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Rhabdomyolysis - 3/5/2013

posted Mar 5, 2013, 8:49 AM by Rohit Das   [ updated Mar 5, 2013, 10:55 AM by Purnema Madahar ]

Patient venue for this daily…37 year old woman who presented with about a week of sacral and bilateral thigh pain in the context of previous viral URI symptoms. Notable subsequent workup revealed a CPK that peaked at ~53,000 and a urinalysis that showed “large” blood, but essentially no RBCs microscopically. Despite a normal creatinine, this is all consistent with the diagnosis of rhabdomyolysis, probably induced by a viral infection. So:

·         What is the pathophysiology behing rhabdomyloysis, regardless of the ultimate cause?

·         What are the causes of rhabdomyolysis and what’s the distribution epidemiologically? How is it diagnosed?

·         How frequent is AKI in rhabdomyolysis, and what’s the mechanism?

·         What are some principles for treating rhabdomyolysis?

What is the pathophysiology behing rhabdomyloysis, regardless of the ultimate cause?

·         First of all, some history…this is crazy…so the first claimed reports of rhabdomyolysis are actually implied in the Bible, in the context of his holiness sending quail to feed a large population of his starving minions. A “plague” then broke out, killing all those poor people. Apparently, quails consume large amounts of hemlock, a plant species known to cause severe rhabdomyolysis when consumed by humans…unbelievable. Further characterization of the syndrome occurred in the early 1900s in the context of a large earthquake in Sicily, Italy as well as from torture victims in World War I. In the 1940s, experimental induction of myoglobin related AKI led to a better understanding of why rhabdomyolysis has particularly bad implications…

·         Rhabdomyolysis is a syndrome – specifically, muscle pain in the context of high creatine kinase levels and myoglobinuria. It has numerous causes, which we’ll delve a bit in depth into in a little while. Ultimately, though, the responsible pathophysiologic mechanism is the same – increase in intracellular Calcium. Normally, extracellular [Ca2+] is around 10,000 higher than intracellular [Ca2+]…because of this ridiculously favorable concentration gradient, any minute change in cell permeability leads to marked changes in calcium homeostasis and consequent badness for individual cells. Cellular mechanisms for maintaining that gradient are very precise, and there are two main ways by which those mechanisms are disturbed in the context of rhabdomyolysis:

o   ATP Depletion – several of the etiologies of rhabdomyolysis directly lead to decreased production of ATP. Why does this matter? As you may have gathered, the cell needs a lot of energy to maintain the intracellular-extracellular calcium gradient, via various ATP dependent cation transporters present in the plasma cell membrane (also called the sarcolemma in muscle cells). Additionally, the sarcoplasmic reticulum and mitochondria, which are intracellular organelles that essentially act as Ca2+ depots, also help to maintain low intracellular [Ca2+], but also via ATP dependent mechanisms. So, depletion of that very important energy source leaves the cell susceptible to increases in intracellular [Ca2+].

o   Sarcolemma Rupture – similarly, several of the etiologies lead to direct “microtrauma” of the muscle cell plasma membrane, leaving Calcium to move as it wishes to…into the cell. Furthermore, as cells die, mitochondria and the sarcoplasmic reticulum obviously become dysfunctional, and the Ca2+ they have stored moves into the cytoplasm, further contributing to this disaster.

·         Why is high intracellular [Ca2+] bad? A lot of reasons…it leads to activation of various proteases that eat plasma cell and mitochondrial membranes, maintains constant muscle contraction thereby further compounding ATP depletion (a truly vicious cycle), causes mitochondrial dysfunction (leading to even MORE ATP depletion) and increases production of reactive oxidative species. Needless to say, this all ultimately contributes to muscle cell apoptosis and death.

What are the causes of rhabdomyolysis and what’s the distribution epidemiologically? How is it diagnosed?

