What is Rhabdomyolysis? Understanding Causes, Symptoms, and Treatment

INTRODUCTION

Rhabdomyolysis is a serious medical condition characterized by the rapid breakdown of damaged skeletal muscle. This disintegration of muscle tissue leads to the release of intracellular components, such as myoglobin, creatine kinase (CK), aldolase, and lactate dehydrogenase, along with electrolytes, into the bloodstream and extracellular space. The severity of rhabdomyolysis can vary greatly, ranging from an asymptomatic state with elevated CK levels to a life-threatening condition marked by extremely high CK levels, electrolyte imbalances, acute kidney injury (AKI), and disseminated intravascular coagulation.¹ While traumatic injury is a frequent cause, rhabdomyolysis can also arise from various non-traumatic factors including drugs, toxins, infections, muscle ischemia, electrolyte and metabolic disorders, genetic predispositions, strenuous exertion, prolonged immobilization, and temperature-related conditions like neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH).² The core feature of both traumatic and non-traumatic rhabdomyolysis is massive muscle necrosis, often manifesting as limb weakness, muscle pain (myalgia), swelling, and commonly, dark urine (myoglobinuria) without the presence of red blood cells (hematuria).³

Historical accounts of rhabdomyolysis date back to the Old Testament, in the Book of Numbers, which describes a plague among Jews after they consumed large quantities of quail during their exodus from Egypt.⁴ This plague is largely interpreted as a reference to the signs and symptoms of myolysis, a condition observed in the Mediterranean region following quail consumption.^{5, 6} This myolysis is believed to stem from the poisonous hemlock that quail ingest during their spring migration.^{7, 8} In modern medicine, early descriptions emerged in German medical literature in the early 1900s, termed Meyer-Betz disease.⁹ Bywaters and Beall are often credited with providing the first comprehensive understanding of the pathophysiological mechanisms of rhabdomyolysis and accurately linking it to AKI.^{10, 11}

Clinically, rhabdomyolysis is classically presented with a triad of symptoms: muscle pain, weakness, and myoglobinuria, often described as tea-colored urine. However, this symptom triad is only observed in less than 10% of patients, and over half of patients may not report muscle pain or weakness, with discolored urine being the initial symptom.² Elevated CK level is the most reliable laboratory indicator for muscle injury that could lead to rhabdomyolysis, assuming no concurrent cardiac or brain injury.¹ While attempts to correlate CK elevation with the severity of muscle damage or kidney failure have yielded mixed results, CK levels above 5,000 IU/L are generally considered indicative of significant muscle injury.^{1, 9} Initial treatment for rhabdomyolysis is largely supportive, focusing on managing the ABCs (airway, breathing, circulation) and implementing measures to protect kidney function, primarily through vigorous fluid resuscitation.

EPIDEMIOLOGY OF RHABDOMYOLYSIS

Historically, determining the precise incidence of myopathic events and rhabdomyolysis in clinical research has been challenging due to the absence of standardized clinical definitions. In 2002, the American College of Cardiology (ACC), American Heart Association (AHA), and National Heart, Lung, and Blood Institute (NHLBI) issued a joint Clinical Advisory on the Use and Safety of Statins to address this issue.¹² Their recommended definitions for muscle toxicity and rhabdomyolysis are outlined in Table 1.

Table 1: Definitions of Muscle Toxicity and Rhabdomyolysis by Clinical Advisory

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Acute kidney injury (AKI) stands as the most critical and life-threatening complication of rhabdomyolysis. The link between these two conditions is significant. It is estimated that 10% to 40% of rhabdomyolysis patients develop AKI, and rhabdomyolysis is implicated in up to 15% of all AKI cases.¹³ Studies have suggested potentially higher rates of AKI in children with rhabdomyolysis, ranging from 42% to 50%.^{14, 15} However, obtaining more precise epidemiological estimates is complex due to diverse clinical scenarios, healthcare settings, and confounding factors introduced by co-existing medical conditions.

