1. health and fitness
2. disorders

Controversies in The Treatment
of Hyponatremia
Hilmer O. Negrete MD
The Renal Group
Boardman, OH
May 2, 2013
Learning Objectives
• To recognize the conditions that are associated
with complications of hyponatremia and its
treatment
• To better understand and apply the goals of
therapy in hyponatremia
• To understand new options in preventing
complications of the treatment of hyponatremia
• To understand the role of use of Vaptan in the
treatment of Hyponatremia
Mortality after hospitalization with mild,
moderate, and severe hyponatremia
Waikar, SS et al Am J Med 2009 Sep;122(9): 857-65
Renal Division, Brigham and Women's Hospital, Harvard Medical School
• Hyponatremia (Na <135 mEq/L) was observed in
14.5% of patients
• Patients were older (67.0 vs. 63.1 years, P <.001)
• Had more comorbid conditions (P <.001)
• Increased risk of death
• in hospital (odds ratio 1.47)
• at 1 year (hazard ratio 1.38)
• at 5 years (hazard ratio 1.25)
• Resolution of hyponatremia during hospitalization
attenuated the increased mortality risk conferred by
hyponatremia.
Hyponatremia in the Elderly
• Overall incidence of hyponatremia, Na < 137 mEq/L
~ 7% (Caird et al, Brit Heart J 35:527, 1973)
• Prevalence as high as 18-20% in chronic care
facilities, with 53% of incidence of one or more
episodes of hyponatremia (Kleinfeld et al, J Am
Geriatr Soc 43:1410, 1995)
• Mortality rate 16% for patients over 65, versus 8%
for those with normal Na on admission (Terzian et
al, J Gen Int Med 9:89, 1994)
Joseph Verbalis, MD,“Improving Hyponatremia Outcomes in the Hospitalized
Patient” Society of Hospital Medicine (SHM) Annual Meeting, April 8-11, 2010
Increasing risk for hyponatremia with age
at admission and acquired at hospital
Hawkins RC Clin Chim Acta 337: 169–172, 2003
Osmotic Determinants of Body Water
Distribution
Intracellular
Extracellular
40% Body Wt
20% Body Wt
H2O
K+
H2O
Prot
Na+
H2O
H2O
Interstitium
Plasma
Serum Sodium Concentration
and Hyponatremia
• Reflects body fluid tonicity
• Abnormal sodium concentration usually
means disorder of water balance
Serum [Na+] =
Total Na+E + Total K+E
Total Body Water
Maintenance Water Homeostasis
• Osmotic regulation
–
–
–
–
Plasma tonicity
Hypothalamic osmoreceptors
ADH (AVP- vasopressin)
Thirst
• Hemodynamic regulation
– Arterial filling (Effective circulatory volume)
– Aortic arch, carotid sinus, cardiac atria
• Kidney
– Water excretion (urine dilution)
Plasma and Urine Osmolality and
Vasopressin
Underfilling Arterial Circulation
Renin, Angiotensin II
Aldosterone
Sympathetic Nervous System
Vasopressin (ADH)
Increase Renal
Sodium Reabsorption
Increase Renal
Water Reabsorption
Low Urine Sodium
UNa < 30 mEq/L
High Urine Osmolality
Uosm > 100 mOsm/kg
(Exceptions: Diuretics, Adrenal
insufficiency, Renal salt wasting,
Cerebral salt wasting?)