·         There are way too many causes of rhabdomyolysis to go over in one sitting (please use the review article for a more comprehensive review), but generally speaking, they can be subcategorized…

o   Trauma Related Etiologies – war, earthquakes, a piano falling on you, immobilization, compartment syndrome, lightning bolts, burns…

o   Nontraumatic Exertional Etiologies – occurs either due to MARKED physical exertion with normal muscle (supply < demand), or due to normal exertion in the context of metabolic myopathies where oxygenation of muscle is impaired

o   Nontraumatic/Nonexertional Etiologies – this is what we see most of the time – drugs, toxins, infections, electrolyte issues, inflammatory myopathies…and the list goes on  and on and on…

·         In a decent epidemiological study of 475 retrospectively identified patients (study is attached), the most common cause were toxins (around 50% - alcohol, prescribed drugs, illicit drugs). Of those deemed to be due to prescribed medications, the most common were antipsychotics (40%) and statins (20%). Around 60% of cases had “multiple etiologies,” 10% of cases were due to metabolic issues (hypokalemia/natremic, hyperglycemic issues, hypothyroidism), and around 10% had no cause identified. Retrospective study…but sheds some nice epidemiological light on a syndrome with a very wide clinical spectrum…

·         Though the final diagnosis of rhabdomyolysis is dependent ultimately on laboratory findings, it should definitely be suspected in patients presenting with proximal muscle pain (majority of cases…around 60%) in the context of reddish-brown urine (also occurs around 50-60%) of the time.  Some important lab aspects of the diagnosis:

o   CPK (Creatinine Phosphate Kinase) – normal function of this muscle enzyme is to transfer a phosphate from creatinine phosphate to ADP, thus forming creatinine and ATP. It is a very sensitive marker of muscle injury and comes in many “isoforms” specific for its different locations in the body. In rhabdomyolysis, CPK levels rise at 12 hours after injury, peak around 3 days after the insult, and start downtrending 5 days out. Regarding absolute amounts, CPK levels are usually >5-fold normal, and usually above 5,000 IU/L.

o   Detection of serum myoglobin is pathognomonic for rhabdomyolysis, but not useful for diagnosis – although it peaks very rapidly and is the first enzyme that increases, it also rapidly disappears from the plasma due to its short half-life and quick metabolism - it dissapears around 24 hours after onset of symptoms. There are other markers of muscle injury that naturally also become elevated – aldolase, LDH, AST…but these markers have very low specificity and are therefore not worth checking.

o   Urinalysis – myoglobin is detected in the urine when the filtered amount is above the threshold for nephrons to reabsorb it – this occurs around when >1.5g of myoglobin is filtered (corresponding concentration of around 100 mg/dL). My point here – you can have myoglobin in your serum, but unless it reaches a certain amount, you won’t find it in the urine – SO, it is not necessary for diagnosis, and as mentioned, myoglobinuria occurs in around 50-60% of cases. Since myoglobin is a heme-containing protein, it reacts with the urine dipstick, but is differentiated from hematuria by the absence of RBCs microscopically.


How frequent is AKI in rhabdomyolysis, and what’s the mechanism?

·         The numbers are here are very variable…reported incidences range from 13 to 50% and dependent on the cause. Renal failure seems to occur most frequently in the context of toxin-related and trauma-related etiologies, and also more incident in patients with multiple different etiologies. Though the degree of CPK elevation does not always correlate with renal failure, there is a weak correlation – in one study, 60% of patients who developed AKI had CPK levels greater than 20,000, whereas only 10% of patients of who didn’t develop AKI had such levels. Furthermore, AKI rarely occurs when CPK levels are <10,000.

