Rhabdomyolysis has been defined as the dissolution that leads to a “nonspecific clinical syndrome causing extravasation of toxic intracellular contents from the myocytes into the circulatory system” ((Alterman, 2007, p 64). I am pursuing this subject for my critical review. Searching for the matter related to rhabdomyolysis was interesting and revealed a large amount of literature related to the subject. I have selected some for my review. They are all articles from peer reviewed journals. The significance of looking out for rhabdomyolysis and making a timely diagnosis has been mentioned in all the articles.
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Timely and aggressive interventions are absolutely necessary for saving the life of a patient. Starting with the pathophysiology, I have gone on to review the various articles on rhabdomyolysis which provide a better picture of the illness.
Rhabdomyolysis has been recognized as a serious medical emergency right from the days of the Second World War. Bombings caused huge buildings to collapse on soldiers and civilians alike. Massive crush injuries were the result. Originally rhabdomyolysis was known to be caused by trauma. The concept has changed. (Alterman, 2007). Non traumatic causes now account for more rhabdomyolysis than traumatic causes. Clinical findings confirmed by lab findings clinch the diagnosis.
The causes are so varied that prevalence or incidence of rhabdomyolysis is difficult to gauge at any point of time. The rhabdomyolysis occurs only as a part of the illness and hence may not be recorded as such. Many researches based on the causes and resulting rhabdomyolysis are discussed here.
No statistics are available on this illness, probably due to the several varying and unrelated causes for the condition.
Etiology and Pathophysiology
Causes can be hereditary or acquired. The hereditary ones include a lack or insufficiency of various enzymes that participate in the catabolism of the energy molecules (Giannoglou, 2006, p 93). McArdle’s Disease, which is related to rhabdomyolysis, has reduced quantities of muscle phosphorylase which is necessary for glycogenolysis (Giannoglou, 2006, p 94). The acquired causes are traumatic and non traumatic.
The acquired traumatic causes could be accidents, crush injuries, natural disasters and severe muscular exertion (Giannoglou, 2006, p 94). The muscle injury is direct and there is a rupture of the sarcolemma. Due to the transmembrane chemical gradient, ionized calcium would enter the cell in massive proportions. In addition increased heat production as in exercise would worsen the condition and disturb the energy production of the cell (Giannoglou, 2006, p 94).
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The non traumatic causes are most frequent in peacetime or when there is no war.
The leading causes are due to alcohol abuse, drugs like hypolipidemic agents, antipsychotics and diuretics, seizures and coma (Giannoglou, 2006, p 94). Ischaemic-origin rhabdomyolysis is caused by reducing the oxygen supply necessary for production of energy (Giannoglou, 2006, p 94). Infections and inflammatory myopathies release toxins which stimulate the production of cytokines which directly disrupt the cellular membrane (Giannoglou, 2006, p 94). Metabolic and electrolyte disorders cause a deficiency of mitochondrial enzymes which facilitate the oxidative phosphorylation and production of ATP or energy. Drugs and temperature syndromes either block the production of energy or cause membrane lysis (Giannoglou, 2006, p 94).
Pathophysiology involves an increase in the intracellular free ionized calcium by cellular energy depletion or direct plasma membrane rupture (Giannoglou, 2006, p 90). This calcium activates many processes within the muscle finally leading to its death. It activates proteases, enhances the contractility of the skeletal muscle, triggers mitochondrial dysfunction and elevates the production of reactive oxygen species.
The causes are numerous but the final pathogenetic pathway is the same (Giannoglou, 2006, p 94). When cell death occurs, the lysis of muscle cells occur and their toxic content would be released into the extracellular fluid (Giannoglou, 2006, p 95). The toxic materials damage nearby capillaries and cause oedema and ischaemia finally. This further exacerbates the energy depletion and further ischaemia is the result. Circulating leucocytes adhere to the injured capillaries and migrate to the destroyed muscle cells to release reactive oxygen species and proteases in the reperfusion state. Cellular impairment worsens. The muscle cells are damaged in the reperfusion state of the cell paradoxically (Giannoglou, 2006, p 95).
Homeostasis of intracellular calcium
The integrity of the muscle cell membrane when affected causes the increased permeability of the membrane. The large amount of free ionized extracellular calcium
is 10000 times higher than the intracellular calcium (Giannoglou, 2006, p 91). Any change in permeability causes a chemical gradient of calcium into the cell causing the functional integrity to suffer (Giannoglou, 2006, p 91). The homeostasis is upset. It has special regulatory proteins to overcome this. The non-membrane proteins are soluble in the plasma. The transmembrane proteins are the main regulators of cell calcium concentration.