Hyponatremia
Serum OSM
Low
Hypotonic
Hyponatremia
Normal
High
Marked hyperlipidemia
(lipemia, TG >35mM)
Hyperproteinemia
(Multiple myeloma)
“Pseudohyponatremia”
Hyperglycemia
Mannitol
“Translocation
Hyponatremia”
*Note: all have ↑ADH
•SIADH: inappropriate
•Rest: appropriate
ECFv *
Low
Renal loss (UNa > 20)
Extra-renal loss (UNa <10)
•Diuretics
•Bleeding
•Thiazide
•Burns
•K-sparing
•GI (N/V, diarrhea)
•ACE-I, ARB
•Pancreatitis
•IV RTA, Hypoaldo
• Cerebral salt wasting
Normal
•Hypothyroidism
•AI
•SIADH
•Reset Osmostat
•Water Intoxication
1° Polydipsia
TURP post-op
High
•CHF
•Cirrhosis
•Nephrosis
Pathogenesis of hypotonic hyponatremia as
derived from the Edelman equation
Adrogué H J , and Madias N E JASN 2012;23:1140-1148
Generation of hypotonic hyponatremia in
function of Electrolytes and water
Net IC
Net Free
water
Nae+
Ke+
TBW
[Na]s
Normal State
0
0
Normal
Normal
Normal
Normal
CHF (early)
Positive
0
Increased
Normal
Increased
Normal
CHF (late)
0
Positive
Increased
Decreased
Increased
Decreased
Diarrhea
(early)
Negative
0
Decreased
Decreased
Decreased
Normal
Diarrhea (late)
0
Positive
Decreased
Decreased
Decreased
Decreased
SIADH
0
Positive
Normal
Normal
Increased
Decreased
Psychogenic
Polydipsia
0
Positive
Normal
Normal
Increased
Decreased
Hypokalemia
Negative
Positive
Normal/In
creased
Decreased
Normal
Decreased
Adrogué H J , and Madias N E JASN 2012;23:1140-1148
Hypovolemic Hyponatremia
• Key Point
– Driven by both Sodium and water losses
– The net loss of Sodium > Water
• Causes
–
–
–
–
GI Losses (Diarrhea, emesis)
Diuretic use
Adrenal Insufficiency
Salt wasting nephritis
• Treatment:
– Restoration of volume with Isotonic fluid
Euvolemic Hyponatremia
• Key Point:
– Water retention without significant change in total
sodium
• Causes
– Syndrome of Inappropriate antidiuretic hormone
secretion (SIADH)
– Thiazide use
– Hypothyroidism
– Beer-drinker’s potomania
– Reset Osmostat
Hypervolemic Hyponatremia
• Key Point
– Gain of both sodium and water
– Water > sodium
• Decrease effective circulating blood volume
• Causes
– Congestive Heart Failure
– Cirrhosis
– Nephrotic Syndrome
Diagnostic and Therapeutic Approach to the
Hyponatremic Patient
Schrier R W JASN 2006;17:1820-1832
Effect of water on sodium
concentration
Intracellular
Extracellular
40% Body Wt
20% Body Wt
WATER
H2O
H2O
Prot
[K +]
[Na+]
Cell swelling
H2O
H2O
Interstitium
Plasma
Post operatively Hyponatremia
A woman with postoperative hyponatremia
Adrian Schreiber, MD et al American Journal of Kidney Diseases Volume
44, Issue 1 , Pages e3-e6, July 2004
Central Pontine Myelinolysis
John D. Fleming, M.B., B.S., and Suresh Babu, M.B., B.S. N Engl J Med
2008; 359 December 4, 2008
Effects of Hyponatremia on the Brain
and Adaptive Responses
Effects of Hyponatremia on the Brain and Adaptive Responses.
Adrogué HJ, Madias NE. N Engl J Med 2000;342:1581-1589.
Controversies in the Treatment of
Hyponatremia
What is the optimal rate of
correction of Hyponatremia?
What is the Optimal Rate of
correction?
• Is the hyponatremia acute or chronic?
• Does the patient have severe symptoms or
intracranial pathology?
Acute versus chronic hyponatremia
• In practice the duration of hyponatremia is
often unknown
• Patients with chronic hyponatremia may
develop acute reductions in the serum sodium
concentration
• The clinical approach to the patient should be
primarily determined by the severity of
symptoms
How aggressive? How Fast?
• Level 1: No or minimal symptoms
– Headache, irritability, inability to
concentrate, altered mood, depression
OK TO CORRECT SLOWLY
Joseph Verbalis, MD,“Improving Hyponatremia Outcomes in the Hospitalized
Patient” Society of Hospital Medicine (SHM) Annual Meeting, April 8-11, 2010
How aggressive? How Fast?
• Level 3: Severe symptoms
– Seizures, obtundation, respiratory distress,
coma
Emergency!
CORRECT RAPIDLY
Joseph Verbalis, MD,“Improving Hyponatremia Outcomes in the Hospitalized
Patient” Society of Hospital Medicine (SHM) Annual Meeting, April 8-11, 2010
How aggressive? How Fast?
• Level 2: Moderate symptoms
–Nausea, confusion, disorientation,
altered mental status
WHAT IS THE BEST PLAN?
Joseph Verbalis, MD,“Improving Hyponatremia Outcomes in the Hospitalized
Patient” Society of Hospital Medicine (SHM) Annual Meeting, April 8-11, 2010
Neurologic sequelae after treatment of severe
hyponatremia: a multicenter perspective.
R H Sterns, J D Cappuccio et al.
