Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Bayer ML, Magnusson SP, Kjaer M. Early versus delayed rehabilitation after acute muscle injury. N Engl J Med 27;377:3-. DOI:.56/NEJMc7834
Supplementary appendix Early versus Delayed Rehabilitation after Acute Muscle Injury Monika L. Bayer, S. Peter Magnusson, Michael Kjaer Table of contents Page I List of Investigators and collaborators... 2 II Overview over study design and intervention... 3 Study design... 3 Study Inclusion criteria/ Study Exclusion criteria/ Study intervention... 4 Outcome measures/ Statistical analysis/ Study funding... 5 III Information on subjects, sports activities and injury characteristics... 6 Table S. Characteristics of participants across study groups... 6 Table S2. Injury severity, MRI data and type of injured muscle... 7 Table S3. Information on pain, injury history and rehabilitation... 8 IV Outline rehabilitation program... 9 V Overview participant flow Figure S... VI Images of rehabilitation exercises... 2 a. Rehabilitation after hamstring muscle strain... 2 b. Rehabilitation after calf muscle strain... 5 c. Rehabilitation after quadriceps muscle strain... 8 VII References... 2
I. List of Investigators and collaborators Investigators Monika L. Bayer, Ph.D. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark S. Peter Magnusson, P.T., D.M.Sci. Department of Physical Therapy, Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Michael Kjaer, M.D., D.M.Sci. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Collaborators Maren Hoegberget-Kalisz, M.D. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Jens L. Olesen, M.D., Ph.D. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Rene B. Svensson, Ph.D. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Mikael Boesen, M.D., Ph.D. Radiology, Frederiksberg Hospital, University of Copenhagen, Denmark 2
II. Overview over study design and intervention Study design The clinical trial (NCT25298) is a two-arm randomized controlled trial with parallel assignment, random group allocation was conducted through minimization using the computer based MinimPy 3. Variables for minimization were gender and muscle group. The study participants were not masked/ blinded for group allocation, i.e. rehabilitation onset either two days or nine days post injury. After approval from the ethical committee (Approval Number: H--24-5) and registration/release at clinicaltrials.gov, information about the project was sent out to coaches and physical therapists associated with football, track and field, hockey, Rugby, American football, Badminton and tennis clubs in the greater Copenhagen region. Personal visits to the clubs followed initial contact (spring/ summer 24) and a reminder of the project was sent via mail/ provided by phone calls on a regular basis thereafter. Additionally, information about the project was disseminated through Google Ads using search terms such as hamstring strain, thigh strain, calf strain in both Danish and English. The injured athlete or an associated coach contacted the coordinating researcher after sudden onset of pain in either the thigh or the calf during training or match. Potential eligibility was assessed by phone provided that the acute muscle strain occurred less than 48 hours prior to contact and medical examination was realistic in the time frame < 48 hours post injury. The injured athlete was invited for a medical examination at the Institute of Sports Medicine Copenhagen. An experienced sports physician assessed the clinical severity of the injury through a standardized examination protocol including medical history, pain at palpation, clear strength deficits and ultrasonography of the injured muscle group. For the ultrasound scan, the injury site was identified by the area of maximal tenderness during palpation and onset of pain during knee flexion/ knee extension or plantar flexion. The muscles were evaluated with respect to muscle fiber disruption, involvement of the muscle-tendon (aponeurosis) unit and echogenicity 2. An MRI scan was performed in the seven days following the strain injury. The severity of the injury was graded by a radiologist with years of experience in musculoskeletal injuries who was blinded for information other than a suspected injury to the thigh or calf muscle. For MRI grading, the classification system published in the British Journal of Sports Medicine was applied. Out of 75 injured athletes, 52 were eligible for enrolment. Ineligibility was due either to a negative ultrasound scan, an unclear location, or to the injury not involving the muscle-tendon unit. Two athletes declined to participate (figure S, page 2). 3
