Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Early Mobilization and Intensive Rehabilitation in the Critically Ill (EMIR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02864745
Recruitment Status : Unknown
Verified October 2019 by Frantisek Duska, Charles University, Czech Republic.
Recruitment status was:  Active, not recruiting
First Posted : August 12, 2016
Last Update Posted : October 11, 2019
Sponsor:
Collaborator:
Faculty Hospital Kralovske Vinohrady
Information provided by (Responsible Party):
Frantisek Duska, Charles University, Czech Republic

Tracking Information
First Submitted Date  ICMJE May 6, 2016
First Posted Date  ICMJE August 12, 2016
Last Update Posted Date October 11, 2019
Actual Study Start Date  ICMJE October 4, 2016
Estimated Primary Completion Date March 10, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2016)
Quality of life as per 36-Item Short Health Survey (SF-36) score [ Time Frame: at 6 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 9, 2016)
Quality of life as per SF36 [ Time Frame: at 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2016)
  • 4-item Physical Fitness in Intensive Care test [ Time Frame: at 28 days or discharge from ICU whichever occurs earlier ]
    functional outcome at ICU d/c
  • Muscle mass measured by rectus m. crosssectional 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 ]
    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 days ]
    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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 9, 2016)
  • 4-item Physical Fitness in Intensive Care test [ Time Frame: at 28 days or discharge from ICU whichever occurs earlier ]
    functional outcome at ICU d/c
  • Muscle mass measured by rectus m. crossectional area on B-mode US [ 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 ]
    The cummulative the difference between nitrogen intake and output
  • Muscle power per 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 days ]
    Number of days, out of 28 after admission, patient has NOT been supported by mechanical ventilation
  • Number of RHB interruptions due to physiological deterioration [ Time Frame: at 28 days or discharge from ICU whichever occurs earlier ]
  • Number of episodes of elevated ICP [ 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 ]
Current Other Pre-specified Outcome Measures
 (submitted: August 12, 2016)
Estimated cost of care in Euro per patient per hospital stay [ Time Frame: at 6 months ]
Original Other Pre-specified Outcome Measures
 (submitted: August 9, 2016)
Estimated cost of care in EUR per patient per hospital stay [ Time Frame: at 6 months ]
 
Descriptive Information
Brief Title  ICMJE Early Mobilization and Intensive Rehabilitation in the Critically Ill
Official Title  ICMJE Functional Electrical Stimulation-assisted Cycle Ergometry in Critically Ill: Linking Deranged Muscle Physiology to Long-term Functional Outcome
Brief Summary ICU acquired weakness contributes (ICUAW) to poor functional outcome in survivors of critical care. Most damage occurs during the first week of critical illness when patients are unable to cooperate with conventional active rehabilitation. Functional electrical stimulation-assisted cycle ergometry (FES-CE) may improve muscle function and long-term outcome. Methods: Assessor-blinded pragmatic single-centre randomized controlled trial. Adults (n=150) mechanically ventilated for < 48 hours from 4 ICUs who are estimated to need >7 days of critical care will be randomized to receive either FES-CE-based intensified rehabilitation or routine care, which will continue until ICU discharge. Primary outcome: Quality of life as measured by SF-36 score at 6 months. Secondary outcomes: functional performance at ICU discharge, cross sectional muscle diameter and nitrogen balance, and muscle power. In a subgroup we will assess insulin sensitivity and perform skeletal muscle biopsies to look at mitochondrial function, fibre typing and regulatory protein expression in response to FES-CE.
Detailed Description

