Overview of sodium disorders.

Hypernatremia and hyponatremia are common electrolyte abnormalities seen in patients in all settings. When I think about sodium disorders, I view it very differently than, say, potassium disorders. Hypokalemia requires the spinal reflex of an intern to correct in most situations. Hyperkalemia is often easy to correct to an acceptable level. In contrast, hyponatremia seems be be an electrolyte disorder that carries a large amount of momentum. Hypernatremia can be slow to resolve occasionally. Just like any large ship, brisk movements of serum sodium in hyponatremia can be freighting. Sodium levels outside of the normal range must be respected, and slow progress towards normal values must be the goal. Information below is derived from UpToDate and the references noted below.

Evaluation of Hypernatremia

We’ll start with the easier of the two etiologies — hypERnatremia. Whenever I get a consult for hypernatremia, my initial mental reaction is “give more electrolyte-free water.” There is, of course, more nuance to the diagnosis and management, but not much. When initially examining the chart of a patient with hypernatremia, the first question you should ask is what neurological condition do they have. Normal people who can walk to the sink and get water should not have hypernatremia. The thirst response to hypernatremia is typically so overwhelming that conscious, healthy individuals will simply not allow themselves to develop hypernatremia. They will drink something before this happens. Most often, you will find that they are someone on mechanical ventilation, or they are an individual with extremely poor functional status such as an elderly nursing home patient. It should be your first reaction and duty to figure out how your patient actually allowed themselves to develop hypernatremia.

After that point, it is your next job to figure out how they lost free water in the first place. There are 3 possibilities for this water loss and they are are insensible losses, GI loss, and renal loss. We lose free water every day through sweat and breathing. Burn unit patients have monstrous insensible losses. GI losses are self explanatory. It is likely that you have found a cause of free water loss by this point, but if you are not able to find to find the source by history alone, measure the urine osmolality.

If the urine osmolality is less than the serum osmolality ( essentially a urine osmolality <300 mOsm/kg), then it’s very possible that the patient has either central or nephrongenic diabetes insipidus. At this point, you should give DDAVP and watch urine osmolality closely as part of a workup for diabetes insipidus (DI). Find literature on this and follow the recommendations for DI evaluation.

If the urine osmolality is 300-600 mOsm/kg, then the patient could either have diabetes insipidus or an osmotic diuresis. Collect urine for 24h and calculate a total daily solute excretion (urine osmolality multiplied by total daily urine volume). If the total daily solute excretion is >1000 mOsm/day, then they have an osmotic diuresis (due to high protein feeding, glucosuria, or mannitol).

If the urine osmolality is >600 mOsm/kg, then the free water loss is extra renal.

One important point — it IS possible to have hypervolemia and hypernatremia. Think of the ICU patient who has been septic and 10 liters positive from fluid bolus. They may then become severely acidotic and then get sodium bicarb pushes, thus making them hypernatremic. Also ICU patients are often fluid overloaded from initial sepsis. A week into their hospitallization, they may still be on the vent, but have not had free water and then become hypernatremic despite net fluid overload for the hosptital course.

Treatment of Hypernatremia.

The goal of treatment of for chronic hypernatremia is to lower the serum sodium. Begin treatment with D5W at a rate of 1.35 mL per kg body weight per hour. In a 75kg patient, this would be a D5W rate of 100mL/hr. Monitor serum sodium and adjust. If the patient is receiving tube feeds, you can give free water via this route instead. How fast can you lower the serum sodium? For adults, it was once thought that you shouldn’t lower the serum sodium more than 10mmol/L/day, but a new retrospective study (Chauhan 2019) showed that older adults tend to tolerate faster rates of correction. It’s always important to exercise caution. Is it really necessary to lower serum sodium more than 10mmol/L/day — unlikely. In addition, if you are giving D5W fast enough to attempt to lower serum sodium faster than that, you will likely cause an osmotic diuresis which will lead to more electrolyte free water excretion. That study does provide some relief, though, if we lower serum sodium faster than previously recommended.

Evaluation of Hyponatremia

Information below is derived from UpToDate and the (Verbalis 2015) paper. Lets begin. If you have a patient with hyponatremia, first realize the severity of the matter. Serum sodium from 130-134 mmol/L are not terribly worrisome in hospitalized patients. Sodium levels of 124-130 are associated with gait abnormalities which resolve when serum sodium is brought to normal ranges. Serum sodium below 120 mmol/L is considered severe hyponatremia. Seurm sodium 105 mmol/L or less is extremely worrisome.