JASN February 1, 1994 vol. 4 no. 8 1522-1530
• 56 patients with serum Na levels of < or = 105
mmol/L collected from ASN Members
• Results:
– 14 developed post-therapeutic complications (10
permanent, 4 transient) after correction to a serum
sodium > 120 mmol/L.
– No neurologic complications were observed among
patients corrected by < 12 mmol/L per 24 h or by < 18
mmol/L per 48 h or in whom the average rate of
correction to a serum sodium of 120 mmol/L was < or
= 0.55 mmol/L per hour
How Urgent Is the Need for Intervention?
• The vast majority of hyponatremic patients do not require urgent
management.
• Conversely, patients with severely symptomatic hyponatremia and
those with neurologic or neurosurgical conditions at risk of
worsening intracranial hypertension represent medical
emergencies.
• When violation of the correction threshold appears likely, urgent
measures to slow or halt further correction are required.
• Overcorrection should be treated as a medical emergency; prompt
relowering of the serum sodium concentration is in order
• Urgent intervention might also be required for coexisting conditions
(severe volume depletion might have caused circulatory shock and
AKI, hypokalemia).
Adrogué H J , and Madias N E JASN 2012;23:1140-1148
Symptomatic versus asymptomatic
hyponatremia
• Severe symptoms are most likely to occur
– Acute (especially less than 24 hours)
– Marked reduction in the serum sodium
concentration (Na <120 mEq/L)
• Neurologic manifestations, including seizures,
impaired mental status or coma, and death
Risk factors for development of
hyponatremia encephalopathy
Moritz ML and Carlos Ayus J
(2007) Nat Clin Pract Nephrol 3: 374–382
Risk Factor
Mechanism
Childhood
Higher brain to intracranial volume ratio
Female sex
Estrogens inhibit brain adaptation to hyponatremia
Higher vasopressin levels than males
Hypoxemia
Impairs adaptation of brain to hyponatremia
Decrease cerebral perfusion
Causes brain injury
Brain injury
Vasogenic cerebral edema
Cytotoxic cerebral edema
Conditions associated with severe
symptoms of hyponatremia
• Exercise-associated hyponatremia, as in marathon runners
• Hyponatremia associated with the use of ecstasy (3,4methylenedioxyamphetamine)
• Self-induced water intoxication in psychogenic polydipsia,
water drinking contests.
• Postoperative hyponatremia due to SIADH
• Patients with known intracerebral pathology
• Recent administration of thiazides
• Induction of delivery with oxytocin
*Young women and children are particularly vulnerable to
hyponatremic brain damage.
Risk factors for the development of
Exercise Associated Hyponatremia (EAH)
• Exercise duration > 4 h or slow running/exercise pace
• Female gender (may be explained by lower body
weight)
• Low body weight
• Excessive drinking (>1.5 L/h) during the event
• Pre-exercise overhydration
• Abundant availability of drinking fluids at the event
• Nonsteroidal anti-inflammatory drugs (not all studies)
• Extreme hot or cold environment
Mitchell H. Rosner and Justin Kirven Exercise-Associated
Hyponatremia CJASN January 2007 2): (1) 151-161
Reversal of Transtentorial Herniation (TTH)
With Hypertonic Saline
Koenig MA, et al Neurology. 2008 Mar 25;70(13):1023-9
• To evaluate the role of 23.4% saline in the
management of TTH
• Results:
– Reversal of TTH was predicted by a >/=5
mmol/L rise in serum sodium concentration
(p = 0.001) hour after 23.4% saline
– No evidence of central pontine myelinolysis
was detected on post-herniation MRI
Effect of increasing Na concentration on brain
water content during Hyponatremia and
Normonatremia
Berl T. Treating hyponatremia: damned if we do and damned if
we don’t. Kidney Int 1990; 37: 1006–1018.
Re-induction of hyponatremia after rapid overcorrection
of hyponatremia reduces mortality in rats
Group 1
Group 2
NaCl alone NaCl+DXM
(n=12)
(n=16)
Group 3
NaCl
+ SNa re-lowering
(n=16)
SNa at day 4 (mEq/l)
108 +/-2*
107 +/-1*
104 +/-2*
SNa 12 h after correction
—
—
133 +/-2* ,†
SNa at 24 h
137 +/-2* ,† 136 +/-1* ,†
117 +/-2
Change in SNa at 12 h
—
—
29 +/-1*
Change in SNa at 24 h
29 +/-1*
29 +/-1*
14 +/-1
Neurological manifestations at day 5
12/12
8/16‡
1/16‡
Mortality at day 10
12/12
13/16§
1/16§
Fabrice Gankam Kengne, Alain Soupart, Roland Pochet, Jean-Pierre Brion and
Guy Decaux Kidney International (2009) 76, 614–621
Outcome of Central Pontine and
Extrapontine Myelinolysis
Menger H, Jörg J, J Neurol. 1999;246(8):700.
