Hospital Medicine

Rhabdomyolysis

I. What every physician needs to know.

Rhabdomyolysis refers to the breakdown of skeletal muscle, with release of the skeletal muscle contents into the circulation. Substances released during rhabdomyolysis include creatine kinase (CK), myoglobin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and electrolytes such as potassium.

Common presenting signs and symptoms are muscle pain, tenderness, and weakness. Non-specific symptoms, such as fever and malaise, are often present. Patients may also complain of dark-colored urine, a result of myoglobinuria. The classic triad of rhabdomyolysis includes muscle pain, dark colored urine and weakness.

Key causes of rhabdomyolysis include drug-induced (such as from statins or cocaine), crush injuries, extreme exertion, ischemia, and infections (such as influenza or coxsackievirus).

When skeletal muscle breaks down, myoglobin is released, and this myoglobin can precipitate in the renal tubules, especially in an acidic environment. Acute kidney injury (AKI) from rhabdomyolysis may also be mediated by the direct nephrotoxicity of the myoglobin, as well as by renal vasoconstriction. AKI is one of the most serious complications of rhabdomyolysis.

The cornerstone of therapy for rhabdomyolysis is hydration with IV isotonic fluids, with a goal of maintaining a urine output of 200-300ml/hr. There is controversy over the optimal IV fluids to use. However, Ringer's lactate should be avoided because it contains potassium.

II. Diagnostic Confirmation: Are you sure your patient has rhabdomyolysis?

The principal laboratory marker used to diagnose rhabdomyolysis is the serum creatine kinase (CK). There is no absolute consensus about what degree of elevation constitutes rhabdomyolysis. Some authors cite a CK level of five times the upper limit of normal. The source of this CK must be skeletal muscle, and other CK isoforms (such as CK-MB fraction) can be checked to ensure the source of the CK elevation is skeletal muscle if the diagnosis is in doubt.

Although the serum CK is the primary laboratory marker of rhabdomyolysis, the presence of urinary myoglobin can corroborate the diagnosis. Since urinary myoglobin (or hemoglobin) will turn the heme component of the urine dipstick positive, a dipstick positive for blood in the absence of red blood cells (RBCs) on the microscopic examination of the urine suggests the presence of myoglobin in the urine. Urine myoglobin can be measured, though this is not commonly done. The amount of myoglobin in the urine is not useful in predicting the likelihood of AKI.

A. History Part I: Pattern Recognition:

The classic triad of rhabdomyolysis is muscle pain, weakness, and dark-colored urine. Based on a series of rhabdomyolysis patients by Gabow et al., the most common presenting symptom was muscle pain. Only a minority of patients had muscle swelling on exam, and this sign often was only apparent after the patient received IV fluids, so re-examining the patient after IV hydration may be useful. Non-specific systemic signs and symptoms may be present, including malaise, fever and tachycardia.

B. History Part 2: Prevalence:

Bosch et al. reported that 7-10% of AKI cases in the United States are due to rhabdomyolysis. A single center study looking at hospital acquired AKI, by Nash et al., found about 1% of AKI cases were due to rhabdomyolysis.

It is useful to divide the causes of rhabdomyolysis into general categories to help identify patients who are at risk for this disease. Bosch et al. have described nine different categories of causes of rhabdomyolysis:

  • Drugs and toxins such as statins, fibrates, alcohol, and cocaine

  • Traumatic or crush injuries

  • Hypoxic such as from arterial thrombosis, clamping of a vessel during a procedure or extended immobility (as when a patient is unconscious)

  • Exertional such as following a marathon, intense exercise or seizure

  • Genetic such as from McArdle's disease (congenital myophosphorylase deficiency)

  • Infections such as influenza, coxsackievirus, HIV, Legionella, and Streptococcus pyogenes

  • Body temperature extremes such as heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, and hypothermia

  • Metabolic and electrolyte disorders such as hypokalemia, hypophosphatemia and diabetic ketoacidosis

  • Idiopathic

Other causes worth noting that do not easily fit into individual categories in the above classification scheme include inflammatory myopathies, such as dermatomyositis and polymyositis, compartment syndrome, hypothyroidism, and electrical injuries.

