Overview

Definition

Rhabdomyolysis is a syndrome marked by muscle necrosis, resulting in the release of toxic intracellular muscle constituents into the circulation (especially myoglobin).

Etiology

• Trauma or muscle compression:
  • Crush injuries
  • Victims of restraints or torture, physically abused children
  • Surgical procedure with prolonged muscle compression
  • Acute lower-limb compartment syndrome Compartment Syndrome Compartment syndrome is a surgical emergency usually occurring secondary to trauma. The condition is marked by increased pressure within a compartment that compromises the circulation and function of the tissues within that space. Compartment Syndrome
  • High-voltage electrical injury
• Non-traumatic exertional rhabdomyolysis:
  • Recent exaggerated skeletal activity
  • Exertion occurring in extremely hot or humid conditions ( heatstroke Heatstroke Heatstroke is an illness characterized as a core body temperature exceeding 40°C (104°F) with accompanying neurological symptoms including ataxia, seizures, and/or delirium. Heatstroke is usually due to the body's inability to regulate its temperature when challenged with an elevated heat load. Heatstroke)
  • Seizure
• Non-exertional and non-traumatic rhabdomyolysis:
  • Alcohol, use of illicit drugs
  • Drugs (e.g., statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins, colchicine)
  • Metabolic disorders and abnormalities (e.g., inherited disorders of glycogenolysis)
  • Electrolyte abnormalities (e.g., hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia)
  • Infections (e.g., viral infections)
  • Toxins (e.g., carbon monoxide)
  • Inflammatory myopathies (e.g., dermatomyositis)
  • Prolonged immobilization 

Pathophysiology

Muscle injury

• Muscle- cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death or necrosis is triggered by different events/etiologies.
• Disturbance in myocyte calcium homeostasis (↑ in intracellular free ionized cytoplasmic and mitochondrial calcium) is the common cause of injury.
• ↑ Intracellular calcium leads to:
  • Activation of enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that produce cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death: 
    • Phospholipases → membrane damage
    • Proteases → membrane- and cytoskeletal-protein degradation
    • Endonucleases → deoxyribonucleic acid ( DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure) and chromatin fragmentation
    • Adenosine triphosphatases (ATPases) → adenosine triphosphate (ATP) depletion
  • ↑ Contractility of skeletal muscle cells
  • Mitochondrial damage
  • Production of reactive oxygen species (ROS)
• Additionally, ATP depletion → dysfunction of the Na+/K+ ATPase and Ca2+ ATPase pumps → loss of myocyte integrity → cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death → release of intracellular components

Renal injury

• Most common systemic complication of rhabdomyolysis
• Factors contributing to renal failure:
  • Hypovolemia:
    • Released enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (including creatine kinase (CK)) can damage capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries
    • Subsequently, there is fluid leakage and sequestration in the extracellular spaces.
    • ↓ Intravascular volume → stimulation of renin-angiotensin-aldosterone (RAA) system
    • RAA effect: reduced renal blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure
  • Release of myoglobin from necrotic muscles:
    • Myoglobin is cytotoxic to nephrons.
    • Myoglobin scavenges nitric oxide: ↑ renal injury
    • Myoglobin also results in lipid peroxidation of renal cell membranes.
    • Other components, including free iron, can generate ROS and damage renal tubules.
  • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis: ↑ lactic acid from damaged/ischemic muscles
  • Hyperphosphatemia in necrotic muscles:
    • Leads to hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia
    • Leads to deposition of calcium phosphate → renal damage
  • Uric acid release: 
    • Nucleosides from cell nuclei → uric acid 
    • Deposition of uric acid crystals increases in an acidic environment, leading to tubular obstruction.

Clinical Presentation

Signs and symptoms

• Classic triad:
  1. Weakness
  2. Myalgia
  3. Tea-colored urine
• < 10% of patients present with the classic triad. 
• Children: Muscle pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain/tenderness, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and viral prodromes are common symptoms. 
• Other patients present with nonspecific symptoms (nausea, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, vomiting).

Additional clues

• History: 
  • Exertion (increased activity) or trauma
  • Immobility
  • Underlying conditions and medications
  • Infections
• Findings that raise suspicion:
  • Dark urine without presenting genitourinary symptoms
  • Abnormal laboratory tests on presentation (electrolyte imbalance)
  • Arrhythmias (from resultant electrolyte imbalance)

Diagnosis

• Laboratory abnormalities:
  • ↑ CK (5 times the normal upper limit)
  • ↑ Myoglobin:
    • Red-to-brown urine
    • Detected by urinalysis as myoglobinuria: positive test for blood on the urine dipstick, but no RBCs on microscopic examination
  • Electrolyte abnormalities: 
    • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
    • Hyperphosphatemia
    • Hyperuricemia: release of purines from the damaged muscle
    • Hypocalcemia: due to soft-tissue and muscle-cell damage → calcium enters myocytes and calcium salts are deposited in the damaged muscle
  • Lactic acidosis
  • Elevation of serum aminotransferases
• Acute renal failure (from hypovolemia, myoglobin toxicity, and/or uric acid and calcium phosphate deposition in the renal tubules), resulting in oliguria or anuria

