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Rhabdomyolysis

Rhabdomyolysis is characterized by muscle necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage and the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of toxic intracellular contents, especially myoglobin, into the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment. Rhabdomyolysis can result from trauma or direct muscle injuries; however, non-exertional and non-traumatic etiologies ( 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, immobilization Immobilization Delirium, medication side effects) can also lead to muscle breakdown. The classic triad of symptoms includes myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy, weakness, and tea-colored urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat, but the presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor can be nonspecific. History and work-up generally point to diagnosis based on elevated creatine Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury kinase levels, abnormal electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes with possible renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome, and dark urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat without RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology (indicating myoglobinuria). Management of rhabdomyolysis is by using intravenous fluid resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome.

Last updated: 12 Feb, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Rhabdomyolysis is a syndrome marked by muscle necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage, resulting in the release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of toxic intracellular muscle constituents into the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment (especially myoglobin).

Etiology

  • Trauma or muscle compression Compression Blunt Chest Trauma:
    • Crush injuries
    • Victims of restraints or torture, physically abused children
    • Surgical procedure with prolonged muscle compression Compression Blunt Chest Trauma
    • 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 Illicit Drugs Drugs that are manufactured, obtained, or sold illegally. They include prescription drugs obtained or sold without prescription and non-prescription drugs. Illicit drugs are widely distributed, tend to be grossly impure and may cause unexpected toxicity. Delirium
    • 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 Colchicine A major alkaloid from colchicum autumnale l. And found also in other colchicum species. Its primary therapeutic use is in the treatment of gout. Gout Drugs)
    • Metabolic disorders and abnormalities (e.g., inherited disorders of glycogenolysis Glycogenolysis The release of glucose from glycogen by glycogen phosphorylase (phosphorolysis). The released glucose-1-phosphate is then converted to glucose-6-phosphate by phosphoglucomutase before entering glycolysis. Glycogenolysis is stimulated by glucagon or epinephrine via the activation of phosphorylase kinase. Glycogen Metabolism)
    • 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (e.g., viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease)
    • Toxins (e.g., carbon monoxide Carbon monoxide Carbon monoxide (CO). A poisonous colorless, odorless, tasteless gas. It combines with hemoglobin to form carboxyhemoglobin, which has no oxygen carrying capacity. The resultant oxygen deprivation causes headache, dizziness, decreased pulse and respiratory rates, unconsciousness, and death. Carbon Monoxide Poisoning)
    • Inflammatory myopathies (e.g., dermatomyositis Dermatomyositis A subacute or chronic inflammatory disease of muscle and skin, marked by proximal muscle weakness and a characteristic skin rash. The illness occurs with approximately equal frequency in children and adults. The skin lesions usually take the form of a purplish rash (or less often an exfoliative dermatitis) involving the nose, cheeks, forehead, upper trunk, and arms. The disease is associated with a complement mediated intramuscular microangiopathy, leading to loss of capillaries, muscle ischemia, muscle-fiber necrosis, and perifascicular atrophy. The childhood form of this disease tends to evolve into a systemic vasculitis. Dermatomyositis may occur in association with malignant neoplasms. Paraneoplastic Syndromes)
    • Prolonged immobilization Immobilization Delirium 

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Pathophysiology

Muscle injury

  • Muscle-cell death or necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage is triggered by different events/etiologies.
  • Disturbance in myocyte calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death (↑ in intracellular free ionized cytoplasmic and mitochondrial calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes) is the common cause of injury.
  • ↑ Intracellular calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes 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 Membrane Damage Cell Injury and Death
      • Proteases Proteases Proteins and Peptidesmembrane- and cytoskeletal-protein degradation
      • Endonucleases deoxyribonucleic acid Deoxyribonucleic acid A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure ( DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure) and chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure fragmentation Fragmentation Chronic Apophyseal Injury
      • Adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphatases (ATPases) adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate (ATP) depletion
    • ↑ Contractility of skeletal muscle cells
    • Mitochondrial damage Mitochondrial Damage Cell Injury and Death
    • Production of reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease (ROS)
  • Additionally, ATP depletion ATP depletion Cell Injury and Death → 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 Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of intracellular components
Injury mechanisms of rhabdomyolysis

