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Hyponatremia in the Hospital Setting

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Critical Care Canada Forum 2011

Toronto, Ontario / November 13-16, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Hyponatremia is an electrolyte disturbance commonly defined as a serum sodium concentration <136 mmol/L. It is one of the most common electrolyte disturbances occurring in clinical practice. Its frequency widely depends on clinical circumstances but reported to occur in 15% to 30% of acutely and chronically hospitalized patients (Upadhyay et al. Am J Med 2006;119(7 Suppl 1):S30-S35). Moreover, the odds ratio (OR) of developing hospital-acquired hyponatremia increases with age.

Morbidity and Mortality

Here at the CCCF, Dr. Sean Bagshaw, Assistant Professor, Division of Critical Care, University of Alberta, Calgary, discussed a recent surveillance study of more than 53,000 patients over 8 years which suggested that as serum sodium progressively dropped below 136 mmol/L in hospital, there was an increase in mortality in patients. Examining the morbidity side of hyponatremia, Dr. Bagshaw showed data from an elegant study that looked at a dynamic walk test in patients with progressive declines in serum sodium. As serum sodium declined, the patients became progressively uncoordinated in their ability to walk, such that their risk of falling increased fourfold, as did their response times on neuropsychiatric tests and error rates. Moreover, the level of uncoordination was suggested to be similar to that seen in subjects with a blood alcohol level of 60 mg/dL. However, after treatment to correct the serum sodium concentration, coordination improved in the patients.

Dr. Bagshaw cited a case-control study by Gankam Kengne et al. (Q J M 2008;101(7):583-8). He reported that age- and sex-matched elderly patients (>65 years) experienced a significant (P<0.01) adjusted OR of 4.16 for bone fractures related to hyponatremia. It has been reported that a rat model of the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) showed that hyponatremia decreased bone mineral density by about 30%. Moreover, as recorded in the National Health and Nutrition Examination Survey (NHANES) III in the US, mild hyponatremia was reported to have an adjusted OR of 2.85 for osteoporosis.

Risk Factors for Hyponatremia

In the Gankam Kengne study, the underlying etiology of the hyponatremia was related to diuretics in 35%, idiopathic SIADH in 35% and selective serotonin reuptake inhibitor (SSRI) use in another 16%. Dr. Bagshaw told delegates, “Further data is accumulating to suggest that hyponatremic patients are often older, often diabetic and have other comorbid illnesses; are at increased risk for falls; and are at increased risk for fractures independent of those effects in adjusted analyses.”

Other data from a US study of 3 hospitals with over 98,000 hospitalized patients indicated that the hyponatremic patients were older, had increased comorbidities (i.e. congestive heart failure, cancer) and had undergone orthopedic procedures, all of which increased their in-hospital mortality. Data from The Netherlands (Hoorn et al. Nephrol Dial Transplant 2006;21(1):70-6) suggested that only about one-third of the hospitalized patients who develop severe hyponatremia (serum sodium <125mmol/L) in the hospital exhibit symptoms and only one-quarter received hyponatremia therapy; perhaps more surprisingly, it took on average almost 10 days to diagnosis the hyponatremia. In this study, the major factors causing the severe hyponatremia were diuretics (22%), surgery (28%), hypotonic intravenous fluids (22%) and antidiuretic hormone-stimulating drugs (22%).

In a secondary analysis of the ESCAPE heart failure trial, Dr. Bagshaw reported, “Approximately 24% of patients had serum sodium <134 mmol/L; about 70% of those had it persist during their hospitalization; and hyponatremia itself was independently associated with a higher hazard of death compared to patients who did not have hyponatremia.”

Classification of Hyponatremia and Management

Here at the CCCF, Dr. Daniel Bichet, Professor of Medicine and Physiology, Division of Nephrology, Université de Montréal, Quebec, suggested that hyponatremia could be classified as dilutional or depletional. In the former category, total body sodium is normal or increased and total body water is increased. He added that the dilutional category could be further subdivided as hypervolemic or euvolemic. As he explained, depletional hyponatremia patients are hypovolemic and exhibit sodium loss and reduced total body water. Dr. Bichet suggested that depletional hyponatremia is more readily recognized since it is associated with diarrhea, vomiting, burns and trauma and can often be treated with isotonic saline.

