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Hyponatremia

VCU School of Pharmacy

April 23, 2015

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Outline

Objectives
Patient TR
Hyponatremia Overview
Hyponatremia Treatment Options
Hyponatremia and Cancer
TR’s Treatment Assessment
Summary

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Objectives

Classify hyponatremia by tonicity, severity, and time of onset
Identify potential causes of hyponatremia
Recognize signs and symptoms of hyponatremia
Identify characteristics of SIADH
Select appropriate hyponatremia treatment based on patient presentation

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Patient TR

TR: 78 yo AA male

CC: Headache

HPI:

Presented to ED on 3/29 with 1-2 days of worsening headache
Daughter reported worsening confusion since radiation
Complained of jaw pain, neck pain, and foaming of mouth since the morning
Noted “shaking” since surgery in Dec. 2014

Vitals: Temp: 98.2F HR: 107 RR: 16 BP: 153/86

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Patient TR

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Patient TR

Allergies: NKDA, adhesive tape

Social History:

Recently discharged from Guggenheimer
Lives at home with daughter
Uses walker

Family History: non-contributory

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Patient TR

Laboratory Data

134 3.5 8

91 34 0.7

Initial Diagnostic Imaging

3/29 ECG: non-specific ST wave changes
3/29 Chest XR: no acute processes
3/29 Head CT: generalized atrophy, no acute processes

107

13.2

38.6

9.6

148

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Patient TR

Initial Assessment & Plan

Headache

Admit with nerve checks every 4 hours
Start NS @ 100ml/hr
Obtain lumbar puncture to rule out meningitis
Continue ceftriaxone (started in ED) until CSF culture is negative
Consult Neurology and ID

Non-small cell carcinoma

Consult Oncology

Seizure prophylaxis

Continue levetiracetam

COPD & HTN

Continue home meds

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Patient TR

Further Diagnostics

Lumbar puncture for meningitis

Clear fluid
CSF glucose: 61
CSF protein: 93
CSF cytology: no metastatic carcinoma
CSF bacterial culture: negative
CSF fungal culture: negative

3/29 Blood culture: negative
Cryptococcal antigen: negative
MRSA nares screen: light MRSA colonization
Perirectal VRE screen: light VRE

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Patient TR

Consults

Neurosurgery

No acute intracranial issues

Infectious Disease

History of sputum culture positive for Serratia
Does not appear to have meningitis
Discontinue ceftriaxone

Oncology

TR has done poorly since brain surgery and radiation in Dec 2014
Not a great candidate for systemic treatment so not advisable to look for further metastases
Prognosis poor regarding mental function

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Patient TR

Hospital Course

3/30 - Meningitis ruled out

Discontinued ceftriaxone after 2 doses

3/31 - Hypomagnesemia developed

Magnesium sulfate 2 g/50 mL IVPB given

3/31 - Possible COPD exacerbation

Started on prednisone 40 mg daily (taper started on discharge)
Continued on chronic COPD medications

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Patient TR

Hospital Course - 3/31 - Blood pressure increased

Discontinued HCTZ, started Amlodipine

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Patient TR

Hospital Course - 4/2 - Acute hyponatremia developed

Discontinued HCTZ

Furosemide 40 mg IV

Furosemide 20 mg IV

Furosemide

20 mg IV

NS @ 100 mL/hr

Furosemide 20 mg IV

NS @ 50 mL/hr

Cardiac Diet = low salt intake

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Patient TR

Hospital Course - 4/3 - Acute hypokalemia developed

KCl 40 mEq PEG

KCl 30 mEq PO

KCl 40 mEq PO

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Patient TR

TR was discharged 4/7 with home hospice

Headache, unknown etiology – resolved
COPD exacerbation – resolved
HTN – stable
Non-small cell carcinoma – stable
Chronic back pain – stable
Hyponatremia – improved

130 mEq/L on discharge

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Hyponatremia Overview – �Sodium-Water Balance

Image from http://www.healthresource4u.com/wp-content/uploads/2013/09/How-Sodium-Works-To-Balance-Fluids.jpg

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Hyponatremia Overview – Vasopressin’s Role

Image from http://www.nature.com/nrendo/journal/v7/n3/images/nrendo.2010.229-f1.jpg

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Hyponatremia Overview – Definitions & Classifications

Image from Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations.

Severity Level	Diagnostic Criteria
Mild	Serum Na+ 130 to < 135 mEq/L
Moderate	Serum Na+ 125 to < 130 mEq/L
Severe	Serum Na+ < 125 mEq/L

Timeline of Development	Diagnostic Criteria
Acute	Development over < 48 hrs
Chronic	Development over > 48 hrs
Indeterminate	Treat as chronic

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Hyponatremia Overview – Potential Causes

Image from http://www.nursingguide.ph/userfiles/hyponatremia_final.jpg

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Hyponatremia Overview – �Signs and Symptoms

Image from http://img.medscape.com/article/774/670/774670-fig1.jpg

Moderately Severe Nausea without vomiting Confusion Headache
Severe Vomiting Cardiorespiratory distress Abnormal and deep somnolence Seizures Coma

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Hyponatremia Overview – �Brain Adaptations

Image from http://blog.ecu.edu/sites/nephrologyondemand/files/2010/08/hypo-na2.png

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Hyponatremia Overview – �Brain Adaptations

Image from Sterns RH. Disorders of Plasma Sodium — Causes, Consequences, and Correction.