PATHOPHYSIOLOGY OF RHABDOMYOLYSIS

While the specific cause of rhabdomyolysis is often identifiable, the exact mechanisms by which various insults lead to muscle injury and necrosis are less understood. However, the final common pathway shared across different causes of rhabdomyolysis is clearer. Regardless of the initial trigger, the ultimate steps leading to rhabdomyolysis involve either direct damage to muscle cells (myocytes) or failure of energy supply within these cells.¹⁶

In normal muscle physiology, ion channels (including Na+/K+ pumps and Na+/Ca2+ exchangers) on the muscle cell membrane (sarcolemma) maintain low intracellular concentrations of sodium (Na+) and calcium (Ca2+), and high intracellular potassium (K+) concentrations. Muscle depolarization triggers an influx of Ca2+ from the sarcoplasmic reticulum (intracellular calcium storage) into the cytoplasm (sarcoplasm). This calcium influx initiates muscle contraction through actin-myosin interaction. These processes are energy-dependent, requiring sufficient adenosine triphosphate (ATP). Therefore, any factor that damages ion channels directly or reduces ATP availability will disrupt the delicate balance of intracellular electrolyte concentrations.

When muscle injury or ATP depletion occurs, there is an excessive influx of Na+ and Ca2+ into the muscle cell. Increased intracellular Na+ draws water into the cell, disrupting cellular integrity. Prolonged high intracellular Ca2+ levels lead to sustained muscle fiber contraction, further depleting ATP.¹⁶ Elevated Ca2+ also activates calcium-dependent proteases and phospholipases, promoting cellular membrane breakdown and further damage to ion channels.¹ The culmination of these intracellular changes is an inflammatory, self-perpetuating cascade of muscle breakdown (myolysis), leading to muscle fiber necrosis and release of muscle contents into the extracellular space and bloodstream.¹⁰ Figure 1 illustrates this process, showing how diverse insults converge on a common pathway to initiate the rhabdomyolysis cascade.

Figure 1: Mechanisms of Rhabdomyolysis

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Mechanisms of rhabdomyolysis. Reproduced with permission from Elsevier.¹⁷ ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; DNA, deoxyribonucleic acid; PLA, polylactic acid; ROS, reactive oxygen species.

CAUSES OF RHABDOMYOLYSIS

Theoretically, any form of muscle damage can trigger rhabdomyolysis. In adults, common causes include drug or alcohol abuse, prescription medications, trauma, neuroleptic malignant syndrome (NMS), and prolonged immobility.¹⁸ In children, viral myositis, trauma, connective tissue disorders, exercise, and drug overdose are more frequently implicated. Viral myositis alone may account for up to one-third of pediatric rhabdomyolysis cases.^{14, 15, 19} Table 2 and Table 3 provide a comprehensive, though not exhaustive, list of physical and non-physical causes, and specific drugs and agents that can induce rhabdomyolysis. Some of the more frequent causes are discussed in detail below.

Table 2: Physical and Nonphysical Causes of Rhabdomyolysis

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Table 3: Drugs and Other Agents That Can Cause Rhabdomyolysis

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Statins and Rhabdomyolysis

Statins, or 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors, are widely used to lower cholesterol and prevent cardiovascular disease. The association between statins and muscle-related side effects, ranging from myalgia to rhabdomyolysis, has been extensively studied since their introduction in the 1980s. Statins are among the most commonly prescribed drugs globally due to their proven benefits in reducing mortality in patients with pre-existing cardiovascular disease, the leading cause of death in industrialized nations.²⁰ However, the risk of statin-induced myopathy, including rhabdomyolysis, is a genuine concern that must be considered when prescribing these medications.

In 2012, the U.S. Food and Drug Administration (FDA) issued a notification regarding potential side effects of statins, including liver injury, cognitive impairment, type 2 diabetes mellitus, and myopathy/rhabdomyolysis. Warning labels for all statin medications were updated to include these risks. Specifically, Mevacor (lovastatin) labels were revised to highlight contraindications when used with various other drugs, such as HIV protease inhibitors and certain antibacterial and antifungal medications.²¹ Concurrently, the FDA removed the recommendation for routine liver enzyme monitoring in patients on statins, as studies showed no benefit in detecting or preventing serious liver injury.²¹ The current FDA recommendation is to obtain baseline liver enzyme levels before initiating statin therapy and to monitor enzyme levels only if clinically indicated thereafter.

