CRUSH INJURY AND RHABDOMYOLYSISTrauma and Critical Care SymposiumPenrose-St. Francis Trauma Center

Colorado Springs May 2, 2013

Darren Malinoski, MDAssociate Professor of SurgeryOregon Health & Science University

ROADMAPGeneral definitionsHistoryPathophysiology of muscle injuryPathophysiology of renal injuryDiagnosisTreatment strategiesThresholds for treatmentNatural disastersResearch at LAC/USC and OHSU

RHABDOMYOLYSIS(Rhabdo): striped muscle dissolution. EtiologiesRelease of cellular contents into the circulationHow to measure/quantifyTreatment?

MYOGLOBINAn 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.

CREATINE KINASECK: 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 rhabdoCK

COMPARTMENT SYNDROMERefers to the local manifestations of neuromuscular ischemia because of increased pressure within the osteofascial compartments. Signs and symptomsDiagnosisFluid sequestration

CRUSH SYNDROMEThe 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 musclesDark tea-colored urineShockAcidosisAcute renal failure

RENAL IMPACTAcute 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

HISTORY OF RHABDOMYOLYSIS1880s: first reported in the German Literature1911: Meyer-Betz described a clinical syndrome consisting of dark brown urine, muscle pain, and weakness1941: 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.

CAUSES OF RHABDOMYOLYSISAlcohol intoxication, immobility, compressionPositioning during surgerySeizure disordersMedications: steroids, paralyticsToxins: alcohol, cocaine, insect bites, reptilesCosta Rican jumping viper venomGenetic DisordersInfection: bacterial and viralTrauma: Crush injury / Vascular Occlusion

PATHOPHYSIOLOGY OF MUSCLE INJURYImmediate cell disruptionDirect pressure on musclesStretch-activated channels opened Ca++ influxIschemia/Anaerobic metabolismLoss of cellular membrane integrityVascular compromiseProlonged compression vs. vascular injuryHistologic changes at 2 hoursNecrosis at 6-8 hours

ISCHEMIA-REPERFUSION INJURYOccurs when patients are extricated from collapsed buildings or when vascular flow is re-established:Swelling of affected extremities / Compartment SyndromeHypovolemia / ShockFree Radical formationLipid Peroxidation cell lysisToxin release: lactic acidosis, aciduria, myoglobinemia, CK, and thromboplastin (can DIC)Electrolyte abnormalities: K, Phos, Ca

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

PATHOPHYSIOLOGY OF RENAL INJURYHypovolemia and ShockMyoglobinuria: 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

Myoglobin cast formation in renal tubules

Myoglobin cast formation in renal tubules

DIAGNOSISHistoryPEXLabs:Serum: CK, myoglobinUrine: inspection, dipstick, myoglobin Is general screening necessary?

TREATMENTPrevention of Muscle InjuryFasciotomyAmputationPrevention of Renal InjuryDialysis

PREVENTION OF MUSCLE INJURYPrompt restoration of blood flowDelivery of intravenous fluid is the FIRST priorityExtricate victims from rubble NEXTReduce fractures and splint extremitiesRepair vascular injuries

TREATMENT OF MUSCLE INJURYFasciotomy Controversies: indications and timingcompartment pressure >30-50mmHgDP

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 fasciotomiesProspective analysis of 210 patients with tibial fracturesContinuous compartment pressure (CP)Fasciotomy for DP >30 mmHg or clinical Dx109 pts either had Dx of compartment syndrome or elevated compartment pressures for less than 6 hrs.101 patients remained with CP > 30 mmHg

White, et al. Elevated Intramuscular Compartment Pressures Do Not Influence Outcome after Tibial Fracture. JOT, 2003.101 pts with elevated CP and normal DP41 patients: CP > 30 mmHg (30 to >70)60 pts: CP < 30 mmHgNone developed compartment syndromeNone required fasciotomyNo significant difference in outcome:Sensory function, Muscle power, Peak torque, Functional indices of recovery

TO CUT or NOT TO CUTIrreversible muscle damage after 6-8 hours

Sheridan, et al. J Bone Joint Surg Am 1976Only 8% of pts with fasciotomy after 12 hours had restoration of normal function46% infection, 21% amputation

