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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

Special Considerations in Hyponatremia Management Sign Up Hospitalized patients with hyponatremia are the focus Sign up to be notified of updates related to of a series of learning opportunities planned by ASHP this educational initiative. Advantage. The learning opportunities are designed to build on each other and illustrate ways in which the findings from disease-based medication-use evaluations www.ashpadvantage.com/muefindings (MUEs) of hyponatremia can help identify areas of patient care needing improvement.

The series began with a live symposium on the use of MUEs to improve care for patients with hyponatremia on December 9, 2014, during the 49th ASHP Midyear Clinical Faculty Meeting and Exhibition in Anaheim, California. Attendees submitted questions about unresolved issues related to JOSEPH F. DASTA, the management of hyponatremia, and those frequently M.S., MCCM, FCCP, Initiative Chair asked questions (FAQs) were used in developing the Professor Emeritus content of a live Ask the Experts webinar in March 2015. The Ohio State University College of Pharmacy The faculty for the series are Joseph F. Dasta, M.S., MCCM, FCCP, and Gretchen M. Brophy, Pharm.D., BCPS, Adjunct Professor FCCP, FCCM, FNCS. The University of Texas College of Pharmacy

The series also includes two e-newsletters. The Austin, Texas April 2015 issue focused on real-world practices in managing hyponatremia based on a patient registry. GRETCHEN M. BROPHY, This issue addresses special considerations in managing Pharm.D., BCPS, FCCP, FCCM, FNCS hyponatremia, along with feedback from participants in Professor of Pharmacotherapy & Outcomes the live activities about how they planned to incorporate Science and Neurosurgery hyponatremia management strategies into practice. Virginia Commonwealth University Other learning opportunities in the series include the Medical College of Virginia Campus following: Richmond, Virginia • On-demand activity based on the Midyear symposium (1.5 hours of continuing pharmacy education),

• Engaging the Experts interviews with the faculty about important issues related to improving hyponatremia For more information and to access these management, and learning opportunities, go to the web portal at www.ashpadvantage.com/muefindings. The series is • New on-demand activity based on the Ask the Experts supported by an educational grant from Otsuka America webinar (1 hour of continuing pharmacy education, Pharmaceutical, Inc. available late May 2015).

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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

disorientation, and altered mental status are associated Considerations in with moderate hyponatremia, and vomiting, seizures, Neurocritical Care obtundation, coma, respiratory arrest, and death may be associated with severe hyponatremia. Hyponatremia is the most common electrolyte disorder in hospitalized patients, and it often goes untreated or The central nervous system effects of hyponatremia are inadequately treated.1,2 The consequences of untreated the result of brain edema and swelling and increased hyponatremia are more serious in neurocritical care patients intracranial pressure. The greater and more rapid the than in other hospitalized patients. Therefore, the clinical decline in serum sodium concentration, the greater the definition of moderate and severe hyponatremia often is increase in brain swelling.8 more conservative for neurocritical care patients than for the general population of hospitalized patients (Table 1). Acute vs. Chronic Hyponatremia Table 1. Clinical Definitions of Hyponatremia in Hyponatremia may be acute (i.e., developing within 48 Hospitalized Patients3-6 hours) or chronic, developing more slowly.8 In patients General with chronic hyponatremia, the brain has time to adapt to Severity Neurocritical Hospitalized the hypotonic state, but the brain does not have sufficient Classification Care Patients Patients time to fully adapt when hyponatremia is acute. Chronic hyponatremia often leads to brain glutamate deficiency Mild 131-134 131-134 and cerebellar dysfunction manifesting as ataxia. (serum sodium, mEq/L) Moderate Fluid restriction with a daily intake 500 mL less than the 120-130 125-130 (serum sodium, mEq/L) urine output to achieve a negative net fluid balance is 7 Severe commonly used for patients with chronic hyponatremia. <120 <124 (serum sodium, mEq/L) Correction of the serum sodium may require several days of fluid restriction.

