Eric G. Neilson, MD Vice President for Medical Affairs

The Sea Within Us Hypertonicity and Hypernatremia: Pathophysiology, Diagnosis, and Treatment
Eric G. Neilson, MD Vice President for Medical Affairs Lewis Landsberg Dean Feinberg School of Medicine

Disclosures of interest
Investments in Seno Medical Instruments, Inc Royalties from Vanderbilt/Millipore

Goals of this lecture Understand the concept of tonicity in its various forms: isotonicity, hypertonicity, and hypotonicity Understand that serum sodium is a surrogate marker of tonicity Understand that hypernatremia is a fairly common electrolyte disorder in assisted living facilities, nursing homes, and the hospital Understand the composition of urine volume and the ‘electrolyte-free water clearance (CefH20) Understand that all hypernatremias reflect hypertonicity Understand that, save for hypertonic Na gain, all other hypertonic hypernatremias result from H20 deprivation in the setting of persistent H20 or hypotonic losses Understand the differential diagnosis of hypertonic hypernatremia Understand the basic strategy for initial treatment of hypertonic hypernatremia

What is tonicity? Tonicity is an old physiologic term that refers to the volume behavior of cells in a solution Hypotonic Isotonic Hypertonic Isotonicity in a cell means bathing in normal ambient plasma H20 where the Na is 137 mEq/L, the K is 4 mEq/L, the glucose is 100 mg/dL, the urea is 10 mg/dl and the osmolarity is ~285 mOsm/L 285 mOsm/L 310 mOsm/L 265 mOsm/L Peter Agre 2003 Water travels across the cell membrane using aquaporin water channels, particularly AQP1-4; AQP1 is in all cells and ADH-responsive AQP2 is found in collecting duct cells of the kidney

More on tonicity Acute changes in cell shape and size cause functional disturbances that makes patients feel sick, particularly when a change in tonicity occurs quickly. Most cells are susceptible to these changes Some cells can defend themselves from such changes better than others by adding or removing solute, particularly brain neurons Solutes that affect tonicity effect transmembrane water flow and are commonly known as effective osmols (typically Na, K, Glucose); effective osmols are trapped on one side of the cell membrane and total body H20 migrates to create a temporal equilibrium that forms the extracellular (ECF) and intracellular (ICF) fluid compartments; not all solutes are effective osmols (alcohol and urea) Na/K ATPase keeps most Na in the extracellular space and most K in the intracellular compartment Physicians use serum sodium (SNa) as a surrogate marker of tonicity

What is the difference between tonicity and serum osmolarity?
mg/dl or mg% of a solute x 10 ÷ molecular weight of the solute = mMol/L mMol/L × “n” of solute particles = mOsm/L; NaCl is two particles and CaCl2 is three mMol/L × valence of a solute = mEq/L So a serum Na of 135 mMol/L also equals 135 mOsm/L and 135 mEq/L Writing convention for cations is not to show their anions, although they are there Effective mOsms effect transmembrane water flow across this impermeable membrane Ineffective mOsms means they do not effect transmembrane water flow CM Effective mOsms Total body H20 TB Na + TB K + TB Glucose TB H20 (ECF; Na+Glucose) (ICF; K) TB H20 Tonicity = (Estimated) = = Effective + Ineffective mOsms Total body H20 TB Na + TB K + TB Glucose + Ineffective mOsms TB H20 Osmolarity = (Measured)* = *Estimated serum osmolarity = Na × 2 + glucose (mg/dL) ÷ 18 + urea (mg/dL) ÷ 2.8 + mOsms of other unmeasured particles; normal serum osmolarity = ~285 mOsms/L

ECF (TB Na + Glucose) ICF (TB K)
Na concentration Why do we measure serum Na concentration? Do a balance study; Na in versus Na out of the body Calculate an anion gap in an acid-base disorder Because it is a surrogate marker of tonicity: Hypertonicity Hypernatremia (Dehydration) -TB H2O CM Effective mOsm TB H20 ECF (TB Na + Glucose) ICF (TB K) TB H20 SNa (mEq/L) = Tonicity = = Hypotonicity Hyponatremia (H2O Intoxication) +TB H2O

