This article has been corrected. See The dramatic title–Rhabdomyolysis: the hidden killer–given to a
recent review of this condition emphasised that dissolution of striated muscle
fibres, with leakage of muscle enzymes, myoglobin, potassium, calcium, and
other intracellular constituents, can occur in anyone under particular
circumstances and that the consequences can be severe and sometimes
fatal.1 There are no
prospective studies of the incidence of rhabdomyolysis and many mild cases
probably go unrecognised.
Rhabdomyolysis is defined as an acute increase in serum concentrations of
creatine kinase to more than five times the upper normal limit–and when
myocardial infarction has been excluded as a cause (CK-MB fraction less than
5%). Visible myoglobinuria (tea or cola coloured urine) occurs when urinary
myoglobin exceeds 250 μg/ml (normal < 5 ng/ml), corresponding to the
destruction of more than 100 g of
muscle.2,3 Myoglobinuria can be
inferred by a positive urine dipstick test for haem, in the absence of red
cells on microscopic examination of urine.
The causes of rhabdomyolysis are legion, but all lead to a critical
increase in sarcoplasmic calcium and intracellular damage by activation of
calcium dependent proteases and phospholipases. Risk is increased by
pre-existing metabolic factors such as hypokalaemia, hypophosphataemia, and
hyponatraemia. Single episodes are most commonly caused by infections (viral,
bacterial, or other), drugs, or physical factors such as compartment
syndromes, ischaemia, reperfusion (including surgical procedures), and
pressure from hard surfaces in comatose patients. Bywaters and Beall described
the development of acute renal failure following crush injuries sustained in
the London blitz,4 and trauma remains an important cause, although the incidence of
rhabdomyolysis after the attacks on the World Trade Center on 9 September 2001
was low, reflecting the high fatality
rate.5
Severe or unaccustomed exertion, particularly in extremes of heat, is a
common precipitant and has been reported in long distance runners,
bodybuilders, and military recruits, and may also follow prolonged seizures,
certain involuntary movement disorders, and rigors. It is also known to occur
in polo ponies and
racehorses.6,7
Alcohol and opiates are the drugs implicated most
often,8 but all
potentially myotoxic drugs (particularly mixtures of drugs) can induce
rhabdomyolysis, as can drugs that induce states of extreme agitation–as
in the serotonergic syndrome caused by amphetamines and ecstasy.
Rhabdomyolysis is also an important component of the neuroleptic malignant
syndrome, induced by dopaminergic blockade or withdrawal of dopaminergic
agents.
Statins are of particular concern because of their widespread and
increasing use. Myotoxicity occurs in about 0.1% of cases, although
cerivastatin was withdrawn in 2001 because the incidence of myotoxicity with
this drug was some 10 times
greater.9 Drug
interactions particularly with fibrates or drugs that interfere with
cytochrome p450, the main isoenzyme involved in the metabolism of statins,
seem to account for most instances. Reassuringly, fatal rhabdomyolysis due to
statins is now rare and occurs in less than one per million
prescriptions.10 Inflammatory myopathy (“myositis”) is rarely a cause of
rhabdomyolysis, and although routine muscle biopsy may show fibre necrosis and
degeneration, it may be entirely normal.
A history of recurrent episodes, a family history of attacks, or episodes
precipitated by exertion or starvation, increases the probability of a
genetically determined metabolic myopathy. Of these, carnitine palmitoyl
transferase II deficiency is probably the commonest, but rhabdomyolysis can
occur with any of the glycolytic enzyme deficiencies, with fatty acid
oxidation disorders, and with many of the mitochondrial cytopathies.
Susceptibility to malignant hyperthermia may also account for some cases.
However, many cases of recurrent myoglobinuria are deemed idiopathic
(Meyer-Betz disease). No doubt they represent undiagnosed or as yet undefined
forms of metabolic
myopathy.2,3
The immediate consequences of rhabdomyolysis include hyperkalaemia, which
may cause fatal cardiac dysrhythmia, and hypocalcaemia due to calcium binding
by damaged muscle proteins and phosphate.
Acute renal failure results from renal vasoconstriction, intraluminal
myoglobin cast formation, and haem protein
nephrotoxicity.11 No randomised trials of treatment have been conducted, but by consensus the
fundamental management principle is intravascular volume expansion by using
saline and sometimes mannitol to maintain urine output at more than 200-300
ml/hour, with careful monitoring of sodium and calcium concentrations.
Alkalinising the urine by using sodium bicarbonate can reduce the risk of
tubular obstruction by myoglobin casts. However, myoglobin is also
intrinsically nephrotoxic and can precipitate acute tubular necrosis through
iron dependent inhibition of oxidative phosphorylation and iron independent
inhibition of
gluconeogenesis.12
In some experimental models, haem protein cytotoxicity could be blocked by
iron chelators and
glutathione,11,12 but this has not been
evaluated clinically. Dantrolene sodium blocks the release of calcium from the
sarcoplasmic reticulum and can reduce calcium mediated myolysis. Occasionally
fasciotomy may be required to prevent irreversible peripheral nerve injury by
muscle swelling in tight fascial
planes.2,3 Disseminated
intravascular coagulopathy is rare in uncomplicated rhabdomyolysis but may
occur in more complex cases–for example, with associated sepsis. When
renal failure ensues despite these measures, continuous haemofiltration or
haemodialysis will be required. The prognosis should be excellent providing
the causative mechanism for the rhabdomyolysis is identified and reversed
where possible.