hyponatremia management: using medication-use evaluation...

Hyponatremia Management: Using Medication-use Evaluation Findings to Improve Care

Presented as a Midday Symposium and Live Webinar at the

49th ASHP Midyear Clinical Meeting and Exhibition

Tuesday, December 9, 2014 Anaheim, California

Action Reminder

Planned and conducted by ASHP Advantage and supported by an educational grant from

Otsuka America Pharmaceutical, Inc.

Please be advised that this activity is being audio and/or video recorded for archival purposes and, in some cases, for repurposing of the content for enduring materials.

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Agenda 11:30 a.m. – 11:35 a.m. Welcome and Introduction Joseph F. Dasta, M.S., FCCM, FCCP 11:35 a.m. – 12:05 p.m. Using Findings from Medication-use Evaluations to Determine

Need for Improving Hyponatremia Management Joseph F. Dasta, M.S., FCCM, FCCP 12:05 p.m. – 12:50 p.m. Translating Findings from Medication-use Evaluations into

Improved Hyponatremia Management Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM, FNCS 12:50 p.m. – 1:00 p.m. Faculty Discussion and Audience Questions All Faculty Food and beverage are no longer provided at Midday Symposia. This ASHP policy considers the varied internal policies of commercial supporters related to the Physician Payments Sunshine Act.

Faculty Joseph F. Dasta, M.S., FCCM, FCCP, Activity Chair Professor Emeritus The Ohio State University College of Pharmacy Adjunct Professor The University of Texas College of Pharmacy Austin, Texas Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM, FNCS Professor of Pharmacotherapy & Outcomes Science and Neurosurgery Virginia Commonwealth University Medical College of Virginia Campus Richmond, Virginia

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• Joseph F. Dasta, M.S., FCCM, FCCP, has served as a consultant for Otsuka America Pharmaceutical, Inc.

• All other faculty and planners report no financial relationships relevant to this activity.

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Activity Overview Hyponatremia is an often overlooked and undertreated electrolyte disorder with serious clinical and economic outcomes in hospitalized patients, and optimal treatment strategies are not well defined. In this activity, the faculty will use practical examples to illustrate ways in which findings from disease-based medication-use evaluations of hyponatremia can help identify areas of patient care needing improvement. Considerations for screening and evaluating patients with hyponatremia will be reviewed, as well as suggestions for developing clinical and systems-based approaches for managing hyponatremia.

Learning Objectives At the conclusion of this application-based educational activity, participants should be able to

• List points that can be used to justify the need for conducting a medication-use evaluation (MUE) of hyponatremia management in a hospital.

• Outline factors to consider when screening and evaluating hospitalized patients for hyponatremia.

• Use MUE results and evidence-based literature to improve the management of hyponatremia in hospitalized patients.

Your educational opportunities related to hyponatremia management extend beyond today’s symposium…

• Available in 2015

o A live webinar on March 26, 2015, where faculty will explore issues raised by participant questions in today’s symposium (1 hour CPE)

o Engage the Experts informational podcasts featuring interviews with the faculty

o e-Newsletters featuring tips for incorporating information from this symposium into practice, as well as updates on emerging information on this topic

o On-demand activity based on today’s live symposium (1.5 hours of CPE, please note that individuals who claim CPE credit for the live symposium or webinar are ineligible to claim credit for the on-demand activity)

For more information and to sign up to receive e-mail updates

about this educational series, visit

www.ashpadvantage.com/muefindings

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http://www.ashpadvantage.com/muefindings


Continuing Education Accreditation

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.5 hours (0.15 CEUs – no partial credit) of continuing pharmacy education credit (ACPE activity #0204-0000-14-

706-L01-P for the live activity and ACPE activity #0204-0000-14-706-H01-P for the on-demand activity). Complete instructions for receiving your statement of continuing pharmacy education credit online are on the next page.

Webinar Information Visit www.ashpadvantage.com/go/muefindings/webinar to find

• Webinar registration link • Group viewing information and technical requirements

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If you do not have a smart device, access the Action Reminder for this activity at www.ashpadvantage.com/go/muefindings/remindme

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CPE Instructions for Pharmacists and Technicians Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity. All ACPE-accredited activities processed on the eLearning site will be reported directly to CPE Monitor. To claim pharmacy credit, you must have your NABP e-Profile ID, birth month, and birth day. If you do not have an NABP e-Profile ID, go to www.MyCPEMonitor.net for information and application. Follow these instructions to process your CPE credit for this activity. 1. Access the e-Learning site at http://elearning.ashp.org/my-activities

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NEED HELP? Contact [email protected]

Date of Activity:

Tuesday December 9,

2014 Code: _ _ _ _ _

CPE Hours: 1.5

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mailto:[email protected]


Joseph F. Dasta, M.S., FCCM, FCCP, Activity Chair Professor Emeritus The Ohio State University College of Pharmacy Adjunct Professor The University of Texas College of Pharmacy Austin, Texas

Joseph F. Dasta, M.S., FCCM, FCCP, is Professor Emeritus at The Ohio State University College of Pharmacy in Columbus and Adjunct Professor at The University of Texas College of Pharmacy in Austin. He retired from The Ohio State University (OSU) in 2007 after 31 years, and he currently lives in Austin. He serves as a health care consultant to pharmaceutical and device companies, and he provides pharmacy consulting services for the intensive care unit (ICU) at a local hospital.

