Rhabdomyolysis

R.Srihari

Topics for discussion

• Background

• Pathophysiology

• Etiology

• Prognosis

• Clinical Features

• Differential Diagnosis

• Management

Background

• Rhabdomyolysis (literally, “dissolution of skeletal muscle”) is a syndrome caused by injury to skeletal muscle and involves leakage of large quantities of potentially toxic intracellular contents into plasma.

• First described in the victims of crush injury during World War II. Bywaters made the first association between ARF and crush injury during the London Blitz when he noted dark brown urinary casts in four patients who developed ARF after entrapment

• It is a final pathway of diverse processes and insults. The final common pathway of rhabdomyolysis may be a disturbance in myocyte calcium homeostasis.

• In adults, rhabdomyolysis is characterized by the triad of

muscle weakness, myalgias, and dark urine.

• In many children with this condition, however, all 3 symptoms

may not be seen together. Myalgias and generalized muscle

weakness are the most common presenting symptoms.

• Life-threatening renal failure and disseminated intravascular

coagulation (DIC) are dreaded complications that appear to be

more common in adults.

Pathophysiology

• Mechanisms of cell destruction in rhabdomyolysis include

– cellular membrane injury

– muscle cell hypoxia

– adenosine triphosphate (ATP) depletion

– electrolyte disturbances that cause perturbation of sodium-potassium

pumps

– generation of oxidative free radicals

• The sarcolemma, a thin membrane that encloses striated

muscle fibers, contains numerous pumps that regulate cellular

electrochemical gradients.

• The intercellular sodium concentration is normally maintained

at 10 mEq/L by a sodium-potassium adenosine triphosphatase

(Na/K-ATPase) pump located in the sarcolemma

• The Na/K-ATPase pump actively transports sodium from the interior of the cell to the exterior.

• As a result, the interior of the cell is more negatively charged than the exterior because positive charges are transported across the membrane.

• The gradient pulls sodium to the interior of the cell in exchange for calcium through a protein carrier exchange mechanism. In addition, an active calcium exchanger promotes calcium entry into the sarcoplasmic reticulum and mitochondria.

• These processes depend on ATP as a source of energy.

• ATP depletion appears to be the end result of most causes of rhabdomyolysis. This depletion disrupts cellular transport mechanisms and alters electrolyte composition

• An increase in intracellular calcium levels results in

hyperactivity of proteases and proteolytic enzymes

and generation of free oxygen radicals

• These enzymes and substances increasingly degrade

myofilaments and injure membrane phospholipid

with leakage of intracellular contents into plasma

• These contents include potassium, phosphate, CK,

urate, and myoglobin.

• Excess fluid may also accumulate within affected muscle

tissue.

• The action of phospholipases in insect and snake venom may

cause hemolysis, muscle damage, endothelial necrosis,

rhabdomyolysis, and acute kidney injury (AKI)

• Additionally, muscle damage is amplified by infiltration of

activated neutrophils

• An inflammatory cascade and reperfusion injury sustains

muscle damage and degeneration

• Myoglobin is an important myocyte compound

released into plasma

• After muscle injury, massive plasma myoglobin

levels exceed protein binding (of haptoglobin) and

can precipitate in glomerular filtrate.

• Excess myoglobin may thus cause renal tubular

obstruction, direct nephrotoxicity (ischemia and

tubular injury), intrarenal vasoconstriction, and acute

kidney injury

• AKI is believed to be due to

– decreased extracellular volume, which results in renal

vasoconstriction.

– due to ferrihemate, which is formed from myoglobin at a pH level of

5.6 or less. Ferrihemate produces free hydroxy radicals and causes

direct nephrotoxicity, often through lipid peroxidation. These heme-

proteins may enhance vasoconstriction through interactions with nitric

oxide (NO) and endothelin receptors

– Renal vasoconstriction and ischemia deplete tubular ATP formation and

enhance tubular cell damage.

– Myoglobin precipitation in renal tubules causes formation of

obstructive casts. AKI rarely occurs in patients with chronic

myopathies unless it is triggered by a second inciting event.

– The risk of renal injury is low when initial CK levels are lower than

15,000-20,000 U/L. Lower CK levels may lead to renal injury in

patients with sepsis, dehydration, or acidosis.

