Muscle Wasting in the Critically Ill

Sponsor

University of Liverpool (Other)

Overall Status

Completed

CT.gov ID

NCT03770442

Collaborator

(none)

Enrollment

Location

Arms

21.6

Actual Duration (Months)

1.5

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Muscle Weakness	Device: Cycling with FES Other: Routine physiotherapy	N/A

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (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.

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Jan 14, 2019

Actual Primary Completion Date :

Nov 1, 2020

Actual Study Completion Date :

Nov 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cycling with FES 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).	Device: Cycling with FES As described already Other Names: RT-300 Supine Restorative Therapies
Active Comparator: Control - routine physiotherapy Usual daily physiotherapy, consisting of limb care and mobilisation, and respiratory care and exercises as appropriate.	Other: Routine physiotherapy As described already

Arm

Intervention/Treatment

Experimental: Cycling with FES

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).

Device: Cycling with FES

As described already

Other Names:

RT-300 Supine

Restorative Therapies

Active Comparator: Control - routine physiotherapy

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

Other: Routine physiotherapy

As described already

Outcome Measures

Primary Outcome Measures

Ultrasound assessment of rectus femoris - Change in cross sectional area (cm2) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
Measurement of cross-sectional area of rectus femoris (cm2)
Ultrasound assessment of rectus femoris - Change in muscle layer thickness (cm) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
Measurement on muscle layer thickness of rectus femoris (cm)
Ultrasound assessment of anterior thigh musculature - Change in muscle layer thickness (cm) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
Measurement of combined muscle layer thickness of rectus femoris and vastus intermedius (cm)
Ultrasound assessment of vastus lateralis - change in muscle layer thickness (cm) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
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) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
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) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
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) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
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) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
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) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
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) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
Measurement of rectus abdominis muscle layer thickness - (cm)
Diaphragm thickness assessment by ultrasound - change in end expiratory thickness (mm) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
Assessment of thickness at end expiration (mm)
Diaphragm thickness assessment by ultrasound - change in end inspiratory thickness (mm) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
Assessment of thickness at end inspiration (mm)
Diaphragm thickness assessment by ultrasound - change in thickening fraction (%) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
Assessment of thickening fraction, derived mathematically from thicknesses at inspiration and expiration (%)
Ultrasound assessment of change in diaphragmatic excursion (cm) [Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.]
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). [Samples taken on days 1, 5, 10 and 14]
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). [Samples taken on days 1, 5, 10 and 14]
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). [Samples taken on day 1 and 14]
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) [Samples taken on day 1 and 14]
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) [At 3 month follow up]
Distance achieved during a 6 minute shuttle walk of 20 metres length
Follow up testing - Hand grip dynamometry (hand grip strength, Newtons) [At 3 month follow up]
Strength of hand grip in both hands
Follow up - Lower limb strength assessment - Force generated at maximal contraction for knee extension (Newtons) [At 3 month follow up]
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. [At 3 month follow up]
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). [At 3 month follow up]
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) [At 3 month follow up]
Using the Power Breathe K2 device
Incidence of delirium during the trial period - using the CAM-ICU tool. [Days 1-14]
Assessed by twice daily Cambridge Assessment Method for the ICU (CAM-ICU) assessments
Incidence of renal replacement therapy during the trial period [Days 1-14]
Daily monitoring to see if patient has required renal replacement therapy (defined as either haemofiltration or haemodialysis).
Total dose of noradrenaline given per day [Day 1-14]
Daily monitoring of doses of inotropic and vasopressor drugs
Overall fluid balance (in mls) at the end of each study day [Day 1-14]
Daily noting of 24 hour fluid balance
Total Insulin doses (in international units) required per day [Day 1-14]
Daily monitoring of exogenous insulin requirements
Blood glucose concentration (mmol/L) [Day 1-14]
Daily monitoring of glucose levels
Heart rate variability [Days 1 - 14 but only on the days where cycling takes place (ten sessions)]
Measured via a wireless skin patch
Safety - number of times an endotracheal/tracheostomy tube is dislodged during the cycling sessions [Days 1 - 14 but only on the days where cycling takes place (ten 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 [Days 1 - 14 but only on the days where cycling takes place (ten 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 [Days 1 - 14 but only on the days where cycling takes place (ten sessions).]
Expressed as a simple count of how many times a central or arterial line dislodges.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts 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.