More on acetazolamide

A few weeks ago while on acetazolamide for altitude sickness prophylaxis the whole group noted tingling and paresthesias. What was curious is that the symptoms were most pronounced in the morning. The paresthesias were primarily on the hands and feet with a rare complaint of symptoms on the face.

I suspected that these symptoms are due to hyperventilation induced hypophosphatemia and the high carbohydrate breakfast (oatmeal) caused a bolus of insulin that further lowered the phosphorous. Does anyone know the etiology? Does hyperventilation cause hypophosphatemia if the increase in ventialtion is compensatory for metabolic acidosis?

FYI: the acetazolamide taste alteration makes carbonated beverages inedible.

Journal Club: dialysis time, not the critical factor in graft survival

One of the inherent truths in transplant is that the longer someone is on dialysis the worse the outcome after transplant. Patient with higher dialysis vintage prior to transplant are more likely to lose their graft and die following transplant. This was first shown by Cosio Et al. and subsequently verified by other researchers.

Cosio’s primary figure showing dramatically increased mortality with increasing time on dialysis

Though Cosio et al. was the first (?) to find this association the most elegant data comes from Meier-kreiesche, Et al. who looked at graft survival when a paired sets of cadaveric kidneys is donated to recipients with differing duration of dialysis. By looking at paired kidneys they were able to neutralize any confounding factors from the donor. The primary analysis looked at kidneys that were split between one recipient with less than 6-months of dialysis and another with more than 2-years of dialysis. The end-point was graft survival:

They also calculated patient survival and they likewise found a significant splay based on time on dialysis:

Five- and ten-year unadjusted overall patient survival for paired kidneys was 89% and 76%, respectively, in the group on dialysis less than 6 months compared to 76% and 43%, respectively, in the group on dialysis for more than 2 years (P<0.001 each).

The obvious implication was that dialysis was bad for you. The longer you were on dialysis the more baggage you were carrying at the time of transplant and that baggage comes back to haunt the recipient with a shorter life and shorter kidney survival. From the conclusion:

…the longer patients wait on dialysis for a transplant the longer patients are exposed to the chronic effects of end-stage renal failure and dialysis. It is well documented that patients on dialysis have alterations in the concentration of a number of substances (e.g., homocysteine, advanced glycosylation end products, and lipoproteins) that may predispose these patients to both cardiovascular and renal allograft vascular damages. In addition, the poor nutrition, chronic in- flammatory state, altered immunologic function, and inade- quate clearance that often accompanies patients with ESRD on dialysis may predispose these patients to poorer toler- ance to the immunosuppressive agents after transplantation.

On our journal club last week we looked at a study by Schold, et al. that analyzed time on dialysis prior to transplant by dividing it into time prior to wait list and time after being listed. They found that all of the risk from prolonged dialysis comes from the time prior to being placed on the transplant wait list:

The data was more dramatic for graft loss than for mortality. The intersting part of this is trying to explain this discrepancy.  Why would time on dialysis prior to wait listing be any different that time on dialysis after wait listing? There is no biological difference so the authors conclude that the difference must be in a subtle, previously unmeasured difference in co-morbidity or access to care. The authors go on to pre-suppose that efforts to reduce patient exposure to dialysis may not yield the benefits one might expect if these other factors are not also corrected.

Acetazolamide was a smashing success

My camping club, Aggressive Deer Adventures had a great trip to Kings Canyon National Park. The group consisted of 7 men, all 40-something who lived at around 600 feet above sea level. The whole trip took place between eight thousand and twelve thousand feet.

Every one started on low dose acetazolamide (125 mg bid) 36 hours before we left home.

Not one of us developed anything more than a small headache on travel day. Complete success.

SIADH: Day 9

The patient had SIADH due to viral encephalitis. We started tolvaptan 30 mg and his SIDAH rapidly reversed with the sodium rising from 124 to 128 overnight and up to 136 in the following week. Along with his improved sodium the patients mental status improved. I attribute that more to improvement in the encephalitis than the normalized osmolality but the association is there.

I stopped the Tolvaptan after 8 days and the next morning here are his urine chemistries:


Urine sodium 20, urine osmolality was 614. Somehow, I got a urine chloride rather than the urine potassium I ordered. The sodium nudged up to 137 off the tolvaptan. It looks like the SIADH has resolved with the urine sodium falling from 148 prior to the drug to 70 after the first dose to 20 off the drug completely.

Also note that even though the urine osmolality (614) is greater than serum osmolality, the serum sodium can still rise. This is because the electrolyte free water is still positive, despite a negative solute free water.