Mr. Dasta earned his Bachelor of Science degree in pharmacy from West Virginia University School of Pharmacy. He began his academic career at OSU following completion of his Master of Science degree and residency in hospital pharmacy there in 1976. He developed one of the first practice sites and post-doctoral training programs in critical care pharmacy at OSU, through which he trained 11 residents and 9 fellows who are prominent practitioners, researchers, and leaders in the profession and pharmaceutical industry. He received OSU’s Jack L. Beal Post-baccalaureate Alumni Award in 2008.

Mr. Dasta was one of the first pharmacist members of the Society of Critical Care Medicine (SCCM), and he helped establish the role of pharmacists in this multidisciplinary society. He was a member of SCCM Council, the governing body of SCCM, from 2007-2010. SCCM honored him by creating the Joseph F. Dasta Critical Care Pharmacy Outcomes Research Grant in 2000. Ten years later, he was the first pharmacist to receive the SCCM Distinguished Investigator Award. Mr. Dasta’s contributions have also been recognized by other organizations. He received the Education Award from the American College of Clinical Pharmacy (ACCP) in 2002 and the Russel Miller award in 2013. Professor Dasta received the Sustained Contributions to the Literature Award from ASHP in 2010. He serves on the editorial board of Critical Care Medicine and Annals of Pharmacotherapy.

Mr. Dasta is a fellow of ACCP and the American College of Critical Care Medicine. He has authored more than 200 peer-reviewed publications, abstracts, brief communications, and book chapters, and he has given over 250 lectures on topics related to critical care and health outcomes. Mr. Dasta’s research has focused on health economics and patient safety of acute care pharmaceuticals. Specific areas of interest include hyponatremia, acute pain, sedation, sepsis, acute kidney injury, acute heart failure, and hypertensive emergencies.

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Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM, FNCS Professor of Pharmacotherapy & Outcomes Science and Neurosurgery Virginia Commonwealth University Medical College of Virginia Campus Richmond, Virginia

Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM, FNCS, is Professor of Pharmacotherapy & Outcomes Sciences and Neurosurgery at Virginia Commonwealth University (VCU) School of Pharmacy on the Medical College of Virginia Campus in Richmond. She is also Neurocritical Care Clinical Pharmacist at VCU Health System.

Dr. Brophy earned her Doctor of Pharmacy degree from University of Arizona College of Pharmacy in Tucson. Her postgraduate training includes residencies in critical care and pharmacy practice at University of Kentucky Medical Center in Lexington. She is a board-certified pharmacotherapy specialist, and she is also certified in emergency neurological life support.

Dr. Brophy’s research interests include effective treatment strategies for patients with neurological injuries, and she is often invited to speak on these topics.

Dr. Brophy is an active member of professional organizations, including American College of Clinical Pharmacy (ACCP), American College of Critical Care Medicine, ASHP, Neurocritical Care Society (NCS), and Society of Critical Care Medicine (SCCM). She currently serves as secretary of the Neurocritical Care Society and is Co-chair of the NCS guideline committee. She is a fellow of ACCP, SCCM, and most recently NCS. She has been recognized with the Presidential Citation from SCCM six times since 2003, and she received the NCS Presidential Citation in 2013, its inaugural year.

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Joseph F. Dasta, M.S., FCCM, FCCP, Activity ChairProfessor Emeritus

The Ohio State University College of PharmacyAdjunct Professor

The University of Texas College of PharmacyAustin, Texas

Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM, FNCSProfessor of Pharmacotherapy & Outcomes Science and Neurosurgery

Virginia Commonwealth UniversityMedical College of Virginia Campus

Richmond, Virginia

Disclosures

• Joseph F. Dasta, M.S., FCCM, FCCP, has served as a consultant for Otsuka America Pharmaceutical, Inc.

• All other faculty and planners report no financial relationships relevant to this activity.

Learning Objectives

At the conclusion of this educational activity, participants should be able to

• List points that can be used to justify the need for conducting a medication-use evaluation (MUE) of hyponatremia management in a hospital

• Outline factors to consider when screening and evaluating hospitalized patients for hyponatremia

• Use MUE results and evidence-based literature to improve the management of hyponatremia in hospitalized patients

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Joseph F. Dasta, M.S., FCCM, FCCPProfessor Emeritus

The Ohio State University College of PharmacyAdjunct Professor

The University of Texas College of PharmacyAustin, Texas

Hyponatremia Definition

• Commonly defined as serum sodium concentration <135 mEq/L, but cut-off values often vary by laboratory

• What value to use in a MUE?

• Degree of severity is associated with serum sodium concentration

Upadhyay A et al. Am J Med. 2006; 119(Suppl 1):S30-5.Kumar S et al. Lancet. 1998; 352:220-8.