Epidemiologic data regarding the causes of rhabdomyolysis show that alcohol, illicit drugs, medications, and trauma/compression are among the most common causes of rhabdomyolysis.

It is important to realize that patients may have rhabdomyolysis due to multiple causes, spanning more than one category. For instance, a patient may have consumed a large quantity of alcohol and then lost consciousness and be immobile for an extended period of time. Or, a patient with congestive heart failure may be on dual lipid-lowering therapy with a statin and fibrate, while also being hypokalemic due to therapy with a loop diuretic. Or, a military recruit may have been performing extensive drilling in extreme heat.

Certain combinations of medications put patients at particular risk for rhabdomyolysis. For instance, combining statin therapy with fibrate therapy (gemfibrozil is higher risk than fenofibrate). Other drug combinations that put patients at elevated risk for rhabdomyolysis include statins used concomitantly with cyclosporine, antifungal medications, macrolides, HIV protease inhibitors, amiodarone, nefazodone, and verapamil.

Hospitalists, who often participate in the care of surgical patients, need to be aware that rhabdomyolysis can occur in the post-operative setting. There have been a number of case reports of post-operative rhabdomyolysis occurring, particularly among bariatric patients. In one series of such patients, risk factors for rhabdomyolysis after bariatric surgery included greater BMI and longer duration of surgery.

In bariatric patients, it is likely that the immobilization and weight on the gluteal muscle result in necrosis, which can then be exacerbated by the development of compartment syndrome in the area. Rhabdomyolysis has been described after a variety of surgeries in addition to bariatric surgery, including laparoscopic radical nephrectomy and spine surgery. Thus clinicians should consider the possibility of rhabdomyolysis when AKI develops post-operatively without another clear etiology. Rhabdomyolysis can also be the result of compartment syndrome that develops spontaneously, and not as a result of surgery.

Inflammatory myopathies, such as polymyositis and dermatomyositis, which in one series accounted for nearly 6% of rhabdomyolysis cases, also need to be considered as possible etiologies.

C. History Part 3: Competing diagnoses that can mimic rhabdomyolysis:

When patients present complaining of muscle pain, it is important to distinguish between myalgias and actual rhabdomyolysis. This distinction is particularly important among patients taking statins. The rate of myalgias, which refer to muscle aches without CK elevations, is relatively high, occurring in about 5-10% of patients taking statins. The rates of frank rhabdomyolysis among patients taking statins is much lower, at about 0.1 to 0.2 cases per 1000 person-years. The dose of the statin and the particular statin chosen also affect the risk of rhabdomyolysis, which increases as the dose of the statin increases. The risk of rhabdomyolysis by specific statin appears to be, in order from the highest: simvastatin, atorvastatin, pravastatin and fluvastatin.

The laboratory tests used to help diagnose rhabdomyolysis need to be interpreted with caution. CK is the key laboratory marker used in diagnosing rhabdomyolysis, though CK elevations can result from damage to cardiac muscle, in addition to skeletal muscle. Thus, if there is any doubt about the source of the CK elevation, CK isoforms such as CK-MB fraction should be obtained.

However, extreme exertion can produce a modest elevation in the CK-MB fraction, as demonstrated in a study of runners who had completed a marathon and found a mean CK-MB fraction of 8.3%. Other laboratory markers that are elevated in rhabdomyolysis include the alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Among rhabdomyolysis patients with a CK greater than 1000 U/L, 93.1% had an abnormal AST and 75.0% had an abnormal ALT. Care needs to be taken to determine whether these elevations in AST and ALT are from muscle or liver.

Urinary tests are also useful in diagnosing rhabdomyolysis. A dipstick positive for blood in the absence of hematuria on urine microscopy examination is suggestive of rhabdomyolysis. However, hemolysis can yield similar results. Pigmented granular casts can also be seen in rhabdomyolysis.