Injury mechanisms of rhabdomyolysis:
1. Energy (ATP) depletion inhibits Na+/K+ ATPase function and increases intracellular sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia.
2. The 2Na+/Ca2+ exchanger increases intracellular calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes.
3. Ca2+ ATPase is not able to pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols out intracellular calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes due to energy depletion.
4. Intracellular calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes activates proteases Proteases Proteins and Peptides such as phospholipase 2 (PLA2), which destroy the structural components of cell membranes and allow the entry of more calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes.
5. Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes overload disrupts mitochondrial integrity and induces apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage, leading to necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage of muscle cells.

Image: “Injury mechanisms of rhabdomyolysis” by Universidad Autónoma de Baja California, Facultad de Medicina y Psicología, Tijuana, Baja California, Mexico. License: CC BY 4.0

Renal injury

  • Most common systemic complication of rhabdomyolysis
  • Factors contributing to renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome:
    • Hypovolemia Hypovolemia Sepsis in Children:
      • 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 Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury 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: Histology
      • 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 Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure
    • Release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of myoglobin from necrotic muscles:
      • Myoglobin is cytotoxic Cytotoxic Parvovirus B19 to nephrons.
      • Myoglobin scavenges nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs: ↑ renal injury
      • Myoglobin also results in lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-induced Liver Injury of renal cell membranes.
      • Other components, including free iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements, 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 Hyperphosphatemia A condition of abnormally high level of phosphates in the blood, usually significantly above the normal range of 0. 84-1. 58 mmol per liter of serum. Hypocalcemia 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 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes → renal damage
    • Uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology
      • Nucleosides Nucleosides Purine or pyrimidine bases attached to a ribose or deoxyribose. Nucleic Acids from cell nuclei → uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis 
      • Deposition of uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis crystals increases in an acidic environment, leading to tubular obstruction.
Kidney injury in rhabdomyolysis

Acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury ( AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury) in rhabdomyolysis ( 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*: creatine Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury kinase, aldolase Aldolase Becker Muscular Dystrophy, lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma):
After muscle destruction, myoglobin and 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 are released into the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment, damaging 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: Histology and leading to leakage and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. Hypovolemia Hypovolemia Sepsis in Children and reduced renal blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure are associated with AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury. Myoglobin cytotoxicity affects the kidney due to lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-induced Liver Injury and production of reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease. Tubular obstruction by myoglobin is also associated with AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury.

Image: “Kidney injury in rhabdomyolysis” by Chavez et al AL Amyloidosis. License: Public Domain

Clinical Presentation

Signs and symptoms

  • Classic triad:
    1. Weakness
    2. Myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy
    3. Tea-colored urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat
  • < 10% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with the classic triad. 
  • Children: Muscle pain Muscle Pain Ion Channel Myopathy/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 Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with nonspecific symptoms ( nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, 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 Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia).

Additional clues

  • History: 
    • Exertion (increased activity) or trauma
    • Immobility
    • Underlying conditions and medications
    • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Findings that raise suspicion:
    • Dark urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat without presenting genitourinary symptoms
    • Abnormal laboratory tests on presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor (electrolyte imbalance)
    • Arrhythmias (from resultant electrolyte imbalance)
Tea coloured urine due to rhabdomyolysis

Tea-colored urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat of a patient being treated for rhabdomyolysis

Image: “ Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat appearance” by the Department of General Medicine, Sri Ramachandra University Chennai, Tamil Nadu, India. License: CC BY 3.0

