Current Concepts in Neurohormones: Vasopressin and the Kidney

ASN Renal Week, Official Symposium, November, 2005

Panel Discussion


Dr. Schrier
Dr. Sterns
Question index:
Questions received during this symposium have been paraphrased
and the answers submitted by the panelists are presented.


There is increasing use of various drugs that block aldosterone; spironolactone, eplerenone, in patients who often have some degree of renal insufficiency who may also be taking ACE inhibitors, angiotensin receptor blockers, beta blockers – the incidence of hyperkalemia, how threatening is that, do you think? There are certain papers that suggest that it is hardly being seen - it is hard to believe!
There is an increased tendency to use intravenous vasopressin for blood pressure support in patients with heart failure that are hypotensive. I would like to know your thoughts about this, particularly in those that are hyponatremic to start with.
The speculation that the hyponatremia may have some non-neurological effect to determine the course of a variety of diseases that are associated with chronic hyponatremia – there is one study that you quote, I have heard you do this a few times, where hypertonic saline was given to patients in congestive heart failure and over the course of the next several weeks or months, they did not die as fast as the other group. Now, that is a reasonable speculation, but you do not want these folks who are now going out of the room to be giving hypertonic saline to patients in congestive heart failure. I am reminded of the stunts that are done on television where they tell you, “Don’t try this at home. This can only be done by a professional.”
In regards to the management of severe hypotonicity, I just wanted to relate a recent case I heard about a 40-year-old man who came in, had drunk himself down to a serum sodium concentration of 99, had a very maximally diluted urine, and was a little confused. He went to the ICU and they said - this is severe hypotonicity, we have to give him hypertonic saline. And this was somebody who had had full capacity to excrete maximal free water, and then the next day, the serum sodium concentration was 128 which I think exceeds all of our comfort levels, the speed at which it was increased, and had it been a woman and not a man, it might have been even worse. The question is, when somebody develops this hypotonicity, you do not know how long a time period it has gone on. They have the capacity to excrete free water so quickly, that in fact, even without giving them anything, they can overcorrect. How would you recommend approaching those patients?
Do you think the hypertonic saline reverses hyponatremia by increased serum sodium or by increasing the urinary water loss on top of that?
Do you believe that the risk of osmotic demyelination syndrome is similar when sodium is increased by hypertonic saline vs. by use of an aquaretic?

Panelist Responses
(Back to question index) There is increasing use of various drugs that block aldosterone; spironolactone, eplerenone, in patients who often have some degree of renal insufficiency who may also be taking ACE inhibitors, angiotensin receptor blockers, beta blockers – the incidence of hyperkalemia, how threatening is that, do you think? There are certain papers that suggest that it is hardly being seen - it is hard to believe!

Dr. Schrier: There is a review in the New England Journal within the last year that looks at the hospitalizations due to hyperkalemia and the mortality due to hyperkalemia after the RALES study (which described use of epleronone, an aldosterone blocker) and they clearly showed an increased incidence of hyperkalemia. So, I think, particularly, when aldosterone blocking drugs are being used on the background of a beta blocker and an ACE inhibitor in patients who have decreased renal function, you have to be careful. On the other hand, I think that our hepatologists have known for a long period of time that the #1 diuretic to use in cirrhosis for sodium-water retention is one that blocks the aldosterone system. Until the RALES study aldosterone blocking drugs were not used in cardiac patients, and in the RALES study - at least the claim was, that there was no effect on the kidney as far as sodium was concerned. There was a change in potassium. So, there may have been a little effect, but this effect is extrarenal. It is primarily on the heart as I discussed. So, I think we can use aldosterone blocking drugs, but we have to be careful as far as the hyperkalemia is concerned.

(Back to question index) There is an increased tendency to use intravenous vasopressin for blood pressure support in patients with heart failure who are hypotensive. I would like to know your thoughts about this, particularly in those that are hyponatremic to start with.

Dr. Schrier: I think the interesting thing would be to do a number of studies once we are looking at changes in osmolality, because at least there are some in vitro data that suggest that the vascular responses and maybe cardiac responses to the neurohumoral agents are attenuated, are altered, in the presence of hyponatremia. What was your question? I am sorry I got off on a tangent there.

My question related to patients with heart failure who are hyponatremic to start with, and in whom you come in and give intravenous vasopressin for blood pressure support.

