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Rhabdomyolysis
Caroline Tschibelu, MD
Chirag N. Shah, MD
image BASICS
DESCRIPTION
  • Breakdown of skeletal muscle cells and release of intracellular contents into the circulation
  • Rhabdomyolysis typically manifests with muscle aches, pains and weakness, and reddish brown (tea-colored) urine, but up to 50% of patients are asymptomatic.
EPIDEMIOLOGY
Incidence
Annually in the United States: 26,000 hospitalized cases
ETIOLOGY AND PATHOPHYSIOLOGY
  • Direct muscle trauma (most common cause)
    • Crush injuries
    • Extended periods of muscle pressure (during surgery, unconscious from alcohol ingestion)
    • Burns, electrocution, lightning strike
  • Muscle exertion
    • Intense and/or prolonged physical exercise (marathon runners, athletes, contact sports)
    • Seizures
    • Delirium tremens
  • Drugs and toxins
    • Alcohol
    • Cocaine (most common recreational drug), methamphetamine, phencyclidine
    • Antipsychotics (due to neuroleptic malignant syndrome, malignant hyperthermia, and severe dystonia)
    • Zidovudine
    • Antimalarials
    • Heroin
    • HMG-CoA reductase inhibitors (statins) (risk <0.01%), higher with high dose and in combination with fibrates
    • Fibrates
    • Colchicine
    • Corticosteroids
    • Carbon monoxide
    • Snake envenomation
    • Bath salts (1)[B]
    • Synthetic cannabinoid: Abuse of synthetic marijuana has been associated with severe rhabdomyolysis (2)[C].
  • Muscle ischemia
    • Thrombosis, embolism, sickle cell disease
    • Compartment syndrome
    • Tourniquets
  • Infections
    • Viral: influenza A and B, coxsackievirus, HIV, varicella
    • Bacterial: Streptococcus or Staphylococcus sepsis, gas gangrene, necrotizing fasciitis, Salmonella, Legionella
    • Malaria
  • Hypothermia
  • Hyperthermia
  • Autoimmune and genetic disorders
    • Polymyositis, dermatomyositis
    • Muscular dystrophies
    • Disorders of lipid metabolism (e.g., carnitine palmitoyltransferase deficiency)
    • Disorders of carbohydrate metabolism (i.e., phosphofructokinase deficiency, phosphoglycerate mutase, myophosphorylase deficiency, aka McArdle disease/deficiency)
    • Glycogen storage diseases (e.g., phosphorylase B kinase deficiency) and others (e.g., lactate dehydrogenase A deficiency)
  • Metabolic and endocrinologic:
    • Hypothyroidism or thyrotoxicosis
    • Electrolyte imbalances (e.g., hyponatremia, hypernatremia, hypokalemia, hypocalcemia, hypophosphatemia)
    • Diabetic ketoacidosis
    • Hyperosmolar state
Genetics
  • Hereditary causes of rhabdomyolysis are rare but should be suspected for children, patients with recurrent attacks, or patients who have attacks after minimal exertion, mild illness, or starvation.
  • The main inherited disorders are described earlier in “Etiology and Pathophysiology.”
RISK FACTORS
See “Etiology and Pathophysiology.”
GENERAL PREVENTION
  • Avoid excessive exertional muscle injury. Preventing hypovolemia is important to prevent renal hypoperfusion, acidemia, and subsequent renal failure.
  • Avoid precipitating drugs, metabolic and electrolyte abnormalities.
image DIAGNOSIS
PHYSICAL EXAM
  • May have obvious muscle tenderness/injury and swelling on exam, or muscle exam may be completely normal
  • Tea-colored urine is indicative of myoglobinuria.
  • Decreased urine output may indicate renal failure.
DIFFERENTIAL DIAGNOSIS
  • For acute renal failure with rhabdomyolysis: Any disease that causes acute tubular necrosis may be confused with rhabdomyolysis.
  • Renal pigment injury from hemoglobin resembles pigment injury from myoglobin.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Creatine kinase (CK) is the most important diagnostic enzyme: Elevated >5 times the upper limit of normal or >1,000 U/L. CK levels >5,000 U/L are causally related to acute renal failure (ARF) (3)[A] and should prompt aggressive fluid resuscitation.
  • CK levels peak at ˜24 hours and return to normal after 3 to 5 days, making it a more sensitive marker than myoglobin. CK is also a cheaper and an easier surrogate than myoglobin. Myoglobin is the enzyme responsible for kidney failure (3)[A].
