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Hyponatremia!!!

Hyponatremia!!!

Hyponatremia!!!

Sunil Agrawal, MD, FASN Disclosures

• Employed by Specialist of Oklahoma

• Otsuka Speaker Bureau for Jynrque

• Local DaVita Medical Director - In-Center and Home Dialysis !!!

Confused?

PTSD from training!! NOW WHAT????? HYPONATREMIA!!!

Natural Inclination:

FLUID RESTRICTION

THIS NOT THE ANSWER MOST OF THE TIME!!! (ignores causation)

USUALLY HAVE TO RESITRICT:

< 800 ml/Day!!! Outline

• Introduction

• Brief Physiology of Water Handling

• Diagnosis

• Special Cases of Hyponatremia

• Treatment → Acute vs. Chronic

• Summary Introduction

• What is Hyponatremia? • : <135 • Acute <48 hours • Chronic >48 hours or duration unkown

• Why do we care? • 15-22% of Hospital Patients • Substantial Morbidity and Mortality • Growing Geriatric Population at Risk • “Companion Diagnosis” with many Disease States Introduction

• Hyponetremia → Free water intake > water secretion

• Serum [Na+]∝ Na + K / Total Body Water • Decrease in numerator • Increase in denominator Water Physiology Water Physiology

• Concentrating and Diluting Capacity: • → 1200 mOsm/kg, UOP <1 L/ day • Diluting → 50 to 100 mOsm/kg, UOP ~ 14 L / day • Kangaroo Rat → concentration capacity of 6,000 mOsm/kg! Water Physiology

• What is responsible for changes in urine volume and tonicity? • ADH → • Made in • Cleaved to active ADH, neurophysin II, & copeptin • Stored in Water Physiology

Stimulated by: • ADH ✓ Hypertonicity • Releases due to ✓ increase in Posm • >285 mOsm/kg • Acts on the collecting duct of the (high permeability to water) • Passive water absorption Water Physiology

• ADH receptors: • V1a – Vasoconstriction and Increase Prostaglandin release (E2 and prostacyclin), • Platelet aggregation • Cytokine Release • Glycogenolysis • V2 – Mediates ADH action • Free water absorption • V3 (V1b) – Acts on the pituitary, ACTH release Water Physiology

• Actions of ADH: • Renal: • Water reabsorption via the Aquoprin 2 • Reabsorption of • Renal Prostoglandin secretion • Na and K in the collecting duct? • Extrarenal: • Vasoconstriction • Release of factor VIII and von Willebrand's factor Water Physiology

• Countercurrent Multiplication:

• Active NaCl transport from ascending loop of Henle

• Low water permeability of ascending loop of Henle

• High water permeability of decending loop of Henle

• Passive reabsorption of Urea in collecting duct Water Physiology

• Aquaporin Water Channels • 16 known channels → likely more • Found in extrarenal locations • Aquaporin 1-4 most studied • Aquaporin 1 associated with proximal tubule • Aquaporin 2 associated with ADH • Aquaporin 4 associated with the blood-brain barrier Water Physiology

• Why go through physiology?

• ADH Derangement!!!! Diagnosis Diagnosis

• The two most important diagnostic tests: • HISTORY • PHYSICAL EXAM

• Typical Classifications: • Serum Osmolality • Volume Status Diagnosis

What to order:

✓ Urine Sodium*

✓ Urine Creatinine

✓ Urine

✓ Urine Osmolality

✓ Serum Osmolality

✓ Serum Uric Acid

✓ TSH* Famous Renal Attending: Dr. Neph Ron

✓ Cortisol*

✓ Frequent of Serum Sodium Quick Definitions

• Difference between Osmolarity • What is Tonicity? and Osmolality: • the concentration of osmoles → (known as effective osmoles) • Osmolality → is the number of that do not freely cross cell osmoles of solute in a kilogram membranes. of solvent • Concentration of the particles that is dissolved in a fluid*

• Osmolarity →is the number of osmoles of solute in a liter of . • Concentration of an osmotic solution

*can be directly measured by osmometer Diagnosis

• Step #1:

• Serum Osmolarity: • Hypertonic (Posmo >290) • Isotonic (Normal Posmo 275-290) • Hypotonic (Posmo <275)*

*Physical Exam → very important Diagnosis

• : • Pseudo-hyponatremia • Secondary to increase lipids and proteins • • Paraproteinemia • Plasma: 93% Water, 7% Proteins • Decrease in fraction of the plasma sample in aqueous • Can be avoided by using Direct Potentiometry (ISE) → no dilution of sample • To confirm Dx → check Lipid panel or Osmolar Gap Diagnosis

• Special Cases of Isotonic Hyponatremia: • Transurethral prostate surgery • Endoscopic Intrauterine Surgery • Typically Due to Type of Irrigant: • Glycine → directly neurotoxic • Sorbitol • Why Isotonic? • Rapidly Absorbed with water • Expansion of space with fluid Diagnosis

• Osmolar Gap → can be helpful det cal • OG = Plasmaosm – Plasmaosm cal • Plasmaosm = 2Na + BUN/2.8 + Glu/18 + EtOH/4.6 • Delta > 10 considered Abnormal Diagnosis

• Hypertonic Hyponatremia

• Increase Osmolar Gap > 10

• Typically Caused by: • • Ig Infusion (sucrose) • Maltose • → corrected by 2.4 meq/L per 100 mg/dl of glucose Decision Tree of Serum Osmolality Diagnosis

• • Most common presentation of Hyponatremia • ADH typically the driving force • PHYSICAL EXAM VERY IMPORTANT! • Hypervolemic • Hypovolemic • Euvolemic Diagnosis

• What to look for on exam: • Vitals • JVP • Skin Turgor • Mucous Membranes • Peripheral Diagnosis

• Urinary Indices: • Urinary Sodium: • Is the Kidney Sodium Avid? • Pre-Renal State → UNa <10 • Hypovolemic * • Extra-Renal Volume Loss • Hypervolemic • CHF, , Nephrosis

* use →  UNa,  PNa, PK, ECV Diagnosis

• Urine Sodium Continued:

• What if the Urine sodium is > 20? • Hypovolemic → Renal loss of volume • Hypervolemic → Renal Failure

• CONFUSED? Diagnosis

• Remember: • Sodium Avid state → kidney fucntioning properly • Higher urine sodium in the face of hypovolemia and the kidney is to blame! Break Diagnosis

• Urine Osmolarity: • Helpful only if <100 mOSm/L • Primary Polydipsia (Euvolemic Hyponatremia) • Low Solute “tea and toast” (Euvolemic Hyponatremia) • Not Helpful to decern states with elevated ADH all will have Uosmo > 100 mOsm/L Diagnosis

• Euvolemic Hyponatremia: • To be SIADH, Or not to be SIADH, that is the question…. • Most misunderstood state • Clinical Exam of ECV not very sensitive Diagnosis

• What to look for in SIADH: • Additional Data:

① Euvolemic by Exam • Fractional Excretion of uric acid >10% ② Serum Osmolarity <275 mOsm/kg • Uric Acid < 4 mg/dl (low BUN)

③ Urine Sodium > 40 meq/L • Worsening hyponatremia with Normal ④ Urine Osmolarity > 100 mOsm/L • Plasma vasopressin level inappropriate relative to ⑤ Normal Adrenal, , serum osmolality and Kidney Function

⑥ Absence of Advanced CKD, cirrhosis, or HF Diagnosis

• Differential to SIADH that must be R/O:

• Cerebral Salt Wasting • Decrease in EFV • increase in HCT/alb/BUN/creatinine

• Reset Osmostat Diagnosis

• Common Etiologies of • Drugs: SIADH • Ecstasy (MDMA) • Tumors: • • Pulmonary/mediastinal • Acei • Small Cell Lung CA • SSRI • Pancreatic CA • Opioids • Leukemia • Amiodarone • CNS disorders: • Pulmonary Disease: • Mass lesions • Infection • Inflammation • COPD • Gullian-Barre • Others: • Delirium Tremens • AIDS/HIV • ICH • Trauma Summary of Hypotonic Hyponatremia

