The primary aim of this study is to investigate the efficacy of 8 weeks of Low-load blood flow restricted exercise (BFRE) compared to receiving standard care only (no preoperative training) before total knee replacement (TKR) on postoperative 30-seconds chair stand test (30s-CST). We hypothesize that 8 weeks of preoperative BFRE will increase chair stand performance 3 months postoperatively. Secondary aims are to investigate the efficacy of 8 weeks of preoperative BFRE compared to receiving standard care only on changes in muscle strength 3 months after TKR and investigate associations to functional capacity and quality of life. Furthermore, it will be investigated if 8 weeks of BFRE induces muscle hypertrophy and increases satellite cell and myonuclei content of the vastus lateralis muscle.

BFRE is resistance training with low loads (30% 1repetition maximum (RM) performed with concurrent partial blood flow restriction by means of pneumatic cuff compression around the working limb.

Group 1 (BFRE):

BFRE group: Will perform 3/weekly supervised BFRE sessions for 8 weeks from a physiotherapist educated in administering BFRE. Each session will consist of a 10-min warm up followed by two different unilateral lower-limb resistance training exercises: leg press and knee extension. Each exercise will be performed with the affected lower limb only and consist of 4 rounds interspaced by 30 seconds of rest. 1st round: 30 repetitions (reps); 2nd round: 15 reps; 3rd round: 15 reps; 4th round: until exhaustion. Between each exercise the patients will rest for 5 minutes without blood flow restriction.

Patients will rest in a standardized resting position between each set to maintain the desired resting cuff-pressure.

The occlusion pressure will be set at 60% of total limb occlusion pressure and starting load intensity will be 30% 1repetition maximum (1RM) in both exercises. If patients can perform more than 15 repetitions in the 4th exercise set, the exercise load will be increased with the minimum extra load possible.

Group 2 (control Group):

CON group: Will follow standard procedures before a TKA and be encouraged to live their lives as usual up until TKA.

The study is a multicenter (2 sites), randomized (allocation 1:1), assessor blinded, controlled trial Outcomes will be measured at baseline (9-10 weeks before surgery), in the week of surgery and 3- and 12 months postoperatively. Muscle biopsies will be taken from all patients undergoing surgery at Horsens Regional Hospital. Muscle biopsies will be taken at baseline, during surgery and 3 months postoperatively.

The 12 months follow-up assessment will be analyzed and presented in papers during a subsequent Post Doc-period.

All patients will be scheduled to receive TKR and receive a standard multimodal surgical program with standardized perioperative care. Specifically, all patients will be invited to a preoperative information meeting 2-3 weeks prior to surgery where nurses, surgeons, and physiotherapists will be providing detailed information about pain management, nutrition, the surgical procedure (i.e. basic knowledge about a prosthesis, risks related to smoking, restrictions related to living with a TKR, long-term results, and living with a TKR), physical activity, postoperative home-based rehabilitation, load-management, etc.

On the day of surgery patients will be hospitalized at one of the two orthopedic departments and TKR procedures will be performed by an orthopedic surgeon. The day after surgery patients will be trained once or twice per day by a physiotherapist towards fulfilling the following discharge criterions: independency in in-and-out of bed and sit-to-stand activities, independency in walking and stair-negotiation with crutches, ADL activities, and home-based exercises during the hospitalization period. Patients will generally be discharged within ~1-2 days after fulfilling all the above discharge criteria. After discharge, all patients will receive a standard home-based rehabilitation program aimed at increasing knee mobility and lower extremity muscle strength. However, if considered necessary by the physiotherapist in charge of the patient, patients can receive additional supervised knee-specific exercise therapy at private physiotherapy clinics, municipal rehabilitation centers, or specialized hospital-based rehabilitation.

Inclusion Criteria:

• Patients ≥ 50 years scheduled for TKA at Horsens- or Silkeborg Regional Hospital.

Exclusion Criteria:

• Severe cardiovascular diseases (New York Heart Association class III and IIII), previous stroke incident, thrombosis incident
• Traumatic nerve injury in affected limb
• Unregulated hypertension (Systolic ≥180 or diastolic ≥110 mmHg)
• Spinal cord injury
• Pregnancy
• Planned other lower limb surgery within 12 months
• Cancer diagnosis and currently undergoing chemo-, immuno-, or radiotherapy
• Inadequacy in written and spoken Danish
• an existing prosthesis in the index limb
• living more than 45 minutes from either Horsens Regional Hospital or Silkeborg Regional Hospital.

Horsens Regional is responsible for handling all personal data provided by both sites in accordance to the Clinical Trial Agreement and the EU General Data Protection Regulation (GDPR)

Silkeborg Regional Hospital and Aarhus University Horspital agree that information directly related to the protocol and trial, including data, material, Intellectual Property and results generated from the trial shall be the property of Horsens Regional Hospital, and shall be treated in strict confidence, and shall not be disclosed to any third party, or use for its benefit or the benefit of any third party, without the prior written consent of Horsens Regional Hospital, except for data that is (i) publicly known or available from other sources who are not under a confidentially obligation to the other party; (li) has been made available by the other party without confidentiality obligation; or (iii) is independently developed or otherwise already known by or available to the other party without a confidentiality obligation; or (iv) is already required disclosed by law.