Background. Functional disability, a natural consequence of weakness, is a frequent and long-lasting complication in survivors of critical illness. 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. 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 normalise physiological function by artificial means. Recently, there has been a paradigm shift away from this approach towards a more conservative treatment philosophy for patients in the ICU. 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. 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. Indeed, these strategies, together with early physical therapy are the only safe 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 2-5 of ICU stay or as an activity beginning before ICU discharge. Standard early rehabilitation cannot be started early enough, and functional electrical stimulation-assisted cycle ergometry 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 within18-48 hours of onset of acute critical illness or severe injury and is greatest during the first 2 to 3 weeks of critical illness. 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 10-14% 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 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. In order to achieve maximum efficacy, passive cycling and neuromuscular electrical stimulation (NMES) can be delivered simultaneously and synchronised to produce a coordinated pattern of movements. The technique is called FES-CE (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. 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. In critical illness, pilot studies have shown NMES itself (without synchronization and the use of bicycle) to be safe, feasible and effective in maintaining muscle strength and mass. The only study of FES-CE in critically illness is the pilot trial of Parry et al., where the feasibility and safety of FES-CE was demonstrated in a small cohort of critically ill patients (8 patients received the FES-CE 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).

Hypotheses H1: As most of the damage to the structure and function of skeletal muscle occurs during the first week, intensified rehabilitation, which includes FES-CE and starts within 48 hours after ICU admission, improves functional outcome of ICU survivors at 6 months when compared to the routine standard of care. H2: Intensified early rehabilitation compared to routine standard of care, shall preserve muscle mass and improve muscle power at ICU discharge. H3:Intensified early rehabilitation compared to routine standard of care shall increase insulin-mediated whole-body oxidative glucose disposal and mitochondrial functional indices. Sample size calculation:In studies of critical illness outcome at 6-months using 36-Item Short Form Health Survey (SF-36) scores, the standard deviation varied between 10-13 points. In order to have 80% power to detect 5 point difference in SF-36 score between control and intervention at the level of significance p<0.05 in the population with standard deviation (SD) of 13, we would need 108 subjects (54 in each arm). In order to allow for deaths and dropouts, the plan is to randomize 150 subjects.

Randomization. As soon as possible, but always within 48 hours of admission, participants will be randomly assigned (1:1) to receive either standard care or the intervention using offsite-independent randomization protocols (www.randomization.com). Randomization will be stratified according to presence or absence of sepsis and the availability of a biopsy at baseline. Concealed allocation will be performed using sequentially numbered opaque sealed envelopes only accessible by research personnel with no involvement in the trial.

Once consent/assent is obtained, and prior to randomisation; participants will be referred to a study physiotherapist who will administer baseline testing of muscle mass/cross-sectional area (CSA) using diagnostic ultrasound (US), and baseline blood samples will be taken Both groups will receive usual best medical and nursing care in the ICU, which include daily sedation holds when applicable and delirium 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 rehabilitation is protocolled according to patients' condition and degree of cooperation 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 48 h of ICU admission, continuing until ICU discharge. Supine cycling will be delivered as per protocol on supine cycloergometer attached to a neuromuscular stimulator Surface electrodes will be applied to the gluteal, hamstrings, quadriceps and calf 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, 2012. 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.

Study Procedures The ICUs are paperless and fully computerized, so vital functions and other physiological parameters are monitored and data is routinely stored to secure hospital data bases via a protected dedicated network. This includes data about nutritional intake and urinary output. Urine samples will be collected daily, surfaced with toluene and stored in a deep freeze facility for later determination of nitrogen content and 3-methyl histidine levels (to calculate muscle catabolism rate and nitrogen balance). In addition, all study patients will undergo an assessment by a study physiotherapist, which includes a measurement of rectus muscle cross-sectional area on both legs and whenever the patient regains consciousness, also muscle power by Medical Research Concil (MRC) score (standardized testing of muscle power [0-5] on 12 muscle groups on all 4 limbs, giving the score 0-60 (60 suggesting normal muscle power). Blood will be taken, plasma separated and frozen at -80 C for later analysis of cytokines and hormone levels. This assessment will be repeated at 7-day intervals and at ICU discharge. At ICU discharge, the patients and relatives will be asked to provide contact details for follow up. After 6 months, the patient or family will be contacted for structured interview as required for SF-36 questionnaire, and collected using Research and Development Organization (RAND) methodology. Whilst participants and intervention physiotherapist cannot be blinded to group allocation, research staff assessing outcome will be from separate clinical departments and thus remain blinded to treatment allocation.