·         There are three main mechanisms by which rhabdomyolysis and muscle breakdown causes renal failure:

o   Direct Tubular Injury – this is due to not completely clear mechanisms, but it’s thought that cellular release of myoglobin and subsequent oxidation of free heme-Iron (from Fe2+ to Fe3+) leads to production of free radicals, which consequently leads directly to renal tubular cell injury and dysfunction. This predominantly occurs at the proximal tubules of nephrons.

o   Tubular Obstruction – one of the key factors for myoglobin’s nephrotoxicity is the presence of acidic urine. In the setting of rhabdoymyolysis and release of organic and phosphoric acids from muscle cells, urine IS usually acidic. This leads to disassociation of heme from myoglobin (essential to the first mechanism above), and also allows it to interact with Tamm-Horsfall proteins (a.ka., uromodulin – very abundant protein in human urine), which causes myoglobin to precipitate and obstruct nephrons, usually at the level of the distal tubules.

o   Renal Vasoconstriction – this is multifactorial – due to volume depletion from third-spaced fluid within damaged muscle, increased amount of vascular mediators that limit renal blood flow and interestingly deficits in Nitric Oxide (a vasodilator) which is “scavenged” by myoglobin in the renal microcirculation.

·         Some other aspects of rhabdomyolysis-related AKI - it leads to disproportionate increases in creatinine as compared to other causes (either due to cohorts being confounded by patients who are really muscular…or actually due to direct increase in serum creatinine from muscle release) and also leads to LOW FeNa levels, mainly due to the third mechanism mentioned above – this is a nice way to differentiate rhabomyolysis-related AKI from ATN.

 

What are some principles for treating rhabdomyolysis?

·         The main goal is to prevent renal failure, and if already present, to ameliorate it. Additionally, there are a host of very important electrolyte issues that need to be managed – hyperkalemia, hyperphosphatemia and hypocalcemia…yes, things can become very complicated.

o   VOLUME – this is paramount, and based on the principles of trying to maintain adequate renal perfusion in volume-depleted patients, “wash-out” obstructing tubular casts, and to increase urinary excretion of potassium. There is a lot of controversy about which TYPE of fluid to administer – normal saline vs. sodium bicarbonate (the latter based on myoglobin’s dependence on urine acidity for renal toxicity). In a retrospective study of 2000 trauma-related rhabdomyolysis, administration of bicarbonate made no difference…small RCTs have also yielded similar conclusions. Anyway, current recommendations are to administer fluids at an average rate of 400-500 cc/h, with a goal urine output of 3cc/kg/hour (~200 cc/h). If the urine pH is <6.5, sodium bicarbonate can be considered – BUT, this requires monitoring, as worsening of hypocalcemia necessitates stopping treatment.

o   ELECTROLYTES – needless to say, need to be on top of assessing for and treating hyperkalemia, which can be severe. Hypocalcemia should only be treated if symptomatic or if coexisting severe hyperkalemia is present. Interestingly, as patients recover from rhabdomyolysis, they often become HYPERcalcemic via numerous mechanisms – mobilization of calcium from muscle, decrease in serum phosphorus (and therefore less Ca-Ph binding) and increased calcitriol production (unclear mechanism). This “recovery” hypercalcemia is a very unique aspect of rhabdomyolysis worth being aware of…

·         So what’s the prognosis? Pretty good - most patients (80% was a number I found…) recover their renal function completely, and the need for HD is rare, but obviously a poor prognostic factor. Studies citing high mortality rates are in the context of bad etiologies – limb ischemia, immobility due to critical illness, etc…

 

Attached is a nice pathophysiology-oriented review article, a NEJM review on rhabdoymyolysis-related AKI, and the epidemiologic study I mentioned above. The patient presented above did pretty well – CPK at discharge was around 3,000, and she never developed renal failure thanks to some quality house staff management. No quail for her.

 

The Syndrome of Rhabdomyolysis: Pathophysiology and Diagnosis
Giannoglou et. al., Eur J Int Med 2007, Volume 18: 90-100

Melli et. al., Medicine (Baltimore) 2005, Volume 84: 377-85

Bosch et. al., NJEM 2009, Volume 361: 62-72
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