1. CRUSH INJURY AND RHABDOMYOLYSIS Trauma and Critical Care Symposium Penrose-St. Francis Trauma Center Colorado Springs – May 2, 2013 Darren Malinoski, MD Associate Professor of Surgery Oregon Health & Science University

2. ROADMAP • General definitions • History • Pathophysiology of muscle injury • Pathophysiology of renal injury • Diagnosis • Treatment strategies • Thresholds for treatment • Natural disasters • Research at LAC/USC and OHSU

3. RHABDOMYOLYSIS • (Rhabdo): striped muscle dissolution. • Etiologies • Release of cellular contents into the circulation • How to measure/quantify • Treatment?

4. MYOGLOBIN • An oxygen-binding protein found within skeletal muscle that contains a single heme prosthetic group with an iron atom at the center that serves as the oxygen-binding site. Higher affinity for oxygen than hemoglobin which facilitates delivery to muscle.

7. CREATINE KINASE • CK: intramuscular enzyme that catalyzes the formation of ATP: ADP + creatine phosphate  ATP + creatine • Several isoenzymes: CK-MM (striated muscle), CK-MB (cardiac), CK-BB (brain) • Normal plasma range 45-397 IU/L; plasma level of CK is proportional to degree of rhabdo CK

8. COMPARTMENT SYNDROME • Refers to the local manifestations of neuromuscular ischemia because of increased pressure within the osteofascial compartments. • Signs and symptoms • Diagnosis • Fluid sequestration

9. CRUSH SYNDROME • The systemic manifestations of muscle injury after direct trauma or ischemia-reperfusion injury. Commonly found in victims of earthquakes who have been caught under the rubble of collapsed buildings. • SIGNS AND SYMPTOMS: • Tense, edematous, painful muscles • Dark tea-colored urine • Shock • Acidosis • Acute renal failure

10. RENAL IMPACT • Acute Renal Failure (ARF): a decline in renal function severe enough to require some form of renal replacement therapy. • Many definitions • Mortality ranges from 5-50% when renal failure follows crush injury

11. HISTORY OF RHABDOMYOLYSIS • 1880’s: first reported in the German Literature • 1911: Meyer-Betz described a clinical syndrome consisting of dark brown urine, muscle pain, and weakness • 1941: Bywaters and Beall report 4 cases of crush syndrome during the bombing of London during WWII. They recognized the association between swollen extremities, hypovolemia, vaso-constriction, and eventual oliguria / renal failure.

14. CAUSES OF RHABDOMYOLYSIS • Alcohol intoxication, immobility, compression • Positioning during surgery • Seizure disorders • Medications: steroids, paralytics • Toxins: alcohol, cocaine, insect bites, reptiles • Costa Rican jumping viper venom • Genetic Disorders • Infection: bacterial and viral • Trauma: Crush injury / Vascular Occlusion

15. PATHOPHYSIOLOGY OF MUSCLE INJURY • Immediate cell disruption • Direct pressure on muscles • Stretch-activated channels opened – Ca++ influx • Ischemia/Anaerobic metabolism • Loss of cellular membrane integrity • Vascular compromise • Prolonged compression vs. vascular injury • Histologic changes at 2 hours • Necrosis at 6-8 hours

16. ISCHEMIA-REPERFUSION INJURY • Occurs when patients are extricated from collapsed buildings or when vascular flow is re-established: • Swelling of affected extremities / Compartment Syndrome • Hypovolemia / Shock • Free Radical formation • Lipid Peroxidation  cell lysis • Toxin release: lactic acidosis, aciduria, myoglobinemia, CK, and thromboplastin (can  DIC) • Electrolyte abnormalities: K, Phos, Ca

17. -Malinoski, Slater, Mullins. Crit Care Clin, 2004.

