32: Why normal saline makes hyponatremia worse in SIADH

In this episode I’ll share with you what he taught me and I’ll:

1. Review the pathophysiology of hyponatremia from SIADH
2. Explain how normal saline makes it worse
3. Discuss basic treatment of severe, symptomatic hyponatremia from SIADH and what to do if you correct the sodium too fast
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I’ve got to thank a critical care doc I work with – Pulmonology Tony – for taking the time to teach me about hyponatremia from SIADH several years ago.

Before we get to the topic for today’s show I want to update you on 2 projects I’m working on. The first is the Pharmacy Nation Slack group. This is a free group with other pharmacists from around the world collaborating with each other using real-time messaging to help better care for patients. I hope you join me and the over 80 other Pharmacy Nation members there – request an invite at pharmacynation.org!

Since I’ve started this podcast, I’ve noticed there are a lot of pharmacists and other medical professionals sharing their expertise with the world using blogs and facebook pages and twitter accounts. But there are only a handful of high quality medical podcasts that are being published regularly. I’m hoping to change that. That’s why I’m putting together a step-by-step course on how to start a medical podcast – so that other medical professionals can bring their knowledge, expertise, and voice to the world of podcasting. To learn more about the course, and to sign up to be notified when it is available, head over to howtostartamedicalpodcast.com.

Learning about SIADH

The approach to the diagnosis and treatment of hyponatremia is complex.  I recommend you read a review article such as this one or read the monograph in a tertiary reference such as UpToDate to get a more in-depth understanding of hyponatremia.

One of the best ways that I have found to learn concepts about treating diseases is to focus on the basic underlying pathophysiology of the disease. Back in pharmacy school I didn’t focus much on anatomy & physiology – but in practice I’ve learned that was one of the most important classes in my training. Each time I study about the best way to treat a disease (with or without medications) I focus on learning the pathophysiology.

That’s how Pulmonology Tony helped me understand hyponatremia in SIADH. SIADH stands for Syndrome of Inappropriate Anti-Diuretic Hormone. In this syndrome, there is too much antidiuretic hormone in circulation. Anti-diuretic hormone promotes water retention and solute loss in the collecting duct of the nephron. Too much ADH, and you end up with too much water retention & solute loss. The solute that is lost is primarily sodium, and this combined with excess water retention is what leads to hyponatremia in SIADH. SIADH can be caused by CNS damage or CNS disorders, cancer, lung disease, and medications. The list of medications that have been associated with causing SIADH is long! The most common classes that I see cause SIADH in patients are antiepileptics, antipsychotics, and antidepressants. You can find a detailed list here.

Symptoms vary with the duration and severity of hyponatremia. Hyponatremia from SIADH can often be severe – with a sodium 120 mEq/L or lower. Patients may present with seizure or coma at this level if the hyponatremia is acute.

Mild to moderate symptoms of hyponatremia are relatively nonspecific and include headache, nausea, vomiting, fatigue, gait disturbances, and confusion. In patients with more acute hyponatremia, such symptoms could rapidly change without warning to seizures, respiratory arrest, and herniation.

How normal saline makes SIADH worse

On the surface, it is easy to think that giving normal saline (154 mEq/L) to a patient with hyponatremia from SIADH will help raise the serum sodium. But in the case of SIADH, giving normal saline will actually lower the serum sodium even more. Here is why:

Sodium and water handling by the kidney are regulated independently: sodium by aldosterone and atrial natriuretic peptide; and water by ADH. In SIADH, sodium handling is intact and only water handling is out of balance from too much ADH. Therefore when administering 1 liter of normal saline to a patient with SIADH and a high urine osmolality, all of the sodium will be excreted, but about half of the water will be retained – worsening the hyponatremia. This is because the concentration of sodium in the urine of a patient with SIADH is going to be higher than the concentration of sodium in normal saline.