After determining the severity, you next evaluate the chronicity. Unless you have lab values with time stamps that show you that hyponatremia developed within 48 hours, then you assume that it’s chronic. Treatment of acute hyponatremia is different and will not be covered here. When seeing a patient with chronic hyponatremia, the first step is to determine if the hyponatremia is true. Before anything else is done, get a serum osmolality. True hyponatremia will have a serum osmolality of < 280 mOsm/kg. At this point, hyponatremia is split into subytpes based on volume status — hypovolemia, euvolemic, and hypervolemic. Follow the simple diagnosis algorithm to arrive at a diagnosis. The most important aspect of diagnosing the cause of hyponatremia is thinking through the pathophysiology of hyponatremia and finding one which is suitable for your patient. Because of this, there will be a reasonably extensive discussion of the mechanism of hyponatremia etiologies below.

Hypovolemia: Etiologies include GI loss, diuretic therapy, cerebral salt wasting and mineralocorticoid deficiency. Gastric contents and stool are hypotonic and so protracted vomiting or diarrhea without replacement of fluid would be expected to lead to volume depletion and hypernatremia. However, if patients ingest fluid and food low in sodium in conjunction with a baroreceptor-mediated stimulus to AVP secretion, hypOnatremia will result instead. Diagnosis of this can be aided with urine electrolytes. Urine sodium will be low in GI loss due to diarrhea, but may be elevated in prolonged vomiting because bicarbonaturia obligates excretion of an accompanying cation. In this instance, the urine chloride, which is a more reliable indicator of volume depletion with vomiting, should be low. Thiazides are more likely than loop diuretics as they cause sodium loss without altering the medullary concentrating capability. In one study of hyponatremia in patients using diuretics, 73% of diuretic induced hyponatremia was caused by thiazides alone, 20% were caused by thiazides in combination with anti-kaliuretic agents and 8% were due to furosemide alone (all of the 8% of the furosemide group had heart failure which is also a cause of hyponatremia therefore it may only be an association, not a cause. However, it has been reported to increase AVP and therefore may result in further stimuli that may lead to worsened hyponatremia). Onset of hyponatremia with thiazides is variable. 31% occurred within 5 days and another 31% in 14 days, but more recent studies have not confirmed these results. Also some other studies have shown that patients who developed thiazide induced hyponatremia actually gain weight and have lower serum uric acid levels suggesting a role for abnormal thirst and water intake in its pathogenesis. Cerebral salt wasting is a rare disorder that is difficult to diagnose. In a study of 187 patients with hyponatremia following neurosurgical procedures, only 3.7% had CSW and 2.7% had CSW + SIADH. The key differentiation between CSW and SIADH hinges upon establishing a period of urinary sodium loss and volume depletion that preceded the development of hyponatremia. In CSW, a period of sodium loss and volume depletion activates an appropriate ADH release which then leads to water retention and hyponatremia. Hypoaldosteronism does not cause significant hyponatremia. Patients with mineralocorticoid deficiency from primary adrenal insufficiency caused by adrenal destruction have renal sodium wasting that leads to hypovolemia and secondary volume stimulus to AVP release. Ingestion of water or administration of hypotonic fluids may lead to water retention and hyponatremia as with volume depletion from other causes.

Euvolemic hyponatremia: always occurs as a result of a relative or absolute excess fo body water. SIADH is the most common cause and criteria defined by Bartter and Schwarts are used to diagnose this. It includes a serum osmolality of <275, urine omolality of >100, clinical euvolemia, urine Na >20-30 mmol/L and absence of other causes of euvolemic hyponatremia and normal renal function and absence of diuretic use, particularly thiazide diuretics. Nephrogenic syndrome of inappropriate anti-diuresis is associated with genetic mutatons of V2R and leads to 10% of SIADH cases. Patient with isolated ACTH suppression or deficiency do not have mineralcorticoid deficiency and so they do not have in appropriate renal sodium wasting or hyperkalemia. In these patients, hyponatremia results from a failure to fully suppress AVP release in response to hypoosmolality (these patients are actually euvolemic). Hypothyroidism should not be thought of as a cause of hyponatremia unless the patient meets criteria for myxedema coma. Exercise associated hyponatremia is due to nonosmotically stimulated AVP secretion. Low solute intake is due to the fact that >50 mOsmol of urinary solute excretion are required to excrete each liter of maximally dilute urine and hyponatremia results when fluid intake exceeds the maximum volume of urine that can be excreted based on the available urine solute Primary polydipsias more likely to cause s marked diurnal variation in sodium (eg 141 at 0700 and 130 at 1600) as the kidney can excrete over 20L water per day with peak excretion water rates of ~800mL/hr. Medications used to treat psych disorders can cause hyponatremia.

