A Patient-Centric, Process of Care Guide

Empowering Pharmacists toImprove Management of

Hyponatremia

Learning Objectives

• Discuss the clinical consequences of undertreatment of hyponatremia, including clinical manifestation, related comorbidities and clinical and resource burden

• Describe the pathophysiology of hyponatremia, including euvolemichyponatremia in SIADH and hypervolemic hyponatremia in heart failure

• Classify patients with hyponatremia based on clinical presentation and comorbidities and recommend appropriate correction therapy

• Outline current recommendations and guidelines for the treatment of hyponatremia

• Summarize the pathophysiology of disease and related mechanisms-of-action, efficacy and safety/tolerability evidence for hyponatremia pharmacotherapies

• Identify and commit to three or more practice improvements pharmacists can make to improve the process of care for hyponatremia

Renal Losses

Diuretic excess

Mineral corticoid deficiency

Salt-losing deficiency

Bicarbonaturia with renal tubal acidosis

and metabolic alkalosis

Ketonuria

Osmotic diuresis

Extrarenal Losses

Vomiting

Diarrhea

Third spacing of fluids

Burns

Pancreatitis

Trauma

Glucocorticoid deficiency

Hypothyroidism

SIADH secretion

Drug-induced stress

Acute or chronicrenal failure

Nephrotic syndrome

Cirrhosis

Cardiac failure

Diagnostic Algorithm for Hyponatremia

SIADH = syndrome of inappropriate antidiuretic hormone. Adapted from Kumar S, Beri T. Diseases of water metabolism. In: Berl T, Bonventre JV, eds. Atlas of Diseases

of the Kidney. Vol. 1. Philadelphia, PA: Current Medicine, Inc; 1999:1.1-1.22.

Legend: ↑ increase; ↑ ↑ greater increase; ↓ decrease; ↓ ↓ greater decrease; ↔ no change

Assessment of volume status

Hypovolemia

Total body water ↓

Total body Na+ ↓ ↓

Euvolemia (no edema)

Total body water ↑

Total body Na+ ↔

Hypervolemia

Total body water ↑ ↑

Total body Na+ ↑

U[Na+] >20 mEq/L U[Na+] <20 mEq/L U[Na+] >20 mEq/L U[Na+] >20 mEq/L U[Na+] <20 mEq/L

AVP Release and Sites of Action

Anxiety and stress (V1)

Myocyte hypertrophy (V1)

Blood:Platelet aggregation (V1)

Von Willebrand factor (V2)

Body fluid:Water retention (V2)

Vascular tone:Vasoconstriction (V1)

Vasodilation (V2)

Glycogenolysis (V1)

Posterior pituitaryAVP release

AVP = arginine vasopressin.Adapted from Ferguson JW, et al. Clin Sci (Lond). 2003;105(1):1-8.

AVP Regulation of Water Reabsorption from Renal Tubular Cells

AQP = aquaporin; GTP = guanine nucleotide binding protein; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; PKA = protein kinase A.Mayinger B, et al. Exp Clin Endocrinol Diabetes. 1999;107(3):157-165.

Co

llecting

du

ctAVPAVP V2

receptor

Basolateral membrane

Luminal membrane

H2O

H2OAQP2

Exocytic insertioncAMP

ATP

PKA

Recyclingvesicle

AQP2

Endocytic retrieval

GTP(Gs)

Vas

a re

cta Collecting Duct CellAQP3

AQP4

Risk Stratification

• First Decision: Presentation Acute vs. Chronic?

– How aggressive?

– How fast?

• Second Decision: Duration of hyponatremia

– Acute = less than 48 hours in duration

• Concerned about neurologic sequellae

– Osmotic differential between brain and blood

– Brain swelling

– Chronic = greater than 48 hours in duration

• Symptoms may be more modest

– Brain has time to adapt

LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression

LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion, disorientation, altered mental status

LEVEL 3 - SEVERE SYMPTOMS:vomiting, seizures, obtundation,respiratory distress, coma

Hyponatremia Treatment Options

Fluid restrictionConsider vasopressin antagonist or hypertonic saline if…•Unable to tolerate fluid restriction or failure of fluid restriction

•Need for rapid correction of Na+

Vasopressin Antagonist or Hypertonic Saline***

Hypertonic Saline

***Vasopressin antagonists may be preferred if volume overloaded

Traditional Pharmacological Treatment Strategies

• Text

Footnotes and references. This refuses to adhere to a template. Copy and paste this text box into whatever slides need it, and replace the text.

