mechanisms of muscle catabolism and recovery and contribute to improved short-term clinical outcomes as well as long-term functional recovery and quality of life in this vulnerable patient population.

Inclusion criteria

• Adults aged 18 years or older
• Severe burn injury involving more than 30% of total body surface area (TBSA)
• Admission to the intensive care unit
• Expected need for invasive mechanical ventilation and continuous sedation for at least 7 days
• Ability to obtain written informed consent from the patient or a legally authorized representative

Exclusion criteria

• Pre-existing severe neuromuscular or neurodegenerative disease
• Known contraindication to inhalational sedation with isoflurane
• Pregnancy or breastfeeding
• Participation in another interventional clinical trial that could interfere with the study outcomes
• Any condition that, in the opinion of the investigator, would make participation in the study unsafe or interfere with protocol adherence