Serum Sodium Concentration (mEq/L)

Mild Moderate Severe

131-135 120-130 <120

Hyponatremia Classification

Cawley MJ. Ann Pharmacother. 2007; 41:840-50.

Dilutional Hyponatremia

Total body sodium near normalTotal body water increased

Euvolemic(no edema)

SIADHHypothyroidism

Secondary adrenal insufficiency

Hypervolemic(edema)

Heart failureCirrhosis

Nephrotic syndrome

Depletional Hyponatremia

Hypovolemic

Sodium lostTotal body water reduced

Diarrhea PancreatitisVomiting Diuretic excessBurns Renal salt wastingTrauma Primary adrenal

insufficiency

SIADH = syndrome of inappropriate antidiuretic hormone

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Importance of Hyponatremia

• Known since the 1950s

• Still incompletely understood and underappreciated

• Most common electrolyte disorder– 6-15% of hospitalized patients at admission and an

additional 5% during the hospital stay

• 25% of patients in ICU are hyponatremic

• If not treated appropriately, can lead to significant morbidity, mortality, and costs

Deitelzweig S el al. Hosp Prac. 2011; 39:87-98.Upadhyay A et al. Sem Nephrol. 2009; 29:227-338.ICU = intensive care unit

Outcomes of Patients with Hyponatremia*

Zilberberg MD et al. Curr Med Res Opin. 2008; 24:1601-8.

Adjusted incremental hospital cost = $2289

Variable**Hyponatremia

(n = 10,900)

No Hyponatremia(n = 187,400)

Hospital mortality (%) 5.9 3.0

Ventilated (%) 5.0 2.8

ICU (%) 17.3 10.9

Median LOS (days) 8.6 7.2

Hospital costs ($) 16,500 13,560

*From a database of 200,000 patients.**All variables significantly different between groups at p < 0.001.

Management Considerations• Administer sodium (add to numerator)

• Cause water loss (subtract from denominator)

• No U.S. national guidelines – Updated expert panel 2013

• Available treatment approaches– Fluid restriction

– Normal saline

– Hypertonic saline (3%)

– Loop diuretics

– Vasopressin receptor antagonists

– Stop offending drug

Verbalis JG et al. Am J Med. 2013; 126:S1-S42.

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Definition of Hyponatremia: MUE

• Serum sodium (Na) ≤130 mEq/L

• Increases the chance of the patient having symptoms and hence likely to receive therapy– Neurologically injured patient may be treated at

sodium <135 mEq/L

• Exclude if blood glucose >250 mg/dL near the time of sodium measurement

• Exclude patients receiving renal replacement therapy– Minimize pseudohyponatremia

Overview of MUE

• Disease-based evaluation

• Observational data collection – National general ward and ICU databases

• Real-world management of hyponatremia

• Document treatment approaches used

• Determine topics needed to educate clinicians – Targeted educational effort

Assessing Efficacy of Individual Therapies

• Difficult to do since many patients receive combination therapy

• Many combinations possible

• Therapies can change over time

• We selected to review patients receiving monotherapy within the first 24 hours of diagnosis of hyponatremia

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Initial Therapies Used in Patients with Hyponatremia

• Fluid restriction 38%

• No active therapy 19%

• Normal saline 13%

• Tolvaptan 4%

• Hypertonic saline 1.5%

• Conivaptan <1%

• Mean (SD) number of unique therapies used 2 (1)

SD = standard deviation

Treatment Episodes

• Defined: Sodium corrected to >130 mEq/L but fell to <130 mEq/L during the stay

• Average 2.1 episodes per patient

• Total of 40% had >2 treatment episodes during the hospital stay

• Implication: after hyponatremia is corrected, patients often revert to the hyponatremic state

Patients Receiving No Active Therapy

• 19% of the total population

• Categorized by severity of hyponatremia– Severe hyponatremia 2.5%

– Moderate hyponatremia 16%

– Mild hyponatremia 27%

• Of patients receiving no active therapy– 50% received hyponatremic-inducing drug

– Offending drug discontinued in only 12%

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Decreased Serum Sodium During Therapy for Hyponatremia

• Define sodium fall as more than 2 mEq/L

• Categorized by type of monotherapy– Fluid restriction 9.5%

– Normal saline 8.5%

– Tolvaptan 2.5%

– Hypertonic saline 1.5%

What change in sodium (mEq/L) would you expect from fluid restriction as monotherapy in the first 24 hours?

a. 1.1

b. 2.2

c. 3.3

d. 4.4

Response to Monotherapy in the First 24 Hours

MonotherapyMean Change in Sodium in

First 24 Hours (mEq/L)No therapy 1.8

Fluid restriction overall 2.2

Fluid restriction < 1 L 2.5

Fluid restriction > 1 L 2.0

Normal saline 3.0

Tolvaptan 5.8

Hypertonic saline 6.0

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Effects of Fluid Restriction (FR) on Therapeutic Response

• Fluid restriction had little effect on increasing sodium concentration over the duration of therapy

