No Dr. Topf, no EKG changes

On Monday night I was called by one of our fellows regarding a patient in the ED with a potassium of 8.5. They had already given insulin, glucose and kayexalate and the follow-up potassium was 8.1. This is not much improvemnt and less than you typically see. The patient was in acute renal failure with a creatinine of 3 and was anuric.

I asked if the patient had any EKG changes and according to the ER doc the patient had just a touch o’QRS widening. What do you think?

Peaked symmetric T’s

Link for more on EKG changes in hyperkalemia

That night his CPK was 5,000. The next day it rose to 341,680.

Now dat’s a spicy meatball!

– Initially posted using BlogPress from my iPhone

Hypokalemia and rhabdomyolysis

Hypokalemia can induce rhabdomyolysis. The purported mechanism is that hypokalemia antagonizes one of the natural causes of exercise induced vasodilation. Normally, during exercise muscles release intracellular potassium causing local pockets of hyperkalemia which triggers vasodilation and increases perfusion to the active myocytes. Total body potassium depletion and hypokalemia decrease local hyperkalemia preventing the vasodilation which results in tissue hypoxia and rhabdomyolysis.

 In The Fluid and Electrolyte Companion we illustrated it thusly:

I remember thinking how funny it was that we used bowling to represent exercise (though we did slide in those runners behind the bowler).  Oh clipart, how much nerdtainment you have given me.

This past week-end one of my patients experienced this. He is a high school student who loves to fish. He has congenital type 2 RTA, so is predisposed to hypokalemia. The exercise that triggered his rhabdo:  fishing. He presented to the ER following a day of fishing with complaints of muscle cramps and weakness. His potassium was reported as less than 2, with CPKs in the 800 range.

One of the unexpected consequences of the rhabdomyolysis was that his cramping continued after the potassium was corrected. In fact, it was actually much worse muscle spasm and tetany of the hands. Turns out, this second round of neuromuscular symptoms weren’t due to hypokalemia but rather rhabdomyolysis induced hypocalcemia. He had a normal total calcium and a low ionized calcium. The muscular symptoms responded to a gram of IV calcium gluconate.

How do you go from an EGD to acute kidney injury?

We had an interesting consult a few weeks ago.

The patient was an elderly gentleman who recently underwent an EGD for gastritis-like symptoms. A few days after the procedure he received a call from his gastroenterologist telling him that he had H. Pylori and needed to start an antibiotic. He was prescribed PrevPac for 10 days. He almost immediately began to feel worse. His wife ultimately stopped giving him the PrevPack after about four days of increasing weakness, lethergy and nausea. Despite stopping the new medicine the patient continued to deteriorate. He was admitted about 2 weeks after the EGD.

His creatinine had risen from a baseline of 1.2 mg/dL to 4.5 mg/dL. Our initial thought was that he was pre-renal. We prescribed 0.9% saline but the patient didn’t respond, and his creatine continued to rise.

One clinical pearl that I repeatedly teach fellows is not to under treat pre-renal azotemia. If you think the patient is volume depleted give enough fluid that the next day if the creatinine has not improved you will be convinced that the patient is no longer volume depleted. You want to fully rule-out volume depletion after the first day.

This patient didn’t respond to fluids so we reevaluated the history. PrevPac, what’s in that?

  • Lansoprazole
  • Amoxicillin
  • Clarithromycin
Clarithromycin is a potent inhibitor of CYP3A4 so it interacts with a lot of medications. Our patient was on simvastatin. Let’s check out what does Dr. Google has to say about that:
We check his CPK and its 8,000 almost a week after he stopped taking the Clarithro.

Rhabdo induced acute kidney injury due to a drug interaction.

Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Clarithromycin is a potent inhibitor of CYP3A4, the major enzyme responsible for simvastatin metabolism.

Effects of Clarithromycin on the Pharmacokinetics of SimvastatinCompared with simvastatin alone, coadministration of clarythromycin and simvastatin significantly increased the peak concentration and the area under the curve for simvastatin by approximately 8-fold (p<0.0001). Levels of simvastatin acid were also significantly (about 14-fold) higher during clarythromycin treatment compared with simvastatin alone (p<0.0001).

If the figures on pharmacokinetics from that last article are to be believed then 500 mg of clarithromycin magnifies 80 mg of daily simvastatin to an equivalent daily dose of 640 to 1,120 mg.

