Elsevier

Neuromuscular Disorders

Volume 24, Issue 8, August 2014, Pages 651-659
Neuromuscular Disorders

Review
Rhabdomyolysis: Review of the literature

https://doi.org/10.1016/j.nmd.2014.05.005Get rights and content

Highlights

  • Summary of the pathophysiology, clinical presentation, aetiology, diagnosis, and management of rhabdomyolysis.

  • Comprehensive overview of acquired and genetic causes of rhabdomyolysis.

  • Diagnostic algorithm for use in clinical practice.

Abstract

Rhabdomyolysis is a serious and potentially life threatening condition. Although consensus criteria for rhabdomyolysis is lacking, a reasonable definition is elevation of serum creatine kinase activity of at least 10 times the upper limit of normal followed by a rapid decrease of the sCK level to (near) normal values. The clinical presentation can vary widely, classical features are myalgia, weakness and pigmenturia. However, this classic triad is seen in less than 10% of patients. Acute renal failure due to acute tubular necrosis as a result of mechanical obstruction by myoglobin is the most common complication, in particular if sCK is >16.000 IU/l, which may be as high as 100,000 IU/l. Mortality rate is approximately 10% and significantly higher in patients with acute renal failure. Timely recognition of rhabdomyolysis is key for treatment. In the acute phase, treatment should be aimed at preserving renal function, resolving compartment syndrome, restoring metabolic derangements, and volume replacement. Most patients experience only one episode of rhabdomyolysis, mostly by substance abuse, medication, trauma or epileptic seizures. In case of recurrent rhabdomyolysis, a history of exercise intolerance or a positive family history for neuromuscular disorders, further investigations are needed to identify the underlying, often genetic, disorder. We propose a diagnostic algorithm for use in clinical practice.

Introduction

Rhabdomyolysis was first reported in Germany in 1881 [1] and described in more detail after the Battle of London, during the Second World War [2]. Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibres, which leads to leakage of potentially toxic cellular contents into the systemic circulation [3], [4]. The syndrome is characterised by elevation of serum creatine kinase (sCK) activity to at least 10 times the upper limit of normal followed by a fast decrease. There is no consensus on the definition of rhabdomyolysis. Some adhere to the afore-mentioned increase whereas others consider a smaller increase in sCK elevation (>5 times) sufficient for a diagnosis of rhabdomyolysis [3], [5]. The American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute Clinical Advisory on the use and safety of statins defined statin-induced rhabdomyolysis as a sCK elevation greater than 10 times the upper limit of normal [6], [7]. In most patients, sCK is normal between acute episodes of rhabdomyolysis except, for patients with muscular dystrophies, myositis or a defect in glycogen metabolism. Rhabdomyolysis may be accompanied by myoglobinuria, due to an excessive amount of myoglobin in urine, presenting as dark tea or cola-coloured urine [8]. In this review, we summarise the existing literature regarding the pathophysiology, clinical presentation, aetiology, diagnosis, and management of rhabdomyolysis. Literature has been collected by a search of PubMed using the terms rhabdomyolysis, myoglobinuria, creatine kinase, hyper-CK-emia, myoglobin, transient creatine phosphokinase elevation, and metabolic myopathy.

Section snippets

Epidemiology

Knowledge about the actual frequency of rhabdomyolysis is limited. There is no prospective study on incidence of rhabdomyolysis and many mild cases of rhabdomyolysis probably go unrecognised. Approximately 26,000 cases of rhabdomyolysis are reported annually in the United States [3], [9]. In 0.074% of patients admitted to a large university hospital over a 7-year period a CK serum activity of more than 5000 IU/l was found [10]. A study among military trainees over a period of 6 years found an

Pathophysiology

Irrespective of the cause of rhabdomyolysis, the pathophysiologic events follow a common pathway. Normally, ion pumps and channels in the sarcolemma maintain a low intracellular Na+ and Ca2+ and a high intracellular K+ concentration [16]. Direct injury to the sarcolemma or failure of energy production can cause rhabdomyolysis. Shortage of energy results in pump dysfunction (Na/K-ATPase, Ca2+ ATPase pump), which leads to increased cellular permeability to sodium ions and consequently increased

Symptoms and signs

The presentation of rhabdomyolysis varies widely between patients and ranges from asymptomatic sCK elevation to a life-threatening condition with electrolyte disturbance, cardiac arrhythmia, ARF and disseminated intravascular coagulation (DIC).

Classical clinical features are (sub)acute-onset myalgia, transient muscle weakness and pigmenturia (dark tea or cola-coloured urine), caused by an excessive amount of myoglobin (>1.5–3.0 mg/l) in the urine [3], [17], [18], [19], [24], [25], [26]. However,

Laboratory tests

The diagnosis of rhabdomyolysis is based on a more than 10 times elevated sCK. The degree of sCK elevation is proportional to the muscle injury. Approximately 2–12 h after the onset of muscle injury sCK increases. A peak concentration occurs at 24–72 h and then sCK declines to baseline values in the course of 3–5 days [17], [18], [24], [25], [33]. CK has a significant longer half-life (1.5 days) in comparison with myoglobin (2–4 h) [25]. The rapid renal clearance of myoglobin results in a low plasma

Differential diagnosis

The differential diagnosis of hyperCKemia (serum CK activity more than 10 times the upper limit of normal) is extensive and includes myositis, muscular dystrophies, and endocrine disorders such as hyperthyroidism or hypothyroidism. Patients with subacute onset myositis may also suffer from myalgia. In contrast with acute onset in rhabdomyolysis, symptoms and signs in myositis develop over a period of weeks. In rhabdomyolysis serum CK activity returns to normal in days to weeks, whereas in

Causes

Many causes of rhabdomyolysis have been identified (Table 2). They can be categorised into acquired and inherited causes. In 75% of patients a first episode of rhabdomyolysis is provoked by an acquired cause [36]. The most common acquired causes are: substance abuse (34%), medication (11%), trauma (9%) and epileptic seizures (7%) [28]. Less frequent causes include metabolic disturbance, infections, local muscle ischaemia [37], [38], [39], generalised muscle ischemia [24], prolonged

Investigations to identify rhabdomyolysis and the underlying cause

The first step in practice is taking a detailed history asking for symptoms of rhabdomyolysis, like (sub)acute-onset myalgia, transient muscle weakness and pigmenturia. When the history is compatible with rhabdomyolysis it is important to ask about provoking factors including infection, fasting, intensity and duration of exercise, temperature, general anaesthesia, the use of medication, alcohol or drug abuse and the exposition to toxic agents. In addition second-wind or out-of-wind phenomenon

Management

In the acute phase treatment should be aimed at preserving renal function and restoring metabolic derangements. Early and adequate volume replacement with NaCL 0.9% (no potassium or lactate containing solutions!) is of utmost importance in preventing acute renal failure [25], [76], [77], [78]. Volume expansion increases renal blood flow and, consequently, glomerular filtration and urination. The infusion should begin at a rate of 1.5 L/h to maintain a urine output of 200–300 ml/h. Intravenous

Prognosis

The prognosis of rhabdomyolysis depends on the complications resulting from the rhabdomyolysis and the underlying cause. When treated early and aggressively, an episode of rhabdomyolysis has an excellent prognosis [18], [24], [33], [35], [92]. The mortality rate from rhabdomyolysis is about 8–10% [19], [25], [33]. Prognosis is substantially worse if ARF develops [10], [27]. A Dutch study found 17% mortality in patients without ARF and 51% in those with ARF (P < 0.01, N = 93, with sCK > 5000 U/L). Ward

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