• Normal saline alone increased sodium by 2.4 mEq/L– Adding FR increased sodium by 3.3 mEq/L

• Adding FR to any other therapy did not affect the degree of sodium correction

Incidence of Overcorrection

• Defined as increase in Na > 12 mEq/L in 24 hr– 18 mEq/L in 48 hr

• Overall 8%

• Categorized by type of monotherapy– No therapy 1.8%

– Fluid restriction 1.9%

– Normal saline 3.0%

– Tolvaptan 12.5%

– Hypertonic saline 15%

• No cases of osmotic demyelination syndrome documented

What percent of hyponatremic patients do you think are discharged from the hospital with a serum sodium >130 mEq/L?

a. 10%

b. 30%

c. 50%

d. 75%

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Correction to Various Benchmarks at Discharge (% of Patients)

Initial Therapy Na > 130 mEq/L Na > 135 mEq/L

All 50 21

No therapy 40 17

Fluid restriction 28 9

Normal saline 15 3

Hypertonic saline 24 9

Tolvaptan 65 33

Overview: Correction of Hyponatremia at Discharge

• 50% were discharged with serum sodium <130 mEq/L

• 79% were discharged with serum sodium <135 mEq/L

• These data suggest many patients with hyponatremia are being discharged from the hospital with varying degrees of hyponatremia

ICU Database: Percentage of Patients Receiving Monotherapy

• Categorized by type of monotherapy– Normal saline 34%

– Hypertonic saline 0.5%

– Fluid restriction 0.1%• Of note: 38% in non-ICU patient population

– Tolvaptan 0.04%

• 14% of patients received no therapy

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ICU Database

• 85% received some form of therapy

• 30% of treated patients were discharged from ICU with a sodium < 130 mEq/L

• Hence many patients are being transferred from the ICU with moderate hyponatremia

Summary

• We provide a process of generating data on how hyponatremia is being managed at your hospital– Can be sorted by medical or surgical service

or by prescriber

– Can be used to formulate a targeted educational strategy to improve prescribing and enhancing the care of hyponatremic patients

Key References

Cawley MJ. Hyponatremia: current treatment strategies and the role of vasopressin antagonists. Ann Pharmacother. 2007; 41:840-50.

Verbalis JG, Goldsmith SR, Greenberg A et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013; 126:S1-S42.

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Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM, FNCSProfessor of Pharmacotherapy & Outcomes Science and Neurosurgery

Virginia Commonwealth UniversityMedical College of Virginia Campus

Richmond, Virginia

At the conclusion of this educational activity, participants should be able to• List points that can be used to justify the need for conducting a

medication-use evaluation (MUE) of hyponatremia management in a hospital

• Outline factors to consider when screening and evaluating hospitalized patients for hyponatremia

• Use MUE results and evidence-based literature to improve the management of hyponatremia in hospitalized patients

Learning Objectives

• Identifying drug causes of hyponatremia

• Monitoring serum sodium concentration and patient symptoms

• Recommending appropriate therapy

• Avoiding interventions that may exacerbate hyponatremia

• Providing leadership within their institutions for improving the management of hyponatremia– Educate clinicians

– Develop protocols

• Useful resource: 2013 expert panel recommendations

Pharmacist’s Role in Hyponatremia Management

Verbalis JG et al. Am J Med. 2013; 126(10 Suppl 1):S1-42.

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• National database – Of patients receiving no active therapy

• 50% received hyponatremic-inducing drug

• Offending drug discontinued in only 12% of patients

• Potential agents– Carbamazepine, oxcarbazepine, SSRIs, sulfonylureas

• Monitor for withdrawal symptoms

• Consider medication half-life for correction

• Discontinue agent and consider an alternative agent

Drug-induced Hyponatremia

SSRIs = selective serotonin reuptake inhibitors

Definition of Hyponatremia

Serum Sodium Concentration (mEq/L)131-134 120-130 <120

Mild

hyponatremiaModerate

hyponatremiaSevere

hyponatremia

Clinical definitions may vary based on disease state

Hyponatremia and Falls

• 122 patients with asymptomatic chronic hyponatremia (serum sodium 126 ± 5 mEq/L) and 244 normonatremic controls– Incidence of falls: 21.3% versus 5.35% in controls– OR: 9.45 – OR adjusted for age, sex, and covariates: 67.43 (P<0.001)

• Frequency of falls the same—regardless of level of hyponatremia

• Attention errors increased 1.2-fold (P=0.001) in hyponatremic patients compared with normal controls– Similar to increase seen after moderate alcohol intake in

healthy volunteers

Renneboog B et al. Am J Med. 2006; 119:71.e1-8.OR = odds ratio

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Serum Sodium (mEq/L)

135-144

(n=82,377)

<135

(n=12,562)

130-134

(n=10,469)

125-129

(n=1591)

120-124

(n=353)

<120

(n=149)

Multivariable-adjusted hazard ratio in-hospital mortality

1 (ref) 1.47(1.33-1.62)

1.37(1.23-1.52)

2.01(1.64-2.45)

1.67(1.09-2.56)

1.46(0.73-2.91)

Multivariable-adjusted hazard ratio 1-year mortality

1 (ref) 1.38 (1.32-1.46)

1.35 (1.28-1.43)

1.53 (1.36-1.71)

1.78 (1.44-2.21)

1.03 (0.68-1.56)

Multivariable-adjusted hazard ratio 5-year mortality

1 (ref) 1.25 (1.21-1.30)

1.24 (1.19-1.29)

1.33 (1.23-1.44)

1.29 (1.09-1.53)

1.09 (0.84-1.41)

In-hospital and Long-term Mortality

Waikar et al. Am J Med. 2009; 122:857-65.