Randomized controlled trials estimate the incidence of myopathic events in statin users between 1.5% and 5.0%. However, real-world clinical practice data shows a wider range, from 0.3% to 33%.^22–24 This discrepancy may be due to two primary factors. First, the lack of a consistent definition for myopathic events can lead to underreporting and underdiagnosis. Second, many clinical trials exclude patient populations at higher risk of muscle toxicity, such as those with renal or hepatic insufficiency, pre-existing muscle complaints, hypertriglyceridemia, and poorly controlled diabetes.^{25, 26}

Risk factors for statin-induced rhabdomyolysis include high statin dosages, older age, female sex, renal or hepatic impairment, and diabetes mellitus.¹ Table 4 provides a more detailed list of potential risk factors.

Table 4: Proposed Risk Factors for Statin-Induced Rhabdomyolysis

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Despite the relatively common occurrence of general muscle toxicity with statin use, rhabdomyolysis specifically caused by statins is rare.²³ It’s argued that the mortality reduction associated with statin use significantly outweighs the risk of rhabdomyolysis.²⁷ An analysis of 30 randomized controlled trials (n=83,858) found a similar number of rhabdomyolysis cases in statin-treated patients (7 cases) compared to placebo-treated patients (5 cases).²⁸ The FDA Adverse Event Reporting System (FAERS) reported an increase in rhabdomyolysis rates per million statin prescriptions from 1.07 cases (1998-2000) to 3.56 cases (2002-2004).²⁹ FAERS data also indicated the lowest rhabdomyolysis rates with pravastatin (1.63 cases) and the highest with rosuvastatin (13.54 cases).²⁹ However, FAERS data relies on self-reporting and uses higher CK elevation thresholds for rhabdomyolysis diagnosis compared to ACC/AHA/NHLBI definitions, potentially limiting its accuracy.²⁹

A study based on 2001 FAERS data by Davidson et al. examined fatal rhabdomyolysis rates for different statins.²⁹ The 2001 data showed one reported case of fatal rhabdomyolysis per 5.2 million lovastatin prescriptions, 8.3 million simvastatin prescriptions, 23.4 million atorvastatin prescriptions, and 27.1 million pravastatin prescriptions.²⁹ Staffa et al. reported no fatal rhabdomyolysis events in a separate study involving fluvastatin.³⁰ According to Cervellin et al., 2001 FAERS data showed a fatal rhabdomyolysis rate of one case per 316,000 prescriptions for cerivastatin, a statin withdrawn from the market in 2001 due to high rhabdomyolysis rates, particularly when combined with fibrates, especially gemfibrozil.² Cerivastatin was shown to increase rhabdomyolysis risk up to 12-fold.³¹ An FDA study over 29 months found the highest rhabdomyolysis occurrence with simvastatin (36%) and cerivastatin (32%), and lower occurrences with atorvastatin (12%), pravastatin (12%), lovastatin (6%), and fluvastatin (2%).³²

Cytochrome P450 Inhibitors and Drug Interactions

The risk of myopathy and rhabdomyolysis associated with statin therapy is further complicated by potential drug interactions. Drug interactions contribute to approximately 60% of statin-induced rhabdomyolysis cases.³³ These interactions often arise because both statins and commonly co-administered drugs are metabolized by the cytochrome P450 enzyme system.

Statins differ in their metabolism. Some statins (atorvastatin, simvastatin, and lovastatin) are metabolized by cytochrome P450 3A4 (CYP3A4) and are termed 3A4 substrates. Others (pravastatin, fluvastatin, and rosuvastatin) are not primarily metabolized by CYP3A4.³⁴ CYP3A4 is also responsible for metabolizing over 50% of marketed drugs.³⁴ Co-administration of CYP3A4 inhibitors with statins can significantly increase plasma statin levels, leading to increased statin toxicity.³⁴ Common CYP3A4 inhibitor drugs often prescribed with statins include fibrates (especially gemfibrozil), calcium channel blockers, histamine H2 antagonists, certain antibiotics (e.g., clarithromycin), antifungals (e.g., itraconazole), antidepressants, antiretroviral drugs (e.g., protease inhibitors), and immunosuppressants (e.g., cyclosporine).

