hyponatremia treatment guidelines: 2012 and beyond

Diabetes Insipidus and SIADH

Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

1

hyponatremia treatment guidelines:

2012 and beyond


Professor of Medicine and Physiology

Chief, Endocrinology and Metabolism

Director, Georgetown-Howard Universities

Center for Clinical and Translational Science

Georgetown University

Washington, DC USA

consultant: Astellas, Ferring,

Cardiokine, Otsuka

advisory board: Astellas, Otsuka

data safety board: Ferring

grant support: NHLBI, NIA, NCATS,

Otsuka

Joseph G. Verbalis: disclosures




2

body fluid compartments

water is the largest component of our body; since the major determinant of body water is AVP-regulated water excretion by the kidneys, it follows logically that AVP must be the most important hormone in the body

AVP stimulation and effects

hyperosmolality,

hypovolemia,

angiotensin II

vasoconstriction renal H2O

reabsorption

baroreceptors,

natriuretic

peptides

AVP

–+

V1a Receptors V2 Receptors




3

receptor-mediated effects of AVP

receptor

subtype site of action activation effects

V1a

vascular smooth

muscle cells

platelets

lymphocytes and

monocytes

liver

vasoconstriction

platelet aggregation

cytokine release

glycogenolysis

V1banterior pituitary

ACTH and ββββ-endorphin

release

V2

renal collecting duct

principal cellsfree water absorption

AVP regulation of water reabsorption

from renal tubular cells

AVPAVP V2

Receptor

AQP3

AQP4

Basolateral

membrane

Luminal

membrane

H2O

H2OAQP2

Exocytic

InsertioncAMP

ATP

PKA

Recyclingvesicle

AQP2

Endocytic

Retrieval

GTP(Gs)

Co

llectin

g d

uct

Vasa r

ecta

Collecting Duct Cell




4

prevalence of dysnatremias at initial

presentation to a health care provider

0.49

28.2

1.430.060.17

21

0.53 0.010.03

7.2

0.720.01

0

5

10

15

20

25

30

Na < 116 Na < 135 Na > 145 Na > 165

Pre

va

len

ce

(%

)

Acute hospital care

Ambulatory hospital care

Community care

Hawkins. Clin Chim Acta 337:169-172, 2003

(data from 303,577 samples on 120,137 patients available for analysis)

relationship between hospital admission

serum [Na+] and in-hospital mortality

Wald et al. Arch Intern Med 170:294-302, 2010

0.20

0.15

0.10

0.05

110 115 120 125 130 135 140 145

Admission Serum [Na+] Concentration (mEq/L)

Pre

dic

ted

Pro

bab

ilit

y o

f

In-H

osp

ital M

ort

ality




5

chronic hyponatremia is also associated

with increased adverse outcomes

significantly increased

risk of fracture

increased mortality over a 12-year period

of outpatient follow-up

Hoorn et al. J Bone Mineral Res 26:1822-8, 2011

hyponatremic disorders

hypovolemia/dehydration

polydipsia

SIADH

extracellular fluid volume expansion

congestive heart failure

hepatic cirrhosis

bilateral ureteral obstruction




6

hyponatremia

can be

caused by

dilution from

retained

water, or by

depletion

from

electrolyte

losses in

excess of

water




7

U-Na+ excretion for

identification of EABV

Fenske W. et al, JCEM 92:2991- 2997, 2008

with diuretics without diuretics

SIADH: essential criteria

• true plasma hypoosmolality

• urine concentration inappropriate for

plasma osmolality (Uosm > 100 mOsm/kg

H2O)

• clinical euvolemia, no diuretic therapy

• absent renal sodium conservation (UNa > 30

mmol/L)

• normal thyroid, adrenal and renal function

modified from Bartter & Schwartz, Am J Med 42:790-806, 1967




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Robertson et al. Am J Med 72:339, 1982

plasma AVP levels are inappropriately elevated in >95% of patients with SIADH

0

7

10

11

9

8

6

5

43

21

230 240 250 260 270 280 290 300 310

Plasma Osmolality, mOsm/kg H2O

Pla

sm

a V

as

op

res

sin

, p

g/m

L

Normal

Range

stimuli to AVP secretion

related to fluid

homeostasis:

hyperosmolality

hypotension

hypovolemia

angiotensin II

independent of

fluid homeostasis:

nausea

hypoxia

hypercarbia

hypoglycemia

stress: cytokines

physical activity




9

1

296

294

292

290

288

286

284

282

280

278

276

plasma

osmolality

(mOsm/kg H2O)

plasma

AVP

(pg/ml)

urine

osmolality

(mOsm/kg H2O)thirst

osmotic

threshold

AVP

osmotic

threshold

100

300

2

3

4

5

6

7

8

9

0

0 250 500 750 10000

200

400

600

800

1000

Urine volume (ml/h)

maximal

urine

excretion

rate (ml/h)

1000500

250

nephrogenic

SIAD

caused by an

activating

mutation of the

AVP V2R at the

same site that

also can cause

DI via an

inactivating

mutation

Feldman et al.