They have several carrier proteins located at the plasma membrane of the muscle cell or sarcolemma or on the membranes of the intracellular organelles like the sarcoplasmic reticulum or the mitochondria (Giannoglou, 2006, p 91).
The plasma membrane carrier proteins have the calcium channels, the sodium-calcium exchangers, and the calcium pump. The channels and the exchanger facilitate the energy- consuming entry of calcium into the cytoplasm. The pump facilitates the energy consuming transportation of calcium outside the cell into the extracellular space (Giannoglou, 2006, p 93). The pump at the sarcoplasmic reticulum allows the entrance of calcium whereas the calcium release into the cytoplasm occurs through a complex transmembrane transportation system. The calcium is carried into the mitochondria through a uniporter system and released into the cytoplasm by the exchanger (Giannoglou, 2006, p 93).
Increase in intracellular calcium
The causes of increased intracellular calcium are many. The common basis for all the mechanisms is the either the energy depletion in the muscle cell or the rupture of the plasma membrane (sarcolemma) (Giannoglou, 2006, p 93).
Clinical Presentation of Rhabdomyolysis
Though clinical features vary, the typical triad is muscular pain, weakness and reddish brown urine. The pain is usually in the central muscle group and involves thighs and shoulders. The best diagnostic tool is the myoglobinuria as seen from the reddish urine and confirmed in the lab. The final diagnosis is by the lab findings (Giannoglou, 2006, p 96). In severe cases, malaise, fever, nausea and tachycardia are seen.
Macroscopic picture is a reddish brown urine. The pH is acidic. Detection of myoglobin clinches the diagnosis (Giannoglou, 2006, p 96). Microscopic examination shows a few RBCs. Immunoassay and radioimmunoassay establish the diagnosis of myoglobinuria. Sediment would show dead epithelial cells and myoglobin casts.
Biochemical results would show increased levels of serum CPK which is the diagnostic feature. Hyperkalaemia is the most life threatening electrolyte imbalance. Phosphorus mand uric acid levels would be increased in the blood. Metabolic acidosis is seen. The serum urea /creatinine ratio which is usually 10:1 becomes 5:1 or less.
Critical review of associated Literature
Prolonged Surgery and Rhabdomyolysis (Alterman, 2007)
The postoperative period of a young patient, who had undergone a prolonged urological procedure, was wrought with the complication of rhabdomyolysis. The position of the patient on the operation table was the left lateral decubitus. The 22 year old was previously healthy except for nephrolithiasis (Kidney stone) and a ureteric stricture which arose from ureterocalicostomy surgery as a child. Preoperatively all his urine and blood examinations revealed normal results : urinalysis and measurements of complete blood count, serum electrolytes, blood urea nitrogen, serum creatinine, blood creatine phosphokinase (CPK), and liver enzymes (Alterman, 2007, p 65).
Medication did not include nephrotoxic ones. The repeat ureterocalicostomy lasted nine hours due to technical difficulties. Hypodynamic stability was maintained. Total fluid input and output, oxygenation and ventilation and nasopharyngeal temperatures were normal. Blood transfusion was not required. The neuromuscular block by neostigmine and atropine was reversed successfully.
In the Post Anesthesia Care Unit, the vital signs remained normal (Alterman, 2007, p 65). The only complaint was an oedematous and reddish left thigh which was producing severe pain. The CPK value was highly elevated. The blood gas analysis showed changes of metabolic acidosis. A rhabdomyolysis due to muscle injury of the left thigh was diagnosed (Alterman, 2007, p 65). The cause was prolonged pressure of the left thigh against the table in the left lateral position. Due treatment was provided. The patient was monitored closely and was discharged after a week. Blood results were all normal.
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The extended period of immobilization had caused tissue compression in this obese youth. Other causes of rhabdomyolysis in surgery are “malignant hyperthermia, hypoperfusion, urological surgical procedures (nephrectomy), intense vasospasm in hypertensive crisis and bariatric surgery” (Alterman, 2007, p 66). Compartment syndrome is a cause and complication of rhabdomyolysis due to reduced circulation in the compartment. When recirculation occurs in the reperfusion state, toxic intracellular contents are released into the circulation causing rhabdomyolysis (Alterman, 2007, p 66).
