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.

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.

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.

Translational research will take place in the Institute of Aging and Chronic Disease. Only the participant number of the sample will be shared with any staff working with tissue samples.

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.