Welcome to my rhabdomyolysis page. This is actually a copy of an assignment I did for my fourth year medicine neuropathology course back in 1997. Whilst doing this assignment I found that there was not much information about this topic on the web, so I thought it might be useful to put online. So here it is, everything I was able to find about rhabdomyolysis. I hope you find it helpful. If you would like more information please speak to your doctor. I am not a specialist in this area and would not be of any help beyond what I have put in this web page, which was done quite a while back, and has not been revisited since. Nevertheless, I hope this information is of value.

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Rhabdomyolysis is a common disorder which may result from a large variety of diseases, trauma, or toxic insults to skeletal muscle. It may be defined as a clinical and biochemical syndrome resulting from an injury which damages the integrity of the sarcolemma of skeletal muscle, leading to the release of potentially toxic muscle cell components into the circulation.(1,2,3) This may result in potential life-threatening complications including myoglobinuric acute renal failure, hyperkalaemia and cardiac arrest, disseminated intravascular coagulation, and more locally, compartment syndrome.

The primary diagnostic indicator of rhabdomyolysis is an elevated serum creatine phosphokinase (CK) to at least five times the normal value.(2) This elevation is generally to such a degree that myocardial infarction and other causes of a raised CK are excluded. Additionally, the CK-MM isoenzyme predominates in rhabdomyolysis, comprising at least 98% of the total value.(4) The other important finding frequently seen in rhabdomyolysis is myoglobinuria. Myoglobin, a haem protein which functions as an oxygen store in type 1 skeletal muscle fibres, normally has a rapid renal clearance which maintains a low plasma level up to a certain serum concentration.(5) As myoglobin is released into the circulation from necrotic muscle cells it first becomes detectable in the urine at serum concentrations ranging from 300ng/ml to 2 g/ml and produces visible pigmenturia (classically a "coca-cola" coloured urine) at concentrations exceeding 250 g/ml.(6) This discolouration is caused by myoglobin plus metmyoglobin in the urine.(7) Biochemical tests for pigmenturia are strongly suggestive of myoglobinuria in the absence of haemoglobinaemia and haematuria.(7) Other important biochemical findings in rhabdomyolysis include hyperkalemia, hypocalcaemia, hyperphosphataemia, hyperuricaemia, and raised levels of other muscle enzymes including lactate dehydrogenase, aldolase, aminotransferases, and carbonic anhydrase III (which is a very specific marker for skeletal muscle injury).(2) Metabolic acidosis may result from release of phosphate, sulphate, uric acid, and lactic acid from the muscle cell.(1)

The causes of rhabdomyolysis can be broadly divided into hereditary (table 1) and acquired (table 2) groups. The hereditary causes consist primarily of enzyme defects causing disorders of carbohydrate metabolism(8), mitochondrial lipid metabolism(8), and other inherited disorders such as malignant hyperthermia (8,9) and neuroleptic malignant syndrome(10).

Table 1 : Inherited causes of rhabdomyolysis. (from Poels and Gabreels
(1993) Clin Neurol Neurosurg 95 : 175-192.

Deficiencies of glyco(geno)lytic enzymes
myophosphorylase (McArdle's disease)
phosphorylase kinase
phosphofructokinase (Tarui's disease)
phosphoglycerate mutase
phosphoglycerate kinase
lactate dehydrogenase

Abnormal Lipid Metabolism
carnitine palmitoyltranferase deficiency I and II
carnitine deficiency

Other genetic disorders
idiopathic rhabdomyolysis
myoadenylate deaminase deficiency
malignant hyperthermia
neuroleptic malignant syndrome

Acquired causes may be divided into traumatic, ischaemic, metabolic, infectious, inflammatory, and toxic groups(table 3) (11), as well as exercise and heat related causes.

Table 2 : Acquired causes of rhabdomyolysis. (from Poels and Gabreels
(1993) Clin Neurol Neurosurg 95 : 175-192.

drugs and toxins (see Table 3)

Excessive muscle exercise
sports and military training
status epilepticus
status asthmaticus
prolonged myoclonus, acute dystonia

Direct muscle injury
burning, freezing
electric shock, lightning stroke

Ischemic injury
vascular occlusion
sickle cell trait

Metabolic disorders
diabetic ketoacidosis
nonketotic hyperosmolar coma


Heat-related syndromes
toxic shock syndrome
heat stroke

Inflammatory myopathies

anticholinergic syndrome
withdrawal of L-Dopa

Table 3 : Drugs and toxins known to cause rhabdomyolysis. (11)