Unusual positioning has been associated with skeletal muscle injury (Alterman, 2007, p 66). Compartment syndrome and rhabdomyolysis have a greater risk of occurrence if associated with factors like obesity, peripheral vascular disease and prolonged operation time. Intermittent CPK evaluations could warn us of changes due to rhabdomyolysis in prolonged operations. Once diagnosed, treatment should be aggressive (Alterman, 2007, p66).
Burns and Rhabdomyolysis (Lee, 2005)
The skin is a protective covering for the body. It prevents bacterial invasion and plays the role of a vital barrier for maintaining fluid homeostasis (Lee, 2005, p638).
40% of the total body mass is subcutaneous tissue (Lee, 2005, p634). Flame burns causes extensive damage in the form of necrosis to vital tissues including the total thickness of skin, subcutaneous fat, muscles, nerves, blood vessels and bone. The protective barrier is lost. Fluid homeostasis is disturbed. Rhabdomyolysis occurs with the release of toxic components into the circulation (Lee, 2005, p634).
The usual treatment for rhabdomyolysis hardly works here. The prognosis is poor. Rhabdomyolysis causes hypovolaemia, hemoglobinuria, myoglobinuria, oliguria and finally renal failure. Burns patients have adult respiratory distress syndrome caused by inhalation injury. The patients with severe burns die of multiple organ failure and respiratory failure. Very early and vigorous therapy needs to be instituted at the site of occurrence itself to sustain circulation (Lee, 2005, p634).
A 25 year old woman substance abuser, sustained burns including inhalation injury when she was in a half- confused state in a closed room (Lee, 2005, p634)
She was diagnosed as having rhabdomyolysis and acute adult respiratory syndrome. The deep burns constituted 10% of total body surface area and the mixed thickness burn was 5%. The flame burns caused vital tissue necrosis. Vigorous hydration and urinary alkalinisation were used to prevent renal failure. By the fifth day she developed oliguria and tachypnoea. However on the ninth day she showed signs of recovery. Split-thickness skin grafts were used to cover the burnt area.
The diagnostic features of rhabdomyolysis were the extensive muscle damage with increased levels of serum CK and pigmenturia and the detection of urinary myoglobin. (Lee, 2005, p637). An assessment says that destruction of 2 gm. of skeletal muscle can produce an elevation of CK by 10 times. Severity, survival and mortality are related to myoglobinemia, myoglobinuria and CK levels which are good biological markers of extent and depth of muscle damage.
A highly elevated CK (creatine kinase) level predicts the onset of renal failure (Lee, 2005, p 637). Mortality for rhabdomyolysis secondary to flame burns is high. Fluid resuscitation in burns requires an amount of fluid much greater than that recommended by the Parkland formula (Lee, 2005, p638). Ringer lactate solution is used for fluid replacement to produce a urinary output of 1-1.5 ml /kg/minute. If urine output is not satisfactory, loop diuretics and mannitol are used. Urinary alkalinization is done by using sodium bicarbonate (3 ampules in 1 L 5% dextrose in water). This reduces the nephrotoxicity caused by myoglobinuria.
Emergency haemodialysis is the only option in fatal rhabdomyolysis (Lee, 2005, p638). Progressive renal failure, refractory pulmonary oedema, severe acid-base disturbances and hyperkalaemia are the indications for haemodialysis. The necrotic tissue must be surgically removed as early as possible. Lee concludes that the management of fatal rhabdomyolysis is yet to be standardized (2005, p638).
Hypothermia and rhabdomyolysis with anti-psychotic drug Olanzapine (Hung, 2008)
Anti-psychotic drugs sometimes produce hypothermia and rhabdomyolysis.
The agitation associated with schizophrenia and bipolar I disorder is treated with the short-acting intramuscular injection of Olanzapine (Hung, 2008, Pg.1). However this treatment has to be carefully instituted in adolescents. Oral Olanzapine also has caused hypothermia in old patients and who have had other illnesses. Rhabdomyolysis has been reported with Olanzapine. Occurrences of the two complications together with anti-psychotic drugs have not been reported (Hung, 2008, p 1).
A 17 year old Chinese youth was admitted for a first episode of psychosis to the acute care ward. He had auditory hallucinations, bizarre delusions, disorganized speech, irritability and violent behavior of one month. Based on the DSM IV criteria, he was diagnosed to be having schizophreniform disorder (Hung, 2008, p1). He was absolutely healthy otherwise and his vital signs were normal. Body temperature was normal too (36.5°C.). Physical and lab examinations were normal. After 3 weeks, he still showed no response.
He was switched to oral olanzapine. Though he slept for a short while, he got up agitated. Then he was given an intramuscular injection of 5mg. He was found drowsy, drooling, hypothermic (34.9°C) and hypotensive (90/50 mm Hg.) after 2 hours. Normal muscle tone was present but a mild hand tremor was noticed on neurological examination (Hung, 2008, p1). Blood examination showed an abnormal increase of CK (5525 U/L (normal 15–130 U/L), myoglobin 732.6 μg/L (normal b80 μg/L) and hepatic aspartate transferase 68 U/L (normal 13–40 U/L) while other results were normal (Hung, 2008, p 2). Urine examination was normal. Electrocardiogram showed a sinus bradycardia.
The brain magnetic resonance imaging showed no abnormalities. However the CK went on rising to 6026 U/L. All medications were stopped. Hypothermia was treated by heating lamps. Alkalinised fluid was given intravenously for forced diuresis. The body temperature reached normal at 36.3°C and his consciousness became clearer (Hung, 2008, p 2). Within 3 days he had to be started on drugs due to his psychosis. By 2 weeks his lab results were normal. His oral treatment was stepped up. Follow up for the next seven months did not show a repeat of the hypothermia and rhabdomyolysis.
CK diffuses across the cell membrane as there is a very high transmembrane gradient into the circulation in rhabdomyolysis and the mechanism for this increased membrane permeability is due to 5-HT2A receptor blockade (Hung, 2008, p 2). Olanzapine binds to the 5-HT2A receptor with an affinity to the muscle cells. This causes an accumulation of serotonin in the sarcolemma which causes muscle injury and elevations in the CK and myoglobin levels. Intramuscular olanzapine has twice to fivefold the peak concentration of the oral preparation and takes only a shorter time to peak. So a higher risk of adverse effects is seen with the intramuscular preparation. The injection could have caused a sudden elevation of the drug in the blood leading to serotonin receptor blockage and causing the hypothermia and rhabdomyolysis (Hung, 2008, p 2).
Lightning and rhabdomyolysis (Piccolo, 2007)
One of the first causes of death by natural disaster is lightning (Piccolo, 2007).
30% of people struck by lightning die and many survivors would have permanent disabilities. The major complication is acute renal failure. 10% of people affected by high voltage electric injury and lightning and surviving the injury have rhabdomyolysis. 30% of these cases of rhabdomyolysis progress to acute renal failure. Seriously injured patients have a transient keraunoparalysis characterized by “limb paralysis, sensory symptoms, pallor, coolness and absent pulses” (Piccolo, 2007). This is due to sudden release of excessive catecholamines.
A 29 year old moderately built person injured by lightning was brought to hospital after 19 hours. He had second and third degree burns covering 30% of the total surface area of the body. Compartment syndrome was diagnosed over the lower limbs (Piccolo, 2007). The patient developed rhabdomyolysis on the second day with CPK at 18550 U/L and had renal failure too. Peritoneal dialysis was done for 12 days and then haemodialysis for 18 days (Piccolo, 2007).
His renal functions finally recovered 32 days after the injury. He was intubated on the 3rd day due to pulmonary oedema. Tracheostomy was performed and he was continuosly sedated. This patient has recovered but has generalized demyelinising polyneuropathy. After 5 months he cannot extend the leg at the knee and does not have dorsiflexion of the feet. Prognosis is uncertain. Compartment syndrome must be especially ruled out after the lightning injury. Early diagnosis of rhabdomyolysis and early intervention would help the patient recover. Death due to the renal failure could be prevented. Haemodialysis is better than peritoneal dialysis for recovery of renal functions following rhabdomyolysis (Piccolo, 2007).
Acute alcohol intoxication and rhabdomyolysis (Chaparoska, 2008)
Alcohol produces direct toxic effect and ischaemia due to acute alcoholic intoxication. Both trigger acute rhabdomyolysis (Chaparoska, 2008). Analysis was done on 76 patients between 18 and 60 years in whom rhabdomyolysis was diagnosed, based on clinical features and lab findings on CPK, GOT, GTP and LDH. Alcohol intoxication was found to be the commonest cause of rhabdomyolysis among the 76 and 38 patients
answered to this cause. 15 patients also were taking other drugs like tranquilisers, anticonvulsants or narcotics (Chaparoska, 2008). 70 of the 76 patients developed renal failure which required dialysis. 41 patients recovered, 9 required maintenance dialysis and 26 died. The rhabdomyolysis patients had a tendency to have serum urea and creatinine increased at the beginning accompanied by hyperkalaemia. The right interpretations of the results would help in the early diagnosis of rhabdomyolysis and timely intervention would save the patient from death (Chaparoska, 2008).