A 2004 pharmacokinetic study by Jacobson evaluated drug interaction profiles and showed that simvastatin and atorvastatin (3A4 substrates) exhibited significant pharmacokinetic changes when co-administered with CYP3A4 inhibitors, leading to up to a 5-fold increase in myopathy incidence.³⁵ Fluvastatin (primarily metabolized by cytochrome P450 2C9) and pravastatin (not a major CYP450 substrate) showed less significant pharmacokinetic changes when administered with 3A4 inhibitors.³⁵ Similarly, Law and Rudnicka found higher rhabdomyolysis incidence with lovastatin, simvastatin, and atorvastatin, and lower incidence with fluvastatin and pravastatin, mirroring FAERS data.³⁶ They attributed this difference to the CYP3A4 metabolism of lovastatin, simvastatin, and atorvastatin, versus the non-CYP3A4 metabolism of fluvastatin and pravastatin.

The interaction between statins and fibrates is particularly clinically significant due to frequent comorbidities in patients. A review of 36 clinical trials involving statin-fibrate combination therapy found a 0.12% prevalence of myopathic events.³⁷ The Davidson et al. FAERS study also examined rhabdomyolysis rates with fenofibrate or gemfibrozil combined with various statins.²⁹ While both fenofibrate and gemfibrozil increased rhabdomyolysis risk compared to statin use alone, fenofibrate combination resulted in fewer rhabdomyolysis reports (4.5 cases per million prescriptions) than gemfibrozil combination (87 cases per million prescriptions).²⁹ Notably, only 2.3% of fibrate/statin rhabdomyolysis reports involved cerivastatin and fenofibrate, while 88% involved cerivastatin and gemfibrozil.³⁸ Recent research suggests gemfibrozil’s inhibition of statin glucuronidation, reducing statin elimination and increasing plasma concentrations, contributes to the increased myotoxicity seen with gemfibrozil/statin therapy.³⁸ Fenofibrate has not shown to affect statin glucuronidation or oxidation.^{39, 40}

Trauma-Induced Rhabdomyolysis

Blunt and crush injuries are common causes of trauma-induced rhabdomyolysis. Interestingly, in crush injuries from disasters like bombings, earthquakes, or building collapses, rhabdomyolysis onset often occurs after the acute compression is relieved, allowing muscle breakdown products to enter circulation.¹⁷ High-voltage electrical injuries, such as electrocution or lightning strikes, are also significant causes of trauma-induced rhabdomyolysis. It’s estimated that up to 10% of electrical accident survivors develop rhabdomyolysis.¹⁰

Exertional Rhabdomyolysis

Diagnosing exertional rhabdomyolysis can be challenging because strenuous exercise naturally elevates serum CK levels in almost all individuals, potentially up to 10 times the normal upper limit.⁴¹ CK level increases vary significantly among individuals, and exertional rhabdomyolysis susceptibility can differ even under identical exercise conditions.⁴¹ Increased temperature and humidity during exercise may also increase rhabdomyolysis risk.⁴² A study of military recruits in basic training showed 22.2 cases of exertional rhabdomyolysis per 100,000 recruits annually.⁴³ This study also indicated a low incidence and recurrence risk of exertional rhabdomyolysis in young, physically active individuals.

Temperature, Neuroleptic Malignant Syndrome (NMS), and Malignant Hyperthermia (MH)

Heat stroke, NMS, and MH can all lead to rhabdomyolysis.

Heat stroke, defined by a core body temperature exceeding 40.5°C, can cause rhabdomyolysis alongside hypotension, lactic acidosis, hypoglycemia, disseminated intravascular coagulation, and multi-organ failure.⁴³ Exertional heat stroke is less common in women, possibly due to estrogen’s protective effect on muscle.⁴⁴ Women presenting with rhabdomyolysis seemingly due to heat stroke should be evaluated for underlying muscle disease or other contributing factors.⁴⁴

NMS, often associated with antipsychotic medications (particularly first-generation or atypical antipsychotics like haloperidol), can induce rhabdomyolysis, likely due to heat generation from muscle rigidity and tremors.⁴³ The mechanism is thought to involve central nervous system dopamine receptor blockade or withdrawal of dopaminergic agonists.¹