18. PATHOPHYSIOLOGY OF RENAL INJURY • Hypovolemia and Shock • Myoglobinuria: when plasma concentration exceeds 0.5-1.5 mg/dL, myoglobin filtered into urine. • Cast formation/tubular obstruction * • Free radical formation and lipid peroxidation * • Vaso-constrictor formation: PAF, endothelins *intensified by acidic urine

19. Myoglobin cast formation in renal tubules

20. Myoglobin cast formation in renal tubules

23. DIAGNOSIS • History • PEX • Labs: • Serum: CK, myoglobin • Urine: inspection, dipstick, myoglobin • Is general screening necessary?

24. TREATMENT • Prevention of Muscle Injury • Fasciotomy • Amputation • Prevention of Renal Injury • Dialysis

25. PREVENTION OF MUSCLE INJURY • Prompt restoration of blood flow • Delivery of intravenous fluid is the FIRST priority • Extricate victims from rubble NEXT • Reduce fractures and splint extremities • Repair vascular injuries

26. TREATMENT OF MUSCLE INJURY • Fasciotomy • Controversies: indications and timing • compartment pressure >30-50mmHg • DP <30 mmHg (diastolic minus compartment) • Amputation • if limb salvage is not possible • if the patient will die from intractable hyperkalemia, acidosis, or infection

27. White, et al. Elevated Intramuscular Compartment Pressures Do Not Influence Outcome after Tibial Fracture. JOT, 2003. • Hypothesis: Absolute intramuscular pressure measurements are non-specific and lead to unnecessary fasciotomies • Prospective analysis of 210 patients with tibial fractures • Continuous compartment pressure (CP) • Fasciotomy for DP >30 mmHg or clinical Dx • 109 pts either had Dx of compartment syndrome or elevated compartment pressures for less than 6 hrs. • 101 patients remained with CP > 30 mmHg

28. White, et al. Elevated Intramuscular Compartment Pressures Do Not Influence Outcome after Tibial Fracture. JOT, 2003. • 101 pts with elevated CP and normal DP • 41 patients: CP > 30 mmHg (30 to >70) • 60 pts: CP < 30 mmHg • None developed compartment syndrome • None required fasciotomy • No significant difference in outcome: • Sensory function, Muscle power, Peak torque, Functional indices of recovery

29. TO CUT or NOT TO CUT… • Irreversible muscle damage after 6-8 hours • Sheridan, et al. J Bone Joint Surg Am 1976 • Only 8% of pts with fasciotomy after 12 hours had restoration of normal function • 46% infection, 21% amputation • Bradley. Surg Gynecol Obstet. 1973 • Meta-analysis: 80% of pts with paralysis had unsatisfactory outcomes

30. TO CUT or NOT TO CUT… • Matsuoka, et al. J Trauma. 2002 • Increased disability in pts who underwent fasciotomy >12 hours after injury (47% vs 16%) • Seddon. J Bone Joint Surg Br. 1956 • Spontaneous recovery of muscle function up to 3 months after injury • Recommends delayed fasciotomy and release of ischemic contractures to maximize outcome • Better and Finkelstein condemn delayed fasciotomy due to risk of overwhelming infection

31. FASCIOTOMY • Two incisions • Lateral incision: • Anterior compartment • Lateral / Peroneal compartment • Medial incision: • Posterior compartments • One incision • Lateral: all four compartments

33. LATERAL INCISION: anterior and lateral compartments

34. Delayed Primary Closure of fasciotomy wound.

35. Split Thickness Skin Graft to close fasciotomy wound after several weeks.

36. PREVENTION OF RENAL INJURY • Goal is to prevent rise in serum Cr and the need for renal replacement therapy. • Treatment of shock and hypovolemia • Restoration of adequate intravascular volume • 6-12 L of saline in first 24hrs is recommended • Urine flow rate of 100-200cc/hr is ideal • Correction of underlying cause of shock • Measure serial CK levels in high-risk patients • Treatment threshold 5000-30,000 U/L

