Exertional Rhabdomyolysis

1. Exertional Rhabdomyolysis Liz Delasobera, MD (some slides c/o USU database)

2. 3 Things To Remember • Know how to risk stratify rhabdo patients • Low risk – treat like concussion (step-wise return to play/duty) • High risk – more tests and experts, restrict play • Heat illness=rhado until proven otherwise • Admit for CK > 5-10K for IVF, to check serial labs (CK, DIC, lytes), and to eval for compartment syndrome

3. Our Roadmap • The Basics: Definitions, Epidemiology, Pathophysiology, Risk Factors • Diagnosis: Differentiating Subtypes of Rhabdo, Signs, Symptoms, Differential • Treatment: Short and Long-Term, Prognosis/Return to Play, Prevention • Cases: Test your knowledge

4. Definition of Rhabdomyolysis • Skeletal muscle breakdown with release of myocyte contents into the circulation caused by a variety of stresses • Characterized by laboratory findings of myonecrosis with clinical spectrum dependent upon amount of muscle injury and associated co-morbid factors

5. Definition of Exertional Rhabdomyolysis • Most frequently ascribed to running activity and often associated with exertional heat illness • Ranges from asymptomatic muscle injury with minor laboratory alterations to immediate life threatening syndrome with severe metabolic alterations and cardiac dysrythmias

6. Definition of Exertional Rhabdomyolysis • Not always pathologic – can be a normal response to strenous exercise (“physiologic rhabdomyolysis”) • Becomes more serious (“clinically relevant rhabdomyolysis”) when coupled with dehydration, SC trait, certain drugs, dietary supplements, caffeine/alcohol, exertional heat illness, and other poorly understood factors • Devastating consequences: • Renal failure • DIC • Compartment syndrome • Death

7. Epidemiology • Subclinical rhabdo common in vigorous exercisers and collision sports • More serious cases seen mostly in endurance athletes and military personnel • 26,000 + per year in US • 30% develop renal involvement

8. Pathophysiology • Intense exercise -> hypoxia of tissues -> failure of Na/K pump (K+ out of cell, Na+/Ca+ into cell); anaerobic glycolysis and lactic acidosis -> cell death • Muscle injury causes release of myoglobin and muscle enzymes (CPK, LDH, AST, ALT) • Evolving compartment syndrome due to swelling (muscle damage) and fluid shifts • Renal failure due to myoglobin and uric acid in tubules + dehydration + nephrotoxic metabolites of myoglobin

9. Risk Factors

10. Our Roadmap • The Basics: Definitions, Epidemiology, Pathophysiology, Risk Factors • Diagnosis: Differentiating Subtypes of Rhabdo, Signs, Symptoms, Differential • Treatment: Short and Long-Term Treatment of Rhabdo, Prognosis/Return to Play, Prevention • Cases: Test your knowledge

11. Subtypes of Rhabdo • Exertional limited rhabdo • Exertional rhabdo with heat stroke • Exertional rhabdo without heat stroke • Non-exertional rhabdo • Trauma • Medications

12. Limited Exertional Rhabdo • Overload of limited muscle group (ex, quads) • Symptoms 1-3 days after event (delayed muscle soreness) and persists >5 days after event • Muscles tender, warm, swollen, painful with stretch and flex/extension • CPK elevations in 10-50 K range • Cola colored urine (urine myoglobin) – can be only symptom • Usually self limited

13. Exertional Rhabdo With Heat Stroke • Most of muscle injury as a result of intense hyperthermia (heat stroke) • Risk factors • Unacclimated • Sickle cell trait • High BMI • Dehydrated • Meds/supplements

14. Exertional Rhabdo With Heat Stroke • Clinically present with: • More global muscle injury • Less muscle soreness and quicker recovery • Chemistries more reflective of early liver and renal injuries • High CPK (25,000+) • Treatment goals: • Restore normal body temperature and perfusion • Effectively manage metabolic/electrolyte/organ sequelae

15. Exertional Rhabdo Without Heat • Intense exertional effort, typically > 5 minutes and 15 METS • Setting: rapid conditioning or non-familiar exercise (ex, Basic Training) • Pain or weakness out of proportion • Usually involves large muscle groups • May manifest hours after the insult • May be additive from earlier training stress with fulminant end state • Acute management is similar to extertional rhabdo with heat except that cooling is unnecessary

16. Differential Diagnosis • Guillan-Barre Syndrome (post viral) • Electrolyte Abnormalities • Periodic Paralysis • Compartment Syndrome • Neuroleptic Malignant Syndrome • Polymyositis/Myopathy • Porphyria

17. Making the Diagnosis of Rhabdo • General signs and symptoms • Pain • Swelling • Tenderness • Weakness • Mental status changes • Hyperthermia • Cramping • “Discolored” or brown urine

18. Making the Diagnosis of Rhabdo • Physical exam • Swollen, tender, warm muscle groups • Tight muscle compartments • Objective weakness • Intense pain with passive stretch of muscle • Altered gait (lower extremities)

