11/16/2011 1 Joseph F. Dasta, M.Sc., FCCM, FCCP Professor Emeritus The Ohio State University College of Pharmacy Adjunct Professor The University of Texas College of Pharmacy Faculty Disclosures Faculty Disclosures Joseph F. Dasta, M.Sc., FCCM, FCCP Professor Emeritus The Ohio State University College of Pharmacy Adjunct Professor The University of Texas College of Pharmacy Disclosures Consultant, Otsuka America Pharmaceutical All conflicts have been resolved through peer review. Learning Objectives Learning Objectives • Describe the risk factors, risk stratification and treatment options for hospitalized patients with hyponatremia • Explain new data on treatment options, current guidelines and goals of therapy to improve guidelines and goals of therapy to improve outcomes in patients with hyponatremia • Review institutional protocols and the role of the health-system pharmacist in the management of hyponatremia Hyponatremia: Definition Serum [Na + ], mEq/L <125 125‐134 135‐144 Severe hyponatremia Mild hyponatremia Normonatremia • Commonly defined as serum sodium concentration ([Na + ]) <135 mEq/L, but cut‐off values vary • Generally considered a disorder of wate r rather than a disorder of salt • Results from increased water retention • When considering hyponatremia, think of edema Verbalis JG, et al. Am J Med 2007;120:S1-S21 Incidence of Hyponatremia in Acute Hospital Care Incidence of Hyponatremia by Serum [Na + ], mEq/L <116 <126 <136 Hawkins RC. Clin Chim Acta. 2003;337(1-2):169-172. Present on admission 0.5% 2.5% 28.2% Hospital-acquired 0.7% 3.7% 14.4% TOTAL 1.2% 6.2% 42.6%
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Joseph F. Dasta, M.Sc., FCCM, FCCPProfessor Emeritus The Ohio State University College of PharmacyAdjunct Professor The University of Texas College of Pharmacy
Faculty DisclosuresFaculty Disclosures
Joseph F. Dasta, M.Sc., FCCM, FCCPProfessor Emeritus The Ohio State University College of PharmacyAdjunct Professor The University of Texas College of Pharmacy
Disclosures
Consultant, Otsuka America Pharmaceutical
All conflicts have been resolved through peer review.
Learning ObjectivesLearning Objectives
• Describe the risk factors, risk stratification and treatment options for hospitalized patients with hyponatremia
• Explain new data on treatment options, current guidelines and goals of therapy to improveguidelines and goals of therapy to improve outcomes in patients with hyponatremia
• Review institutional protocols and the role of the health-system pharmacist in the management of hyponatremia
Hyponatremia: Definition
Serum [Na+], mEq/L
<125 125‐134 135‐144Severe
hyponatremia Mild hyponatremia Normonatremia
• Commonly defined as serum sodium concentration ([Na+]) <135 mEq/L, but cut‐off values vary
• Generally considered a disorder of water rather than a disorder of salt
• Results from increased water retention
• When considering hyponatremia, think of edemaVerbalis JG, et al. Am J Med 2007;120:S1-S21
Multivariable‐adjusted hazard ratio in‐hospital mortality
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)
Mortality Associated with Hyponatremia
Mortality Associated with Hyponatremia
Multivariable‐adjusted hazard ratio 1‐year mortality
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
1.25 (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)
Waikar et al. Am J Med. 2009;122(9):857-865.
Hyponatremia:Persistent, Acquired, Resolved
Hyponatremia:Persistent, Acquired, Resolved
Waikar et al. Am J Med. 2009;122(9):857-865.
• Mortality was highest in patients with persistent or acquired hyponatremia and lower in those with hyponatremia that resolved
• Mortality was lowest in those with normonatremia
Annual Cost of Hyponatremia in the United States
• Prevalence‐based cost‐of‐illness study– Included information from databases, published literature,
and expert physician panel• Low and high scenarios were estimated and
incorporated in a cost‐of‐illness model• Results (estimates)
– Prevalence of 3.2 to 6.1 million persons annually– 1 million hospitalizations annually with a principal or
secondary diagnosis of hyponatremia• 58‐67% of patients had a longer length of stay due to symptomatic hyponatremia
– Direct costs of $1.6 to $3.6 billion annually
Boscoe A et al. Cost Eff Resour Alloc. 2006; 4:10.
Economic Impact of HyponatremiaEconomic Impact of Hyponatremia
Callahan et al. Postgraduate Med. 2009;121(2):186-191.
Hyponatremia inPatients with Pneumonia
• Commercial database (2004‐2005)– 39 hospitals – 7965 patients with pneumonia– 8% were hyponatremic (serum sodium <135 mEq/L)
Zilberberg MD et al. BMC Pulm Med. 2008; 8:16.
