This document discusses hypernatremia, including its pathophysiology, clinical presentation, evaluation, and treatment. It notes that hypernatremia is usually a water problem caused by inadequate water intake or excessive water loss. The pathophysiology involves vasopressin and thirst responses. Causes include diabetes insipidus, diuretic use, gastrointestinal losses, and others. Evaluation involves assessing sodium and osmolality levels along with urine studies. Treatment goals are to correct water deficit and stop ongoing losses, usually through slow correction with hypotonic fluids and encouraging water intake.

1. A New Perspective
on Hypernatremia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrology
Steve Chen
Na

2. SodiumSodium
Reference Range:
136 – 145 meq/L

3. SodiumSodium
Hypernatremia is Na+
> 145 meq/L

4. Pathophysiology(1)Pathophysiology(1)
– AVP is synthesized and stimulated inAVP is synthesized and stimulated in
osmoreceptors of specialized neurons whoseosmoreceptors of specialized neurons whose
cell bodies are located in thecell bodies are located in the supraoptic andsupraoptic and
paraventricularparaventricular nuclei of the hypothalamusnuclei of the hypothalamus
when the plasma osmolality reaches a certainwhen the plasma osmolality reaches a certain
threshold (approximately 280 mOsm/kg)threshold (approximately 280 mOsm/kg)
– Thirst is thought to be mediated byThirst is thought to be mediated by
osmoreceptors located in theosmoreceptors located in the anteroventralanteroventral
hypothalamushypothalamus. The osmotic thirst threshold. The osmotic thirst threshold
averages approximately 288-295 mOsm/kgaverages approximately 288-295 mOsm/kg

5. Pathophysiology(2)Pathophysiology(2)
– Hypernatremia is usually a “water problem,”Hypernatremia is usually a “water problem,”
not a problem of sodium homeostasisnot a problem of sodium homeostasis
 Norma renal response to ADHNorma renal response to ADH V2 receptorV2 receptor
– Conservation of free water via water channelConservation 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++
properlyproperly
– Urine osmolality 200-300 mosm/kgUrine osmolality 200-300 mosm/kg
– Urinary NaUrinary Na++
60-100 meq/kg60-100 meq/kg
Blood pressure decreases of 20-30% result in AVP↑ and thirst

6. Pathophysiology(3)Pathophysiology(3)
– Rapid hypertonicityRapid hypertonicity
 Loss of 10% of body weightLoss 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 shrinkageTearing of cerebral blood vessels, then 2° brain shrinkage
– Gradual hypertonicityGradual hypertonicity
 Idiogenic osmoles prevent brain shrinkageIdiogenic osmoles prevent brain shrinkage

8. Clinical courseClinical course
 The overall incidence of hospitalized patients withThe overall incidence of hospitalized patients with
hypernatremia ranges fromhypernatremia ranges from 0.3-5.5%0.3-5.5%
 Higher prevalences ofHigher prevalences of 9-26%9-26% are seen in critically illare seen in critically ill
patients, in whom major risk factors forpatients, in whom major risk factors for
hypernatremia include mechanical ventilation,hypernatremia include mechanical ventilation,
coma, and sedationcoma, and sedation
 The groups most commonly affected byThe groups most commonly affected by
hypernatremia arehypernatremia are elderlyelderly people andpeople and childrenchildren
 Mortality rates ofMortality rates of 30-48%30-48% have been shown inhave been shown in
patients in ICUs who have serum sodium levelspatients in ICUs who have serum sodium levels
exceeding 150 mmol/Lexceeding 150 mmol/L

9. Symptoms & SignsSymptoms & Signs
 Clinical Features: mainly CNSClinical Features: mainly CNS
– Acute symptoms atAcute 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

11. TypesTypes of Hypernatremiaof Hypernatremia
Hypernatremia with low body sodium
content:
Hypotonic fluid deficits (loss of water and electrolytes)
Hypernatremia with normal body sodium
content:
Nearly pure-water deficits
Hypernatremia and increased body sodium
content:
Hypertonic sodium gain (gain of electrolytes > water)

