Hyponatremia!!!Sunil Agrawal, MD, FASN

Disclosures

• Employed by Nephrology Specialist of Oklahoma

• Otsuka Speaker Bureau for Jynrque

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

HYPONATREMIA!!!

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

Confused?

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?• Serum Sodium : <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:

• Concentration → 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 → vasopressin

• Made in hypothalamus

• Cleaved to active ADH, neurophysin II, & copeptin

• Stored in posterior pituitary

Water Physiology

• ADH

• Releases due to increase in Posm

• >285 mOsm/kg

• Acts on the collecting duct of the kidney (high permeability to water)

• Passive water absorption

Stimulated by:✓ Hypertonicity✓ Hypovolemia

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 Urea

• 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 Potassium

✓ Urine Osmolality

✓ Serum Osmolality

✓ Serum Uric Acid

✓ TSH*

✓ Cortisol*

✓ Frequent Monitoring of Serum Sodium

Famous Renal Attending: Dr. Neph Ron

Quick Definitions

• Difference between Osmolarity and Osmolality:

• Osmolality → is the number of osmoles of solute in a kilogram of solvent• Concentration of the particles

that is dissolved in a fluid*

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

solution

*can be directly measured by osmometer

• What is Tonicity?• the concentration of osmoles →

(known as effective osmoles) that do not freely cross cell membranes.

Diagnosis

• Step #1:

• Serum Osmolarity:

• Hypertonic (Posmo >290)

• Isotonic (Normal Posmo 275-290)

• Hypotonic (Posmo <275)*

*Physical Exam → very important

Diagnosis

• Isotonic Hyponatremia:

• Pseudo-hyponatremia

• Secondary to increase lipids and proteins

• Hyperlipidemia

• 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

• OG = Plasmaosmdet – Plasmaosm

cal

• Plasmaosmcal = 2Na + BUN/2.8 + Glu/18 +

EtOH/4.6

• Delta > 10 considered Abnormal

Diagnosis

• Hypertonic Hyponatremia

• Increase Osmolar Gap > 10

• Typically Caused by:

• Mannitol

• Ig Infusion (sucrose)

• Maltose

• Hyperglycemia → corrected by 2.4 meq/L per 100 mg/dl of glucose

Decision Tree of Serum Osmolality

Diagnosis

• Hypotonic Hyponatremia

• 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 Edema

Diagnosis

• Urinary Indices:

• Urinary Sodium:• Is the Kidney Sodium Avid?

• Pre-Renal State → UNa <10• Hypovolemic *

• Extra-Renal Volume Loss

• Hypervolemic

• CHF, Cirrhosis, Nephrosis

* Diuretic 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 fucntioningproperly

• Higher urine sodium in the face of hypovolemia and hypervolemia the kidney is to blame!

Break

Diagnosis

• Urine Osmolarity:

• Helpful only if <100 mOSm/L

• Primary Polydipsia (Euvolemic Hyponatremia)

• Low Solute “tea and toast” (EuvolemicHyponatremia)

• Not Helpful to decern states with elevated ADH all will have Uosmo > 100 mOsm/L

Diagnosis

• EuvolemicHyponatremia:

• To be SIADH, Or notto be SIADH, that is the question….

• Most misunderstood state

• Clinical Exam of ECV not very sensitive

Diagnosis

• What to look for in SIADH:

① Euvolemic by Exam

② Serum Osmolarity <275 mOsm/kg

③ Urine Sodium > 40 meq/L

④ Urine Osmolarity > 100 mOsm/L

⑤ Normal Adrenal, Thyroid, and Kidney Function

⑥ Absence of Advanced CKD, cirrhosis, or HF

• Additional Data:

• Fractional Excretion of uric acid >10%

• Uric Acid < 4 mg/dl (low BUN)

• Worsening hyponatremia with Normal Saline

• Plasma vasopressin level inappropriate relative to serum osmolality

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 SIADH• Tumors:

• Pulmonary/mediastinal

• Small Cell Lung CA

• Pancreatic CA

• Leukemia

• CNS disorders:• Mass lesions

• Inflammation

• Gullian-Barre

• Delirium Tremens

• ICH

• Trauma

• Drugs:• Ecstasy (MDMA)