Variable
Serum Sodium
p ValueNormal
(n = 7316)Hyponatremia
(n = 649)Mechanical ventilation (%) 2.3 3.9 0.014Mean LOS in ICU (days) 5.3 6.3 0.07Median hospital costs (in 2005 $) 5732 7086 0.001
$1324 median increase in hospital costs (range $98 –2682) in 2005 dollars
Hyponatremia in HF• Nearly 1 million hospitalizations for HF occur annually in the United
States (7 million HF patients in the U.S.)– Most are related to worsening systemic congestion– Use of diuretics, the mainstay therapy for congestion, contributes to
electrolyte abnormalities and worsening renal function
• Hyponatremia is common in patients with cardiac disease‐ 20% ‐ 28% of patients hospitalized with HF had concomitant
hyponatremia
• Hyponatremia concomitant with CHF significantly increases hospital LOS (P=.0001)
CHF = congestive heart failure. Gheorghiade M, et al. JAMA. 2004;291(16):1963-1971. Cleland JG, et al. Eur Heart J. 2003;24(5): 442-463. Crook MA, et al. Ann Clin Biochem. 1999;36(Pt 2):158-162. Gheorghiade M, et al. Circulation. 2003;107(21):2690-2696. Krumholz HM, et al. Am J Manag Care. 1999;5(6):715-723.
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P < .0001Admission Serum Sodium
[Na+] < 135 mEq/L
[Na+] ≥ 135 mEq/L
Hyponatremia in Heart FailureHyponatremia in Heart Failure45
40
35
30
25
34.8
42.5
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
In-Hospital Mortality (%)
Post-Discharge Mortality (%)
Death or RehospitalizationSince Discharge (%)
20
15
10
5
0
P < .0001
6.4 5.5
LOS (days)
P < .0001
6.0 3.27.1
12.4
Neurohormonal Activation in Heart Failure
Baroreceptor dysfunction
↓ Afferent inhibitory signals
Vasomotor center
↑ Sympathetic nervous system activity
↑ Renin secretion
↑ Vasopressin secretion
↑ Angiotension II
↓ Limb blood flow
↓ Renal blood flow↑ Aldosterone
↑ Sodium reabsorption↑ H2O reabsorption
KC1
Vasopressin Affects in Heart Failure
BRAIN
Supraoptic Paraventricular
neuronsneurons
Pituitary, posterior
lobe
Angiotension II hyperosmolality + Vasopressin - Baroreceptors natriuretic
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.
AVP = arginine vasopressin.Adapted from Ferguson JW, et al. Clin Sci (Lond). 2003;105(1):1-8.
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AVP Regulates Water andElectrolyte Balance
10 -
5 -
Thirst
asm
a AV
PWater excess
Plasma osmolality decreases
(<280 mOsm/kg)
Water deficit
Plasma osmolality increases
(>280 mOsm/kg)
0 -|
280|
290|
300|
310
Pla
Plasma Osmolality (mOsm/kg)
( g)
Plasma AVP declines
Renal water excretion Plasma osmolality normalizes (285-295 mOsm/kg)
( g)
Plasma AVP rises
Renal water excretion
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. Robertson GL, et al. Am J Med. 1982;72(2):339-353. Rossi NF, et al. Crit Care Clin. 1987;3(4):759-777.
Vasopressin Levels Inappropriately Elevated in Patients with SIADH
Zerbe R et al. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med. 1980;31:315-327. Annual Review of Medicine.Copyright 1980 by Annual Reviews, Inc. Reproduced with permission of Annual Reviews, Inc.
AVP Regulation of Water Reabsorption from Renal Tubular Cells
LEVEL 3 - SEVERE SYMPTOMS:vomiting, seizures, obtundation,respiratory distress, coma
Emergency!Correct RAPIDLY
LEVEL 1 - NO OR MINIMAL SYMPTOMS:headache, irritability, inability to concentrate, altered mood, depression
nausea, confusion, disorientation, altered mental status
OK to correct more slowly
• Raise [Na+] by <8-12 mEq in the 1st 24 hrs
• Raise [Na+] by <18 -24 mEq in the 1st 48 hrs
• Symptomatic: 1 mEq/L/h until neurologic symptoms resolve or [Na+] >120 mEq/L
Serum Sodium Safe Rate of CorrectionSerum Sodium Safe Rate of Correction
or [Na ] 120 mEq/L
— Slow rate of correction once symptoms resolve or Na+ 120-130 mEq/L
Verbalis JG et al. Am J Med. 2007;120:S1-S21.Kumar S et al. In: Atlas of Diseases of the Kidney. 1999:1.1-1.21.Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589.
Approaches to Management
• Traditional: add to the numerator
Sodium
Total Body WaterSerum Sodium =
• More rational approach: subtract from the denominator– Diuretic vs. aquaretic– Fluid restriction
• Assumes it is inexpensive
Prospective Observational Hyponatremia Registry*
• Goals– Describe clinical and laboratory data in patients either admitted with hyponatremia or occurring during hospitalizationG i i i ht i t h i th i b i d i– Gain insight into how various therapies are being used in hospital settings
– Quantify resources used in real‐world setting
• Experience through September 2011– Is first study to evaluate current practices– Enrolled 1487 patients (target of 2500 in US)
Dasta J et al. ACCP Annual Meeting; 2011 Oct 18. Poster 95E.
*Includes hospitals in U.S. and outside U.S.