Dr. Bichet recommended some general principles for treatment of dilutional hyponatremia. He told delegates that there are neurological consequences of both failure to treat promptly as well as excessively rapid treatment, and as such presence and absence of significant neurological signs and symptoms should guide treatment. Life-threatening, usually acute symptoms include stupor/coma, convulsions and respiratory arrest, whereas the usually chronic and less impaired symptoms include headache, irritability, nausea/vomiting, mental slowing, confusion/delirium and disorientation.

Short-term treatment consists of 3 modalities: isotonic saline infusion; hypertonic saline infusion; and use of vaptans (vasopressin V<sub>2</sub> receptor antagonists). The longer-term treatments include fluid restriction, demeclocycline, furosemide + sodium chloride, mineralocorticoids, urea and the vaptan tolvaptan. One algorithm for treatment of euvolemic hyponatremia based on symptom severity starts with mild or no symptomsàuse of fluid restriction or vaptan in select circumstances; moderate symptomsàvaptan or hypertonic saline, followed by fluid restriction; severe symptomsàhypertonic saline, followed by fluid restriction and vaptan. Dr. Bichet emphasized the importance of maximizing patient safety and that goals of therapy should be more modest in chronic as opposed to acute hyponatremia (i.e. changes of 6-8 mmol/L over 24 hours and 14-16 mmol/L over 72 hours).

Vasopressin Physiology

Vaptans are the newest agents for treating hyponatremia. In a brief review of vasopressin physiology, Dr. Bichet reminded the audience that this hormone can be stimulated by a drop in mean arterial pressure as well as by plasma osmolality. The vasopressin receptors are divided into 3 subtypes: V<sub>1a</sub> has its primary site of action on vascular smooth muscle and causes vasoconstriction and myocardial hypertrophy; V<sub>1b</sub> is primarily located in the anterior pituitary and is responsible for ACTH release; and V<sub>2</sub> is primarily located in the renal collecting ducts and is responsible for free water reabsorption.

Tolvaptan has been studied by Schrier et al. (N Engl J Med 2006;355(20):2099-112) in patients with euvolemic or hypervolemic hyponatremia associated with heart failure, cirrhosis or SIADH (SALT-1 and SALT-2 trials). In the pooled analysis of these 2 studies, the vaptan was shown to increase serum sodium from baseline to day 4 in patients with SIADH of 4.8 mmol/L, in patients with heart failure by 3.5 mmol/L and in patients with cirrhosis by 3.5 mmol/L. The placebo comparator increased serum sodium by 0.2, 0.5 and 0.4 mmol/L, respectively. By day 30, tolvaptan increased serum sodium from baseline in patients with SIADH of 7.4 mmol/L, in patients with heart failure by 6.6 mmol/L and in cirrhosis by 4.2 mmol/L; the placebo comparator increased serum sodium by 1.5, 2.4 and 1.5 mmol/L, respectively. Dr. Bichet also emphasized that fluid intake was not affected by tolvaptan and that the patients were still able to generate a negative fluid balance. Adverse events were as expected with loss of water: dry mouth, constipation, thirst, weakness, mild/ clinically nonsignificant hyperglycemia and increased urinary frequency. Dr. Bichet told delegates, “Tolvaptan would not be used in depletional hyponatremia because if you have evidence of volume contraction, then you need to increase the amount of sodium and water presented to the distal tubule by infusing your patients with saline. But here in dilutional hyponatremia, either hypervolemic or euvolemic, there is a benefit.”

Summary

Hyponatremia is a very common electrolyte disorder occurring in hospitalized patients. It needs to be treated since it can cause substantial morbidity (falls, fractures, mental confusion) and mortality in acute, severely hyponatremic patients. Patients with a wide variety of underlying diseases (older age, diabetes, heart failure, cancer, cirrhosis, SIADH) and therapies (SSRIs, diuretics) can present with hyponatremia in the critical care hospital setting. Treatment approaches differ based on classification of the patient as having either depletional or dilutional hyponatremia. The V<sub>2</sub> receptor antagonists represent a novel treatment modality targeting the renal collecting tubules and removal of free water in the dilutional hyponatremic patient.

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