Dysnatremias:Hyponatremia

A story of water and volumeElaine M. Kaptein, MD

ekaptein@usc.edu

No disclosures

OBJECTIVES

• Physiology/pathophysiology of total body water and volume

• Evaluation and treatment of hyponatremia• Challenges in assessing intravascular volume• Sodium concentrations of body fluid losses

and parenteral and enteral “fluid” inputs to estimate water and volume components

• Apply this information to the clinical setting

Regulation of Total Body Water and SodiumWATER: Antidiuretic hormone (ADH)

-Stimulates thirst and renal water reabsorption- Increased by hyperosmolality, hypothalamic

hypoperfusion, nausea, vomiting, stress and narcotics

- decreased by hyponatremia

INTRAVASCULAR VOLUME: Renin-Angiotensin-Aldosterone (RAAS)

- Stimulates sodium reabsorption by the kidney - Increased by renal hypoperfusion- Decreased by hypervolemia, ACEI, ARBs,

Spironolactone

Distribution of TBW

Proportions given for 70kg male1, may vary in illness2.

TBW = ~50% of TB Wtin women and ~60% in muscular men

1. Randall HT. Water and electrolyte balance in surgery. The Surgical Clinics of North America. 1952: 445-469.2. Randall HT. The shifts of fluid and electrolytes in shock. Annals of the New York Academy of Sciences. 1952; 55: 412-428

SODIUM POTASSIUM

Plasma

ECF

Normal conditions

MJ Kaptein, MD

Serum Sodium Concentration

Serum [Na+] = exchangeable body (sodium+potassium)

total body water= amount of sodium/volume of ECF waterNormal serum [Na+] is 140 mEq/L of serumNormal saline is 154 mEq/L of waterWHY? Only 91% of serum is water

HYPONATREMIA S[Na+]<134 mEq/L

S[Na+] can be measured by 1) Autoanalyzer for BMP or CMP - indirect2) Flame photometer for ABG or VBG – direct

QUESTION: When are the same and when are they different?

Case Presentation

• A 49 year old male presents with malaise, fatigue and bone pain.

• Na 128, K 4.4, Cl 95, CO2 28, Cr 1.3, BUN 20• Ca 10.9, Total Protein 17.1 g/dL, Albumin 4.0

g/dL, Triglycerides 60• WBCc 4.1, Hg 8.6 g/dL• Serum osmolality 285 mOsm/kg H20

(NORMAL)

ISOTONIC HYPONATREMIA

PSEUDOHYPONATREMIA =LABORATORY ARTIFACT due to HIGH

concentrations of • Lipids• ProteinsS[Na+] is underestimated by measurements that

require a specific volume of serum and serum dilution (Indirect methods).

HYPONATREMIA S[Na+]<134 mEq/L

S[Na+] can be measured by 1) Autoanalyzer for BMP or CMP - indirect2) Flame photometer for ABG or VBG - directQUESTIONS:1) Are they always the same? No. WHY?2) What is the mechanism of pseudohyponatremia?

Normal plasma

80%plasma

water

20% protein/lipid

91%plasma

water

9% protein/lipid

Hyperproteinemic/lipemic plasma

Pseudohyponatremia with flame photometry

Na 154 Na

154

Apparent concentration of Na in serum by indirect method (BMP)154 x 0.91 = 140mEq/L serum 154 x 0.8 = 123 mEq/L

S[Na+] is normal if measured directly with ion-sensitive electrodes in undiluted PLASMA in the ABG lab in the presence of excess lipids or protein.

Causes of iso-omolar isotonic hyponatremiaPSEUDOHYPONATREMIA

SETTING: • Presence of endogenous proteins or lipids that

displace serum water and cause pseudohyponatremia (laboratory artifact)

Serum is ISO-OSMOLAR and ISOTONICEXAMPLES:• Triglycerides, cholesterol and protein• Intravenous immunoglobulins• Monoclonal gammapathies

Treatment of Pseudohyponatremia

• Recognize the problem• Treat the primary disorder

Hyperosmolar ISOTONIC hyponatremiawith UREMIA

Serum osm = 2 x S[Na+] + glucose/18 + BUN/2.8Serum tonicity = 2 x S[Na+] + glucose/18

UREA:• Increases serum OSMOLALITY but NOT TONICITY• Distributed equally between ICF and ECF• Does NOT result in water shifts between ECF and ICF in steady

state, • Uremic serum is ISOTONIC but hyperosmolar.