Traditional Pharmacological Treatment Strategies

Hyponatremia: Practical Approach on the Use of Hypertonic Saline

Comparison of Sodium Chloride Injection

Drug Facts and Comparisons 2013. St. Louis, MO: Wolters Kluwer Health; 2011.

Rate of Sodium Correction

• Initial rate of sodium correction not to exceed 1-2 mEq/L/hr

• High risk of Osmotic Demyelination Syndrome (ODS) do not exceed 8 mEq/L in 24 hours

– Hypokalemia, alcoholism, malnutrition,advanced liver disease or serum sodium < 105mEq/L

• Normal risk of ODS rate of sodium correction should be limited to < 12 mEq / L /24 hr or 18 mEq/L in 1st 48 hr

Verbalis JG et al. Amer J Med 2013;126, S1-S42. Laureno R et al. Ann Intern Med 1997;126:57- 62. Cawley MJ. Ann Pharmacotherapy 2007;41:840 - 50

Calculation of Sodium Requirement:

Adrogué-Madias EquationChange in serum sodium = infusate Na – serum Na

TBW + 1

Infusate Na = sodium concentration of infusate

0.9% (154mEq/L); 3% (513mEq/L)

Serum Na = patient’s serum sodium concentration

TBW = total body water = weight x correction factor

(Correction factor of 0.6 L/kg men, 0.45 L/kg women)

1 = 1 liter of solution

Adrogue HJ et al. N Engl J Med 2000;342:1581-9

Calculation Example

70-kg unresponsive male, serum sodium 110 mEq/L

•If 1 L of 3% sodium chloride injection is administered how much of a change in serum sodium will occur?

– Infusate Na (3%) = 513 mEq/L– Patient’s serum Na = 110mEq/L– TBW = 0.6 L/kg x 70 kg

Change in serum sodium = infusate Na – serum NaTBW + 1

Change in serum sodium = 9.4 mEq/L

Calculation Continued

Estimated effect of 1 liter of 3% sodium chloride would be 9.4 mEq/L or 0.94 mEq per 100 mL

How do you administer the infusate?

•Calculate total volume to administer in 24 hr, given 12 mEq/L is max increase in serum Na in 24 hr

100 mL x 12 mEq/L = 1,277mL

0.94 mEq/L

•Calculate recommended rate of infusion

100 mL x 1.5 mEq/L/hr* = 160 mL/hr 1st 4 hr

0.94 mEq/L ~32 mL/hr for 20 hr

* Recommended rate of sodium correction for severe symptoms at normal risk for ODS

Calculation Continued

• Calculation of infusion rate

– Multiply body weight in kg by desired rate of increase in sodium in mEq/L/hr • (ex., 70kg patient, a 3% NaCl infusion at 70 ml/hr will

increase sodium ~1 mEq/L/hr, while infusing 35ml/hr will increase serum sodium ~0.5 mEq/L/hr)

– Monitor sodium levels frequently (q 4-6 hr)

Rate of Sodium Correction is more important thanthe infusion rate………..

Verbalis JG et al. The Amer J Med 2013;126:S1-S42. Ellison DH et al. N Engl J Med 2007;356:2064-2072

Hyponatremia Patient Case Study

Heart Failure

1. Gheorghiade et al. Eur Heart J. 2007;28:980-988. 2. Gheorghiade et al. Arch Intern Med. 2007;167:1998-2005. 3. Gheorghiade et al. JAMA. 2004;291(16):1963-1971. 4. Klein et al. Circulation. 2005;111:2451-2460.