Bradley. Surg Gynecol Obstet. 1973Meta-analysis: 80% of pts with paralysis had unsatisfactory outcomes

TO CUT or NOT TO CUTMatsuoka, et al. J Trauma. 2002Increased disability in pts who underwent fasciotomy >12 hours after injury (47% vs 16%)

Seddon. J Bone Joint Surg Br. 1956Spontaneous recovery of muscle function up to 3 months after injuryRecommends delayed fasciotomy and release of ischemic contractures to maximize outcome

Better and Finkelstein condemn delayed fasciotomy due to risk of overwhelming infection

FASCIOTOMYTwo incisionsLateral incision:Anterior compartmentLateral / Peroneal compartmentMedial incision:Posterior compartmentsOne incisionLateral: all four compartments

LATERAL INCISION: anterior and lateral compartments

Delayed Primary Closure of fasciotomy wound.

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

PREVENTION OF RENAL INJURYGoal is to prevent rise in serum Cr and the need for renal replacement therapy.Treatment of shock and hypovolemiaRestoration of adequate intravascular volume6-12 L of saline in first 24hrs is recommendedUrine flow rate of 100-200cc/hr is idealCorrection of underlying cause of shockMeasure serial CK levels in high-risk patientsTreatment threshold 5000-30,000 U/L

PREVENTION OF RENAL INJURYAlkalinization of urine with NaHCO3- (K+)Mannitol Dopamine, acetazolamide, and Lasix Experimental therapies:DeferoxaminePAF-receptor blockadeBosentan endothelin receptor blockadeAnti-oxidants

MannitolMannitolSodium Bicarbonate

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 injury1979: 7 men with rhabdo due to building collapse who did not receive IV fluid for at least 6 hours; all 7 developed ARF1982: 7 men with traumatic rhabdo who received IV fluid before extrication and forced mannitol-alkaline diuresis within 2 hours of extrication; none developed ARF

TREATMENT THRESHOLDSERUM CREATINE KINASE LEVELS$151-2 hour turnaroundElimination T1/2: 42 hrsMore prevalent in the literature - >3000 ptsPeak levels of 5000 to 75,000 risk ARDAll pts with increased CK levels have positive urine dipstick**URINE OR SERUM MYOGLOBIN LEVELS$971-3 day turnaroundElimination T1/2: 12 hrsStudies with small numbers -

DIALYSISRisk factors for developing ARF:CK level >20,000Delay in diagnosis or treatmentExtent of injuryDehydrationPreexisting renal diseaseAdvanced ageAdministration of nephrotoxic agentsNormalization of Hyperkalemia is the main priority.Need for dialysis is temporary in most cases

EARTHQUAKES AND RHABDOMYOLYSIS1988: Armenian Republic of Soviet Union100,000 injured, 15,254 extricated from rubble, crush injury third most common injury but leading cause of death, 323 patients required hemodialysis, poorly organized disaster response1991: Limon, Costa RicaCrush injury was the leading cause of injury and death

EARTHQUAKES AND RHABDOMYOLYSIS1995: Kobe, Japan41,000 injured, 5000 died, 54% of victims with crush injury developed ARF and 13% died1999: Marmara, TurkeyRenal Disaster Relief Task Force created in 1995 after Armenian earthquake462 patients underwent dialysis, with

Oda et al. Analysis of 372 Patients with Crush Syndrome Caused by the Hanshin-Awaji Earthquake. Journal of Trauma 1997; 42: 470-476Retrospective review of 6107 charts at 95 hospitals; 372 patients with crush syndromeARF= Cr > 2.5; 200 (54%) ARF, 123 (33%) required dialysisMany patients had a delay until treatment, either due to transportation problems or failure to accurately diagnose crush injury.Risk factors for ARF: 75,00050 patients died (13.4%); causes of death within 5 days of the earthquake were mainly hyperkalemia and hypovolemia.

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

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.

Trauma patient with crush injury to the flank

CT scan of same patient.