Drug-induced coma, seizures,dyskinesia Other drugs
Barbiturates Amphetamines
Heroin Phenmetrazine
Methadone Phencyclidine
Glutethimide Phenylpropanolamine
Chlorpromazine Morphine
Diazepam Dihydrocodeine
Rohypnol LSD
Lithium Salicylates
Amoxapine Clofibrate/Bezafibrate
Phenelzine` Epsilon-aminocaproic acid
Phenformin/fenfluramine Isoniazid
Meprobamate Loxapine
Antihistamines/paracetamol Theophyllin
Oxprenolol Pentamidine
Ethanol Vasopressin

Post-anaesthetic Toxins
Suxamethonium Ethanol
Malignant hyperpyrexia Isopropyl alcohol
Carbon monoxide

Neuroleptic malignant syndrome Mercuric chloride
Haloperidol Ethylene glycol
Stelaziine Copper sulphate
Fluphenazine Zinc phosphide
Other neuropleptics Strychnine

Hypokalaemia Paraphenylenediamine
Diuretics Toluene (paint sniffing)
Carbenoxolone Gasoline sniffing
Amphotericin B Lindane/benzene
Liquorice Snake bite
Hornet/wasp sting
Brown spider bite
Haff disease
Quail ingestion

Although the causes of rhabdomyolysis are so diverse, the pathogenesis appears to follow a final common pathway, ultimately leading to muscle necrosis and release of muscle components into the circulation. Whatever the injurious process, the end result is an increased cellular permeability to sodium ions due to either plasma membrane disruption or reduced cellular energy (ATP) production.(1) Accumulation of sodium in the cytoplasm leads to an increase in intracellular calcium concentration (which is normally very low relative to the extracellular concentration).(2) This accumulation of calcium is due both to direct injury to the cell and to increased activity of an Na+/Ca2+ exchanger protein which brings more calcium into the cell as it attempts to remove the excess sodium. Depletion of ATP also contributes directly to calcium accumulation due to a reduction in the activity of the Ca2+ ATPase which normally acts to pump calcium out of the cell and sequester it in the sarcoplasmic reticulum.(3)
Therefore, the common pathogenetic feature of all disease processes causing rhabdomyolysis is an acute rise in the cytosolic and mitochondrial calcium concentration in affected muscle cells, which sets off a chain of events that ultimately results in muscle cell necrosis. This includes activation of degradative enzymes such as phospholipase A2 (PLA) and neutral proteases, leading to membrane phospholipid and myofibril damage.(3) Jackson et al. (12) suggest that the most significant of these is activation of PLA, and that most of the membrane and mitochondrial damage in rhabdomyolysis can be attributed to this. PLA mediated attack on mitochondrial and sarcolemmal membrane phospholipids leads to the formation of lysophospholipids and free fatty acids. These further potentiate the injury by causing direct membrane damage themselves and through alterations in ionic transport, which results in further influx of sodium and calcium.(3) Thus the reaction becomes self-perpetuating. Depletion of ATP and mitochondrial damage may be the primary event which sets off this cascade (as in most hereditary causes of rhabdomyolysis and exertional rhabdomyolysis) or it may occur secondarily to the rise in calcium concentration. Either way, mitochondrial damage and depletion of ATP contributes to the pathogenesis via the following :
(1) Failure of Ca2+ ATPase leading to failure of calcium sequestration and reduced efflux of calcium from the cell.
(2) Failure of Na+/K+ ATPase leading to increased intracellular sodium and increased Na+-Ca2+ exchange, further contributing to the increased intracellular calcium.2
(3) Generation of toxic oxygen free radicals such as superoxide causes further cellular damage.(3)

A simple schematic representation of these processes is shown in Figure 1 . Ultimately, the combination of all of these processes is a self-sustaining reaction which results in muscle cell lysis (figure2) and release of intracellular components into the extracellular fluid and circulation.(3) Locally, accumulation of these products may result in microvascular damage, capillary leak and increased intracompartmental pressures, and reduced tissue perfusion and ischaemia, which may further potentiate the muscle damage.

As has already been stated, there are many different causes of rhabdomyolysis, and although the final reaction is fairly stereotyped, the mechanism by which this reaction is triggered is quite variable. I will now discuss some of the specific hereditary and acquired causes of rhabdomyolysis in more detail.