New Engl J Med

352:1884-90, 2005




10

patients 14 52

duration < 12 hrs 3 days

serum [Na+] 112 ± 2 118 ± 1

stupor or coma 100% 6%

seizures 29% 4%

mortality 50% 6%

low [Na+] deaths 36% 0%

acute chronic

Arieff et al. Medicine 56:121, 1976 (hospital

consults in one year; [Na+]<128 mmol/L)

acute hyponatremia is associated

with high morbidity and mortality




11

normal brain hyponatremic brain

acute hyponatremia can cause death from

cerebral edema and brain herniation

“A 22-year-old man died after completing

his first London Marathon because he

drank too much water. David Rogers

collapsed at the end of the race and died

yesterday in Charing Cross Hospital.”

“Today it emerged the fitness instructor

from Milton Keynes died from

hyponatraemia, or water intoxication.

This is when there is so much water in

the body that it dilutes vital minerals such

as sodium down to dangerous levels. It

can lead to confusion, headaches and a

fatal swelling of the brain.”

p[Na+] = 122 mmol/L

drank Lucozadehttp://www.dailymail.co.uk/news/article-

450341/Marathon-victim-died-drinking-MUCH-water.html

London marathon, April 22, 2007




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patients 14 52

duration < 12 hrs 3 days

serum [Na+] 112 ± 2 118 ± 1

stupor or coma 100% 6%

seizures 29% 4%

mortality 50% 6%

low [Na+] deaths 36% 0%

acute chronic

Arieff et al. Medicine 56:121, 1976 (hospital

consults in one year; [Na+]<128 mmol/L)

chronic hyponatremia is associated

with much less severe symptomatology

1. true loss of

brain solute

2. can reduce or

eliminate brain

edema despite

severe

hypoosmolality

3. time dependent

process

brain volume

regulation

THIS IS NOT A NORMAL BRAIN!Gullans & Verbalis

Ann Rev Med

44:289-301, 1993




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symptomatic hyponatremia:

neurological manifestations

• headache

• irritability

• nausea / vomiting

• mental slowing

• unstable gait / falls

• confusion / delerium

• disorientation

• stupor / coma

• convulsions

• respiratory arrest

life-threatening;

usually acute

symptomatic but

less impaired;

usually chronic

the degree of symptomatology

is a surrogate for the duration

of hyponatraemia

pontine and extrapontine myelinolysis:

clinical manifestations

• tremor

• incontinence

• hyperreflexia, pathological

reflexes

• quadriparesis, quadriplegia

• dysarthria, dysphagia

• cranial nerve palsies

• mutism, locked-in syndrome




14

central pontine myelinolysis:

white areas in the middle of the pons indicate massive demyelination of descending axons (corticobulbarand corticospinaltracts)

Wright, Laureno & Victor

Brain 102:361-385, 1979

safe correction of hyponatremia entails balancingthe risks of the hyponatremia versus the risks of the correction; these, in turn, depend on the degree of brain volume regulation that has occurred

Verbalis

Trends Endocrinol Metab

3:1-7, 1992




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2. even lower (≤8 mmol/L in any 24h period) if

any of the following are present:

• serum Na ≤105 mEq/L

• hypokalemia

• alcoholism and/or malnutrition

• liver disease

managing the rate of correction

of hyponatremia

1. maximum correction for chronic hyponatremia:

≤12 mmol/L in the first 24 h

≤18 mmol/L in the first 48 h

3. maximum correction for acute hyponatremia:

not ascertained, but much lower risk

treatments for hyponatremia

isotonic saline infusion

hypertonic saline infusion

vaptan (conivaptan, tolvaptan)

fluid restriction

demeclocycline

furosemide + NaCl

mineralocorticoids

urea

vaptan (tolvaptan)

long-term

short-term




16

hypertonic saline correction

• choose desired correction rate of plasma

[Na+] (e.g., 1.0 mEq/L/h)

