By: Gadison Quick, PharmD; PGY1 Pharmacy Resident
Mentor: Kerry Yamada, PharmD, BCPS; PGY-1 Pharmacy Residency Coordinator, Truman Medical Center – Kansas City, Mo
Program Number: 2020-11-01
Approval Dates: December 1, 2020 to May 1, 2021
Approved Contact Hours: 1 hour
TAKE CE QUIZ
Electrolyte disorders like hyponatremia or hypernatremia are not diseases, but rather a pathophysiologic process indicating a disturbance in water homeostasis.1 Sodium is abundantly used throughout every major body system to maintain homeostasis. One of sodium’s many vital roles is to help maintain normal fluid volumes throughout various intracellular and extracellular compartments.2 Sodium and blood osmolarity are highly dependent upon each other, hence the phrase “where goes water, goes salt”. Physiologically, we see if the serum sodium concentrations (SNa) are elevated (>145mEq/L), fluid will move into plasma to dilute the high sodium concentration. Likewise, if SNa is low (<135mEq/L) fluid will move out of the plasma to concentrate and correct the sodium concentration. Understanding the pathophysiology related to changes in sodium concentrations, as well as serum osmolarity (SOsm) will help identify the underlying causes of sodium disorders and allow for a proper treatment course in clinical practice. This review will not be highlighting gaps in therapy, or new treatments, but rather review the complexity of sodium disorders in practice. It is necessary to periodically review the foundations of physiology to appreciate treating the patient rather than the number.
Symptomatic vs Asymptomatic Hyponatremia
Hyponatremia defined as a SNa <135mEq/L is a common electrolyte disorder that possess a therapeutic challenge when treating in clinical practice. Hyponatremia can be categorized based on sodium concentration, timing of onset, presence of symptoms, serum osmolarity, and fluid status. The vast categorization of hyponatremia can easily confuse practitioners and make identifying and treating the underlying cause difficult. Currently there are two sets of guidelines developed discussing the management of hyponatremia. One by professional organizations within the United States (“American guideline”) and one from within Europe (“European guideline”).3
Recognizing symptomatic hyponatremia is vital for patient outcomes, as severe symptomatic hyponatremia is life threatening and requires emergent intervention. Key symptoms to monitor for when assessing symptomatic hyponatremia can be divided into either moderately severe or severe symptoms. Moderately severe symptoms include nausea, vomiting, altered mental status, and headache. Severe symptoms can include cardiac arrest, deep somnolence, seizures, or coma. Both the European and American guidelines recommend aggressive therapy with infusion of hypertonic saline in the presence of symptoms. However, dosing differs between guidelines. The American guidelines recommend a 10 minute infusion of 100ml of 3% saline repeated 3 times as needed versus the European guideline recommendations of 2 150ml boluses of 3% saline each over 20 minutes. Although both guidelines recommend a rapid, intermittent treatment using hypertonic saline, there is also literature to support an alternative dosing strategy with a slow continuous infusion of hypertonic saline to minimize the risk of overcorrection. The SALSA trial is one trial currently being conducted comparing rapid intermittent infusion of hypertonic saline versus slow continuous infusion of hypertonic saline. Additionally, Garrahy et al5 compared rapid, intermittent infusion vs slow, continuous infusion of hypertonic saline in symptomatic hyponatremia patients with syndrome of inappropriate antidiuretic hormone (SIADH). This study concluded intermittent bolus dosing of hypertonic saline resolved serum sodium levels quicker, and had a positive effect on patient’s Glasgow-Coma Scale (GCS) score. Additionally, this study did not have any cases of osmotic demyelination syndrome (ODS) in either group, therefore this study reinforces guideline recommendations to use rapid, intermittent doses of hypertonic saline in symptomatic hyponatremic cases.
Asymptomatic hyponatremia is much more common in practice, but requires careful evaluation in order to identify the underlying cause. A stepwise approach is key when determining the correct underlying factor. The first step in this stepwise approach is to determine if your patient is truly hyponatremic without other confounding factors like hyperglycemia. Second, check the serum osmolarity. Various institutions may have different absolute cutoffs for osmolarity, but a standard serum osmolarity (SOsm) ranges from 275-290mOsm/kg. Identifying the serum osmolarity will help you determine whether this is a hypotonic, isotonic, or hypertonic disorder. Third, evaluate the fluid status. Does your patient have signs of dehydration or excess fluid? For example, signs of dehydration or low fluid volume can include hypotension, tachycardia, polydipsia, weight loss, dry mucous membranes, sunken eyes, decreased skin turgor, and increased capillary refill time. On the other hand, signs of excessive fluid status can included hypertension, shortness of breath, weight gain, peripheral edema, ascites, and a positive jugular venous distension (JVD). Lastly, ordering a urinalysis to assess urine sodium and urine osmolarity will allow you to assess for salt wasting syndromes, or dilution of sodium.
