Functional disability, a natural consequence of weakness, is a frequent and long‐lasting complication in survivors of critical illness[1–3]. Over recent decades, mortality from acute critical illness has decreased with a consequent increasing number of ICU survivors. Understanding the post-ICU morbidity experienced by these survivors has become increasingly important. The greatest burdens that survivors of critical illness face are related to neuromuscular dysfunction and neuropsychological maladjustment. In particular, neuromuscular abnormalities during critical illness are common, with a median prevalence of 57% . In both patients with chronic critical illness and survivors of severe critical illness, neuromuscular weakness may be substantial and persistent, resulting in important decrements in physical function and quality of life for years after discharge [1,2].
In the past, routine features of general care provided in the ICU included liberal use of sedation and immobilization of the patient, which were thought to be necessary for facilitating interventions to normalize physiological function by artificial means. Over the last decade, there has been a paradigm shift away from this approach towards a more conservative treatment philosophy for patients in the ICU [4,6,7]. This paradigm shift is consistent with the observation that long‐term physical problems in survivors of critical illness, particularly those with respiratory failure, may result from the protracted ICU stay and period of immobilization during which the patient is receiving organ support that is essential for survival [2,4]. In line, daily interruption of sedation policy has been widely adopted and proven to be beneficial and early mobilization culture is spreading quickly across ICUs [9–13]. Indeed, these strategies, together with early physical therapy [9,11,12,14–20] are the only safe [12,20–22] and effective interventions in the prevention of long-term neuromuscular disability in survivors of intensive care. It should be stressed that in these studies, early rehabilitation is defined as starting between day 2 and 5 of ICU stay [9,11,12,14–19], or as an activity beginning before ICU discharge .
Standard “early” rehabilitation cannot be started early enough, and FES‐CE may be a solution to this dilemma. The first week on the ICU is critical as muscle mass and function is lost quickly. Immobility‐associated muscle loss is evident as early as within 18‐48 hours of onset of acute critical illness or severe injury [23,24] and is greatest during the first 2 to 3 weeks of critical illness[25,26].. Up to 40% loss of muscle strength can occur within the first week of immobilization, with a daily rate of strength loss between 1.0% and 5.5%. A 10 to 14% decrease in cross-sectional measurements of the rectus femoris muscle has been observed within the first week of ICU stay . Conventional rehabilitation during the first few days in the ICU is indeed limited in patients who are sedated and mechanically ventilated, and typically consists of passive limb movements, with or without the use of stretch reflex [16,20]. Schweickert  provided the earliest (within 48 hours of intubation) and largest dose of rehabilitation (26±14 min a day for patients on mechanical ventilation) and reported improvements of physical function at hospital discharge, but no measurements beyond. Active rehabilitation is delayed until the neurological condition of the patient improves enough to facilitate participation. In the sickest patients, who are at particular risk of developing ICUAW, sedation and immobility may be prolonged well beyond first week, when established damage to the muscle has already occurred.
There are several ways to deliver more effective physical exercise therapy to patients who are sedated and mechanically ventilated. For example physical exercise can be delivered effectively and safely by passive supine cycling on a bicycle ergometer [15,18,28–30]. More recently, electrical neuromuscular stimulation (NMES) has been developed to mimic active exercise in patients, who lack voluntary muscle activity[31–39]. During NMES, cutaneous electrodes placed over specific muscle groups electrically trigger muscle contractions. In order to achieve maximum efficacy, passive cycling and NMES can be delivered simultaneously and synchronised to produce a coordinated pattern of movements. The technique is called FESCE (functional electrical stimulation-assisted cycle ergometry). There is a large body of experience with these methods in the rehabilitation of patients with stroke and spinal cord injuries (reviewed in: ). The method is effective in preventing the loss of muscle mass  and has been shown to improve anabolic resistance and insulin sensitivity in quadriplegic patients[42,43].
The only study of FESCE in critically illness is the pilot trial of Parry et al. , where the feasibility and safety of FESCE was demonstrated in a small cohort of critically ill patients (8 patients received the FESCE intervention, versus 8 controls). Patients in the intervention group showed significant improvements in the Physical Function in Intensive Care Test and a faster recovery of functional milestones (e.g. time to stand from lying, and walking on the spot). However, the mechanism by which this occurred is unknown. There are no data on the effect of FESCE on long‐term functional outcome in ICU survivors. In healthy volunteers  and patients with spinal cord injury, unloaded FESCE can increase whole-body oxygen consumption. It is unknown whether these effects, including improving insulin sensitivity and protein metabolism , can also be achieved in critically ill patients.