Hyponatremia with severe renal failure is due to increased water intake with reduced water excretion by the kidney.

Dysequilibrium syndrome occurs with rapid reduction of BUN with HD • When ECF urea decreases RAPIDLY, water shifts into cells causing

cerebral edema. • Avoided by slow decrease in BUN in uremic patients

Hypertonic Hyponatremia• Glucose, Contrast (low-osmolar non-ionic is 2-3 x

serum osmolality), mannitol, maltose retention with IVIG

• Osmoles shift water from ICF to the ECF and dilutes S[Na+]

• Glucose or mannitol: 2.0 mEq/L reduction in S[Na+] for every 100 mg/dL increase in glucose or mannitol, PLUS osmotic diuresis which may increase S[Na+] due to loss of ½ NS.

Diagnostic approach to hyponatremia1. Measure serum osmolality (Freezing point depression)2. Estimate serum osmolality

– Iso-osmolar isotonic - Hyperlipidemia or hyperproteinemia– Hyperosmolar isotonic – Uremia, alcohols

with uremia, calculate TONICITY (Subtract BUN/2.8)– Hypo-osmolar hypertonic - Glucose, mannitol, contrast

correct serum [Na+] for hyperglycemia effect– Hypo-osmolar hypotonic - Excess free water

2. If hypo-osmolar and hypotonic, assess ECF and intravascular volume status

– Increased – Decreased– Euvolemic

Hypotonic Hyponatremia

• Increased total body water relative to sodium due to greater water intake than water losses

• Body fluid losses have variable [Na+] and water content

• Normal subjects can excrete 10 to 20 liters/day of water by the kidneys if

1) AVP levels can decrease to zero, 2) adequate urine osmoles (urea, sodium,

potassium) and 3) renal function is normal.

Hypotonic hyponatremia

• Intake - dextrose and water IV, oral “fluids” which have low [Na+] (Except broth, V8, tomato juice) PLUS

• Impaired urine water excretion due to excess ADH or impaired renal failure

• Nonosmotic ADH release - morphine, pain, nausea, surgery, anesthesia, pre-renal states

Case Presentation• A 37 year old female weighing 60 Kg is admitted for

elective knee surgery. Serum sodium was 141 mEq/L.• Pre-op meds included 10 mg of Valium and 6 mg of

morphine. Post-op meds included phenergan for nausea and demerol for pain. She received a total of 2400 ml of “fluids” during this time.

• She was discharged 30 hours after surgery despite some nausea.

• In the evening she was noted to have progressive confusion followed by a seizure. In the ER she was found to be comatose.

Case Presentation• On admission she was euvolemic with a serum sodium

of 106 mEq/L. • She was started on IV normal saline and 5 hours later

following a seizure, her serum sodium was 105 mEq/L. • Her urinary sodium was 110 mEq/L, and urine

potassium was 40 mEq/L. Her urine output over 5 hours was 500 mL.

• WHY did S[Na+] decrease?– High ADH PLUS isotonic and hypotonic fluid intake

• What are the consequences? Acute hyponatremia and seizures

• How should she be treated?

Cerebral edemaSeizures

Treatment of Acute Hyponatremia

• Indications for 3% Saline– Seizures and coma

• Use of lasix and replacement of ½ of urine volume with NS if euvolemic– lasix impairs renal concentrating ability

Treatment of hyponatremia: Compilation of guidelines

Based on duration and symptoms1) Acute or severely symptomatic hyponatremia

1) Bolus hypertonic saline2) Water restriction

2) Chronic or not severely symptomatic hyponatremia1) Water restriction2) Increase renal free water excretion (Different recs)

1) Vasopressin receptor antagonists – expensive and rapid effect2) Urea administration – not available3) Loop diuretics

Hypotonic HyponatremiaONSET

If correction >2 mEq/hrgive urine water losses

as D5W and/orDDAVP 2 to 4 ug IV q 8 hrs IV

Increase S[Na] by 1 mEq/L/hrfor 4 to 6 hours oruntil seizures stop

Do not increase >4-6mEq/L/24 hours

3% Saline &Lasix

ACUTE (<48 hr) orComa

Seizures

Rapid correction =Demyelination

in 2-6 days (CT/MRI)

Increase S[Na]<0.5 mEq/L/hr<6 mEq/L/24 hr

<12 mEq/L/48 hr

LasixWater restrictTreat cause

CHRONIC (>48 hr) orMinimal or

No symptoms

Sterns TH: Management of hyponatremia in the ICU Chest 2013: 144(2):672

Assess Acuity and Symptoms

HYPOTONIC HYPONATREMIA

Volume expansionRestrict free water?