Approaching hyponatremia in a stepwise process can help the practitioner approach each case in a more simplified manner. The next step to treating hyponatremia is to recognize the various categories, that being hypotonic hyponatremia, isotonic hyponatremia, and finally hypertonic hyponatremia. The latter two are less complex, and easier to recognize; therefore will be discussed first before moving onto hypotonic hyponatremia. First, isotonic hyponatremia, also known as “pseudo-hyponatremia” is classified as a falsely low SNa. The falsely low SNa is due to excess substances in the plasma. These excessive substances can include triglycerides, cholesterol, and plasma protein. Mathematical equations can be utilized to predict the true SNa but the treatment of this process is to treat the underlying cause.
Plasma triglycerides (g/L)x 0.002=mEq/L decrease in Na
Plasma Protein- 8(g/L)x 0.025=mEq/L decrease in Na
Second is hypertonic hyponatremia. The etiology of hypertonic hyponatremia is similar to isotonic hyponatremia in that SNa is falsely low due to an excess of serum substances, specifically in this case glucose. Hypertonic hyponatremia is commonly seen in hyperglycemic states like diabetic ketoacidosis (DKA) or hyperosmotic hyperglycemic state (HHS). Similar to isotonic hyponatremia, there is a mathematical equation used to predict the true SNa, as well as the treatment goal to treat the underlying cause.
Corrected Sodium=measured sodium+1.6 ((serum glucose-100))/100
Moving onto the third and last, but easily the most complex hyponatremic disorder is hypotonic hyponatremia. This category of hyponatremia can be more complex because this disorder is further categorized based on patient fluid status. Because of the vast sub-categorization within this disorder, it is worth mentioning again the importance to use the previously mentioned stepwise approach to identify the underlying disorder. First using the stepwise approach, hypotonic hypovolemic hyponatremia, can be identified by recognizing SNa <135mEq/L, SOsm <275mOsm/kg, and finally incorporating patient specific symptoms of dehydration. The next step is to identify urine sodium (UrNa) and urine osmolarity (UrOsm). Measurement of UrNa and UrOsm can help distinguish between disorders like SIADH and hypervolemic hyponatremia.6 Increased concentrations of UrNa and UrOsm in this case can be due from renal losses of sodium, including an excess of diuresis, or a deficiency in aldosterone. Diuretics work by blocking the reabsorption of electrolytes, and subsequently water, and therefore in states where diuretics are used in excess, a higher ratio of sodium, and other electrolytes can be found in the urine. Secondly, aldosterone is an endogenous mineralocorticoid secreted by the adrenal glands, and regulated by the renin-angiotensin-aldosterone system. Aldosterone is secreted in response to low systemic blood pressure, or increased serum potassium. It works by regulating the nephrons to retain a higher amount of sodium and water, while also secreting more potassium into the filtrate to increase blood pressure and decrease potassium. In states with a deficiency of aldosterone, the nephron fails to retain sodium and a higher concentration of sodium is eliminated in the urine. On the other hand, if the urine study shows a diluted sodium and osmolarity, the loss of sodium is from a non-renal source, whether that be gastrointestinal in the form of emesis or diarrhea, blood loss or skin loss, in the form of burns, open wounds, or excessive diaphoresis. Regardless of the source of non-renal loss, treating the underlying cause will correct the low SNa.