MH is a genetic disorder, autosomal dominant in 50% and autosomal recessive in 20% of cases.¹ Symptoms resemble NMS, including muscle rigidity, hyperventilation, tachycardia, fever, hemodynamic instability, and lactic acidosis.⁴³ MH typically occurs during general anesthesia in susceptible individuals. Incidence is estimated at 1 in 15,000 anesthetic uses in children and 1 in 50,000-100,000 in adults.⁴⁵

Muscle Ischemia and Rhabdomyolysis

Prolonged oxygen deprivation to muscle tissue can cause cell necrosis, leading to rhabdomyolysis and AKI. Localized muscle ischemia can result from blood vessel compression during surgery or otherwise, thromboses, emboli, compartment syndrome, carboxyhemoglobinemia, or sickle cell disease.¹⁷ Hypothermia, though rare, can also cause rhabdomyolysis by reducing muscle perfusion.^{1, 17}

Infection-Related Rhabdomyolysis

Rhabdomyolysis has been associated with various infections, from localized bacterial muscle infections (pyomyositis) to sepsis without direct muscle infection.^{1, 46} Proposed mechanisms include tissue hypoxia from sepsis or dehydration, toxin release, fever, direct bacterial muscle invasion, or rigors/tremors.¹ Legionella bacteria are classically linked to bacterial rhabdomyolysis.⁴⁷ Viral infections, particularly influenza A and B viruses, are also implicated.^{48, 49} Rhabdomyolysis has also been described with HIV,⁵⁰ coxsackie virus,⁵¹ Epstein-Barr virus,⁵² Cytomegalovirus,⁵³ herpes simplex virus,⁵⁴ varicella zoster virus,⁵⁵ and West Nile virus.⁵⁶

SYMPTOMS AND CLINICAL PRESENTATION OF RHABDOMYOLYSIS

Presenting symptoms of rhabdomyolysis are often influenced by the underlying cause, as well as complications like kidney failure or muscle injury. The classic triad of symptoms includes myalgia, weakness, and tea-colored urine. Urine color is affected by muscle mass, urine concentration, and kidney function. A study of 87 cases (CK >500 IU/L) by Gabow et al. found that 26% of patients tested negative for myoglobin using urine dipstick tests.⁵⁷ Mannix et al. reported common presenting symptoms in pediatric rhabdomyolysis, regardless of kidney injury, were muscle pain, fever, and viral prodromes.¹⁹ Dark urine was reported in only 3.6% of pediatric cases.¹⁹ Patients may also exhibit tense and swollen muscles upon physical examination. As mentioned, the classic triad is seen in less than 10% of patients, and over 50% may not report muscle pain or weakness. Systemic symptoms like tachycardia, malaise, fever, nausea, and vomiting are non-specific. Complications such as AKI, disseminated intravascular coagulation, and multi-organ failure may develop subsequently.²

DIAGNOSIS OF RHABDOMYOLYSIS

Diagnosing rhabdomyolysis requires a high degree of clinical suspicion, a thorough patient history, and physical examination. Given that the classic triad is infrequent, rhabdomyolysis should be considered in any patient with known risk factors such as trauma, sepsis, muscle disease, and immobilization. Indirect clues include muscle injury with unexplained elevations in serum phosphate or aspartate transaminase. A neuromuscular examination focusing on extremities, assessing color, pulse, sensation, muscle strength, and size, can provide valuable physical signs, even in nonverbal patients.¹⁶

The gold standard laboratory test for diagnosis is plasma CK measurement. While a definitive CK cutoff is not universally established, a level five times the upper limit of normal (e.g., 1,000 IU/L) is commonly used.² CK level is generally considered predictive of AKI risk, with levels >5,000 IU/L strongly associated with kidney damage. CK has a half-life of approximately 1.5 days, so elevated levels persist longer than myoglobin, which has a half-life of 2-4 hours and typically normalizes within 6-8 hours after muscle injury.² Plasma myoglobin is less sensitive than CK due to its short half-life, leading to potential false-negative results.¹⁶ Urine myoglobin can be detected by urine dipstick tests, which may show positive results for erythrocytes because the orthotoluidine component of the dipstick turns blue in the presence of myoglobin.

SELECTED COMPLICATIONS OF RHABDOMYOLYSIS

Rhabdomyolysis can lead to several complications, including compartment syndrome and acute kidney injury. Figure 2 lists these and other common complications, along with initial treatments for each.