GI lossRenal lossBLEEDING

Hypovolemic

Treat primary causeRestrict free water

Lasix, replace Na losses

R/O HypothyroidHypoadrenalHypopituitary

SIAD

Normovolemic

?give volumeRestrict water

Hypovolemic

Restrict water

Euvolemic

Restrict NaRestrict free water

Loop diureticsMobilize edema?

Hypervolemic

ASSESSINTRAVASCULAR

VOLUME

CHFCIRRHOSISNEPHROTIC

Hypervolemic

Q. What isECF and INTRAVASCULAR

VOLUME?

• Hospitalized and critically ill patients are frequently not in steady state.

• They frequently have mismatch• between blood pressure and intravascular volume• between extravascular and intravascular volume

• Physical exam, CVP, and PCWP have limited sensitivity and specificity to determine intravascular volume.

• We need a practical way to assess intravascular volume status to guide volume therapy.

Relative intravascular volume

Ultrasound of the inferior vena cava collapsibility index forestimation of relative intravascular volume.IVC CI = (IVCmax - IVCmin) / IVCmax x100%

Advantages of bedside IVC US

• Assessment of intravascular volume at the time of clinical evaluation to guide volume administration, diuresis or ultrafiltration

• Multiple assessments of intravascular volume as needed after therapeutic interventions or change in patient status

• No delay between need for assessment and results of IVC US

Principles for treatment of concurrent sodium and water disorders

A case of new onset hyponatremia

• A 64 year old female is admitted to ICU with a S[Na+] of 102 mEq/L. She had a S[Na+] a month earlier of 135. She was given HCTZ for treatment of calcium containing renal stones.

• She is pale with male pattern baldness. Bp90/60 HR 65, lying in bed mildly confused.

What tests would you order and how would you treat her?

Hyponatremia and Diuretics

• Thiazide diuretics - impair urine dilution and can accentuate hyponatremia without overt hypovolemia

• Loop diuretics – impair urine concentration and can cause overt hypovolemia

64 year old female

• She is given normal saline boluses• TSH 4.5 mIU/L, cortisol 3 ug/dL• What is her diagnosis?• Total and Free T4 very low• History from daughter – the last born• Traumatic delivery, no breastfeeding, no

menstruation since, loss of body hair.

Case PresentationHow should she be treated?• Normal saline until euvolemic, then replace half

of urine output with NS, measure urine [Na+]• No indication for 3% saline• Monitor serum sodium concentrations q2 hours• If rate of S[Na+] rise is too rapid, give D5W to

match ½ of urine output • Give DDAVP to slow rate of water loss in urine

64 year old female

• Diagnosis? Hypopituitarism• Treatment? Saline, L-T4, hydrocortisone 100

mg• She makes 5 to 6 liters of urine in the next 24

hours. • Our recommendation: q2 hour S[Na+] to

increase S[Na+] no more than 1.5 mEq/hour. If too rapid correction, check urine Na and match UO of H2O with D5W

64 year old female

• 24 hours later S[Na+] 127 mEq/L from 102 mEq/L because only NS given and large urinary free water excretion. Patient more alert and BP normal

• Now what?• Recommend giving free water and DDAVP to

reverse rapid correction. • No central demyelination occurred

64 year old female

Why did the S[Na+] rise so rapidly in this patient?1) Volume depletion corrected, ADH decreased

and distal water delivery increased2) T4 and cortisol increase free water clearanceLESSON: Watch patients with intravascular volume

depletion very closely to avoid too rapid S[Na+] correction and match water losses with replacement D5W or oral H2O, and give DDAVP q 8-12 hours IV if needed.

Avoid over-rapid [Na+] correction• Match urinary water losses with D5W

Measure urine [Na+]

• Administer 2 to 4 ug of parenteral DDAVP to stop water diuresis (1D)

• If [Na+] rises too rapidly, give D5W IV to decrease to the appropriate level (1D)

• Calculate free water required to maintain S[Na+] at desired level with frequent monitoring

European Journal of Endocrinology (2014) 170, G1–G47

Osmotic Demyelination Syndrome

• Occurs 2 to 6 days after rapid correction of hyponatremia

• Pontine and extrapontine myelinolysis on MRI • Slowly evolving pseudobulbar palsy and

quadriparesis, movement disorders, behavioral disturbances or seizures.

