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Case: An unusual ICU referral
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Some years ago at Genius General Hospital, the ICU was asked to accept a patient from the medicine ward with cirrhosis, confusion, and hyponatremia (Na 125 mM) for hypertonic saline therapy. There was concern that the patient's confusion was due to his hyponatremia.
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Chart review showed that his hyponatremia was chronic, and not much worse than his baseline. Additionally, although he was being prescribed lactulose for hepatic encephalopathy, he was refusing most of the doses. The intensivist's impression was that the patient's confusion was most likely due to hepatic encephalopathy. It was recommended that the patient's lactulose dose be increased as simultaneous management for both his hepatic encephalopathy and hyponatremia.
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With effective lactulose therapy, the patient's sodium increased gradually and his confusion lifted. He did not require ICU transfer. It is unclear whether his confusion resolved due to treatment of hepatic encephalopathy or hyponatremia. Indeed, hyponatremia may be a component of the pathogenesis of hepatic encephalopathy, so these disorders are probably intertwined (Iwasa 2015).
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Introduction
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The last two posts on hyponatremia have focused on the use of hypertonic sodium chloride and sodium bicarbonate. This might create the incorrect impression that hyponatremia is due to a sodium deficiency. Instead, the core physiologic abnormality of hyponatremia is generally water excess. As discussed last week, the renal retention of water is typically what drives hyponatremia.
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This distinction becomes important when managing hypervolemic hyponatremia (mostly patients with heart failure or cirrhosis). These patients have an excess of both sodium and water, with a disproportionate excess of water. This occurs due to reduced cerebral perfusion causing excessive secretion of vasopressin and renal water retention:
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Aside from emergencies, hypertonic saline works poorly in hypervolemic hyponatremia, because it will worsen volume overload. Fluid restriction and furosemide may be better options. However, these may be poorly tolerated or ineffective.
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Recent research has focused on vasopressin inhibitors in this situation (“vaptans,” e.g. conivaptan and tolvaptan). By blocking vasopressin, these medications may facilitate renal excretion of water (figure below). However, explored previously, vaptans pose a risk of causing excessive water loss in the urine, with over-correction of the sodium. Additionally, due to potential liver toxicity, the FDA has recommended that tolvaptan be avoided in patients with liver disease and that it should never be used for longer than 30 days.
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This post will explore the potential use of osmotic laxatives and osmotic diuretics for the management of non-emergent, hypervolemic hyponatremia. This is usually mild and chronic, so the treatment goal is often a very gradual increase in sodium (e.g. ~3 mM/L per day). These therapies might also be useful for SIADH.
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Dosing: Targeting the amount of electrolyte-free water loss
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The change in serum sodium per liter of electrolyte-free water excreted can be estimated using the formula below:
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This usually yields a value of about 2-4 mM/L increase in sodium concentration per liter water output. Thus, targeting a net loss of ~0.75 liter/day of free water may be a reasonable initial target for most patients. Note that fluid intake must be restricted.
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Osmotic laxatives: Lactulose
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Basic physiology of osmotic laxatives
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The colon is permeable to water, so the osmolarity of stool is equal to blood (~300 mOsm/L). Therefore, ingestion of any nonabsorable substance with an osmolarity of >>300 mOsm/L will function as an osmotic laxative. Water will be drawn into the gut until the bowel contents reach an osmolarity of ~300 mOsm/L. Ultimately, bowel contents are excreted. The entire process results in the excretion of water.
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Dosing of lactulose
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Even while taking lactulose, there are still some electrolytes within the stool. Hammer 1989 found that with administration of 125 grams/day of lactulose, the average sum of sodium and potassium concentrations was 50 mEq/L. Thus, only ~66% of the stool volume is electrolyte-free water at this lactulose dose. This is a rough number, because with increasing lactulose dose the fraction of free water in the stool increases. Overall this suggests targeting a slightly higher stool output, perhaps 1-1.5 liters/day.
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Lactulose dosing is a bit tricky, because there is some ability of colonic bacteria to metabolize lactulose. Therefore, there is a threshold dose below which there is little laxative effect. Studies on healthy volunteers suggest that a dose around 125 grams/day might correspond with a target a stool output of about 1.3 liters/day (Hammer 1989). Given that most lactulose solutions contain 0.66 grams/ml, this corresponds to 45 ml four times daily. Since individual responses vary, it may be safest to start with a lower dose (e.g. 30 ml four times daily) and titrate upward. These doses are within the dose range used for acute hepatic encephalopathy.