Hypervolemic hyponatremia is either due to HF, cirrhosis, AKI, CKD or nephrotic syndrome. The main cause of hyponatremia in HF is nonosmotic release of AVP. Hyponatremia occurs in cirrhosis (but rarely in the absence of ascites) and the mechanism is a nonosmotic release of AVP. The pathophysiology of hyponatremia in cirrhosis is associated with portal hypertension and a resultant arterial vasodilation of the splanchnic circulation due to endothelial or inducible nitric oxide synthase with increased nitric oxide. As a result of vasodilation, stretch receptors in the carotids are unloaded with a resultant decrease in the CNS tonic inhibition of the sympathetic efferent outflow which activates RAS as well as the nonosmotic secretion of AVP. In AKI, the UOP of relatively fixed and water intake in excess of UOP and insensible losses will cause hyponatremia. The same process is true for those with advanced CKD. Hyponatrema in nephrotic syndrome is less frequently reported, but when the serum albumin falls below 2 g/dL, intravascular volume depletion may result in nonosmotic AVP secretion. One very important point is that if someone has AKI or CKD and hyponatremia, the measured serum osmolality may be in the normal range. This does not mean that they have pseudohyponatremia due to multiple myeloma or lipoprotein X. Any kind of renal failure will cause the accumulation of osmotically-active solutes which are not measured on lab testing. In summary, someone with hyponatremia due to AKI or CKD may have a normal measured serum osmolality. If you get an ABG with lytes, you will find that this sodium on direct potentiometry will match the low serum sodium seen on a BMP with indirect potentiometry.

correct the serum sodium

Next, pick a rate of correction of serum sodium. In chronic hyponatremia, brain cells extrude substances like sodium, potassium, chloride as well as organic solutes such as myoinositol, glutamate and glutamine from their cytoplasm, allowing intracellular osmolality to equal plasma osmolality without a large increase in cell water. Therefore, when hyponatremia develops over several days, brain swelling is minimized so that patients with chronic (>48h) hyponatremia have more modest symptoms and almost never die of brain herniation. Osmotic demyelination is the most feared complication of rapid correction of chronic hyponatremia. Brain regions that have the slowest reuptake of organic osmolytes are most severely affected. The actual pathogenesis of this is not fully known, but it is possible that osmotic shrinkage of endothelial cells opens the blood-brain barrier allowing the entry of complement and other cytotoxic plasma components. Another possibility is that during recovery from hyponatremia, the loss of cell water coupled with the movement of potassium and sodium back into the cells leads to an initial increase in cell cation concentration that occurs before the repletion of organic osmolytes. Thes combined changes may directly injure and induce opoptosis of astrocyte, leading to a disruption of the function of myelin producing oligodendrocytes, relase of inflammatory cytokines and activation of microglia. Clinical manifestations are typically delayted for 2-6 days after overly rapid elevation in the serum sodium concentration and include dysarthria, dysphagia, paraparesis/quadraparesis, behavioral disturbances, lethargy, confusion, disorientation, obtundation, coma, occasionally seizures, and brain herniation and death. Severely affected patients may become “locked in” during which they are awake, but unable to move or communicate.

The rate of correction in acute hyponatremia should aim for a 4-6 mmol/L correction as this level of rise is sufficient to correct symptoms of acute hyponatremia and this is best done with infusion of 100mL 3% normal saline over 10 minutes and repeated twice if needed.

For patients with chronic hyponatremia, the overall main goal, if the patient does not have severe symptoms, is to go slow with correction and take your time. In someone without severe symptoms, the worst outcome would be to over-correct and push the patient into ODS. If a patient with chronic hyponatremia has severe sypmtoms, you should increase the serum sodium quickly, but not by much. For these patients, you should aim to increase the serum sodium rapidly by 4-6mmol/L. Do so by an infusion of 100mL 3% normal saline over 10 minutes and repeated twice if needed. This can be done through a peripheral line.

