Hyponatremia

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Why hyponatremia important ?

Common electrolyte abnormality- inpatient and outpatient

Up to 15 % of inpatients 1

Acute-• 8.4% in childen• 55% in adults

• Chronic• 14-27%

1. Baylis PH. Int J Biochem Cell Biol. 2003;35:1495-1499.

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Important cause of mortalityMortality more if hyponatremia develops after

hospitalisationIncreased duration of hospital stayIncreased mortality continues even after dischargeEven mild hyponatremia though till now

considered benign is associated with osteoporosis and fractures

Adrogué HJ. Am J Nephrol. 2005;25:240-249Gill ,clin endocrino 2006Clayton ,QJM 2006European Jr of Endocrinology,2010

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Definition of Hyponatremia

Normal serum sodium level

: 135 – 145mEq/L

Hyponatremia is defined as a serum sodium level less than 135mEq/L

Severe - serum Na < 120mEq/L

SYMPTOMS

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Clinical ManifestationsClinical Manifestations

Hyponatremia not a disease but a manifestation of a variety of disorders.

Clinical symptoms hyponatremia itself

Disease causing hyponatremia recognition of hyponatremia incidental.

Acute

Low serum Na More Na in brain

Water enters brain cells

Cerebral oedema

Chronic

Adaptation

Pathogenesis

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S [Na] > 125 mmol/Lor

Gradual onset

AsymptomaticGI sym

HeadacheLethargy

ConfusionObtundation

Stupor Seizures

ComaRhabdomyolysis

Brain stem compressiomPulm oedema

Na+ level <120mEq/Lor

Rapid decrease(<48hr)

Symptoms depend onmagnitude of the hyponatremia rapidity of its development.

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Symptoms & signs

Gait disturbancesFractures

• reduction in total hip bone mineral density of 0.037 g/cm2 for every 1 mmol/l drop in plasma sodium concentration.

European Jr Endocrinology 2010

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Etiology -Hyponatremia

HyperglycemiaMannitol

Hyperlipidemia

Hyperproteinemia

SIADHGC defHypothyroidExercise indPsychogenic

CHFNSCirrhosis

CRFGI loss3rd space loss

Salt wasting dzRTADiureticsCerebral salt wasting

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Determine if true Hyponatremia?

IA Pseudohyponatremia/Normal plasma osmolality

(275-295)

1. Hyperlipidemia - ion-specific electrodes avoid thision-specific electrodes avoid this

2. Hyperproteinemia-Multiple myeloma

IB Increased plasma osmolality /Translocational/redistributive

(osmo > 295)A. Hyperglycemia 1.6 mEq/L for every 100 mg/dL [glucose)1.6 mEq/L for every 100 mg/dL [glucose)

B. Mannitol

II. Hypoosmolal hyponatremia (serum osmolality<275mOsm/kg)

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Hypovolemic

Hypervolemic

Euvolemic

2 stepcheck volume status

Hypovolemic- Low CVP Responds to NS

Low urine Na(<20 mmol/l)

Non renal • Volume Depletion

• GI, lung or skin losses -burns

• Third space sequestration

• CSW • Excess water

intake

High urine Na >20 mmol/l

Renal• Salt wasting

nephropathy• Mineralocorticoid

deficiency-high K• Osmotic diuresis-

KB• Cerebral salt

wasting

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Step 3

Check renal or non renalUrine Na

Diuretics

Thiazides Urine excreted- NS Lose more salt than loop Reason for hypoNa

• Interfere with urine dilution

Common in elderly females

Occurs within 2-4 weeks

Discontinue diuretics

Loop Diuretics Urine excreted 1/2 NS

Lose > water than thiazides

Reason for hypoNa:• Impair generation of

medullary hypertonicity

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Cerebral Salt Wasting Causes: Head injury, surgery, tumors, Infections Signs/symptoms:

• Polyuria, Dehydration/hypovolemia/Hypotension• High urine Na > 20 mmol/L

Pathogenesis: renal Na loss d/t plasma ANP, BNP • Volume depletion could be protective for ICP

