502 P STEVENS

Rhabdomyolysis
Rhabdomyolysis is disintegration of striated muscle. It is Electrolyte disturbance: hyperkalaemia, hypocalcaemia,
characterized by muscle necrosis leading to release of hyerphosphataemia and hyperuricaemia. Creatinine levels
intracellular constituents into extracellular fluid and the are elevated out of proportion to urea levels and acidosis,
circulation. Causes include trauma, overexertion, substance and deranged liver function may also be apparent in 25% of
abuse, muscle enzyme deficiencies, electrolyte abnormalities, patients.
infections, drugs, toxins and endocrinopathies (Table 29.3.1). Essential laboratory investigations
Mechanisms of injury include direct injury to the cell mem-
brane, muscle cell or hypoxia, leading to ATP depletion and • CK
sodium–potassium pump failure. Extracellular calcium ions • Urea, electrolytes and creatinine
leak into the cell and increase free cytosolic ionized cal- • Calcium, phosphate and urate
cium with activation of calcium-dependent proteases and • Blood gases and urinary pH
phospholipases, resulting in muscle destruction. Following • Clotting studies
muscle injury potassium, phosphate, myoglobin, creatine
kinase (CK), creatinine and nucleosides (metabolized to
urate) leak into the circulation. The muscle necrosis, inflam- Table 29.3.1 Causes of rhabdomyolysis
mation and oedema lead to fluid accumulation in affected
muscles and intravascular volume depletion. Trauma and compression
Crush injury, road traffic accident prolonged immobilization, electrical
Early complications (within 12–24h) include hyperkalaemia, injury
hypocalcaemia and cardiac dysrhythmias, hepatic dysfunc-
Ischaemic limb injury
tion and early compartment syndrome. Late complications
(≥24h) include acute renal failure, DIC, late compartment Exertional causes
syndrome and (following recovery) hypercalcaemia. Marathon running, status epilepticus
Prompt recognition and early intervention are therefore Heat-related causes
vital. Heat stroke, malignant hyperthermia and neuroleptic malignant
Clinical manifestations syndrome
Clinical manifestations are varied, dictated by the underly- Substance abuse
ing cause and by the ensuing complications. Classic triad— Alcohol, cocaine, amphetamine, lysergic acid, Ecstasy
muscle pain, weakness and passage of dark urine. Muscles Toxins
may be tender and swollen. The most frequently involved Carbon monoxide, heavy metals, snake & insect venom
muscles are in the calves and lower back. Where pressure
necrosis is part of the pathogenesis, there may be overlying Drugs
skin changes. In >50% of cases these ‘local’ manifestations Antipsychotics and antidepressants, sedative hypnotics, statins and
fibrates, theophyllines
may be absent. Urinary myoglobin concentration provides
coloration ranging from pink-tinged through to muddy- Metabolic and endocrine causes
brown/black. Hypo- and hypernatraemia, hypocalcaemia, hypophosphataemia,
hypocalcaemia, hypo- and hyperthyroidism, hyperosmolar conditions
Systemic features include fever, malaise, nausea, vomiting, (HONK)
tachycardia, confusion and agitation. Oliguria/anuria may
be apparent, and severe hyperkalaemia may lead to cardiac Infectious causes
dysrhythmia and arrest. Viruses: influenza and parainfluenza, coxsackie virus, adenovirus,
echovirus, herpes viruses, CMV, HIV, EBV
Laboratory features Bacteria: Streptococcus, Legionella, Salmonella, Staphylococcus,
Laboratory findings confirm the diagnosis and to an extent Listeria, Tularaemia
predict the prognosis in terms of complications. CK levels Other: Falciparum malaria, sepsis syndrome
are the most sensitive indicator of muscle damage and Genetic enzyme deficiencies
begin to rise within 12h of injury, peaking at 1–3 days and Myophosphorylase, phosphorylase kinase, phosphofructokinase,
declining 3–5 days after injury. Supervention of compart- phosphoglycerate mutase, lactate dehydrogenase, carnitine palmityl
ment syndrome may lead to a secondary rise. The peak CK transferase, acyl-coenzyme A dehydrogenase, mycoadenylate
level is said to be predictive of acute renal failure, levels of deaminase
>16 000U/l being more likely to be associated with acute Autoimmune causes
renal failure. Polymyositis, dermatomyositis
Myoglobin has a molecular weight of 18 800Da and in
serum is bound to haptoglobin. Normal plasma levels of
myoglobin are very low (<30mcg/l). When >100g of skele-
tal muscle are damaged, haptoglobin-binding sites are satu- Complications of rhabdomyolysis
rated and myoglobin is filtered and appears in the urine. Early complications
Normal urinary levels of myoglobin are <5ng/ml, visible Potassium, phosphate, creatinine, organic acids, myoglobin
myoglobinuria (tea- or coca-cola-coloured urine) occurs and nucleosides are all released into the circulation. Severe
when levels exceed 250mcg/ml. Myoglobin has a very short hyperkalaemia may lead to cardiac dysrhythmias and even
half-life (2–3h) and serum levels return to normal within cardiac arrest, particularly in association with severe
6–8h. Therefore, although myoglobin may be measured in hypocalcaemia and acidosis.
both blood and urine, the clinical utility of such measure-
ments is questionable.

Early or late complications
Compartment syndrome may occur either early or later in
the course of rhabdomyolysis and may be exacerbated by
hypotension. Fluid sequestration occurs and, as most mus-
cles are within rigid compartments, this oedema leads to a
rise in compartment pressure and impaired perfusion
(compartment syndrome). Compartment pressures
>30mm Hg produce clinically significant muscle ischaemia
and secondary rhabdomyolysis. Prolonged pressure may
also lead to nerve damage.
