Rhabdomyolysis Pathophysiology and Management

Steven Hsu, M.D. Assistant Professor of Clinical Medicine Houston Methodist Hospital Weill Cornell Medical College Disclosure

• No relationship to disclose Objectives

• Overview of rhabdomyolysis and causes • Mechanism behind the pathophysiology • Diagnosis and treatment • Role for infusion nursing care

What’s “Rhabdo”?

• Destruction of skeletal muscle and release of its contents into circulatory system- myoglobin, LDH, AST, ALT, potassium, phosphate

• Myoglobin may cause acute kidney injury and renal failure

• Fluid shift into muscle can result in swelling, myonecrosis, and compartment syndrome

Huerta-Aladin AL, et al. Critical Care 2005 Bosch X, et al. NEJM 2009 Background

• 1811 in German literature, 1910 described Meyer-Betz Syndrome (muscle pain, weakness and brown urine) • 1941-London bombing (oliguria, limb swelling, shock, pigmented cast) • 1943- Bywaters & Stead- myoglobin recognized, treatment plan formulated • 1950- Korean War, dialysis reduced mortality (84%->53%) • Natural Disasters: Crush syndrome up to 20% in earthquakes, early hydration and dialysis save lives

Sauret JM, Am Fam Physician 2005 Background • 26,000 cases/yr, globally unknown • 15-50% complicated by acute kidney injury • Accounts for 7-10% of AKI in the U.S. • Risks: 1. Morbid obese 2. Crush syndrome 3. Statins 4. Post-operative, longer OR time

• Increase with disasters Common Causes

TRAUMATIC/COMPRES SION

• Multiple Trauma • Crush Injury • Surgery • Burn • Electrocution Causes

Non-Traumatic Exertional • Prolonged/extreme exertion • Seizures • Metabolic myopathies • Malignant hyperthermia • Neuroleptic Malignant Syndrome

Zimmerman JL. CHEST 2013. Non-Exertional

• Alcohol • Illicit drugs • Drugs • Infection • Electrolytes • Endocrine disorder • Extreme temperature • Immobilization (long hour surgery) • Immune-mediated • Organic toxins (snake/insect bites) • Sick cell • Cyanoide/CO exposure Mannix R., Pediatrics, 2006 Pathophysiology

Hypoxia Enzyme Deficiency Direct Hypokalemia Injury

K+, Phos ↑ Myoglobin↑ Uric acid↑ Ca++↓ Met Acidosis

Fluid trapped Edema Hypovolemia

Chavez LO, et al., Crit Care 2016 Pathphysiology

Myoglobin Hypovolemia Acidosis

Acute Kidney Injury What’s Myoglobin?

• Heme-containing protein • Carrying 1 oxygen from capillary to mitochondria • Filtered by glomerulus • >100mg/dL= tea color urine

MYOGLOBINURIA Myoglobin Damage

RENAL VASOCONSTRICTION

DIRECT AND ISCHEMIC INJURY

TUBULAR OBSTRUCTION

Chavez LO, et al., Crit Care 2016 Bosch X, et al. NEJM 2009 Clinical Manifestation • Asymptomatic to severe complications • “Triad”: Muscle pain, weakness, dark urine

Local: muscle and joint pain limb weakness, stiffness, and swelling

Systemic: Confusion Seizures Dark urine Decrease urination Weight gain Complications

Early • Hypovolemia/shock • Hyperkalemia • Hypocalcemia • Cardiac arrhythmias/sudden cardiac death

Late • Acute renal failure • Compartment syndrome • Disseminated intravascular coagulation (DIC) • Sepsis/ARDS Laboratory Findings

• Creatine kinase: >5x ULN (1500-100,000) Rises within 2 to 12 hours following the onset of muscle injury and reaches its maximum within 24 to 72 hours. A decline is usually seen within three to five days of cessation of muscle injury • AST, LDH↑ • Myoglobinuria (Urine+ for blood but no RBC on microscope) • Rise in Creatinine • Anion gap metabolic acidosis • Electrolytes ➢ Hyperkalemia ➢ Hyperphosphatemia ➢ Hyperuricemia ➢ Hypocalcemia

Scalco RS, et al. BMJ Open Sport & Exercise Medicine Imaging

Kim JH, et al. Medicine (Baltimore). 2018 Nasser A, et al. West J Emerg Med. 2016 https://radiopaedia.org/articles/rhabdomyolysis Diagnosis

Elevation in serum creatine kinase (> 5x ULN) ➢ + acute neuromuscular illness or dark urine with or without any other symptoms ➢Higher CK level correlates with degree of injury ➢Less correlation with AKI or mortality ➢Low probability of AKI if CK <5000 IU/L

Generally NOT required: • Myoglobin in serum • Muscle biopsy • Electromyography • Magnetic resonance imaging

Zimmerman JL., CHEST 2013 Management • Rapid recognition • Discontinuation of muscle injury • Prevention of kidney injury • Identification and treatment of complications This includes:

• Treat underlying cause • Early aggressive fluid resuscitation • Electrolyte management • Alkalinization of urine • Hemodialysis • Fasciotomy • Antioxidant? What kind of fluid? • Optimal fluid and rate of repletion are unclear • No studies comparing efficacy/safety of different types and rate of fluid administration Practical Approach

-Initial Resuscitation: 1-2 L/hr Isotonic Saline -100-200 ml/hr (if hemolysis induced injury) -Correct electrolyte abnormalities

Titrate IVF UOP goal: 200-300ml/hr

Serial CK measurements

CK<5000 Stop Treatment Renal failure

• 10-60% incidence of AKI • Higher mortality when develops • Risk factor: cause, intravascular volume, comorbidities, lab results • Greater risk in trauma patients Options?