Na content versus Na concentration
Total body Na contributes to the effective arterial blood volume (EABV) Arterial side = 15% of blood volume (Baroreceptor); Venus side = 85% (Capacitance) EABV = (ECF Na/H20 + Stroke Volume + Pulse + Contractility + Vascular Tone) Volume Depletion (Orthostasis) Volume Expansion (Edema) ∫ EABV Perceived EABV Baroreceptors in the carotid bodies and aortic arch sense and respond to changes in EABV associated with changes in blood pressure; may be baroreceptors in atria and liver Neurosignaling: Adrenergic hormones (norepinephrine and epinephrine) Aldosterone release ( Na reclamation; Principal Cells) Anti-diuretic hormone ( H20 reclamation; Principal Cells)

How should we think about urine volume and its role in maintaining plasma tonicity?
Urine Volume (V) = Electrolyte-Free H20 Clearance (CefH20) + Electrolyte Clearance (Ce) CefH20 Ce V Urine Free H20 fraction Electrolyte isotonic to plasma Tonicity Concept applied to urine CefH20 = V - Ce x V Urine Na (UNa) + Urine K (UK) Serum Na (SNa) Since Ce = ( ) x V UNa + UK SNa CefH20 = V - Solute Excretion (mOsm)/day Average Urine mOsm/L/day Because V ultimately = We can therefore derive the Electrolyte-Free H2O Clearance: ( ) CefH20 = UNa + UK SNa Solute Excretion (mOsm) Urine mOsm/L 1 -

What determines water reclamation?
Proximal tubule is composed of ‘leaky’-epithelial junctions and the collecting duct is composed of ‘tight’-epithelial junctions The beauty of the nephron is that it reclaims most of the filtered Na isotonically along the proximal tubule and most of the remaining Na by the time filtrate passes into the collecting duct, thus effectively separating the regulation of Na handling from H20 handling The presence or absence of ADH binding to V2 receptors (V2r) along the collecting duct then determines whether H20 is reabsorbed into the interstitium or left in the filtrate for subsequent excretion as urine. V2r activation moves cytosolic AQP2 to the apical and basal cell membranes How effective ADH is in reclaiming H20 along the collecting duct is dependent on the integrity of concentration gradient created in the medullary interstitium Aldosterone/ Spironolactone ENaC/ Amiloride Na/H Na/P04 Na/Gl NaCl Paracellular Na/K/2Cl Furosemide Na/Cl Thiazide ADH/V2r AQP2 ~1% Na Variable H20 H20 Impermeable mOsm/L 300 1200 ~50 mOsm/L

Relationship between Posm, Uosm, and ADH
Stylized relationship between Plasma Osmolality, ADH levels, and Urine Osmolality Verbalis J, Brenner & Rector, 9th edition, 2011

ADH release by osmotic and non-osmotic stimuli
OVLT ADH synthesized in the supraoptic and paraventricular nuclei of the hypothalamus is released from the posterior pituitary by signaling of: Osmoreceptors in the OVLT responding to changes in plasma tonicity, or Other neural paths to the brain from non-osmotic stimuli related to volume depletion, nausea, pain, sedation, and selected drugs

ADH release by hypertonicity or isotonic volume depletion
Dunn et al., J Clin Invest 52: , 1973 ADH release is more sensitive to small increases in plasma tonicity than small decreases in EABV, but is exponentially stronger when changes in EABV are greater. Sensitivity of ADH release to changes in plasma tonicity increases as EABV decreases.

Symptoms of hypertonic hypernatremia
Hypertonic hypernatremia is recognized as a SNa above 145 mEq/L. Most symptoms in adults become obvious as the SNa reaches 160 mEq/L. How obvious the symptoms are depends on how quickly the patient becomes hypertonic; if hypertonicity develops very slowly, there may be few classic symptoms until coma appears. Aggressive treatment is usually undertaken when patient has SNa above 155 mEq/L, regardless of symptoms, although the exact level that triggers urgent therapy typically reflects the comfort level of the treating physician. SNa 145 mEq/L Seizures Coma Somnolence Lethargy Thirstiness

Brain response to hypertonic hypernatremia
(SNa falls ≤8 mEq/L/day) (SNa falls ≥8 mEq/L/day) Water