Late complications
DIC may develop following rhabdomyolysis, usually >72h
following injury. Acute renal failure is the most serious
complication, developing in 16.5% of patients. It results
from a combination of renal vasoconstriction, hypovolaemia,
mechanical obstruction by intraluminal cast formation
and direct cytotoxicity from the haem moiety of myoglobin.
In the presence of low urine flow rates and low urinary
pH, myoglobin interacts with Tamm–Horsfall protein and
precipitates, causing obstructive cast formation. Hyper-
uricaemia and urinary excretion of uric acid exacerbate
tubular obstruction through formation of uric acid casts.
Degradation of precipitated myoglobin initiates lipid per-
oxidation and renal injury, and release of free iron catalyses
free radical production and further enhances ischaemic
damage.
During recovery, hypercalcaemia may occur. Calcium that
has accumulated in muscles at the time of initial muscle
necrosis is released from storage sites during recovery, and
this is enhanced if calcium supplementation has been
administered during the hypocalcaemic stage This can be
associated with hyperparathyroidism and hypervitaminosis
D in some cases, leading to overt hypercalcaemia.
Management of rhabdomyolysis
Initial stabilization and resuscitation, and prevention of
acute renal failure
As much as 10–12l of fluid may be sequestrated in dam-
aged muscle, and IV hydration should be started as early as
possible (Table 29.3.2). In patients with crush injury, this
means implementation of IV therapy even whilst the
patient is still trapped. The longer it takes for rehydration
to be initiated, the more likely it is that acute rebal failure
will supervene.
Rationale for mannitol and bicarbonate therapy
Mannitol is said to increase renal blood flow and the GFR,
potentially suck fluid out of the interstitial compartment
reducing muscle swelling and thus risk of compartment
syndrome, promote a diuresis and prevent precipitation
of obstructive tubular casts, and serve as a free radical
scavenger.
Bicarbonate therapy is said to correct acidosis, reduces risk
of hyperkalaemia and increases urinary pH, preventing pre-
cipitation and degradation of myoglobin in the urinary
tubules.
Both mannitol and bicarbonate therapy are standard
therapy, but neither has been subject to clinical trials.
Observational data suggest that they provide no additional
benefit over and above volume expansion with saline.
Addition of mannitol and bicarbonate had no impact on
development of acute renal failure, need for dialysis or
mortality.
CHAPTER 29.3 Rhabdomyolysis 503
Table 29.3.2. Management of rhabdomyolysis
1. Obtain immediate IV access and start isotonic saline 500ml/h
then titrate to maintain a urine output of 200–300ml/h
2. Consider CVP monitoring (elderly, presence of cardiac failure,
renal failure)
3. Treat any underlying conditions where indicated
4. Add IV sodium bicarbonate and titrate to urinary pH >6.5
where metabolic acidosis and/or hyperkalaemia are present
5. Consider IV mannitol (test dose of 200mg/kg IV over 3–5min
to ensure adequate renal function, then 10ml/h)
6. Monitor for, and treat, complications
7. Repeat CK assay to determine peak CK level
8. Consider fasciotomy in compartment syndrome
Compartment syndrome
Delay in management of compartment syndrome can lead
to irreversible muscle and nerve damage. Neurological
symptoms and signs may indicate the need for fasciotomy,
but measurement of intramuscular pressure provides an
objective guide. Pressures consistently exceeding 30mm
Hg with no tendency to reduce are a clear indication.
Renal replacement therapy
Where acute renal failure is established, or in the presence
of severe hyperkalaemia and acidosis, RRT may be required.
Fluid overload is rarely an indication for RRT in rhabdomy-
olysis. Haemodialysis offers distinct advantages through its
greater efficiency and lack of need for continuous antico-
agulation. Peritoneal dialysis is the least desirable mode of
RRT in patients with rhabdomyolysis due to inefficiency
and difficulties with administration.
Adjuvants
Free radical scavengers and antioxidants and dantrolene
sodium have all been used experimentally, but do not yet
have a proven clinical role.
Further reading
Akmal M, Massry S. Reversible hepatic dysfunction associated with
rhabdomyolysis. Am J Nephrol 1990; 10: 49–52.
Better OS, Stein JH. Early management of shock and prophylaxis
of acute renal failure in traumatic rhabdomyolysis. N Engl J Med
1990; 322: 825–9.
Brown C, Rhee P, Chan L, et al. Preventing renal failure in patients
with rhabdomyolysis: do bicarbonate and mannitol make a differ-
ence? J Trauma 2004; 56: 1191–6.
Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomy-
olysis. Medicine (Baltimore) 1982; 61: 141–52.
Knochel JP. Mechanisms of rhabdomyolysis. Curr Opin Rheumatol
1993; 5: 725–31.
Lane JT, Boudreau RJ, Kinlaw WB. Disappearance of muscular cal-
cium deposits during resolution of prolonged rhabdomyolysisin-
duced hypercalcemia. Am J Med 1990; 89: 523–25.
Orrell RW, Lane RJM. Myoglobinuria. In: Lane RJM, ed. Handbook of
muscle disease. New York: Marcel Dekker, 1996: 607–11.
Ward MM. Factors predictive of acute renal failure in rhabdomyoly-
sis. Arch Intern Med 1988; 148: 1553–7.
Zager RA. Rhabdomyolysis and myohemoglobinuric acute renal
failure. Kidney Int 1996; 49: 314–2.