  • Serum myoglobin levels peak within a few hours and return to normal after ˜24 hours, as it is cleared quickly from the circulation. Urine/serum myoglobin levels may be useful markers early on, but normal levels do not rule out rhabdomyolysis because of its rapid clearance.
  • Urinalysis: Dipstick test positive for blood without erythrocytes in sediment is suggestive of injury from either hemoglobin or myoglobin. However, rhabdomyolysis often presents with hematuria, which is a limitation to using dipstick due to false-positive results.
  • Marked elevations of potassium from the muscle injury sometimes are compounded by ARF.
  • Initial hypocalcemia: Calcium enters the injured muscle cells and precipitates as calcium phosphate, leading to calcification of ischemic muscle cells. Only correct initial hypocalcemia if patient is symptomatic or has ECG changes; it will self-resolve during the renal recovery phase.
  • Hypercalcemia during renal recovery phase: Unique to rhabdomyolysis-induced ARF for 20-30% of patients (3)[A]. As renal function improves, there is mobilization of the precipitated calcium, increase in calcitriol, and hyperphosphatemia resolves.
  • Extreme hyperuricemia may be present and can cause acute uric acid nephropathy in the setting of rhabdomyolysis.
  • Elevations in BUN and creatinine are indicative of acute renal failure.
  • Reversible hepatic dysfunction can occur. However, elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactic dehydrogenase may be due to muscle injury and may not indicate any hepatic injury.
  • Disseminated intravascular coagulation (DIC) can occur, with increase in coagulation times, fibrin degradation products, and D-dimer; decreases in platelets and fibrinogen.
  • Place patient on a 12-lead ECG if rhabdomyolysis is suspected because hyperkalemia can induce fatal arrhythmias.
Follow-Up Tests & Special Considerations
  • Delayed renal failure/electrolyte abnormalities despite normal initial levels
  • Ongoing muscle injury is manifested by rising creatine phosphokinase (CPK).
  • Any renal imaging is similar to other evaluations of acute renal failure.
Diagnostic Procedures/Other
Muscle compartment pressures if compartment syndrome is suspected
Test Interpretation
  • Muscle necrosis
  • Myoglobin-related renal injury may resemble acute tubular necrosis from other causes.
image TREATMENT
GENERAL MEASURES
  • Aggressive hydration is often necessary. With severe muscle trauma (crush injuries), up to 12 L of fluid may be sequestered in the muscles, leading to intravascular volume depletion and explaining the low urine output despite fluid resuscitation, which increase the risk for renal failure.
  • P.921

  • Monitor CK levels to ensure that rhabdomyolysis has ended.
  • Monitor renal function and electrolytes.
  • Continuous monitoring of potassium levels to prevent hyperkalemic arrhythmias and potential hypokalemia and arrhythmias.
  • If DIC/hepatic dysfunction occurs, patients will need treatment and monitoring appropriate to these conditions.
MEDICATION
First Line
  • When rhabdomyolysis is identified, appropriate intervention may prevent renal failure.
  • Aggressive fluid resuscitation is the most important intervention: normal saline (NS) and 5% glucose solution with a target urine output of 200 mL/hr. Alternating NS and 5% glucose is recommended to prevent volume overload. Infusion rate should be 500 mL/hr (4)[C].
  • Alkalinization of the urine is thought to decrease myoglobin-induced nephrotoxicity in the tubules (sodium bicarbonate to increase urine pH >6.5):
    • Use is controversial without strong evidence of efficacy.
    • Side effects include worsening hypocalcemia.
    • Sodium bicarbonate may be of use in patients with very high CK levels, an acidotic state, or coexisting hyperkalemia.
    • Place 150 mEq (3 ampules) NaHCO3 in 1 L of D5W and infuse at 200 mL/hr.
Second Line
  • IV mannitol as a bolus if urine output remains low, 1 to 2 g/kg, not to exceed 200 g in 24 hours and cumulative dose up to 800 g. It is used to prevent ARF (5)[C]. Plasma osmolality should be closely monitored and stopped if diuresis is not adequate (>20 mL/hr).
    • Increases prostaglandins production leading to renal vasodilation and diuresis, making the kidneys less susceptible to myoglobin injury. Also an osmotic agent, filtered but not reabsorbed by the tubules, it increases sodium delivery and diuresis. This may remove necrotic cell debris and fluids trapped in damaged muscle cells preventing rise in compartment pressure and compartment syndrome.
    • Use of mannitol is controversial in this setting because no good evidence indicates that it improves outcomes more than aggressive IV hydration. It is a free-radical scavenger and has renal protective effects when used early, before tubular occlusion.
    • Consider adding furosemide to force diuresis if necessary (40 to 120 mg/day).