Complementary Studies: Insulin resistance and mitochondrial function These studies will be performed in addition to other study procedures in a subgroup of patients, who give specific consent to it. First measurement will be performed at baseline prior to randomization, ideally the next morning after admission. Second measurement on day 7 of ICU stay, i.e. after at least 5 days of intervention. Muscle biopsy. Will be performed from vastus lateralis muscle by needle biopsy technique. The sample will be separated into three parts (50-100mg each). One part will be immediately frozen in liquid nitrogen for analysis of protein/DNA ratio and protein expression studies. The second part will be frozen in liquid nitrogen-cooled isopentane for muscle fibre typing and immunohistochemistry analysis. The third part put into culture media on ice for the preparation of homogenates and measurement of citrate-synthase activity, spectrophotometric analysis of the activity of respiratory complexes I-IV and western blot analysis of respiratory complexes. In the fresh muscle homogenates, the investigators will use high-resolution respirometry to determine the function of individual respiratory complexes in the cytosolic context and measure basic functional metabolic indices. the investigators will specifically look at the degree of mitochondrial uncoupling, respiratory chain capacity and the function of individual complexes, including glycerol-3-phosphate shuttle. Frozen muscle samples will be stored at deeply frozen for analysis of DNA/protein ratio, messenger ribonucleic acid (mRNA) and proteins involved in the regulation of proteolysis, substrate oxidation and anabolic pathways of skeletal muscle as well as immunohistochemistry and typing of muscle fibres. In addition, the investigators will look at the change of these indices after seven days of critical illness and the influence of the intervention vs. standard of care. the investigators will look at correlation of these parameters with muscle power (i.e. compare bioenergetics profile of skeletal muscle in those who develop ICUAW and in those who do not) and insulin resistance. Insulin sensitivity and substrate oxidation will be measured after overnight fasting by hyperinsulinaemic euglycemic clamp.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Critical Illness
Intervention  ICMJE
  • Device: functional electrical stimulation-assisted cycle ergometry
    Early intensive rehabilitation protocol, which includes the use of functional electrical stimulation-assisted cycle ergometry
  • Other: standard rehabilitation
    This group will receive standard rehabilitation, which will be monitored, but not protocolised.
Study Arms  ICMJE
  • Experimental: Early rehabilitation arm
    These patients will receive very early (<48 hours after ICU admission), protocolised, intensive rehabilitation, which will include functional electrical stimulation-assisted cycle ergometry.
    Intervention: Device: functional electrical stimulation-assisted cycle ergometry
  • Active Comparator: Standard-of-care
    These patients will receive standard rehabilitation delivered by non-study physiotherapist.
    Intervention: Other: standard rehabilitation
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: August 9, 2016)
150
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 10, 2020
Estimated Primary Completion Date March 10, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • ≥18 years;
  • Mechanical ventilation, or imminent need of it at presentation;
  • Predicted ICU length of stay ≥7 days;

Exclusion Criteria:

  • Known primary systemic neuromuscular disease or permanent neurological damage at admission
  • Severe lower limb injury or amputation
  • Bedridden premorbid state
  • Assessed by medical staff as approaching imminent death or withdrawal of medical treatment within 24 h
  • Pregnancy
  • Presence of external fixator or superficial metallic implants in lower limb
  • Open wounds or skin abrasions at electrode application points
  • Presence of pacemaker, implanted defibrillator or other implanted electronic medical device
  • Transferred from another ICU after 24 hours of consecutive mechanical ventilation
  • Presence of other condition preventing the use of FES--CE or considered unsuitable for the study by a responsible medical team
  • Prior participating in another functional outcome-based intervention research study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Czechia
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02864745
Other Study ID Numbers  ICMJE 16-28663A
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-dentified individual patients data will be made available in a public database. Protocol has been published in Trials.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Responsible Party Frantisek Duska, Charles University, Czech Republic
Study Sponsor  ICMJE Charles University, Czech Republic
Collaborators  ICMJE Faculty Hospital Kralovske Vinohrady
Investigators  ICMJE
Study Director: Petr Waldauf Faculty Hospital Kralovske Vinohrady
PRS Account Charles University, Czech Republic
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP