Rhabdomyolysis

Abstract

Rhabdomyolysis, associated with more than 100 conditions, is due to destruction of skeletal muscle cells and leakage of intracellular contents into the circulation. Treatment consists of early detection, aggressive fluid replacement, alkaline diuresis, and management of complications.Despite their highly varied histories, profound rhabdomyolysis developed in each of the critically ill patients described in the “Patient Profiles” (see box). What is rhabdomyolysis? Why does it occur in such dissimilar populations? Which patients are at risk? What are the signs and symptoms? And how is it treated?Myo refers to muscle, rhabdo means striated (as in striated or skeletal muscle), and lysis is breakdown. Therefore, rhabdomyolysis (pronounced rab′-do-mi-ol′-i-sis)1 is a dissolution of skeletal muscles that produces a nonspecific clinical syndrome that causes extravasation of toxic intracellular contents from the myocytes into the circulatory system. Regardless of the initial precipitating factor, leaky skeletal muscle cells constitute the common rhabdomyolysis pathway.2–6Although somatic muscles account for 40% to 50% of total body mass, these tissues are so resilient that skeletal muscle disease is rarely a primary indication for admission to an intensive care unit.3,7 Nonetheless, when pushed beyond their tolerance or capacity for self-repair, skeletal muscles undergo acute destruction. This destruction leads to electrolyte disturbances, hypovolemia, metabolic acidosis, coagulopathies, and myoglobinuric renal failure. Although rhabdomyolysis is occasionally the chief complaint, it is more commonly only one of several interrelated diagnoses in a critically ill patient.8Understanding rhabdomyolysis requires an awareness of normal intracellular and extracellular distribution of ions and what happens when this precise balance is disrupted. Electrolyte allocation between the myocyte’s internal and external environments is markedly different (Table 1). Ions in the body are either predominately intracellular or extra-cellular; no electrolyte has an equal distribution. Sodium, calcium, chloride, and bicarbonate ions are chiefly extracellular, whereas potassium, magnesium, and phosphate ions are largely intracellular.11 For the body to function optimally, the relative differences in the concentrations of these ions inside and outside the muscle cells must be preserved. Myocytes also contain proteins and molecules that differentiate them from other cells and from the contents of the extracellular space.3,9,10Three important mechanisms maintain the distinction between intracellular and extracellular molecules (Table 2). The first of these is the cell membrane, which physically contains the larger particles of the myocyte. Damage to this essential structure allows intracellular contents to escape and extracellular contents to enter.10 Direct injury to the cell membrane can occur as a result of crushing, tearing, burning, pounding, poisoning, or dissolving.3,12Second, the sodium-potassium pump plays an important role in preserving essential intracellular-extracellular distribution of electrolytes. However, this pump is energy dependent, fueled by adenosine triphosphate (ATP).9,12 A steady supply of oxygen is required to produce sufficient quantities of ATP. Therefore, under anaerobic conditions, both the pump and the cell membrane it is designed to maintain, quickly break down.3 Hypoxia can be induced in muscle cells by a number of conditions, such as shock states, vascular occlusion, and tissue compression. Additionally, in patients experiencing excessive use of energy, due to such causes as seizures, strenuous exercise, hyperthermia, or prolonged sympathetic stimulation, oxygen delivery and ATP production may simply be unable to keep up with demand, and pump dysfunction swiftly ensues.4,9Cell membranes can also be disrupted as a consequence of severe electrolyte imbalances, most commonly copious losses of sodium or potassium, that upset the delicate sodium-potassium pump. Significant potassium deficits can be precipitated by vomiting, diarrhea, or extensive diuresis.12 Serum hyponatremia occurs as a result of water intoxication.13Whenever the cell membrane breaks down, either physically or functionally, a massive influx of sodium occurs (Table 3). Where sodium goes, water follows, rapidly swelling the cells.9,12,14 Large amounts of intravascular fluid (up to 12 L) can leave the circulation and become sequestered as edematous fluid in damaged muscle tissues. This fluid shift produces an intravascular hypovolemia and subsequent hemodynamic instability.7,15 The dramatic decrease in plasma volume then leads to vasoconstriction, prerenal failure, and, eventually, acute intrarenal failure.11 Chloride and calcium also move into the cells, causing serum hypocalcemia and calcium deposition in skeletal muscle and renal tissues.4 Intracellular calcium levels in the myocytes of patients with exertional rhabdomyolysis can be up to 11 times the normal value.16 This deposition of calcium in soft tissues can be so pronounced that it is detectable on images obtained by computed tomography,17 magnetic resonance imaging,18 technetium-99 bone scanning,19 and sonography.20Among the intracellular components that leak out of damaged skeletal muscle,15 the most immediately important one is potassium.16 Because the electrolyte is shifting from an intracellular area of high concentration into the serum, where a low concentration is the norm, lethal hyperkalemia can rapidly develop.21 Patients with hyperkalemia are at risk for car-diotoxic effects and dysrhythmias, which are further aggravated by coexisting hypocalcemia and hypovolemia.7 Phosphate also leaves the cells, producing hyperphos-phatemia. Because hyperphos-phatemia potentiates hypocalcemia, still more calcium is driven from the serum and into damaged muscle and kidney tissue.4,7,14Injured myocytes also leak lactic acid and other organic acids, promoting metabolic acidosis and aciduria.15 Purines released from disintegrating cells are metabolized to uric acid and can lead to hyperuricemia.10,22 Furthermore, purines are nephrotoxic, directly damaging fragile renal tubules on contact.3Myoglobin is the dark red protein that gives muscles their characteristic red-brown color. Like hemoglobin, myoglobin is an oxygen-carrying molecule that supplies oxygen to the myocytes.4 Lysis of as little as 100 g of skeletal muscle results in myoglobinuria.15 Destruction of 200 g of muscle causes a noticeable reddish-brown discoloration of the urine.8 Unfortunately, myoglobin is also nephrotoxic in patients with coexisting oliguria and aciduria.10Both thromboplastin (a clot-promoting agent) and tissue plasminogen (a thrombolytic substance) are released from injured muscle tissue, making patients with rhabdomyolysis susceptible to disseminated intravascular coagulation.9,10,15,22–24 Rhabdomyolysis also produces extreme increases in the serum levels of creatine kinase (CK). CK has no toxic effects, and elevated plasma levels of the kinase are simply a marker of increased permeability of muscle membranes.21 However, grossly high values are pathognomonic for rhabdomyolysis, because no other condition will cause such extreme CK elevations.8,25A basic understanding of the pathophysiology of rhabdomyolysis indicates why this abnormality is associated with more than 100 seemingly unrelated disorders8 (Table 4). Although initially recognized solely as a posttraumatic sequela, nontraumatic causes of rhabdomyolysis are now estimated to be at least 5 times more frequent than traumatic causes.3 Importantly, however, most patients who eventually experience rhabdomyolysis have several risk factors.4,9,21 In a study by Gabow et al,26 59% of the subjects had a history of multiple associated conditions.Some of the earliest reported cases of rhabdomyolysis occurred during the bombing of London in World War II. Acute renal failure commonly developed in patients wounded in building collapses.8,27 This condition came to be known as the “crush injury syndrome,” and this term is often used to refer to rhabdomyolysis despite current understanding of other precipitating factors.4,15 Direct muscle trauma after natural or human-made disasters remains responsible for large-scale occurrences of rhabdomyolysis.3,7 For example, after the 1988 Armenian earthquake, more than 1000 cases of rhabdomyolysis-induced myoglobin-uric renal failure were reported; 323 of these patients required dialysis.28 Such numbers have important implications for disaster planners in bomb-or earthquake-prone regions.9,28,29Other common causes of crushing injuries are farm and industrial accidents and motor vehicle collisions. Particularly at risk for rhabdomyolysis are patients who are entrapped and whose access to care is delayed.14 Bite injuries can macerate and devitalize large areas of muscle tissue; in one instance, rhabdomyolysis occurred after a wolf attack.30 Deep burns are another source of direct muscle damage.31 Electrical injuries, including lightning strikes, are associated with a particularly high occurrence of rhabdomyolysis because electrical current travels through the body, devitalizing tissue all along the path of the current.9,14,32 The acute necrotizing myopathy of certain carcinomas can also destroy enough muscle mass to initiate rhabdomyolysis.4Both beatings and sport fighting, such as boxing and karate, can cause rhabdomyolysis.5 Tortured or assaulted patients, particularly those admitted to the hospital from jail, where attacks tend to be prolonged and vicious, should be considered at risk for rhabdomyolysis,4 as should victims of severe child abuse.33 Indeed, persons subject to repetitive blows of any kind are at risk. Incidents of rhabdomyolysis have occurred in bongo drum players,4 personal watercraft riders,34 computer keyboard users,35 jackhammer operators, and mechanical bull riders.25 Direct muscle injury can also be due to iatrogenic interventions. For example, a patient had rhabdomyolysis and myoglobinuric renal failure after 15 cardio-version attempts and prolonged chest compressions.36Excessive physical exertion results in a state in which ATP production cannot keep up with demand, subsequently exhausting cellular energy supplies and disrupting muscle cell membranes.3,4,12 Rhabdomyolysis can be caused by any kind of intense physical exercise and has been documented in weight lifters, marathon runners, police cadets, and military recruits in boot camp.5,12,37–41Protracted tonic-clonic seizures not only pound the muscles repeatedly but also exert a tremendous metabolic demand that predisposes patients to rhabdomyolysis.4,12 Rhab-domyolysis due to extreme hyperactivity can occur in psychotic patients, both those with mania and those with drug-induced psychoses.42–44 Rhabdomyolysis developed in an agitated patient after restraint in a straitjacket,43 in patients with delirium tremens,25 and in a patient with pronounced decerebrate posturing.45 Even racehorses are subject to a form of exertional rhabdomyolysis.46Muscle ischemia, whatever its cause, interferes with oxygen delivery to the cells, thereby limiting production of ATP. Generalized ischemia from shock and hypotension are common factors contributing to rhabdomyolysis in trauma patients.9 By binding to hemoglobin, carbon monoxide causes a total body ischemia.4 Severe status asthmaticus,47 inhalation of hydrocarbons,48 and near-drowning also produce profound systemic hypoxemia,49 and each of these conditions can precipitate rhabdomyolysis.Skeletal muscle ischemia can also be caused by localized compression.4 Sources include intraoperative use of tourniquets,50 tight dressings or casts, and prolonged application of air splints or pneumatic antishock garments,9 particularly in patients with hypotension.Rhabdomyolysis can be caused by tissue compression due to extended periods of immobilization.2 This etiology includes immobilization related to intraoperative positioning, particularly the lithotomy position.51,52 Cases of rhabdomyolysis are common in intoxicated or comatose persons “found down” and in elderly patients unable to rise after a fall.53 Rhabdomyolysis has also been reported in a patient immobilized because of an acute spinal cord injury.54Compartment syndrome is both a cause and a complication of rhabdomyolysis. As pressure within the fascial compartment increases, blood flow decreases, tissues become necrotic, and the dying muscle cells release osmotically active particles that draw additional water into the compartment, further exacerbating the condition.4–6,12As devastating as ischemia is to tissue, evidence suggests that many of the events that eventually lead to myolysis occur during the reperfusion phase. Once circulation is restored, large amounts of toxic intracellular contents are released into the bloodstream.3,9,55 This ischemia-reperfusion treatment dilemma is a clinical conundrum for practitioners.Muscle ischemia precipitated by arterial or venous occlusions has several causes. White clot syndrome due to severe heparin-induced thrombocytopenia,56 air emboli from diving injuries,57 and microvascular occlusion of severe sickle cell crisis or vasculitis can all affect blood flow to the tissues enough to cause muscle cell death.5,39,58Both heat and cold can precipitate rhabdomyolysis.12 By reducing muscle perfusion, cold induces tissue ischemia and freezing causes cellular destruction. Conversely, excess heat, regardless of its cause, also destroys myocytes.4,5 In addition to the effects of direct thermal injury, every 1°C in body increases metabolic demand by oxygen delivery can no keep up with cellular why exertional in is associated with the of patients have a to these patients are these profound causing body to and producing muscle to hyperthermia, is This syndrome is by certain such as and and syndrome can quickly rhabdomyolysis related to and sodium has been is the most common precipitating electrolyte Because it is the chief intracellular a total body of potassium will the sodium-potassium causing the cell membrane to toxic intracellular contents to escape from muscle of or can lead to massive potassium Importantly, this can occur in the of normal or elevated serum potassium which are by the release of potassium from dying produces electrolyte losses that can be associated with several cases of rhabdomyolysis after of have been This contains a when in large causes renal potassium and certain produce renal acidosis, which interferes with electrolyte and can lead to potassium has also been to such as and to aggressive in a patient with an injury and associated with rhabdomyolysis are either electrolyte or and are all whereas disease produces a and both sympathetic and metabolic to those of or the body to a of extreme that cannot be conditions rhabdomyolysis, including of and cause muscle but occasionally acute results in The and are also conditions that to rhabdomyolysis in and and and necrotizing are the many conditions that can destroy quantities of muscle tissue through of or direct to as water in to the dark in this form of causes include A and and and are the of causes of is the in this In addition to its on the which can lead to periods of prolonged has a primary toxic on and cases of rhabdomyolysis after or have been use of such as acid and has been to rhabdomyolysis, but the abnormality is particularly common after of that either or the sympathetic including and Even of such as and have been associated with the of and toxic are to rhabdomyolysis, including certain and the of Because are designed to both and the contain that Rhabdomyolysis after multiple by or and after by the has been of are associated with the of rhabdomyolysis. include such common as and Cases of rhabdomyolysis have occurred with both and toxic of these However, patients with rhabdomyolysis often have several other risk making it to a precipitating have a primary toxic on the whereas and chiefly muscle ischemia through prolonged and tissue to critically ill patients are those in the of rhabdomyolysis, including and certain on the of rhabdomyolysis are because occurrence is highly on the rhabdomyolysis is associated with hyperthermia, injuries, and extensive electrical it is with such conditions as sickle cell and use of initial of rhabdomyolysis can be (Table and early requires a high of A history of risk factors should the of risk are patients with evidence of tissue crushing, ischemia, or of rhabdomyolysis may be to muscle and and can be in critically ill the initial clinical of rhabdomyolysis is the of with a than large quantities of can from to to and care are often the first to this history and physical can the of rhabdomyolysis is by CK levels are the most of injury in rhabdomyolysis.12 CK levels are to Patients with patients who had and any one who a marathon may have a CK of several rhabdomyolysis, however, total CK levels are values are from to In extreme the CK may be this high are for no other condition will cause such extreme CK the released from damaged skeletal muscle, for the of serum CK in patients rhabdomyolysis, levels of this is of no in patients who have Serum levels of myoglobin also but this is not a of rhabdomyolysis because myoglobin is rapidly from the blood is for and acidosis and for sodium bicarbonate acute renal failure and increased release of from skeletal muscle cause the serum concentrations of and to in rhabdomyolysis. However, is elevated to a the normal of to to or of in serum occurs in rhabdomyolysis. the serum levels of potassium and phosphate as these components are released from the levels then decrease as are in the Serum concentration of calcium initially as calcium into the cells and then Electrolyte levels in each patient on the of the rhabdomyolysis, where the patient is in the of the and what have been are for of disseminated intravascular and should be are a in patients with rhabdomyolysis will the of casts, and uric acid and may electrolyte with renal are a to for because the on the that with also with Therefore, a indicates the of both and However, the is hemoglobin, or both are and further is to the or of of the clinical of rhabdomyolysis are related to its include in electrolyte levels in serum and metabolic acidosis, myoglobinuric renal failure, disseminated intravascular and acute muscle in serum particularly are the most immediately consequence of Treatment is because patients are have an in acidosis in rhabdomyolysis is due to a of increases in lactic uric and potassium in the who the initial and of rhabdomyolysis are still susceptible to due to myoglobinuric renal to of patients with rhabdomyolysis to acute renal In rhabdomyolysis for to of all cases of acute renal failure in the renal failure can be either or and the in several The of myoglobin produces a with subsequent of the This with large myoglobin molecules are in the results in the of that the renal causing an in pressure and the of not only of but also the of myoglobin molecules into In an the from the of the myoglobin Once myoglobin is into its the in that lead to and renal cell However, despite high myoglobin can through the it is of these is aggravated by hypovolemia and subsequent renal Therefore, both volume and high is an important of rhabdomyolysis of clot and factors from tissues predisposes patients to particularly patients at risk for disseminated intravascular Although rhabdomyolysis attacks skeletal acute of the and muscles can occur in patients with rhabdomyolysis. to both and patients at high risk for rhabdomyolysis, and early of the abnormality are the first in Although is both muscle and renal cells are This allows to first any or circulatory (Table in is the of muscle in to the release of intracellular This is in patients, such as those with rhabdomyolysis due to compartment but not in such as those with rhabdomyolysis due to the toxic effects of include of entrapped patients and to a on a should be and pneumatic antishock should be and tight and dressings as as and of burns and other should be include compartment in injured or and as by each in treatment is to of toxic intracellular contents from the circulation and from the Although that volume and are each important no on and The one rhabdomyolysis treatment however, that the most important to acute renal failure in rhabdomyolysis is intravascular volume and a the intravascular volume renal by out and limiting the are in with renal In patients, the of volume is an of to an this high may of fluid of to 1000 and all patients should have a in to fluid the is to a of or to the of myoglobin into its nephrotoxic is by sodium bicarbonate to the is to diuresis, keep the and of in the and are to maintain a can be to the but it may the the not to other is for the management of electrolyte metabolic acidosis, or fluid that renal by is Although in the has been in patients with myoglobinuric renal failure. most patients eventually normal kidney care of patients with rhabdomyolysis includes of and to further fluid In to fluid and the of and patients should be for the of renal failure Patients with rhabdomyolysis may from arterial and pressure to with of volume must be to that it remains and arterial is on a to due to aggressive of sodium include limiting the use of nephrotoxic and to further kidney levels should be every to 12 The most will in the first 12 to and then decrease during the several Importantly, renal is largely on the and of treatment and not on the CK Patients with CK values than who early and aggressive treatment may experience no subsequent renal Conversely, patients with CK levels than can have care is or must be and must be levels 12 to after and are with patients are of calcium to hypocalcemia is not calcium from the soft tissues and can cause patients with rhabdomyolysis for signs of hyperkalemia or may be in patients at risk for rhabdomyolysis due to muscles can from of rhabdomyolysis with and after rhabdomyolysis is access to aggressive including is most are related to other injuries or disease and are not a direct result of is a clinical syndrome in which the contents of injured muscle cells leak into the circulation. This leakage results in electrolyte acidosis, hypovolemia, and acute renal failure. than 100 conditions, both traumatic and can lead to rhabdomyolysis. consists of early detection, treatment of the cause, volume replacement, and aggressive or Patients with rhabdomyolysis often intensive and care are in both the early and the management of this chief of the care and of the management for the rhabdomyolysis treatment