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Muscle Wasting in the Critically Ill

Primary Purpose

Muscle Weakness

Status

Completed

Phase

Not Applicable

Locations

United Kingdom

Study Type

Interventional

Intervention

Cycling with FES

Routine physiotherapy

About this trial

This is an interventional prevention trial for Muscle Weakness focused on measuring ICU acquired weakness (ICU-AW), FES, Functional Electrical Stimulation, Rehabilitation

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients will be recruited in the Intensive Care Unit of the Royal Liverpool University Hospital. All patients will be over 18, and have a critical illness that requires mechanical ventilation with an initial period of sedation. This study will focus on patients with a definite or suspected case of sepsis from any source.

Sepsis has been recently redefined as: "Life threatening organ-dysfunction caused by dysregulated host response to infection" whilst septic shock has become a subset of sepsis, defined as: "circulatory and cellular/metabolic dysfunction associated with a higher risk of mortality(44).

For the purposes of this study, a patient will be regarded as septic if they have evidence of infection-related organ failure (e.g. sepsis-associated coagulopathy, altered mental state, cardiovascular dysfunction, acute kidney injury, and altered liver function) and require invasive mechanical ventilation with either definite or suspected evidence of infection. This is to allow prompt treatment with FES rather than waiting for a positive microbiological result to be obtained.

Within the definition of sepsis "from any source" a list of following is illustrative but not exhaustive:

Urogenital sepsis (including urosepsis, pyelonephritis, endometritis and chorioamnionitis)
Pneumonia (including community acquired, hospital acquired, and aspiration pneumonia. Ventilator associated pneumonia would be excluded.)
Neurological infections such as encephalitis and meningitis.
Cellulitis, osteomyelitis and infections of soft tissue NOT affecting the lower limb.
Surgical infections, including post-operative laparotomy with evidence of peritoneal soiling, and evidence of infection prior to the operation, in patients who require 2 or more organ system support after the operation.
Intra-abdominal sepsis, including biliary sepsis, hepatitis, and acute pancreatitis. In the case of acute pancreatitis, evidence of infection is required to fulfil the criteria. Acute pancreatitis with sterile tissue/fluid samples would not be suitable.

Exclusion Criteria:

Patients under 18
Patients who decline consent
Pregnancy
Neuromuscular disease
Rhabdomyolysis
Lower limb trauma
Patients unlikely to survive to 96 hours post admission
Consent unobtainable within 48 hours of admission
Morbid obesity (BMI>40).
Presence of a pacemaker or Implantable Cardiac Defibrillator (ICD).
Unlikely to be mechanically ventilated for more than 48 hours.

Sites / Locations

Intensive Care Unit, Royal Liverpool University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Cycling with FES

Control - routine physiotherapy

Arm Description

Ten sessions of 14 days in patients consented within 48 hours of arriving in critical care who are sedated and mechanically ventilated with a diagnosis of sepsis from any source. Sessions last a maximum of 30 minutes (with an ideal minimum of 20 minutes), using the Restorative Therapies (RT) 300 Supine with the Sage 12-channel stimulator. Stimulation will provided to the quadriceps, hamstrings, calves and abdomen. Both legs and both sides of the abdomen will be stimulated. Stimulation current settings are individualised for each patient and each muscle group. These patients will also receive their routine physiotherapy that they would have received if they were in the control group (or not in the trial at all).

Usual daily physiotherapy, consisting of limb care and mobilisation, and respiratory care and exercises as appropriate.

Outcomes

Primary Outcome Measures

Ultrasound assessment of rectus femoris - Change in cross sectional area (cm2)

Measurement of cross-sectional area of rectus femoris (cm2)

Ultrasound assessment of rectus femoris - Change in muscle layer thickness (cm)

Measurement on muscle layer thickness of rectus femoris (cm)

Ultrasound assessment of anterior thigh musculature - Change in muscle layer thickness (cm)

Measurement of combined muscle layer thickness of rectus femoris and vastus intermedius (cm)

Ultrasound assessment of vastus lateralis - change in muscle layer thickness (cm)

Measurement of the thickness of the vastus lateralis between the superficial and deep aponeuroses (cm)

Ultrasound assessment of vastus lateralis - change in fascicle pennation angle (degrees)

Measurement of the pennation angle of the muscle fascicles as they insert into the deep aponeuroses of the vastus lateralis muscle (degrees)

Ultrasound assessment of vastus lateralis - change in fascicle length (cm)

This is a single measure, derived by trigonometry (the Sine of the pennation angle multiplied by the muscle thickness).