Disorders of Muscle Carbohydrate Metabolism
The first genetic disease described which causes rhabdomyolysis is McArdle's disease (myophosphorylase deficiency), an autosomal recessive condition in which there is selective necrosis of type 2 muscle fibres.(8) These fibres are more dependent on glyocolysis for generation of ATP and therefore will be more sensitive to an enzyme defect which prevents the formation of glucose from glycogen. Hence it is ATP depletion which is responsible for rhabdomyolysis in this disease. Muscle pain and rhabdomyolysis are induced by vigorous exercise,and relieved by rest in this disease, consequently patients can adjust their life styles to prevent symptoms by avoiding vigorous exercise which requires activation of type 2 fibres. Other inherited diseases affecting the glycolytic/ glycogenolytic pathways include
phosphofructokinase deficiency (Tarui's disease), and phosphoglycerate mutase deficiency.(8)

Carnitine Palmitoyltransferase Deficiency
Where the disorders of carbohydrate metabolism affect primarily anaerobic type 2 muscle fibres, diseases of lipid metabolism such as Carnitine palmitoyltransferase deficiency (CPD), have a greater effect on aerobic type 1 fibres which depend on the oxidation of long chain fatty acids to produce energy. CPD, an autosomal recessive disorder, has been shown to be the most common hereditary disease causing rhabdomyolysis.(3) In this disease muscle pain and rhabdomyolysis develop after prolonged exercise with inadequate nutrient intake, not in the initial phase as in the glycogen storage disorders. Treatment of this disease involves frequent high carbohydrate meals and avoidance of prolonged exercise.(8)

Malignant Hyperthermia
Another genetic disease which may result in rhabdomyolysis is malignant hyperthermia (MH) (Figure 3). In this disease, episodes of hyperthermia and rhabdomyolysis are triggered by exposure to volatile anaesthetics such as halothane, or succinylcholine, a depolarising muscle relaxant.(9) MH appears to be an autosomal dominant condition with variable penetrance(7), and may involve a defect in the ryanodine receptor of the calcium release channel of the sarcoplasmic reticulum.(7) These patients have higher than normal resting sarcoplasmic calcium concentrations, and exposure to the above agents may trigger further uncontrolled calcium release, leading to excessive muscle contraction, hyperthermia, and rhabdomyolysis.(8) The diagnosis of MH susceptibility can be made only by muscle biopsy and a positive in vitro response to provocative agents such as halothane, succinylcholine, and caffeine. This in vitro response shows a patchy, moth-eaten appearance of type 1 fibres(13) (Figure 4). Type 1 fibres are predominantly affected in MH due to their lower capacity for anaerobic metabolism, and therefore more rapid ATP depletion in the hypermetabolic state of MH.

Neuroleptic Malignant Syndrome
A similar disorder is the Neuroleptic Malignant Syndrome (NMS), in which there is a gradual development of hyperthermia, muscle rigidity, fluctuating consciousness, and autonomic instability.(10) Rhabdomyolysis and myoglobinuria may result. Drugs which can cause NMS include phenothiazines, butyrophenones, and other antipsychotics and antidepressants. It is believed that the underlying defect in NMS may be a central or presynaptic one, in contrast to the peripheral defect in MH. (10)

There are also many non-hereditary causes of rhabdomyolysis, which are much more common than the hereditary causes.

Exertional Rhabdomyolysis
Exertional rhabdomyolysis and heat stroke are probably the most common causes of severe rhabdomyolysis. This occurs most commonly in untrained people undertaking vigorous exercise in hot, humid weather.(3) The pathogenesis of rhabdomyolysis in these cases appears to be due to a combination of mechanical and thermal muscle injury and ATP depletion, both of which ultimately lead to calcium accumulation. Excess muscle activity may also lead to rhabdomyolysis in conditions such as generalised seizures, status epilepticus, status asthmaticus, myoclonus, and severe dystonia. (2)

Crush Injury and Trauma
In crush injury and other forms of trauma, rhabdomyolysis is generally due to direct muscle injury and ischaemia. However, in addition to this, in the crush injury, reperfusion after prolonged ischaemia is also believed to play a significant role in muscle damage.(14) This is believed to be mediated by the formation of oxygen free radicals, the action of granulocytes, and increased calcium uptake after ischaemia (which is due to exchange of calcium for excess intracellular sodium which has accumulated during the ischaemic period).