Taking the same stepwise approach to hypotonic euvolemic hyponatremia, objectively will show a low SNa <135mEq/L, low SOsm <275mOsm/kg, but with an absence of patient symptoms for both dehydration, and edema. Examining the urine study, a diluted urine osmolarity can be due from beer potomania, or psychogenic polydipsia. Beer potomania is a unique syndrome of hyponatremia,7 as alcohol, in this case, beer combined with a poor diet causes a dilution hyponatremia. Remembering water reabsorption in the nephrons of the kidney is dependent on the reabsorption of solutes and electrolytes, if a patient were to have poor intake of solutes and electrolytes, the kidney would not be able to reabsorb water in normal homeostasis, leading to more free water in the urine, and thus a diluted UrOsm. Secondly, in psychogenic polydipsia (PPD), there is a disruption in the thirst control mechanism related to the endocrine system. Although PPD is most commonly seen in chronic schizophrenia, other mental illnesses including psychotic depression and bipolar disorder can portray polydipsia behavior.8 The pathogenesis of the polydipsia may be related to a hypersensitivity to vasopressin, an increase in dopamine activity, or a defect in osmoregulation.8 The mainstay of treatment for PPD is fluid restriction, as excessive fluid intake can lead to life-threatening water intoxication, manifesting as symptomatic hyponatremia. On the other hand, when examining the urine study, and UrOsm is concentrated, the underlying disorder can include hypothyroidism, glucocorticoid deficiency, or most commonly SIADH. Hypothyroidism is a common disease affecting millions of Americans, and countless others across the globe every year. Patients with moderate to severe hypothyroidism and mainly patients with myxedema may exhibit reduced sodium levels.10 The main mechanism related to hypothyroidism-associated hyponatremia is due to a decreased capacity of free water excretion secondary to elevated antidiuretic hormone (ADH) levels. The hypothyroidism-induced decrease in cardiac output (CO) stimulates carotid baroreceptors to release more ADH to retain fluid, and increase CO. This overtime causes a buildup of ADH, and subsequently a dilution of SNa. Next, relating hyponatremia to glucocorticoid deficiency, the mechanism of hyponatremia seen in glucocorticoid deficiency is similar to what was previously discussed with hypothyroidism-induced hyponatremia. A lack in the principle glucocorticoid cortisol may cause a reduction in systemic blood pressure and CO, stimulating a release of ADH. However, a second mechanism may be related to glucocorticoid deficiency-induced hyponatremia in that cortisol deficiency results in increased hypothalamic secretion of corticotropin releasing hormone (CRH), an ADH secretagogue.10 Lastly, and most commonly observed in practice in euvolemic hyponatremia is SIADH, which is a condition defined by the unsuppressed release of ADH. ADH is a hormone that stimulates water reabsorption in the kidney, primarily through stimulating the insertion of aquaporins to help the nephron reabsorb more water. When left unsuppressed, copious amounts of water gets reabsorbed back into the serum, causing SNa to be diluted. SIADH is most commonly treated non-pharmacologically through fluid restricting, however pharmacologic options are available including loop diuretics, vasopressin receptor antagonists (aka “vaptans”), and demeclocycline. Conivaptan (Vaprisol®) and tolvaptan (Samsca®) are examples of vaptans. Conivaptan is only available IV, while tolvaptan is available PO. These medications should be used cautiously as they can unpredictably change SNa and in some instances overcorrect. Secondly, these medications are hepatotoxic, and should be avoided in hepatic dysfunction. Demeclocycline (Declomycin®) is a tetracycline antibiotic that blocks ADH. It is only orally available, has a long onset of action, and is not recommended in patents with renal or hepatic dysfunction. One last point is as pharmacists, it is important to monitor for medication-induced disorders. Although there is a plethora of medications that have been linked to SIADH, the five most common drug classes related to medication-induced SIADH include antidepressants, anticonvulsants, antipsychotics, cytotoxic agents, and pain medications, and more specifically selective serotonin reuptake inhibitors (SSRIs), and carbamazepine are among the most common agents.
Lastly, in hypotonic, hypervolemic hyponatremia, patient’s objectively will have a SNa <135mEq/L, SOsm <275mOsm/kg, but ultimately are fluid overloaded. Signs and symptoms of fluid overload have been previously mentioned in the content and should be applied here. This category of hyponatremia may be the most straightforward as it can be theorized the excessive fluid dilutes sodium, causing SNa to drop below normal limits. Disease states that can cause a buildup of fluid in this scenario can include liver cirrhosis, heart failure, and kidney failure. Treating the underlying disease state, in combination with fluid diuresis can help raise the SNa back within to normal limits.