>95,000 hospitalized adults at 2 academic hospitals in Boston

Classification Algorithm

HyperglycemiaMannitol

>295 mEq/LHyper-osmolar

HypervolemiaIncreased ECF volume

Cole CD et al. Neurosurg Focus. 2004; 16:E9.Diringer MN et al. Neurologist. 2006; 12:117-26.

Kumar S et al. In: Schrier RW, ed. Atlas of diseases of the kidney. 1999; 1.1-1.22.

Serum sodium <135 mEq/L

<275 mEq/LHypo-osmolar

Assess serum osmolality

Assess volume status

EuvolemiaNormal ECF volume

HypovolemiaReduced ECF volume

275-295 mEq/LNormo-osmolar

PseudohyponatremiaSodium-free irrigant solutions

ECF = extracellular fluid

U[Na+] >20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] <20-30 mEq/L

U[Na+] <20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] <20-30 mEq/L

Diagnostic Algorithm for HyponatremiaDiagnostic Algorithm for Hyponatremia

Nephrotic syndromeCirrhosisCardiac failure

Renal lossesDiuretic excessMineralocorticoid deficiencyCerebral salt wastingRenal salt wasting Bicarbonaturia with renal

tubal acidosis and metabolic alkalosis

KetonuriaOsmotic diuresis

Euvolemia• Total body water ↑• Total body Na+ ↔

Assessment of volume statusAssessment of volume status

Hypovolemia• Total body water ↓• Total body Na+ ↓↓

Extrarenal lossesVomitingDiarrheaThird spacing of fluidsBurnsPancreatitisTrauma

Glucocorticoid deficiencyHypothyroidismSIADH

- Drug-induced(e.g., carbamazepine, oxcarbazepine, SSRI, sulfonylureas)

- Stress

Acute or chronic renal failure

Hypervolemia• Total body water ↑↑• Total body Na+ ↑

Adapted from Kumar S et al. In: Atlas of diseases of the kidney. 1999; 1.1-1.22.Spasovski G et al. Eur J Endocrinol. 2014; 170:G1-47.


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See page 32 for enlarged view

• INCREASED ECF VOLUME • Congestive heart failure (CHF) (25%), nephrotic

syndrome, cirrhosis (20%), pregnancyHYPERVOLEMIC

• NORMAL ECF VOLUME • SIADH (20%): tumors, CNS disorders, drug effects, and

pulmonary diseases• Hypothyroidism, secondary adrenal insufficiency

EUVOLEMIC

• DECREASED ECF VOLUME • Diuretics, diarrhea, vomiting, burns, trauma, pancreatitis,

primary mineralocorticoid deficiency, renal/cerebral salt wasting syndrome, third space losses

HYPOVOLEMIC

Differential Diagnosis of Hyponatremia and Registry Results

Cawley MJ. Ann Pharmacother. 2007; 41:840-50.Verbalis JG. Handb Clin Neurol. 2014; 124:37-52.

Spasovski G et al. Eur J Endocrinol. 2014; 170:G1–47.

Brain: Primary Target

• The degree of brain swelling determines the increase in intracranial pressure and the clinical symptoms ofhyponatremia

• The greater and more rapid the fall in serum sodium is, the greater the increase in brain swelling

• Acute hyponatremia is defined as hyponatremia that develops in less than 48 hr – No time for full adaptation

• Chronic hyponatremia is defined as hyponatremia that develops gradually (>48 hr) – Brain has time to fully adapt to the hypotonic state

• Chronic hyponatremia leads to brain glutamate deficiency– Cerebellar function impaired; ataxia

Rondon-Berrios H et al. Int Urol Nephrol. 2014; 46:2153-65.

Hyponatremia in Brain-injured Patients

43%38%

52%

35%

46%

0%

10%

20%

30%

40%

50%

60%

Na+ < 135 mEq/L

Overall [172/400]

Tumor [36/95]

SAH [55/106]

ICH [36/102]

TBI [45/97]

Hyponatremia: Sodium < 135 mEq/L Severity of hyponatremia: Mild 131-134 mEq/L, Moderate 125-130 mEq/L,

Severe ≤124 mEq/L

28%14%

2% MildModSevere

Human T et al. Neurocrit Care. 2013; 19:S153.

