The Doctor’s Advocate | Fourth Quarter 2018
An Ounce of Prevention

Mitigating the Risk of Osmotic Demyelination Syndrome

Howard Marcus, MD, FACP

The management of severe hyponatremia is often a significant challenge, particularly in high-risk patients. The clinician is faced with the dilemma of having to prevent life-threatening complications and treating the symptoms of severe hyponatremia, while minimizing the risk of central pontine myelinolysis (CPM), a serious neurological disorder that results from an overly rapid serum sodium (Na+) correction.

Pathology and Pathophysiology of CPM and Severe Hyponatremia

CPM, also known as osmotic demyelination syndrome, was described in 1959 as a demyelinating disease affecting alcoholics and the malnourished. In 1976, a link between CPM and rapid sodium correction was suggested and later established. Patients who develop CPM follow a biphasic clinical course, initially presenting with severe hyponatremia and a restoration to normonatremia. This is followed days later by central nervous system (CNS) demyelination and neurological deterioration. Symptoms of demyelination of the pons may include dysarthria, dysphagia, and quadriparesis. Extrapontine demyelination may also occur, resulting in catatonia, mutism, and dystonia—thus, the more comprehensive term, osmotic demyelination syndrome.

It is important to differentiate between acute severe hyponatremia (defined as a serum Na+ of less than 120 mEq/L that has developed in less than 48 hours) and chronic hyponatremia (with a known duration of more than 48 hours or duration unknown). Clinical settings in which acute hyponatremia may occur include self-induced water intoxication and associated psychosis, extreme exertion (as with marathon runners), and acute postoperative hyponatremia. The cited case examples from The Doctors Company are of unknown duration and, therefore, represent chronic hyponatremia.

Plasma Na+ concentration affects cell volume. Hypotonicity makes cells swell, and hypertonicity makes them shrink. Patients with severe hyponatremia are at risk for CNS complications, including brainstem herniation.

In the setting of severe hyponatremia over time (24 to 48 hours), brain cells protect their volume and their survival by adjusting intracellular solute contents mainly through the medium of organic osmolytes. These adaptations allow brain cells to maintain intracellular solute concentrations equal to the osmolality of the hypotonic plasma with little change in cell volume and, therefore, their preservation in the hyponatremic milieu.

However, when serum Na+ levels rise, increasing plasma tonicity toward the normal range, brain cells must “readapt” intracellular solute concentrations to normal plasma Na+ levels. This may require up to a week. Rapid correction of serum Na+ and plasma tonicity can result in hypertonic stress to astrocytes that have not yet adapted to the now-normal plasma homeostasis, thus triggering apoptosis and brain demyelination.

A list of causes of hyponatremia includes volume depletion that may be caused by severe exercise, nausea and vomiting, diuretics, adrenal insufficiency, and extensive burns. Increased osmolality and, to a lesser degree, volume depletion, are stimuli for antidiuretic hormone (ADH) secretion resulting in retention of free water. This contributes to hyponatremia. Additional causes of hyponatremia include congestive heart failure, chronic liver disease, syndrome of inappropriate ADH secretion (including postsurgical excess secretion of ADH), primary polydipsia, beer drinkers’ potomania (beer is hypotonic when drunk in large volumes), alcohol intoxication, and renal failure.

The goals of therapy in the management of severe hyponatremia are to prevent further declines in serum Na+, decrease intracranial pressure, relieve symptoms of hyponatremia, and avoid excessive correction of hyponatremia in patients at risk for CPM. As in the case examples that follow, patients at high risk of CPM often have a history of alcohol abuse and malnutrition as well as intracranial pathology, hypokalemia, and hypoxia. Additional risks for morbidity include severe symptoms such as seizures, confusion, and obtundation and a serum Na+ level of less than 110 mEq/L.

Restoration of euvolemia—including by infusion of normal saline (NS)—suppresses the release of ADH, allows excretion of free water, and results in a rise in Na+ level. Treatment of adrenal insufficiency with steroids, discontinuation of thiazides, treatment of vomiting, and resolution of surgical stress may also bring about “autocorrection,” a physiologic suppression of ADH resulting in rapidly rising Na+ levels. Desmopressin (brand name DDAVP) may be a useful adjunct to treatment of high-risk patients with severe chronic hyponatremia. The seemingly paradoxical administration of desmopressin to patients with severe hyponatremia treated with slow infusion of hypertonic saline helps to prevent an excessively rapid increase in serum Na+ levels.