Treatment:• Volume replacement - large volumes of NS• Oral Na supplementation for a period of time

Berendes Lancet 1997, Isotani Stroke 1994, Wijdicks Stroke 1991

Mather J Neuro Nsurg Psych 1981; Wijdicks Ann Neuro 1985

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TreatmentHypovolemic hyponatremia

Isotonic saline Restoration of euvolemia removes the

hemodynamic stimulus for AVP release Excretion of the excess free water

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Hypovolemic

Hypervolemic Euvolemic

Hypervolemic -High CVP Increased total body water that exceeds the increase in total body Na+

Low urine Na <20 mmol/l

•CHF•Cirrhosis with

ascites• Nephrotic

syndrome

High urine Na >20 mmol/l

•Advanced renal failure

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Step 3Check urine Na

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TreatmentHypervolemic hyponatremia

Restriction of Na+ and water intake Promotion of water loss in excess of Na+Vasopressin antagonists approved for use Correction of underlying disorder

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Hypovolemic

Hypervolemic Euvolemic

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Euvolemic – Normal CVP

Normal sodium stores (N ECF) & total body excess of free water.

SIADH/Reset osmostat Primary polydipsiaHypothyroidismGlucocorticoid deficiencyExercise inducedBeer potomaniaPost op

Step 3

All have high urine NaU osm <100 in PP, BP

SIADH (Bartter’s Criteria)60% of all euvolemic hyponatremia F

Essential criteria Hyponatremia pl osm<275 Euvolemia clinical u osmolality > 200

mOsm/kg N renal, cardiac, hepatic,

adrenal, pituitary, thyroid No H/o antidiuretic drugs No emotional or physical

stress Urinary sodium > 20 mEq/l Cr N, N ABG, K+ handling

Supplemental features uric acid<4BUN<10 failure to correct

hypoNa after NS infusion

correction of hypoNa after fluid restriction

S ADH

Step 4

Check urine osmolalityK/Cr/ Cr/Urea/uric acidT3/T4/TSHCortisolCT as needed

U SP gravity can be used if u osm not possible, U osm 100= u sp gr 1.005

Disorders associated with SIADH

PulmonaryPulmonary abscessTuberculosisAspergillosisPositive-pressure breathingAsthmaPneumothoraxCystic fibrosisLung cancers

CancersSmall cell carcinoma of the lungCarcinoma of the duodenumCarcinoma of the pancreasThymomaLymphomaEwing’s sarcomaMesotheliomaCarcinoma of the bladderProstatic carcinomaOlfactory neuroblastoma

CNS-ADH secrEncephalitis /Meningitis , traumaBrain abscess/Brain tumorsGBS/Acute intermittent porphyriaSubarachnoid/subdural hematomaCerebellar and cerebral atrophyCavernous sinus thrombosisNeonatal hypoxiaHydrocephalusDelirium tremensCVA, Acute psychosisPeripheral neuropathyMultiple sclerosis

PULMONARY

CANCERS

CNS

SIADHSIADH CSWCSWCNS problemCNS problem yesyes yesyes

Urine NaUrine Na High (renal)High (renal) High (renal)High (renal)

Urine osmUrine osm High >100 mosm/kgHigh >100 mosm/kg < 100 mosm/kg< 100 mosm/kg

Urine OutputUrine Output decreaseddecreased polyuricpolyuric

CVPCVP High (Euvolemic)High (Euvolemic) Low (Hypovolemic)Low (Hypovolemic)

BUNBUN N or ↓BUN ↑BUN

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DRUGSDRUGSAntidiuretic hormones:Antidiuretic hormones: Vasopressin,oxytocinDiuretics:Diuretics: Thiazides,furosemide, CNS-active drugs:CNS-active drugs: Vincristine,carbamazepine, Psychotropic drugs Inhibitors of prostaglandinInhibitors of prostaglandin Chlorpropamide, Salicylates,Acetaminophen, NSAIDS,COX 2 IOthers:Others: Clofibrate,Cyclophosphamide, Somatostatin