Mechanisms of muscle wasting and ICUAW. Pathophysiology of ICUAW is complex and multifactorial (reviewed in ), and there is a growing body of evidence suggesting the role of sarcopenia and metabolic derangement of skeletal muscle.
Firstly, insulin resistance is a well‐known comorbidity in critical illness  contributing to and aggravating complications such as severe infections, organ dysfunction, and death, and has also been implicated in the ICU acquired weakness. Two main consequences of insulin resistance are hyperglycaemia and “anabolic resistance”. It has been observed that the provision of protein and energy to support the enhanced hypermetabolic demands of ICU patients is unable to prevent the rapid loss of muscle mass [Clifton, 1984]. Indeed, skeletal muscle insulin resistance is the likely reason why nutritional support further exacerbates hyperglycaemia. Insulin therapy is often used in ICU patients to try and combat this, but it appears to be ineffective in ICU acquired weakness and its safety in the ICU setting has been questioned . Physical activity is an attractive alternative intervention target as it has profound effects on substrate metabolism in contracting skeletal muscle, with a single bout of muscle contraction known to increase muscle glucose uptake several fold and sensitise the muscle to insulin and the anabolic effects of amino acids for up to 24 hours, including in individuals where insulin and anabolic resistance is evident . It is not known whether intensified rehabilitation can improve insulin effect on glucose uptake and whether it influences the stimulatory effect of insulin and amino acids on muscle protein synthesis.
Secondly, mitochondrial dysfunction in skeletal muscle may play a role in the developmen of ICUAW. Mitochondrial depletion and dysfunction of mitochondrial respiratory complexes I and IV has been demonstrated in acute severe sepsis in association with multi-organ failure and death  and early activation of mitochondrial biogenesis predicted survival . Our group has recently demonstrated in two pilot studies [54,55] that, compared to healthy controls, there is a 50% reduction of mitochondrial functional capacity in skeletal muscle in the patients with protracted critical illness and ICUAW. This is accompanied by a significant relative increase in the abundance and functional capacity of respiratory complex II, which delivers electrons to the respiratory chain from fatty acid oxidation. Weber‐Carstens demonstrated in patients with ICUAW that insulin fails to activate GLUT‐4 translocation to cellular membranes in patients with ICUAW, causing skeletal muscle “intracellular glucose starvation” and a failure of AMP‐activated protein kinase to respond to the impairment of ATP production. Most notably, in 5 subjects, these abnormalities were alleviated by NMES. In light of this, relative increase of Complex II capacity observed in our pilot study may represent a functional adaptation of muscle to the increased reliance on fatty acid oxidation. It is not known, whether the severity of mitochondrial functional alteration reflects the degree of insulin resistance and the severity of muscle weakness and whether the delivery of very early FESCE has a potential to influence these changes.
In the light of this, we hypothesize:
H1: As most of the damage to the structure and function of skeletal muscle occurs during the first week, intensified goal-directed rehabilitation, which includes FESCE and starts within 48 hours after ICU admission, improves functional outcome of ICU survivors at 6 months when compared to the standard of care.
H2: The intervention, as compared to standard of care, shall preserve muscle mass and improve muscle power at ICU discharge.
H3: The intervention, as compared to standard of care shall increase insulin-mediated whole-body oxidative glucose disposal and mitochondrial functional indices.
- To investigate, in a pragmatic, prospective, randomized, controlled, assessor‐blinded trial the effects of very early intensive rehabilitation using a goal-directed protocol that includes FESCE in mechanically ventilated ICU patients predicted to need protracted ICU stay.
- To perform a more detailed metabolic studies, including serial muscle biopsies and using euglycaemic hyperinsulinaemic clamps in a nested subgroup. Insulin sensitivity in the whole study population will be compared by glucose control and consumption of intravenous insulin required to control blood glucose.
Primary outcome: Physical component of SF-36 quality of life questionnaire measured in ICU survivors at 6 moths. Based on the study of Kayambu , where this measure was 60±29 points in the control group, our study is powered to detect a change by 15 or more points, which is within limits determined as clinically important for patients with COPD, asthma and myocardial infarction . SF-36 has been validated in the Czech Republic and endorsed by Institution for Health Information and Statistics (https://www.uzis.cz/en/node/8159).