Study Inclusion criteria Minimum 8 years of age Acute onset of pain during forceful movements involving the thigh or calf muscles Contact/ examination within 48 hours Positive ultrasound scan with visible tissue damage: Muscle fiber disruption from the associated connective tissue (tendon/ aponeurosis) in orthogonal planes with hypoechoic areas Willingness to return to sports on the same level as prior to the injury Willingness to comply with the rehabilitation regime and follow up Study Exclusion criteria Unclear ultrasound scan including no visible muscle fiber disruption and hypoechoic areas only Chronic diseases such as diabetes, arthritis or renal diseases, any disease compromising the immune state Daily intake of non steroidal anti inflammatory drugs (NSAIDs) within three months prior to the injury Any observed organ dysfunctions/ contraindication to MRI including egfr <65 (due to contrast infusion, data not provided) Smoking Study intervention Both study groups performed an identical rehabilitation program. The early rehabilitation group began the training 48 hours after injury, the delayed group with a delay of 7 days, i.e. 9 days after the injury. The delayed group was advised to rest until rehabilitation onset. Throughout the study, the subjects were not given any other treatment than rehabilitation and subjects were not permitted to take any kind of analgesics or NSAIDs. All exercises were instructed and supervised by a trained physical therapist on a weekly basis. Participants kept training logs with information including the compliance with the rehabilitation exercises, pain scores during the last set of each of the exercises, performance of other training modalities than rehabilitation (type of training, duration and maximum pain scores). If training logs were not returned at the weekly visits with the physical therapist, interviews were conducted to register compliance and possible engagement in other training modalities. 4
Outcome measures The primary outcome was the time to return to play, which was defined as the number of days from the injury to return to sport, i.e. the first time the subject is fully fit to take part in all types of physical activity post injury (training and/or match). Statistical analysis An a priori sample size was calculated based on existing data on clinical recovery after muscle injury, regain of normal function 3. N= 2 is needed to detect a 3% difference at a p<.5 level with a power of 8%. To account for drop outs, a total of 25 patients in each of the studied groups were recruited and included in the study. The Mann-Whitney U test was used to detect statistical differences between groups in RTS as well as differences in age, height or mass. All statistical analyses were conducted with SigmaPlot 3. software. Study funding The study was funded by Bispebjerg Hospital, Greater Region of Copenhagen Grant, the Danish Rheumatism Association, Lundbeck Foundation, Novo-Nordisk Foundation, Danish Council for Independent Research and Anti Doping Denmark. The funders were not involved in the design and conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or approval of the manuscript. 5
III. Information on subjects, sports activities and injury characteristics Table S. Characteristics of participants across study groups. Descriptive, weekly sports participation and sports activities, as means (±SD) and median (range), or numbers. Early Group N= 2 Delayed Group N= 22 Age (years) 32.6 (±9) 29 (9-47) 34.6 (±) 3 (2-54) Height (cm) 79.6 (±7) 77.4 (±8) 8 (6-88) 76 (65-98) Weight (kg) 8.2 (±2.3) 78. (±2) 78 (63-8) 75 (6-2) Gender Male/female 7/3 9/3 Sports participation* Participation <3 x/ week Participation >3 x/ week 2 22 Sports Football Basketball Handball American Football Rugby Track and field athletics Tennis Badminton Fitness Injury situation Sprinting Jumping 8 4 4 7 3 3 4 4 2 P-value (if applicable).4.8.7 NA NA NA NA *Sports participation is the average number of training sessions in the respective type of sport on a weekly basis over the last year. 6