With any patient with chronic hyponatremia, the most important point is to not over-correct the serum sodium so as to not place the patients at risk for ODS. The population at risk are those with serum sodium <120mmol/L of >48h duration. For chronic hyponatremia, a correction of 6mmol/L per day appears sufficienct for patients with the most severe manifestations of hyponatremia and so therefore, this should be the goal of therapy. Aiming for this target that is well within the limits of correction, is the best option. For patients that are low risk for ODS, a correction of 4-8mmol/L/d is best. For those at high risk (SHAAM: Serum sodium <105mmol/L; Hypokalemia; Alcoholism; Advanced liver disease; Malnutrition) should have a goal correction of 4-6mmol/L/d. The limits not to exceed are 8mmol/L in any 24h period for those at high risk. For those at normal risk, 10-12 mmol/L in any 24h period and 18 mmol/L in any 48h period.

MANAGEMENT OF EXCESSIVE CORRECTION OF CHRONIC HYPONATREMIA

Patients who have been hyponatremic for only a few hours due to self-induced water intoxication related to psychosis or endurance exercise often develop a spontaneous water diuresis that rapidly brings serum sodium back to normal. Although it may exceed the goals of correction for low risk patients (10-12mmol/L/d in 24h and 18mmol/L/d in 48h, the risk of ODS is low and no additional measure are necessary.

Very careful monitoring is needed for patients with chronic hyponatremia below 120mmol/L is indicated via measuring serum sodium levels Q4-6h and measurement of UOP until serum sodium rises above 125mmol/L. To prevent over-correction, once the target correction (not the limit) for the day is reached, measures to increase serum sodium should be stopped. For the rest of the day , further correction from urinary losses should be prevented by replacing losses with 5% dextrose in water or oral water or terminating further urinary loss by administering 2-4ug DDAVP parentally. Alternatively, rather than waiting for an unwelcome aquaresis in patients with potentially reversible causes of hyponatremia (think thiazide diuretics), DDAVP may be given Q6-8h in combination with slow infusion of 3% saline treated to achieve a 6mmol/L/d increase in serum sodium as this creates an iatrogenic SIADH that prevents inadvertent over-correction. DDAVP is stopped when serum sodium rises above 128mmol/L.. In hyponatremic patients, if over-correction occurs then slowing of the serum sodium can be achieved by administering 2-4ug DDAVP in combination with repeated 3mL/kg infusion of 5% dextrose in water over 1h, remeasuring serum sodium after each infusion and continuing until the serum sodium has fallen below the limits of correction for the patients.

TREATMENT OF SPECIFIC HYPONATREMIAs

Hypovolemic hyponatremia: if a patient is hyponatremic and has signs of volume depletion, then the treatment is straightforward and requires correction of volume depletion although the bulk of the treatment effort will include preventing over-correction. Monitoring urine volume and osmolality will permit detection of aquaresis and allow clinicians to anticipate over-correction. With volume depletion, normal saline leads to an increase in both the serum and urine sodium once intravascular volume has been restored. If volume status is equivocal (hypovolemic vs euvolemic) then normal saline will increase urine sodium, but serum sodium will remain unchanged or fall as administered sodium will be excreted in a small volume of concentreated urine and the water is retained. In cases where the initial serum sodium is <120mmol/L or significant CNS symptoms from hyponatremia are present or the primary diagnosis is SIADH then hypertonic saline should be used as the initial diagnostic volume challenge to avoid any risk of lowering the serum sodium. In hypovolemic hyponatremia due to GI losses, normal saline is the mainstay of treatment. KCl should be added if hypokalemia and alkalosis is present due to vomiting as potassium is echangeable with intracellular sodium and potassium supplementation will also raise serum sodium. If acidosis is present from diarrhea, then an isotonic mixture of NaCl and sodium bicarbonate can be used.

Hyponatremia from thiazide diuretics should include holding the medication and patients should be closely followed for over-correction as this may be rapid with holding the drug. Hypertonic saline is indicated to raise the serum sodium by 4-8 mmol/L when seizures or significant AMS is present, but volume of hypertonic saline should be small in anticipation of water diuresis that will ensue. Furosemide should note be used with hypertonic saline due to the risk of precipitating hypotension. If hypokalemia is present, it should be remembered that potassium supplementation will increase the serum sodium without any change in eater balance. Encouraging water intake or administering DDAVP could be useful in this situation. Monitoring serum sodium every 6-8h is needed if serum sodium is <120mmol/L.

In cerebral salt wasting, hypovolemia should be corrected as this will worsen CNS injury. After that point, maintained in neutral sodium balance. Hyertonic saline is more predictable to raise serum sodium than salt tablets or fludrocortisone and so it is recommeneded above the others.