Hypervolemia Euvolemia Hypovolemia SIADH Cirrhosis Cerebral salt wasting (Glucocorticoid def) Mineralocortcoid def Renal “Failure” Primary Slat-wasting nephropathy Glucosuria Sepsis Third space losses Sweat Losses Diagnosis

Summary of Serum Osmolality

Hypertonic Isontonic Hypotonic Hyponatremia Hponatremia Hyponatremia

Serum Osmo: Serum Osmo: Serum Osmo: >295 msmo/kg 275-295 msmo/kg <275 msmo/kg

Hyperglycemia Pseudohyponatremia Hypervolemia Mannitol Paraproteins Euvolemia Glycine Hyperlipidemia Hypovolemia Special Cases Edematous Disorders Exercise Associated Hyponatremia Exercise Associated Hyponatremia • Incidence: variable ~ 0-2% (depending on source) • Typically seen in the following activities: • Intense Endurance: • • Triathlons • Ultradistance • Military Operations Exercise Associated Hyponatremia

• Risk Factors: • Low BMI

• High fluid intake during and • Female Gender* after • Athletic Drinks DO NOT • Less Experinced Runners reduce risk • All re hypotonic • NSAIDs* compared to Plasma Osmo • High sodium sweat concentration • Minimal /Weight • Heat acclimation can gain during activity reduce Na in sweat • Longer race time (~ 5 h 10 min)* Exercise Associated Hyponatremia

• Water Loading alone? • Need ADH surge • Possible eitologies on increased ADH: • and/or • Hypoglycemia • Plasma volume contraction • Angiotensin II • Nonspecific stresses such as pain and emotion Exercise Associated Hyponatremia

• Other Possible Mechanisms: • IL-6 produced from contraction muscles* • Oxytocin (especially in women)

• How to reduce risk: • Drink to thirst • Pre-weights • Education Post Operative Hyponatremia Post Operative Hyponatremia

• ADH are increase ≥ 2 days after surgery

• Hypotonic Fluid Administration can be risky

• Seen in pediatric population

• REMEMBER → Fluids are medications! Drug Induced Hyponatremia Drug Induced Hyponatremia

• One the most common causes of hyponatremia

• HCTZ → most common cause of community acquired hyponatremia • Those at risk: elderly, women, low BMI

• Vasopressin Analogs: • Oxytocin •

• drugs:

• TCA(s)

• SSRI(s) • Especially Venlafaxine (Effexor) Drug Induced Hyponatremia

• Vasopressin Analogs (continued): • Antiepileptic Drugs • • Lamotrigine • • Narcotics Drug Induced Hyponatremia

• Drugs that potentiate renal vasopressin • NSAIDs • Tylenol • Cyclosphosphamide

• Unknown Mechanism • Ectasy • • Amitriptiline “Beer”

• Occurs when large quantities of low solute fluid is consumed (w/o food)

• Can be explained by -free water clearance (Una + Uk) / (Pna + Pk) • If calculated 5 L/d, and >5L/day consumption → will result in hyponatremia Treatment Treatment

① MUST establish if Acute v. Chronic • > 48 hours • If not confident of history assume chronic

② Does the Patient have symptoms

③ Does the patient have risk factors to develop neurologic Sequela Treatment Treatment

• Symptoms of Severe Acute Hyponatremia: ICU and In-Hospital Mortality • • • Herniation • Respiratory Distress/Depression • Death Treatment

• Symptoms of Chronic Hyponatremia: (can very subtle) • • Ataxia/Gait disturbances • Increase in Falls • Muscle and weakness • Decrease in mental acuity • Nausea and Vomiting Treatment

• Risk Factors for Neurologic Sequela • Runners • Children → due to brain size • Hypoxic Patients • Elderly on HCTZ • Postoperative menstrating females → Treatment

• Guidelines for Rx of Acute Hyponatremia (severe) • Probably okay to correct to normal, but would not exceed 12 meq/L/day Frequent Labs draws • Hypertonic Normal saline (3%) 1-2 meq/L/hr • ~ 100 ml will increase by 2 meq/L (bolus) • Can give blous up to 2X • Textbook Rate: 1-2 ml/kg/h • **1 ml of 3% saline per kg → change serum Na ~ 1 meq/L • **Peripheral vein ok to use • An increase of 4-6 meq/L is usually enough to abort symptoms • Stop aggressive treatment with neurologic symptoms cease or serum sodium >120 meq/L* • Can consider administration with Treatment