Table S2. Injury severity, MRI data and type of injured muscle, as means (±SD) and median (range), or numbers. Injury severity* Grade 3A Grade 3B Grade 4 Cranial-caudal length, cm Anterior-posterior depth, cm Medial-lateral width, cm Volume, cm 3 Injured muscles Hamstrings Biceps Femoris Caput Longum (BFCL) BFCL + Semitendinosus (ST) ST Semimembranosus Early Group N= 2 3.9 (±8.3) 2 (2-32.4) 3.2 (±.6) 3 (.3-5.9) 2.2 (±2.) 2 (.3-8.3) 78.5 (±26.9) 45 (-55) 7 3 Delayed Group N= 22 9 2 5.3 (±8.7) 4 (5-42.3) 3.8 (±2.3) 4 (.6-.8) 2.3 (±.3) 3 (.4-4.9) 8 (±238.3) 38 (3-2) 2 9 2 P-value (if applicable) NA.7.4.4.5 NA Calf M. gastrocnemius medialis M. gastrocnemius med. + soleus 8 7 9 8 Quadriceps (M.rectus femoris) *Injury severity was graded on MRI scans performed in the first week after the injury by a radiologist with years of experience in musculoskeletal injuries who was blinded for information other than a suspected injury to the thigh or calf muscle. The classification system published in the British Journal of Sports Medicine was applied. Length/ depth/ width refer to the extent of the edema, which was measured in three planes: maximal length, Z (craniocaudal); width, X (mediolateral); and depth, Y (anteroposterior) on Short Tau Inversion Recovery (STIR) MRI scans. 7
Table S3. Information on pain, injury history and rehabilitation. Data presented as means (±SD) and median (range) or numbers. NRS pain score* at onset of rehabilitation Symptoms (soreness, pain) preceding the strain injury Yes No Previous ipsilateral strain (> 2 months prior to injury) Yes No Compliance to the rehabilitation program $ < 5% > 5% > 75% Early Group N= 2 3.9 (±.8) 4 (3-5) 2 5 5 3 7 Delayed Group N= 22 3.5 (±.4) 3 (2-7) 22 5 7 2 P-value (if applicable). NA NA *NRS pain score refers to the maximum pain score during the introduction to the rehabilitation exercises (on day 2 post injury and day 9 post injury for the early/delayed group, respectively) Previous ipsilateral muscle strains > 2 months preceding the index injury were registered $ Compliance was calculated from training logs/ interviews during weekly visits including number of sets, repetitions and training session 8
IV. Outline rehabilitation program Rehabilitation Phase Schedule: Week Intervention: Static stretching of the injured muscle groups in different joint positions. Interval/ Duration: Three times a day 3 seconds for each muscle group Range of motion: Limited to painful sensation of <5 on the pain Numeric Rating Scale (NRS) Goal: Limited loading of the injured muscle-tendon (aponeurosis) unit. Activation of cells in the injured muscle-connective tissue complex to avoid stress-shielding. Rehabilitation Phase 2 Schedule: Week 2-4 Intervention: Isometric exercises of the injured muscle groups with increasing resistance and gradually longer duration. Interval/ Duration: Daily Range of motion: Limited to painful sensation of <5 on the pain Numeric Rating Scale (NRS) Goal: Loading of the injured muscle-tendon (aponeurosis) unit without muscle length changes. Activation of cells in the injured muscle-connective tissue complex to stimulate synthesis of muscle and connective tissue. Rehabilitation Phase 3 Intervention: Dynamic resistance exercises (concentric and eccentric phase) of the injured muscle groups with increasing load: 5 RM (repetition maximum) in week 5 to RM in week 8. Interval/ Duration: Three times a week with a rest day in between Range of motion: Full range of motion for both concentric and eccentric exercises, slow movements. 9
Goal: Stimulation of skeletal muscle and connective tissue synthesis. Importance of eccentric movements following muscle strain injuries reported in previous studies 4,5. Rehabilitation Phase 4 Intervention: Heavy slow resistance exercises with main focus on the eccentric phase. Implementation of functional drills such as sprints and jumps. Interval/ Duration: Three times a week with a rest day in between Range of motion: Full range of motion for both concentric and eccentric exercises, slow movements. Explosive forces during functional exercises Goal: Stimulation of skeletal muscle and connective tissue synthesis and neuromuscular adaptations. Importance of eccentric movements following muscle strain injuries reported in previous studies 4,5. Functional tests to determine Return to Sports (RTS) A tester blinded to group allocation cleared subjects for RTS. The functional test was scheduled when subjects were symptom-free during all rehabilitation exercises. If RTS was not achieved during the rehabilitation period, close contact was continued with the subject and the test was scheduled based on progression (in relation to symptoms) in training. The functional tests consisted of a 3-minute running warm-up followed by 3-4 submaximal 5- meter sprints. If symptom-free, four maximal sprints were performed: two on uneven ground (grass) and two on even ground (tarmac). After each sprint, the subjects were asked for the score on the NRS. After jogging for approximately minutes, subjects were asked to perform six oneleg jumps with hands placed on the hips, alternating between the non-injured and the previously injured leg. After each jump, the subjects were asked for the score on the NRS. If NRS, the subject was cleared for RTS.