• Highest risk: S[Na+]<105 mEq/L, rapid increase in [Na+], hypokalemia, alcoholism, malnutrition, liver disease, thiazides or antidepressants.

• Potentially reversible in 1/3 over several weeks

PROBLEM

Determining ongoing water and sodium requirements in hospitalized patients remains difficult since sodium concentrations of most body fluid losses are not known and can not be routinely measured, except for urine.

Sodium concentrations of body fluids: A systematic literature

review

Kaptein EM, Sreeramoju D, Kaptein JS, Kaptein MJClinical Nephrology 2016

Mean sodium concentrations of body fluid losses

NS

Sodium concentrations of body fluid losses

Body Fluid [Na+] mEq/L Normal saline (%) Water (%)

Gastric 50 33 67

Bile 185 100 0

Pancreatic 156 100 0

Small bowel 120 75 25

DIARRHEA

cholera 128 85 15

non-osmotic laxatives 88 50 50

secretory diarrhea 53 33 67

sorbitol 63 40 60

lactulose 26 15 85

Idolax/polyethylene glycol 15 10 90

Pleural, peritoneal, dialysate, (wounds) 137 100 0

Sodium concentrations of parenteral and enteral solutions

These are pharmaceuticalsCHECK [Na+] for each solutionDivide by 154 mEq/L to assess proportion of NS and H20

Background

Proportions for a 70kg male1, may vary in illness2

1) Randall HT. Water and electrolyte balance in surgery. The Surgical Clinics of North America. 1952: 445-469.2) Randall HT. The shifts of fluid and electrolytes in shock. Annals of the New York Academy of Sciences. 1952; 55: 412-428

• RBCs stay intravascular. • Isonatremic solutions

equilibrate across the ECF (IV plus EV).

• Hypervolemia or hypovolemiareflect total body sodium excess or deficit.

• Free water (FW) equilibrates across both ECF and ICF.

• Free water gain/loss primarily affects serum [Na+].

• Hypernatremia / hyponatremiareflects free water deficit or excess.

MJ Kaptein, MD

Water is NOT volume

Proportions for a 70kg male, may vary in illness

3) Konstam MA, Gheorghiade M, Burnett JC, Jr., Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C: Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The everest outcome trial. JAMA 2007;297:1319-13312007;297:1319-1331

• EVEREST trial using a vaptan to block renal ADH effect showed 4.5 liter aquaresis did not change CHF morbidity or mortality3, suggesting free water has minimal volume effect.

• Hyponatremia was improved.• Conclusion: water is not volume• [Na+] of all fluids lost and gained

can be divided by [Na+] of plasma water (normally 154 mEq/L) to determine what proportion will distribute as isonatremic solution.

MJ Kaptein, MD

ENTRIES IN YELLOW AREAS gain/loss NS (mL) gain/loss H2O (mL)

ONLY (as positive values) [Na+] (mEq/L) NET (mL) 0 0BODY FLUID LOSTGastric 49.0Bile 185Pancreatic 156Small bowel 117Diarrhea - non-osmotic 69.0Osmotic diarrhea - sorbitol 63.0Osmotic diarrhea - lactulose 26.0Osmotic diarrhea - PEG 13.0Pleural/peritoneal fluid 137Dialysis Ultrafiltrate 134UrineInsensible losses 0.0PARENTERAL SOLUTIONSPRBCs 370Plasma/cryo/platelets 1305% / 25% albumin 130Normal saline 154½ Normal saline 77.0Plasma-lyte A 140Ringer's lactate 130D5W 0.0NaHCO3 concentrate 1000100 mEq NaHCO3 in 1L D5W 100TPNENTERAL SOLUTIONSPulmocare 57.0Nutren 2.0 56.5Fibersource HN 52.2Impact Peptide1.5 50.9Nutren Pulmonary 50.8Isosource HN 48.7Diabetisource AC 46.1Novasource Renal 41.1Osmolyte 40.4Jevity 40.0Replete Fiber 38.1

Case 1

• 65 year old male with CHF and hyponatremia• On a vaptan, no diuretic, and a 2 g/d sodium diet

and “fluid” restriction of 1000 mL per day.• Assuming insensible losses are 500 mL per day.• He loses 4.5 kg over 4 days• No change in CHF symptoms• Hyponatremia improved• What would his losses have been?