D. Physical Examination Findings.

Physical exam findings with rhabdomyolysis include muscle pain and weakness. Muscle swelling is less common and may be present only after the patient is given IV fluids. Other signs include non-specific systemic ones, such as malaise, fever and tachycardia. Patients may also complain of dark- or tea-colored urine.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The serum CK is the key blood test to make the diagnosis. A CK level of five times the upper limit of normal is a commonly used definition, though there is no absolute consensus, and higher cut-offs have been used in studies looking at statin-associated rhabdomyolysis. Though not diagnostic, AST, ALT, and LDH may also be elevated.

In rhabdomyolysis, the elevation in AST is usually greater than the elevation in ALT. Thus elevations of "liver enzymes" can also be the result of rhabdomyolysis, and one must be careful to distinguish the source of these laboratory abnormalities. Electrolyte abnormalities that can be seen with rhabdomyolysis include hyperkalemia and hyperphosphatemia, as the intracellular contents of the damaged muscle cells enter the bloodstream. Hypocalcemia and an acidosis may also be present.

Urine tests suggestive of rhabdomyolysis include urine dipstick testing positive for blood with urine microscopy negative for urine RBCs, since myoglobin turns the heme portion of the urine dipstick positive. Hemolysis can give this same pattern of a urine dipstick positive for blood without RBCs on urine microscopy. Urine myoglobin can be measured by some laboratories. However, one study concluded that urine myoglobin does not predict AKI in rhabdomyolysis patients. Thus urine myoglobin does not appear to add much clinical value beyond that which can be obtained from more readily available urine testing.

The goal of laboratory testing with rhabdomyolysis is both to diagnose its presence and severity, and also to help determine its etiology. Urine toxicology testing is useful given that drugs of abuse such as cocaine and heroin can be a cause of rhabdomyolysis.

Other testing that can be performed to try to uncover the cause of the rhabdomyolysis includes a full set of electrolytes (looking for hypokalemia, hypophosphatemia or diabetic ketoacidosis), thyroid-stimulating hormone (TSH) (looking for hypothyroidism) and tests directed at uncovering a potentially causative infection (such as a nasal swab for influenza).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging studies are generally unnecessary in making the diagnosis of rhabdomyolysis as the diagnosis can usually be made on the basis of clinical presentation, serum tests and urine tests. Of the available imaging modalities, MRI is the most useful in showing the anatomic effects of rhabdomyolysis. There may be a role for MRI with rhabdomyolysis in the specific situation where the rhabdomyolysis is due to compartment syndrome, and MRI imaging will assist the surgeons in deciding on the approach for fasciotomy.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Urine myoglobin generally does not add diagnostic value beyond more readily available urine tests, and its long turnaround time makes it unlikely to be helpful clinically. Imaging is generally unnecessary in cases of rhabdomyolysis, except in the narrow circumstances where surgeons are considering a fasciotomy for compartment syndrome, and the imaging will help guide their approach.

A. Immediate management.

The most important aspect of the management of rhabdomyolysis is aggressive IV hydration. IV hydration is important to both help dilute out the nephrotoxic myoglobin, and also because a large amount of fluid can be sequestered in inflamed, injured muscle. This fluid sequestration within injured muscle means that patients with rhabdomyolysis often have an effective fluid deficit upon presentation.

IV hydration should be started as soon as possible in the pre-hospital setting if feasible. Once the patient is in an inpatient setting, the rate of IV fluid administration should initially be approximately 400-500ml/hr. The IV fluid rate should be adjusted so as to maintain a urine output of 200-300ml/hr.

IV Fluid type

There is no consensus about the optimal fluid to use. Since a goal is to replete intravascular volume, using an isotonic fluid is recommended. Using an alkaline fluid has some theoretical advantages, including the increased solubility of myoglobin at a higher pH (and so perhaps also less nephrotoxicity). Also, infusing large volumes of normal saline risks creating a dilutional hyperchloremic metabolic acidosis.

