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11/16/2011
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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
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.
6 6 36
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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2
[Na+] <135 mEq/L
(n=12,562)
[Na+] 130‐134 mEq/L
(n=10,469)
[Na+] 125‐129 mEq/L (n=1591)
[Na+] 120‐124 mEq/L (n=353)
[Na+] <120 mEq/L(n=149)
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
peptides
Inhibition of renin secretion
Renal H2O reabsorpitonVasoconstrictionIncreased arterial
barorecptor sensitivity
Prevalence of sodium disturbances in cirrhosis
Prevalence of sodium disturbances in cirrhosis
27.9
35.1
25
30
35
40
%
4.4
11.1
15.8
4.51.3
0
5
10
15
20
</=120 121-125 126-130 131-135 136-140 141-145 >145
serum sodium (mEq/L)
Adapted from P.Angeli et al. Hepatology 2006; 44:1535-1542
Hyponatremia Mortality Impact in Cirrhosis
• Liver Transplant candidates in the VA system, 97-03 (n= 507)—Hepatitis C (68%), EtOH (67%)—MELD 16.2 + 6.7—Hyponatremia (<130 mEq/L): 31%—Persistent Ascites/Hydrothorax: 38%
• Predictors of 6 month mortality
Odds Ratio p
MELD 1.25 (1.16-1.35) <0.001
Na < 135 mEq/L 2.76 (1.31-5.81) 0.008
Persistent Ascites 2.72 (1.31-5.71) 0.008
Heuman DM, et al. Hepatology. 2004;40(4):802-10.
• Predictors of 6-month mortality
Increased Risk of Falls with “Asymptomatic” Hyponatremia
Group n Falls Odds Ratio
Adjusted Odds Ratio*
9.45 67.43“Asymptomatic”Chronic
Hyponatremia 122 21.3%9.45
(2.64-34.09)p <.001
67.43 (7.48-607.42)
p <.001
Normonatremic controls 244 5.35% 1.00 1.00
*adjusted for age, sex and covariates
Adapted from: Renneboog B, et al. Am J Med. 2006;119(1): 71. e1-8.
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Hyponatremia & Gait Stability
Serum [Na+] = 124 mEq/L Serum [Na+] = 135 mEq/L
Serum [Na+] = 139 mEq/LSerum [Na+] = 130 mEq/L
Reprinted from Renneboog B et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;199:71.e1-71.e8. ©2006, with permission from Elsevier.
Serum [Na+] = 124 mEq/L Serum [Na+] = 135 mEq/L
Pathophysiologic Mechanism ofMechanism of
Water and Salt Balance
Hyponatremia Classification
Dilutional Hyponatremia
Total body sodium near normalTotal body water increased
Depletional Hyponatremia
Hypovolemic
CawleyMJ. Ann Pharmacother. 2007; 41:840‐50.