• Gastrointestinal (GI) ischemia is common in

patients with fluid and electrolyte imbalances

This ischemia leads to endotoxin absorption,

cytokine production, and perpetuation of the

systemic inflammatory response.

Etiology

trauma

burns

compression syndrome

infection

seizures

heat intolerance

heat stroke

vascular occlusion

prolonged shock

electrolyte disorders

low phosphate levels

shaking chills

• Electrolyte derangement:

– hypophosphatemia is believed to cause rhabdomyolysis because of the resulting shortage of phosphate necessary for the production of ATP.

– Hypokalemia creates a negative potassium balance, which causes rhabdomyolysis.

– Hypokalemia due to dehydration and exercise may also cause rhabdomyolysis

– Hyponatremia and hypernatremia have also been associated with rhabdomyolysis.

• Drugs of abuse:– Ethanol

– Methanol

– Ethylene glycol

– Isopropanol

– Heroin

– Methadone

– Barbiturates

– Cocaine

– Amphetamines

– Ketamine hydrochloride

– Phencyclidine

– 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)

– Lysergic acid diethylamide (LSD)

• Rhabdomyolysis may also result from the use of prescription and nonprescription medications, including the following :– Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase

inhibitors)

– Antihistamines (particularly in children)

– Salicylates

– Caffeine

– Fibric acid derivatives (eg, bezafibrate, clofibrate, fenofibrate, and gemfibrozil)

– Neuroleptics/antipsychotics

– Anesthetic and paralytic agents (malignant hyperthermia syndrome)

– Amphotericin B

– Quinine

– Corticosteroids

– Colchicine

– Theophylline

– Cyclic antidepressants

– Selective serotonin reuptake inhibitors (the

serotonin syndrome)

– Propofol (continuous infusion)

– Protease inhibitors

Prognosis

• The overall mortality for patients with rhabdomyolysis is approximately 5%

• However, the risk of death for any single patient is dependent on the underlying etiology and any existing comorbid conditions that may be present and may be significantly higher in patients with AKI and extremely elevated CPK levels.

• Rapid intervention and appropriate supportive treatment of rhabdomyolysis-related kidney injury and renal failure improve outcomes in traumatic crush injuries.

• If treatment modalities are implemented early, many patients recover completely.

Clinical Features

• The classic triad of rhabdomyolysis comprises the following:– Myalgias

– Generalized weakness

– Darkened urine

• In practice, however, the presentation of rhabdomyolysisvaries considerably.

• The classic triad is actually seen in only about 50% of adult patients, and it may be even less common in children.

• Additional nonspecific symptoms include fevers, nausea, and vomiting.

• Patients may have muscular pain and tenderness, decreased muscle strength, soft tissue swelling, and skin changes consistent with pressure necrosis

• The most commonly involved muscle groups in adults include the calves and the lower back.

• Back, chest, and calf pain often mimics other common conditions such as deep vein thrombosis or angina.

Complications

• Electrolyte abnormalities are prominent features of rhabdomyolysis:

– Hyperphosphatemia

– hyperkalemia

– hypocalcemia (early)

– hypercalcemia (late)

– Hyperuricemia

– hypoalbuminemia

• Hyperkalemia may be a result of both muscle

injury and renal insufficiency or failure.

• This abnormality may cause life-threatening

arrhythmias and should be immediately

addressed.

• Hypocalcemia is another common metabolic abnormality, resulting from deposition of calcium phosphate.

• It may also be due to a decreased level of 1,25-dihydroxycholecalciferol in patients with renal failure.

• Severe hypocalcemia may lead to cardiac arrhythmias, muscular contractions, and seizures. These events may further damage affected muscles.

• Late findings of hypercalcemia may be related of Ca leakage from damaged muscles and poor clearance if the case is complicated by kidney injury.

• Compartment syndrome may be either a

complication of or the inciting cause of

rhabdomyolysis.

• If muscle injury has occurred, measure

compartment pressures; if the pressure is

higher than 30 mm Hg, fasciotomy is

indicated.

• Acute kidney injury (AKI) occurs in 17-35% of adult

patients and in 5-42% in 2 pediatric case series.

• Etiologies of AKI may be related to hypovolemia,

vasoconstriction, and myoglobin toxicity.

