Taking control of severe hyponatremia with DDAVP

Imagine an elderly patient presenting with hypovolemic hyponatremia (sodium of 115 mM) and moderate confusion.  How would you treat this patient?

The typical approach might be a slow infusion of 3% sodium chloride.  The presence of neurologic symptoms supports the use of hypertonic saline.  However, patients with hypovolemic hyponatremia are at high risk for over-correcting their sodium.  A common compromise between these two concerns would be to use hypertonic saline, but at a low infusion rate.

This approach has two seemingly contradictory flaws (figure below).  First, it is initially too conservative.  Moderately symptomatic hyponatremia is potentially dangerous, especially if the sodium should continue to fall.  For example, European  guidelines recommend a single bolus of 2 ml/kg 3% saline, perhaps enough to increase the sodium by 1-2 mM/L.  Second, slow initial therapy will still leave the patient at high risk of overcorrection (explained further below). 

The Adrogue-Madias equation is typically used to predict the change in sodium in response to an IV fluid (e.g. it is built into MDCalc).  This is a simple formula based on taking a weighted average of the sodium concentration of the infused fluid with the sodium concentration of the total body fluid.  The same principles could be used to determine the final sodium concentration if two solutions with different sodium concentration were mixed in a laboratory:

The Adrogue-Madias formula works well for predicting immediate changes in sodium concentration (e.g. bolusing fluid).  The weakness of the formula is that it doesn't take the kidneys into account.  Thus, over time the Adrogue-Madias formula loses predictive ability, because it is often unpredictable how the kidneys are going to handle water. 

Over-correction of hypovolemic hyponatremia is a common example of failure of the Adrogue-Madias formula.  The physiology of hypovolemic hyponatremia is shown below.  In response to cerebral hypoperfusion, the brain secretes vasopressin (a.k.a. anti-diuretic hormone).  Vasopressin has vasopressor effects and also causes retention of free water by the kidneys, both in efforts to support perfusion.  Free water retention causes hyponatremia.  This is not a "mistake," but rather evolutionary wisdom favoring perfusion over normonatremia. 

If a patient with hypovolemic hyponatremia is volume resuscitated, at a certain point perfusion improves and this shuts off vasopressin (figures below).  Without vasopressin, the kidneys rapidly excrete water, causing a dangerously fast normalization of the serum sodium. 

Although this example focuses on hypovolemic hyponatremia, overcorrection will also occur after treatment of any reversible cause of hyponatremia (e.g. psychogenic polydipsia, drug-induced hyponatremia, etc.).

There are two treatments to managing water over-excretion.  One treatment is to attempt to replace free water excreted from the kidney, for example with intravenous 5% dextrose (D5W).  This requires careful attention to urine output and serum sodium, with ongoing titration of the D5W.  Wrestling with normal kidneys is difficult.  Usually at some point something exciting happens in the ICU, attention is diverted, and before you know it the sodium is too high.  High rates of D5W may induce hyperglycemia.  Others have reported difficulty with this strategy (Perianayagam 2008; Gharaibeh 2015).

A more powerful approach to excessive water excretion is to provide desmopressin (DDAVP, 2 micrograms IV q8hr;  Sood 2013).  DDAVP stimulates the V2-vasopressin receptors in the kidney, causing renal retention of water (figure above).  This eliminates unpredictable excretion of water from the kidneys:

With blockade of renal water excretion, the Adrogue-Madias equation will be more accurate.  This allows control of the sodium based on fluid administration:

For example, if you wish to stop the rise of sodium, DDAVP may be given and fluid intake stopped.  This will halt intake and output of free water, so the sodium should remain stable.  This approach is easier to achieve than titrating a D5W infusion:  just order the DDAVP, stop fluid inputs, and you're done.  If the patient is neglected for a few hours, the sodium will probably be fine. 

The risk of osmotic demyelination syndrome depends on the average change in sodium over time, so if the sodium over-corrects this can still be remedied by decreasing the sodium to its original target.  Combining DDAVP with carefully calculated doses of D5W may achieve this.

This is obviously not the preferred strategy for managing sodium.  However, it is important to recognize that sodium over-correction is not an unfixable problem.  Even if the patient seems OK neurologically, it is probably safest to lower the sodium.  By the time symptoms of osmotic demyelination syndrome emerge, the optimal window for intervention has passed. 

Consider a patient admitted with chronic, asymptomatic hyponatremia due to hypovolemia.  Nothing dramatic must be done initially.  Fluid resuscitation may be undertaken with careful monitoring of the serum sodium concentration.  At some point, vasopressin levels will fall and the sodium will start really climbing.  Once the sodium has increased a fair amount (i.e. perhaps ~8 mM) or urine output accelerates, DDAVP and fluid restriction may be initiated to stop the rise in sodium.  When the DDAVP has been stopped, the sodium will continue to rise:

The physiology underlying this strategy is supported by an observational study of this approach by Rafat 2014.  They showed that DDAVP administration decreased the urine output and increased the urine tonicity, causing a halt in the rate of sodium correction over time:  

The weakness of this strategy is that it initially requires constant vigilance to detect overcorrection, with intervention at just the right moment.  This is not foolproof.  For example, in the Rafat series, about half of patients stillover-corrected their sodium.