However the few (retrospective) studies that have been performed looking at the use of bicarbonate (with mannitol) versus saline have not shown a benefit to the use of bicarbonate-containing fluids. Nonetheless, as recommended by Bosch et al., in patients who have a urine pH below 6.5, it is reasonable to use bicarbonate-containing fluids (such as 1 liter of D5W with 100 mmol of bicarbonate) alternating with 1 liter bags of normal saline. Careful monitoring of the urine pH and electrolytes is necessary, especially when alkalinization is undertaken.

IV fluids that contain potassium, such as Ringer's lactate, should be avoided because one should not give supplemental potassium to patients who are already at risk for hyperkalemia.

Mannitol

The benefit of mannitol in treating rhabdomyolysis is unclear. One study looking at the benefits of mannitol and bicarbonate in treating rhabdomyolysis found no benefit overall, though there was a trend toward benefit in the subgroup of patients with a CK greater than 30,000 U/L. However, most of the benefits have been shown in animal studies. Risks associated with the use of mannitol include AKI due to renal vasoconstriction, and electrolyte disturbances, such as hyperkalemia and hyponatremia. These adverse effects are primarily seen with higher doses of mannitol (i.e. >200g/day).

When using mannitol, the osmolal gap should be regularly measured (one to four times per day, depending on dose) as it correlates with the serum concentration of mannitol. The osmolal gap is the difference between the measured osmolality and calculated osmolarity. Measured osmolality is determined by the clinical laboratory. Using serum values, calculated osmolarity can be determined using the formula (2 x Na) + (glucose/18) + (BUN/2.8). When the osmolal gap exceeds 55 mmol/kg H2O, the risk of AKI is increased and stopping mannitol should be considered. Mannitol should also be discontinued if the patient becomes oliguric so as to avoid mannitol accumulation.

Given that the benefit of mannitol in humans is not well established and that there are significant risks associated with its administration, the use of mannitol can be considered in rhabdomyolysis patients with a CK greater than 30,000U/L, when the clinician is comfortable with the use of mannitol.

Furosemide

The logic behind administering furosemide to treat rhabdomyolysis is that it could increase urinary flow and so help "wash away" the nephrotoxic myoglobin. However there is not good evidence to support the use of furosemide in the treatment of rhabdomyolysis, and so its use is not recommended. In some cases, furosemide may have a role in treating the hyperkalemia that can accompany rhabdomyolysis.

Ascertain and remove the cause of the rhabdomyolysis

In many cases of rhabdomyolysis, such as with exertion of trauma, removing the cause is not an issue. However, if the rhabdomyolysis is drug-induced, it is important to immediately stop the suspected culprit medication. Patients who have recurrent episodes of rhabdomyolysis that are deemed "idiopathic" warrant an evaluation for one of the genetic myopathies, such as McArdle's disease. Additional testing to try to ascertain the cause of rhabdomyolysis is discussed above.

Hemodialysis

Patients with severe rhabdomyolysis may have hyperkalemia and acidosis that cannot be adequately managed with medical therapy. In such cases, hemodialysis may be required. This situation most often arises in the setting of extensive rhabdomyolysis, such as may occur with crush injuries. When hemodynamic instability is also present, continuous renal replacement modalities may be indicated. If it looks like a patient is on a clinical trajectory such that hemodialysis may be required, renal consultation should be obtained promptly.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Next to removing the cause of the rhabdomyolysis and aggressive IV hydration with isotonic fluids, the most important aspect of treating a patient with rhabdomyolysis is managing the electrolytes. Hyperkalemia and hypocalcemia are among the key electrolyte disturbances in rhabdomyolysis. In severe rhabdomyolysis, close monitoring of electrolytes (e.g. every 4 hours) is critical.

Hyperkalemia

Hyperkalemia occurs as a result of intracellular potassium leaking into the serum due to the destruction of skeletal muscle. When a patient is found to be hyperkalemic, an EKG should be obtained to look for EKG changes consistent with hyperkalemia (which, if present, necessitates emergent treatment). Hyperkalemia patients should also be placed on continuous telemetry monitoring. As with hyperkalemia generally, treatment consists of shifting the potassium intracellularly for temporary lowering of the potassium, followed by removing the potassium from the body for a more sustained lowering of the potassium.