Current Treatment StrategiesAGENT 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
•Consider pharmacy implications of “Reduce input to 1200 ml/d”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
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Current Treatment Strategies
AGENT LIMITATIONS
Isotonic saline • Ineffective in dilutional hyponatremia
• Should not be used in setting of edema
• No safety data
• Complex calculations• 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 and risk of over correction
ICU Patient Example: Total Daily VolumeSignificant volume from IV drugs
Medications mL/dayNorepinephrine 8 mg/250 mL IV at 10 micrograms/minute 450
Vancomycin 1 gram in 250 mL IVPB Q24H 250
Piperacillin/Tazobactam 2.25 grams in 50 mL IVPB Q6H 200
Lorazepam 50 mg/250 mL IV at 5mg/hour 600
38
p g g
Azithromycin 500 mg in 250mL IVPB QAM 250
Normal saline 1000 mL IV at 100 mL/hour 2,400
Insulin aspart low-dose correction scale SQ Q4H -
Ipratropium/albuterol 2.5/0.5mg in 3 mL NEBULIZER Q6H -
Famotidine 20 mg in 50 mL IVPB QAM 50
Heparin 5000 UNITS/1 mL SUBCUTAENOUSLY Q8H -
TOTAL FLUID: 4,200
• When to consider using HTS– Symptomatic hyponatremia (seizure, coma)– Acute severe hyponatremia (<24 hr, <120 mEq/L)– Hyponatremia worsening on 0.9% NaCl– Induced hypernatremic states
• Use equations to calculate rate/duration
The Role of Hypertonic SalineThe Role of Hypertonic Saline
• Use equations to calculate rate/duration—Medication safety issues?
– Adrogué‐Madias formula, used to predict rise in [Na+] after HTS, may underestimate correction rate, increasing risk for inadvertent overcorrection
– 10% rate of overcorrection; Higher risk for overcorrection when Na+ < 120 mEq/L
1. Zietse R et al. NDT Plus. 2009;2(Suppl 3): iii12–iii19.2. Fall PJ. Postgrad Med. 2000;107:75-82.
Newest Option for Hyponatremia:Vasopressin Antagonists
Non‐peptide AVP receptor antagonists
Conivaptan Lixivaptan Satavaptan Tolvaptan
Receptor V1a/V2 V2 V2 V2
Route of administration IV Oral Oral Oral
Urine volume ↑ ↑ ↑ ↑Urine volume ↑ ↑ ↑ ↑
Urine osmolality ↓ ↓ ↓ ↓
Na+ excretion/24 hrs ↔
↔ low dose↑ high dose
↔ ↔
Lee CR, et al. Am Heart J 2003;146:9-18.FDA Approved
CONIVAPTAN
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Conivaptan: Pivotal Phase III Trial• R, MC, DB, PC
– n = 84 patients
• Loading dose followed by 4 day continuous infusion– Placebo– Conivaptan 40mg/day– Conivaptan 80mg/dayConivaptan 80mg/day
• Primary endpoint– ∆ in serum sodium from baseline (AUC)
• Secondary endpoints– Time from 1st dose to sodium > 4mEq/L– Time sodium > 4mEq/L from baseline– Number patients with > 6mEq/L increase in sodium or normal (>135mEq/L)
Zeltser D, et al. Am J Nephrol 2007;27:447-57.
Sodium ResponseSodium Response
From Zeltser D et al. Am J Nephrol. 2007;27:447-457.
Aquaresis with ConivaptanAquaresis with Conivaptan
2500
2000
1500
VAPRISOL 40 mg/d
Placebo
EWC
(mL)
Day 1/Hour 24
Day 2/Hour 24
Day 4/Hour 24
Data on file. Astellas Pharma US, Inc.
1000
500
0
ResultsEndpoint Placebo
N = 29Con 40mg IV
N = 29Con 80mg IV
N = 26∆ in baseline Na AUC, mean (SE), mEq*h/L
12.9 (61.2) 490.9 (56.8) † 716.6 (60.4) †
Time 1st dose to Na> 4mEq/L from BL,
median hrs (95% CI)
NE 23.7 (95%CI 10.0, 24.0) †
23.4 (95%CI 6.0, 24.0) †
Total time Na above BL 14 2 (5 25) 53 2 (5 17) † 72 7 (5 43) †Total time Na above BL, mean (SE), h
14.2 (5.25) 53.2 (5.17) † 72.7 (5.43) †
Change in Na from BL to end of treatment,mean (SE), mEq/L
0.8 (0.80) 6.3 (0.74) † 9.4 (0.79) †
Increase Na > 6mEq/L or > 135mEq/L,n (%)
6 (20.7%) 20 (69.0%) † 23 (88.5%) †
† p < 0.001, NE = not estimable Zeltser D, et al. Am J Nephrol 2007;27:447-57.
OR for discharge to short- or long-term care facility
1.12 1.73 1.64
Pharmacist Roles and ResponsibilitiesPharmacist Roles and Responsibilities
• Monitor for hyponatremia• Consider drug related causes• Educate clinicians on hyponatremia• Participate in clinical decision making• Participate in formulary decision making• Be the catalyst for protocol development• Ensure optimal management of hyponatremia