• obtain or estimate patient’s weight (e.g.,

70 kg)

• multiply weight X desired correction rate

and infuse as ml/h of 3% NaCl (e.g., 70 kg

X 1.0 mEq/L/h = 70 ml/h infusion)




17

Nielsen et al., JASN 10:647-663, 1999

X




18

diuresis:

increased excretion of urine by the kidney; includes water and typically increased solute excretion as well

aquaresis:

increased excretion of water by the kidney without increased solute, i.e., electrolyte-sparing excretion of free water by the kidney

what aquaresis

really looks

like!

courtesy nephology fellows,

Lenox Hill Hospital, New York, NY




19

tolvaptan: SALT studies and

SALT-WATER open label extension study

Berl et al. J Am Soc Nephrol 4:705-712, 2010

0

1

2

3

4

5

6

7

8

*

*

*

Delt

a i

ncre

ase i

n s

eru

m

So

diu

m (

mm

ol/L

) *P<.05

Control Tolvaptan

cirrhosis HF SIADH

SALT: mean increases in serum [Na+]

after 30 d in patients with

cirrhosis, HF, and SIADH

Schrier et al. NEJM 355:2099-2112, 2006




20

tolvaptan: SALT trials, SIADH patients

changes in SF-12 general health survey scores after 30 days of oral administration

placebo (n=39)

tolvaptan (n=41)

(physical function, body pain,

general health, physically limited

accomplishment)

(vitality, social function, calmness,

sadness, emotionally limited

accomplishment)

p=0.019

p=0.051

-0.16

3.64

0

2.5

5

7.5

Physical Component Score Mental Component Score

-0.45

5.47

Verbalis et al. Eur J Endocrinol 164:725–732, 2011

treatment of hyponatremia results in an

improvement of the MCS to the mean of

average U.S. adults

30 40 50

SF-12 Mental Component Summary (MCS)

Adult

Mean

Adult

Median

554535

Depression

Cutpoint

hyponat

after

rx

hyponat

before

rx

treatment




21

general guidelines:

• restrict all intake that is consumed by

drinking, not just water

• aim for a fluid restriction that is 500 ml/d

below the 24-hour urine output

• do not restrict sodium unless indicated

fluid restriction

predictors of failure of fluid restriction:

• high urine osmolality (>500 mOsm/kg H2O)

• urine Na+ + K+ greater than the serum [Na+]

• 24-hour urine output <1,500 ml/d

• increase in serum [Na+] <2 mmol/L in 24h




22

Furst H et al. Am J Med Sci 319:240-244, 2000

urine/plasma

electrolyte

ratio

recommended

fluid consumption

>1.0 0 mL

0.5–1.0 Up to 500 mL

<0.50 Up to 1 L

approach to raising plasma osmolality

by fluid restriction

hyponatremia treatment algorithmeuvolemic hyponatremia (SIADH)

vaptan, followed by fluid

restriction

hypertonic NaCl , followed by

fluid restriction ± vaptan

LEVEL 3 – SEVERE SYMPTOMS:

vomiting, seizures, obtundation,

respiratory distress, coma

LEVEL 2 – MODERATE

SYMPTOMS: nausea, confusion,

disorientation, altered mental status




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osmotic demyelination syndrome (ODS)

no cases of CPM have been reported following correction of hyponatremia with vaptans in >5,000 patients to date

Wright, Laureno & Victor

Brain

102:361-385, 1979

hyponatremia treatment algorithmeuvolemic hyponatremia (SIADH)

vaptan, followed by fluid

restriction

hypertonic NaCl , followed by

fluid restriction ± vaptan

fluid restriction, but vaptan under

select circumstances:• inability to tolerate fluid restriction or

failure of fluid restriction

• unstable gait and/or high fracture risk

• very low sodium level (<125 mEq/L) with

increased risk of developing symptomatic

hyponatremia

• need to correct serum [Na+] to safer

levels for surgery or procedures, or for

ICU/hospital discharge

• prevention of worsened hyponatremia with

increased fluid administration

• therapeutic trial for symptom relief

LEVEL 3 – SEVERE SYMPTOMS:

vomiting, seizures, obtundation,

respiratory distress, coma

LEVEL 2 – MODERATE

SYMPTOMS: nausea, confusion,

disorientation, altered mental status

LEVEL 1 – NO OR MINIMAL

SYMPTOMS: headache, irritability,

inability to concentrate, altered mood,

depression




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hyponatremia

increased the risk

of fracture in CKD

independently of

osteoporosis

1,408 female patients

from Cork, Ireland

adjusted for age, T-score,

amenorrhea, steroid use,

liver disease, smoking

and EtOH use, liver

disease, and

osteoporosis treatments

Kinsella et al. Clin J Am Soc Nephrol 5:275-280, 2010

4.50

4.00

3.50

3.00

2.50

2.00

1.50

1.00

0.50

0.00

<135 136–137 138–140 141–142 143–145 >145

95%

Co

nfi

den

ce In

terv

al

Serum Sodium (mmol/L)

serum [Na+] = 124 mEq/L

-500 -400 -300 -200 -100 -100 -2000

-40

-60

-80

0

-100

-120

140

-20

120

100

80

60

40

20


-500 -400 -300 -200 -100 -100 -200

80

60

40

20

-20

-40

-60

-80

0

-100

-120

correction of hyponatremia normalizes gait

stability in “asymptomatic” hyponatremia


100 200 200-500 -400 -300 -200 -100

80

60

40

20

-20

-40

-60

-80

0

-100

-120


100 200 200-400 -300 -200 -100

80

60

40

20

-20

-40

-60

-80

0

-100

-120

100

Renneboog et al. Am J Med 119:71, 2006




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increased risk of falls with

“asymptomatic” hyponatremia

Group n % Falls Odds ratio Adjusted

odds ratio*

“asymptomatic”

chronic

hyponatremia

122 21.3%

9.45

(2.64–34.09)

p<0.001

67.43

(7.48–607.42)

p<0.001

normonatremic

controls244 5.35% 1.00 1.00

*adjusted for age, sex and covariates

Renneboog et al. Am J Med 119:71, 2006

hyponatremia induces marked

bone loss in rats

normonatremic hyponatremic

[Na+] = 140 [Na+] = 115

Verbalis, Barsony, et al. JBMR 25:554-663, 2010




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hyponatremia induces a 5-fold increase in

osteoclasts compared to normonatremic

controls by TRAP staining

normonatremic

hyponatremic

20

10

5

0

TR

AP

+ M

NC

/are

a

*

15

Solid + dDAVP

Liquid + dDAVP


odds ratio for hyponatremia as a predictor

of osteoporosis in NHANES III database

bone mineral density by of hip measured by DEXA;

results adjusted for age, sex, BMI, physical activity, serum

vitamin D (ng/mL) and diuretic use

100.0

10.0

1.0

0.1

od

ds

ra

tio

(9

5%

CI)

total hip

(p=0.043)

femoral neck

p<0.003)

7.66

2.85

1.03

2.87

5.81

1.41

mean serum [Na+] = 133.0 ± 0.2 mmol/L





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why does hyponatremia

cause osteoporosis???

one-third of total body sodium is stored in

bone, and mobilization of this sodium from

bone during prolonged deprivation

requires the resorption of bone matrix,

similar to the release of stored calcium to

compensate for calcium deprivation

Bergstrom & Wallace. Bone as a sodium and potassium reservoir.

J Clin Invest 33:867-873, 1954.

Edelman, James, Baden & Moore. Electrolyte composition of bone

and the penetration of radiosodium and deuterium oxide into dog

and human bone. J Clin Invest 33:122-131, 1954.

hyponatremia-induced activation of ROS

pathways in serum and in osteoclasts

differentiated from RAW264.7 cells

Barsony et al.

JBC

286(12):10864-75, 2011




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1. osteoporosis

2. hypogonadism

3. cardiac fibrosis

4. sarcopenia

5. decreased

body fat

Barsony et al. AGE, Jan 5 2012 [Epub ahead of print]




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Barsony et al. AGE, Jan 5 2012 [Epub ahead of print]

evidence-based medicine

the Japanese eat a low fat diet and have lower rates of

cardiovascular disease than the English and Americans

the French eat a high fat diet and have lower rates of


the Chinese drink little alcohol and have lower rates of


the Italians drink much alcohol and have lower rates of


evidence-based conclusions?eat and drink whatever you want

it’s speaking English that kills youcourtesy of Dr. Peter Liu, University of Toronto




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tolvaptan:

need to

continue

therapy after

discharge

depends on

the etiology

of the SIADH

hyponatremia treatment guidelines: 2012 and beyond

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