• The findings in 44 patients (42 of whom were chronic
alcoholics) with central pontine myelinolysis
• Results:
• 34 patients for whom follow-up data were available, 32
survived, 11 completely recovered, 11 had some deficits
but were independent, 10 were dependent (4 through
disorders of memory or cognition, 3 with tetraparesis, 2
with cerebellar ataxia, 1 with polyneuropathy).
• Magnetic resonance imaging had no prognostic
significance.
• Outcome was independent of the severity of neurological
deficits during the acute phase, degree of hyponatremia or
MRI initial or persistent findings
Clinical and Radiologic Correlations of
Central Pontine Myelinolysis Syndrome
Mayo Clin Proc. 2011 November; 86(11): 1063–1067.
• PATIENTS AND METHODS: 24 Patients Diagnosed with CPM from
January 1, 1999, through December 31, 2010.
• RESULTS:
– Of 24 patients, 14 (58%) had only CPM, and 10 (42%) had extrapontine
involvement. Hyponatremia was documented in 18 patients (75%),
with median sodium nadir of 114 mmol/L.
– Eighteen patients (75%) had alcoholism, and malnutrition was
documented in 12 (50%).
– Presenting symptoms included encephalopathy (n=18 [75%]), ataxia
(n=11 [46%]), dysarthria (n=7 [29%]), eye movement abnormalities
(n=6 [25%]), and seizures (n=5 [21%]).
– Favorable outcome was seen in 15 patients (63%) at last follow-up.
• CONCLUSION: Clinical outcome in patients with CPM is not
predicted by the volume of radiologic T2 signal abnormality on MRI
or the severity of hyponatremia
Causes of Hyponatremia Associated
With Unintentional Overcorrection
Cause of Hyponatremia
Mechanism of Escape From Antidiuresis
Hypovolemia
Volume repletion reverses baroreceptor-mediated vasopressin secretion
Beer potomania, tea and toast
diet
Increased solute intake enhances delivery of glomerular filtrate to distal
diluting sites
Thiazide diuretics
Discontinuation of diuretic restores diluting function of the distal tubule
SSRI
Discontinuation of antidepressant eliminates drug-induced SIADH
Desmopressin
Discontinuation of synthetic vasopressin eliminates antidiuretic state
Hypopituitarism
Cortisol replacement restores ability to suppress vasopressin secretion
Addison disease
Volume and cortisol replacement
Hypoxemia
Correction of hypoxemia eliminates non-osmotic stimulus for vasopressin
Nausea, surgery, pain, or stress
Spontaneous resolution of SIADH
Richard. H. Stern et al American Journal of Kidney Diseases
Volume 56,Issue 4, 774-779, October 2010
Hypertonic versus Isotonic saline
• Hypertonic saline is required for patients with severe
hyponatremic encephalopathy and concentrated urine.
• In view of the high potential for overcorrection, its
prescription should be based on a quantitative approach
guided by a simple formula
• Isotonic saline will correct volume depletion and the
associated hyponatremia. However, great vigilance is
required to prevent overcorrection, because brisk diuresis
can ensue when extracellular fluid volume nears
restitution.
• Isotonic saline is unsuitable for correcting the
hyponatremia of the SIADH culminating in worsening of the
serum sodium.
Potassium Supplementation and
Hyponatremia
• Hyponatremia associated with potassium depletion requires
prompt but cautious repletion.
• Prescribing multiple doses of potassium without close
monitoring of both serum potassium and sodium values is
fraught with risk for hyperkalemia and osmotic demyelination.
• Catastrophic overcorrection of the serum sodium is well
documented in such settings, especially because potassium
depletion is a risk factor for osmotic demyelination.
Adrogué H J , and Madias N E JASN 2012;23:1140-1148
Correction Goals for Severe Chronic
Hyponatremia (Na <120 mEq/L) Rule of Sixes:
• For all patients with chronic hyponatremia, the
goal is 6 mEq/L during the initial 24 hours.
• For those with severe symptoms (seizure, severe
delirium, and unresponsiveness), the goal is
preloaded in the first six hours, postponing
subsequent efforts to increase serum sodium
level until the next day.
• This is not a target of therapy, but rather a
therapeutic threshold that should not be crossed.
