Rhabdomyolysis

Diagnosis

The surrogate biomarker for rhabdomyolysis , creatine kinase (CK) , is a poor substitute because it is not possible to differentiate, based upon this value, between rhabdomyolysis and hyperCKemia. The generally accepted definition of rhabdomyolysis includes an elevation of CK either >1,000 IU/L or greater than five times the upper limit of normal in a clinical context of acute muscle weakness, myalgia, and muscle swelling ( Fig. 36.1 ).

There are exceptions; focal rhabdomyolysis may result in lower CK levels with the same underlying pathologic processes. Additionally, levels above the limit of 1,000 I/U can be found in patients with acute denervating diseases, in patients with hyperCKemia from intense exercise, and in patients with non-muscle-related diseases. A diagnosis of rhabdomyolysis should not be considered in patients without acute clinical symptoms and acute CK changes from the baseline value. Levels over 5,000 I/U are rarely found in acute or chronic non-muscle-related diseases.

In addition to muscle damage and pain, toxins released into the circulation from the myocyte damage can lead to systemic problems including cardiac arrythmias, encephalopathy, and, most commonly, acute kidney injury.

HyperCKemia

HyperCKemia is diagnosed when the serum elevation of CK is beyond the upper limits for age, gender, race, and muscle mass but in the absence of associated symptoms. Given the sensitive CK fluctuations with exercise, the assessment of hyperCKemia needs to be taken into consideration with the patient’s hydration status, previous activity, and timing from any possible inciting event. CK typically begins to increase 24 hours after the onset of a muscle injury or stress, peaks at around 24–36 hours, and, in a monophasic illness, starts to decline. The normal half-life of CK, in a patient without renal failure, is between 24 and 48 hours ( Fig. 36.2 ).

Careful consideration of laboratory norms for CK is essential in interpreting elevated levels during an acute event because normal values correlate to overall muscle bulk, race, and gender. Additionally, frequent exercise in athletes can lead to persistently elevated CK (350–500 IU/L) during training. Obtaining a baseline CK level after a period of rest is required. There is no risk of renal damage in hyperCKemia given that there is no myoglobin released into the circulation.

Myoglobinuria

Myoglobinuria is the presence of elevated myoglobin levels in the urine. Myoglobin is a chemical compound that carries oxygen in the myocyte. Upon damage to the cell membrane, it can be released into the blood at higher levels than typically seen. When levels are >0.5–1.5 mg/L, it saturates the serum haptoglobin and α ₂ -immunoglobulin and the excess is filtered by the glomerulus. Myoglobin sequesters fluid, leading to hypovolemia and renal vasoconstriction. It can release the free iron, which may damage the renal tubules, or it may react directly with the lipid membrane of the kidney, resulting in damage to the proximal tubules.

While there are direct laboratory detection methods, the time to obtain results is not rapid enough to use this value to direct treatment; urine heme when not in the presence of red blood cells is frequently used as a surrogate marker to indicate myoglobinuria in the appropriate acute setting and when clinically suspected. In this situation, the urine red blood cell (RBC) count should be checked to determine if the heme +++ results in myoglobin or hematuria. Measuring myoglobin levels remains a valuable differentiator between rhabdomyolysis and hyperCKemia. Normal urine myoglobin levels are <10 mg/dL (and 100 mg/dL in blood); elevated levels indicate rhabdomyolysis.

The typical red- or tea-colored urine described in rhabdomyolysis is not always noted and requires a urine myoglobin concentration >100 mg/dL. In a patient who has been fluid resuscitated, the urinary dilution can mask both the visible and laboratory detection of myoglobinuria. It is important to collect samples during the acute phase of presentation or when fluids are weaned because the urine can then become positive.

Myositis

Myositis is an inflammatory process in the muscle not related to underlying chronic apoptotic muscle disease. In patients with myositis, there is an underlying immune or rheumatologic process resulting in inflammatory cells causing muscle damage, which involves the myocyte membrane. This is in contrast with primary (genetic) muscle diseases in which there can be signs of inflammation secondary to the apoptotic process of cell death. In some cases, such as dysferlinopathies, these can be mistaken for an inflammatory myopathy on the biopsy. However, in isolated myositis, there is not the same release of other biomarkers from the myocytes into the serum as seen in acute rhabdomyolysis. Additionally, other than infectious myositis, most of these disease processes are subacute to chronic in nature with only rare presentations as acute rhabdomyolysis.

Clinical Presentation

History

The first part of the history of a patient with possible rhabdomyolysis is the history of the acute episode, while the second part is to evaluate for an underlying etiology. The acute history will help differentiate the potential for rhabdomyolysis from other causes of pain and weakness ( Table 36.1 ); once diagnosed, the etiology of the rhabdomyolysis needs to be evaluated.