Hyponatremia is common in patients with brain injury, Using an appropriate rate of correction of hyponatremia affecting 43% of these patients.5 The incidence of the is vital. A slow rate of correction is associated with electrolyte disorder is high in patients with subarachnoid cerebral edema but an excessively rapid rate of correction hemorrhage (52%), traumatic brain injury (46%), brain can cause osmotic demyelination syndrome (ODS), tumors (38%), and intracerebral hemorrhage (35%). a neurologic disorder with substantial morbidity and Hyponatremia is mild (serum sodium 131-134 mEq/L) in mortality.9 Symptoms of ODS include dysarthria, dysphagia, most (63%) patients with acute neurologic injury, but it can oculomotor dysfunction, and quadriparesis with a “locked- be moderate (serum sodium 125-130 mEq/L) or severe in” state characterized by an inability to move other than (serum sodium <124 mEq/L) in some patients (32% and blinking the eyelids. Other risk factors for ODS include 5%, respectively). alcoholism, cirrhosis, malnutrition, and severe burns.10

The severity of symptoms correlates with the extent to Acute hyponatremia may develop after surgery, which the serum sodium concentration is diminished. Mild especially prostate resection and endoscopic uterine hyponatremia is characterized by headache, irritability, surgery, or it may be the result of polydipsia, exercise, or inability to concentrate, altered mood, and depression, or use of a colonoscopy bowel preparation or various drug an absence of discernible symptoms.7 Nausea, confusion,

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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

therapies.6 These drug therapies include a wide variety of agents associated with the syndrome of inappropriate Overview of antidiuretic hormone (SIADH, Figure 1). Hyponatremia Treatment Options in patients with SIADH is the result of an increase in Treatment options for hyponatremia include arginine vasopressin (AVP, also known as antidiuretic fluid restriction, sodium chloride (normal saline hormone) release, effect, or both.12,13 Diuretics also and hypertonic saline infusions and salt tablets), contribute to hyponatremia through their effects on vasopressin receptor antagonists (e.g., conivaptan, sodium and water homeostasis. tolvaptan), demeclocycline, and mineralocorticoids In patients with drug-induced hyponatremia, the (e.g., fludrocortisone). Each option has advantages and 15,16 offending agent should be discontinued if the risk disadvantages. Fluid restriction is inexpensive but exceeds the benefits.14 Alternative therapy that does not the response is limited with a slow onset, and patient cause hyponatremia should be used if needed. If it is not nonadherence is a concern. Sodium chloride infusions possible to discontinue the offending agent, reducing provide a rapid response in symptomatic patients but the dosage may suffice to correct hyponatremia from require dose and rate calculations, and the infusions some medications. Fluid restriction should be used in should not be used in patients with edema-forming conjunction with these strategies for patients with chronic disorders. Vasopressin receptor antagonists (i.e., drug-induced hyponatremia. vaptans) target excessive AVP and promote aquaresis (i.e., increased free water excretion without a substantial effect on electrolyte excretion), but they cannot be used Figure 1. in patients with hypovolemic states. Demeclocycline Drug Therapies Associated with SIADH6,11 also targets excessive AVP, but the response is delayed, and the drug can cause nephrotoxicity in patients with • Antidepressant agents (selective serotonin congestive heart failure or cirrhosis. reuptake inhibitors, tricyclic antidepressants) The approach to treating hyponatremia may be based • Carbamazepine largely on symptomatology.7 Patients with no or minimal • Chlorpropamide symptoms may be managed initially with fluid restriction, • Clofibrate although vasopressin receptor antagonist therapy may be • Cyclophosphamide indicated in certain circumstances: • Desmopressin (DDAVP) • Inability to tolerate or failure to respond to fluid • Ifosfamide restriction; • Methamphetamine (MDMA, XTC) • Unstable gait, high fracture risk, or both; • Neuroleptic agents • Very low sodium level (<125 mEq/L) with an increased • Nonsteroidal anti-inflammatory agents risk of developing symptomatic hyponatremia; • Oxcarbazepine • Need to correct serum sodium to a safer level for • Oxytocin surgery, a procedure, or discharge from the intensive • Thiazide diuretics care unit (ICU) or hospital; • Vincristine • Prevention of worsened hyponatremia with increased fluid administration; and SIADH = syndrome of inappropriate antidiuretic hormone • A therapeutic trial.