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Hyponatremia Overview – �Diagnostic Algorithm

Image from Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients.

To diagnose the type and cause of hyponatremia, algorithms have been developed and are quite helpful.

--Must rule out isotonic or hypertonic situation by looking at the plasma osmolality

--Then look at the urine osmolality to determine if the kidneys are appropriately diluting the urine

--Then look at the ECF (extracellular fluid) volume status to determine likely causes

--Hypovolemia = loss of sodium or potassium with water retention → can be caused by gastrointestinal disease, excessive exercise, diuretics (especially thiazides), or cerebral salt wasting

--Euvolemia = relative or absolute excess of body water, usually from the reduced electrolyte-free water excretion due to anti-diuretic actions of AVP on the kidney → can be caused by SIADH (syndrome of inappropriate anti-diuretic hormone), glucocorticoid deficiency, hypothyroidism

--Hypervolemia = from edema due to renal sodium and water retention where kidneys cannot excrete water effectively → caused by HF, Cirrhosis, or kidney disease (acute or chronic)

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Hyponatremia Overview – �SIADH

Image from Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations.

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Hyponatremia Treatments

Symptomatic Acute Hyponatremia

Severe symptoms

100 mL of 3% NaCl infused IV over 10 min x 3 prn

Mild to moderate symptoms

3% NaCl infused at 0.5-2 mL/kg/h

If truly acute, rate of correction does not need to be limited, but if unsure, limits should be followed

Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations.

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Hyponatremia Treatments

Avoiding Risk of Osmotic Demyelination Syndrome (ODS)

Goal

Minimum correction by 4-8 mmol/L per day
Lower goal of 4-6 mmol/L per day if high risk for ODS

Limits not to exceed

High risk of ODS: 8 mmol/L in any 24-h period
Normal risk of ODS: 10-12 mmol/L in any 24-h period; 18 mmol/L in any 48-h period

Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations.

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Hyponatremia Treatments

SIADH

If acute, treat accordingly
If chronic

Observe limits of correction
Isotonic 0.9% NaCl is not effective and may worsen the hyponatremia
Fluid restriction is considered first line

Several days of restriction are generally needed to see an increase in osmolality
Do not limit Na+ or protein

Discontinue any drugs known to be associated with SIADH
Pharmacologic therapies should be considered if urinary parameters indicate low renal electrolyte-free water excretion or if the serum Na+ has not corrected after 24-48 hours of fluid restriction

Demeclocycline
Urea
Vasopressin receptor antagonists (Vaptans)

Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations.

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Hyponatremia Treatments

Fluid Restriction Recommendations

Image from Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations.

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Hyponatremia Treatments�“Vaptan” Drug MOA

Image from http://www.nature.com/nrendo/journal/v7/n3/images/nrendo.2010.229-f1.jpg

Vaptan drugs = competitive antagonists

Tolvaptan (Samsca) is approved in the US for Treatment of clinically significant hypervolemic or euvolemic hyponatremia associated with heart failure or SIADH with either a serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and resistant to fluid restriction (V2 selective) --PO

Conivaptan (Vaprisol) is approved in the US for Treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients (V1A and V2 receptor antagonist) – IV only

MOA: competitive antagonist of V2 receptors increases urine water excretion by blocking the effects of endogenous AVP (arginine vasopressin aka anti-diuretic hormone) at V2 receptors in renal collecting duct, thereby increasing free water clearance, reducing the urine osmolality and therefore raising serum sodium concentrations

Recommendations concerning vaptans

--exclude hypovolemic hyponatremia before initiating

--do not use with other treatments

--do not use immediately after stopping 3% NaCl

--monitor q 6-8 hrs for 1^st 24-48 hrs

--use tolvaptan should be limited to 30 days due to hepatotoxicity and not used in underlying hepatic disorders→requires hospitalization for initiation to monitor for overcorrection

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Hyponatremia and Cancer

2012 review article

--Hyponatremia is common in patients with lung cancer. It is more common in small cell lung cancer (10-15% of cases), but it is seen in a small % non-small cell lung cancer (2-4%)

--SIADH is a particularly common cause in cancer patients with euvolemic hyponatremia

--looked at 13 studies, of which 6 showed hyponatremia as an independent risk factor for poor outcome

--Causes identified for hyponatremia in cancer patients included SIADH (often by ectopic production of AVP by tumors) or by effects of anticancer and palliative medications or things like diarrhea and vomiting