The proactive DDAVP strategy represents the most definitive approach to controlling sodium.  This is performed as follows:

An example of how this strategy would work for a patient with severe symptomatic hyponatremia is shown below.  DDAVP is started immediately to block renal free water excretion.  Boluses of hypertonic therapy are provided initially to improve symptoms and raise the sodium by ~5 mM.  Given that the target rise in sodium over the first day is ~6 mM, after the initial increase in sodium, fluid intake is stopped for one day causing the sodium to be stable.  Subsequently, an infusion of hypertonic saline is started to gradually increase the sodium to normal. 

As shown below, a proactive DDAVP approach has two advantages in symptomatic hyponatremia compared to less aggressive management.  First, immediately increasing the sodium will rapidly bring the sodium to a safe level and relieve symptoms.  Second, proactive DDAVP prevents endogenous over-correction.

For patients who have asymptomatic hyponatremia, a proactive DDAVP strategy would consist of simultaneously starting DDAVP and an infusion of 3% saline:

Perhaps the most important contraindication to DDAVP is inability to control oral fluid intake (e.g. due to psychogenic polydipsia).  If DDAVP is given and the patient continues to have significant fluid intake, this will exacerbate the hyponatremia. 

Patients with pure hypervolemic hyponatremia (e.g. heart failure, cirrhosis) will not benefit from this approach.  These patients usually have mild hyponatremia and rarely over-correct their sodium, so there is little rationale for DDAVP.  Additionally, hypertonic saline therapy would worsen volume overload.  However, for a patient with multifactorialhyponatremia (e.g. a patient with profound hyponatremia due to mild heart failure, beer potomania, and thiazide diuretics), a proactive DDAVP strategy may still be considered along with furosemide diuresis. 

For patients with SIADH due to a chronic stimulus (e.g. malignancy), there is little benefit from administering DDAVP.  However, DDAVP won't hurt either (it will probably have no effect).  For patients with SIADH due to reversible factors (e.g. nausea, medications), DDAVP may be beneficial because such patients may over-correct after the cause of SIADH is removed.  Overall, a proactive DDAVP strategy should work fine for any patient with SIADH.  

Sood 2013 reported a series of 24 patients admitted with sodium <120 mM treated with a combination of DDAVP and hypertonic saline infusion.  These authors were targeting a rise of sodium of <6 mM within the first 24 hours, and achieved an average increase of 5.8 mM/L.  None of the patients had excessive correction.  Overall the Adrogue-Madias equation appeared to predict changes in sodium reasonably well:

Although this is an uncontrolled case series, it does support the efficacy and safety of this approach.  The only noted adverse event was one patient who developed pulmonary edema requiring diuresis. 

A recent systematic review of DDAVP use concluded that the proactive strategy was associated with the lowest incidence of over-correction.  However, this evidence was mostly derived from the Sood study (MacMillan 2015). 

This physiology illustrates the danger of vaptans (e.g. conivaptan, tolvaptan) in hyponatremia.  Vaptans inhibit the vasopressin receptor, causing renal excretion of free water: 

Rapid water excretion may cause sodium over-correction.  Vaptans may cause patients to transition from hyponatremia to hypernatremia with subsequent osmotic demyelination syndrome (Malhotra 2014).  The ability to inadvertently push patients into a hypernatremic state is uniquely dangerous compared to most mechanisms of sodium over-correction (which stop once the sodium normalizes).  Thus, the European 2014 consensus guidelines recommend against using vaptans.

An expert panel funded by the manufacturer of tolvaptan recommended that vaptans could be used in some situations.  Surprisingly, a recent NEJM review article supported the use of vaptans, accepting this expert panel over the European 2014 consensus guidelines.  The review admits that there are no RCTs comparing vaptans to other therapies for hyponatremia.

According to this review, to prevent over-correction the urine output must be replaced with intravenous D5W after the sodium has increased to the target level.  This is exactly the opposite of using DDAVP:  vaptans induce uncontrolled renal water excretion, which must then be replaced.  As discussed above, trying to keep up with renal free water excretion can be difficult.

Perhaps the greatest challenge of managing severe hyponatremia is avoiding sodium over-correction, which may cause permanent neurologic disability.  Understanding the physiology of sodium over-correction allows us to anticipate this, but it is still unclear when it will occur.  DDAVP appears to be the most effective approach to reversing, arresting, or preventing sodium over-correction.  Unfortunately there is little evidence regarding exactly how we should use this.  For patients at the highest risk of osmotic demyelination syndrome, it may be safest to start DDAVP proactively in order to avoid over-correction entirely.