A New Perspective on Hypernatremia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrology

Steve Chen

Na

SodiumSodium

Reference Range:136 – 145 meq/L

SodiumSodium

Hypernatremia is Na+ > 145 meq/L

Pathophysiology(1)Pathophysiology(1)

– AVP is synthesized and stimulated in AVP is synthesized and stimulated in osmoreceptors of specialized neurons whose osmoreceptors of specialized neurons whose cell bodies are located in the cell bodies are located in the supraoptic and supraoptic and paraventricularparaventricular nuclei of the hypothalamus nuclei of the hypothalamus when the plasma osmolality reaches a certain when the plasma osmolality reaches a certain threshold (approximately 280 mOsm/kg)threshold (approximately 280 mOsm/kg)

– Thirst is thought to be mediated by Thirst is thought to be mediated by osmoreceptors located in the osmoreceptors located in the anteroventral anteroventral hypothalamushypothalamus. The osmotic thirst threshold . The osmotic thirst threshold averages approximately 288-295 mOsm/kgaverages approximately 288-295 mOsm/kg

Pathophysiology(2)Pathophysiology(2)

– Hypernatremia is usually a “water Hypernatremia is usually a “water problem,” not a problem of sodium problem,” not a problem of sodium homeostasishomeostasis

Norma renal response to ADHNorma renal response to ADH V2 receptor V2 receptor – Conservation of free water via water channel Conservation of free water via water channel

( ( Aquaporin 2Aquaporin 2 ) )– ↓↓ Urine output with osmolality > 1000 mosm/kgUrine output with osmolality > 1000 mosm/kg

Failure of ADH responseFailure of ADH response– Inability to excrete NaInability to excrete Na++ properly properly– Urine osmolality 200-300 mosm/kgUrine osmolality 200-300 mosm/kg– Urinary NaUrinary Na++ 60-100 meq/kg 60-100 meq/kg

Blood pressure decreases of 20-30% result in AVP↑ and thirst

Pathophysiology(3)Pathophysiology(3)

– Rapid hypertonicity Rapid hypertonicity Loss of 10% of body weight Loss of 10% of body weight

– “ “Doughy” skin turgorDoughy” skin turgor CNS cellular dehydrationCNS cellular dehydration

– Hemorrhage: Hemorrhage: ICH/SAHICH/SAH– Tearing of cerebral blood vessels, then 2° brain Tearing of cerebral blood vessels, then 2° brain

shrinkageshrinkage– Gradual hypertonicityGradual hypertonicity

Idiogenic osmoles prevent brain shrinkageIdiogenic osmoles prevent brain shrinkage

Clinical courseClinical course The overall incidence of hospitalized patients The overall incidence of hospitalized patients

with hypernatremia ranges from with hypernatremia ranges from 0.3-5.5%0.3-5.5% Higher prevalences of Higher prevalences of 9-26%9-26% are seen in are seen in

critically ill patients, in whom major risk factors critically ill patients, in whom major risk factors for hypernatremia include mechanical for hypernatremia include mechanical ventilation, coma, and sedation ventilation, coma, and sedation

The groups most commonly affected by The groups most commonly affected by hypernatremia are hypernatremia are elderlyelderly people and people and childrenchildren

Mortality rates of Mortality rates of 30-48%30-48% have been shown in have been shown in patients in ICUs who have serum sodium levels patients in ICUs who have serum sodium levels exceeding 150 mmol/Lexceeding 150 mmol/L

Symptoms & Signs Symptoms & Signs

Clinical Features: mainly CNSClinical Features: mainly CNS– Acute symptoms at Acute symptoms at NaNa++ > 158 meq/L > 158 meq/L

OsmolOsmol– Restless, irritabilityRestless, irritability 350-375350-375– Tremulousness, ataxiaTremulousness, ataxia 375-400375-400– Hyperreflexia, twitching, spasticityHyperreflexia, twitching, spasticity

400-430400-430– Seizures and deathSeizures and death > 430> 430

TypesTypes of Hypernatremia of HypernatremiaHypernatremia with low body sodium

content: Hypotonic fluid deficits (loss of water and electrolytes)

Hypernatremia with normal body sodium content:

Nearly pure-water deficitsHypernatremia and increased body

sodium content: Hypertonic sodium gain (gain of electrolytes > water)