    • Diuresis should not be used in anuric renal failure. Customize the regimen for elderly and patients with heart disease.
  • Hyperkalemia can result from massive release of intracellular potassium stores or ARF. Severe hyperkalemia may be life-threatening. Treatment is warranted when ECG changes are present (tall, thin T waves; PR prolongation; QRS widening; P wave flattening).
  • Treatments aiming at resolving hyperkalemia:
    • Calcium gluconate: to stabilize the cardiac membrane. IV 1 to 2 ampules (0.5 mL 10% Calcium gluconate = 4 mg elemental calcium; give 4 mg/kg/hr for 4 hours)
    • If acidosis is present: 1 to 2 ampules (2 to 3 mL/kg) sodium bicarbonate IV. Remember that sodium bicarbonate administration worsens hypocalcemia.
    • If tolerated: Oral sodium polystyrene sulfonate (Kayexalate) as much as 20 g (1 g/kg) can be given via enema.
    • Insulin and albuterol will transiently drive potassium into the cells. Administration of glucose can prevent the hypoglycemic effects of insulin.
    • Precautions: See “Etiology and Pathophysiology,” especially drug combinations. Continuous monitoring of potassium levels to prevent overcorrecting with potential hypokalemia and arrhythmias.
    • Indications for dialysis include resistant and symptomatic hyperkalemia (ECG), oliguria (<0.5 mL/kg over 12-hour period), anuria, volume overload, or persistent acidosis (pH <7.1).
ISSUES FOR REFERRAL
  • Usually managed as an inpatient
  • Diagnosis of muscle entrapment/compartment syndromes may require surgical intervention (fasciotomy) to stop rhabdomyolysis.
  • Early escharotomy for compartment syndrome related to burn
  • Renal dialysis may be indicated in ARF.
ADDITIONAL THERAPIES
During the oliguric phase, symptomatic hypocalcemia is possible but rare and may benefit from IV calcium gluconate.
SURGERY/OTHER PROCEDURES
For muscle entrapment/compartment syndrome
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Patients with significant elevations of CK should be admitted for IV hydration and serial laboratory monitoring.
  • Usually required for symptomatic patients or other complications
IV Fluids
Volume expansion with normal saline to increase urine output to at least 150 mL/hr
Nursing
Monitoring of vital signs and urine output
Discharge Criteria
CK usually peaks 24 to 36 hours after muscle injury, so monitoring should confirm that the CK is trending down. Renal function should be stable/improving. Electrolytes should be normal. Patients with mild CK elevation, trending down, and normal renal function may be discharged after observation phase.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Outpatient assessment within a few days to recheck CPK, electrolytes, and renal function
Patient Monitoring
  • Contingent on disease: essential for metabolic myopathies
  • Myotoxic drugs should be discontinued/monitored closely.
DIET
  • With renal failure, restrict protein intake to lower BUN level.
  • Limit potassium intake.
  • With anuria, essential to restrict volume intake
PROGNOSIS
Contingent on primary cause of rhabdomyolysis and on recovery from ARF without complications
REFERENCES
1. Murphy CM, Dulaney AR, Beuhler MC, et al. “Bath salts” and “plant food” products: the experience of one regional US poison center. J Med Toxicol. 2013;9(1):42-48.
2. Durand D, Delgado LL, de la Parra-Pellot DM, et al. Psychosis and severe rhabdomyolysis associated with synthetic cannabinoid use: a case report. Clin Schizophr Relat Psychoses. 2015;8(4):205-208.
3. Parekh R, Care DA, Tainter CR. Rhabdomyolysis: advances in diagnosis and treatment. Emerg Med Pract. 2012;14(3):1-15.
4. Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care. 2014;18(3):224.
5. Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med. 2010;48(6):749-756.
Additional Reading
&NA;
  • Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62-72.
  • Shawkat H, Westwood MM, Mortimer A. Mannitol: a review of its clinical uses. Contin Educ Anaesth Crit Care Pain. 2012;12(2):82-85.
See Also
&NA;
Algorithm: Acute Kidney Injury (Acute Renal Failure)
Codes
&NA;
ICD10
  • M62.82 Rhabdomyolysis
  • T79.6XXA Traumatic ischemia of muscle, initial encounter
  • T79.6XXD Traumatic ischemia of muscle, subsequent encounter
Clinical Pearls
&NA;
  • Acute CPK elevation into the thousands (often tens of thousands) is necessary before one sees myoglobinuric renal failure.
  • The cornerstone of treatment of rhabdomyolysis is aggressive fluid administration.
  • Frequent monitoring of potassium, calcium, and creatinine is necessary in the acute period.