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ASHP Advantage e-Newsletter
March
March2012
2011
Management of Hyponatremia
in Hospitalized Patients
Role of Pharmacists
in Improving Patient Care
Educational Initiative Targets Need for Improved Management
of Hyponatremia
ASHP Advantage is coordinating a series of learning
opportunities on the management of hyponatremia
in hospitalized patients. The learning opportunities
are designed to build upon each other to educate
pharmacists about the characteristics and treatment of
hyponatremia of varying degrees, as well as to provide
pharmacists with practical strategies for improving the
management of hyponatremia for inpatients and after
discharge. The series is supported by an educational
grant from Otsuka America Pharmaceutical, Inc.
The educational activities included both live and ondemand formats, and faculty members are nationally
recognized experts in critical care and electrolyte
disturbances. A live symposium was conducted on
December 5, 2011, during the 46th ASHP Midyear
Clinical Meeting and Exhibition in New Orleans,
Louisiana. The symposium was simultaneously webcast,
enabling a total of more than 1000 individuals to
participate. Attendees submitted questions about
unresolved issues related to the management of
hyponatremia, and these were addressed by Initiative
Chair Joseph F. Dasta, M.S., FCCM, FCCP, and faculty
member Michael J. Cawley, Pharm.D., RRT, CPFT, in a live
webinar on February 15, 2012. These frequently asked
questions also serve as the basis of content explored in
the two e-newsletters that are part of the educational
initiative.
If you missed the Midyear symposium, it is now
available as a web-based activity and is approved for
two hours of continuing pharmacy education credit.
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Its on-demand format is convenient since it may be
completed at any time. For more information and to
access the web-based activity, go to the web portal at
www.ashpadvantage.com/hyponatremia.
Faculty Roundtable
Visit the Hyponatremia web portal or click here to
listen to Professor Joseph Dasta and fellow faculty Drs.
Michael Cawley and Henry Cohen discuss important
aspects of managing hyponatremia in hospitalized
patients. The discussion is available in three parts, each
lasting 10 to 12 minutes:
‰‰ Overview of Hyponatremia
‰‰ Issues Related to Treatment Options
‰‰ Role of Pharmacists
Why Focus on Hyponatremia?
While there is not uniform agreement in the range
for normal serum sodium concentration, in general
hyponatremia is considered to be a serum sodium
concentration less than 135 mEq/L.1 Hyponatremia is
the most common electrolyte disorder in hospitalized
patients, affecting 6-15% of patients at the time of
admission and an additional 5% of patients during their
hospital stay.2,3 One in four patients in the intensive
care unit is hyponatremic. If not treated appropriately,
hyponatremia can lead to substantial morbidity and
mortality.4,5 Even small reductions in serum sodium
concentration are associated with prolonged hospital
lengths of stay and increased costs.6
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ASHP Advantage e-Newsletter
Figure 1. Classification of Hyponatremia1
Dilutional Hyponatremia
Total body sodium near normal
Total body water increased
Hypervolemic (edema)
Heart failure
Cirrhosis
Nephrotic syndrome
Depletional
Hyponatremia
Hypovolemic
Sodium lost
Total body water reduced
Euvolemic (no edema)
SIADH = syndrome of inappropriate antidiuretic hormone
Hyponatremia can be classified as either depletional or
dilutional (Figure 1).1 Depletional hyponatremia is relatively uncommon. It is characterized by hypovolemia
with reduced total body water and sodium. The majority of cases of hyponatremia are dilutional and characterized by increased total body water and near normal
total body sodium. Dilutional hyponatremia may be
further classified as hypervolemic or euvolemic.1,7
Heart failure is a common cause of hypervolemic
hyponatremia, and edema typically is present. Edema
usually is absent in euvolemic hyponatremia, the most
common cause of which is syndrome of inappropriate antidiuretic hormone (SIADH).7 Tumors and a wide
variety of disorders, conditions, and medications (e.g.,
carbamazepine, selective serotonin-reuptake inhibitors)
can lead to SIADH.3
The management of hyponatremia in the hospital
setting is based on the severity of the electrolyte
abnormality and neurologic symptoms3,7,8:
‰‰ Asymptomatic: fluid restriction to 500-1000 mL/day
‰‰ Moderate symptoms (e.g., confusion, altered mental
status): 3% sodium chloride ± loop diuretic or
vasopressin receptor antagonist followed by fluid
restriction
‰‰ Severe (<120 mEq/L) symptoms (e.g., seizures,
coma): 3% sodium chloride ± loop diuretic
followed by fluid restriction ± vasopressin receptor
antagonist
This e-newsletter features frequently asked questions
(FAQs) addressed by the faculty pertaining to current
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March 2012
information about the use of traditional therapies,
such as hypertonic saline, for the management of
hyponatremia in hospitalized patients. Answers to
FAQs about new and emerging therapies and cost
considerations related to the use of these therapies
for the management of hyponatremia in hospitalized
patients will be provided in the next e-newsletter.