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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

Patients with symptoms of moderate hyponatremia should through large veins, and the infusion site should be receive vasopressin receptor antagonist therapy, followed changed every 24 hours. by fluid restriction, if needed. Patients with symptoms of 19 severe hyponatremia should receive hypertonic saline Tolvaptan is administered orally. The drug should be initially, followed by fluid restriction with or without initiated and reinitiated only in a hospital setting. The vasopressin receptor antagonist therapy. recommended initial oral dosage of tolvaptan is 15 mg once daily without regard to meals. The dosage may be increased In a registry of 3087 patients with hyponatremia (serum to 30 mg once daily, followed by a maximum of 60 mg once sodium 130 mEq/L or less) at 225 hospitals in the United daily as needed to raise the serum sodium concentration. States or European Union, fluid restriction was the Dosage increases should be made at intervals of at least 24 least effective initial monotherapy for hyponatremia.2 hours. Fluid restriction should be avoided during the first The median increase from baseline in serum sodium 24 hours of tolvaptan therapy. Bioavailability of tolvaptan concentration within the first 24 hours of therapy was after nasogastric administration may be less than after higher with hypertonic saline (5 mEq/L), tolvaptan taking intact tablets.22 (4 mEq/L), and normal saline (3 mEq/L) than fluid restriction (2 mEq/L). As noted previously, vaptans should be used primarily to manage patients with symptoms of mild or moderate In a multicenter, retrospective, observational study of 137 hyponatremia.7 Serum sodium concentrations should be ICU patients with neurologic injury who were treated for monitored frequently (e.g., every 6-8 hours) during the hyponatremia (serum sodium <135 mEq/L), hypertonic active phase of correction with vaptan therapy (i.e., the saline was the most commonly used initial intervention first 24-48 hours of therapy). (62%).17 In patients with a treatment response (defined as an increase from baseline in serum sodium of at least 4 Both conivaptan and tolvaptan are substrates of CYP 18,19 mEq/L after 24 hours), the median increase from baseline 3A4. Use of these drugs is contraindicated in patients in serum sodium concentration after 24 hours was greater receiving potent CYP 3A4 inhibitors (e.g., ketoconazole, with conivaptan (7 mEq/L), hypertonic saline (6 mEq/L), itraconazole, indinavir) because concomitant use of CYP and fluid restriction (5 mEq/L) than other interventions. 3A4 inhibitors can increase exposure to the vaptan. The use of conivaptan with other CYP 3A4 substrates (e.g., midazolam, simvastatin, amlodipine) and the use Use of Vaptans of tolvaptan with CYP 3A4 inducers (e.g., rifampin) Conivaptan and tolvaptan were developed for the and moderate CYP 3A4 inhibitors (e.g., erythromycin, treatment of euvolemic and hypervolemic hyponatremia fluconazole, aprepitant, diltiazem, verapamil) should and approved by the Food and Drug Administration (FDA) be avoided. Because tolvaptan is also a substrate of in 2004 and 2009, respectively. 18,19 Conivaptan antagonizes P-glycoprotein (P-gP), tolvaptan dosage reduction may

vasopressin V1a and V2 receptors. Tolvaptan is a selective be needed if the drug is used in patients receiving P-gP 19 antagonist of vasopressin V2 receptors. The effects of both inhibitors (e.g., cyclosporine). drugs in patients with hyponatremia are mediated primarily 20,21 In 2013, a safety warning was added to the FDA-approved by V2 receptor antagonism in the kidneys. labeling for tolvaptan because of liver enzyme elevations Conivaptan is administered intravenously (i.v.) as a observed in patients with polycystic kidney disease who 20-mg loading dose over 30 minutes, followed by received the drug at higher-than-recommended doses 20-40 mg over 24 hours for 2-4 days as needed to raise in a clinical trial.19,23 Tolvaptan should not be used in the serum sodium concentration.18 To minimize the risk of patients with underlying liver disease, including cirrhosis.19 infusion site reactions, the drug should be administered