Euvolemic(no edema)
SIADHHypothyroidism
Secondary adrenal
insufficiency
Hypervolemic(edema)
Heart failureCirrhosisNephroticsyndrome
Sodium lostTotal body water reduced
Diarrhea PancreatitisVomiting Diuretic excessBurns Renal salt
wastingTrauma Primary adrenal
insufficiency
Common Medications Associated with SIADH
Medications CategoryCaptopril, enalapril ACE inhibitor
Amiodarone Antiarrhythmic
Carbamazepine Anticonvulsant
Clozapine, chlorpromazine, flupnenazine, haloperidol Antipsychotic
Theophylline Bronchodilator
Carboplatin cisplatin cyclophosphamide ifosfamideCarboplatin, cisplatin, cyclophosphamide, ifosfamide, vinblastine, vincristine Chemotherapeutic
Amiloride/hydrochlorothiazide, chlorothiazide, furosemide, indapamide Diuretic
“Ecstasy” (3,4,methylenedioxymethamphetamine [MDMA]), nicotine Recreational
Citalopram, duloxetine, fluoxetine, paroxetine, sertraline, venlafaxine SSRI
Chloropropamide, glibenclamide, glimepiride, glipizide Sulfonylurea
Amitryptyline Tricyclic antidepressant
Desmopressin acetate (DDAVP), oxytocin Vasopressin analogue
Diagnostic Algorithm for Hyponatremia
Assessment of volume status
HypovolemiaTotal body water ↓Total body Na+ ↓ ↓
Euvolemia (no edema)Total body water ↑Total body Na+ ↔
HypovolemiaTotal 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
Renal LossesDiuretic excessMineral corticoid
deficiencySalt-losing
deficiencyBicarbonaturia with
renal tubal acidosis and metabolic alkalosis
KetonuriaOsmotic diuresis
Extrarenal LossesVomitingDiarrheaThird spacing of
fluidsBurnsPancreatitisTrauma
GlucocorticoiddeficiencyHypothyroidismSIADH secretionDrug-induced stress
Acute or chronicrenal failure
Nephrotic syndromeCirrhosisCardiac failure
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
[Na+] q [Na+] q [Na+] q [Na+] q [Na+] q
AVP Release and Sites of ActionAnxiety and stress (V1)
Myocyte hypertrophy (V1)
Posterior pituitaryAVP release
Blood:Platelet aggregation (V1)Von Willebrand factor (V2)
Body fluid:Water retention (V2)
Vascular tone:Vasoconstriction (V1)
Vasodilation (V2)
Glycogenolysis (V1)
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
Collecting du
AVP
H2O
Exocytic insertionAMP
ATPAQP2GTP
(Gs)
Vasa
rect
a Collecting Duct CellAQP3
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.
uctAVPAVP V2
receptor
Basolateral membrane
Luminal membrane
H2OAQP2
insertioncAMP
PKA
Recyclingvesicle
Endocytic retrieval
(Gs)
AQP4
Symptomatic Hyponatremia: Neurological ManifestationsSymptomatic Hyponatremia: Neurological Manifestations
• Headache• Irritability• Nausea/Vomiting• Mental Slowing
ChronicMental Slowing
• Confusion/Delerium • Disorientation• Stupor/Coma• Convulsions• Respiratory Arrest
Acute
Risk Stratification
• Acute vs. Chronic– 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
• Duration of hyponatremia– How aggressive?– How fast?
Sodium and the BrainSodium and the Brain
+ +++
Na+ moves from high concentrations to low
Water follows Na+
Time-dependent
+ +
+
+
+
+
++ ++
++
++
++
BRAIN EDEMA
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6
+++
Na+ moves from high concentrations to low
Water follows Na+
Implications for treatment
Sodium and the BrainSodium and the Brain
++
+ ++
++
Rapid fluid shifts out of the brain: OSMOTIC DEMYELINATION SYNDROME (ODS)
How Aggressive? How Fast?How Aggressive? How Fast?
LEVEL 2 - MODERATE SYMPTOMS: nausea confusion disorientation
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.
Conivaptan: open label extension study
a+ ] (m
Eq/L
)
130
135
140Conivaptan 20 mg/d (n=11)Conivaptan 40 mg/d (n=93)
Conivaptan Study day
0 5 15 30 35
Mea
n se
rum
[Na
0
125
130
120
10 20 25
Conivaptan hydrochloride injection.Prescribing information; February 2006.
Conivaptan Adverse Events
Placebo (n=29)
Con 40 mg (n=29)
Con 80 mg (n=26)
Phlebitis 6.9% 24.1% 30.8%Hypotension 6.9% 13.8% 19.2%Postural Hypotension 0% 13.8% 3.8%I j ti Sit
Zeltser D, et al. Am J Nephrology. 2007; 27: 447-457.
