1. Exertional Rhabdomyolysis LTC Fred H. Brennan, Jr., DO Director, Tri-Service Primary Care Sports Medicine Fellowship Program Uniformed Services University of the Health Sciences Bethesda, MD

2. Objectives Define rhabdomyolysis and exertional rhabdomyolysis Epidemiology Pathophysiology Risk factors Causes of rhabdomyolysis Rhabdomyolysis syndromes

3. Objectives Clinical picture Diagnosis Treatment Prognosis/return to duty/medical board Prevention Summary

4. Case 1 27 year old male sergeant ; always healthy Push ups and weight lifting 1 week later…still with chest soreness Physical: very tender pectoralis muscles

5. Case 1 Labs –CK = 10,000! –ESR = 30 –UA = no blood or RBC’s –Chem 7= normal Diagnosis: Limited rhabdo Treatment: Admitted, IV fluids, observed Follow up

6. Definition of Rhabdomyolysis Rhabdomyolysis is a condition or syndrome of skeletal muscle breakdown with release of myocyte contents into the circulation which may arise from a variety of stresses that cause injury to muscle tissue. It is characterized by laboratory findings of myonecrosis with clinical spectrum dependent upon amount of muscle injury and associated comorbid factors.

7. Definition of Exertional Rhabdomyolysis "Exertional rhabdomyolysis" is the term applied to rhabdomyolysis arising from exercise or exertion. It is most frequently ascribed to running activity and often associated with exertional heat illness (heat stroke). However any extreme muscle overload activity may precipitate rhabdomyolysis. It is a spectrum illness ranging from insignificant asymptomatic muscle injury with minor laboratory alterations to fulminant immediate life threatening syndrome with severe metabolic alterations and cardiac dysrythmias.

8. Epidemiology Subclinical rhabdo common in vigorous exercisers and collision sports (how common ?) More serious cases seen in endurance athletes and military personnel Symptoms downplayed 26,000 + per year in US

9. Predisposing Factors Intrinsic/Inherited -Genetic-Muscle Diseases/Enzyme Def. (McArdles, CPT II) -Metabolic Diseases or Disorders (Diabetes, Thyroid Disease, Chronic Electrolyte Disorders or Acidosis) -Sickle Cell Trait -Autoimmune/Inflam Disorders -Familial Recurrent Myoglobinuria Extrinsic/Acquired -Recent Trauma or Crush -Excessive Muscle Overload or Exertion and/or low fitness levels -Heat Illness (Heat Stroke) -Infection (EBV, HIV, influenza) -Drug or Toxin Exposure (alcohol, statins, amphets, cocaine,ephedra?) -Dehydration

10. Pathophysiology Muscle injury with release of myoglobin and muscle enzymes (CPK, LDH, AST, ALT) Severe states with metabolic acidosis, electrolyte issues (potassium,phos,calcium), renal failure, DIC, fluid shifts Evolving compartment syndrome due to swelling and fluid shifts

11. Pathophysiology Physical Injury Non-Physical Injury Decreased Intracellular ATP Sarcoplasmic Calcium Influx Reperfusion Injury Compartment Syndrome *these all increase -Phospho Lipase A -Ca Dep Phospho -Nucleases -Proteases -Free radical -Local PMN Rhabdo

12. Pathophysiology and Clinical Picture Depends on: –Volume of injured tissue –Ability of body to handle the damage –Other contributors like hyperthermia, muscle ischemia, dehydration, continued muscle overload

13. Exertional Rhabdomyolysis Syndromes Isolated muscle injury or “limited rhabdo” Rhabo due to exertional heat illness Exertional rhabdo without heat illness

14. Limited Rhabdo Overload of limited muscle group (quads) Symptoms 1-3 days after event Muscles tender, warm, swollen, painful with stretch CPK elevations in 10-50 K range; also urine myoglobin common Usually self limited with treatment and no sequelae

15. Exertional Rhabdo With Heat Stroke Most of muscle injury as a result of intense hyperthermia (heat stroke) Multisystem “sick” Risk factors –Unacclimated –Sickle cell trait –High BMI –Dehydrated –Lack of “heat respite” –Meds/supplements

16. Exertional Rhabdo With Heat Stroke Clinically presents differently: –More global and less severe muscle injury –Less muscle soreness and quicker recovery –Chemistries more reflective of early liver and renal injuries; also high CPK (25,000 +) Treatment goals: –Restore normal body temperature and perfusion –Effectively manage metabolic/electrolyte/organ sequelae *Heat Stress Control and Heat Casualty Management. TB MED 507/AFPAM 48-152. Headquarters Department of the Army and Air Force. Washington DC, 7 March 2003. *AR 40-501

17. Case 2 22 year old soldier s/p Division 12 mile road march Sick call: “My calves and quads are killing me” PE: limping; calves and quads not tight but very tender to gentle squeeze

18. Case 2 Labs –CK = 50,000! –UA = + blood with no RBC’s Diagnosis: Exertional rhabdo Treatment: Admitted, IV fluids, monitor labs Follow up

19. Exertional Rhabdo Without Heat Intense exertional effort, typically > 5 minutes and 15 METS Setting: rapid conditioning or non-familiar exercise (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

20. Making the Diagnosis History Listen to your patient! Clinical setting (environment, recurrent or acute stress, other risk factors) Evolution of symptoms