P < .0001

P < .0001

In-Hospital Mortality (%)

Post-Discharge Mortality (%)

Death or RehospitalizationSince Discharge (%)

Admission Serum Sodium

[Na+] < 135 mEq/L

[Na+] ≥ 135 mEq/L

45

40

35

30

25

20

15

10

5

0

P < .0001

6.4 5.5

LOS (days)

P < .0001

6.03.2

7.1

12.4

34.8

42.5

Hyponatremia in Heart Failure

0.5 -

0.4 -

0.3 -

0.2 -

0.1 -

|0

|200

|400

|600

|800

|1000

|1200

|1400

|1600

|1800

Time (days)

Cu

mu

lati

ve P

rob

abili

tyo

f D

eath

Sodium Level <136 mEq/L

Sodium Level ≥136 mEq/L

Log-rank P<.001

Number at RiskSodium Level 870 835 749 626 524 387 273 169 91 33

<136 mEq/LSodium Level 107 91 81 70 65 60 47 37 21 4

≥136 mEq/L

Survival in HF Decreased with Concomitant Hyponatremia*

*Survival rates were significantly reduced if patients with acute ST-elevation myocardial infarction had concomitant hyponatremia ([Na+] <135 mEq/L) on

admission (P<.0001). Adapted from Goldberg A, et al. Arch Intern Med. 2006;166(7):781-786.

Patient Chart Overview

• John is a 78-year-old, 75 kg hispanic male admitted to the CCU in acute decompensated heart failure. He has been extremely fatigued with SOB for several weeks prior to admission. After 6 days of treatment the patient is now receiving intravenous diuretics and vasodilator therapy and is now moved to a step down unit for medication stabilization prior to discharge.

• Medical history

– Ischemic cardiomyopathy (LVEF 23%)

– s/p AMI x 2 in 2007 and 2010

– HTN x 35 years

– Hyperlipidemia x 32 years

– Osteoporosis x 20 years

CCU = coronary care unit; LVEF = left ventricular ejection fraction

Patient Chart Overview

• Family history

– Unremarkable

• Social history

– Smokes 1.5 packs per day x 29 years (D/C 5 years)

– No alcohol use

• Physical assessment

– Vital signs: HR: 92 bpm, BP: 116/82 mm Hg, RR: 14 bpm, Temp: 38.9°C

– Weight: 81 kg (dry weight 77 Kg), Height: 157 cm

– Chest: Crackles bilateral bases

– Abdomen: Distended

– Skin: + 2 pitting edema in both arms and legs

– Neurologic

• Cranial nerves II-VIII grossly intact

• A&O x 3

HR = heart rate; BP = blood pressure; RR = respiratory rate; bpm = breaths per minute; A&O = alert and oriented.

Patient Chart Overview

• Laboratory (day 7 of admission)

– Serum sodium: 125 mEq/L

– Serum osmolality: 264 mOsm/kg

– Urine sodium: 18 mEq/L

– Urine osmolality: 255 mOsm/kg

– Serum creatinine: 1.2 mg/dL

• Intake/output (total over 7 days)

– 5360 mL/3200 mL (+ 2160 mL)

• Current medications

– Furosemide 40 mg IV every 8 hours

– Lisinopril 5 mg qday

– Carvedilol 6.25 mg BID

– Spironolactone 12.5 mg by mouth daily

Optimal Treatment Strategies

AGENT LIMITATIONS

Fluid restriction • Slow to correct over days (1-2 mEq/L/day)

• Poorly tolerated due to thirst

• Should not be used with high AVP level and urine osmolality

Diuretics • Allows relaxation of fluid restriction

• Potential for ototoxicity, volume depletion, and K+ and Mg+

depletion

Demeclocycline • Not FDA approved for hyponatremia

• Slow to correct over days

• Nephrotoxic in cirrhosis and heart failure

Oral Sodium Chloride

• Nausea and vomiting

• Rarely can give large enough dose to be effective

• No data

Optimal Treatment Strategies

AGENT LIMITATIONS

Isotonic saline • Ineffective in dilutional hyponatremia

• Should not be used in setting of edema

• No safety data

• Complex calculations

Hypertonic saline • No consensus regarding appropriate infusion rates

• Overcorrection can cause osmotic demyelination syndrome

• Should not be used in setting of edema

• No safety data

• Complex calculations

Optimal Treatment Strategies

AGENT OPTIONS

Standard Heart Failure Treatment Measures

• Consider Increase in ACEi dose

• Consider increase in Carvedilol dose

Vaptan Clinical Considerations

• Tolvaptan

– Indicated for clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with HF, cirrhosis, and SIADH

– Available in 15-mg and 30-mg tablets

– Dosing: 15 mg orally once daily. Dosing may be increased at intervals ≥24 hours to 30 mg once daily to a maximum of 60 mg once daily

– Should only be initiated and re-initiated in a hospital setting. Healthcare providers must review the FDA-approved medication guide with every patient

– Coadministration with potent CYP3A4 enzyme inhibitors (ketoconazole, itraconazole, indinavir) is contraindicated

Tolvaptan [package insert]. Rockville, MD: Otsuka America Pharmaceutical, Inc; 2009.

