Rhabdomyolysis

Defined as dissolved skeletal muscle content, rhabdomyolysis is exactly that. It can present in many ways, from completely asymtpomatic to life-threatening end-organ damage.  In the early 1900's the syndrome of rhabdomyolysis was recognized as a cause of acute kidney injury following crush injuries. A case series corroborated this following the bombing of London in 1940, where patients injured from falling buildings were found to develop similar symptoms. Non-traumatic causes and the overall pathophysiology of rhabdomyolysis were not well recognized until decades later.


The final common pathway in causing rhabdomyolysis is increased intracellular calcium. Whether there is direct trauma to the sarcomere from trauma, or ischemia causing depleted ATP, all patients with rhabdomyolysis develop increased intracellular calcium. These leads to a worsening of intracellular energy stores, as Na/Ca exchangers actively use ATP to maintain normal electrolytes gradients. Increase reactive oxygen species leads to direct toxicity to cell membranes, and muscle death an intracellular content release occurs.

The causes of rhabdomyolysis are many, but can be broken down into several categories. I like the way its categorized on UptoDate, as it really allows you to structure your differential diagnosis. :

1. Traumatic - crush, trauma, immobolization from fall/coma (as in our patient today), burn, compartment syndrome

2. Non-traumatic exertional - significant exercise (marathon runner), myopathies that are exposed through exercise - (McCardle syndrome, carnitine palmitoyltransferasedeficiency)
Some people might include seizure in this category as it is a direct result of muscle contraction and exertion

3. Non-traumatic non-exertional - inflammatory myopathies, endocrine causes (hypothyroidism, DKA, pheo), infectious causes (viral, bacterial and parasitic causes - malaria), drugs (statin, alcohol, colchicine, herbal products, opioids, illicit drugs - cocaine) and electrolytes abnormalities (hypokalemia, hypophosphatemia)

The diagnosis can be suspected clinically, but we rely on laboratory findings to confirm rhabdomyolysis. The triad of weakness, dark urine and myalgias is typically present. On examination, muscles can appear swollen and tender on palpation. Additional urinalysis testing can be helpful. Myoglobinuria can be identified on dipstick at a level of 150mg/L, but can not be differentiated from hemoglobin. Microscopic examination will show minimal/no red blood cells if pure myoglobinuria. The pH of urine in this setting tends to be acidic. Proteinuria can be seen in up to 50% of cases. If there is more than 300mg/L of myoglobin in the urine, there will start to be a colour change to reddish/brown.

The main concern in managing rhabdomyolysis is the development of acute kidney injury. Its estimated that 10% of all AKI are related to rhabdomyolysis. However, the CK level doesn't correspond directly with increasing chance of AKI. That being said, renal injury usually develops at levels above 15,000. Mechanisms of renal injury include direct tubular toxicity, renal vscocrinstriction and tubule blockage due to myoglobinuria, not CK. This is interesting considering we measure CK levels, and not myoglobin levels in the serum (which are actually quite insensitive for the diagnosis if rhabdomyolysis). The direct tubular toxicity (mainly proximal tubule) is thought to be related to myoglobin biproducts, including free iron and production of reactive oxygen species, which can lead to direct tubular cell injury. Renal vasoconstriction is likely multi-factorial, given these patients are oven volume deplete, ill and reduced vasodilating agents (ie. NO). Tubular blockage occurs when myoglobin accumulates in distal tubules (most common). This process is enhanced by acidic urine, and volume depletion, which can cause increased Tamm-Horsfall protein casts with myoglobin can precipitate in.

Treatment is mainly focused on volume expansion to prevent AKI and treating the underlying cause. Certain IV fluids are promoted in the treatment for several reasons:

1. Normal saline - good volume expander if hypotensive/significantly dehydrated. Issues with this include the significant chloride load, which put patient at risk for metabolic acidosis. This may worsen some the physiologic mechanisms that can lead to myoglobin induced kidney injury (vasoconstriction, precipitation and tubular injury).
2. RL - reasonable choice given lack of chloride.
3. Sodium bicarbonate - will allow alkalinization of the urine, which will theoretically prevent the above issues with myoglobin. However, no RCTs have shown this strategy to improve outcomes. It seems reasonable to include this in therapy, especially if patients is hyperkalemic secondary to muscle injury.
4. Mannitol - suggested as a volume expander as it can lead to an osmotic diuresis and improved GFR, theoretically clearing tubules of myoglobin and cast debris.

Here is an article identifying some predictors for AKI in rhabdomyolysis.

Predictors of AKI and Rhabdo