Statin-induced rhabdomyolysis (Antons, 2006)
Statin-induced rhabdomyolysis is higher in incidence in practice rather than in controlled trials. The risks involved in statins inducing rhabdomyolysis are greater in patients with renal, hepatic and thyroid dysfunction and hypertriglyceridaemia (Antons, 2006, p 400). Exercise, Asian race, preoperative status are factors which increase the risk of statin-induced rhabdomyolysis. Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. They have been found to reduce atherosclerotic end-points in 30% of patients in randomized trials. They are prescribed only for half of the patients who require them due to the uncertainty about rhabdomyolysis.
Rhabdomyolysis is seen 6 times more with fibrate monotherapy than statin monotherapy. It is seen 12 times more in a combined statin and fibrate therapy (Antons, 2006, p 400). Rhabdomyolysis presents with muscle symptoms only half the time. However when it is related to statins, the presentation is usually diffuse myalgia involving the low back and proximal muscle pain in weeks. One survey showed that fatigue (74%) was also as nearly a common presentation as muscle pain (88%).
Symptoms are usually seen one year from start of statin. The cause of statin-induced rhabdomyolysis is unknown. Muscle toxicity due to deficiencies in the synthetic reductase pathway point to some explanations: “cholesterol deficiency with secondary abnormal membrane behaviors, coenzyme Q10 deficiency causing abnormal mitochondrial respiratory function, or prenylated protein abnormalities causing imbalances in intracellular protein messaging” (Antons, 2006, p 402). Muscle pain if increased by exercise and relieved when statins are stopped, points to statin myotoxicity. Associated dyspnoea and fatigue along with muscle symptoms usually point to statin-induced myopathy
Once the diagnosis is made, statins must be stopped. The management of the patient’s lipids becomes a challenge. Physicians have a tendency to treat the lipid problem with another medicine as there is no clear evidence that lipophilicity is related to myotoxicity (Antons, 2006, p 405). 55% of patients were found to have recurrence of symptoms when the original statin was replaced with another one. The best therapy for patients who cannot take statins would be to stick to a low fat diet.
Rhabdomyolysis is a severe medical life threatening emergency. Prompt diagnosis and immediate interventions can reduce the complications and save lives. Though the aetilogy is multifactorial, the pathway of pathology is much the same especially in the last phase, which involves an increase in the intracellular calcium. The diagnosis can be made by the history of muscle pain, the brownish red urine, the lab findings of elevated serum and urine myoglobin and CPK and the decrease in the urea/creatinine ratio.
Alterman, Igal, Sidi, Ami; Azamfirei, Leonard; Copotoiu, Sanda and Ezri, Tiberiu; (2007), “Rhabdomyolysis: another complication after prolonged surgery”, Journal of Clinical Anesthesia (2007) 19, 64–66, Elsevier Ltd. Web.
Antons, Kenneth A.; Williams, Craig D.; Baker, Steven K. and Phillips, Paul S. ; “Clinical Perspectives of Statin-Induced Rhabdomyolysis”, The American Journal of Medicine (2006) 119, 400-409, Elsevier Inc. Web.
Chaparoska, Daniella and Pivkova, Alexsandra; (2008), “Acute renal failure in patients with rhabdomyolysis”, Abstracts / Toxicology Letters 180S (2008) S32–S246. Web.
Giannoglou, George D.; Chatzizisis, Yiannis S. and Misirli, Gesthimani; “The syndrome of rhabdomyolysis: Pathophysiology and diagnosis”, European Journal of Internal Medicine 18 (2007) 90–100, Elsevier Inc. Web.
Hung, Chi-Fa; Huang, Tsan-Yu and Lin, Pao-Yen; (2008), “Hypothermia and rhabdomyolysis following olanzapine injection in an adolescent with schizophreniform disorder”, General Hospital Psychiatry.
Lee , Ming-Tsung, Lee, Xiao-Lun and Hsieh, Chun-Sheng; (2005), “Survival of near fatal rhabdomyolysis following flame burn in a 25-year-old patient”, Burns 32 (2006) 634–639, Elsevier Ltd. Web.
Piccolo A.P., Pedroso D.F.F., Moraes V., Ramos R., Piccolo-Daher S., Piccolo-Daher R., (2006), “Rhabdomyolysis and nerve deficits after lightning injuries—Review of the literature and a case report”, Burns 33 S (2007) S1–S172. Web.