• AKI and disseminated intravascular coagulation

(DIC, a late complication) are the most severe

complications of rhabdomyolysis, often developing

12-72 hours after initial muscle damage.

• AKI may account for as many as 35% of adult cases.

• Renal failure may also develop in patients treated

with optimal measures.

• Mechanisms of renal injury are multifactorial and

may include

– renal vasoconstriction

– intraluminal myoglobin cast formation

– heme-protein cellular toxicity

– Myoglobin and hemoglobin toxic effect on the

glomerulus are enhanced by aciduria and hypovolemia.

Differential Diagnosis

• Traumatic injuries (including nonaccidental abuse in children)

• Viral infections

• Myalgias from other etiologies

• Bacterial infections

• Cold exposure

• Malignant hyperthermia

• Muscle phosphorylase deficiency

• Phosphofructokinase deficiency

• Carnitine palmityl transferase deficiency

• Phosphoglycerate mutase deficiency

• Hyperosmotic conditions

• Guillain-Barré syndrome

• Inflammatory myositis

Management-Investigations

• Complete blood count (CBC), including hemoglobin, hematocrit, and platelets

• Serum chemistries, including blood urea nitrogen (BUN), creatinine, glucose, calcium, potassium, phosphate, uric acid, and liver function tests (LFTs)

• Prothrombin time (PT)

• Activated partial thromboplastin time (aPTT) – Thromboplastinreleased from injured myocytes can cause disseminated intravascular coagulation (DIC)

• Serum aldolase

• Lactate dehydrogenase (LDH)

• Creatine kinase

• The diagnosis of rhabdomyolysis can be confirmed using certain laboratory

studies

• The most reliable and sensitive indicator of muscle injury is creatine kinase

(CK). Assessing CK levels is most useful because of its ease of detection in

serum and its presence in serum immediately after muscle injury.

• CK levels rise within 12 hours of muscle injury, peak in 24-36 hours, and

decrease at a rate of 30-40% per day.

• CK levels decline 3-5 days after resolution of muscle injury

• Failure of CK levels to decrease suggests ongoing muscle injury or development of a compartment syndrome.

• The peak CK level, especially when it is higher than 15,000 U/L, may be predictive of renal failure.

• Total CK elevation is a sensitive but nonspecific marker for rhabdomyolysis. CK levels 5 times the reference range suggest rhabdomyolysis, though CK levels in rhabdomyolysis are frequently as high as 100 times the reference range or even higher

• Myoglobin:• Plasma myoglobin measurements are not reliable, because

myoglobin has a half-life of 1-3 hours and is cleared from plasma within 6 hours.

• Myoglobin levels not measured at the right time may produce a false-negative result, though a positive result may help confirm the diagnosis.

• Urine myoglobin measurements are therefore preferable.

• A urine myoglobin assay is helpful in patients with coexisting hematuria (confirmed with microscopic examination) when the presence of myoglobin is suspected.

• A urine dipstick test for blood that has positive findings in the absence of red blood cells (RBCS) suggests myoglobinuria

• Myoglobinuria may be sporadic or resolve early in the course of rhabdomyolysis.

• Urine dipstick findings are positive in fewer than 50% of patients with rhabdomyolysis; thus, a normal test result does not rule out this condition.

• MRI is the imaging modality of choice for

evaluating the distribution and extent of injury of

affected muscles, especially when fasciotomy or

involvement of deep compartments is considered

• ECG should be performed early in the course of

evaluation to evaluate for cardiac dysrhythmias

related to hyperkalemia or hypocalcemia

Management

• Assess the ABCs

(A irway, B reathing, C irculation), and provide

supportive care as needed

• Ensure adequate hydration, and record urine

output.

• Insert a Foley catheter for careful monitoring of

urine output.

• Identify and correct the inciting cause of

rhabdomyolysis (eg, trauma, infection, or toxins)

• General recommendations for the treatment of

rhabdomyolysis include fluid resuscitation and

prevention of end-organ complications (eg, acute

renal failure [ARF])

• Other supportive measures include correction of

electrolyte imbalances.

• Serial physical examinations and laboratory

studies are indicated to monitor for

– compartment syndrome

– hyperkalemia

– acute oliguric or nonoliguric renal failure

– disseminated intravascular coagulation (DIC).

