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September 7-9, 2018Kiawah Island Golf Resort
Kiawah Island, SC
2018 Annual Meeting
Carolinas Chapter - American Association of Clinical Endocrinologists
SATURDAY PRESENTATIONS
This continuing medical education activity is jointly provided by the Carolinas Chapter-AACE and Southern Regional Health Education Center
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
1
Joseph G. Verbalis: disclosures
consultant: Cumberland, Ferring, Otsuka
advisory board: Corcept, Otsukadata safety board: Ferringgrant support: NIA, NCATS
2
hyponatremia: association with
adverse outcomes
3
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 145Admission Serum [Na+] Concentration (mEq/L)
Pred
icte
d Pr
obab
ility
of
In-H
ospi
tal M
orta
lity
St. Elizabeth’s MC2000-2007n = 53,236
4
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)
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, 20116
hyponatremia: brain adaptation to
hyponatremia
7
patients 14 52duration < 12 hrs 3 daysserum [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
8
normal brain hyponatremic brain
acute hyponatremia can cause death from cerebral edema and brain herniation
Gross, Kidney Int 60:2417-27, 20019
“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
10
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
11
patients 14 52duration < 12 hrs 3 daysserum [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
12
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
13
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, 199314
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
15
hyponatremia: brain deadaptation:
osmotic demyelinationsyndrome
16
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
17
osmotic demyelination syndrome: clinical manifestations
• tremor• incontinence• hyperreflexia, pathological
reflexes• quadriparesis, quadriplegia• dysarthria, dysphagia• cranial nerve palsies• mutism, locked-in syndrome
18
normonatremic rat hyponatremic rat, 24 hours after
rapid correction
C3d immunohistochemical staining
19
differentiating goals from limits of correction of hyponatremiare-lowering of serum [Na+] is only recommended in patients with high risk of ODS
Verbalis et al, Am J Med 126:S1-42, 2013
20
Verbalis et al, Am J Med 126:S1-42, 2013
patients at high risk of ODS
21
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)
22
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, 201823
Verbalis et al, Am J Med
126:S1-42, 2013
guidelines for managing excessive corrections of hyponatremia to decrease risk of ODS
24
hyponatremia: symptom-based treatment
recommendations
25
treatments for hyponatremia
isotonic saline infusionhypertonic saline infusionvaptan (conivaptan, tolvaptan)
fluid restrictiondemeclocyclinefurosemide + NaClmineralocorticoidsureavaptan (tolvaptan)
long-term
short-term
26
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
27
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
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 reachedFOR ALL SALINE CORRECTIONS: • follow serum [Na+] and urine output every 2-4 hrs
during the active correction
29
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
30
hyponatremia can be caused by dilution from retained water, or by depletionfrom electrolyte losses in excess of water
31
U-Na+ excretion for identification of EABV
Fenske W. et al, JCEM 92:2991- 2997, 2008
with diuretics without diuretics
32
Nielsen et al., JASN 10:647-663, 1999
X
33
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
34
tolvaptan: SALT studies andSALT-WATER open label extension study
Berl et al. J Am Soc Nephrol 4:705-712, 201035
012345678
*
**
Del
ta in
crea
se in
ser
umSo
dium
(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
X36
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
37
7.4.3 Patients with SIAD
Spasovzki G et al. Nephrol Dial Transplant 29:Suppl 2:i1-i39, 2014 38
urea increases [Na+] via an osmotic diuresis
Sterns et al. Kidney Int 87:268-70, 2015
39
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%
40
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
41
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
42
42
choice of appropriate initial therapy
Verbalis et al, Am J Med 126:S1-42, 201343
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
44
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 45
hyponatremia: effects of treatment
on outcomes
46
hyponatremia improvement is associated with reduced risk of mortality
Corona et al. PLOSone 10(4) Apr 23, 201547
Verbalis et al, Am J Med 126:S1-42, 2013
update of hyponatremia treatment guidelines first published in 2007
48
49