Frequently Asked Questions
Q
A
What is known about the real-world use of
therapies for hyponatremia?
There is a paucity of information about the
treatment of hyponatremia. Data from a
prospective observational hyponatremia registry may
provide insight into how various therapies are used in
hospital settings.9 This first of its kind registry includes
clinical and laboratory findings from patients either
admitted with hyponatremia or with hyponatremia
developing during hospitalization within or outside
the United States. As of December 2011, almost 1800
patients had been enrolled in the registry, with a target
enrollment of 2500 patients in the United States.
Preliminary analysis of the findings reveals that 40%
of patients were discharged from the hospital with a
serum sodium concentration less than 130 mEq/L (i.e.,
hyponatremia), which may reflect problems with the
use of currently available therapies for hyponatremia
(e.g., failure to recognize and treat hyponatremia,
improper use of currently available therapies, or lack
of efficacy of currently available therapies despite
attempts at optimal use of these therapies). Further
insight is anticipated as additional data are collected in
the registry.
Q
Can you provide information about the proper
use of hypertonic sodium chloride to treat
hyponatremia, including how to determine the amount
of sodium chloride needed and the infusion rate? Is
there a maximum recommended rate of infusion?
A
Hypertonic saline (i.e., 3% sodium chloride) is
appropriate for patients with hyponatremia
who are symptomatic (i.e., with an altered neurologic
examination, confusion, seizure, or coma) or in a critical
care unit.10-12 Overly rapid correction of hyponatremia
can result in osmotic demyelination syndrome (ODS),
a brain demyelinating disease that causes significant
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ASHP Advantage e-Newsletter
morbidity and mortality.7,8,13 The rate of infusion of
sodium chloride for patients with severe symptoms
should not exceed 1-2 mEq/L/hr.1 Furthermore, the
sodium correction should not exceed 12 mEq/L over a
24-hour period or 18 mEq/L over the first 48 hours.1,7
These rate limits minimize the risk for ODS.
The need for complex calculations to determine the
sodium deficit and sodium chloride infusion rate is
a potential problem related to the use of hypertonic
saline. More than one method is available to perform
these calculations, and no one method is the gold
standard. The sodium deficit calculation provides only
a rough estimate because its accuracy depends on the
frequency of serum sodium monitoring.14 The onset
of effect of hypertonic sodium chloride depends on
the sodium concentration of the infusate and the rate
of infusion because its bioavailability is 100% by the
intravenous route.
Sodium Deficit Method
The sodium deficit method entails determining the
difference between the current and desired serum
sodium concentrations (mEq/L) and multiplying the
result by the total body water (TBW). A serum sodium
of 120 mEq/L is a suitable goal for patients with severe
hyponatremia. The TBW (L) can be estimated by
multiplying the body weight (kg) by a correction factor
of 0.6 L/kg for men and 0.45 L/kg for women.
Here is an example. Consider a 45-kg woman with an
acute seizure and a serum sodium concentration of 106
mEq/L in whom a sodium of 120 mEq/L is desired. For
this patient, the sodium deficit is 284 mEq, which was
determined as follows:
(120 mEq/L–106 mEq/L) x 45 kg x 0.45 L/kg = 284 mEq
March 2012
Faculty
Joseph F. Dasta, M.S., FCCM, FCCP
Initiative Chair
Professor Emeritus
The Ohio State University College of Pharmacy
Columbus, Ohio
Adjunct Professor
The University of Texas College of Pharmacy
Austin, Texas
Michael J. Cawley, Pharm.D., RRT, CPFT
Associate Professor of Clinical Pharmacy
Philadelphia College of Pharmacy
University of the Sciences
Philadelphia, Pennsylvania
Henry Cohen, M.S., Pharm.D., BCPP, FCCM, CGP
Professor of Pharmacy Practice
Arnold & Marie Schwartz College of Pharmacy and
Health Sciences
Long Island University
Chief Pharmacotherapy Officer
Kingsbrook Jewish Medical Center
Brooklyn, New York
of sodium, the initial rate of infusion would be 58 mL/hr
(determined by dividing 30 mEq/hr by 0.513 mEq/mL).
If sodium chloride 0.9%, which contains 154 mEq/L
(0.154 mEq/mL) of sodium, were used, an infusion rate
of 195 mL/hr would be needed to correct the same 284mEq deficit.
