September 7-9, 2018Kiawah Island Golf Resort

Kiawah Island, SC

2018 Annual Meeting

Carolinas Chapter - American Association of Clinical Endocrinologists

SATURDAY HANDOUTS

This continuing medical education activity is jointly provided by the Carolinas Chapter-AACE and Southern Regional Health Education Center

Hyponatremia –Joseph G. Verbalis, MD

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recent advances in the evaluation and treatment

of hyponatremia

Joseph G. Verbalis, MDProfessor of Medicine and PhysiologyChief, Endocrinology and Metabolism

Director, Georgetown-Howard UniversitiesCenter for Clinical and Translational Science

Georgetown UniversityWashington, DC USA

Joseph G. Verbalis: disclosures

consultant: Cumberland, Ferring, Otsuka

advisory board: Corcept, Otsuka

data safety board: Ferring

grant support: NIA, NCATS

hyponatremia: association with

adverse outcomes

Hyponatremia –Joseph G. Verbalis, MD

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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)

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St. Elizabeth’s MC2000-2007n = 53,236

Holland-Bill et al. Eur J Endocrinol 173:71-81, 2015

hyponatremia on admission is associated with increased subsequent 30-day and 1-year mortality (279,508 acutely hospitalized patients in Denmark 2006-2011)

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

Hyponatremia –Joseph G. Verbalis, MD

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hyponatremia: brain adaptation to

hyponatremia

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

normal brain hyponatremic brain

acute hyponatremia can cause death from cerebral edema and brain herniation

Gross, Kidney Int 60:2417-27, 2001

Hyponatremia –Joseph G. Verbalis, MD

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“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/Ldrank Lucozade

http://www.dailymail.co.uk/news/article-450341/Marathon-victim-died-drinking-MUCH-water.html

London marathon, April 22, 2007

Hew-Butler et al. Br J Sports Med 49:1432, 2015

recommendations:

• drink only to thirst, no forced hydrationortake USATF sweat test to gauge true fluid requirements

• decrease water/sport drink stops at endurance events• point of care electrolyte testing at medical tent

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

Hyponatremia –Joseph G. Verbalis, MD

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1. true loss of brain solute

2. can reduce or eliminate brain edema despite severe hypoosmolality

3. time dependent process

brain volume regulation

Gullans & Verbalis Ann Rev Med

44:289-301, 1993

brain electrolyte and osmolyte losses after 7d of sustained hyponatremia

nearly 1/3 of brain volume regulation occurs as a result of losses of organic osmolytes

Gullans & Verbalis, Annu Rev Med 44:289-301, 1993

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 Med44:289-301, 1993

Hyponatremia –Joseph G. Verbalis, MD

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hyponatremia: brain deadaptation:

osmotic demyelinationsyndrome

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

osmotic demyelination syndrome: clinical manifestations

• tremor

• incontinence

• hyperreflexia, pathological reflexes

• quadriparesis, quadriplegia

• dysarthria, dysphagia

• cranial nerve palsies

• mutism, locked-in syndrome

Hyponatremia –Joseph G. Verbalis, MD

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normonatremic rat hyponatremic rat, 24 hours after

rapid correction

C3d immunohistochemical staining

differentiating goals from limits of correction of hyponatremia

re-lowering of serum [Na+] is only recommended in patients with high risk of ODS

Verbalis et al, Am J Med 126:S1-42, 2013

Verbalis et al, Am J Med 126:S1-42, 2013

patients at high risk of ODS

Hyponatremia –Joseph G. Verbalis, MD

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lower [Na+] and BUN levels predict greater rates of correction of hyponatremia with tolvaptan

Morris et al,

AJKD 71:772, 2018

n=28 patients with SIADH)

rapid correction of hyponatremia occurs frequently, but ODS occurs rarely

increase in [Na+] >8 mmol/L/24h: 606/1490 = 41%osmotic demyelination by MRI: 8/1490 = 0.5%

George et al, CJASN 13:984-92, 2018

Verbalis et al,

Am J Med

126:S1-42, 2013

guidelines for managing excessive corrections of hyponatremia to decrease risk of ODS

Hyponatremia –Joseph G. Verbalis, MD

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hyponatremia:

symptom-based treatment

recommendations

treatments for hyponatremia

isotonic saline infusionhypertonic saline infusionvaptan (conivaptan, tolvaptan)

fluid restrictiondemeclocyclinefurosemide + NaClmineralocorticoidsureavaptan (tolvaptan)

long-term

short-term

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 butless impaired;usually chronic

the degree of symptomatologyis a surrogate for the duration

of hyponatraemia

Hyponatremia –Joseph G. Verbalis, MD

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hyponatremia treatment algorithm based on neurological symptoms

ALL: hypertonic NaCl1, followed by fluid restriction ± vaptan2

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

1 some authors recommend simultaneous treatment with desmopressin to limit speed of correction.2 no active therapy should be started within 24 hrs of hypertonic saline to decrease the chance of overly rapid correction of [Na+] and risk of ODS. 28