TABLE 36.1

Differential Causes of Acute Muscle Weakness and Pain

Disease	Typical Weakness Pattern	Pain Pattern	Other Symptoms
Rhabdomyolysis	Diffuse or muscles used with exertion, often larger muscles are preferred	Same as muscle pain	Dark or red urine Elevated CK
Guillain-Barré syndrome	Ascending weakness	Neuropathic pain (typically distal)	May have areflexia, autonomic symptoms
Myasthenia gravis	Proximal weakness with/without ocular or bulbar symptoms, often fatigable	No pain	Pupillary-sparing fatigable weakness
Botulism	Descending weakness that involves pupils	No pain	Often GI symptoms
Myalgia	In area of pain	Often muscle or joint pains, large muscles preferred	Often in association with other disease, CK is often normal
Psychogenic	May have non-neurologic pattern of weakness, weakness that varies based upon how it is examined, give-way weakness	Pain and weakness are not always congruent in a physiologic distribution	May have other features of a psychogenic illness Normal CK during an acute episode is not rhabdomyolysis
Nonrheumatologic connective tissue disease (e.g., Ehlers-Danlos syndrome)	Often no overt weakness	Pain is often after activity but more joint related than muscle	Normal CK during an acute episode May have a history of fatigue with endurance activity but normal strength

CK, creatine kinase; GI, gastrointestinal.

A child with rhabdomyolysis may present with a variety of symptoms. Most patients present with muscle pain. The remaining 20% do not present with overt signs of muscle disease. Dark urine (myoglobinuria) may be reported in ∼5% of patients; an even smaller number develop acute renal failure.

Patients with focal muscle swelling may develop a compartment syndrome resulting in local neurovascular features and may develop more systemic disease such as acute kidney injury or encephalopathy with associated seizures, somnolence, and/or other cognitive changes. Cardiac arrythmias may also be present.

Given the half-life and timing of the typical peak for both myoglobin and CK, the timing of the disease onset is important. Patients presenting early in their course may not have an elevation of their CK, whereas patients who have milder symptoms or do not present during the acute episode may have normal or near-normal lab results. Symptoms of previous episodes for which the patient did not seek clinical care can suggest an underlying etiology; any signs of possible muscle disease including features of muscle dysfunction (weakness, cramps, pain) at baseline as well as during different types of activity (anaerobic vs aerobic and concentric vs eccentric exercise) as well as family history and inciting events or risk factors can be helpful in differentiating these diseases ( Fig. 36.3 ).

Because of the phenotypic variation between some of the underlying genetic disorders that can predispose a patient to rhabdomyolysis, evaluation for diagnostic or subtle symptoms should be considered ( Table 36.2 ; see Fig. 36.3 ).

TABLE 36.2

Genetic Disorders Associated with Rhabdomyolysis

Gene	OMIM	Cytogenetic Location	Inheritance	Disorder
Muscle Structure and Function
ATP2A1	601003	16p11.2	AR	Brody myopathy
DMD	300376	Xp21.2	XLR	Dystrophin-associated muscular dystrophy: Becker type
AMPD1	600467	1p13.2	AR	Myopathy due to myoadenylate deaminase deficiency
SCN4A	168300	17q23.3	AD	Paramyotonia congenita
ISCU	255125	12q23.3	AR	Myopathy with lactic acidosis
CAV3	123320	3p25.3	AD	Familial hyperCKemia
CASQ1	114250	1q23.2	AD	Myopathy, vacuolar, with CASQ1 aggregates
Mitochondria/Energy Metabolism
HADHA HADHB	600467	2p23.3	AR	Mitochondrial trifunctional protein deficiency (MTPD)
MCKAT	602199	Not known	AR	Mitochondrial medium-chain 3-ketoacyl-coenzyme A thiolase (MCKAT) deficiency
CPT2	600467	1p32.3	AR	CPT II deficiency, myopathic, stress induced
ACADVL	600467	17p13.1	AR	VLCAD deficiency
PYGM	600467	11q13.1	AR	McArdle disease, or glycogen storage disease type V (GSD5)
PGAM2	261670	7p13	AR	Glycogen storage disease type X
LDHA	612933	11p15.1	AR	Glycogen storage disease type XI
ALDOA	611881	16p11.2	AR	Glycogen storage disease type XII
SLC25A20	212138	3p21.31	AR	Carnitine-acylcarnitine translocase deficiency
POLG	600467	15q26.1	AD	Autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-1 (PEOA1) is caused by variants in the nuclear-encoded DNA polymerase-gamma gene
DGUOK	617070	2p13.1	AR	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4
MRM2	600467	7p22.3	AR	Mitochondrial DNA depletion syndrome 17
ATP5F1D	618120	19p13.3	AR	Mitochondrial complex V (ATP synthase) deficiency
FDX2	600467	19p13.2	AR	Mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL)
MRPS14	618378	1q25.1	AR	Combined oxidative phosphorylation deficiency 38
TSFM	600467	12q14.1	AR	Combined oxidative phosphorylation deficiency-3 (COXPD3)
Metabolic
SLC25A42	600467	19p13.11	AR	Metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN)
PGK1	600467	Xq21.1	XLR	Phosphoglycerate kinase-1 deficiency
Other
CACNA1S MHS4 MHS6 MHS3 MHS2 RYR1	600467 601887 610888 154276 154275 145600	1q32.1 3q13.1 5p 7q21 17q11.2 19q13.2	AD	Malignant hyperthermia susceptibility (multiple types including King-Denborough syndrome)
CACNA1S	188580	1q32.1	AD	Thyrotoxic periodic paralysis associated with malignant hyperthermia allele
CTDP1	600467	18q23	AR	Congenital cataracts, facial dysmorphism, and neuropathy
PGM1	600467	1p31.3	AR	Congenital disorder of glycosylation, type It (CDG1T)
XK	300842	Xp21.1	XL	McLeod syndrome with or without chronic granulomatous disease
CYP2C8	601129	10q23.33	Risk allele	Statin-induced rhabdomyolysis cytochrome P450-drug metabolism, altered, CYP2C8-related
TRAPPC2L	618331	16q24.3	AR	Progressive encephalopathy with episodic rhabdomyolysis (PEERB)
TANGO2	616878	22q11.21	AR	Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN)
SLC16A1	245340	1p13.2	AD	Erythrocyte lactate transporter defect
QARS1	615760	3p21.31	AR	Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy (MSCCA)
LPIN1	268200	2p25.1	AR	Myoglobinuria, acute recurrent, autosomal recessive
HRAS	218040	11p15.5	AD	Costello syndrome/congenital myopathy with excess of muscle spindles
SIL1	248800	5q31.2	AR	Marinesco-Sjögren syndrome