Per

cent

age

of P

atie

nts

Severity of HyponatremiaIncidence of Hyponatremia

14%

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See page 32 for enlarged view

Postoperative phase

Post-resection of prostate and endoscopic

uterine surgeryPolydypsia Exercise

Diuretics Methamphetamine (MDMA, XTC)

Colonoscopy bowel prep

IV cyclophosphamide

OxytocinDesmopressin,

terilpressin, vasopressin

Causes of Acute Hyponatremia (< 48 hr)

Spasovski G et al. Eur J Endocrinol. 2014; 170:G1–47.

SevereSeizures, coma, respiratory arrest,

obtundation, and vomiting

ModerateNausea, confusion, disorientation, and altered

mental status

No Symptoms/MinimalHeadache, irritability, inability to concentrate, altered mood,

and depression, or absence of discernible symptoms

Symptoms of Hyponatremia

Verbalis JG. Handb Clin Neurol. 2014; 124:37-52.

• Initial sodium levels should be measured upon admittance or emergency department evaluation

– Individual patient sodium goals should be established based on underlying disease state

• Factors affecting frequency of serum sodium monitoring

– Severity of hyponatremia

– Therapy chosen

• Reassess need and frequency of monitoring sodium every 12-24 hr– Minimize blood draws to avoid anemia

• Sodium levels should be measured prior to discharge to ensure levels are safe for discharge

Monitoring Serum Sodium

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Treatment of Hyponatremia*

• Discontinue offending drug

• Sodium chloride– Isotonic – 13%

– 3% Hypertonic – 1.5%

– Salt tablet (17 meq)

• Fluid restriction (FR) – 38%

• Vasopressin receptor antagonists (vaptans)**– Tolvaptan 4%

– Conivaptan <1%

• Mineralocorticoids

• No active therapy – 19% – Excluding stopping

offending drug, but including FR

• Demeclocycline

*Percentages are from national database for initial therapy**Also called AVP (arginine vasopressin) receptor antagonists


Patient Case

• CJ is a 39-year-old white female with sudden onset “worst headache of her life.” Work up in emergency department reveals a subarachnoid hemorrhage and she goes to OR for aneurysm clipping.

• Admit: Ht 5’3” Wt 51 kg

• 5 days later CJ’s sodium has decreased from 143 to 128 meq/Land her GCS changes from 15 to 14 and she is only oriented to person

• Angiogram shows mild vasospasm

• MIV is normal saline at 100 mL/hr through her peripheral IV line

GCS = Glasgow Coma ScaleMIV = maintenance IV

What is the best management option for CJ?

a. Hypertonic saline

b. Osmotic therapy (mannitol or furosemide)

c. Conivaptan or tolvaptan

d. Fluid restriction

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No/Minimal

• Fluid restriction

• Vaptan in select circumstances

Moderate

• Vaptan• Fluid

restriction

Severe

• Hypertonic sodium chloride

• Fluid restriction +/-vaptan

Treatment Recommendations

• Inability to tolerate fluid restriction orfailure of fluid restriction

• Unstable gait and/or high fracture risk• Very low sodium level (<125 mEq/L)

with increased risk of developingsymptomatic hyponatremia

• Need to correct serum sodium to saferlevels for surgery or procedures or forICU or hospital discharge

• Prevention of worsened hyponatremiawith increased fluid administration

• Therapeutic trial


No/Minimal

• Fluid restriction

• Vaptan in select circumstances

Moderate

• Vaptan• Fluid

restriction

Severe

• Hypertonic sodium chloride

• Fluid restriction +/-vaptan

Treatment Recommendations


Treatments for HyponatremiaTreatment Clinical Issues

Saline infusionRapid response in symptomatic patientsComplex calculationsNot to be used in edema-forming disorders

Fluid restrictionInexpensiveSlow and limited responseAdherence concerns

Demeclocycline

No need to limit water intakeTargets excessive AVPSlow responseNephrotoxic in CHF and cirrhosis

Loop diuretics Allows relaxation of fluid restrictionMay cause volume, K+, and Mg+ depletion

AVP receptor antagonists(vaptans)

Targets excessive AVPAquaresis (solute free urine output)Not to be used in hypovolemic states

Kumar S et al. In: Schrier RW, ed. Atlas of diseases of the kidney. Vol 1. 1999:1.1-1.22.Goldsmith SR. Am J Cardiol. 2005; 95(Suppl):14B-23B.