Figure 2: Complications of Rhabdomyolysis

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Complications of rhabdomyolysis. Reproduced with permission from Springer.⁵⁹ IV, intravenous; Rx, treatment.

Compartment Syndrome as a Rhabdomyolysis Complication

Post-traumatic or ischemic muscle damage in muscle groups enclosed by inelastic fascia can lead to increased pressure within the muscle compartment (intracompartmental hypertension).⁵⁸ When crushed muscle becomes engorged with blood and edematous after compression is relieved, a condition known as rebound hyperperfusion occurs, further increasing pressure and damage. This excessive blood flow and impaired lymphatic drainage can compromise arteriolar perfusion. Once pressure is high enough to collapse arterioles, muscle and nerve perfusion ceases, resulting in compartment syndrome.² Compartment syndrome is typically seen when intracompartmental pressure exceeds 30 mmHg. Further muscle damage can manifest as a “second wave phenomenon,” a persistent or rebound elevation in CK levels 48-72 hours after the initial insult.¹⁷

Acute Kidney Injury (AKI) as a Rhabdomyolysis Complication

Acute kidney injury is the most severe complication of rhabdomyolysis, developing in approximately 33% of patients within days of initial presentation.¹⁷ AKI in rhabdomyolysis is primarily attributed to the nephrotoxic effects of myoglobin accumulation in the kidneys. Hypovolemia, often associated with rhabdomyolysis, further contributes to renal hypoperfusion and AKI.

Various clinical factors, including serum CK, creatinine, potassium, and calcium levels, as well as urine myoglobin levels, are used to assess AKI risk, but no single parameter is definitively predictive.¹⁷

MANAGEMENT OF RHABDOMYOLYSIS

Regardless of the underlying cause of suspected rhabdomyolysis, preventing AKI is a primary treatment goal. Fluid management is crucial to address potential fluid accumulation in muscle compartments and associated hypovolemia, preventing prerenal azotemia. Aggressive hydration is the cornerstone of treatment, typically initiated at a rate of 1.5 L/h.⁵⁹ Another approach involves alternating hourly infusions of 500 mL saline solution with 500 mL of 5% glucose solution containing 50 mmol of sodium bicarbonate for every 2-3 liters of total solution. Treatment goals include achieving a urinary output of 200 mL/h, urine pH >6.5, and plasma pH <7.5.² Table 5 summarizes the goals of early aggressive fluid resuscitation in rhabdomyolysis. The efficacy of urinary alkalinization with sodium bicarbonate or sodium acetate, and the use of mannitol to promote diuresis, remain unproven.⁶⁰ Any medications known to increase rhabdomyolysis risk, such as statins, should be immediately discontinued. Fasciotomy may be necessary in cases of compartment syndrome to limit muscle and kidney damage.

Table 5: Aims of Early Vigorous Fluid Resuscitation in Rhabdomyolysis

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ANESTHETIC CONSIDERATIONS FOR PATIENTS WITH RHABDOMYOLYSIS

Data specifically addressing anesthetic management in rhabdomyolysis patients is limited, possibly due to the condition’s relative rarity. However, retrospective studies on patients with muscular dystrophies, who have increased anesthetic-related risks including rhabdomyolysis, offer some guidance.⁶¹ A review of 232 patients with Duchenne muscular dystrophy used total intravenous anesthesia (TIVA) without volatile anesthetic agents, employing opioids and non-depolarizing muscle relaxants as needed based on the surgical procedure.⁶¹ Succinylcholine was avoided, and neuromuscular blockade was monitored using acceleromyography. Nitrous oxide and propofol were used for induction. This study reported no serious anesthetic complications or rhabdomyolysis cases.⁶¹ A review of 117 patients with dystrophinopathies found succinylcholine may trigger rhabdomyolysis, hyperkalemia, and cardiac arrest, but lacked conclusive evidence regarding inhalational anesthetics.⁶² This review also reported no rhabdomyolysis cases with TIVA and no definitive evidence for or against volatile anesthetic use in this population.⁶² It’s important to note that no anesthetic agent is entirely risk-free; rhabdomyolysis has been reported with non-triggering anesthetics, barbiturates, benzodiazepines, propofol, ketamine, and even fasting.⁶²