Can re-lowering Na levels prevent
complications of overcorrection?
What strategies do we have to prevent
overcorrection?
Treating Profound Hyponatremia:
A Strategy for Controlled Correction
Richard H. Sterns et al. American Journal of Kidney Diseases
Volume 56,Issue 4, 774-779, October 2010
• A 45-year-old man with a history of alcoholism (1/2 bottle of vodka
and 15-24 cans of beer daily) with recurrent alcohol withdrawal
seizures and delirium was found unresponsive in his apartment.
• On arrival at the emergency department, he was combative and
disoriented, requiring sedation
• Medications: thiazide diuretic, a selective serotonin reuptake
inhibitor (SSRI) for depression 2 weeks earlier after discharge from
the hospital for an alcohol withdrawal seizure.
• Laboratory Data: Serum Na: 96 mEq/L, Urine Osmolality 732
mOsm/kg , Urine Sodium 7 mEq/L
• Diagnosis: Profound hyponatremia caused by the combination of
thiazide diuretic, SSRI, beer potomania, alcohol withdrawal, and
hypovolemia.
Treating Profound Hyponatremia:
A Strategy for Controlled Correction
Richard H. Sterns et al. American Journal of Kidney Diseases
Volume 56,Issue 4, 774-779, October 2010
DDAVP Is Effective in Preventing and Reversing
Inadvertent Overcorrection of Hyponatremia
Perianayagam A , Sterns RH et al. Clin J Am Soc Nephrol . 2008;3(2):331–336
• Objective: To assess the effectiveness and safety
of desmopressin acetate
– Avoid overcorrection of hyponatremia and
– To lower the plasma sodium concentration after
inadvertent overcorrection.
• Methods:
– Six patients (group 1) were given desmopressin
acetate after the 24-h limit of 12 mmol/L had already
been reached or exceeded
– Fourteen patients (group 2) were given desmopressin
acetate in anticipation of overcorrection
DDAVP Is Effective in Preventing and Reversing
Inadvertent Overcorrection of Hyponatremia
Perianayagam A , Sterns RH et al. Clin J Am Soc Nephrol . 2008;3(2):331–336
• Results:
– In all 14 patients correction was prevented from
exceeding either the 24- or 48-h limits.
– Plasma sodium concentration of 14 of the 20
patients fell by 2 to 9 mmol/L.
– In all six group 1 patients (already overcorrected)
and in five of the group 2 patients (prevention) ,
the plasma sodium concentration was actively
lowered again by the concurrent administration of
desmopressin acetate and 5% dextrose in water
DDAVP Is Effective in Preventing and Reversing
Inadvertent Overcorrection of Hyponatremia
Perianayagam A , Sterns RH et al. Clin J Am Soc Nephrol . 2008;3(2):331–336
DDAVP Is Effective in Preventing and Reversing
Inadvertent Overcorrection of Hyponatremia
Perianayagam A , Sterns RH et al. Clin J Am Soc Nephrol . 2008;3(2):331–336
Group 1
Patients
Precorrection
Na Levels
Peak Na
level
Before
Correction
Lowest Na
levels
after
Correction
Amount
of
Relowering
Time
of
Relowering
Rate of
ReLowering
(mmol/h)
1
122
138
134
4
4.5
0.89
2
115
135
129
6
20
0.3
3
109
121
112
9
17.5
0.51
4
108
125
118
7
8.25
0.85
5
129
142
134
8
14.5
0.55
6
112
124
120
4
10
0.40
** All patients received D5W after the administration of DDVAP
Hypertonic Saline and Desmopressin: A Simple
Strategy for Safe Correction of Severe
Lonika Sood, Richard H Sterns et al
American Journal of Kidney Diseases 61:4, 571-578 April 2013
• 25 patients admitted to a community teaching hospital
between October 1, 2008, and September 30, 2011, who
were treated for serum sodium level <120 mEq/L with
concurrently administered desmopressin and hypertonic
saline solution.
• Desmopressin was administered prior to the initiation of
hypertonic saline, and the dose varied from 1-2 µg at
approximately 6- to 8-hour intervals either intravenously or
subcutaneously, except for one patient weighing 120 kg who
was given 4 µg.
Hypertonic Saline and Desmopressin: A Simple
Strategy for Safe Correction of Severe
Lonika Sood, Richard H Sterns et al
American Journal of Kidney Diseases 61:4, 571-578 April 2013
• To determine dose-response relationships, the increase in
serum sodium level prior to the start of the hypertonic saline
solution infusion was estimated to the closest values 4, 24,
and 48 hours later by using the Adrogué HJ , Madias Formula.