Factoids regarding hypertonic hypernatremia
Seven key points: Hypertonicity produces cellular dehydration, unlike isotonic volume depletion. The reduction of TBW from Na loss to recognizable volume depletion ( EABV) in a 70 Kg person is 3.5 L (~5% TBW, all from the ECF) compared to the equivalent loss of 10 L of TBW from hypertonic dehydration across both ICF and ECF;10 L reduction in TBW would produce a SNa of 173 mEq/L, which is a medical emergency. Thus, most dehydration by itself rarely produces recognizable volume depletion. Volume depletion or decreased renal solute load impairs a H20 diuresis in the absence of ADH. Save for exposure to acute hypertonic salt resulting in a dampening shift of TBW from ICF to ECF, hypertonicity is always associated with some reduction in TBW. There are only two ways to develop hypertonic hypernatremia (dehydration); you must receive hypertonic salt, or suffer persistent H20 losses not replaced by intake. When you see persistent hypertonic hypernatremia you know that absent thirst or patient access to H20 is also a problem. Hypertonicity is mostly seen in the elderly, infirm, infants, and those intubated.

Diagnosis of hypertonic hypernatremia
Polyuric ( CefH20) Hypodipsia Fever Sweating Vomiting Diarrhea Cathartics Non-Polyuric ( CefH20) Hypertonic Na Gain Drinking Sea Water Hypertonic Feeding Hypertonic Enemas Receiving 3% NaCl Receiving NaH2C03 1o Aldosteronism Edema Solute Diuresis Pure H20 Diuresis Glucose Mannitol Urea Diuretics NaCl NaH2C03 Central Diabetes Insipidus Alcohol Pituitary Tumors Post-Surgery Trauma Cysts Granulomatosis Pregnancy Meningoencephalitis Genetic Mutations -ADH Nephrogenic Diabetes Insipidus Hypercalcemia Hypokalemia Renal Disease -MCD -SCD Drugs -Lithium -V2RA -Methoxyflurane -Amphotericin B Genetic Mutations -V2R (x-linked) -AQP2 (AD)

Mechanism of acute hypertonic Na gain
Normal Conditions Hypertonic Na Gain Drinking Sea Water Hypertonic Feeding Hypertonic Enemas Receiving 3% NaCl Receiving NaH2C03 1o Aldosteronism ECF ICF Acute exposure to hypertonic Na solutions will result in a shift in TBW from ICF to ECF, resulting in brain shrinkage, cerebral blood vessel tears, limbic demyelination, elevation of EABV, and acute pulmonary edema.

Mechanisms of non-polyuric hypertonic hypernatremia
Primary hypodipsia is a rare genetic variant because it reduces genetic fitness; hypodipsia in adults is typically seen in the infirm elderly who have diminished thirst and don’t have access to H20. Insensible daily losses are ~500 ml/day/m2 or 800 ml/day for a 70 Kg person of which 60% is through the skin and 40% through respiration. Fever and sweating produce greater hypotonic losses of about L/day including ~20 mEq/L of Na and ~10 mEq/L of K. Gastrointestinal losses from vomiting or osmotic diarrhea are hypotonic (secretory diarrhea not so much; they tend to produce an isotonic loss that doesn’t result in hypertonicity). Failure to replace H20 (and in some cases Na) will leave the patient dehydrated and/or volume depleted. Expected increases in ADH produces some degree of oliguria ( CefH20) depending on renal solute load. Hypodipsia Fever Sweating Vomiting Diarrhea Cathartics Non-Polyuric ( CefH20) Edema

Urine volume and polyuria
There is no such thing as a normal urine volume; urine volume is simply the amount required to excrete a solute load created by diet and metabolism If most of the population excretes a urine volume around 1.5 – 2.5 L/day, then clinical convention suggests greater than 3 L/day of urine probably reflects polyuria 100 Calories on an average diet/day = ~20 mOsm/day of renal solute load; 3,000 Calories = 600 mosm/day 10 grams of protein/day = ~50 mOsm of urea/day in renal solute load; ~100 grams of Protein = 600 mOsm/day Raman Am J Physiol (Renal) 286: F394-F401, 2004 Urine V = Solute Excretion (mOsms)/day Average Urine mOsms/L/day 600 mOsms/day 300 mOsms/L = 2 L Urine volume on average diet; because the urine mOsms/L/day are not fixed, the urine volume is more flexible when it has to be to excrete H20 600 mOsms/day 70 mOsms/L = 8.6 L Urine volume on an average diet after persistent inhibition of ADH (central) or tubular unresponsiveness to ADH (nephrogenic)