As previously discussed, some hyponatremic disorders are treated with fluids, while others are treated with fluid restriction. When the underlying condition warrants the need for fluids. It is imperative to know how much sodium the body is deficient in, and how much fluid is theoretically necessary to correct the problem. There is a mathematical equation that can be used to figure out the total body deficit of sodium. Once calculating the total body deficit of sodium, a practitioner can translate that amount to a volume of fluid needed to correct the electrolyte imbalance.
Total Body Na Deficit (mEq)=(desired Na-serum Na) x TBW
TBW=weight (kg) x correction factor
Each liter of crystalloid fluid contains a different amount of sodium. As previously mentioned, once the total body sodium deficit is calculated, one can theoretically predict how much volume of fluid is needed to correct the electrolyte.
Although less commonly seen in clinical practice, hypernatremia on the other hand can also present in practice. It is seen as the opposite of hyponatremia by having an excess of solute, and a deficit of water. Hypernatremia can be categorized by volume status just like hyponatremia. The same causes of hypovolemic hyponatremia can further progress and lead to hypovolemic hypernatremia. As a reminder, these causes can include emesis, diarrhea, skin loss through open wounds, or burns, as well as excessive diaphoresis. Other causes that have not been previously mentioned include water loss from hyperventilation, and nasogastric sanctioning. In euvolemic hypernatremia, a condition known as diabetes insipidus can cause a lack of ADH, leading to excessive water wasting in the urine and a more concentrated serum. Diabetes insipidus (DI) is commonly known to be the exact opposite to SIADH and can be divided into either central DI or nephrogenic DI. In central DI, there is a disruption in normal ADH production, storage, and release. On the other hand, in nephrogenic DI, the aquaporins responsible for water reabsorption are not able to insert themselves into the nephron, failing to reabsorb water. Lastly, hypervolemic hypernatremia is usually the result of a large amount of fluid, overcorrecting hyponatremia with hypertonic saline, sodium bicarbonate, or even hormonally via Cushing syndrome, or primary hyperaldosteronism. Cushing syndrome is an excess of glucocorticoids, which can impair the hypothalamic-pituitary axis (HPA) and cause a lack of osmoregulation through ADH. The mechanism of aldosterone has been previously discussed, but reiterating it to hypervolemic hypernatremia, an excess of aldosterone causes sodium and water reabsorption, leading to increase volume, and increase SNa. Regardless of volume status as it relates to hypernatremia, it is always key to calculate the water deficit to correct the problem.
Water deficit (liters)=TBW x [((serum Na)/140)-1]
Using the mathematical equation provided above will help practitioners know how much fluid to theoretically give to allow the SNa to retreat to within normal limits. However, it is vital to closely monitor as in clinical practice, this water deficit calculation can often over-predict, putting patients at risk for rapid changes in SNa. When replacing the deficit, replace half of the deficit over the first 24 hours, and the remaining over the next 24-72 hours, always keeping into account never to decrease SNa >10-12mEq/L per 24 hours.
Rate of Correction
The rate of correcting SNa should be closely monitored, as the consequences of a rapid increase in SNa can lead to osmotic demyelination syndrome, while a rapid decrease in SNa can lead to cerebral edema. Regardless, both are deadly and difficult to reverse once a patient begins to exhibit symptoms. Both the European and American guidelines agree the correction of SNa should not exceed 10mEq per 24 hours. Additionally the American guidelines elaborate on this recommendation, and further recommend an even more conservative approach of 8mEq/24 hours correction in patients at high risk for ODS. Patients who are at high risk for ODS include hyperkalemia, alcoholism, liver disease, and malnutrition.4 The more conservative approach in these patients come from case reports of post-therapeutic neurologic complications after correction with once thought to be safe conservative therapy.
In summary, sodium is one of the most abundant solutes disturbed throughout the body and human cells rely on osmoregulation to maintain homeostasis. When there is a breakdown in this osmoregulation, an uneven distribution of solute and water causes a shift in normal cell physiology, which can manifest into life-threatening complications. Early recognition of symptomatic hyponatremia is vital to provide positive patient outcomes. As noted, sodium imbalances can be vastly sub-categorized based on the underlying cause and can easily confuse practitioners. Therefore by taking a stepwise approach when investigating the objective data available can help the provider identify the most pertinent underlying cause of the electrolyte imbalance. Practitioners can then easily calculate a theoretical amount of either solute or fluid needed to correct the imbalance. Remembering to correct the imbalance slowly over hours to days will help ensure life-threatening complications of overcorrection are avoided.