• Salt tablets and/or potassium were converted to 3% saline
solution equivalents: 1 g of salt tablets was taken to equal 34 mL, 1
mEq of oral potassium chloride elixir was taken equal to 2 mL, 1 mEq of
400 mmol/L of intravenous potassium chloride was taken to equal 2 mL.
Hypertonic Saline and Desmopressin: A Simple
Strategy for Safe Correction of Severe
Lonika Sood, Richard H Sterns et al
American Journal of Kidney Diseases 61:4, 571-578 April 2013
• Mean increase in serum sodium levels:
– First 4 hours: 2.6 ± 2.0 mEq/L
– First 24 hours: 5.8 ± 2.8 mEq/L
– Second 24 hours: 4.5 ± 2.2 mEq/L
• No patient had correction by >12 mEq/L in 24
hours or >18 mEq/L in 48 hours
Hypertonic Saline and Desmopressin: A Simple
Strategy for Safe Correction of Severe
Lonika Sood, Richard H Sterns et al
American Journal of Kidney Diseases 61:4, 571-578 April 2013
Hypertonic Saline and Desmopressin: A Simple
Strategy for Safe Correction of Severe
Lonika Sood, Richard H Sterns et al
American Journal of Kidney Diseases 61:4, 571-578 April 2013
Hypertonic Saline and Desmopressin: A Simple
Strategy for Safe Correction of Severe
Lonika Sood, Richard H Sterns et al
American Journal of Kidney Diseases 61:4, 571-578 April 2013
• In conclusion, combined infusion of 3% saline
solution and desmopressin appears to be a valid
strategy for correcting severe hyponatremia
effectively and safely.
• This approach appears to reduce the chance of
inadvertent overcorrection.
• It still requires substantial oversight by the
nephrologist, who must identify patients who are
poor candidates for the protocol
What is the best formula to
calculate the rate of correction in
Hyponatremia?
Formulas for calculating initial infusion
rates in Hyponatremia
Ellison DH, Berl T. N Engl J Med 2007;356:2064-2072.
Does the Adrogue–Madias formula accurately
predict serum sodium levels in patients with
dysnatremias?
• Prospective study to evaluate the utility or/and the
accuracy of the Adrogue-Madias formula in
managing patients with hyponatremia (Na <130
mEq/L) and hypernatremia (Na>148 mEq/L)
• Methods: out of 317 patients, 189 patients (59.6%)
had administration of intravenous solutions for the
correction of dysnatremias.
Liamis G, Kalogirou M et al Therapeutic approach in patients with
dysnatraemias. Nephrol Dial Transplant 2006 Jun;21(6):1564-9
Formulas for estimating the effect of
infusates and fluid losses on [Na+]s
Infusate Formula
Projects the effect of gaining 1 L of any
infusate (inf) on sodium levels [Na +]s
Fluid-Loss Formula
Projects the effect of losing 1 L of any
fluid (fl) on sodium levels [Na+]s
Adrogué H J , and Madias N E JASN 2012;23:1140-1148
Does the Adrogue–Madias formula accurately
predict serum sodium levels in patients with
dysnatremias?
Na levels at 12 hours
Anticipated
Na level
Achieved
Na level
Number
P value
Volume depletion
130.2 +/- 4.1
131.3 +/- 5.2
45
NS
SIADH
127.4 +/- 5.7
128.9 +/- 5.9
10
NS
123.8 +/- 6
125.5 +/- 5.6
9
NS
Primary Polydipsia
122.5 +/- 0.7
129 +/- 1.4
2
P: 0.02
Hypernatremia
153.6 +/- 7.5
156.5 +/- 8.9
92
P: 0.021
Diuretic induced
hyponatremia
Liamis G, Kalogirou M et al Therapeutic approach in patients with
dysnatraemias. Nephrol Dial Transplant 2006 Jun;21(6):1564-9
Does the Adrogue–Madias formula accurately
predict serum sodium levels in patients with
dysnatremias?
Na levels at 24 hours
Anticipated
Na level
Achieved
Na level
Number
P value
Volume depletion
130 +/- 4
135.6 +/- 3.3
15
0.002
Diuretic induced
hyponatremia
128.1 +/- 4.8
130 +/- 4.5
15
NS
Hypernatremia
151.5+/- 6.4
153.3 +/- 8.3
67
NS
Liamis G, Kalogirou M et al Therapeutic approach in patients with
dysnatraemias. Nephrol Dial Transplant 2006 Jun;21(6):1564-9
Estimating the Effect of Infusates and Fluid
Losses on Serum Sodium
• Implementation of case-specific therapeutic
measures requires information derived from the
quantitative projections on the patient’s serum
sodium
– prescribed fluid therapy
– ongoing fluid losses
• Easily applicable formulas based on the Edelman
equation allow estimation of the effect of
infusates (infusate formula) and fluid losses
(fluid-loss formula) on the serum sodium
What is the roles of Vaptans in the
Treatment of Hyponatremia?