21. Making the Diagnosis Signs and symptoms –Pain –Swelling –Tenderness –Weakness –Mental status changes –Hyperthermic –Cramping –“Discolored” or brown urine

22. Making the Diagnosis Physical exam –Swollen, tender, warm muscle groups –Tight muscle compartments –Objective weakness –Intense pain with passive stretch of muscle –Altered gait (lower extrems)

23. Making the Diagnosis Labs –Initial studies CPK, UA with micro, Chem 7, CBC, AST, ALT, LDH, Uric acid –Serum or urine myoglobin; may not be available acutely –Other studies Ca, Phos, PT, PTT, FSP, Fibrinogen, ABG Hypo or hypercalcemia can occur

24. Labs CPK tends to peak 1-2 days after the insult Persistent elevation or increasing values suggests ongoing muscle ischemia/injury (compartment syndrome)

25. Labs CPK: uncertainly about what is truly “normal” –Moderate sensitivity but not specific –May be low initially or falsely high in asymptomatic patient – Greater than 5 times normal is considered + …maybe! – > 16,000 U/L (renal damage) + dipstick for blood. But no RBC’s on micro exam

26. Labs AST/ALT/LDH: marker for more severe muscle damage in exertional rhabdo; and for liver injury when exertional and heat related Chem 7, Phos, Calcium, ABG Uric acid: sensitive but not specific; normal is somewhat reassuring CBC PT/PTT FDP

27. Labs Urine myoglobin –Toxic effects on distal tubule –Sludging and obstruction with renal failure; “muddy casts” –Dehydration worsens toxic effects on kidneys –Load and duration of exposure = toxicity –Urine frothy when agitated

28. Making the Diagnosis Other tests –Compartment pressure testing –Nuclear medicine scan for limited rhabdo Muscle biopsy: not acutely –Severe, recurrent, or unusual precipitators –Muscle enzyme or neuromuscular disease –Special stains and techniques (specialty center is best)

29. Making the Diagnosis 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 Normal rise in ammonia and lactate = disorder of lipid metabolism

30. Differential Diagnosis Guillan-Barre Syndrome (post viral) Periodic Paralysis (follows sleep or rest) Hemolysis Intrinisic renal disease Porphria Acute Glom Beets, phenytoin, rifampin, vitamin B 12

31. Algorithm for Treatment of Acute Exertional Rhabdomyolosis Service-member presents with severe muscle pain Screen with spot UA for blood, visualize color of urine Heat stroke panel * Screen for compartment syndrome (Also follow Exertional Heat Injury Algorithm) CPK > 5X nl Or Positive urine dipstick- blood (YES) (BOTH NO) Limited indoor duty for remainder of day Medical re-evaluation on following day Home oral re-hydration ACUTE EXERTIONAL RHABDOMYOLYSIS -Admit to ICU -Urine myoglobin, serum calcium, phosphate, uric acid -ABG if lactic acidosis suspected -Foley catheter -IV hydration with NS to maintain urine output >200cc/hr (consider mannitol or furosemide) - Monitor for development of compartment syndrome Positive urine myoglobin OR Metabolic acidosis Alkalinize urine if lactate <4 or pH < 7.2: * Moderate: Add 1 amp bicarb to 1 bag ½ NS Severe: Add 2 amps bicarb to 1 bag ¼ NS *D/C when myoglobin negative or pH>7.2 Hyperkalemia D50 -Insulin -Inhaled B-agonist Phos > 7mg/dl Or SYMPTOMATIC hypocalcemia Or Acute Renal Failure Or Refractory hyperkalemia Consult nephrologist for possible dialysis Uric acid Consider uricosuric agents

32. Questions: Prognosis, Return to Duty, Medical Board ? 23 year old African American E-3 with exertional rhabdo after 12 mile road march CPK peaked at 20,000 Sickle trait positive Fully recovered after 7 days with no sequelae, now what? What are the chances that this will happen again? Further eval needed?

33. Risk Stratify 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 –Personal or family history of exertional cramps –History of severe muscle pains –Personal or family history of malignant hyperthermia –Personal or family history of sickle cell trait –Drug or supplement use (statins, ephedra, creatine, steroids) –Prior heat casualty –CPK peak > 10,000

34. Risk Stratify Low risk –Rapid recovery –Physically fit –No prior personal or family history –Other rhabdo cases in the same training unit –Involvement of other viral or infectious disease

35. Low Risk Soldier Limited duty profile to exclude field duty, aerobic or anaerobic exercise Re-evaluate in 72 hours (CPK and UA) Adequate sleep in thermally controlled environment When clinically resolved then increase outdoor light-duty activity Follow up in one week and advance to full duty

36. High Risk Soldier Expert consultation Consider –Muscle biopsy –Ischemic forearm test –Rhabdo challenge test –Halothane muscle contraction test Profile until further evaluation is done

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

38. Summary Spectrum disorder Multiple factors influence susceptibility Exertional rhabdo with heat stroke- multisystem problem History and progression of symptoms is important…beware!

39. Summary Maintaining hydration is important Weakness, severe pain, and collapse are ominous signs Brown urine necessitates immediate evaluation, even if asymptomatic Risk stratify and profile/evaluate accordingly