RECENT PUBLICATIONS AND UNPUBLISHED DATA FROM USC/LAC AND OHSU

RHABDOMYOLYSIS AT OHSUTreatment Protocol in 1992Mannitol and Bicarbonate infusionsTreatment threshold = CK >10,000 U/LInterim Analysis 1997Threshold raised to 20,000 U/LUrine myoglobin levels abandonedSecond Analysis 2002CK > 20,000 U/L = risk factor for dialysisCK > 10,000 U/L = risk factor for AKI/death

2000 trauma ICU admissions85% elevated CK18% CK > 5000 U/L 19% vs 8% ARDBicarbonate and Mannitol no sig differenceTrend in CK >30,000 U/L groupLimitations

A FORCED ALKALINE DIURESIS DECREASES THE INCIDENCE OF ACUTE RENAL DYSFUNCTION IN PATIENTS WITH TRAUMATIC RHABDOMYOLYSIS

Malinoski, Slater, Schreiber, MullinsOregon Health & Sciences University

OBJECTIVETo determine if the increase in the treatment threshold from CK 10,000 to 20,000 U/L would lead to an increase in ARD.

HYPOTHESIS:A forced alkaline diuresis is beneficial ONLY in patients with a peak CK > 20,000 U/L.MannitolBicarbonate

METHODSRetrospective review - 1/93 to 10/03 Selection criteria:CPK >2000 U/L (normal 4-397)No prior history of CRI or other cause of ARFARD = serum Cr >2.0 mg/dLProtocol instituted for CPK >10K/20K U/LPrimary endpoint: ARD

STATISTICAL ANALYSISUnivariate analysis Parametric data: Pearson Chi-square, Fishers exact, or independent samples T-testNon-parametric: Mann-Whitney UMultivariate analysis:Logistic regression analysisAll variables with p

CK levels checked in pts at risk for crush injury:painful, swollen extremities; prolonged compression; urine dipstick positive .Protocol initiated when CK level >20,000 or patient has dark urine

Urine output is monitored hourlyAdditional mannitol boluses if neededTitration of drips

Monitor urine pH (goal>6.5), ABG, serum electrolytes, creatinine, and osmolarityConsider acetazolamide for serum pH > 7.5

Volume status must be watched in elderly patients and those with a history of heart diseaseIf oliguria persists after 2 hours, cessation of the protocol is necessary and renal replacement therapy should be initiated

RESULTSN = 77

80 patients77 included3 excludedCK 20K34Normal Cr = 16ARD = 5Normal Cr = 3ARD = 3Normal Cr = 20ARD = 14ARF = 4CK 10-20K16Normal Cr = 14ARD = 2NO PROTOCOLPROTOCOL**4 pts in CK > 20K did not receive protocol

Primary Endpoint = ARDMore common than ARFSerum Cr > 2 mg/dL is a common definition of renal failure in the literatureAssociated with an increased risk of death17% vs 51%, p

Prevalence of ARD in patients with peak CK > 10,000 U/L

p=0.022, Fishers Exact Test

**If Peak CK 2000-9999 vs > 10,000 U/L used, OR = 9.8, p=0.013

PROTOCOL COMPLICATIONS3 pt (3.9%) with reversible CHF

1 pt (1.3%) with pH=7.78

1 pt with abdominal compartment syndrome after analysis completed

STUDY CONCLUSIONSA peak CK > 20,000 U/L is a definite risk factor for developing ARD.

A forced alkaline diuresis is protective in patients with traumatic rhabdomyolysis.

Due to a trend towards increased renal dysfunction, we recommend using a forced alkaline diuresis in patients with peak CK >10,000 U/L.

UNFINISHED BUSINESSTREATMENT OF MUSCLE INJURY

LATE FASCIOTOMIES

IDEAL TREATMENT FLUID RANDOMIZED CONTROLLED TRIAL

THANK YOUDont forget DVT prophylaxis

*Release of cellular contents into circulationEtiologiesCreatine Kinase (CK) levels TreatmentWhat level is significant???

*Increased plasma levels myoglobinuriadipstick positive urineFree radical formation and lipid peroxidationSerum and urine levels vs. CK***Searched registry for : ARF, crush injury, rhabdomyolysis, myoglobinuria, fasciotomy*changed after interim analysis*2 patients excluded due to MODS and late ARF req HD (>7d after injury)1 patient excluded due to 80cc/hr at time of cvvh. No HCO3-, lasix, kayexelate used

*All manageable.*Power analysis: 1000 pt needed to show decrease in incidence of ARF from 10 to 5% with p=0.05 and power=0.80