Vaptan Clinical Considerations

• Conivaptan

– Indicated for euvolemic/hypervolemic hyponatremia in hospitalized patients

– Administer IV via large veins due to infusion-site reactions (63% to 73%)

• Change infusion site every 24 h

– Hypervolemic hyponatremia associated with heart failure: Data are limited. Use other treatment options

– Dosing: 20 mg IV LD @ 30min followed by 20 mg as a continuous infusion @ 24 h

– Duration of infusion limited to 4 days

– Limited data on drug-drug compatibility

– Contraindicated with potent CYP3A4 enzyme inhibitors (ketoconazole, itraconazole, indinavir)

Conivaptan [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2010.

LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression

LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion, disorientation, altered mental status

LEVEL 3 - SEVERE SYMPTOMS:vomiting, seizures, obtundation,respiratory distress, coma

Hyponatremia Treatment Options

Fluid restrictionConsider vasopressin antagonist or hypertonic saline if…•Unable to tolerate fluid restriction or failure of fluid restriction

•Need for rapid correction of Na+

Vasopressin Antagonist or Hypertonic Saline***

Hypertonic Saline

***Vasopressin antagonists may be preferred if volume overloaded

Hyponatremia Patient Case Study

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Causes of Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Upadhyay A et al. Sem Nephrol 2009;29:227-338

Recognition of SIADH

• Hyponatremia with low serum osmolality

• Excessive renal excretion of sodium

– (> 20mEq/L)

• Limited clinical evidence of volume depletion or overload

– Normal skin turgor and blood pressure (euvolemia)

• Normal renal, adrenal and thyroid function

Bartter FC, et al. Am J Med 1967;42:790-806

Patient Case

• Rebecca is a 67 year-old female who presents to the ED with her husband who states “ my wife has become more confused and forgetful over the past 12-24 hours”

• Medical History

– HTN x 16 years

– COPD x 10 years

– Osteoporosis x 11 years

– Depression diagnosed 4 weeks ago

Patient Case

• Family history– Unknown

• Social history(-) alcohol, (-) tobacco, (-) IVDA

• Physical assessment– Vital signs: HR: 84bpm, BP 128/82mmHg, RR: 12BPM, Temp: 98.6F – Weight: 61kg (admission weight), Height: 167cm– General

• Confused– Chest

• Clear A & P– Abdomen

• Unremarkable– Skin

• Unremarkable– Neurologic

• Cranial nerves II-VIII grossly intact• A & O x 1 (person)

HR= heart rate; BP = blood pressure; RR = respiratory rate; bpm = breaths per minute; A7O = alert and oriented

Patient Case

• Laboratory (admission)

– Serum sodium 112 mEq/L

– Serum osmolality 265 mOsm/kg

– Urine sodium 25 mEq/L

– Serum creatinine 1.1 mg/dL

• Current medications

– Tiotropium bromide 18 mcg capsule

• 2 inhalation of one capsule, once daily with HandiHaler device

– Cardizem 240mg by mouth daily x 8 yrs

– HCTZ 25 mg by mouth daily x 5 years

– Oscal 600mg by mouth twice daily x 10 years

– Venlafaxine 100mg by mouth daily x 30 days

Drug-Induced Hyponatremia (SIADH)

• Risk factors for the development of hyponatremia with SSRI’s:

– Older age

– Female gender

– Concomitant use of diuretics

– Lower body weight

– Lower baseline serum sodium level

• Hyponatremia develops within weeks of treatment and resolves after two weeks after therapy discontinued

• Treatment for severe hyponatremia includes hypertonic saline +/- loop diuretic

Jacob S, et al. Annals of Pharmacotherapy 2006;40:1618-1622.