Injection Site Inflammation 0% 6.9% 11.5%
Pyrexia 0% 10.3% 7.7%Hyperkalemia 3.4% 0%Injection-site Thrombosis 0% 10.3% 0%
Overcorrection 0% 6.9% 7.7%
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Special Populations: Neurology
Series n Dosing Timing 6mEq/L Rise Safety
#1 22 Bolus + Infusion
24 hrs 86%
24h post D/C =
No excessive correction5 pts with
2 retrospective case series, neuro ICU patients
24h post D/C = 47%
5 pts with phlebitis
#2 24 Bolus only* 72 hrs Single Bolus:56%
Double Bolus:52%
1 pt with excessive correction
No phlebitis
*Concomitant 1.25% or 2% saline permitted Wright, et al. Neurocritical Care 2009;11:6-13
Murphy T, et al. Neurocritical Care 2009;11:14-19
Acute Hyponatremia: Neuro ICU Results
Murphy et alN=24
Wright et alN=22
Baseline [Na+] 131.4 + 3.0 130.5
Peak [Na+] within 8 hours 137.1 + 2.8 140.4
[Na+] change from baseline 6.31 + 3.0 9.9
> 4 mEq/L change by 8 hours 12/16 (75%)
> 6 mEq/L change by 8 hours 9/16 (56%) 19/22 (86%)
Correct >135 mEq/L by 8 hours 12/16 (75%) 130.5
TOLVAPTAN
SALT – 1 and SALT – 2
• Two MC, R, DB, PC trials– Tolvaptan 15 mg (increased to 30 – 60 mg)– Placebo
• Primary Endpoints:
Study of Ascending Levels of Tolvaptan in Hyponatremia
• Primary Endpoints:– ∆ in AUC for the serum Na+ concentration
• Baseline to day 4 • Baseline to day 30
Schrier RW, et al. NEJM. 2006; 355(20):2099 -2112.
SALT – 1 Results
Endpoint Placebon = 103
Tolvaptann = 103
p-value
All Patients: Day 4 0.25 ± 2.08 3.62 ± 2.68 < 0.001
All Patients: Day 30 1.66 ± 3.59 6.22 ± 4.10 < 0.001
Mild (130 135 l/L) D 4 0 32 ± 2 27 2 52 ± 1 95 0 001
AUC for serum Na+ (mmol/L)
Mild (130 – 135 mmol/L): Day 4 - 0.32 ± 2.27 2.52 ± 1.95 < 0.001
Mild (130 – 135 mmol/L): Day 30 0.68 ± 2.78 3.87 ± 3.01 < 0.001
Marked (< 130 mmol/L): Day 4 0.76 ± 1.77 4.56 ± 2.88 < 0.001
Marked (< 130 mmol/L): Day 30 2.54 ± 4.01 8.24 ± 3.84 < 0.001
SALT – 2 Data not shown but similar
Note: Na+ concentration similar to placeob within 5 days of D/C
Schrier RW, et al. NEJM. 2006; 355(20):2099 -2112.
SALT – 1 and SALT – 2 (continued)SALT – 1 and SALT – 2 (continued)
Schrier RW et al. N Engl J Med. 2006;355:2099-2112.
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10
SALTWATER Open-Label ExtensionSALTWATER Open-Label Extension Special Populations: Heart Failure
• R, DB, PC, MC• Patients:
—Hospitalized for HF, EF < 40%, HF symptoms— Not required to have HYPONATREMIA
EVEREST TRIALS: Short-term
• Treatment— Tolvaptan 30 mg daily— Placebo
• Primary Endpoint— Global clinical status and body weight
• Discharge or 7 days
Gheorghiade M, et al. JAMA 2007;297:1332-43.
Special Populations: Heart Failure
• Extension of short term trials
• Minimum 60 day treatment (median = 9.9 mos)– Tolvaptan/Placebo
• On top of standard HF therapy
EVEREST TRIALS: Long-term
• Primary Endpoint– All‐cause mortality
• Superiority/Non‐inferiority
– Composite: CV death or hospitalization for HF• Superiority
• Secondary Endpoint– Δ in dyspnea, body weight, edema
Konstam MA, et al. JAMA 2007;297:1319-31.