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)

OR:

• 100-200 ml bolus infusion (5-10 min) of 3% NaCl, repeat every 30 min until goal reached

FOR ALL SALINE CORRECTIONS:

• follow serum [Na+] and urine output every 2-4 hrs during the active correction

hyponatremia treatment algorithm based on neurological symptoms

HYPOVOLEMIC: solute repletion (isotonic NaCl iv or oral sodium replacement)3

EUVOLEMIC: vaptan, limited hypertonic NaCl, or urea, followed by fluid restrictionHYPERVOLEMIC: vaptan, followed by fluid restriction

ALL: hypertonic NaCl1, followed by fluid restriction ± vaptan2

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

LEVEL 2 – MODERATE SYMPTOMS: altered mental status,

disorientation, confusion, unexplained nausea, gait instability

1 some authors recommend simultaneous treatment with desmopressin to limit speed of correction.2 no active therapy should be started within 24 hrs of hypertonic saline to decrease the chance of overly rapid correction of [Na+] and risk of ODS.3 with isotonic NaCl infusion, serum [Na+] must be followed closely to prevent overly rapid correction and risk of ODS due to secondary water diuresis. 30

Hyponatremia –Joseph G. Verbalis, MD

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hyponatremia can be caused by dilution from retained water, or by depletionfrom electrolyte losses in excess of water

U-Na+ excretion for identification of EABV

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

with diuretics without diuretics

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

X

Hyponatremia –Joseph G. Verbalis, MD

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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

tolvaptan: SALT studies andSALT-WATER open label extension study

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

0

1

2

3

4

5

6

7

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) *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

X

Hyponatremia –Joseph G. Verbalis, MD

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osmotic demyelination syndrome (ODS)one case of CPM has been reported following correction of hyponatremia using a vaptan as monotherapy in >5,000 patients to date; two cases of ODS have been reported with combined use of tolvaptan and hypertonic (3%) NaCl

Wright, Laureno & Victor. Brain 102:361-385, 1979

7.4.3 Patients with SIAD

Spasovzki G et al. Nephrol Dial Transplant 29:Suppl 2:i1-i39, 2014

urea increases [Na+] via an osmotic diuresis

Sterns et al. Kidney Int 87:268-70, 2015

Hyponatremia –Joseph G. Verbalis, MD

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hyponatremia (HN) registry: initial therapies utilized in patients with a clinical diagnosis of SIADH

Greenberg et al. Kidney Int 88:167-77, 2015

salt tabs utilized in 8%

salt tablets can also increase [Na+] via an osmotic diuresis

urea: 30g = 500 mOsmols

NaCl tabs: 1g = 34 mOsmols

how many salt tablets does it take to equal the osmotic diuresis of 30g of urea?

500/34 = 15g of NaCl

hyponatremia treatment algorithm based on neurological symptoms

HYPO: solute repletion (isotonic NaCl iv or oral sodium replacement)3

EU: vaptan, limited hypertonic NaCl, or urea, followed by fluid restrictionHYPER: vaptan, followed by fluid restriction

ALL: hypertonic NaCl1, followed by fluid restriction ± vaptan2

ALL: fluid restriction

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

LEVEL 2 – MODERATE SYMPTOMS: altered mental status,

disorientation, confusion, unexplained nausea, gait instability

LEVEL 1 – NO OR MINIMAL SYMPTOMS: difficulty concentrating, irritability, altered mood, depression,

unexplained headache

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Hyponatremia –Joseph G. Verbalis, MD

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choice of appropriate initial therapy

Verbalis et al, Am J Med 126:S1-42, 2013

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

urine/plasmaelectrolyte

ratio

recommendedfluid consumption

>1.0 0 mL

0.5–1.0 Up to 500 mL

<0.50 Up to 1 L

use of urine electrolytes to predict stringency of fluid restriction

success rates in treating hyponatremia by physicians in the HN Registry

diagnosis & treatment

Δ [Na+] ≥ 5 mmol/L

[Na+] ≥ 130 mmol/L

[Na+] ≥ 135 mmol/L

SIADH, no rx(n=168) 41% 45% 20%

SIADH, FR (n=625) 44% 29% 10%

SIADH, NS (n=384) 36% 20% 4%

SIADH, tolvaptan (n=183) 78% 74% 40%

SIADH, 3% NaCl (n=78) 60% 25% 13%

at discharge, serum [Na+] was <135 mmol/L in 75% of patients, and ≤130 mmol/L in 43% of patients

Verbalis et al. Am J Med 129(5):537.e9-537.e23, 2016

Hyponatremia –Joseph G. Verbalis, MD

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hyponatremia:

effects of treatment

on outcomes

hyponatremia improvement is associated with reduced risk of mortality

Corona et al. PLOSone 10(4) Apr 23, 2015

Verbalis et al, Am J Med 126:S1-42, 2013

update of hyponatremia treatment guidelines first published in 2007

Hyponatremia –Joseph G. Verbalis, MD

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