Insulin 10 units IV (preceded by 50 ml of 50% dextrose to avoid hypoglycemia) will shift potassium into the cells. After administration of IV glucose and insulin, a decrease in serum potassium is usually evident within 30 minutes of treatment, and the effect lasts 4-6 hours. Another option for shifting potassium into cells is beta-2 agonists, such as albuterol, which have an onset of action of 30 minutes and an effect that lasts for approximately 2 hours. When serious hyperkalemic EKG changes are present, such as QRS widening, 1g of calcium chloride or calcium gluconate should be given over 10 minutes.

Giving IV sodium bicarbonate as a means of shifting potassium into cells has less data to support it. However, rhabdomyolysis may have other indications for alkalinization. Sodium bicarbonate cannot be mixed with calcium, as they can precipitate.

Methods to remove potassium from the body include sodium polystyrene sulfonate resins (such as Kayexalate), which remove potassium from the GI tract via stooling. Such resins can take 2 or more hours to take effect. Intestinal necrosis is a complication that can be seen with sodium polystyrene sulfonate resins, probably due to the sorbitol with which they are mixed.

Loop diuretics can be used to achieve kaliuresis. However, many patients with rhabdomyolysis are volume depleted, and so should not receive loop diuretics. In cases where hyperkalemia is refractory to medical treatment or when there is severe hyperkalemia and AKI, hemodialysis may be indicated.

Hypocalcemia

Deposition of calcium in damaged muscle can result in hypocalcemia. In addition, there can be precipitation of calcium phosphate given the hyperphosphatemia that may accompany rhabdomyolysis. Treatment of hypocalcemia should only be undertaken if the hypocalcemia is symptomatic, or if there is serious hyperkalemia (e.g. with EKG changes), since hypocalcemia can exacerbate the adverse cardiac effects of hyperkalemia. After the initial hypocalcemia, there can be rebound hypercalcemia, as deposited calcium is mobilized from muscle, and due to an increase in calcitriol levels.

Other electrolyte abnormalities

Additional electrolyte perturbations that can be present with rhabdomyolysis include hyperphosphatemia and hyperuricemia, due to their release from damaged cells. An acidosis may also be present.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

AKI is one of the most serious complications of rhabdomyolysis. In one series by Melli et al. describing 475 patients with rhabdomyolysis hospitalized at a large academic medical center, the overall incidence of AKI was 46%. The group of rhabdomyolysis patients with the highest incidence of AKI were those who abused illicit drugs and alcohol, those with medication-related rhabdomyolysis, and those who had suffered crush injuries. There was a significant correlation (R2=0.12) between the serum creatinine and the peak serum CK. The mortality rate was 3.4%.

In another series of 157 patients with rhabdomyolysis described by Ward, CK levels again had value in predicting AKI, which occurred in 16.5% of patients. In a multiple regression analysis, other factors that helped predict AKI were dehydration, along with the degree of hyperkalemia, hyperphosphatemia and hypoalbuminemia. Rhabdomyolysis from sepsis, burns and drug-induced were the causes most likely to lead to AKI. In the group of patients with AKI, the mortality rate was upwards of 40%. Thus a key goal in the management of rhabdomyolysis is to prevent AKI by providing IV fluids to maintain urine output and dilute out the nephrotoxic myoglobin.

C. When is the Patient Ready for Discharge.

Once there is sufficient improvement in the rhabdomyolysis, as measured by the decline in CK, the patient can, in preparation for discharge, be transitioned from IV to oral fluids. There is no absolute consensus about the CK level threshold below which IV fluids can be safely discontinued, as the available data is limited. Different authors have recommended a CK level threshold of either 5000 or 1000U/L.

I believe it is most prudent to use the lower CK level of 1000 U/L as the point below which the patient can be transitioned from IV hydration to oral hydration. The reasons to favor this more conservative threshold are that CK levels may not show a linear decrement, and the costs of IV hydration are modest, especially in comparison to the costs of AKI. Once a patient is taken off IV fluids, the patient should still be instructed to maintain oral hydration.

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