An increase in plasma Na+ concentration of 4–6 mEq/L is enough to reverse symptoms in patients with severe hyponatremia. Because patients presenting with chronic hyponatremia have minimal brain swelling (due to intracellular adaptation), they are at minimal risk of herniation but at high risk for CPM.

Treatment Recommendations for Chronic Severe Hyponatremia

The goal of initial therapy is to raise the serum Na+ concentration by 4–6 mEq/L in a 24-hour period. In patients with severe symptoms, that should be achieved quickly—over six hours or less. The Na+ should then be maintained at a constant level for the remainder of the 24-hour period. This strategy has been described as the “Rule of Sixes”: “Six a day makes sense for safety, so six in six hours for severe symptoms and stop.” Here are some additional treatment recommendations:

• The maximum rate of Na+ correction is 8 mEq/L in a 24-hour period. Most cases of CPM occur when sodium concentration is raised by more than 10–12 mEq/L in 24 hours or more than 18 mEq/L in 48 hours.
• Patients with severe symptoms and severe hyponatremia should receive 100 mL bolus of 3 percent saline followed, if symptoms persist, by two additional doses (300 mL total), with each bolus infused over 10 minutes. The goal of therapy is an increase in Na+ of 4–6 mEq/L over a few hours. One mL of 3 percent saline per kg body weight should increase plasma Na+ by 1 mEq/L.
• Patients without severe symptoms and with severe hyponatremia should receive 3 percent saline at 15–30 mL/hour.
• When volume depletion is obvious and potentially life threatening, volume expansion should be continued until blood pressure is restored. Three percent saline should be used for the initial volume challenge to avoid risk of lowering the serum Na+.
• Isotonic saline should be avoided unless Na+ is over 120 mEq/L. Rapid correction of hypovolemia removes the stimulus to ADH release and allows excess water to be excreted in a dilute urine. This can result in a too-rapid Na+ correction.
• In patients at risk for a brisk water diuresis (autocorrection) and those at high risk for developing CPM simultaneously, consider desmopressin at 1–2 mcg parenterally every six to eight hours to prevent overly rapid serum Na+ correction. Autocorrection can be suspected if the cause of hyponatremia has been reversed, urine output has increased, and the urine is dilute (specific gravity less than 1.005).
• When indicated, patients should receive potassium replacement, which acts to correct both hyponatremia and hypokalemia.
• Na+ should be initially monitored at least every four hours. Once a correction of 4–6 mEq/L is achieved, switch to a hypotonic potassium solution if indicated. If Na+ begins to fall again, resume hypertonic saline.

Note: These recommendations focus on high-risk, severe, chronic hyponatremia. Additional factors may include a hypo-, hyper-, or euvolemic state; concomitant acute illnesses; and other comorbidities. Many readily available resources or decision support tools provide comprehensive guidelines for the management of severe hyponatremia. Severe hyponatremia is a complex management problem for which urgent consultation with an intensivist or a nephrologist should be considered.

Case Examples

A 40-year-old male with a history of alcohol abuse (a case of beer daily), methamphetamine use, and schizophrenia presented with syncope, seizures, and a head contusion. The Na+ was 101 mEq/L (normal 135–145 mEq/L). The patient was started on NS in the ER and then admitted to the ICU. He was diagnosed with “beer drinkers’ potomania” and recognized to be at risk for CPM. Repeat Na+ in the ICU was 105 mEq/L. That evening around 7:00 PM, the patient was treated with a 500 cc bolus of NS. Orders were written for electrolytes every four hours and to notify the physician if the serum Na+ level increased by more than 5 mEq/L. At 10:30 PM, the serum Na+ was 113 mEq/L, but the on-call physician was not notified. ICU nurses continued to administer boluses of NS. The morning serum Na+ was 125 mEq/L. The patient was discharged after six days, but he returned 10 days later with progressive weakness and findings of CPM on CT and MRI scans.

A 26-year-old female taking hydrochlorothiazide with a history of epilepsy, alcohol abuse, polydipsia, and chronic liver disease presented with vomiting and anorexia for two weeks. The admission Na+ was 106 mEq/L. The patient was treated with NS and transferred to a higher-level hospital. The serum Na+ obtained seven hours later was 116 mEq/L. NS was continued with a Na+ of 125 mEq/L at 24 hours after admission. A D5W infusion over the next 24 hours resulted in a minimal reduction of Na+ to 122 mEq/L. The patient was discharged in stable condition, but she returned five days later with progressive neurological symptoms, including an inability to swallow, difficulty speaking, and an inability to walk. A brain MRI showed CPM, and the patient was diagnosed with locked-in syndrome (a loss of all mobility and muscle control with only the ability to move her eyes).