V. Overview participant flow Figure S. Participant flow
VI. Images of rehabilitation exercises a. Rehabilitation after hamstring muscle strain Figure S2. Static stretching with straight and bent knee. Week -2. Figure S3. Isometric exercise with elastic band. Progression achieved by increasing band resistance and increasing duration. Week 2-4. Figure S4. Isometric pelvic lift. Progression achieved by increasing knee angle, duration and advancing from two-leg lift to single leg lift (injured leg only as shown). Week 2-4. 2
Figure S5. Leg curl with full range of motion. Progression achieved by increasing weight (5RM to RM). Week 5-8. Figure S6. Seated leg press feet high on platform and start/ finish knee angle < 9 deg. Progression achieved by increasing resistance (5RM to 4RM). Week 5-8 two-leg concentric and eccentric movement (not shown), week 9-2 two-leg concentric movement, one-leg eccentric movement (injured leg only, as shown). Figure S7. Supine slider with full knee extension. Progression achieved by advancing from two-leg sliding (week 9 and, not shown) to one-leg (injured leg only, week and 2, as shown) and increase in repetitions. 3
Figure S8. Nordic Hamstrings exercise. Progression achieved by increasing knee angle during downward movement and increase in repetitions. Week 9-2. Figure S9. Sprints with high knees on spot (as shown) and in forward movement (not shown). Progression through increase in number of steps. Week 9-2. 4
b. Rehabilitation after calf muscle stain Figure S. Static stretching with straight knee. Week -2. Figure S. Static stretching with bent knee. Week -2. Figure S2. Isometric calf exercise with straight and bent knee. Progression achieved by increasing weight and increasing duration. Week 2-4. 5
Figure S3. Calf raises with straight knee. Progression achieved by increasing resistance (5RM to 4RM). Week 5-2. Week 5-8 both legs concentric and eccentric movement (as shown), week 9-2 both legs for concentric movement, injured leg only during eccentric movement (not shown). Exercises performed in three different foot positions (supplementary fig. 4). Figure S4. Three different foot positions: Neutral - toes inward bound - toes outward bound Figure S5. Calf raises with bent knee. Progression through increasing resistance (5RM to 4RM). Week 5-8 two-leg concentric and eccentric movement (not shown), week 9-2 two-leg concentric, one-leg eccentric movement (injured leg only, as shown). 6
Figure S6. Explosive jumps with straight knees. Progression through increase in jump height and number of jumps. Week 9-2. 7
c. Rehabilitation after Quadriceps muscle strain Figure S7. Static stretching standing position. Week -2. Figure S8. Static stretching kneeling position. Week -2. Figure S9. Isometric exercise with elastic band. Progression achieved by increasing band resistance and increasing duration. Week 2-4. 8
Figure S2. Isometric front squads. Progression achieved by increasing external weight and increasing duration. Week 2-4. Figure S2. Leg extension with full range of motion. Progression through increasing resistance (5RM to 4RM). Week 5-8 two-leg concentric and eccentric movement (not shown), week 9-2 two-leg concentric movement, one-leg eccentric movement (injured leg only, as shown). Figure S22. Dynamic deep squats. Progression through increasing resistance (5RM to 4RM). Week 5-2. 9
Figure S23. Dynamic leg extension standing position as explosive kicks. Progression achieved by increasing resistance and increasing speed in forward movement ( kick ). Week 9-2. Figure S24. Walking lunges (week 5-8), jump lunges (week 9-2). Progression through increase in number of repetitions and external weight (weighted vest, as shown) if possible. 2
VII. References. Mueller-Wohlfahrt H-W, Haensel L, Mithoefer K, et al. Terminology and classification of muscle injuries in sport: the Munich consensus statement. Br J Sports Med 23;47(6):342 5. 2. Connell DA, Schneider-Kolsky ME, Hoving JL, et al. Longitudinal study comparing sonographic and MRI assessments of acute and healing hamstring injuries. Am J Roentgenol 24;83(4):975 84. 3. Sherry MA, Best TM. A Comparison of 2 Rehabilitation Programs in the Treatment of Acute Hamstring Strains. J Orthop Sport Phys Ther 24;34:6 25. 4. Askling CM, Tengvar M, Thorstensson A. Acute hamstring injuries in Swedish elite football: a prospective randomised controlled clinical trial comparing two rehabilitation protocols. Br J Sports Med 23;47:953 959. 5. Askling CM, Tengvar M, Tarassova O, Thorstensson A. Acute hamstring injuries in Swedish elite sprinters and jumpers: a prospective randomised controlled clinical trial comparing two rehabilitation protocols. Br J Sport Med 24;48:532 9. 2