Hypernatremia with Hypernatremia with lowlow total total body sodium contentbody sodium content

Water loss in excess of sodium lossRenal: Diuretic drugs (loop and thiazide diuretics) Osmotic diuresis (hyperglycemia, mannitol, urea [high-protein tube feeding]) Post-obstructive diuresis Diuretic phase of acute tubular necrosis Non-renal: GI - Vomiting, diarrhea, lactulose, cathartics, NG suction, GI fluid drains, and fistulas Skin - Sweating (extreme sports, marathon runs), burn injuries

Hypernatremia with Hypernatremia with normalnormal total total body sodium content:body sodium content: water intake < water intake <

insensible lossinsensible loss Lack of access to water

( incarceration, restraints, intubation, immobilization) Altered mental status : medications, disease Neurologic disease: dementia, impaired motor function Abnormal thirst:

Geriatric hypodipsia Osmoreceptor dysfunction (reset of the osmotic threshold) Injury to the thirst centers in hypothalamus: metastasis/granulomatous diseases/vascular abnormalities/trauma Autoantibodies to the sodium-level sensor in the brain 

Loss of water through the respiratory tract

Hypernatremia with Hypernatremia with normalnormal total total body sodium content:body sodium content: Vasopressin (AVP) Vasopressin (AVP)

deficiency (CDI)deficiency (CDI)

Pituitary injury - Posttraumatic, neurosurgical, hemorrhage, ischemia (Sheehan’s), idiopathic-autoimmune, lymphocytic hypophysitis, IgG4-related disease

Tumors - Craniopharyngioma, pinealoma, meningioma, germinoma, lymphoma, metastatic disease, cysts

Aneurysms - Particularly anterior communicating Inflammatory states and granulomatous disease - Acute

meningitis/encephalitis, Langerhans cell histiocytosis, neurosarcoidosis, tuberculosis

Drugs - Ethanol (transient), phenytoin Genetic - Neurophysin II ( AVP carrier protein) gene defect

Hypernatremia with Hypernatremia with normalnormal total total body sodium content:body sodium content: Vasopressin (AVP) Vasopressin (AVP)

hyporesponsive (NDI)hyporesponsive (NDI) Genetic - V2-receptor defects, aquaporin defects (AQP2 and AQP1); 90%

byAVPR2 mutations (X-liked recessive), AQP2 gene mutation Structural - Urinary tract obstruction, papillary necrosis, sickle-cell nephropathy

Tubulointerstitial disease - Medullary cystic disease, polycystic kidney disease, nephrocalcinosis, Sjögren’s syndrome, lupus, analgesic-abuse nephropathy, sarcoidosis, M-protein disease, cystinosis, nephronophthisis

Others - Distal renal tubular acidosis, Bartter syndrome, apparent mineralocorticoid excess 

Electrolyte disorders - Hypercalcemia, hypokalemia Any prolonged state of severe polyuria - By washing out the renal

medullary and by down-regulating kidney AQP2 water channels (partial DI)

Hypernatremia with Hypernatremia with normalnormal total total body sodium content:body sodium content: Drug related Drug related NDINDI

Lithium (40% of patients)Amphotericin BDemeclocyclineDopamineOfloxacinOrlistatIfosfamide

Hypernatremia with Hypernatremia with normalnormal total total body sodium content:body sodium content: Possible drug related Possible drug related

NDINDI

Contrast agents Cyclophosphamide Cidofovir Ethanol Foscarnet Indinavir Libenzapril Mesalazine Methoxyflurane Pimozide Rifampin Streptozocin Tenofir Triamterene hydrochoride Cholchicine

Hypernatremia and Hypernatremia and increasedincreased total body sodium contenttotal body sodium content

Following administration of large quantities of hypertonic saline solutions

Iatrogenic Na administration: FFP, NaHCO3… Sea water intake Mineralocorticoid or glucocorticoid excess

Sodium modeling in hemodialysis Hypertonic alimentation solutions

Flow chart of DDFlow chart of DD ECF volume Increased Hypertonic Na

Not increased

Minimun volume of maximum concentrated urine

Yes

Extra-renal Insensible water loss GI

No Urine osmole excretion rate > 750 mosmol/day

Osmotic diureticDiuretics

YesNo

Renal response to DDAVP Urine osmolality ↑

CDIYes

No

NDI

Hypernatremia + HypovolemiaHypernatremia + HypovolemiaA hypertonic urine with a UNa+ < 10 mEq/L