A 33-year-old female with a history of diabetes insipidus on regular doses of desmopressin presented with vomiting for three days and an altered mental status. Her admission serum Na+ was 112 mEq/L. Orders were written for 2 percent saline, electrolytes every four hours, and to increase Na+ to 120 mEq/L. Desmopressin was not ordered. Repeat Na+ at six hours was 125 mEq/L, 123 mEq/L at 10 hours, and 143 mEq/L at 24 hours. After discharge, the patient developed CPM, resulting in a tracheostomy, a percutaneous endoscopic gastrostomy tube, and nursing home care.

Case Critique

In the first two cases cited, the patients met multiple high-risk criteria based on a history of alcohol abuse, poor nutritional status, severe symptoms, and very low serum Na+ levels. Both patients were treated with a continuous infusion of NS instead of small volumes of 3 percent saline plus desmopressin. The initial serum Na+ level should be considered as the baseline for treatment—not the Na+ level obtained after transfer from another institution—particularly when treatment has already started. In the third case, desmopressin should have been administered to prevent rapid increase in serum Na+ in this patient with diabetes insipidus.

Fluid/electrolytes and CNS physiology are complex. Even intensivists and ICU nurses may not encounter severe, symptomatic high-risk hyponatremia on a routine basis, focusing instead on achieving a “normal” Na+ level that may cause them to overlook the risk of an increase in Na+ beyond 8 mEq/L over a 24-hour period in the setting of severe hyponatremia. As with any critical and complex management challenges, explicit written orders and verbal communication explaining treatment goals lead to better results.

Risk Management Discussion

A careful look at closed claims relating to severe hyponatremia revealed specific challenges in managing this complex problem. It is worth focusing on generic issues that contributed to bad outcomes and resulted in claims. Top factors included clinical judgment, communication, selection and management of therapy, and documentation:

• Inaccurate clinical judgment was the primary contributing factor. Clinical judgment factors cover a wide range of substandard care, including failure to consider available clinical information (for example, lab values, diagnostic test results, symptoms, and nursing observations) and failure or delay in ordering diagnostic tests. Inadequate physiological monitoring, which also falls into this category, includes misinterpreting tests and inadequately monitoring the effects of medications.
• Communication among providers is critical. Poor communication contributed to patient harm when important information was inadequately communicated to other healthcare practitioners. In some hyponatremia cases, physicians were aware of the potential morbidity due to rapid sodium replacement but did not communicate the importance to nursing staff of a slow increase in the Na+. Staff may have been focused on achieving a “normal” sodium level too rapidly.
• Selection and management of therapy can result in clinical judgment factors as well. Improper selection and management of medications included failing to order medication, failing to order the most appropriate medication, and ordering the wrong medication.
• Other cases involved insufficient, missing, or inconsistent documentation. Physicians who failed to see or find important clinical information documented in the medical record were, therefore, unaware of changes in the patient’s condition, or they were unaware of changes in the therapy. These types of oversights resulted in lack of coordination of care and, in these situations, caused harm.

Risk Mitigation Strategies

The following strategies can help physicians avoid some issues uncovered by these cases:

• Communicate treatment goals to the healthcare team. Timely diagnosis and management often depend on how quickly diagnostic studies are performed and interpreted. It is critical that the entire team understand the studies and know what to look for and when to be concerned. Adequately brief the team about treatment goals.
• Be accessible and responsive to the healthcare team. Build rapport. Don’t create an environment in which team members hesitate to reach out because they are afraid of the response.
• Communicate concerns and fears for a specific patient when handing off to covering physicians or briefing the healthcare team. Provide a detailed warning in advance about patients who have a confusing presentation or deteriorating conditions.
• Build rapport with other physician specialists that you contact for patient referrals. Stay engaged after other specialists join the case. Clarify your responsibility to coordinate care with the rest of the clinical team, including specialists.
• Review all documentation to ensure that you are aware of consultation reports, consultant orders, and any subtle changes in the patient’s condition noted by the healthcare team.

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