AD, autosomal dominant; AR, autosomal recessive; ATP, adenosine triphosphate; CPT II, carnitine palmitoyl transferase II; VLCAD, very long-chain acyl-CoA dehydrogenase; XLR, X-linked recessive.

Diagnostic Evaluation

Patients are typically diagnosed with rhabdomyolysis based upon serum CK, which is used as a marker for muscle breakdown (see Fig. 36.1 ). However, very focal rhabdomyolysis can result in CK levels that are not as elevated.

A two-tiered acute approach for patients with possible rhabdomyolysis is recommended given that most pediatric patients have either exertional or infectious etiologies ( Tables 36.4 and 36.5 ). This allows a thoughtful approach to the patient in which etiologic studies may not change management. There is no strong evidence for biochemical or gene sequencing in a patient with a first episode of rhabdomyolysis and no family history of muscle disease.

Muscle Biopsy

While histopathology can be diagnostic of a known (often genetic or immunologic) etiology, the yield of a biopsy during an acute episode is very low. This is because the acutely damaged muscle has a similar end-stage appearance due to the diffuse injury, which often masks the more subtle features of the underlying cause. In almost all cases, a muscle biopsy, if needed, should be deferred for at least 3 months after the resolution of the last acute episode to ensure the highest yield.

The muscles selected should be those known to be affected, ideally with a manual muscle strength score between 3–4+ out of 5, and not those with diffuse atrophy. The most common muscle studies are the hamstring muscles, or the vastus lateralis, followed occasionally by the biceps and gastrocnemius. Genetic testing and biochemical analysis are frequently pursued prior to obtaining a muscle sample because they are less invasive and less expensive.

Treatment

During an acute episode of rhabdomyolysis, the mainstay of treatment is use of sufficient fluids to help diurese the serum electrolytes, chemicals, and toxins. In theory, by ensuring excretion of these chemicals, the nonmuscle complications can be avoided. In adults, the recommendations are to give a fluid bolus followed by starting the patient on 1.5–2 times greater than maintenance fluids. No evidence-based guidelines exist for children; some recommend the titrating of fluids to maintain a urine output 3–4 times normal, or 3–4 mL/kg/hour in a child. Another method is to titrate the fluids to maintain a physiologic creatine kinase half-life, which, in theory, would ensure an appropriate urine output. This method addresses the patient’s physiology ( Fig. 36.4 ).

Before discharge the patient must demonstrate appropriate oral intake with continued CK clearance and no myoglobin in the urine. Patients must also have improved and tolerable symptoms but are not expected to have fully resolved their pain or mild weakness. Nonetheless, with underlying myocyte injury, mild pain, weakness, and some limited endurance are expected to last for weeks to months after resolution of the acute event.

Renal Injury Risk

A serious complication of rhabdomyolysis is the potential risk for renal injury. Fortunately, the risk remains relatively low (∼5–10% in children). While some evidence suggests that patients with rhabdomyolysis and a CK <5,000 IU/dL are at lower risk of renal involvement, this may reflect patients with hyperCKemia and not rhabdomyolysis. In one study, no patients with initial urinary heme (myoglobin) dipstick results of <2+ developed acute renal failure, compared with ∼18% of patients with urinary heme (myoglobin) dipstick results of ≥2+. The degree of elevation of the CK does not accurately correlate with the risk of rhabdomyolysis in pediatric patients.

Compartment Syndrome

Compartment syndrome is another serious complication because the swelling can result in vascular and neurologic compression and secondary ischemic injury. Frequent evaluations of distal perfusion and peripheral neurologic findings are warranted until the patient is convalescing. Neurovascular evaluations of the distal extremities are warranted every 2–4 hours during the early phases of injury. Signs of compartment syndrome include pain out of proportion to the examination as well as that induced by manual passive limb movement. Consultation with an orthopedic or general surgeon is warranted to help evaluate the need for a fasciotomy to relieve the pressure.