Drug-Induced Hyponatremia (SIADH)

• Retrospective controlled study

• 199 elderly psychiatric inpatients (mean age 74.2 years)

• 74 prescribed SSRI or venlafaxine

• 10 of 14 patients on venlafaxine developed hyponatremia

• 39% of patients on an SSRI or venlafaxine had hyponatremia vs 10% of controls

• Elderly patients on SSRI or venlafaxine should have

• serum sodium levels checked before and after

• commencement of antidepressant therapy

Kirby D et al. Int Geriatr Psychiatry 2002;17:231-7.

Potential Risk of Liver Injury with Tolvaptan

• Double blind, 3 year placebo controlled trial in 1445 patients with Autosomal Dominant Polycystic Kidney Disease

• 3 patients significant increases in ALT and Tbili

• 4.4% (42/958) on tolvaptan and 1% (5/484) on placebo exhibited greater than 3x ULN of ALT

• Maximum daily dose was 90mg morning and 30mg in afternoon which is higher than 60mg daily for hyponatremia

• Previous trials did not identify liver damage with tolvaptan

• Reduce the risk of new liver injury by limiting duration of therapy

ALT- Alanine aminotransferase, Tbil – Total bilirubin, ULN – Upper limit of normal

Torres VE et al. N Engl J Med 2012;367:2407-2418.

Tolvaptan Safety – Increased liver enzymes suggestive of liver injury

• All 3 patients with liver enzyme abnormalities improved after tolvaptan was discontinued

• This finding of liver injury prompted an FDA alert:

• Tolvaptan should be avoided in patients with underlying liver disease, including cirrhosis.

• Warning that patients on tolvaptan who exhibit any symptoms suggestive of liver disease should undergo liver tests and that tolvaptan should be stopped immediately if liver injury is suspected

• Warnings include limiting the treatment duration to no more than 30 days and to avoid use in patients with liver disease

http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm350185.htm . Accessed February 2014

U.S. Guidelines andEuropean Guidelines

Hyponatremia Classification

U.S. Expert Panel Recommendations

European Clinical Practice Guideline

Hypovolemic hyponatremia Vaptan is NOT a treatmentoption

Vaptan NOT a treatment option

Euvolemic hyponatremia,Asymptomatic

Vaptan is a treatment option Do NOT recommend vaptan

Euvolemic hyponatremia,Moderate to severe CNS symptoms

Vaptan is NOT a treatment option

Recommend AGAINST vaptan

Hypervolemic hyponatremiaAsymptomatic

Vaptan is a treatment option(NOT for those with liver disease)

Recommend AGAINST vaptan

Hypervolemic hyponatremiaModerate to severe CNS symptoms

Vaptan is NOT a treatment option

Recommend AGAINST vaptan

Verbalis JG, et al. Am J Med. 2013;126(10 suppl 1):S1-S42. Spasovski G, et al. Eur J Endocrinol. 2014;170(3):G1-G47.

Practical Considerations for the Use of Tolvaptan*

• LFT’s and/or Tbili levels > 2x upper limit of normal avoid starting drug

• LFT’s and/or Tbili levels ↑ 2x upper limit of normal during treatment would discontinue drug (drug or disease etiology?)

• Monitor LFTs and/or Tbili weekly until normal

• When Tolvaptan is not an option:

– Low sodium diet + spironolactone

– Fluid restriction

– Loop diuretic

– Paracentesis

– Transjugular intrahepatic portosystemic shunt (TIPS)

* Recommendations only based upon clinical experience. These recommendations are not endorsed by NACCME or Otsuka America Pharmaceuticals

Pharmacist Roles and Responsibilities

• Monitor for hyponatremia

• Consider drug related causes

• Educate clinicians on hyponatremia

• Optimize selection of pharmacological treatments

• Maintain vigilance in monitoring during treatment

• Protocol development

Conclusion

• Hyponatremia is associated with increased mortality and increase in economic impact.

• The presence or absence of significant neurologic signs and symptoms is very important in guiding therapy.

• Overly aggressive rapid correction of hyponatremia can result in osmotic demyelination syndrome.

• An increase in serum [Na+] should be limited to:

– <12 mEq/L/24 hours or 18 mEq/L in 1st 48 hrs for normal risk of ODS

– < 8 mEq/L/24 hours if at high risk of ODS

• Pharmacists have an increased role and responsibility in caring for the patient with hyponatremia