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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

The treatment duration should be limited to 30 days to Safety Considerations with minimize the risk of liver injury, and the drug should be discontinued if symptoms of liver injury occur. Hypertonic Saline Hypertonic saline usually is reserved for patients with Elevated intracranial pressure (ICP) from cerebral edema severe neurologic symptoms of hyponatremia in whom is a concern in patients with severe traumatic brain the condition is acute and requires urgent intervention.7 injury. In theory, increasing serum sodium concentrations Excessively rapid increases in serum sodium concentration through the use of vaptans could provide an osmotic (>12 mEq/L in a 24-hour period) should be avoided gradient that reduces cerebral edema and ICP. Aquaporin because of the risk of ODS. Therapy should be designed (AQP)-4 channels are thought to play a key role in the to provide an increase in serum sodium by approximately development of cerebral edema, and these channels may 0.5-1 mEq/L/hr until neurological symptoms resolve or be modulated by vasopressin V receptors.24 Vasopressin 1a the serum sodium exceeds 120 mEq/L.27 Therapy should V and V receptors are expressed in the brain, and 1a 2 be titrated slowly to achieve an increase in serum sodium experimental models have demonstrated that vasopressin concentration of 10-12 mEq/L in the first 24 hours and V receptor antagonism is helpful in reducing brain edema 1a less than 18-24 mEq/L within the first 48 hours.6,8,28 Data by down regulating AQP-4 channels.20 from the hyponatremia registry suggest that the risk of overly rapid correction of hyponatremia is higher with Because conivaptan antagonizes both vasopressin V1a the use of hypertonic saline than other therapies for and V2 receptors, the effect of single 20-mg i.v. bolus 2 doses on ICP was evaluated in an open-label, randomized, hyponatremia. controlled study of 10 normonatremic patients with Serum sodium concentrations should be checked severe traumatic brain injury.25 The drug was compared frequently (every 2-4 hours) during treatment with with usual care. Four hours after treatment, the serum hypertonic saline until values stabilize and daily after sodium concentration was significantly higher (p = 0.02) treatment is discontinued. Recurrence of hyponatremia and the ICP was significantly lower (p = 0.046) in the was common in the hyponatremia registry.2 conivaptan group compared with the usual care group. After 48 hours, there was no significant difference Hypertonic sodium chloride 23.4% has been used to treat between the two groups in the mean serum sodium patients with traumatic brain injury and elevated ICP.29 concentration (p = 0.71). There were no drug-related However, the 23.4% concentration should not be used to serious adverse events in either group. treat hyponatremia because it can induce a hypernatremic and hyperchloremic state. A single 20-mg i.v. bolus dose of conivaptan was given to a 22-year-old patient with hyponatremia and severe traumatic brain injury.26 Substantial aquaresis occurred, Practice Changes with a maximum effect 3-5 hours after the dose. A An awareness of the special considerations in managing significant reduction in ICP was observed 4 hours after hyponatremia is essential for optimizing patient the dose (i.e., the ICP reduction was temporally associated outcomes, but integrating these concepts into practice with the maximum aquaresis), and the ICP reduction can be a challenge for pharmacists. Approximately three lasted throughout the 8-hour observational period after months after the December 2014 Midyear symposium, the dose. Hyponatremia was corrected within 8 hours attendees were asked how they had changed or planned after the dose. to change their practice after participating in the activity. Their responses are described here to give others ideas about how to incorporate hyponatremia management strategies into practice.