Extra-renal fluid losses (GI, dermal)

An isotonic or hypotonic urine with a UNa+ >20 mEq/L Renal fluid loss (diuretics, osmotic diuresis, intrinsic renal disease)

Hypernatremia + HypovolemiaHypernatremia + Hypovolemia Pure-water losses Urine osmolality normally should be maximally

concentrated (>800 mOsm/kg H2 O) (the maximum Uosm in an elderly patient may be only 500-700 mOsm/kg)

Non-renal causes with appropriately high urine osmolality - Isolated hypodipsia, increased insensible losses

Renal water loss indicated by inappropriately low urine osmolality - Diabetes insipidus (DI): often U osm < 300 mOsm/kg H 2 O [central, nephrogenic, partial, gestational DI]

Diabetes insipidus (DI)Diabetes insipidus (DI) First obtain a plasma AVP level  Determine the response of the urine osmolality to a dose

of AVP (or preferably, the V2-receptor agonist DDAVP) An increase in urine osmolality of greater than 50%

reliably indicates central diabetes insipidus An increase of less than 10% indicates nephrogenic

diabetes insipidus Responses between 10% and 50% are indeterminate If the patient has polyuria without hypernatremia and will be evaluated for

diabetes insipidus, the plasma sodium has to be above 145 mOsm/kg H2 O prior to testing (via water deprivation test, hypertonic saline)

Hypernatremia lab studies Hypernatremia lab studies Serum electrolytes (Na +, K +, Ca 2 +)Glucose levelUreaCreatinineUrine electrolytes (Na +, K +)Urine and plasma osmolality24-hour urine volumePlasma AVP level (if indicated)

Hypernatremia Hypernatremia Q1: What is the ECF volume?

A gain of Na is rarely the sole cause of hypernnatremia

Q2: Has the body weight changed? Water shift (transient) during extreme exercise or seizures because of increased intracellular osmoles : 10-15meq/L

Q3: Is the thirst response to hypernatremia normal? ↑1% Na is powerful urge to drink ﹝ ﹞

Q4: Is the renal response to hypernatremia normal? Urine osmolarity > 1000mOsm/KgH2O Urine volume < 20mL/H unless there is a high rate of excretion of effective osmoles

Free-water clearance (cHFree-water clearance (cH22 O) O)cH2 O = Vurine [1-(UOsm/SOsm)] This includes all osmoles, including urea, which

does not contribute to the plasma tonicity because it freely equilibrates across cell membranes

To more accurately assess the effect of the urine output on osmoregulation, calculate the electrolyte–free-water clearance (cH2Oe), to estimate the ongoing renal losses of hypotonic fluid

cH2 Oe = Vurine [1-(UNa +UK)/SNa])

Goals of therapyGoals of therapy

To correct water deficit

To stop ongoing water loss

Principles of therapyPrinciples of therapyCorrection should be done over

48 to 72 hours

Hypotonic solution like 5% dextrose

Plasma Na should be lowered by 0.5 meq/L/hr or not more than 12meq/L/ 24 hrs

Total Water Deficit = A+B+CTotal Water Deficit = A+B+CIf it results only from water loss, then Current

total body osmoles = Normal total body osmoles CBWa x plasma Na = NBWa x 140 ﹝ ﹞Water deficit (A)

= NBWa - CBW a = CBWa x

plasma Na /140- 1﹛ ﹝ ﹞ ﹜ Estimated insensible loss (B) = 30-50ml/HRenal water loss, ongoing (C)

CBW = weight (kg) x correction CBW = weight (kg) x correction factorfactor

Correction factors are as follows Children: 0.6 Nonelderly men: 0.6 Nonelderly women: 0.5 Elderly men: 0.5 Elderly women: 0.45

Guidelines of therapyAdministration of IV Fluids

– (Isotonic Salt ~ Free)Encourage foods: low in Na+

Push P.O. FluidsMonitor Neurological statusMonitor for Arrhythmias

PolyuriaPolyuria

Polyuria based on an unexpectedly low urine osmolality (UO)