Polyuric ( CefH20) Hypodipsia Fever Sweating Vomiting Diarrhea Cathartics Non-Polyuric ( CefH20) Hypertonic Na Gain Drinking Sea Water Hypertonic Feeding Hypertonic Enemas Receiving 3% NaCl Receiving NaH2C03 1o Aldosteronism Edema Solute Diuresis Glucose Mannitol Urea Diuretics NaCl NaH2C03 Pure H20 Diuresis Central Diabetes Insipidus Alcohol Pituitary Tumors Post-Surgery Trauma Cysts Granulomatosis Pregnancy Meningoencephalitis Genetic Mutations -ADH Nephrogenic Diabetes Insipidus Hypercalcemia Hypokalemia Renal Disease -MCD -SCD Drugs -Lithium -V2RA -Methoxyflurane -Amphotericin B Genetic Mutations -V2R (x-linked) -AQP2 (AD)

Solute versus water diuresis
A pure water diuresis produces an urine osmolarity of ~200 mOsm/L; often it is in the range of mOsms/L because as urine flow rate increases there is less tubular time to remove solutes, including NaCl. A solute diuresis produces an urine osmolarity of ~ mOsm/L because as urine flow rate increases there is less tubular time to remove H20. Such urine losses are relatively H20 rich leaving the residual TBW hypertonic; mostly seen in the elderly, infants, the intubated and the infirm. Solute Diuresis URINE FLOW RATE ml/min Water Diuresis

Mechanism of solute diuresis
In the case of glycosuria from diabetes, glucose filtration exceeding its proximal Tm and more H20 stays in the tubular fluid to hydrate residual glucose. This additional tubular H20 reduces the Na concentration which reduces its effective transport out of the tubule beginning in the ascending limb of Henle through to the principal cells expressing ENaCs along the collecting duct. Tubular fluid flow rate (polyuria) and solute load increases such that it washes out the interstitial gradient. The Na uptake by ENaC produces relative electronegativity which facilitates K loss, particularly if the polyuria persists. The hypotonic loss of renal H20 raises the tonicity of the residual TBW, and thirst ensues. If access to H20 is restricted, hypernatremia worsens. Aldosterone: ENaC Na/K ATPase Na/H Na/P04 Na/Gl NaCl Paracellular Na/K/2Cl Na/Cl ADH/V2r AQP2 H20 Impermeable mOsm/L 300 1200 ~50 mOsm/L

Mechanisms of central diabetes inspidus
Dose effect of reducing the number or functionality of ADH-producing neurons on urine osmolality Central Diabetes Insipidus Alcohol Pituitary Tumors Post-Surgery Trauma Cysts Granulomatosis Pregnancy Meningoencephalitis Genetic Mutations -ADH

Triphasic pattern of diabetes insipidus after pituitary surgery
Loh and Verbalis NCP Endocrinol Metabolism 3: , 2007

Mechanism of nephrogenic diabetes insipidus
Aldosterone: ENaC Na/K ATPase Na/H Na/P04 Na/Gl NaCl Paracellular Na/K/2Cl Na/Cl ADH/V2r AQP2 H20 Impermeable mOsm/L 300 1200 ~50 mOsm/L Nephrogenic Diabetes Insipidus Hypercalcemia Hypokalemia Renal Disease -MCD -SCD Drugs -Lithium -V2RA -Methoxyflurane -Amphotericin B Genetic Mutations -V2R (x-linked) -AQP2 (AD)

H20 deprivation test in the setting of polyuria (Central diabetes insipidus, nephrogenic diabetes inspidus, and polydipsia) If SNa is >145 mEq/L and/or the Uosm is > than the Posm, primary polydipsia can be excluded Start the test in the morning after 2-3 hours of fasting. Measure UV, Uosm, and weight every hour, and SNa and Posm every 2 hours. Continue the test until either 1) the Uosm >600 mOsm/L, 2) the Uosm is stable on 2-3 hourly measurements despite a rising Posm, or 3) the Posm >295 or the SNa >145 mEq/L. When either conditions 2 or 3 above are met, give dose of 4 mcg of desmopressin intravenously and follow UV and Uosm every 30 minutes for two hours. Type of diabetes insipidus Response to desmopressin Central diabetes insipidus Uosm rises >100% Partial central diabetes inspidus Uosm rises 15-50% (>300 mOsm) Nephrogenic diabetes inspidus No increase in Uosm Partial nephrogenic diabetes inspidus Small rise in Uosm (<300 mOsm)