Rhabdomyolysis induces acute kidney injury from myoglobin. Myoglobin can precipitate in the presence of acidic urine. The heme component of myoglobin can generate free-radicals which can damage lipid membranes. Patients develop vasoconstriction in response to rhabdomyolysis, both from the direct effect of the myoglobin on the renal vasculature and due to the movement of intravascular fluid into the damaged muscles. This gives a pre-renal picture on the fractional excretion of sodium.

Evaluating volume status can be tricky because patients will often have peripheral edema from the inflammation associated with the rhabdomyolysis. Additionally the BUN:Cr will often be low as the creatinine tends to rise quicker in rhabdomyolysis than in other forms of renal failure. This is usually explained by the release of intramuscular creatinine rather than just a failure to clear creatinine. The younger age and increased frequency of men suffering from rhabdomyolysis may also play a role in this observation.

The electrolyte abnormalities of rhabdomyolysis:

  • Hyperkalemia
  • Hyperphosphatemia
  • Hypocalcemia (early)
  • Hypercalcemia (late)
  • Hyperuricemia
  • Anion gap metabolic acidosis

 The NEJM recently did a nice review of rhabdomyolysis which presents the recent inconclusive data on alkalinization (not proven to be helpful but the animal/disease models make it look like the right thing to do), mannitol and diuretics and use of high flux dialyzers.

The Annals of Internal Medicine recently published a review of Statin-Related Myopathy. Here is what they had to say about drug interactions:

Because simvastatin, lovastatin, and atorvastatin are primarily metabolized through the cytochrome P450 3A4 (CYP3A4) isoenzyme (43), inhibitors of CYP3A4 could theoretically increase serum statin levels and exposure to susceptible tissues. Drugs known to interact with statins include protease inhibitors, cyclosporine, amiodarone, and fibrates (44, 45). Protease inhibitors are potent CYP3A4 inhibitors and thus can increase up to 30 times the plasma concentrations of certain statins (45, 46). Consequently, both simvastatin and lovastatin should be avoided in pa- tients receiving protease inhibitors (42, 45, 47). Cyclosporine is a potent inhibitor of not only CYP3A4 but also several membrane transporters, and it increases the phar- macokinetic area under the curve of statins by 2- to 25- fold, with many reported cases of rhabdomyolysis (44). Statin dosages in patients receiving cyclosporine have therefore been limited to 5 mg/d for rosuvastatin, 10 mg/d for simvastatin and atorvastatin, and 20 mg/d for lovastatin (42, 47–49).

Pravastatin is not metabolized by the P450 system but is excreted renaly. Fluvastatin and rosuvastatin are metabolized by an alternative enzyme, CYP2C9.

Propofol induced lactic acidosis

I was consulted on a patient with acute renal failure and severe acidosis without an obvious source. The intensivist postulated this could be propofol induced B-type lactic acidosis. I had not previously encountered this entity.

Apparently propofol can block the electron transport train of the mitochondria causing lactic acidosis. Clinically the patients present with lactic acidosis, rhabdomyolysis and acute renal failure.

Propofol Infusion Syndrome Associated with Short-Term Large-Dose Infusion During Surgical Anesthesia in an Adult

Interesting article showing propofol decreasing oxygen utilization in animal model

Pediatric case in which the doctors captured increased levels of various types of carnitine indicative of altered mitochondrial oxygen utilization.

Craven et al found 24% rate of unexplained metabolic acidosis with propofol use, suggesting a much more common mild form of the disease.

My patient was exposed to only a single dose of propofol so I am skeptical but the lack of an alternative compelling etiology is leaving me considering this disease.


Just got my second rhabdomyolysis patient in the last 2 months. Both had anuric acute renal failure and both had CPKs over 100,000.

In fellowship, the dogma was that sodium bicarbonate was ineffective and could do harm. The reasoning was that alkalinizing urine made calcium-phosphate less soluble, increasing the likelihood of calcification in the tubule extending the renal damage.

Recently, I found a paper from the Journal of Trauma 2004 by Brown and Rhee (Alternative) which showed compelling trends for improved outcomes with mannitol and bicarbonate. What was so impressive to me was that as the disease got more severe (higher CPK) the experimental group appeared to do relatively better. The authors were prevented from reaching a significant p value primarily by having too few patients with severe rhabdo.

I will use the handout from a prior morning report on the subject for the teaching session on Monday.

Rhabdo for Morning Report