19. Labs • Initial studies • CPK, UA with micro, Chem 7, Calcium, Phos, CBC, AST, ALT, LDH, Uric acid • Serum or urine myoglobin - may not be available acutely • Other studies to consider • PT, PTT, Fibrinogen, ABG

20. Labs • CPK tends to peak 1-2 days after the insult • Persistent elevation or increasing values suggests ongoing muscle ischemia/injury (compartment syndrome) • Laboratory definition of rhabdo is CPK 5x normal and/or heme + blood without RBCs • CPK > 16,000 U/L is threshold for renal damage

21. Labs • AST/ALT/LDH: marker for more severe muscle damage in exertional rhabdo, and for liver injury when heat related • Uric acid: sensitive but not specific - normal is reassuring

22. Labs • Urine myoglobin • Usually a “send out” lab • This is the toxic effects on distal tubule • Sludging and obstruction leads to “muddy casts” (frothy urine) • Dehydration worsens toxic effects • Load and duration of exposure = toxicity

23. Other Tests • Compartment pressure testing • MRI scan for limited rhabdo (concern for myopathy, abscess, etc) • EKG (electrolyte changes) • Muscle biopsy: not acutely • Severe, recurrent, or unusual precipitators • Concern for neuromuscular disease • Special stains and techniques needed (specialty center) to get various diagnoses

24. Other Tests • Ischemic Forearm Test • Forearm exercise with BP cuff inflated > 200 mm Hg • Serial lactate and ammonia levels from antecubital vein • Muscle enzyme deficiencies • Low lactate production = disorder of carbo metabolism (McArdle’s) • Low ammonia production = myoadenylate deficiency

25. Our Roadmap • The Basics: Definitions, Epidemiology, Pathophysiology, Risk Factors ✔Diagnosis: Differentiating Subtypes of Rhabdo, Signs, Symptoms, Differential • Treatment: Short and Long-Term Treatment of Rhabdo, Prognosis/Return to Play, Prevention • Cases: Test your knowledge

26. Short Term Treatment • Admit for total CK > 5-10K (literature varies on the exact level) • IVF hydration for goal UOP 200 mL/hr (usually 400 mL/hr IVF) needs up to 12 L in first 24 hours • Treat electrolyte abnormalities except hypocalcemia • Low Ca is a result of Na/K pump but also from deposition of calcium in muscles – replete Ca leads to higher deposition levels, only tx if having EKG changes, severe hyperkalemia, tetany, etc

27. Short Term Treatment • Urine alkalinization (myoglobin and uric acid more soluble, less nephrotoxic) with bicarb (definitely if CK>100K otherwise contraversial) • If bicarb >15 some literature suggests using oral acetazolamide • Furosemide may be needed to maintain kidney fxn • Fasciotomy as needed • Dialysis in extreme cases • Get ortho and renal involved early for help with making these decisions!

28. Long Term: Risk Stratifying • First step to stratify low vs high risk is differentiating btwn physiologic and clinically relevant rhabdo: • CK level 5X  normal or greater • OR • UA that is positive for blood in the absence of RBCs • If both of these negative then rest for 24 hours and repeat, if UA is still negative and CK is normal then dx is physiologic rhabdo and can gradually return to play/duty • If either of these 2 steps are abnormal then they have clinically relevant rhabdo, need to further risk stratify

29. Long-Term: Risk Stratifying • Low Risk (at least one of these most be true): • Rapid clinical and CK recovery with exercise restriction (<1 week) • History of intense training • No personal or family history of rhabdomyolysis or previous reporting of exercise- induced severe muscle pain, muscle cramps, or heat injury • Existence of other rhabdomyolysis cases in the same training unit, team, etc • Drug or supplement use • Concomitant viral illness or other infectious disease -Quick recovery -Good reason for this (intensity, others with same sxs, etc) -Extrinsic predisposiing factors (virus, drugs, etc) without intrinsic (no FHx, etc)

30. Suspicion for High Risk: Delayed recover (> 1 week) Complications (renal failure, metabolic problems etc.) Muscle injury with low intensity workout Personal or family history of rhabdo/exertional cramps History of severe muscle pains in past Personal or family history of malignant hyperthermia Personal or family history of sickle cell trait Prior heat casualty CPK peak > 10,000 Long-Term: Risk Stratifying

31. Treatment of Low Risk • Limited duty/exertion • If CK greater than 5-10K admit for IVF (goal UOP 200 mL/hour – usually give 400 mL/hr IVF) • Re-evaluate labs 72 hours (CPK, creatinine, lytes, and UA) • Adequate sleep in thermally controlled environment • When UA is nl and total CK less than 5x nl, then gradual return to play/duty over 2 weeks (3 phases) • If CK doesn’t go down within 5x upper limit nl in 1-2 week then change to high risk algorithm

32. Low Risk Soldier Return to Duty • Phase 1: • Strict light indoor duty for 72hrs • Must sleep eight consecutive hours nightly • Must remain in thermally controlled environment • Must follow-up in 72 hrs for repeat CPK/UA. When CPK/UA has returned to normal, begin Phase 2, otherwise remain in Phase 1 and return every 72 hrs for repeat CPK/UA until normal. • If persistently abnormal at week 2, refer for expert consultation. • Phase 2: • Begin light-outdoor duty • Follow-up with care provider in one week. If no issues then begin Phase 3 • Phase 3: • Return to regular outdoor duty and physical training • Follow-up with care provider as needed, warn of symptoms, pre-disposing factors, etc

