We discussed about a case of salicylate poisoning in noon conference today.

We had some interesting discussion about the role of Acetazolamide in salicylate poisoning.

Acetazolamide is a non bacteriostatic sulfonamide which acts as a carbonic anhydrase inhibitor and thereby causes bicarbonate , sodium and potassium loss in urine. It causes urine alkalization and this is favourable for salicylate excretion in its ionic form. However , acetazolamide has a tendency to decrease systemic Ph because of bicarbonate loss in urine and can potentially increase the neurotoxicity of salicylate. In the clinical setting where we are constantly infusing sodium bicarbonate to achieve alkalemia, the systemic acidosis caused by acetazolamide may not have clinical implication, especially since it is a long acting drug which needs several hours to cause systemic acidosis. If we are aggressively infusing sodium bicarbonate(after a bolus of 2-3 mEq/kg) to prevent systemic acidosis, starting acetazolamide appears reasonable.

There are several case reports of using acetazolamide successfully in older literature(1950-1980)

I do not see any evidence for its use or contra-indication in recent literature.

Many of the salicylate poisoning patients have concomitant hypokalemia and volume contraction.

Hypokalemia leads to increased ammoniageneis and subsequent increased net acid excretion. Volume contraction leads to  secondary hyperaldosteronism and subsequent hypokalemia and alkalemia(by increasing net acid excretion). Both hypokalemia and volume contraction do not favor the excretion of salicylate !

The focus should be on aggressively managing hypokalemia(even if not manifested at the time of presentation, we notice hypokalemia while treating with sodium bicarbonate) , alkalinizing the blood and urine. It is not now considered a standard of care to give acetazolamide for salicylate poisoning since it aggravates hypokalemia, volume contraction and systemic acidosis (although theoretically it can help alkalinize urine -which may not occur in the setting of volume contraction and hypokalemia-both factors resist urine alkalinization)and potentially worsens neurotoxicity of salicylate!

Can we consider acetazolamide to sustain high urine pH after aggressively correcting the volume, hypokalemia and achieving systemic alkalosis? The answer is anybody’s guess!

 

Yuvaraj

 

 

Metabolic alkalemia is difficult to sustain since Kidneys can excrete excess bicarb and correct alkalosis quickly. When there is chloride depletion or hypokalemia, kidneys have decreased ability to excrete the excess bicarb and metabolic alkalemia ensues.

This takes us to the next question!

1) Why does chloride deficient state decreases the ability to excrete excess bicarb?

2) How does hypokalemia contribute to maintaining metabolic alkalosis?

Chloride deficient state increases bicarb reabsorption in proximal tubule and distal tubule(To maintain electro neutrality either chloride or bicarb( two predominant anions) has to be reabsorbed with sodium, so in chloride deficient state bicarb is reabsorbed). Also, in the cortical collecting duct(beta intercalated cell) chloride from the lumen is exchanged for bicarb from inside the cell. In the chloride deficient state, this is limited. I guess, these are good enough reasons for maintaing the alkalosis in chloride deficient states(what ever be the initial pathology that initiated the alkalosis)

Hypokalemia increases ammonia generation in proximal tubule and thereby facilitates acid excretion(even in alkalemic state). Hypokalemia also causes intracellular acidosis(protons exchanged for K  trying to mitigate hypokalemia)and extracellular alkalosis. This in proximal tubule will lead to increased acid excretion and bicarb reabsorption. Also, most cases of hypokalemia are associated with hyperaldosteronism (either primary or secondary ) which by itself increases acid excretion by activating H/K pump and also by K excretion in principal cell(in response to Na absorption through ENaC) which inturn is exchanged for proton .

Now we understand that to maintain metabolic alkalosis, there should be either chloride depletion or potassium depletion and it makes much more sense to classify metabolic alkalosis as

1) Metabolic alkalosis secondary to chloride depletion

2) Metabolic alkalosis secondary to potassium depletion

 

 

Chloride depletion occurs in vomiting, NG suction, diuretics (chloruretic diuretics in contrast to kaliuretic diuretics)

K depletion occurs  in the following conditions

• Primary hyperaldosteronism
• Cushing’s syndrome
• Secondary hyperaldosteronism
• Kaliuretic diuretics
• Excessive licorice intake
• Bartter’s syndrome 
  Severe potassium depletion

The rest of the causes of metabolic alkalosis are usually not sustainable without chloride deficient state or a potassium deficient state(milk alkali syndrome, persistent bone resorption-where kidneys will step up alkali excretion)

Vomiting, NG suction, Diuretic use, Hyperaldosteronism(primary and secondary) and Severe potassium depletion accounts for 90% of the cases of metabolic alkalosis!

Hope this helps to quickly know the differentials of metabolic alkalosis and to quickly think about the pathogenesis .

 

Yuvaraj

 

 

Follow up/ 03/17/2014 from commentary section

Dr.Weiner’s lecture today gives us the reason why Hypokalemia in RTA is not associated with increase in ammonia production!. The defect in Type 2 RTA is NBE2 in the basolateral membrane(most likely pathogenesis) . This increases bicarb concentration intracellularly in the proximal tubular cells and thereby the systemic acidosis is masked and the proximal tubular cells spill bicarb in the urine much more than what can be reabsorbed by distal mechanism.
In Type 1 RTA although NH3 production is increased proximally, this has to be reabsorbed in the ascending loop of Henle(NKCl cotransporter is used for ammonia reabsorption) and subsequently this reabsorbed ammonia should be secreted in the distal tubule to help H+ excretion. The defect in H+ ATP prevents NH4 + production. So the net Ammonium production is decreased in type 2 RTA and this contributes to acidosis.

 

66 y/o f with long history of Sjogren’s syndrome and RA presented with hypokalemia, hyponatremia and metabolic alkalosis. She had a TTKG> 10 when her K was 2.9 indicating K wasting. She had normal calcium level and magnesium level. Aldosterone level was elevated and Plasma renin activity was not suppressed.

24 hour urine K was increased and calcium was pending.

 

We suspected Gitelman syndrome!

I was very hesitant to agree with this diagnosis given the age of onset of symptomatology and the long history of Sjogren syndrome. A diagnosis which will go with her history of autoimmune disorder would have made more sense.

On reviewing  Sjogren syndrome related hypokalemia, I understood that,

1) SS can lead to Type 1 RTA (hypokalemia and acidosis) – However, the pt had alkalosis and not acidosis

2) SS can lead to Na wasting  and this subsequently leads to K wasting in principle cell(in exchange for sodium). This mechanism is entirely different from RTA

3) Autoantibodies targeted against NCC and subsequently leading to Aquired Gitelman syndrome.

 

Well, the third possibility sounds reasonable in this clinical setting!

Follow the link to study more about aquired Gitelman in Sjogren syndrome

http://synapse.koreamed.org/Synapse/Data/PDFData/0158EBP/ebp-7-5.pdf3)

Yuvaraj

 

Update from commentary section

There are other references for the aquired Gittelman Syndrome which I am presenting below.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041481/

http://www.ncbi.nlm.nih.gov/pubmed/18805608/

http://www.ncbi.nlm.nih.gov/pubmed/20888090

http://www.ncbi.nlm.nih.gov/pubmed/12955689

Yuvaraj