AVP Regulation of Water Reabsorption
Joseph Verbalis, MD,“Improving Hyponatremia Outcomes in the Hospitalized
Patient” Society of Hospital Medicine (SHM) Annual Meeting, April 8-11, 2010
Non-Peptide AVP Receptors Antagonist
(Vaptans)
Conivaptan
Tolvaptan
Lixivaptan
Satavaptan
Receptor
V2/V1a
V2
V2
V2
Route of
administration
Intravenous
Oral
Oral
Oral
FDA approved
Available in
USA
Available in
USA
Formulation
20 mg/100 cc
D5W
Tablets 15, 30
mg
Treatment of SIADH with Conivaptan
Decaux G, Am J Med 110 : 582 –584, 2001
Long-term effect of tolvaptan on serum sodium in
the SALTWATER trial
Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW,Bichet DG,Ouyang J, Czerwiec FS; for the
SALTWATER Investigators et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am
Soc Nephrol 21:705–712, 2010
Where Vaptans do and do not fit in The
Treatment of Hyponatremia
Anna J Jovanovich and Tomas Berl
Kidney International April 2013 83:4, 563–567
• “Upon analysis of the available literature, we
conclude that there is presently no role for
vaptans in acute symptomatic hyponatremia”
• Vaptans are efficacious in raising serum sodium in
long-standing ‘asymptomatic’ hyponatremia.
• However, the cost of the only Food and Drug
Administration-approved oral agent (tolvaptan)
makes its use prohibitive for most patients in this
setting.
AVP Receptors Antagonists in the
Treatment of Hyponatremia
• Further studies are needed to assess the proper
use of AVP Receptors Antagonists in the following
areas:
– Correction of symptomatic hyponatremia alone or
with Hypertonic saline
– To assess the benefits of correction of hyponatremia
in hospitalized patients (outcomes and length of stay)
– To assess the long term use in minimally symptomatic
hyponatremia in order to reduce the risk of
neurocognitive dysfunction and gait instability
Does Treatment of chronic
hyponatremia change Outcomes?
Relationship between serum Na and
mortality
Arun Chawla, Richard H. Sterns, et al Mortality and Serum Sodium:
Do Patients Die from or with Hyponatremia? CJASN May 2011 vol.
6 no. 5 960-965
Populations in Which Hyponatremia Is
Associated With Mortality (Odds ratio)
•
•
•
•
General Population (1.17-8.0)
Hospitalized patients (1.37-1.55)
Patients in the ICU (1.3)
Pre-operative hyponatremia (1.4)
Patie Hoorn et al "Hyponatremia and Mortality: Moving Beyond Associations."
American journal of kidney diseases : (2013)doi:10.1053/j.ajkd.2012.09.019
Diseases in Which Hyponatremia Is
Associated With Mortality (Odds ratio)
•
•
•
•
•
•
•
Congestive Heart Failure (1.8)
Cirrhosis (2.1)
Myocardial Infarct (2.0)
Pulmonary embolism (1.53)
Pulmonary hypertension (3.6-10.2)
Pneumonia (1.3)
CKD (1.12-1.32)
Patie Hoorn et al "Hyponatremia and Mortality: Moving Beyond Associations."
American journal of kidney diseases : (2013)doi:10.1053/j.ajkd.2012.09.019
Hyponatremia and mortality:
How innocent is the bystander?
Hoorn EJ , Zietse R . Clin J Am Soc Nephrol . 2011;6(5):951–953
Hyponatremia and Mortality
• Hyponatremia increasingly is being recognized as
an independent predictor of mortality
• Prospective studies are necessary to determine
whether hyponatremia in itself contributes to
mortality and whether correcting hyponatremia
improves outcomes.
• Until such studies are available, the presence of
hyponatremia should be regarded as a risk factor
for adverse outcomes and patients should be
monitored accordingly.
Patie Hoorn et al "Hyponatremia and Mortality: Moving Beyond Associations."
