The Different Faces of Hyponatremia: Multifaceted Patients and Multidisciplined Providers

1. The Different Faces of Hyponatremia: Multifaceted Patients and Multidisciplined Providers Alpesh N. Amin, MD, MBA Professor of Medicine Chair, Department of Medicine Executive Director, Hospitalist Program University of California, Irvine School of Medicine Arthur Greenberg, MD Professor of Medicine Division of Nephrology Department of Medicine Duke University School of Medicine Durham, North Carolina Paul J. Hauptman, MD Professor of Internal Medicine Division of Cardiology Assistant Dean, Clinical and Translational Research St. Louis University School of Medicine St. Louis, Missouri Steven l. Zacks, MD, MPH, FRCPC Associate Professor of Medicine Division of Gastroenterology and Hepatology The University of North Carolina at Chapel Hill School of Medicine

2. Prevalence and Epidemiology of Hyponatremia • 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 a. From Schrier R.[1] b. From Boscoe A, et al. [2]

3. Patients At Risk for Hyponatremia • 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

4. Treatment Challenges • 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

5. Definition of Hyponatremia Hyponatremia: serum sodium ≤ 135 mEq/La *Neurologic manifestations are also influenced by the speed of onset of hyponatremia a. From Adrogué HJ, Madias NE et al.[3] b. From Thompson.[4]

6. Clinical Symptoms in Hyponatremia From Adrogué HJ, et al.[3] More likely to occur with serum sodium < 125 mEq/L Common symptoms Potential complications • Headache • Nausea • Vomiting • Muscle cramps • Lethargy • Restlessness • Depressed reflexes • Disorientation • Seizures • Coma • Permanent brain damage • Respiratory arrest • Brainstem herniation • Death • Potential complications are associated with: • Severe, rapidly evolving hyponatremia • Excessive water retention in euvolemia • Menstruation

7. 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 Case PresentationNeurosurgical Hyponatremia

8. 2004 2012

9. 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

10. 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

11. Diagnostic Approach to Hyponatremia N Genuinely hyponatremic? Pseudohyponatremia Hyperglycemia Radiocontrast Mannitol N Genuinely hypotonic? N Not AVP Mediated Primary polydipsia Beer potomania Diluting defect? AVP Mediated Assess extracellular volume Low High Normal GI fluid Loss Adrenal insufficiency Diuretics Cerebral salt wasting Burns and third space fluid loss Marathon runners SIADH Glucocorticoid deficiency Hypothyroidism (Reset osmostat) NSAID • Edema-forming states • Heart failure • Cirrhosis • Nephrosis

12. 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)

13. Neurosurgical SIADH I Tumor Resection UOsm 708 Sodium, mmol/L 3% NaCl Dexamethasone or Hydrocortisone Postoperative Day

14. Neurosurgical SIADH II Tumor Resection UOsm 708 Sodium, mmol/L 3% NaCl Dexamethasone or Hydrocortisone Postoperative Day

15. Neurosurgical SIADH III Tumor Resection UOsm 708 Sodium, mmol/L Tolvaptan, 15 mg 3% NaCl Dexamethasone or Hydrocortisone Postoperative Day

16. Neurosurgical SIADH IV Tumor Resection UOsm 708 UOsm 650 Sodium, mmol/L Tolvaptan, 15 mg 3% NaCl Dexamethasone or Hydrocortisone Postoperative Day

17. Neurosurgical SIADH V Tumor Resection UOsm 280 UOsm 708 UOsm 650 Sodium, mmol/L Tolvaptan, 30 mg Tolvaptan, 15 mg 3% NaCl Dexamethasone or Hydrocortisone Postoperative Day

18. Hyponatremia in Heart Failure Increased sodium reabsorption in the kidney Angiotensin II Vasopressin Aldosterone

19. 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

20. ESCAPE Predicted probability of freedom from death and death or HF rehospitalization across levels of sodium after adjusting for important covariates Relationship between clinical events and patients with persistent hyponatremia, corrected hyponatremia, or normonatremia IMAGES NO LONGER AVAILABLE 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 From Gheorghiade M, et al.[5]

21. EFFECTMultivariable Predictors of Mortality • Age • Systolic blood pressure • Respiratory rate • Serum sodium • Hemoglobin • Blood urea nitrogen From Lee DS, et al.[8]

22. 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]

23. Serum Sodium Concentration and Relative Risk of Death After Adjustment for MELD Score From Kim WR, et al.[11]