Alkalinization: Sodium bicarbonate: Forced alkaline diuresis • May reduce renal heme toxicity, decrease the release of free iron from myoglobin, the formation of vasoconstricting F2-isoprostanes, and the risk for tubular precipitation of uric acid • No clear clinical evidence that an alkaline diuresis is more effective than a saline diuresis in preventing AKI • Restrospective studies compared its benefit with on 27 trauma patients to historic patients • Benefit: hyperchloremic acidosis, hyperkalemia • Pitfall: May worsens hypocalcemia and calcium/phosphate deposition in muscle

Huerta-Alardín AL, Critical Care 2005 Diuretics Mannitol Forced diuresis • May minimize intratubular heme pigment deposition and cast formation, and/or by acting as a free radical scavenger, thereby minimizing cell injury • Net clinical benefit of remains uncertain • Not routinely recommended Loop diuretics ➢Limited experience ➢Caution with hypovolemia ➢Can cause acidification of urine Dialysis • Indications 1. metabolic acidosis Myoglobin (17 kD) is not readily 2. fluid overload removed by conventional 3. Hypercalcemia/hyperkalemia dialysis, CRRT appears better 4. worsening renal failure

Panizo N., . Kidney Blood Press Res 2015 • Hypocalcemia ▪ Treat only if symptomatic • Acute Compartment Syndrome ▪ Monitor compartment pressure ▪ Surgical intervention What’s more?

Molecular Mechanism Novel therapies • Oxidative stress • Iron chelator • Inflammation (Desferrioxamine) • Apoptosis • Antioxidants • Vasoconstriction (acetaminophen, N- acetylcysteine, Vitamin C, E, zinc, selenium • Antiinflammatory (Pentoxyphylline) • Vasoconstriction inhibitor (L- Carnitine) • Extracorporeal removal (Cytosorb)

Boutaud O., Proc Natl Acad Sci, 2010 Panizo N., . Kidney Blood Press Res 2015 Prevention • Do: Adequate hydration and electrolytes • Don’t: Over excise in extreme temperature, over use alcohol or illicit drug • Aware: Cholesterol medications, SSRIs, antipsychotics, colchicine, lithium, chemotherapy, antibiotics Outcomes

• Vary with patient, cause, comorbidities • Mortality 1.7-46% • Higher mortality associated with renal failure • Most renal failure recovers 1-3 months Infusion Care is the KEY!

• High index of suspicion • Assess and reassess • Early and aggressive ISOTONIC fluid resuscitation should started ASAP to prevent pigment nephropathy • Avoid K+ containing solution • Start IVF prehospital • Titrate to UOP 200-300cc/hr (3mL/kg/hr) • Large volume 6-12L in 24 hours in absence of volume overload Thank you! References

• Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore). 2005 Nov;84(6):377-85. PubMed PMID: 16267412.

• Chavez LO, Leon M, Einav S, Varon J. Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice. Crit Care. 2016 Jun 15;20(1):135.

• Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care 2005; 9:158.

• Zimmerman JL, Shen MC. Rhabdomyolysis. Chest. 2013 Sep;144(3):1058-1065. doi: 10.1378/chest.12-2016.

• Panizo N, Rubio-Navarro A, Amaro-Villalobos J, M, Egido J, Moreno J, A: Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury. Kidney Blood Press Res 2015;40:520-532. doi: 10.1159/000368528

• Kim JH, Kim YJ, Koh SH, Kim BS, Choi SY, Cho SE, Song JH, Kim CH, Lee KH, Cho SG. Rhabdomyolysis revisited: Detailed analysis of magnetic resonance imaging findings and their correlation with peripheral neuropathy. Medicine (Baltimore). 2018 Aug;97(33):e11848.

• Nassar A, Talbot R, Grant A, Derr C. Rapid Diagnosis of Rhabdomyolysis with Point-of-Care Ultrasound. West J Emerg Med. 2016 Nov;17(6):801-804.

• Rhabdomyolysis, Radiopaedia.org. Https://radiopaedia.org/articles/rhabdomyolysis

• Boutaud O, Moore KP, Reeder BJ, Harry D, Howie AJ, Wang S, Carney CK, Masterson TS, Amin T, Wright DW, Wilson MT, Oates JA, Roberts LJ 2nd. Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2699-704.

• Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics. 2006 Nov;118(5):2119-25.

• Scalco RS, Snoeck M, Quinlivan R, et al, Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy? BMJ Open Sport & Exercise Medicine 2016;2:e000151.