Ketamine and Rhabdomyolysis Risk

Ketamine hydrochloride is a dissociative anesthetic commonly used for procedural sedation in operating rooms.⁶³ It’s hypothesized that ketamine, an analog of phencyclidine, may induce agitation and prolonged muscle activity, potentially leading to rhabdomyolysis.⁶³ A case study of 20 patients aged 15-40 presenting to the emergency room after ketamine abuse showed that 2 developed clinical rhabdomyolysis.⁶⁴

Succinylcholine and Rhabdomyolysis Risk

Succinylcholine is a depolarizing neuromuscular blocking agent widely used to induce muscle relaxation and short-term paralysis, often prior to tracheal intubation. Succinylcholine is also known to cause succinylcholine-induced malignant hyperthermia (MH), which frequently co-occurs with clinically significant rhabdomyolysis.⁶⁵ Despite potential life-threatening complications, succinylcholine remains popular, especially in trauma settings, due to its rapid onset and short duration of action compared to other muscle relaxants.

While the exact mechanism of succinylcholine-induced rhabdomyolysis is unclear, numerous case reports exist.⁶⁶ Rhabdomyolysis following succinylcholine administration can lead to severe hyperkalemia and potentially cardiac arrest.⁶⁵ Most patients experiencing rhabdomyolysis after succinylcholine administration are subsequently diagnosed with MH or an undiagnosed muscular dystrophy.⁶⁵ In fact, succinylcholine-induced rhabdomyolysis in post-pubertal patients without an underlying predisposing condition is rare.⁶⁷ The mortality rate for patients with undiagnosed muscular dystrophies who develop cardiac arrest from succinylcholine-induced rhabdomyolysis is approximately 30%.⁶⁵ However, the link between succinylcholine and rhabdomyolysis in patients with muscular dystrophies requires further investigation, as rhabdomyolysis can still occur in this population under general anesthesia even without succinylcholine use.⁶⁵

Propofol-Infusion Syndrome (PRIS) and Rhabdomyolysis

Propofol-infusion syndrome (PRIS), first described by Bray in 1998, initially referred to a clinical syndrome in critically ill children sedated with propofol for extended periods.⁶⁸ PRIS has since been observed in adults, with the first adult PRIS-related death reported in 2000.⁶⁹ PRIS is not limited to critically ill patients and has been reported in healthy individuals and those receiving short-term, high-dose propofol infusions.^{70, 71} Rhabdomyolysis is a commonly observed symptom of PRIS, typically occurring later in the syndrome’s progression, among a wide range of other signs and symptoms.⁶⁸ Risk factors for PRIS include severe head injury, airway infection, young age, high cumulative propofol dose, high catecholamine and serum glucose levels, low carbohydrate/high fat intake, critical illness, and inborn metabolic errors.⁶⁸ Rhabdomyolysis has been identified as an independent risk factor for death in PRIS.⁶⁸

The first large prospective PRIS study examined ICU patients receiving propofol infusions for >24 hours across 11 medical centers.⁷² PRIS was strictly defined as metabolic acidosis and cardiac dysfunction, plus at least one of rhabdomyolysis, hypertriglyceridemia, or renal failure.⁷² The study showed a 1.1% PRIS incidence in this population. Notably, 91% of PRIS patients were on vasopressors, and only 18% received propofol at >5 mg/kg/h, suggesting cumulative dose may be a better PRIS predictor than infusion rate.⁷²

CONCLUSION

Rhabdomyolysis is a complex medical condition with significant potential for morbidity and mortality. While often caused by direct trauma, it can also arise from drugs, toxins, infections, muscle ischemia, electrolyte and metabolic disorders, genetic conditions, exertion, prolonged immobilization, and temperature-related states like NMS and MH. The classic symptom triad includes myalgia, weakness, and myoglobinuria, but elevated CK level is the most sensitive indicator of muscle injury-induced rhabdomyolysis. All clinicians should maintain awareness of the common causes, diagnostic approaches, and treatment options for rhabdomyolysis to ensure prompt recognition and management and improve patient outcomes.

Footnotes

The authors have no financial or proprietary interest in the subject matter of this article.

This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.