The Different Faces of Hyponatremia: Multifaceted Patients and Multidisciplined Providers

Alpesh N. Amin, MD, MBAProfessor of Medicine

Chair, Department of MedicineExecutive Director, Hospitalist ProgramUniversity of California, Irvine School of

Medicine

Arthur Greenberg, MDProfessor of MedicineDivision of Nephrology

Department of MedicineDuke University School of Medicine

Durham, North Carolina

Paul J. Hauptman, MDProfessor of Internal Medicine

Division of CardiologyAssistant Dean, Clinical and Translational

ResearchSt. Louis University School of Medicine

St. Louis, Missouri

Steven l. Zacks, MD, MPH, FRCPCAssociate Professor of MedicineDivision of Gastroenterology and

HepatologyThe University of North Carolina at

Chapel Hill School of Medicine

• Most common disorder of electrolytes, affecting 15% to 30% of acutely and chronically hospitalized patientsa

• Approximately 1 million hospitalizations per year are due to hyponatremia as a primary or secondary diagnosis

• Direct cost of managing hyponatremia is estimated to range from $1.6 to $3.6 billion per year in the United Statesb

Prevalence and Epidemiology of Hyponatremia

a. From Schrier R.[1]

b. From Boscoe A, et al. [2]

• Primarily caused by inappropriately elevated plasma AVP, which is secreted in response to increased plasma osmolality or decreased volume/pressure (hypovolemia) and results in water reabsorption

• Etiology varies with classification– Hypovolemia (gastrointestinal/dermal/third-space loss, diuretics)– Euvolemia (SIADH, drugs [diuretics, SSRIs, carbamazepine, TCAs,

phenothiazines, etc])– Hypervolemia (heart failure, cirrhosis, renal failure)

• Clinical manifestation of underlying medical conditions and hyponatremia may provide important diagnostic and prognostic information

Patients At Risk for Hyponatremia

• Acute, severe hyponatremia can cause substantial morbidity and mortality

• Mortality is higher in patients with a wide range of underlying diseases

• Overly rapid correction can cause severe neurologic deficits and death

Treatment Challenges

Definition of Hyponatremia

Severity of Hyponatremiab

Severity Neurologic Manifestations* Sodium

Mild Asymptomatic or associated with subtle changes in mental and physical function 130-135 mEq/L

Moderate Nonspecific symptoms (nausea and malaise) 125-130 mEq/L

Severe Progressive neurologic symptoms ranging from confusion to coma < 125 mEq/L

*Neurologic manifestations are also influenced by the speed of onset of hyponatremia

Hyponatremia: serum sodium ≤ 135 mEq/La

a. From Adrogué HJ, Madias NE et al.[3]

b. From Thompson.[4]

Clinical Symptoms in Hyponatremia

From Adrogué HJ, et al.[3]

• Seizures • Coma• Permanent brain damage• Respiratory arrest• Brainstem herniation• Death

• Headache• Nausea• Vomiting• Muscle cramps• Lethargy• Restlessness • Depressed reflexes• Disorientation

More likely to occur with serum sodium < 125 mEq/L

Potential complications

Potential complications are associated with: •Severe, rapidly evolving hyponatremia•Excessive water retention in euvolemia•Menstruation

Common symptoms

Case PresentationNeurosurgical Hyponatremia

• 30-year-old man with a known third ventricle tumor of 8 years’ duration

• Intractable headaches, seizure disorder• Medications: oxycodone, levetiracetam• Admitted for tumor resection• BP 123/86, no JVD, clear chest, no edema,

normal neurological exam• Sodium 139 mmol/L, BUN 12 mg/dL, creatinine

1.0 mg/dL, glucose 147 mg/dL

2004

2012

Case PresentationNeurosurgical Hyponatremia (cont)

• Brought to the operating room– Craniectomy, bone flap, excision of tumor from left

lateral and third ventricles– Pathology: central neurocytoma, WHO grade III

• Returned to neurosurgical ICU• Initially awake, but deteriorated neurologically• CT of brain showed interval development of

hydrocephalus• Returned to operating room for placement of

ventriculoperitoneal shunt• Returned to neurosurgical ICU

Neurosurgical HyponatremiaPostoperative Days 4 and 5• Maintained on antibiotics, IV fluids, levetiracetam,

IV fentanyl, high-dose dexamethasone• Vital signs stable with pulse averaging 70 bpm range

and BP in the range of 110 to 130/60 to 75• Physical examination revealed waxing and waning

mental status, clear chest, no edema• Intake and output roughly balanced with 2-3 L/d