37. PREVENTION OF RENAL INJURY • Alkalinization of urine with NaHCO3- (K+) • Mannitol • Dopamine, acetazolamide, and Lasix • Experimental therapies: • Deferoxamine • PAF-receptor blockade • Bosentan – endothelin receptor blockade • Anti-oxidants

38. Mannitol Mannitol Sodium Bicarbonate

39. Better OS, Stein JH. Early Management of Shock and Prophylaxis of Acute Renal Failure in Traumatic Rhabdomyolysis. New England Journal of Medicine 1990; 322 (12): 825-829 • Hypothesis: Shock occurs only after extrication, when compressed extremities are released, resulting in ischemia-reperfusion injury • 1979: 7 men with rhabdo due to building collapse who did not receive IV fluid for at least 6 hours; all 7 developed ARF • 1982: 7 men with traumatic rhabdo who received IV fluid before extrication and forced mannitol-alkaline diuresis within 2 hours of extrication; none developed ARF

40. SERUM CREATINE KINASE LEVELS $15 1-2 hour turnaround Elimination T1/2: 42 hrs More prevalent in the literature - >3000 pts Peak levels of 5000 to 75,000  risk ARD All pts with increased CK levels have positive urine dipstick** URINE OR SERUM MYOGLOBIN LEVELS $97 1-3 day turnaround Elimination T1/2: 12 hrs Studies with small numbers - <300 pts Most studies use urine levels which are affected by renal function TREATMENT THRESHOLD

41. DIALYSIS • Risk factors for developing ARF: • CK level >20,000 • Delay in diagnosis or treatment • Extent of injury • Dehydration • Preexisting renal disease • Advanced age • Administration of nephrotoxic agents • Normalization of Hyperkalemia is the main priority. • Need for dialysis is temporary in most cases

42. EARTHQUAKES AND RHABDOMYOLYSIS • 1988: Armenian Republic of Soviet Union • 100,000 injured, 15,254 extricated from rubble, crush injury third most common injury but leading cause of death, 323 patients required hemodialysis, poorly organized disaster response • 1991: Limon, Costa Rica • Crush injury was the leading cause of injury and death

44. EARTHQUAKES AND RHABDOMYOLYSIS • 1995: Kobe, Japan • 41,000 injured, 5000 died, 54% of victims with crush injury developed ARF and 13% died • 1999: Marmara, Turkey • Renal Disaster Relief Task Force created in 1995 after Armenian earthquake • 462 patients underwent dialysis, with <19% mortality rate (this was a dramatic improvement in the delivery of treatment and survival)

45. Oda et al. Analysis of 372 Patients with Crush Syndrome Caused by the Hanshin-Awaji Earthquake. Journal of Trauma 1997; 42: 470-476 • Retrospective review of 6107 charts at 95 hospitals; 372 patients with crush syndrome • ARF= Cr > 2.5; 200 (54%) ARF, 123 (33%) required dialysis • Many patients had a delay until treatment, either due to transportation problems or failure to accurately diagnose crush injury. • Risk factors for ARF: <6 L fluid / day, delay until treatment, and CK >75,000 • 50 patients died (13.4%); causes of death within 5 days of the earthquake were mainly hyperkalemia and hypovolemia.

46. Oda et al. Analysis of 372 Patients with Crush Syndrome Caused by the Hanshin-Awaji Earthquake. Journal of Trauma 1997; 42: 470-476 *black = hypovolemia, diagonal stripe = hyperkalemia, horizontal stripe = other form of shock, vertical stripe = multiple organ failure, open = other causes

47. Oda et al. Analysis of 372 Patients with Crush Syndrome Caused by the Hanshin-Awaji Earthquake. Journal of Trauma 1997; 42: 470-476 ***9% had trunk involvement; extremities do not need to be involved to develop rhabdomyolysis.

48. Trauma patient with crush injury to the flank

49. CT scan of same patient.

50. RECENT PUBLICATIONS AND UNPUBLISHED DATA FROM USC/LAC AND OHSU