• Compartment syndrome necessitates immediate orthopedic consultation for fasciotomy.

• DIC should be treated with fresh frozen plasma, cryoprecipitate, and platelet transfusions.

• Monitor cardiac function.

• Monitor creatine kinase (CK) levels to show resolution of rhabdomyolysis.

• Fluid Resuscitation:

• Expansion of extracellular volume is the cornerstone of treatment and must

be initiated as soon as possible.

• Retrospective studies of patients with severe crush injuries resulting in

rhabdomyolysis suggest that the prognosis is better when prehospital

personnel provide fluid resuscitation

• Support of intravascular volume increases the glomerular filtration rate

(GFR) and oxygen delivery and dilutes myoglobin and other renal tubular

toxins.

• Obtain intravenous (IV) access with a large-bore catheter. For adults,

administer isotonic fluids at a rate of approximately 400 mL/h (may be up

to 1000 mL/h based on type of condition and severity) and then titrate to

maintain a urine output of at least 200 mL/h

• Because injured myocytes can sequester large volumes of extracellular

fluid, crystalloid requirements may be surprisingly large.

• In patients with CK levels of 15,000 IU/L or greater, higher volumes of fluid, on the order of at least 6 L in adults, are required

• Consider central venous pressure measurement or Swan-Ganz catheterization in patients with cardiac or renal disease. These invasive studies can assist in the assessment of the intravascular volume

• Repeat the CK assay every 6-12 hours to determine the peak CK level.

• Aggressive and early hydration with isotonic sodium chloride solution is important for the prevention of pigment-associated renal failure.

• The composition of repletion fluid is controversial and may also include sodium bicarbonate.

• Initial fluid use in young children has been recommended to be 20 mL/kg; in adolescents, 1-2 L/h has been recommended. Subsequent hydration at a level 2-3 times maintenance may be sufficient

• Prevention of AKI:– Alkalization of urine is believed to be helpful and is based

on the observation that acidic urine is necessary to cause

ATN.

– Alkalinization may also reduce the occurrence of cast

formation (ferrihemate and myoglobin).

– Some authorities believe that aggressive hydration

sufficiently causes a solute diuresis that alkalizes the urine.

• Urinary alkalization should be considered earlier in patients with

– acidemia

– dehydration

– underlying renal disease.

• A suggested regimen for adult patients is isotonic sodium chloride solution

(0.9% NaCl) with 1 ampule of sodium bicarbonate administered at 100

mL/h.

• Sodium bicarbonate is used with care because it may potentiate

hypocalcemia.

• The IV bicarbonate concentration is often adjusted to achieve a urine pH

higher than 6.5-7.0. This level of alkalization inhibits precipitation of

myoglobin and hemoglobin in the tubules.

• If the pH of urine less than 6.5, alternate each liter of normal saline with 1

L of 5% dextrose plus 100 mmol of bicarbonate.

• If urine output is adequate, consider the use of diuretics such as mannitol (in adults) and furosemide

• Mannitol, acting as an osmotic diuretic, is thought to increase urinary flow and reduce myoglobin cast obstruction in renal tubules

• Loop diuretics such as furosemide may be used to enhance urinary output in patients who are oliguric despite adequate intravascular volume.

• It is recommended that aggressive volume expansion is to be maintained until myoglobinuria is cleared.

• Correction of Acid-Base imbalance ,

electrolyte imbalance and Metabolic

abnormalities:

– Hyperkalemia

– Hypocalcemia

– Hypercalcemia

– Hyperuricemia

– Metabolic acidosis

• Other Medical Therapy:

– Dialysis may be required in patients with oliguric

renal failure, persistent hyperkalemia, other

electrolyte abnormalities, pulmonary edema,

congestive heart failure, and persistent metabolic

acidosis.

– The role of free-radical scavengers and

antioxidants in rhabdomyolysis (eg, pentoxifylline,

vitamin E, and vitamin C) has been studied in

animal models of ischemia-reperfusion injuries.

– Controlled studies evaluating the efficacy of these

agents have not been performed, and their clinical

use remains unclear

• With adequate hydration ensured, no specific

outpatient medications are needed. Inciting myotoxic

agents should be stopped.

Thank You