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Monitoring osmotic diarrhea
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Lactulose therapy may be monitored on the basis of stool output, patient weight, and serum sodium concentration. If the sodium increases greater than the desired amount, this may be corrected by decreasing the lactulose dose and administering water (either enterally or intravenous D5W).
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Efficacy of lactulose to increase serum sodium
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Practitioners experienced in using lactulose in critically ill patients are familiar with the gradual increase in sodium which is observed when lactulose is administered to patients with limited fluid intake (e.g. NPO or intubated). Such patients often require substantial replacement of free water to prevent hypernatremia. Several reports describe hypernatremia when these trends in sodium were not attended to (e.g., Lukens 2011, Warren 1980, Nelson 1983). In particular, Kaupke 1977 reported a case wherein lactulose dosed at 50ml four times daily caused an average increase in the sodium concentration of 4 mEq/L/day, consistent with dosing considerations discussed above. The ability of lactulose to cause hypernatremia is widely acknowledged in the literature.
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Safety of lactulose
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Lactulose appears to be very safe. It is available over the counter in many countries. Side effects consist predominantly of bloating and flatulence. Lactulose has a long track record of safety in the ICU, even when used aggressively in very ill patients with liver disease.
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Use of lactulose in specific situations
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Cirrhosis: Lactulose may be an ideal agent for patients with cirrhosis, mild hypervolemic hyponatremia, and altered mental status. As in the case above, lactulose may simultaneously treat hyponatremia and hepatic encephalopathy.
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Heart failure: There is no direct evidence regarding the use of lactulose in heart failure. Prior to using lactulose, volume status should be assessed. Hyponatremia in heart failure is typically an indication of poor systemic perfusion. For patients who are not intravascularly volume overloaded, volume loss due to lactulose could further impair hypoperfusion. However, for patients who are intravascularly volume overloaded, lactulose is a logical consideration.
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Limited resources: Lactulose could be useful in situations where there were limited resources (e.g. treatment of a patient with SIADH without the capacity to infuse hypertonic saline and check sodium levels frequently).
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Urea & mannitol
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Urea is an unusual substance because it is absorbed by the GI tract and subsequently excreted extensively in the urine. When excreted in the urine, it pulls water along with it, acting similarly to an osmotic diuretic. However, it is unique compared to other osmotic diuretics, which generally cannot be absorbed via an oral route.
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The ability to promote electrolyte-free secretion of water in the urine has made urea a guideline-recommended therapy for SIADH. Urea also appears to be effective for hypervolemic hyponatremia (Decaux 2014). Unfortunately, urea is not available in the US for unclear reasons. Some authors suggest that urea is too bitter for the delicate “north American palate,” but this is nonsense (Vandergheynst 2015). Perhaps marketing urea is simply unprofitable.
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The closest drug to urea which is available in the USA might be intravenous mannitol. Mannitol functions as an osmotic diuretic, causing excretion of electrolyte-free water in the urine. However, the free water excretion induced by mannitol is variable (Keyrouz 2008). The combination of mannitol and furosemide promotes more consistent water excretion, but further evidence is needed (Pollay 1983, Porzio 2000).
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- Patients with cirrhosis or heart failure often have mild, subacute or chronic hyponatremia which may be difficult to treat (e.g. hypertonic saline is generally avoided because it will cause volume overload).
- Vaptans are one option for treating hypervolemic hyponatremia. However, they are expensive, carry a risk sodium over-correction, and conivaptan is contraindicated in liver disease.
- Urea may be a good option to facilitate excretion of water in the urine, but it is not available in the USA.
- Lactulose is an osmotic laxative, which promotes loss of water in the stool. This may be an inexpensive and safe approach to gently correct hyponatremia.
This blog is co-authored with Dr. Paul Farkas, senior consultant in gastroenterology.
This is the last of a series of three posts on hyponatremia:
- Hyponatremia I: Emergent treatment of hyponatremia or elevated ICP with bicarb ampules
- Hyponatremia II: Taking control of severe hyponatremia with DDAVP
Conflicts of Interest: None
Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.
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I think urea (Ure-Na) is now approved for in the U.S.
Fantastic article. I would love to know more on the use of osmotic laxatives in their control of hyponatremia.