0.9% saline or 0.45% saline in, 2-3 L/d urine out • Decrease in serum sodium level from 140 to 127

mmol/L

Diagnostic Approach to HyponatremiaGenuinely hyponatremic? PseudohyponatremiaN

Genuinely hypotonic?HyperglycemiaRadiocontrastMannitol

N

Diluting defect? Primary polydipsiaBeer potomania

N

Assess extracellular volume

GI fluid LossAdrenal insufficiencyDiureticsCerebral salt wastingBurns and third space fluid lossMarathon runners

SIADHGlucocorticoid deficiencyHypothyroidism(Reset osmostat)NSAID

Edema-forming states•Heart failure•Cirrhosis•Nephrosis

HighLowNormal

Not AVP Mediated

AVP Mediated

Case PresentationNeurosurgical Hyponatremia (cont)• Serum cortisol 0.8 μg/dL (normal, 5.0-25.0 μg/dL )• Free thyroxine 0.68 ng/dL (normal, 0.52-1.21 ng/dL)• Thyroid stimulating hormone 0.23 mIU/L (normal, 0.34-5.66

mIU/L)• Follicle-stimulating hormone 1.0 mIU/mL (normal, 2.5-17.7)• Luteinizing hormone 0.3 mIU/mL (normal, 1.4-7.7 mIU/mL)• Sodium 127 mEq/L• Plasma osmolality 272 mOsm/kg • Urine osmolality 875 mOsm/kg• Urine sodium 245 mmol/L• Uric acid 3.6 mg/dL (normal, 4.0-8.0 mg/dL)

Postoperative Day

Sodi

um, m

mol

/L

TumorResection

3% NaCl

Dexamethasone or Hydrocortisone

UOsm

708

Neurosurgical SIADH I

Postoperative Day

Sodi

um, m

mol

/L

TumorResection

3% NaCl

Dexamethasone or Hydrocortisone

UOsm

708

Neurosurgical SIADH II

Postoperative Day

Sodi

um, m

mol

/L

TumorResection

3% NaCl

Dexamethasone or Hydrocortisone

UOsm

708

Tolvaptan, 15 mg

Neurosurgical SIADH III

Postoperative Day

Sodi

um, m

mol

/L

TumorResection

3% NaCl

Dexamethasone or Hydrocortisone

UOsm

708

Tolvaptan, 15 mg

UOsm

650

Neurosurgical SIADH IV

Postoperative Day

Sodi

um, m

mol

/L

TumorResection

3% NaCl

Dexamethasone or Hydrocortisone

UOsm

708

Tolvaptan, 15 mg

Tolvaptan, 30 mg

UOsm

650

UOsm

280

Neurosurgical SIADH V

Hyponatremia in Heart Failure

Increased sodium reabsorption in the kidney

Angiotensin II Vasopressin Aldosterone

Complicating Factors Associated With Prolonged Length of Stay in Heart Failure

• Hyponatremia• Volume overload• Worsening renal failure• Advanced age• Comorbidities• Marked antecedent weight gain• Lack of (early) resolution of weight gain• Hypotension• Organ hypoperfusion

Predicted probability of freedom from death and death or HF rehospitalization

across levels of sodium after adjusting for important covariates

From Gheorghiade M, et al.[5]

ESCAPERelationship between clinical events and patients with persistent hyponatremia,

corrected hyponatremia, or normonatremia

Plots are for the “average” patient using the mean values of all covariates. Lighter line pairs

represent 95% CI. To convert sodium to mmol/L, multiply by 1.0

Error brackets indicate exact binomial 95% CI intervals

IMAGES NO LONGER AVAILABLE

EFFECTMultivariable Predictors of Mortality• Age• Systolic blood pressure• Respiratory rate• Serum sodium• Hemoglobin• Blood urea nitrogen

From Lee DS, et al.[8]

Hyponatremia in Patients With Cirrhosis• Diuretics cause contraction of central blood volume

resulting in nonosmotic release of AVP• Patients with cirrhosis have increased renin-

angiotensin-mediated free water reabsorption while diuretics block sodium reabsorption

• Hyponatremia is significant because:– The MELD score combined with the serum sodium concentration

was a better predictor of death than the MELD score alonea – It is associated with the development of hepatic encephalopathyb – Hyponatremia is a more sensitive marker of renal dysfunction than

creatinine in patients with cirrhosisc

a. From Kim WR, et al.[11]

b. From Häussinger D, Schliess F.[12]

c. From Ruf AE, et al.[13]

From Kim WR, et al.[11]

Serum Sodium Concentration and Relative Risk of Death After Adjustment for MELD Score