Management

• Initial approach:
  • Airway, breathing, circulation (ABC) assessment for all patients with trauma history
  • Exclude and treat other potential injuries ( compartment syndrome Compartment Syndrome Compartment syndrome is a surgical emergency usually occurring secondary to trauma. The condition is marked by increased pressure within a compartment that compromises the circulation and function of the tissues within that space. Compartment Syndrome, vascular compromise, fractures, dislocations, and wounds).
• Aggressive intravenous fluid resuscitation to correct:
  • Hypoperfusion
  • Lactic acidosis
  • Acute renal impairment
• Bicarbonate therapy (no supporting evidence for pediatric population) may be considered for severe rhabdomyolysis (rising CK or > 5,000 units/L) with:
  • pH < 7.5 (acidosis)
  • No hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia 
  • Bicarbonate level < 30 mEq/L
• Manage electrolyte abnormalities: Hypocalcemia and hyperkalemia are associated with cardiac arrhythmias.
• Monitoring:
  • Electrolytes, renal function
  • Urine output
  • Electrocardiogram Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) and cardiac monitoring
• Removal of offending agents (if medication is suspected)
• Analgesia

Clinical Relevance

• ABC assessment: a mainstay management approach in managing critically ill patients, which constitutes the 1st essential step in many situations, including unresponsive patients, cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest, patients with a history of trauma, or critically ill patients. In patients with trauma, ABC is included in the primary survey, initial evaluation, and management of injuries. 
• Acute renal failure: a sudden drop in the glomerular filtration rate Glomerular filtration rate The volume of water filtered out of plasma through glomerular capillary walls into bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests resulting from kidney damage, which occurs within a few hours to few days. Acute renal failure is classified as prerenal, intrinsic, or postrenal, depending on the etiology. Management is based on causation and often revolves around aggressive fluid hydration. Rhabdomyolysis results in acute tubular necrosis from excessive filtered myoglobin, leading to acute renal failure.
• Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia: serum potassium (K+) level > 5.0 mEq/L. Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia results from several causes. Acute elevation in serum K+ (usually ≥ 7 mEq/L) can lead to cardiac arrhythmias and muscle weakness. Management involves myocardium stabilization, decreasing extracellular K+ levels, and enhancing K+ removal from the body.
• Hypocalcemia: occurs when calcium levels are < 2.2 mmol/L or < 8.5 mg/dL. Calcium levels are regulated by the parathyroid hormone (PTH). If the body fails to maintain normal calcium levels (especially ≤ 7.5 mg/dL), patients present with arrhythmias, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and tetany. Management is by calcium replacement.
• Hyperuricemia: elevated uric acid levels resulting from accelerated purine degradation (observed in high cell-turnover states, including rhabdomyolysis). Large uric acid deposits in renal tubules cause acute renal injury. Management involves aggressive intravenous hydration.
• Compartment syndrome: a surgical emergency occurring secondary to trauma. Compartment syndrome is marked by increased pressure within a compartment, compromising circulation and tissue function. Long- bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones fractures are the most common cause. Patients present with pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, pallor, pulselessness, paresthesia, poikilothermia, and paralysis (the “6 Ps”). Diagnosis is clinical but compartment-pressure measurement can be used. Management is by emergency fasciotomy. 
• Crush syndrome Crush Syndrome Crush syndrome encompasses the systemic manifestations that result from a crush (or traumatic compression) injury. Compartment syndrome and/or rhabdomyolysis can also occur in crush syndrome. Systemic effects include the development of renal failure due to toxins released from damaged muscles, hypovolemia, and acidosis. Crush Syndrome: systemic manifestations (renal failure, shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock) resulting from compressive traumatic injury. Compartment syndrome and/or rhabdomyolysis can occur in Crush syndrome Crush Syndrome Crush syndrome encompasses the systemic manifestations that result from a crush (or traumatic compression) injury. Compartment syndrome and/or rhabdomyolysis can also occur in crush syndrome. Systemic effects include the development of renal failure due to toxins released from damaged muscles, hypovolemia, and acidosis. Crush Syndrome. Field management with intravenous fluids Intravenous Fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids and extrication is crucial in reducing the risk of complications and death. 
• Heatstroke: a condition associated with hyperthermia (elevation of core body temperature above the normal diurnal range of 36ºC–37.5ºC (96.8ºF–99.5ºF) owing to failure in thermoregulation). Heatstroke is either exertional or non-exertional and can be complicated by rhabdomyolysis. Cooling measures with fluid and electrolyte replacement are recommended.