--treatment differs depending on etiology so proper diagnosis of underlying cause is important

--SIADH causes typically require hypertonic saline, though the newer class of “vaptan” drugs may be useful

--Chronic, asymptomatic hyponatremia should be treated more conservatively with fluid restriction

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Hyponatremia and Cancer

Article from 2013 looking at tolvaptan treatment for small cell lung cancer patients with SIADH

--prospective case series with 10 patients with SCLC + severe SIADH (plasma Na+ < 125) + clinical picture of neurocognitive deficit

--study done in Berlin, patients enrolled between June 2010 and April 2012

--used tolvaptan AFTER standard therapy of fluid restriction or 3% hypertonic saline infusions failed to improve clinical symptoms, patients received 15 mg/day of tolvaptan (stopped other treatments 12 hours before dose)

--this trial saw rapid clinical improvement in all of these patients and normalization of serum Na+ levels

--allowed patients to start chemo on time

--obviously limited by small number of patients and treatment prior to use tolvaptan → could also be influenced by the severity/type of cancer, not very generalizable

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Hyponatremia and Cancer

2015 article in BMC Cancer

--retrospective review of patients admitted to specialty cancer hospital in London with plasma sodium <115 + dx of malignancy from 1/1/2007 to 1/1 2012

--primary endpoint was median duration of hospitalization in patients with severe hyponatremia

--secondary endpoints included overall survival in pts whose serum sodium normalized versus those who did not

--57 patients were identified who met the criteria

--mean length of hospital stay was 12 days (primary)

--overall survival in the 56% of patients with corrected sodium was 13.6 months versus 16 days in patients who did not correct

--difference in survival rate is likely due to ability of cancer treatment to continue in patients whose hyponatremia resolved

--aggressive treatment of hyponatremia in cancer patients may allow for better cancer treatment and therefore better outcomes and longer survival

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TR’s Treatment Assessment

Hospital Course – Low sodium on arrival, then dropped

3/31 – Plasma Osmolality = 270
3/31 – Urine osmolality = 606
3/31 – Urine sodium = 183

3/31 – TSH, reflex = 1.91
3/31 – Cortisol, random = 8.8

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TR’s Treatment Assessment

Proper analysis of his treatment regimen requires judgment about whether this was a “chronic” or “acute” hyponatremia. I think there is an argument to be made either way.

With a presumed diagnosis of SIADH based on presentation and lab values, the guidelines I found for the treatment of SIADH-induced hyponatremia suggest treatment with 3% hypertonic saline for acute, symptomatic cases. There was disagreement between the medical resident and attending physician regarding the severity of neurocognitive impairment. Therefore, a conservative course of treatment was taken, adhering more to the chronic recommendations of fluid restriction. The concurrent administration of normal saline at a low rate plus furosemide was not widely regarded as standard therapy. I found one mention in the guidelines suggesting that furosemide 20-40 mg IV can be used to address volume overload, especially in patients at risk for developing HF.

Regarding the research on hyponatremia in cancer, aggressive treatment has been suggested to enable better survival by allowing for continued cancer treatment, but in TR’s case, continued cancer treatment was not the goal. Conservative treatment was favored.

I don’t think the conservative approach was wrong in this patient, given his poor long-term prognosis with the cancer status and desire to be discharge with home hospice, but I think it would have been a reasonable approach to use 3% hypertonic saline at a slow rate of correction as well.

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Summary

Hyponatremia is a very common electrolyte imbalance that can have serious negative outcomes if untreated.
Overall treatment should focus on the underlying cause of the hyponatremia.
Acute treatment is necessary, but repletion must be done gradually to prevent osmotic demyelination.
The severity of symptoms along with the duration (acute versus chronic) help guide the choice of treatment, not just the number.
Hyponatremia in cancer patients may lead to poor prognosis; correction can improve survival, likely by allowing for treatment of the cancer.

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References

Balachandran K, Okines A, Gunapala R, Morganstein D, Popat S. Resolution of severe hyponatraemia is associated with improved survival in patients with cancer. BMC Cancer. 2015;15(1):1–5. doi:10.1186/s12885-015-1156-6.
Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients. Oncologist. 2012;17(12):756–765.
Petereit C, Zaba O, Teber I, Lüders H, Grohé C. A rapid and efficient way to manage hyponatremia in patients with SIADH and small cell lung cancer: treatment with tolvaptan. BMC Pulm Med. 2013;13(1):55. doi:10.1186/1471-2466-13-55.
Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170(3). doi:10.1530/EJE-13-1020.
Sterns RH. Disorders of Plasma Sodium — Causes, Consequences, and Correction. N Engl J Med. 2015;372(1):55–65. doi:10.1056/NEJMra1404489.
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med. 2013;126(10 SUPPL.1). doi:10.1016/j.amjmed.2013.07.006.