– Posted using BlogPress from my iPhone and edited on my 15 inch MacBook with a big dent in the corner.

Altitude sickness and the role of acetazolamide

I am going to Kings Canyon National Park at the end of the month. I will leave Detroit, elevation 600 feet and will travel via planes, trains and automobiles to 9,000 feet for the first night. Then we will begin out hike and cross passes over 12,500 feet.

In the past, I have developed modest altitude sickness going from 600 to 8,000 feet. So, I am nervous about the same problem on this trip. Acetazolamide is supposed to ameliorate altitude sickness.

The body acclimates to decreased oxygen and is so effective that people can function at the top of Mt. Everest without supplemental oxygen. The partial pressure of oxygen at the summit is 43 mmHg which is equivalent to breathing 6% FiO2.

From NEJM 2009, 360: 140-9

The primary means of improving oxygenation is hyperventilation. Hypoxia stimulates ventilation. There is also an increased ventilatory response to carbon dioxide so that that the normal respiratory response to carbon dioxide is exaggerated so that one gets more ventilation at lower CO2 levels. The reason that increased ventilation improves oxygenation has to do with the effect carbon dioxide in the blood has on oxygen transfer in the alveoli. During respiration CO2 leaving the blood dilutes the incoming oxygen at the alveoli, increased respiration, lowers the pCO2 and hence minimizes this dilution.

Antagonizing the hyperventilatory response is respiratory alkalosis. Central chemoreceptors detect alkalosis in the CSF and slow respiration. This is one of the key factors preventing the essential hyperventilation.

Acetazolamide (Diamox) is a carbonic anhydrase inhibitor. Carbonic anhydrase catalyzes the reaction converting bicarbonate to carbon diaoxide and water:

This is the fundamental buffer reaction in the body and it is amazing to me that blocking this essential acid-base reaction is not lethal. Acetazolamide works in the proximal tubule by blocking the reabsorption of filtered bicarbonate.

Acetazolamide induces a proximal renal tubular acidosis (RTA 2). This results in metabolic acidosis. The metabolic acidosis stimulates compensatory hyperventilation. This metabolic acidosis antagonizes the respiratory alkalosis which normally occurs with hyperventilation.

Their maybe additional advantages of acetazolamide including decreased CSF production and antagonizing fluid retention.

Happy climbing.

SIADH: day two

I gave the patient from yesterday 30 mg of tolvaptan. The repeat sodium was 128, up from 124 and urine sodium was down to 70, from 148 and the potassium was 40, down from 48. Urine output rose to 3425 mL.

The electrolyte free water clearance went from negative 1,364 to positive 481 mL.

Tolvaptan FTW.

The SIADH is due to West Nile Virus induced encephalitis.

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Dense SIADH

Check out that urine sodium. The guys pissing normal saline. That’s the highest urine sodium I have ever seen.

Urine sodium 148
Urine potassium 48
Serum sodium 124
Urine output 2350

Electrolyte free water clearance:
-1364 mL

Interpretation: with those urine electrolytes, when urinates 2,300 mL it is as if he actually drank nearly a liter and a half of tap water. And that is why fluid restriction fails in dense SIADH.

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New slang for the fractional excretion of urea: febun

Since the abbreviation for the fractional excretion of sodium is FENa, all the cool kids call it the fena (rhymes with Gina). So the fractional excretion of urea by extension is the FEUrea, which doesn’t quite role off the tongue.

Last month on vacation, we had dinner with an old friend from medical school, now a hospitalist outside Atlanta, and she started talking about ordering febuns. I asked her what a febun was and she explained the fractional excretion of BUN. Ahhh.

My wife, who hated driving my car with the license plate FE UREA immediately declared febun both cute and the official title, at least in the Topf household.

Kidney Stone riddle: the answer

The commenters nailed it.

He had primary hyperparathyroidism and went for a parathyroidectomy. The recurrent laryngeal nerve was severed during the procedure and that left him unable to speak.

He suffered in silence for 6 months before going for a procedure which pushes the vocal cords on the paralyzed side medially. This allows the normal cord to meet the still paralyzed, but medially displaced cord and phonate.

Kidney Stone Riddle

I was at my great aunt’s 90th birthday party on Tuesday and was chatting with a neighbor. He mentioned that after being treated for kidney stones he couldn’t speak for 6 months.

My face screwed up as I tried to figure out what the hell he was talking about. His next sentence explained everything.

What happened?

Other hints: his stone were conventional calcium oxalate stones, and he had recurrent stones.

I’ll leave the answer later today or tomorrow.