Diagnosis

  • Laboratory abnormalities:
    • CK (5 times the normal upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation)
    • ↑ Myoglobin:
      • Red-to-brown urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat
      • Detected by urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children as myoglobinuria: positive test for blood on the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat dipstick, but no RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology 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 Hyperphosphatemia A condition of abnormally high level of phosphates in the blood, usually significantly above the normal range of 0. 84-1. 58 mmol per liter of serum. Hypocalcemia
      • Hyperuricemia Hyperuricemia Excessive uric acid or urate in blood as defined by its solubility in plasma at 37 degrees c; greater than 0. 42 mmol per liter (7. 0 mg/dl) in men or 0. 36 mmol per liter (6. 0 mg/dl) in women. Gout: release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of purines Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. Nucleic Acids from the damaged muscle
      • 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: due to soft-tissue and muscle-cell damage → calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes enters myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology and calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes salts are deposited in the damaged muscle
    • Lactic acidosis Lactic Acidosis Oxazolidinones
    • Elevation of serum aminotransferases
  • Acute renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome (from hypovolemia Hypovolemia Sepsis in Children, myoglobin toxicity Toxicity Dosage Calculation, and/or uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis and calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes deposition in the renal tubules), resulting in oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation or anuria Anuria Absence of urine formation. It is usually associated with complete bilateral ureteral (ureter) obstruction, complete lower urinary tract obstruction, or unilateral ureteral obstruction when a solitary kidney is present. Acute Kidney Injury

Management

  • Initial approach:
    • Airway Airway ABCDE Assessment, breathing, circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment (ABC) assessment for all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome to correct:
  • Bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes therapy (no supporting evidence for pediatric population) may be considered for severe rhabdomyolysis (rising CK or > 5,000 units/L) with:
    • pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance < 7.5 ( acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes level < 30 mEq/L
  • Manage electrolyte abnormalities: 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 and 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 are associated with cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) arrhythmias.
  • Monitoring:
    • Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes, renal function
    • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat 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. Electrocardiogram (ECG) and cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) monitoring
  • Removal of offending agents (if medication is suspected)
  • Analgesia Analgesia Methods of pain relief that may be used with or in place of analgesics. Anesthesiology: History and Basic Concepts
Electrocardiogram while potassium was 8. 0

Patient with rhabdomyolysis and 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:
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. Electrocardiogram (ECG) of a patient treated for rhabdomyolysis, showing peaked T waves and wide QRS. The patient had a serum potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia level of 8 mEq/L.

Image: “ 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. Electrocardiogram (ECG)” by Department of Medicine, Union Memorial Hospital, Baltimore, MD, USA. License: CC BY 2.0

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, 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 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: serum potassium (K+) level > 5.0 mEq/L. 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, 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 fractures are the most common cause. Patients present with 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 Fasciotomy Surgical incision on the fascia. It is used to decompress compartment pressure (e.g. in compartment syndromes; circumferential burns and extremity injuries) or to release contractures (e.g. in dupuytren’s contracture). Compartment Syndrome
  • 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 Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome, 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 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 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 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: a condition associated with hyperthermia (elevation of core body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke above the normal diurnal range of 36ºC–37.5ºC (96.8ºF–99.5ºF) owing to failure in thermoregulation Thermoregulation Body temperature can be divided into external temperature, which involves the skin, and core temperature, which involves the CNS and viscera. While external temperature can be variable, the core temperature is maintained within a narrow range of 36.5-37.5ºC (97.7-99.5ºF). Body Temperature Regulation). 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 is either exertional or non-exertional and can be complicated by rhabdomyolysis. Cooling measures with fluid and electrolyte replacement are recommended.

References

  1. Beck M.A., & Haller P. (2020). Compartment syndrome. In: Tintinalli J.E., & Ma O., & Yealy D.M., & Meckler G.D., & Stapczynski J, & Cline D.M., & Thomas S.H. (Eds.), Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw-Hill.
  2. Chavez L.O., Leon M., Einav S., & Varon J. (2016). Beyond muscle destruction: A systematic review of rhabdomyolysis for clinical practice. Critical care (London, England), 20(1), 135. https://doi.org/10.1186/s13054-016-1314-5
  3. Miller M. (2020). Causes of rhabdomyolysis. Retrieved 14 January 2021, from https://www.uptodate.com/contents/causes-of-rhabdomyolysis
  4. Stanley M, Adigun R. (2020) Rhabdomyolysis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Retrieved 19 January 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448168/

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