ENTRIES IN YELLOW gain/loss NS gain/loss H2O ONLY (as positive values) [Na+] NET (mL) -844 -3656BODY FLUID LOSTGastric 49.0Bile 185Pancreatic 156Small bowel 117Diarrhea - non-osmotic 69.0Osmotic diarrhea - sorbitol 63.0Osmotic diarrhea - lactulose 26.0Osmotic diarrhea - PEG 13.0Pleural/peritoneal fluid 137Dialysis Ultrafiltrate 134

Urine 20 6500 -844 -5656Insensible losses 0.0 2000 0 -2000PARENTERAL SOLUTIONSPRBCs/Platelets - no edema/ascites 616PRBCs/Platelets - moderate edema/ascites 1078PRBCs/Platelets - severe edema/ascites 1540Plasma/cryo 1305% / 25% albumin 130Normal saline 154½ Normal saline 77.0Plasma-lyte A 140Ringer's lactate 130

D5W / H2O 0.0 4000 0 4000NaHCO3 concentrate 1000100 mEq NaHCO3 in 1L D5W 100TPNENTERAL SOLUTIONSPulmocare 57.0Nutren 2.0 56.5Fibersource HN 52.2Impact Peptide1.5 50.9Nutren Pulmonary 50.8Isosource HN 48.7Diabetisource AC 46.1Novasource Renal 41.1Osmolyte 40.4

Case 1• 65 year old male with CHF and hyponatremia• On a vaptan, no diuretic, and a 2 g/d sodium diet and

“fluid” restriction of 1000 mL per day.• Assuming insensible losses are 500 mL per day.• He loses 4.5 kg over 4 days• No change in CHF symptoms• Hyponatremia improved• What would his losses have been?He must have had 6500 of urine output to lose 850 mL of NS and 3650 mL of water which accounts for 4.5 kg weight loss.

Case 2

• A patient with severe CHF is receiving CRRT with total inputs of 4700 mL equaling 3200 mL water and 1500 mL NS and outputs of 4700 mL by UF from the 24 hours prior.

• Total Inputs and Outputs are “even”• Is this patient “Net even” for volume and

water?

ENTRIES IN YELLOW NET gain/loss NS gain/loss H2O ONLY (as positive values) [Na+] (mL) -2590 +1590BODY FLUID LOSTGastric 49.0Bile 185Pancreatic 156Small bowel 117Diarrhea - non-osmotic 69.0Osmotic diarrhea - sorbitol 63.0Osmotic diarrhea - lactulose 26.0Osmotic diarrhea - PEG 13.0Pleural/peritoneal fluid 137

Dialysis Ultrafiltrate 134 4700 -4090 -610Urine

Insensible losses 0.0 1000 0 -1000PARENTERAL SOLUTIONSPRBCs/Platelets - no edema/ascites 616PRBCs/Platelets - moderate edema/ascites 1078PRBCs/Platelets - severe edema/ascites 1540Plasma/cryo 1305% / 25% albumin 130

Normal saline 154 1500 1500 0½ Normal saline 77.0Plasma-lyte A 140Ringer's lactate 130

D5W 0.0 3200 0 3200NaHCO3 concentrate 1000100 mEq NaHCO3 in 1L D5W 100TPNENTERAL SOLUTIONSPulmocare 57.0Nutren 2.0 56.5Fibersource HN 52.2Impact Peptide1.5 50.9Nutren Pulmonary 50.8Isosource HN 48.7Diabetisource AC 46.1Novasource Renal 41.1Osmolyte 40.4

Case 2

• A patient with severe CHF is receiving CRRT with total inputs 4700 mL equaling 3200 mL water and 1500 mL NS and outputs of 4700 mL by UF from the 24 hours prior.

• Total Inputs and Outputs are “even”• Is this patient “Net even” for volume and

water?• RESULT: -2590 NS and +1590 water• May result in hyponatremia.

Case 3

A 58 year old woman with CHF has been receiving a loop diuretic for 1 week. She still has 3+ edema of both legs. Her serum sodium is 125 mEq/L and she is complaining of thirst. Her serum creatinine is stable.How should she be treated?1) Continue fluid restriction2) Give 3% saline3) Give NS and free water restriction4) Give free water and sodium restriction, and continue

the loop diuretic

Case 3

A 58 year old woman with CHF has been receiving a loop diuretic for 1 week. She still has 3+ edema of both legs. Her serum sodium is 125 mEq/L and she is complaining of thirst. Her serum creatinine is stable.How should she be treated?1) Continue fluid restriction2) Give 3% saline3) Give NS and free water restriction4) Give free water and sodium restriction, and continue

the loop diuretic

Principles for treatment of concurrent sodium and water disorders

QUESTIONS?