Alcoholism is another common cause of rhabdomyolysis. This may be secondary to to alcohol related trauma, seizures, or coma, or may be due to a direct toxic effect of ethanol on skeletal muscle, resulting in both a chronic myopathy, and acute rhabdomyolysis.(3)It is believed that ethanol causes direct sarcolemmal injury, leading to increased sodium permeability, and subsequent accumulation of calcium.1 Hypophosphataemia may be an important precipitant of rhabdomyolysis in alcoholics, since the ability of muscle cells to produce ATP would be reduced. (4)

Drugs and Toxins
A large range of drugs and toxins have been seen to cause rhabdomyolysis. Many of these are listed in Table 3. The mechanisms of muscle damage in these instances are diverse.
Some drugs appear to have a direct toxic action on skeletal muscle when given systemically. These include cholesterol lowering drugs (clofibrate, gemfibrozil, HMG CoA reductase inhibitors), emetine (ipecac), zidovudine (AZT), vincristine, and epsilon-aminocaproic acid(Figure 5).(15,11)
An immunological mechanism may be responsible for the myositis seen in patients treated seen in patients treated with D-penicillamine, L-tryptophan, and rarely in other drugs including procainamide, cimetidine, phenytoin, and levodopa.(11)
Amphotericin B, carbenolexone, liquorice, laxatives, and diuretics may cause rhabdomyolysis secondary to sever hypokalaemia.(11)
Another mechanism by which drugs may cause rhabdomyolysis is by excessive neuromuscular stimulation. These drugs include phencyclidine (PCP), and acetylcholinesterase inhibitors.(11)
Drugs such as heroin and barbiturates may contribute to rhabdomyolysis via coma and muscle compression following overdose.(2)
In addition to the range of pharmacologic agents which cause rhabdomyolysis, it can also be caused by the venoms of a number of snakes, spiders, and wasps.(11) Microbial toxins such as the a-toxin of Clostridium perfringens (gas gangrene), can also cause rhabdomyolysis, as can excessive consumption of quail. (11)

The clinical features of rhabdomyolysis are quite variable, no doubt due to the large range of causes of this condition. Broadly, they can be divided into the following2 :
(1) Muscular signs and symptoms
(2) General internal disturbances
(3) Complications

Muscular signs and symptoms
These include pain, weakness, tenderness, and contractures. This may involve specific groups of muscles or may be generalised. Most frequently the involved muscle groups are the calves and lower back, however a significant proportion may show no signs of muscle injury at all.(16) Sometimes haemorrhagic discolouration of the overlying skin may be seen. Typically the muscle disorder is self-limiting and resolves within days to weeks, due to the regenerative capacity of muscle.

General internal disturbances
These include malaise, fever, tachycardia, nausea, and vomiting. Hyperuricaemia may lead to encephalopathy with depression of respiration with hypoxia and respiratory acidosis. (2)

The complications of rhabdomyolysis are due to the local effects of muscle injury, and the systemic effects of released muscle components. These include :

(1) Hypovolaemia - due to haemorrhage, and influx of fluid into necrotic muscle. 4-11 litres of normal saline may be required to maintain cardiac and urine output. (2,16)

(2) Cardiac arrest and arrhythmias - Hyperkalaemia can precipitate severe arrhythmias and cardiac arrest. This toxicity is potentiated by the hypocalcaemia resulting from calcium deposition in necrotic muscle. Therapy often involves the use of ion exchange resins.

(3) Compartment Syndrome - (Figure 6)in acute rhabdomyolysis muscle swelling within a tight fascial compartment can lead to compression of vessels and nerves. This can lead to nerve damage and muscle ischaemia due to reduced capillary flow. Ischaemia will result in further oedema which prolongs the cycle. Prolonged ischaemia and infarction of muscle tissue can result in replacement of muscle by inelastic fibrous tissue and severe contractures (Volkmann's contracture).(17,2) The treatment of suspected compartment syndrome is urgent decompression by open fasciotomy.

(4) Disseminated intravascular coagulation - this is an almost universal finding in patients with rhabdomyolysis (18) and is probably due to activation of the clotting cascade by released muscle components. Fortunately, in most cases, the diagnosis of DIC is made purely by laboratory abnormalities rather than overt clinical bleeding or thrombosis.(16)

(5) Acute Renal Failure - this is probably the most significant and most feared complication of rhabdomyolysis, and is said to occur in about 30% of patients.(16) Conversely, rhabdomyolysis has been said to be a factor in 8% of cases of acute renal failure2 so this is by no means an uncommon condition. The mechanisms of myoglobinuric acute renal failure have been comprehensively explored by Zager (1996) (3) and include the following :

(1) Renal vasoconstriction/hypoperfusion - due to hypovolaemia and haem- protein induce renal tubular ATP depletion
(2) Haem protein cast formation - precipitation of pigment casts in distal tubules may contribute to acute tubular necrosis, especially in aciduria
(3) Ischaemic tubular injury - independent of haemodynamic influences, haem protein can potentiate proximal tubular ischaemic damage
(4) Haem iron induced oxidant stress - intratubular release of haem iron catalyses formation of toxic oxygen free radicals