If renal medulla is damaged, UO is close to that of plasma when ADH acts( 300mOsm/Kg)

If ADH fails, UO is below 300 mOsm/Kg

Urine Specific GravityUrine Specific Gravity

USG defined as weight of solution compared with that of an equal volume of distilled water

USG ∞ particle weight X particle number Urine osmolality ∞ particle number

Normally(neither glucose nor protein in urine), ↑SG 0.001=↑UO 30-35mosmol/Kg SG (1.010) = UO( 300-350)

Polyuria Polyuria

Polyuria as a function of osmole excretion rate= urine osmolality x urine volume (UV)

Normally, osmole excretion rate = 900mOsm/D if urine osmolality is 900, UV is 1 L

In osmotic diuresis, osmole excretion rate =1800mOsm/D , which is exogenous(Glucose) if urine osmolality is 900, UV is 2L in fact, urine osmolality is 450, UV is 4L

Polyuria Polyuria Appropriate Inappropriate

Water diuresis(Uosm<250mosmol/Kg)

IV dilutionPrimary hyperdipsia

CDINDI

Solute diuresis(Uosm>300mosmol/Kg)

Saline loadingPost-obstructive

HyperglycemiaHigh-protein tube feedingNa-wasting nephropathy

Urine osmolatity (mosmol/Kg)

Clinical settings Response to ADH

<300 CDINDI

+--

300 to 800 Osmotic diuresisCDI, partialNDI, partialVolume depletion in CDI

--+--+

>800 Non-renal water loss primary hypodipsia Na overload

----

Variable Essential hypernatremia

Variable

Hypernatremia-Na gainHypernatremia-Na gain

Half normal saline in lithium-induced NDI Normal saline in glucose-induced osmotic diuresis

Hypertonic NaHCO3 in cardiac arrest Dialysis error( hypertonic dialysate) Salt poisoning in infants Ingestion of sea water FFP plus Lasix in burned patients Combination of above and thirst center defect

Reset HyponatremiaReset Hyponatremia Normal osmoreceptor response to change in

plasma osmolarity Osmoreceptor dysfunction (reset of the osmotic

threshold) in thirst center plasma Na 125﹝ ﹞ ～ 130meq/L

Clinical settings: Hypovolemic states: baroreceptor stimulus Quadriplegia: ↓ effective volume Psychosis Defective cellular metabolism: TB meningitis Pregnancy: hCG

Reset Hypernatremia Reset Hypernatremia Inhibition of ADH release and excretion of a dilute

urine after water loading Stimulation of ADH release and excretion of a

concentrated urine after water deprivation Maintenance of new normal plasma Na within ﹝ ﹞

narrow limits(±1-2%): 140±2.8meq/L( 137 ～ 143) Clinical setting: Primary hyper-aldosteronism reset

Na > 145meq/L﹝ ﹞ , restored by hormone manipulation or lowering the effective volume with diuretic

Essential hypernatremiaEssential hypernatremiaPrimary hypo-dipsia (thirst center defect)

plus inhibition of ADH (osmoreceptor defect) New normal plasma Na : wide variation ﹝ ﹞

between 150 and 180meq/LOsmoreceptor relatively insensitive

rather than being reset at a higher level; selectively damaged ; normal response to volume

Chlorpropamide: ↑ ADH effect

SIADH: drug related SIADH: drug related ADH ↑ ADH ↑ADH preparations:

DAVdP(Desmopressin), Aqueous vasopressin, Lysine-vasopressin in nasal spray, Vasopressin tannate in oil

Potentiate ADH effect Chlopropamide, Cabamazepine, NSAIDs

Increase ADH secretion Clofibrate

Drug not requiring ADH Thiazide ± Amiloride

IgG4-related diseaseIgG4-related disease Systemic inflammatory disorders include diffuse

inflammatory changes or pseudotumors of involved organs

Infiltration of T-cells and IgG4 plasma cells + a storiform pattern of fibrosis and obliterative venous vascular changes

Autoimmune pancreatitis and IgG4 cholangiopathy are the most common disorders

Others: sialadenitis, lacrimal gland disease, retroperitoneal fibrosis, inflammatory pseudotumors of the liver, interstitial lung disease, generalized lymphadenopathy of the abdomen, retro-orbital fibrosis, and prostate and thyroid fibrosing disorders