How to treat hypertonic hypernatremia
Acute Na intoxication with neurologic symptoms requires administration of H20 as D5W; if the exposure is within 24 hours then the goal is to correct SNa to 145 mEq/L to minimize risk of cerebral shrinkage and limbic demyelination; if the exposure is longer than 48 hour, the SNa should not fall faster than 8 mEq/L/day to avoid cerebral edema. If there is pulmonary edema, diuretics should be used. Estimation of the target water deficit: current TBW x ( SNa ÷ 140 – 1); TBW in men is 0.6 lean body weight (kg), 0.5 in women, and 0.45 in the elderly. Correction of SNa for a high serum glucose = SNa + [(Glucose – 100 ÷ 100) x 2 mEq/L] If the hypernatremia is the result of sweating, gastrointestinal losses, or solute diuresis, then there has been some Na and K loss that should be replaced, along with the H20, using 0.9% or 0.45% saline with potassium. Rate of fall in SNa from a 1L infusion can be determined by the formula: (infused Na + infused K) – SNa ÷ TBW + 1 L. Will need to add H20 for estimated insensible losses and concurrent renal H20 losses while treating the hypernatremia can be estimated using the formula for CefH20. Central DI is treated acutely with 2 mcg desmopressin intravenously every 12 hours, and when the polyuria resolves and the patient is able, the patient can be switched to intranasal desmopressin. Nephrogenic DI can be partially treated with a combination of low Na/low protein diet, thiazide diuretics, and NSAIDs. X-linked V2r experimentally treated with vaptans.

Tonicity treatment in hypertonic hypernatremia

Initial fluid treatment for hypernatremia
70 Kg elderly man with chronic dementia suffered a seizure at his nursing home. In the ER he was found to have a BP = 120/80, Glucose = 97 mg%, SNa = 168 mEq/L, K = 2.8 mEq/L, Uosm = 153 mOsm, and a pituitary mass. SNa 140 Water Deficit (L) = Current TBW x ( - 1) 168 140 Water Deficit (L) = (70 x 0.5) x ( - 1) = 7 L (infused Na + infused K) - SNa TB H20 + 1 Change in SNa (mEq/L) = Change in SNa (mEq/L) = = -3.5 mEq/L (0 + 40) – 168 35 + 1 Change in SNa is = -3.5 mEq/L after administration of 1 L of D5W; So, initially give 2 mcg desmopressin every 12 hours, stress doses of steroids (±insulin), and 2.2 L of D5W every 24 hrs with further additions of H20 for insensible loss and CefH20 to keep the fall in SNa ~8 mEq/L/day for the next several days.

Complete fluid prescription for hypertonicity
Volume: if depleted add 0.9% saline at a safe hourly rate, if overloaded start diuretic Insensible losses: ~500 ml/day/m2 or 800 ml/day for a 70 Kg person; replace with D5W at a safe hourly rate Tonicity: (infused Na + infused K) – SNa ÷ TBW + 1 L = drop in SNa from one liter infusion; calculate the 24 hour infusion rate to drop the SNa ~8 mEq/L/day Urine loss: measure and replace lost UNa + UK and calculate CefH20 to replace urine water loss Give the H20 infusion separate from the Na

References Bhave, G & Neilson, EG: Body fluid dynamics: back to the future. J Am Soc Nephrol 22: , 2011 Sterns RH: Disorders of plasma sodium—causes, consequences, and correction. N Engl J Med 372: 55-65, 2015 George, A & Neilson, EG: Cellular and Molecular Biology of the Kidney 18th Edition, Harrison’s Principles of Internal Medicine, Chapter 277, 2012 Verbalis, JG: Disorders of water balance, Brenner & Rector’s The Kidney, 9th Edition, 2011 McManus ML, Churchwell KB, Strange K. Regulation of cell volume in health and disease. N Engl J Med 333: , 1995 Gennari FJ & Kassirer JP. Osmotic Diuresis. N Engl J Med 291: , 1974 Bhave, G & Neilson, EG, Volume depletion versus dehydration: how understanding the difference can guide therapy. Am J Kidney Dis 58: , 2011 Feig, PU & McCurdy DK. The hypertonic state. N Engl J Med 297: , 1977 Adrogue, HJ & Madias, NE: Hypernatremia. N Engl J Med 342: , 2000

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