Dr. Schrier : I think in the setting of sepsis and vasodilatation, there is a lot of data suggesting there is a relative resistance to angiotensin and norepinephrine and that vasopressin by altering the effect on potassium channels is more effective. So, I think a pathophysiologic argument can be made that vasopressin has a substantial role in the hypotensive patient who is vasodilated. I notice, however, once people start using it and see how effective it is, that they use it in non-vasodilated states, and the potential problem is that angiotensin and norepinephrine have inotropic effects that vasopressin does not have, so you can get big decreases in cardiac output. If you have vasodilatation and high cardiac output such as cirrhosis, that is not a problem. If you have a low cardiac output circumstance and you are using vasopressin, that could be a problem.

Moderator: We are going to have to cut it here, I am afraid, but part of his question was – if the patient is hyponatremic and you are using vasopressin, you have to restrict water, is I guess the concern.

Dr. Schrier : They are hyponatremic because the vasopressin receptors have already been occupied. It is nice to use V1 agonists like terlipressin that do not have a V2 effect, but quite frankly, I think using vasopressin is fine, because the V2 receptors are already occupied because of nonosmotic release of vasopressin. So, you can get your V1 effect before terlipressin is approved in this country.


(Back to question index) The speculation that the hyponatremia may have some non-neurological effect to determine the course of a variety of diseases that are associated with chronic hyponatremia – there is one study that you quote, I have heard you do this a few times, where hypertonic saline was given to patients in congestive heart failure and over the course of the next several weeks or months, they did not die as fast as the control group. Now, that is a reasonable speculation, but you do not want the people who are now going out of the room to be giving hypertonic saline to patients in congestive heart failure. I am reminded of the stunts that are done on television where they tell you, “Don’t try this at home. This can only be done by a professional.”

Dr. Sterns: An Italian group has done this and has reported results from a double-blind study where the BNP levels come down faster when serum sodium was increased. It is remarkable. No, I am not advocating this approach; it is a very tricky maneuver. It is, however, intriguing and our conventional wisdom is challenged. That is about all I would say. So no, this is not ready for prime time use yet, and I would not try this at home

(Back to question index) In regards to the management of severe hypotonicity, I just wanted to relate a recent case I heard about a 40-year-old man who came in, had drunk himself down to a serum sodium concentration of 99, had a very maximally diluted urine, and was a little confused. He went to the ICU and they said - this is severe hypotonicity, we have to give him hypertonic saline. And this was somebody who had had full capacity to excrete maximal free water, and then the next day, the serum sodium concentration was 128 which I think exceeds all of our comfort levels, the speed at which it was increased, and had it been a woman and not a man, it might have been even worse. The question is, when somebody develops this hypotonicity, you do not know how long a time period it has gone on. They have the capacity to excrete free water so quickly, that in fact, even without giving them anything, they can overcorrect. How would you recommend approaching those patients?

Dr. Sterns: This is a very real problem. We keep focusing on the numerator. In fact, if you look at patients who develop osmotic demyelination, many of them are going through the mechanism that you described. If you look at the case reports, you do not have to give hypertonic saline. You can give them normal saline, etc. To prevent over-rapid correction, you have to either chase the water diuresis by replacing water, or stop the water diuresis with DDAVP. There is very limited experience with DDAVP in this situation. We have been doing this regularly now. It is again tricky. You have got to watch it. As soon as you stop the DDAVP, the water diuresis is going to come back. So, you have to essentially give the patient SIADH and then give them hypertonic saline on top of it to gradually increase the serum sodium until you can decrease or discontinue the DDAVP. This is a tricky maneuver, but it is one that you may have to do on occasion.

(Back to question index) Do you think the hypertonic saline reverses hyponatremia by increased serum sodium or by increasing the urinary water loss on top of that?

Dr. Sterns: Yes, indeed. The free water clearance is a function both of the urine osmolality and solute excretion – absolutely - when you give hypertonic saline, you are both adding to the numerator (sodium) and decreasing the denominator (water), and both will increase the serum sodium level. But you can increase serum sodium by causing a water diuresis alone. You have to watch the urine output.

(Back to question index) Do you believe that the risk of osmotic demyelination syndrome is similar when sodium is increased by hypertonic saline vs. by use of an aquaretic?

Dr. Sterns: Do I think they are comparable? Yes. The only data that you could do that are really real would be an experiment on animals. They are probably the same. I think formal head-to-head trials have not been done, but my belief is that they are the same.


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