American journal of kidney diseases : (2013)doi:10.1053/j.ajkd.2012.09.019
Mild hyponatremia and risk of fracture in
the ambulatory elderly
F. Gankam Kengne QJM: Volume 101, Issue 7 Pp. 583-588
• Case control study of 513 cases of bone fracture
after incidental fall in ambulatory patients aged
65 or older
• Prevalence of hyponatremia (serum Na <135
mEq/l,):
– Patients with bone fracture: 13.06%
– Controls patients: 3.90%
• Hyponatremia was associated with bone fracture
after incidental fall in ambulatory elderly (OR:
4.16).
Options of Therapy in Hyponatremia
Options of Therapy
Comments/Limitations
Normal saline
Ok for hypovolemic hyponatremia but may cause
overcorrection, ineffective in SIAD and hypovolemic
hyponatremia
Hypertonic Saline
No consensus in infusion rate, can cause overcorrection,
not indicated in hypovolemic hyponatremia
Fluid restriction
Slow to correct, poor compliance
Salt tablets
Need to be use with fluid restriction, not indicated in
hypovolemic hyponatremia
Urea
Effective in SIADH, no USP formulation, not approved for
hyponatremia, poor palatability, available in Europe
Demeclocycline
Inconsistent response, nephrotoxic in cirrhosis and CHF
AVP Receptor Antagonist
Effective in chronic SIAD and hypovolemic hyponatremia,
very expensive
Fluid Restriction
• Fluid restriction remains the cornerstone of managing
oligosymptomatic patients with euvolemic or hypervolemic
hyponatremia.
• Although variably effective, fluid restriction does not pose a
risk as long as the defect of water excretion persists.
• On the other hand, repair of the aquaretic defect can lead
to overcorrection and thus risk development of osmotic
demyelination.
• Prescription of stringent sodium restriction in patients with
liver cirrhosis or heart failure helps control volume overload
but counters correction or even aggravates hyponatremia.
Adrogué H J , and Madias N E JASN 2012;23:1140-1148
Repairing the Abnormal State of the
Determinants of Hyponatremia
• Fluid restriction (up to <800 ml/d), excluding
those with ongoing aquaresis
• Increased solute intake (protein, sodium, and
potassium), but limited Na intake in
hypervolemic hyponatremia
• Use of Loop diuretic (in euvolemic and
hypervolemic hyponatremia)
• Use of Vaptans in euvolemic or hypervolemic
patients can be consider
Urine/serum (U/S) electrolyte ratio
• Can point out the effect of Urine output on the
serum Na Levels
– Ratio of 1: Urine output is not affecting the serum
sodium
– Ratio >1, urine contributes to lowering the serum
sodium (perpetuating hyponatremia)
– Ratio ≤0.5, urine contributes to raising the serum
sodium (water diuresis present)
• The larger the urine output, the greater the effect
on serum sodium.
Hospital-acquired hyponatremia—why are
hypotonic parenteral fluids still being used?
• Hospitalized patients have numerous stimuli for arginine
vasopressin production and are at risk of developing
hyponatremia
• Routine administration of hypotonic parenteral fluid to
hospitalized patients can result in fatal hyponatremia
encephalopathy
• 0.9% NaCl (154 mmol/l) should be administered as
prophylaxis against hyponatremia, except in the setting of a
free water deficit or ongoing free water losses
• Patients at greatest risk of developing neurological
complications secondary to hyponatremia are children,
premenopausal females, postoperative patients, and those
with brain injury, brain infection or hypoxemia
Michael L Moritz and Juan Carlos Ayus Nature Clinical Practice Nephrology (2007) 3, 374-382
Managing Profound Hyponatremia
Teaching Points – Part 1
• Prompt correction in symptomatic hyponatremia enough to
improve symptoms
• Correct hyponatremia rapidly in the first few hours and then
slow down, 4-6 mEq/L increased in Sodium levels is enough
correction regardless of the severity of the hyponatremia
• The use of Adrogue-Madias formula in the calculation of the
rate of correction seem to be very helpful but does not
replace the real-life close monitoring of Serum Na
measurements.
Managing Profound Hyponatremia
Teaching Points – Part 2
• Limited correction to prevent neurologic injury (osmotic
demyelination syndrome)
– <10 mEq/L in a 24-hour period
– <18 mEq/L in a 48-hour period
• Stay well below these limits in patients at high risk of osmotic
• Anticipate and manage reversible causes of hyponatremia
• Vaptans are an option for the treatment of euvolemic and
hypervolemic hyponatremia
• Prospective studies are needed to clarify the role of treatment
of chronic hyponatremia in Mortality
•
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