• Guidelines for Rx of Chronic Hyponatremia • Go SLOW! • 0.5 meq/L/hr → max 12 meq/L/day, set goal at 10 meq/L/day (would set goal more modestly) • An increase of 4-6 meq/L is usually enough to abort symptoms • Frequent Lab Draws • Replace Sodium and Potassium losses • Calculate ΔNa → Adrogue-Madias fromula • ΔNa after 1 L= ( [ Na + K ] inf –[Na] s) / TBW + 1 • Assuming no loss of renally or extrarenally Treatment

• of Rapid Correction: Osmotic Demyelination Syndrome (ODS) → rapid correction of Sodium

• Also known as “myelinolysis” • Neurologic Injury → loss of oligodendrocytes • Without inflammation • Usually occurs at center of pons (central pontine myelnosis) • Can occur in gray and white matter symmetrically distributed (extrapontine myelinolysis) • Due to depletion of brain osmolytes → SNAT2 transporter • • Glycine • GABA Treatment

• Risk Factors for Osmotic Demyelination Syndrome • Chronic Hyponatremia • • • Liver Disease • Hypokalmeia • Serum Sodium <105 meq/L Treatment

• Things to watch for: Treatment

• States that have reversible impaired water secretion:

• Hypovolemia • Thiazide diuretics

• Hypoxia • Cortisol Def • SIADH – & drug induced Treatment

• What to do if overcorrection? • Administer D5W • Desmopressin • Frequent Lab Draws • Would check serial urine osmolarity • Set clear goals of therapy • 4-6 meq/L is usually enough Treatment

• Hypotonic Hyponatremia: • Hypovolemic: • Volume Improvement • Blood pressure Improvement • Hypervolmeic: • Diuretic therapy Treatment

• Rx for SIADH • Isotonic Saline • Fluid Restriction • Hypertonic Saline/Salt Tablets • Lasix/Urea tablets • • Vaptans Treatment

• SIADH → Isotonic fluids • What for Desalnization • If Una + Uk < 150 meq/L → will improve sodium • If Una + Uk > 150 meq/L → may need 3% Saline

• Lasix + Urea • Increase urine osmoles thus increase UOP

• Salt Tablets → increase osmoles Urea Treatment

• SIADH → Fluid restriction • Very arbitrary → dependent on clinician • Poor compliance • What to do? • Restrict 500 cc? • Restrict 1 L? • Restrict 1.5L? • Restrict 2L? Treatments

• SIADH → Fluid Restriction

• Can calculate if treatment will be successful: • Electrolyte-free water clearance: • (Una + Uk) / (Sna + Sk) • > 1 unlikely will be successful with fluid restriction • 0.5 – 1 likely will be successful with 500 cc fluid restriction • < 0.5 likely will be successful with 1 L fluid restriction Treatment

• Demecolcycline → induces DI • “The Vaptans” → ADH receptor blockers • Nonselective → • Blocks V1a and V2 • Due to drug-drug interactions, use for short term • CI → hypovolemia and Cirrhosis • Selective → • Blocks V2

• Good for CHF and Chronic Hyponatremia Summary of Treatment

Hypotonic Hyponatremia

EUVOLEMIC HYPERVOLEMIC HYPOVOLEMIC Minimal Symptoms Fluid restriction, vaptan or Fluid restriction, vaptan or Saline +/- fludocortisone urea urea Moderate Symptoms Vaptan or Urea +/- fluid Vaptan or Urea +/- fluid Saline +/- fludocortisone restriction/diuretics restriction/diuretics Severe Symptoms Hypertonic NaCl Hypertonic NaCl (Not Hypertonic NaCl Ideal)

** In the Field: 3% saline 100 ml over 10 min repeat x2 In Hospital: 3% saline 100 ml or 1 ml/kg bolus Followed by 100 ml/hr or 1-2 ml/kg/hr ***only need to raise 4-6 meq to abort symptoms typically Summary The End Questions?

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