33. Treatment of High Risk • Consult with a local rhabdo expert (CHAMP website) • Admit for IV hydration and repeat labs including calcium, K, phos, uric acid • Can not return to play or duty until further eval complete with expert and further testing as indicated • Consider • Muscle Myopathy Panel (McCardle’s, AMP deaminase, CPT2 Deficiency) • EMG • Sickle cell screen • Genetic testing • Ryanodine receptor • Muscle biopsy • Forearm contracture test • Caffeine Halothane contracture test (biopsy muscle and measure force of contraction, test with caffeine and halothane for malignant hyperthemia)

34. Rhabdo Tx Algorithm

35. Prevention of Rhabdo • Acclimate • Gradual progression of training • Careful with meds (statins, supplements etc.) • Proper fluid intake • Identify susceptible individuals (genetics, FHx, SC trait, etc) • Role of antioxidants (glutathone and bioflavinoids, such as quercitin) decreasing myoglobinuria

36. Our Roadmap • The Basics: Definitions, Epidemiology, Pathophysiology, Risk Factors ✔Diagnosis: Differentiating Subtypes of Rhabdo, Signs, Symptoms, Differential ✔Treatment: Short and Long-Term Treatment of Rhabdo, Prognosis/Return to Play, Prevention • Cases: Test your knowledge

37. Case 1 • 23 year old African American F with b/l arm and leg muscle pains after 12 mile run (longer than usual run) • No meds, no illnesses • No heat related illness (winter) • No personal or family history of rhabdo • Sickle trait positive • CPK peaked at 20,000 (nl<120) • Symptoms resolved after 7 days • Dx? Acute tx? Long-term? Return to running?

38. Case 1 • Diagnosis: Rhabdo without heat illness • High risk factors: • CPK peaked at 20,000 • Sickle trait positive • Low risk factors: • Quick resolution of symptoms • No FHx or personal hx

39. Case 1 • Treatment? • Short-term: admit for IVF and serial labs, likely no need for bicarb unless CK >100,000 (d/w renal), watch for signs of compartment syndrome • Long-term: consult with rhabdo expert for special testing and to aid with decisions on return to running/play

40. Case 2 • 27 year old male healthy • Push ups and weight lifting • 1 week later…still with chest soreness • No prior or fhx, no meds, no medical problems • Physical: very tender pectoralis muscles

41. Case 2 • Labs • CK = 8,000 • UA = no blood or RBC’s • Chem 7= normal • Diagnosis and treatment?

42. Case 2 • Dx: Limited rhabdo • Tx: watch for compartment syndromes, hydrate, repeat labs, and gradual return to play assuming CK normalizes in appropriate time period, asymptomatic, etc

43. Case 3 • 18 y/o marathon runner who presents to the ER in the summer after being initially treated in the field for possible heat stroke after falling out of a run • He was described as “out of it” and had an initial rectal temp of 106 F • Others in marathon had heat illness and were transported to hospital • His initial labs demonstrate a urine that dips positive for blood and a CK of 50,000 U/L • Diagnosis? • Treatment and return to play?

44. Case 3 • Diagnosis: Rhabdo with heat • Low risk: • Others with same presentation • Extrinsic risk factors (heat, extreme exercises/exertion) • No known intrinsic risk factors • High risk: • Level of CK

45. Case 3 • Acute tx: • IV hydration and rapid cooling • Repeat labs/lytes frequently • Eval for compartment syndrome, liver injury, DIC, etc • Long term tx: • Consider checking for SC trait • If he had any high risk characteristics (prior heat illness, delayed recovery, complications, etc) or a prolonged recovery or other complications (renal, DIC, etc) would send to heat/rhabdo expert • Otherwise educate patient and allow gradual return to running with close follow-up

46. Case 4 • 32 y/o highly trained athlete who presents to the clinic with “coca-cola urine” and severe bilateral biceps pain • Did 10 sets x 20 reps of with 50 pound hand weights • His CK is 60,000 U/L and his urine dips positive for blood • No prior history, no meds, no illness • He recovered in 5 days – labs and sxs • Diagnosis? Return to sport/lifting?

47. Case 4 • Dx: Limited rhabdo • High risk because of total CK, otherwise no high risk qualities • Short-term: hydrate, etc (always the same unless CK<10K and then can consider outpt w/u) • Long-term: ensure no risk factors (i.e. supplements, FHx, personal hx, SC trait, etc), no complications, and full recovery – then consider return to play with step-wise progression, but change work-out routine

48. 3 Things to Remember • Know how to risk stratify rhabdo patients • Low risk – treat like concussion (step-wise return to play/duty) • High risk – more tests and experts, restrict play • Heat illness=rhado until proven otherwise • Admit for CK > 5-10K for IVF, to check serial labs (CK, DIC, lytes), and to eval for compartment syndrome

49. Thanks!