Ultrasound assessment of the medial head of gastrocnemius - change in muscle thickness (cm)

Measurement of the thickness of the medial head of the gastrocnemius between the superficial and deep aponeuroses (cm)

Ultrasound assessment of the medial head of gastrocnemius - change in fascicle pennation angle (degrees)

Measurement of the pennation angle of the muscle fascicles as they insert into the deep aponeuroses of the medial head of gastrocnemius (angles)

Ultrasound assessment of the medial head of gastrocnemius - change in fascicle length (cm)

This is single measure which is mathematically derived by trigonometry using the known pennation angle (degrees) and thickness (cm): the Sine of the pennation angle multiplied by the muscle thickness.

Ultrasound assessment of the rectus abdominis muscle - change in muscle layer thickness (cm)

Measurement of rectus abdominis muscle layer thickness - (cm)

Diaphragm thickness assessment by ultrasound - change in end expiratory thickness (mm)

Assessment of thickness at end expiration (mm)

Diaphragm thickness assessment by ultrasound - change in end inspiratory thickness (mm)

Assessment of thickness at end inspiration (mm)

Diaphragm thickness assessment by ultrasound - change in thickening fraction (%)

Assessment of thickening fraction, derived mathematically from thicknesses at inspiration and expiration (%)

Ultrasound assessment of change in diaphragmatic excursion (cm)

Assessment of maximal excursion of diaphragm, measured with M-mode ultrasonography (mm)

Secondary Outcome Measures

Measurement of change in blood biomarkers (microRNA analysis for markers of muscle loss, expressed as a percentage fold increase/decrease compared to baseline).

Blood samples taken during the study period and analysed for markers of muscle loss/degradation

Measurement of change in urinary biomarkers (microRNA analysis for markers of muscle loss, expressed as a percentage-fold increase/decrease compared to baseline).

Blood and urine samples taken during the study period and analysed for markers of muscle loss/degradation

Measurement of the number of biomarkers expressed from muscle biopsies (microRNA analysis for markers of muscle loss, expressed as the number and type of micro-RNAs expressed within the samples).

Muscle biopsy samples taken during the study period and analysed for markers of muscle loss/degradation. Number and type of micro-RNAs to be noted).

Measurement of muscle fibre cross sectional area from muscle biopsies (mm2)

Histological staining and analysis of muscle fibre composition, expressed in square millimetres and as a percentage-fold increase/decrease compared to baseline).

Follow up testing - Distance achieved in a 6 minute walk test, metres)

Distance achieved during a 6 minute shuttle walk of 20 metres length

Follow up testing - Hand grip dynamometry (hand grip strength, Newtons)

Strength of hand grip in both hands

Follow up - Lower limb strength assessment - Force generated at maximal contraction for knee extension (Newtons)

Strength of extension at the knee in both legs using a hand held dynamometry device (microFET 2 wireless device). Measured in Newtons.

Follow up testing - Balance assessment - Comparison of changes in center of pressure on a pressure plate.

Comparison of changes in centre of pressure on a pressure plate. The centre of pressure is measured over 20 seconds with the participant standing still. Maximal variation in lateral and anterior-posterior sway is recorded by the pressure plate.

Follow up testing - Psychological assessment - Comparison of total scores obtained from the SF-36 questionnaire (maximum score 100, minimum score zero).

Comparison of scores obtained from the SF-36 questionnaire between the two groups. A lower score indicates greater disability.

Follow Up - Maximal Inspiratory Pressure monitoring in kilopascals (kPa)

Using the Power Breathe K2 device

Incidence of delirium during the trial period - using the CAM-ICU tool.

Assessed by twice daily Cambridge Assessment Method for the ICU (CAM-ICU) assessments

Incidence of renal replacement therapy during the trial period

Daily monitoring to see if patient has required renal replacement therapy (defined as either haemofiltration or haemodialysis).

Total dose of noradrenaline given per day

Daily monitoring of doses of inotropic and vasopressor drugs

Overall fluid balance (in mls) at the end of each study day

Daily noting of 24 hour fluid balance

Total Insulin doses (in international units) required per day

Daily monitoring of exogenous insulin requirements

Blood glucose concentration (mmol/L)

Daily monitoring of glucose levels

Heart rate variability

Measured via a wireless skin patch

Safety - number of times an endotracheal/tracheostomy tube is dislodged during the cycling sessions

Expressed as a simple count of how many times an airway device dislodges

Safety - number of times an nasogastric tube is dislodged during the cycling sessions

Expressed as a simple count of how many times a nasogastric feed tube dislodges.