Adrogué-Madias Equation
Another method used to guide the administration of
hypertonic saline is the Adrogué-Madias equation,
which allows estimation of the effect of infusing 1 L of
an infusate on serum sodium concentration15:
How should the deficit of 284 mEq in this patient be
corrected? As noted previously, the rate of sodium
correction for patients with severe symptoms should
not exceed 1-2 mEq/L/hr. Using the midpoint of that
range (1.5 mEq/L/hr) for this patient and TBW of 20.25
L (calculated as 45 kg x 0.45 L/kg), the rate would be 30
mEq/hr (calculated as TBW x 1.5 mEq/L/hr). This rate
would be used only for the first several hours, checking
the serum sodium frequently (every two hours) to
avoid overcorrection and to stay within the maximum
increase of 12 mEq/L in 24 hours. Using sodium
chloride 3%, which contains 513 mEq/L (0.513 mEq/mL)
Consider the patient used in the previous example.
Using the correction factor of 0.45 L/kg for the 45kg woman with an acute seizure and serum sodium
concentration of 106 mEq/L who will receive 3%
sodium chloride, which contains 513 mEq/L of sodium,
the change in serum sodium would amount to 19.1
mEq/L. Because 12 mEq/L over a 24-hour period
is the maximum recommended increase in serum
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Change in serum sodium =
(infusate sodium – serum sodium)
(total body water + 1)
ASHP Advantage e-Newsletter
March 2012
sodium to avoid neurological sequelae, 632 mL is the
maximum volume of 3% sodium chloride that should
be administered to this patient over a 24-hour period
(this amount is calculated by dividing 12 mEq/L by 19.1
mEq/L per L of infusate = 0.632 L). Since 1.5 mEq/L/hr is
the maximum recommended rate of sodium correction
for the first several hours in patients with severe
symptoms (e.g., 6 mEq/L for 4 hours, with frequent
monitoring of serum sodium at 2-hour intervals), the
3% sodium chloride could be administered to this
patient at a rate of approximately 80 mL/hr for 4 hours
(determined by dividing 6 mEq/L by 19.1 mEq/L per L
of infusate = 0.314 L or 314 mL), followed by a rate of
approximately 16 mL/hr for 20 hours (determined by
subtracting the 320 mL of infusate delivered over the
first 4 hours from the 632 mL needed for the 24-hour
period).
If 0.9% sodium chloride, which contains 154 mEq/L of
sodium, were used instead of 3% sodium chloride in
this patient, the Adrogué-Madias equation predicts
a change in serum sodium of 2.3 mEq/L per liter
of infusate, and 5217 mL would be the calculated
maximum volume that would be administered to this
patient over a 24-hour period. This could work in theory
using an initial rate of 652 mL/hr for 4 hours, followed by
approximately 130 mL/hr for 20 hours. Administering
5 L in 24 hours, however, would not be an appropriate
treatment of hyponatremia and potentially may lead to
significant adverse effects. A more concentrated form of
sodium chloride is needed.
“
These are just two of many strategies for determining the sodium deficit of patients with hyponatremia
and recommended administration rates of hypertonic
saline. The primary reason pharmacists should be familiar with equations like these is not to calculate a precise
administration rate for a patient but rather to determine
whether the prescribed initial rate of hypertonic sodium chloride is reasonable and safe and then to monitor serum sodium closely to avoid overcorrection.
-- Michael J. Cawley, Pharm.D., RRT, CPFT
”
Q
A
Should 3% sodium chloride be administered only
via central venous access?
The maximum recommended osmolarity for a
solution administered into a peripheral vein is
900 mOsm/L because the use of solutions with a higher
osmolarity can lead to thrombophlebitis. The osmolarity
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of 3% sodium chloride is approximately 1026 mOsm/L,
so central venous access is preferred.16 However, central
venous access is not always feasible in the pre-hospital
and emergency department settings. The vessel size,
volume to be infused, and rate of infusion must also be
taken into consideration in making decisions about how
to administer 3% sodium chloride.
Q
A
Can hypertonic sodium chloride be administered
as a bolus in an emergent situation?
Rapid infusion of hypertonic sodium chloride has
been used for patients with seizures, coma, acute
water intoxication (e.g., marathon runners), or traumatic
brain injury.17 Based on this experience, infusion of
100 mL of 3% sodium chloride over 10 minutes to raise
the serum sodium concentration by 2-4 mEq/L or 250
mL of 3% sodium chloride infused over 30 minutes to
raise the serum sodium concentration by 4-6 mEq/L is
recommended.18 Serum sodium concentrations should
be monitored every 2-3 hours for the first 12-24 hours
during 3% sodium chloride administration.
Q
A
Is there a role for oral sodium chloride in the
management of hyponatremia?