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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

A total of 21 participants completed the survey, and the avoid overcorrection, check the patient’s sodium level vast majority of these individuals indicated that they during medication reconciliation, and begin work on the implemented or planned changes related to direct patient hospital’s hyponatremia medication-use evaluation. care: Almost 30% of participants did not foresee any barriers in • Being more vigilant about screening and evaluating implementing these changes, while 27% indicated that lack hospitalized patients for hyponatremia (81% of of time and resources was a potential barrier. Different respondents) and approaches used by physicians for managing hyponatremia and difficulty obtaining data for medication-use evaluation • If hyponatremia is identified, assessing sodium levels were also mentioned as potential barriers. during hospitalization and before discharge to ensure optimal sodium status for that individual (71% of If these practice changes pique your interest, check out respondents). the educational activities available on the initiative website (www.ashpadvantage.com/muefindings) to learn more Changes that take institutional initiative—and hence more about hyponatremia and how pharmacists can improve time (such as targeting improvements based on results of outcomes in hospitalized patients with this electrolyte a national registry or local medication-use evaluation and disorder. developing recommendations for the safe and effective treatment of hyponatremia within the institution)—were implemented or planned by about half of the respondents.

A second group of pharmacists, this time close to 600 Table 2. Strategies for Improving a participants in the March 2015 Ask the Experts webinar Hyponatremia Management in Hospitals on hyponatremia, were asked a similar question, and % of developing a hyponatremia protocol was the practice Anticipated Practice Change Respondentsb change most commonly mentioned (Table 2). When asked (n=424) specifically about changes in patient care, participants Develop a hyponatremia protocol 43 noted that they would most likely do the following (range 47-59%): Increase involvement in fluid 24 resuscitation • Identify drug-related risk factors for hyponatremia and Screen sodium values before modify as needed, 38 discharge • Recognize drug-related causes of hyponatremia and Conduct a hyponatremia 37 discontinue the offending drug, and medication-use evaluation

• Determine appropriate hyponatremia treatment options aBased on polling of participants in a live Ask the Experts webinar and monitor response to therapy. on the management of hyponatremia conducted March 26, 2015. bSelection of more than one practice change was allowed. In addition, participants noted that they would assess chronicity of hyponatremia before recommending treatment, discuss hyponatremia monitoring with ICU staff, aggressively monitor hyponatremia treatment to

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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

17. Human T, Brophy G. Hyponatremia in patients after acute References neurologic injury. Neurocrit Care. 2013; 19(suppl 1):S154. 1. Verbalis JG, Goldsmith SR, Greenberg A et al. Diagnosis, 18. Vaprisol (conivaptan hydrochloride) injection prescribing evaluation, and treatment of hyponatremia: expert panel information. Deerfield, IL: Astellas Pharma US, Inc; 2014 recommendations. Am J Med. 2013; 126(10 suppl 1):S1-42. Apr. http://www.vaprisol.com/pdf/vaprisol_PI_Apr2014.pdf 2. Greenberg A, Verbalis JG, Amin AN et al. Current treatment (accessed 2015 Mar 19). practice and outcomes. Report of the hyponatremia registry. 19. Samsca (tolvaptan) prescribing information. Rockville, MD: Kidney Int. 2015 Feb 11. [Epub ahead of print] Otsuka America Pharmaceutical, Inc.; 2014 Feb. 3. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of http://www.otsuka-us.com/products/Documents/Samsca.PI.pdf hyponatremia. Am J Med. 2006; 119(suppl 1):S30-5. (accessed 2015 Mar 19).

4. Kumar S, Berl T. Sodium. Lancet. 1998; 352:220-8. 20. Decaux G, Soupart A, Vassart G. Non-peptide arginine- vasopressin antagonists: the vaptans. Lancet. 2008; 5. Human T, Brophy G. Hyponatremia in patients after acute 371:1624-32. neurologic injury. Neurocrit Care. 2013; 19(suppl 1):S153. 21. Lee CR, Watkins ML, Patterson JH et al. Vasopressin: a new 6. Spasovski G, Vanholder R, Allolio B et al. Clinical practice target for the treatment of heart failure. Am Heart J. 2003; guideline on diagnosis and treatment of hyponatraemia. 146:9-18. Eur J Endocrinol. 2014; 170:G1-47. 22. McNeely EB, Talameh JA, Adams KF Jr et al. Relative 7. Verbalis JG. Disorders of water metabolism: diabetes insipidus bioavailability of tolvaptan administered via nasogastric tube and the syndrome of inappropriate antidiuretic hormone and tolvaptan tablets swallowed intact. Am J Health-Syst Pharm. secretion. Handb Clin Neurol. 2014; 124:37-52. 2013; 70:1230-7.