Safety - number of times an a central or arterial line device is dislodged during the cycling sessions

Expressed as a simple count of how many times a central or arterial line dislodges.

Full Information

NCT ID

NCT03770442

First Posted

October 15, 2018

Last Updated

November 3, 2020

Sponsor

University of Liverpool

1. Study Identification

Unique Protocol Identification Number

NCT03770442

Brief Title

Muscle Wasting in the Critically Ill

Official Title

Effect of Early Rehabilitation Using an Active/Passive Cycling Device on Muscle Wasting in the Critically Ill: A Randomised Controlled Study

Study Type

Interventional

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Completed

Study Start Date

January 14, 2019 (Actual)

Primary Completion Date

November 1, 2020 (Actual)

Study Completion Date

November 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Liverpool

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Muscle wasting is a common consequence of critical illness, and has a profound impact upon the rehabilitation of those who survive admission to critical to care. The investigators intend to assess if the application of 10 sessions over two weeks of passive cycling with electrical stimulation to the lower limbs and abdomen can prevent muscle loss, or at least cause less muscle loss, compared to patients who receive standard daily sessions of physiotherapy. This will be done by comparing the changes in muscle size on ultrasound between the two groups, comparing functional measures at a 3 month follow up, and by performing translational research using tissue samples taken during the study.

Detailed Description

Patients are mechanically ventilated and sedated with a diagnosis of sepsis (from any source) will be eligible for this study. Provided they meet the inclusion criteria, they will be randomised within 48 hours of admission, to either ten 30 minute sessions of passive cycling with functional electrical stimulation (FES) to the thighs, hamstrings, calves and abdomen over a 14 day period, or to a control group of routine physiotherapy. The trial group will also receive this physiotherapy. On admission to the study, all patients will receive on day 1: Ultrasound measurements of: Rectus femoris cross-sectional area Thickness of rectus femoris and vastus intermedius Thickness, pennation angle and derived fascicle length of vastus lateralis and medial head of gastrocnemius Thickness of rectus abdominis. Thickness of diaphragm A blood sample taken from an arterial line A urine sample taken from a urinary catheter A muscle biopsy taken from the right vastus lateralis They will then receive ten 30 minute sessions of passive cycling with functional electrical stimulation over 14 days, or a control group will receive routine physiotherapy during this period. Repeat ultrasounds will be taken at days 3, 5, 7, 10 and 14. Repeat blood and urine sampling at days 5, 10 and 14. Repeat muscle biopsy at day 14. All cycling, ultrasounds and tissue sampling will end on day 14 regardless of the ventilator status of the patient. In patients who survive to be discharged from critical care, they will be followed up at 3 months for: Repeat ultrasound scan of all muscles listed Six minute walk test Hand grip and lower limb dynamometry, Balance testing (by standing upright on a pressure plate for 20 seconds) Psychological assessment using the 36 item Short Form (SF-36) questionnaire Tissue sampling will be stored in the University of Liverpool for analysis of biomarkers of muscle damage and loss between the two groups.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Muscle Weakness

Keywords

ICU acquired weakness (ICU-AW), FES, Functional Electrical Stimulation, Rehabilitation

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Masking Description

Ultrasound images will be labelled by their participant number, and not by intervention. Therefore, when image analysis takes place, the investigators will not know whether the images come from somebody who received cycling sessions or the control group. Tissue samples will be treated in the same way. In follow up sessions, participants will be asked not to reveal if they can remember whether they cycled or not.

Allocation

Randomized

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cycling with FES

Arm Type

Experimental

Arm Description

Arm Title

Control - routine physiotherapy

Arm Type

Active Comparator

Arm Description

Usual daily physiotherapy, consisting of limb care and mobilisation, and respiratory care and exercises as appropriate.

Intervention Type

Device

Intervention Name(s)

Cycling with FES

Other Intervention Name(s)

RT-300 Supine, Restorative Therapies

Intervention Description

As described already

Intervention Type

Other

Intervention Name(s)

Routine physiotherapy

Intervention Description

As described already

Primary Outcome Measure Information:

Title

Ultrasound assessment of rectus femoris - Change in cross sectional area (cm2)

Description

Measurement of cross-sectional area of rectus femoris (cm2)

Time Frame