Prevention of myoglobinuric ARF involves maintenance of circulating blood volume by adequate fluid replacement of up to 11 litres of normal saline. (2) Administration of frusemide and/or mannitol is used to maintain a diuresis and enhance haem protein elimination. Alkalinization of the urine by the addition of sodium bicarbonate to the intravenous fluids has been suggested (since acidic urine favours myoglobin nephrotoxicity) however this is controversial since bicarbonate may aggravate existing hypocalcaemia. (2,3)

Rhabdomyolysis is a common condition which complicates a a variety of genetic and acquired diseases. It is characterised by muscle cell necrosis and release of muscle cell components into the circulation, most notably creatine phosphokinase (CK) and myoglobin. The primary mechanism through which muscle damage occurs in rhabdomyolysis is sarcoplasmic calcium overload leading to activation of degradative enzymes. This may occur secondary to a number of processes including ATP depletion and increased intracellular sodium concentration, and direct sarcolemmal injury. The complications of rhabdomyolysis can be potentially life threatening, and include cardiac arrest and myoglobinuric acute renal failure. Prompt action must be taken to prevent these complications in a patient with rhabdomyolysis, most importantly aggressive intravenous volume replacement.


1. Knochel, J.P. (1993) Mechanisms of rhabdomyolysis. Current Opinion in Rheumatology 5: 725-731.

2. Poels, P.J.E and Gabreëls, F.J.M. (1993) Rhabdomyolysis : a review of the literature. Clin Neurol & Neurosurg 95: 175-192.

3. Zager, R.A. (1996) Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney International 49 : 314-326.

4. Knochel, J.P. (1992) Hypophosphataemia and rhabdomyolysis. JAMA 92: 455-457.

5. Dayer-Berenson, L. (1994) Rhabdomyolysis : A comprehensive guide. ANNA Journal 21(1): 15-18.

6. Penn, A.S. (1986) Myoglobinuria. In: Engel, A.G, and Banker, B.Q. (Eds) Myology, Vol 2. New York : McGraw-Hill, 1785-1805.

7. Moxley, R.T. (1994) Metabolic and endocrine myopathies. In: Walton, J., Karpati, G., and Hilton-Jones, D. (Eds) Disorders of Voluntary Muscle (6th ed). New York : Churchill Livingstone, 647-716.

8. Brumback, R.A., Feeback, D.L., and Leech, R.W. (1992) Rhabdomyolysis in childhood. Paediatric Neurology 39(4) : 821-858.

9. Gronert, G.A. (1986) Malignant Hyperthermia. In: Engel, A.G, and Banker, B.Q. (Eds) Myology, Vol 2. New York : McGraw-Hill, 1763-1784.

10. Guzé, B.H. and Baxter, L.R. (1985) Neuroleptic Malignant Syndrome. NEJM 313(3): 163-166.

11. Kakulas, B.A. and Mastaglia, F.L. (1992) Drug-induced, toxic and nutritional myopathies. In: Mastaglia, F.L. and Walton, J. (Eds) Skeletal Muscle Pathology (2nd ed). New York : Churchill Livingstone, 511-540.

12. Jackson, M.J., Jones, D.A., and Edwards, R.H.T. (1984) Experimental skeletal muscle damage : the nature of the calcium activated degenerative processes. Eur J Clin Invest 14: 369-374.

13. Anderson, J.R. (1985) Atlas of Skeletal Muscle Pathology. Lancaster : MTP Press.

14. Odeh, M. (1991) The role of reperfusion-induced injury in the pathogenesis of the crush syndrome. NEJM 324(20) : 1417-1422.

15. Argov, Z. and Mastaglia, F.L. (1994) Drug-induced neuromuscular disorders in man. In: Walton, J., Karpati, G., and Hilton-Jones, D. (Eds) Disorders of Voluntary Muscle (6th ed). New York : Churchill Livingstone, 989-1029.

16. Saad, E.B. (1997) Rhabomyolysis and Myoglobinuria. (internet reference : http://www.medstudents.com.br/terin/terin3.htm)

17. Apley, A.G. and Solomon, L. (1994) Concise System of Orthopaedics and Fractures. Oxford : Butterworth-Heinemann.

18. Knochel, J.P. (1990) Catastrophic medical events with exhaustive exercise : "White collar rhabdomyolysis". Kidney International 38: 709-719.

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NOTE : To any fourth year UWA medical students contemplating plagiarising this page to use as your assignment, please think again. I put this page up to make up for the lack of information about rhabdomyolysis on the Web, and a lot of people have benefitted from it. Feel free to use this information as part of your own research, just don't copy it verbatim to save yourself getting in trouble. Thanks.