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What should be monitored in CJ? Select all that apply.

a. Total in’s and out’s

b. Sodium

c. White blood count

d. Neurological status

• Fluid restriction is very patient-specific

• Standard procedure: restrict fluid to ~0.8 L/day

• Slow rate of improvement

• Poor patient adherence

• Measure serum sodium daily – Levels will not change that quickly in the absence of

active therapy or large changes in fluid intake or administration

Monitoring Therapy and Pearls: Fluid Restriction

• When to consider hypertonic saline

– Symptomatic hyponatremia (seizure, coma)

– Acute severe hyponatremia (<24 hr, <120 mEq/L)

– Hyponatremia worsening on 0.9% sodium chloride

– Induced hypernatremic states for prevention or treatment of cerebral edema

• Discontinue hypertonic saline when serum sodium reaches 120-130 mEq/L

– Exception: or predetermined sodium goal

• Monitoring

– Monitor serum sodium and ECF volume status every 2–4 hr

Monitoring Therapy and Pearls: Hypertonic Saline


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Sodium Correction and Deficit Equations

• Corrected serum Na+ =

serum Na+ + (1.6 [serum glucose−100]/100)

• Change in serum Na+ = infusate Na+ – serum Na+

Total body water +1

Total body water (TBW) is approximately 60% of body weight, therefore TBW = 0.6 X wt (kg)

• Infusate rate = 1000 (serum Na+ change per hr) (TBW + 1) (infusate Na+ – serum Na+)

Rondon-Berrios H et al. Int Urol Nephrol. 2014; 46:2153-65. Adrogué HJ et al. N Engl J Med. 2000; 342:1581-9.

How quickly can we raise CJ’s sodium from 128 to 140 meq/L?

a. Over 2 hours

b. Over 6 hours

c. Over 24 hours

d. Over 2 days

• Acute vs. chronic hyponatremia impacts the rate of correction

• Presence or absence of significant neurologic signs and symptoms must guide treatment

• Avoid rapid increases in serum sodium (>12 meq/L/24 hr)

– Goal: Correct approximately 0.5-1 meq/L/hr until neurological symptoms resolve or sodium >120 meq/L

– Then slowly titrate to achieve a target change in sodium of 10-12 meq/L in first 24 hr and <18-24 meq/L in the first 48 hr


Singh TD et al. Eur J Neurol. 2014; 21:1443-50.Adrogué HJ et al. N Engl J Med. 2000; 342:1581-9.

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• Check serum sodium every 2-4 hr when using 3% sodium chloride

• Check serum sodium every 6-12 hr until the sodium is stable and daily after treatment is discontinued– National database: reported an average of 2 episodes

of recurrent hyponatremia per patient, with 40% experiencing more than 2 treatment episodes

– Overcorrection can cause osmotic demyelination syndrome (ODS)


Osmotic Demyelination Syndrome• First described in 1959 • Uncommon neurological disorder caused by damage to the

myelin sheath of brain cells ‒ Central pontine myelinolysis (CPM)

‒ Initial seizures or encephalopathy‒ May improve then severe deterioration

• Dysarthria, dysphagia, oculomotor dysfunction and variable degrees of quadriparesis, “locked-in”

• Most frequent risk factors‒ Rapid correction of hyponatremia‒ Others: alcoholism, cirrhosis, malnutrition, severe burns

• Detectable by MRI • Even patients with severe deficits at presentation can achieve

good recovery

Singh TD et al. Eur J Neurol. 2014; 21:1443-50.

The Vaptans: DosingConivaptan1

• Loading dose: 20 mg IV over 30 min

• Maintenance infusion 20-40 mg over 24 hr (if desired)

• May be administered for additional 1 to 4 days

• To minimize risk of vascular irritation‒ Administer through large veins

‒ Change infusion site every 24 hr

Tolvaptan2

• Should be initiated and reinitiated only in a hospital

• Initial oral dose of 15 mg administered once daily without regard to meals

• Increase to 30 mg once daily after at least 24 hr

• Maximum dose 60 mg daily

• Avoid fluid restriction during first 24 hr of therapy

1Vaprisol (conivaptan hydrochloride) injection prescribing information. Deerfield, IL: Astellas Pharma US, Inc.; 2014 Apr.

2Samsca (tolvaptan) prescribing information. Rockville, MD: Otsuka America Pharmaceutical, Inc. 2014 Feb.

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• Vaptans– Use for mild to moderate symptoms

– Monitor every 6-8 hours during the active phase of correction (24-48 hours)

• Tolvaptan (oral)– Drug interactions: CYP 3A4 and PgP substrate, 3A4 weak

inhibitor

– AUC is approximately 25% lower after nasogastric administration than after taking the intact tablets

– FDA safety warning (2013)

• Tolvaptan should not be used in patients with underlying liver disease, including cirrhosis; use of the drug should be limited to 30 days; and it should be discontinued if symptoms of liver injury occur

• Conivaptan (IV)– Drug interactions: CYP 3A4 substrate and strong inhibitor

Monitoring Therapy and Pearls: Vaptans

• Educate the patient on his or her sodium levels prior to discharge

• For drug-induced causes of hyponatremia, counsel the patient on changes in medication therapy

• Educate the patient on the signs and symptoms of hyponatremia and encourage them to contact their physician if symptoms develop after discharge

• Recommend communication with primary care physician regarding hospitalization, any medication changes, and future follow up

Pharmacist’s Role inDischarge Counseling

• Determine who is at risk of hyponatremia and monitor for signs and symptoms of hyponatremia

– Recognize that target sodium levels may be higher in neurocritical care patients

• Base treatment on severity of symptoms, volume status, and acute vs. chronic presentation

• Identify cause; stop the offending drug

• Monitor therapy every 2-4 hours when giving hypertonic saline and approximately every 6 hours for vaptans

• Limit sodium correction to <12 meq/L/day in the first 24 hours

• Evaluate sodium levels prior to discharge

• Counsel patient on medication updates and recommend follow up with primary care physician

Summary

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Key References

• Verbalis JG. Disorders of water metabolism: diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion. Handb Clin Neurol. 2014; 124:37-52.