8. Rondon-Berrios H, Agaba EI, Tzamaloukas AH. Hyponatremia: 23. Torres VE, Chapman AB, Devuyst O et al. Tolvaptan in patients pathophysiology, classification, manifestations and management. with autosomal dominant polycystic kidney disease. Int Urol Nephrol. 2014; 46:2153-65. N Engl J Med. 2012; 367:2407-18.

9. Sterns RH. Disorders of plasma sodium—causes, consequences, 24. Fukuda AM, Badaut J. Aquaporin 4: a player in cerebral edema and correction. N Engl J Med. 2015; 372:55-65. and neuroinflammation. J Neuroinflammation. 2012; 9:279.

10. Singh TD, Fugate JE, Rabinstein AA. Central pontine and 25. Galton C, Deem S, Yanez ND et al. Open-label randomized trial extrapontine myelinolysis: a systematic review. Eur J Neurol. of the safety and efficacy of a single dose conivaptan to raise 2014; 21:1443-50. serum sodium in patients with traumatic brain injury. 2011; 14:354-60. 11. Gross P. Clinical management of SIADH. Ther Adv Endocrinol Neurocrit Care. Metab. 2012; 3:61-73. 26. Dhar R, Murphy-Human T. A bolus of conivaptan lowers 12. Liamis G, Milionis H, Elisaf M. A review of drug-induced intracranial pressure in a patient with hyponatremia after traumatic brain injury. 2011; 14:97-102. hyponatremia. Am J Kidney Dis. 2008; 52:144-53. Neurocrit Care.

13. Verbalis JG, Goldsmith SR, Greenberg A et al. Hyponatremia 27. Simon E, Batuman V. Hyponatremia treatment and management. treatment guidelines 2007: expert panel recommendations. April 18, 2014. http://emedicine.medscape.com/article/242166- treatment (accessed 2015 Mar 19). Am J Med. 2007; 120(11 suppl 1):S1-S21.

14. Lin CH, Lu CH, Wang FJ et al. Risk factors of oxcarbazepine- 28. Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. 2000; induced hyponatremia in patients with epilepsy. 342:1581-9. Clin Neuropharmacol. 2010; 33:293-6. 29. Kerwin AJ, Schinco MA, Tepas JJ 3rd et al. The use of 23.4% 15. Kumar S, Berl T. Diseases of water metabolism. In: Berl T, hypertonic saline for the management of elevated intracranial Bonventre JV, eds. Atlas of diseases of the kidney. Vol 1. pressure in patients with severe traumatic brain injury: a pilot Philadelphia, PA: Current Medicine, Inc.; 1999:1.1-1.22. study. J Trauma. 2009; 67:277-82.

16. Goldsmith SR. Current treatments and novel pharmacologic treatments for hyponatremia in congestive heart failure. Am J Cardiol. 2005; 95(suppl):14B-23B.

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MAY 2015 | ASHP ADVANTAGE E-NEWSLETTER Hyponatremia Management

Using Medication-use Evaluation Findings to Improve Patient Care

Additional For complete information about educational ASHP Advantage activities that are part of this initiative, visit www.ashpadvantage.com/muefindings. Educational Activities There is no charge for the activities, and and Other Free CE ASHP membership is not required.

Visit the ASHP eLearning site http://elearning.ashp.org/free-activities to browse listings of convenient on-demand continuing education (CE) activities, as well as publications and live webinars. Planned by ASHP Advantage and supported More than 50 hours of free on-demand by an educational grant from Otsuka America CE programming are available. Pharmaceutical, Inc.

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