In mineralocorticoid deficiency, volume repletion with normal saline will be required. If patients with bilateral adrenalectomy experience mineralocorticoid deficiency should be suspected to have glucocorticoid deficiency as well. IV hydrocortisone, 50-100mg Q8h should be given as this will activate the mineralocorticoid receptors as well and replacement with fludrocortisone is not required until the patients is titrated to lower replacement corticosteroids . A spontaneous aquaresis may develop after volume depletion is corrected and so frequent monitoring of serum sodium should be completed.

TREATMENT OF EUVOLEMIC HYPONATREMIA

Sometimes the underlying disorder of euvolemic hyponatremia will resolve hyponatremia such as glucocorticoid replacement in glucocorticoid deficiency or treatment of pneumonia in cases where this is the cause of SIADH.

SIADH: fluid restriction has been considered first line therapy for SIADH with goal intake <800mL. In general, patients with urine sodium >500 mOsm/kg will be unlikely to achieve goals for increase in sodium and so pharmacologic treatment should be considered for first line tx. Hypertonic saline is infrequently effective, but should be given for severe cases with CNS manifestations. Among patients with a urine osmolality more than 2x the serum osmolality (>500mOsmol/kg) a loop diuretic may be used to reduce urinary concentration, thereby increasing water excretion. In SIADH patients with SIADH with unresolving hyponatremia despite fluid restriciton, vaptans (such as conivaptan) can be used. When starting vaptans, allow patients to have free access to water and drink as they like during the first 24-48 hours. You should also measure serum sodium frequently, as in every 6-8h. Don't use for patient’s with serum sodium <120 mmol/L. Vaptans are contraindicated in cirrhotic patients.

Patients with nephrogenic syndrome of inappropriate diuresis (NSIAD) should be treated like SIADH patients.

Patients with glucocorticoid deficiency should be started on stress dose steroids after testing to prove glucocorticoid deficiency is undertaken. Prompt water diuresis following initialttion of glucocorticdoid treatment supports this diagnosis and so close monitoring of serum sodium should be undertaken. Fluid intake should not be limited due to the likelihood of aquaresis. If overcorrection occurs due to this, then D5W should be given or DDAVP administered.

Synthroid should be given in hyponatremia due to hypothyroidism along with fluid rstctition.

Exercise induced hyponatremia should be treated with 100mL 3% sodium chloride bolus and repeated every 30mintues until serum sodium reaches 125mmol/L or until symptoms resolve. Hypertonic saline should be given if sympoms and signs suggest this condition, if serum sodium is <125 mmol/L. treatment with hypertonic saline is optional if serum sodium is 126-130 mmol/L and generally no needed for sodoium >130 mmol/L.

Beer potomania should be treated with an adequate diet.

Primary polydipsia should be treated with behaviror modification although cloxapine is a promising therapy.

HYPERVOLEMIC HYPONATREMIA

Heart failure: treatment includes sodium restriction, fluid intake to less than that of insensible losses and UOP and loop diuretics. It’s not known if long term treatment with loop diuretics helps as these are known to increase AVP levels. A reasonable approach for these patients would be initial fluid restriction with loop diuretics is hyponatremia is mild. Fore severey symptomatic patients with very low or rapidly falling serum sodium, then use hypertonic saline combined with loop diuretics. If patient has mild smptoms due to hyponatremia or if the level of hyponatremia is compromising the use of diuretic, then vaptans shuldb e used.

Cirrhotic patients should be treated with fluid restriction (<750mL) and diuretics. Tolvaptan is contraindicated in pts with liver disease. Conivaptan is a combined V1aR/V2R antagonist and may increase portal blood flow due to V1aR in splanchnic circulation and may precipate varicella bleeding. Do not use vaptans in cirrhotic patients.

Nephrotic syndrome: fluid restriction. In patients with normal eGFR who do not respond to fluid rescctriction, a vaptan can be used.

REFERENCES

Chauhan, K., Pattharanitima, P., Patel, N., Duffy, A., Saha, A., Chaudhary, K., ... & Coca, S. G. (2019). Rate of correction of hypernatremia and health outcomes in critically ill patients. Clinical Journal of the American Society of Nephrology, 14(5), 656-663.

Verbalis, J. G., Goldsmith, S. R., Greenberg, A., Korzelius, C., Schrier, R. W., Sterns, R. H., & Thompson, C. J. (2013). Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. The American journal of medicine, 126(10), S1-S42.