An example of the calculations which prove this can be found here:

A few simple calculations can illustrate this point. Suppose a patient with SIADH and hyponatremia has a urine osmolality that is relatively fixed at 600 mosmol/kg. If 1000 mL of isotonic saline is given (containing 150 meq each of Na and Cl or 300 mosmol), all of the NaCl will be excreted (because sodium handling is intact) but in only 500 mL of water (300 mosmol in 500 mL of water equals 600 mosmol/kg). The retention of one-half of the administered water will lead to a further reduction in the serum sodium concentration even though the serum sodium concentration may initially rise because the isotonic saline is hypertonic to the patient.

Using the calculations in the preceding section on true volume depletion in a woman with a baseline serum sodium (SNa) of 110 meq/L:

New SNa = total effective solute ÷ total body water (TBW)

= 3300 meq (same as baseline) ÷ 30.5 L (500 mL increase)

= 108 meq/L

With sodium handling by aldosterone intact, in order to raise the serum sodium with IV fluids, the sodium concentration of the administered IV fluids must be greater than the concentration of sodium in the urine – not the serum.

Treatment

In addition to stopping potentially causative medications, there are two main treatment strategies for the acute treatment of SIADH.

1. Fluid restriction
2. Sodium chloride

Vasopressin receptor antagonists are a potential 3rd option but they are not covered here since they have not been adequately studied for the initial treatment of acute hyponatremia from SIADH.

Fluid restriction

Fluid restriction with a goal intake of less than 800 mL/day should be considered in all patients with hyponatremia from SIADH. This may be all that is necessary if the patient has mild-moderate symptoms or has severe hyponatremia but is without symptoms.

The effectiveness of fluid restriction alone can be predicted by the urine to serum cation ratio.  A ratio less than 0.5 suggests that the serum sodium concentration will rise with fluid restriction, while a ratio greater than 1 indicates that it will not. Interestingly, if this ratio is greater than 1, loop diuretics will be effective in increasing water loss and raising the serum sodium concentration.

In addition to fluid restriction, the therapy of SIADH-associated hyponatremia often requires the administration of sodium chloride, either as oral salt tablets or intravenous saline.

Sodium chloride

Oral salt tablets can be used in patients with mild-moderate hyponatremia.

When using intravenous saline, the electrolyte concentration of the administered fluid must be greater than the electrolyte concentration of the urine. This usually requires the use of hypertonic saline.

If your patient has severe symptomatic hyponatremia including seizures or other severe neurologic abnormalities or intracerebral diseases, IV hypertonic saline should be given immediately. Give a 100 mL bolus of 3 percent saline, and repeat this once or twice if neurologic symptoms persist or worsen.

In an ideal situation, hypertonic saline would be given via a central line. But just like with vasopressors:

Any port in a storm.

The priority is to fix the neurologic disorder – IV access can be optimized after the hypertonic saline has been started.

What to do if you raise the sodium too high too fast

After the neurologic symptoms are under control, further calculations can be performed to determine how much sodium chloride the patient still needs. Ideally, the serum sodium will not rise by more than 4 to 6 mEq in the first 24 hours of treatment. This target is lower than I remember learning in school, but a lower target provides a better margin of safety should the sodium rise too fast. The risk of correcting the serum sodium concentration too quickly is osmotic demyelination of the nervous system. This syndrome results in irreversible or partially reversible neurologic damage.

The risk is serious enough that if a patient with hyponatremia has a serum sodium rise greater than 9 mEq in 24 hours (or 18 mEq in 48 hrs), re-lowering of the serum sodium should be considered. This is supported by animal data which show it is effective in preventing osmotic demyelination syndrome.

The regimen to use is 6mL/kg of 5% dextrose in water IV, repeated until the serum sodium rise is back below 9 mEq in 24 hours (or 18 mEq in 48 hours). Desmopressin also is given at a dose of 2 mcg every 6 hours IV or subcutaneously.

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If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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