• Oxytocin

• Acei

• SSRI

• Opioids

• Amiodarone

• Pulmonary Disease:• Infection

• COPD

• Others:• AIDS/HIV

Summary of Hypotonic Hyponatremia

Hypervolemia Euvolemia Hypovolemia

Heart Failure SIADH Thiazide diuretics

Cirrhosis Adrenal Insufficiency(Glucocorticoid def)

Cerebral salt wasting

Nephrotic Syndrome Hypothyroidism Mineralocortcoid def

Renal “Failure” Primary Polydipsia Slat-wasting nephropathy

Pregnancy Glucosuria

Sepsis Third space losses

Sweat Losses

Diagnosis

Hypertonic Hyponatremia

IsontonicHponatremia

HypotonicHyponatremia

Serum Osmo:>295 msmo/kg

Serum Osmo:275-295 msmo/kg

Serum Osmo:<275 msmo/kg

HyperglycemiaMannitolGlycine

PseudohyponatremiaParaproteinsHyperlipidemia

HypervolemiaEuvolemiaHypovolemia

Summary of Serum Osmolality

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:• Marathons

• Triathlons

• Ultradistance

• Military Operations

Exercise Associated Hyponatremia

• Risk Factors:

• High fluid intake during and after

• Athletic Drinks DO NOT reduce risk

• All re hypotonic compared to Plasma Osmo

• Minimal Weight loss/Weight gain during activity

• Longer race time (~ 5 h 10 min)*

• Low BMI

• Female Gender*

• Less Experinced Runners

• NSAIDs*

• High sodium sweat concentration

• Heat acclimation can reduce Na in sweat

Exercise Associated Hyponatremia

• Water Loading alone?

• Need ADH surge

• Possible eitologies on increased ADH:

• Nausea and/or vomiting

• 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

• Desmopressin

• Mood Disorder drugs:

• TCA(s)

• SSRI(s)• Especially Venlafaxine (Effexor)

Drug Induced Hyponatremia

• Vasopressin Analogs (continued):

• Antiepileptic Drugs• Carbamazepine

• Lamotrigine

• Nicotine

• Narcotics

Drug Induced Hyponatremia

• Drugs that potentiate renal vasopressin

• NSAIDs

• Tylenol

• Cyclosphosphamide

• Unknown Mechanism

• Ectasy

• Haloperidol

• Amitriptiline

“Beer” Potomania

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

• Can be explained by electrolyte-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:

• Seizure

• Coma

• Herniation

• Respiratory Distress/Depression

• Death

ICU and In-Hospital Mortality

Treatment

• Symptoms of Chronic Hyponatremia: (can very subtle)

• Confusion

• Ataxia/Gait disturbances

• Increase in Falls

• Muscle Cramps and weakness

• Decrease in mental acuity

• Nausea and Vomiting

Treatment

• Risk Factors for Neurologic Sequela

• Marathon Runners

• Children → due to brain size

• Hypoxic Patients

• Elderly on HCTZ

• Postoperative menstrating females → estrogen

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 Furosemide

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 electrolytes renally or extrarenally

Treatment

• Complication of Rapid Correction: Osmotic DemyelinationSyndrome (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• Taurine

• Glycine

• GABA

Treatment

• Risk Factors for Osmotic DemyelinationSyndrome

• Chronic Hyponatremia

• Alcoholism

• Malnutrition

• 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 – stress & 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

• Demeclocycline

• 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 → Conivaptan

• Blocks V1a and V2

• Due to drug-drug interactions, use for short term

• CI → hypovolemia and Cirrhosis

• Selective → Tolvaptan

• Blocks V2

• Good for CHF and Chronic Hyponatremia

Summary of Treatment

EUVOLEMIC HYPERVOLEMIC HYPOVOLEMIC

Minimal Symptoms Fluid restriction, vaptan or urea

Fluid restriction, vaptan or urea

Saline +/- fludocortisone

Moderate Symptoms Vaptan or Urea +/- fluid restriction/diuretics

Vaptan or Urea +/- fluid restriction/diuretics

Saline +/- fludocortisone

Severe Symptoms Hypertonic NaCl Hypertonic NaCl (Not Ideal)

Hypertonic NaCl

** In the Field: 3% saline 100 ml over 10 min repeat x2In 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

Hypotonic Hyponatremia

Summary

The End

Questions?

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