In theory, oral sodium chloride might be an option
for patients with chronic hyponatremia. However,
randomized trials comparing oral with intravenous
sodium chloride for the management of hyponatremia
have not been performed. Traditionally 1-2 g three
times daily has been used when sodium chloride was
given orally, but no consistent dosing strategy for
oral sodium chloride in patients with hyponatremia is
available in the published literature. Gastrointestinal
intolerance (e.g., nausea, vomiting, diarrhea) is a
potential problem with oral therapy. Oral sodium
chloride is not mentioned as an option in hyponatremia
treatment guidelines released in 2007.7
Sign up to be notified of updates
related to this educational initiative. The
second e-newsletter in this series will focus on FAQs
about the clinical and economic impact of newer
agents on the management of hyponatremia.
www.ashpadvantage.com/hyponatremia
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ASHP Advantage e-Newsletter
March 2012
References
1. Cawley MJ. Hyponatremia: current treatment
strategies and the role of vasopressin antagonists. Ann
Pharmacother. 2007; 41:840-50.
2. Deitelzweig S, McCormick L. Hyponatremia in
hospitalized patients: the potential role of tolvaptan.
Hosp Prac. 2011; 39:87-98.
3. Upadhyay A, Jaber BL, Madias NE. Epidemiology of
hyponatremia. Sem Nephrol. 2009; 29:227-338.
4. Wald R, Jaber BL, Price LL et al. Impact of hospitalassociated hyponatremia on selected outcomes. Arch
Intern Med. 2010; 170:294-302.
5. Zilberberg MD, Exuzides A, Spalding J et al.
Epidemiology, clinical and economic outcomes of
admission hyponatremia among hospitalized patients.
Curr Med Res Opin. 2008; 24:1601-8.
6. Callahan MA, Do HT, Caplan DW et al. Economic
impact of hyponatremia in hospitalized patients:
a retrospective cohort study. Postgrad Med. 2009;
121:186-91.
7. Verbalis JG, Goldsmith SR, Greenberg A et al.
Hyponatremia treatment guidelines 2007: expert panel
recommendations. Am J Med. 2007; 120(suppl 1):S1S21.
8. Kumar S, Berl T. Diseases of water metabolism. In: Berl T,
Bonventre JV, eds. Atlas of diseases of the kidney. Vol 1.
Philadelphia: Current Medicine, Inc.; 1999:1.1-1.22.
9. Dasta J, Amin A, Chiong et al. Trends in hyponatremia
management and associated outcomes in hospital
settings: interim results from an observational,
prospective, multicenter, global registry in hospitalized
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patients. Presented at American College of Clinical
Pharmacy Annual Meeting. Pittsburgh, PA; 2011 Oct 18.
Poster 95E.
Laureno R, Karp BI. Myelinolysis after correction of
hyponatremia. Ann Intern Med. 1997; 126:57-62.
Achinger SG, Moritz ML, Ayus JC. Dysnatremias: why are
patients still dying? Med J. 2006; 99:353-62.
Goldsmith SR. Current treatments and novel
pharmacologic treatments for hyponatremia
in congestive heart failure. Am J Cardiol. 2005;
95(suppl):14B-23B.
Janicic N, Verbalis JG. Evaluation and management of
hypo-osmolality in hospitalized patients. Endocrinol
Metab Clin N Am. 2003; 32:459-81.
Mohmand HK, Issa D, Ahmad Z et al. Hypertonic saline
for hyponatremia: risk of inadvertent overcorrection.
Clin J Am Soc Nephrol. 2007; 2:1110-7.
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med.
2000; 342:1581-9.
Roche e Silva M, Velasco IT, Porfirio MF. Hypertonic
saline resuscitation: saturated salt-dextran solutions
are equally effective, but induce hemolysis in dogs. Crit
Care Med. 1990; 18:203-7.
Noakes T, IMMDA. Fluid replacement during marathon
running. Clin J Sport Med. 2003; 13:309-18.
Sterns RH, Nigwekar SU, Hix JK et al. The treatment of
hyponatremia. Semin Nephrol. 2009; 29:282-99.
Additional ASHP Advantage Educational Activities
Visit the ASHP Advantage website to browse listings of convenient on-demand continuing education
(CE) activities, as well as publications, podcasts, and live webinars. More than 40 hours of free ondemand CE programming are available. Learn more and find a full listing of topics and activities at
http://www.ashpadvantage.com.
For complete information about educational activities that are part of this initiative, visit
www.ashpadvantage.com/hyponatremia. There is no charge for the activities, and ASHP membership is not required.
Planned and coordinated by ASHP Advantage and supported by
an educational grant from Otsuka America Pharmaceutical, Inc.
Contact ASHP Advantage for assistance or questions.
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