Thursday, June 24, 2010

Therapeutic misadventures in rhabdo

There are three commonly promoted strategies used in the treatment and prevention of AKI in rhabdomyolysis: 1) Normal saline 2) Bicarbonate containing solutions 3) Mannitol.

Volume resuscitation is clearly paramount when treating rhabdo, but whether bicarbonate or mannitol is beneficial is controversial. The figure below from a recent NEJM review gives a nice overview of the state of the literature.

Regardless of what therapy is ultimately decided upon it’s important to keep in mind that each can lead to unique but potentially counterproductive complications.

Hypocalcemia – Bicarbonate containing solutions have some attractive features based on animal data suggesting that they reduce:
1) Tubular precipitation of Tamm–Horsfall protein–myoglobin complexes
2) Generation of injurious oxidation products
3) Afferent arteriole vasoconstriction induced by metmyoglobin.

Unfortunately, in addition to these theoretical benefits, alkalinization of the blood pH can lead to increased calcium complexing with albumin thus decreasing physiologically active ionized calcium. This complication can be particularly problematic (eg tetany) early in rhabdo when serum calcium is dropping due to movement into damaged muscle and precipitation from serum as calcium phosphate.

Non-Gap Acidosis – Normal saline is used as an intravascular volume expander to replace fluid as it moves into damaged muscle.

Large volumes of NS are sometimes required in rhabdo and can lead to “dilutional acidosis.” There are several proposed mechanisms behind this that are nicely discussed in one of Nate’s prior posts. If clinically significant, lowering of the serum pH and subsequently urine pH could potentiate all of the mechanisms bicarbonate therapy experimentally mitigates.

Osmotic Nephrosis – The use of diuretics is again, controversial (must mean something when that word keeps popping up!) but in volume replete patients mannitol has several sited benefits.

Its main effect is as an osmotic diuretic leading to increased urinary flow and the flushing of nephrotoxic agents through the tubules. It also acts as a free-radical scavenger and an intravascular osmotic agent reclaiming fluid from injured muscles. Unfortunately, when large quantities of mannitol (greater than 200g/day or accumulated doses of greater than 800g) are used they can lead to renal vasoconstriction and direct tubular toxicity. This brand of AKI is termed osmotic nephrosis and histologically appears as tubular cytoplasmic vacuolization.

Pseudohyponatremia – Mannitol has the additional potential complication of hypertonic hyponatremia.

As an effective serum osmole, mannitol raises serum osmolality and pulls free water into the intravascular space diluting the serum sodium concentration. The effect on serum osms can lead to significant serum hypertonicity resulting in seizures as the brain shrinks.

Graham Abra, MD


Anonymous said...

What is the role of loop diuretics and CRRT in elimination of the pigment?

Matt Sparks said...

"Loop diuretics also increase urinary flow and may decrease the risk of myoglobin precipitation, but no study has shown a clear benefit in patients with rhabdomyolysis. Therefore, loop diuretics in rhabdomyolysis-induced acute kidney injury should be used in the same manner as that recommended in acute kidney injury that is due to other causes"

HD is indicated "when acute kidney injury is severe enough to produce refractory hyperkalemia, acidosis, or volume overload, renal-replacement therapy is indicated, principally with intermittent hemodialysis, which can correct electrolyte abnormalities rapidly and efficiently. Conventional HD does not remove myoglobin effectively owing to the size of the protein and is therefore usually mandated by renal indications. However, owing to the pathogenic role of myoglobin in rhabdomyolysis-induced acute kidney injury, preventive extracorporeal elimination has been studied. Although plasmapheresis has been shown to have no effect on outcomes or on the myoglobin burden of the kidneys, continuous venovenous hemofiltration or hemodiafiltration has shown some efficacy in removing myoglobin, principally with the use of super high-flux filters and high volumes of ultrafiltration (convection). However, the evidence is mainly from isolated case reports, and the effect on outcomes is unknown. In addition, some studies have shown that the half-life of serum myoglobin does not differ significantly between patients who are treated conservatively and those who receive continuous venovenous hemodiafiltration. Until randomized studies are performed, preventive hemofiltration cannot be recommended. NEJM Volume 361:62-72 July 2, 2009 Number 1.