Special Populations: Heart Failure
The Endpoints
Short – term results– Global clinical status and body weight
• Improvement with tolvaptan
Long term results
EVEREST TRIALS: Results
Long – term results– All‐cause mortality
• No difference– Composite: CV death or hospitalization for HF
• No difference– Δ in dyspnea, body weight, edema
• Improvement with tolvaptan
Konstam MA, et al. JAMA 2007;297:1319-31
Gheorghiade M, et al. JAMA 2007;297:1332-43
Recent Research in Economics
Recent Research in Economics
of Hyponatremia Management
of Hyponatremia Management
Tolvaptan: Practical Considerations• Indicated for symptomatic hyponatremia
– < 125mEq/L– Unresponsive to correction with fluid restriction– In‐hospital initiation
• Administered by oral route once daily15 mg/30 mg/60 mg– 15 mg/30 mg/60 mg
• Contraindication: Co‐administration with potent CYP3A4 enzyme inhibitors– ketoconazole, itraconazole, indinivar
• Patients should be encouraged to drink when thirsty
• Co‐administration with hypertonic saline: NR
Tolvaptan [package insert]; 2009.
11/16/2011
11
Tolvaptan Adverse Effects
SALT studies• No osmotic demyelination• Excessive Na+ correction = 1.8%
EVEREST• Thirst• Polyuria• Pollakiuria• Hypernatremia
Meta‐analysis of 11 randomized controlled trials in 1094 patients
ange
(mEq
/L)
8
65.70
Net
(Na)
Ser
um C
ha
4
2
Time (days)1 2 3 4
Jaber BL, et al. Am J Med. 2011; 27: 447-57
5 300
3.30
4.204.40
4.90 4.60
No trials 10 10 10 11 5 2
No. participants 1018 1018 1018 1094 258 448
Safety Analysis of VRAsAdverse Event No. Trials Summary Odds
RatioP value
Overly rapid correction of hyponatremia (high dose)*
Development of hypernatremia (high dose)*
Postural hypotension
9 (995)
6 (719)
4 (236)
3.03 (1.82-5.05)
7.75 (2.77-21.65)
2.17 (1.03-4.56)
<0.001
<0.001
0.04yp ( ) ( )Hypotension 6 (807) 1.21 (0.71-2.08) 0.48Thirst 3 (558) 3.25 (1.87-5.63) <0.001Nausea 4 (556) 1.32 (0.69-2.50) 0.40Headache 3 (522) 1.02 (0.53-1.96) 0.94Renal impairment 5 (689) 2.64 (0.80-8.79) 0.11Infusion site phlebitis 1 (84) 4.22 (1.59-11.22) 0.004Death 6 (733) 0.67 (0.38-1.18) 0.17
Jaber BL, et al. Am J Med. 2011; 27: 447-57 *No reported cases of ODS
LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion,
LEVEL 3 - SEVERE SYMPTOMS:vomiting, seizures, obtundation,respiratory distress, coma
Hyponatremia Treatment OptionsHyponatremia Treatment Options
Vasopressin Antagonist or Hypertonic Saline***
Hypertonic Saline
LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression
disorientation, altered mental status
Fluid restrictionConsider vasopressin antagonist or hypertonic saline if…•Unable to tolerate fluid restriction or failure of fluid restriction
•Need for rapid correction of Na+
Hypertonic Saline
***Vasopressin antagonists may be preferred if volume overloaded
Community-Acquired
Hyponatremia*(37.9%)
Hospital Aggravated
Hyponatremia†
(5.7%)
Hospital-Acquired
Hyponatremia‡
(38.2%)
53,236 adult patients admitted to an academic medical center
Hyponatremia Treatment OptionsHyponatremia Treatment Options
Wald R et al. Arch Intern Med. 2010;170:294-302.
OR for in-hospital mortality 1.52 2.30 1.66
Adjusted increasein LOS 14% 40% 64%
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