12. Hypernatremia withHypernatremia with lowlow total bodytotal body
sodium contentsodium content
Water loss in excess of sodium loss
Renal: 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

13. Hypernatremia withHypernatremia with normalnormal total bodytotal body
sodium content:sodium content: water intake < insensible losswater intake < insensible 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

14. Hypernatremia withHypernatremia with normalnormal total bodytotal body
sodium content:sodium content: Vasopressin (AVP) deficiency (CDI)Vasopressin (AVP) 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

15. Hypernatremia withHypernatremia with normalnormal total bodytotal body
sodium content:sodium content: Vasopressin (AVP) hyporesponsive (NDI)Vasopressin (AVP) 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)

16. Hypernatremia withHypernatremia with normalnormal total bodytotal body
sodium content:sodium content: Drug relatedDrug related NDINDI
Lithium (40% of patients)
Amphotericin B
Demeclocycline
Dopamine
Ofloxacin
Orlistat
Ifosfamide

17. Hypernatremia withHypernatremia with normalnormal total bodytotal body
sodium content:sodium content: Possible drug relatedPossible drug related NDINDI
 Contrast agents Cyclophosphamide
 Cidofovir Ethanol
 Foscarnet Indinavir
 Libenzapril Mesalazine
 Methoxyflurane Pimozide
 Rifampin Streptozocin
 Tenofir Triamterene hydrochoride
 Cholchicine

18. Hypernatremia andHypernatremia and increasedincreased totaltotal
body sodium contentbody 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

19. 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 diuretic
Diuretics
Yes
No
Renal response to
DDAVP
Urine osmolality ↑
CDI
Yes
No
NDI

20. Hypernatremia + HypovolemiaHypernatremia + Hypovolemia
A 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)

21. 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]

22. 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)

23. Hypernatremia lab studiesHypernatremia lab studies
Serum electrolytes (Na +
, K +
, Ca 2 +
)
Glucose level
Urea
Creatinine
Urine electrolytes (Na +
, K +
)
Urine and plasma osmolality
24-hour urine volume
Plasma AVP level (if indicated)

24. HypernatremiaHypernatremia
 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

25. 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])

27. Goals of therapyGoals of therapy
To correct water deficit
To stop ongoing water loss

28. Principles of therapyPrinciples of therapy
Correction 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

29. Total Water Deficit = A+B+CTotal Water Deficit = A+B+C
If 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/H
Renal water loss, ongoing (C)

30. CBW = weight (kg) x correctionCBW = 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

31. Guidelines of therapy
Administration of IV Fluids
– (Isotonic Salt ~ Free)
Encourage foods: low in Na+
Push P.O. Fluids
Monitor Neurological status
Monitor for Arrhythmias

33. 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

34. 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)

35. PolyuriaPolyuria
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

36. PolyuriaPolyuria
Appropriate Inappropriate
Water diuresis
(Uosm<250
mosmol/Kg)
IV dilution
Primary
hyperdipsia
CDI
NDI
Solute diuresis
(Uosm>300
mosmol/Kg)
Saline loading
Post-obstructive
Hyperglycemia
High-protein
tube feeding
Na-wasting
nephropathy

37. Urine osmolatity
(mosmol/Kg)
Clinical settings Response to
ADH
<300 CDI
NDI
+
--
300 to 800 Osmotic diuresis
CDI, partial
NDI, partial
Volume depletion in
CDI
--
+
--
+
>800 Non-renal water loss
primary hypodipsia
Na overload
--
--
Variable Essential
hypernatremia
Variable

39. 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

41. 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

42. Reset HypernatremiaReset 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

44. Essential hypernatremiaEssential hypernatremia
Primary hypo-dipsia (thirst center defect)
plus inhibition of ADH (osmoreceptor defect)
 New normal plasma Na : wide variation﹝ ﹞
between 150 and 180meq/L
Osmoreceptor relatively insensitive
rather than being reset at a higher level;
selectively damaged ; normal response to
volume
 Chlorpropamide: ↑ ADH effect

45. SIADH: drug relatedSIADH: 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

47. 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