- 4‐item Physical Fitness in Intensive Care test [Time Frame: at 28 days or discharge from ICU whichever occurs earlier ] as functional outcome at ICU d/c
- Muscle mass measured by rectus m. cross sectional area on B-mode ultrasound [Time Frame: at 7 day intervals up to 28th day or discharge from ICU, whichever occurs earlier]
- Nitrogen balance measured in g/m2 of body surface area [Time Frame: at 7 day intervals up to 28th day or discharge from ICU, whichever occurs earlier] and The cumulative the difference between nitrogen intake and output
- Muscle power per Medical Research Council (MRC) score [Time Frame: at 7 day intervals up to 28th day or discharge from ICU, whichever occurs earlier ]
- Number of ventilator-free days [Time Frame: at 28 day ], i.e. number of days, out of 28 after admission, patient has NOT been supported by mechanical ventilation
- Number of rehabilitation interruptions due to physiological deterioration [Time Frame: at 28 days or discharge from ICU whichever occurs earlier ]
- Number of episodes of elevated intracranial pressure [ Time Frame: at 28 days or discharge from ICU whichever occurs earlier]
- Number of dialysis interruptions [ Time Frame: at 28 days or discharge from ICU whichever occurs earlier]
- Length of ICU stay in days [ Time Frame: at 6 months ]
One hundred fifty participants meeting the eligibility criteria will be recruited in four ICUs at FNKV University Hospital.
Inclusion Criteria: (1) ≥18 years; (2) mechanical ventilation, or imminent need of it at presentation; (3) predicted ICU length of stay ≥7 days;
Exclusion Criteria: (1) known primary systemic neuromuscular disease or spinal cord lesion at admission. (2) severe lower limb injury or amputation; (3) bedridden premorbid state (Charleston Comorbidity Score >4) (4) approaching imminent death or withdrawal of medical treatment within 24 h; (5) pregnancy; (6) presence of external fixator or superficial metallic implants in lower limb; (7) open wounds or skin abrasions at electrode application points; (8) presence of pacemaker, implanted defibrillator or other implanted electronic medical device; (9) predicted as unable to receive first rehabilitation session within 72 hours of admission or transferred from another ICU after more than 24 hours of mechanical ventilation; (10) Presence of other condition preventing the use of FESCE or considered unsuitable for the study by a responsible medical team; (11) prior participating in another functional outcome-based intervention research study.
With the exception that we do not limit the study population with sepsis, we have intentionally chosen similar criteria as the only study under way on FESCE in ICU patients, which is primarily focused on muscle structure and function.
The flow of participants throughout the trial is shown in Figure 1 and study procedures in Figure 2. As soon as informed consent has been obtained, and prior to randomisation baseline testing including anthropometric examination will be performed. In addition, in patients with specific consent a muscle biopsy will be obtained and hyperinsulinaemic clamp will be performed the first morning (8‐11 AM) and prior to the start of enteral nutrition.
Standard care group. Both groups will receive usual best medical and nursing care in the ICU, which include daily sedation holds when applicable and delirium 12 hourly monitoring (by CAM-ICU scale) and management as usual in the routine practice. Respiratory physiotherapy will also be delivered without alterations. The routine standard care arm will undergo mobilisation/rehabilitation delivered by personnel not involved in the study in a usual, routine way. Details of physiotherapy treatment will be recorded but not protocolled in the standard care arm.
Intervention group In the intervention arm, early goal-directed rehabilitation is protocolled according to patients’ condition and degree of cooperation (Figure 3) and there will be pre-defined safety criteria, which are in accordance with current recommendations for active rehabilitation of critically ill ventilated adults . Whilst the safety criteria are binding for the study physiotherapist, the rehabilitation protocol is not and the delivery of physical exercise can be altered according to actual patient’s condition. However, any alteration and the reason for it will be recorded. The intervention will start as soon as possible and always within 72 h of ICU admission, continuing until ICU discharge. Supine cycling will be delivered as per protocol on supine cycle ergometer attached to a neuromuscular stimulator. Surface electrodes will be applied to the gluteal, hamstrings and quadriceps muscles on both legs. The intensity of muscle stimulation will be delivered at a level able to cause visible contractions (confirmed by palpation if uncertain) in all muscle groups without causing undue pain or discomfort to the participant, according to a regime specified by Parry . Once the patient is more alert, and able to participate, they will be provided with standardized encouragement to engage in therapy. To increase the intervention workload, resistance will be increased incrementally and cycling cadence. If a participant is readmitted to intensive care, the intervention will be re-initiated. The intervention continues until day 28 or ICU discharge, whichever occurs earlier.