• Spasovski G et al. Clinical practice guideline on diagnosis and treatment of hyponatremia. Eur J Endocrinol. 2014; 170:G1-47.

• Singh TD et al. Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol. 2014; 21:1443-50.

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U[Na+] >20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] <20-30 mEq/L

U[Na+] <20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] >20-30 mEq/L

U[Na+] <20-30 mEq/L

Diagnostic Algorithm for HyponatremiaDiagnostic Algorithm for Hyponatremia

Nephrotic syndromeCirrhosisCardiac failure

Renal lossesDiuretic excessMineralocorticoid deficiencyCerebral salt wastingRenal salt wasting Bicarbonaturia with renal

tubal acidosis and metabolic alkalosis

KetonuriaOsmotic diuresis

Euvolemia• Total body water ↑• Total body Na+ ↔

Assessment of volume statusAssessment of volume status

Hypovolemia• Total body water ↓• Total body Na+ ↓↓

Extrarenal lossesVomitingDiarrheaThird spacing of fluidsBurnsPancreatitisTrauma

Glucocorticoid deficiencyHypothyroidismSIADH

- Drug-induced(e.g., carbamazepine, oxcarbazepine, SSRI, sulfonylureas)

- Stress

Acute or chronic renal failure

Hypervolemia• Total body water ↑↑• Total body Na+ ↑

Adapted from Kumar S et al. In: Atlas of diseases of the kidney. 1999; 1.1-1.22.Spasovski G et al. Eur J Endocrinol. 2014; 170:G1-47.


• INCREASED ECF VOLUME • Congestive heart failure (CHF) (25%), nephrotic

syndrome, cirrhosis (20%), pregnancyHYPERVOLEMIC

• NORMAL ECF VOLUME • SIADH (20%): tumors, CNS disorders, drug effects, and

pulmonary diseases• Hypothyroidism, secondary adrenal insufficiency

EUVOLEMIC

• DECREASED ECF VOLUME • Diuretics, diarrhea, vomiting, burns, trauma, pancreatitis,

primary mineralocorticoid deficiency, renal/cerebral salt wasting syndrome, third space losses

HYPOVOLEMIC

Differential Diagnosis of Hyponatremia and Registry Results

Cawley MJ. Ann Pharmacother. 2007; 41:840-50.Verbalis JG. Handb Clin Neurol. 2014; 124:37-52.

Spasovski G et al. Eur J Endocrinol. 2014; 170:G1-47.

32


Self–Assessment Questions 1. A clinical pharmacist at ABC Hospital told the pharmacist clinical coordinator that a

nephrologist with whom she works had received several consults in the past two months related to the management of hyponatremia, and the nephrologist had expressed concern that hyponatremia was not being managed well in the hospital. Based on this information, the clinical coordinator was considering doing a medication-use evaluation to determine how hyponatremia was being managed. All of the following outcomes related to hyponatremia in inpatients can be used as justification for conducting the MUE EXCEPT

a. Hyponatremia is the most common electrolyte disorder in hospitalized patients. b. About twice as many patients with hyponatremia require mechanical ventilation

compared with patients without hyponatremia. c. Hyponatremia developing during a hospitalization is considered a “never event”

by Centers for Medicare and Medicaid Services. d. The percentage of patients admitted to the ICU is greater for patients with

hyponatremia compared with patients without hyponatremia. 2. ZT is admitted to your hospital complaining of headache and nausea for the past 3 days,

and he is disoriented. His current serum sodium level is 128 meq/L, and his past medical history is significant for epilepsy and hypertension. ZT is currently taking oxcarbazepine 600 mg twice daily, levetiracetam 500 mg twice daily, amlodipine 10 mg daily, and lisinopril 20 mg daily. He states he is compliant with his medications and “his medications were increased 2 weeks ago.” The nurse starts a peripheral intravenous line and begins giving him sodium chloride 0.9% at 75 mL/hr. ZT is 6’2” and weighs 88 kg. What is the best classification of ZT’s hyponatremia?

a. Mild. b. Moderate. c. Severe. d. Profound.

3. A pharmacy department conducted a disease-based MUE of hyponatremia management,

and the results indicated that overcorrection of serum sodium occurred in 7% of patients with hyponatremia receiving hypertonic saline. The follow-up targeted education should highlight which of the following as the maximum rate recommended for sodium correction in 24 hours in a hyponatremic patient with severe symptoms?

a. 6 meq/L/day. b. 12 meq/L/day. c. 18 meq/L/day. d. 24 meq/L/day.

Answers 1. c 2. b 3. b

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hyponatremia management: using medication-use evaluation...

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