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Primary PolydipsiaPsychiatric disorder, thirst with antipsychotics±Hypothalamic lesions No hyponatremia unless intake >10-15 L/d, or

acute 3-4 L water loadUrine osm below 100Rx: Restrict free water ;classically rapid

correction

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Reset osmostat

Can excrete water load (10 to 15 mL/kg given orally or intravenously). -excrete more than 80 percent within 4 hours

Mild hyponatremiaNo treatment needed

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Beer protomaniaLow Dietary Solute Intake

Elderly, malnourished (“tea and toast” diets) -poor in solutes (Na/K)

Beer drinkers (high water intake, low protein) Pathogenesis

• Minimum urine osmolarity- 60 mosm/l • At least 600-900 msom/kg/d solute load needed to

excrete water >4 l• Beer protomania- daily solute excretion < 250

mosmol /kg, hence maximum urine output can be <4 L day ,if more water ingested -hyponatremia

• Urine appears dilute (osm of< 100)

Rx: NS, increased dietary solute

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Exercise associated hyponatremia (EAH)

Clinical features May be severe: cerebral edema, non cardiac PE

Pathogenesis H2O excess; impaired renal H2O excretion Nonosmolar AVP release esp if water in >out

Treatment Limit water to 400-800 ml/h; drink only when

thirsty No role of NS, 3% Nacl if severe

JCEM 2008;93:2072-78

History & volume status

Serum Osmolality

Urine Osmolality/sp gr

Urine Na

S Cr/urea/K

T3/T4/TSH

CXR

CT Scan Manisha Sahay

Investigations

Hyponatremia

Low<275True

High>295HyperglycemiaMannitol

N 275-295HyperlipidemiaHyperproteinemia Step 2

Volume

SIADHGC defHypothyroidExercise indPsychogenic

< 20 mmol/lCHFNSCirrhosis

>20 mmol/lCRF

Step3 Urine Na

Extra renalGI loss3rd space loss

RenalSalt wasting dzRTADiureticsCerebral salt wasting

Step 3 Urine Na

Hypovolemic Euvolemia High

Step1 S osmolality

Step 4 U Osm/TSH/GC

TREATMENT –EUVOLEMIC HYPONATREMIA

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Hyponatremia

Chronic

AsymptomaticSymptomatic

Long term managementTreat etiologyWater restrictionDemeclocyclineUreaV2 receptor antagonist

Some immediate correctionHypertonic saline + FurosemideChange to water restrictionFrequent serum & urine electrolytesDo not exceed 12 meq/l/d

Emergency Hypertonic saline+ furosemide

Acute <48 hrs Chronic>48 hrs

No immediateCorrection needed

Thurman et al,Therapy in nephrology and Hypertension,Saunders 2003

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Therapeutic Strategy Euvolemic hyponatremia

Treatment varies with• Presence or Absence of Symptoms• Duration• Magnitude of Hyponatremia• Risk for neurological dz- young, females,

elderly,menstruation

Acute/Severe/symptomatic hyponatremia

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Rate of correction of hyponatremia

Acutesevere (S Na+ <115mmol/L) symptomatic

Hypertonic (3% NaCl)

0.5 mmol/l/hr or 12 mmol/l/dayStop

if convulsions subsideif S Na 120 mEq/L Kumar S, Berl T. The Lancet 1998; 352: 220-8 Adrogue HJ, Madias NE. NEJM 2000; 342: 1581-9

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Fluids for correction

Ringer’s = 130 mEq/L0.45%NS = 77 mEq/L3% NaCl- 513 meq/L0.9% NaCl- 154 meq/L

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Total correction in 12 hrs = 6 mmol

Volume of infusate needed =

B Wt X 0.6 X Desired increment in Na (120-114) Infusate Na X 1.5

50 kg50X 0.6x6 = 0.23 litre or 230 ml 513X1.5 230 ml in 12 hours19 ml/hr

Symptomatic/chronichyponatremiaGradual correction

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Chronic symptomatic>48 hrs

3% NaCL< 0.5 to 1.0mmol/L per h (<10 to 12mmol/L over first 24h)

Water restriction

Chronic asymptomatic > 48 hoursNo immediate correctionWater restriction

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Long term management Euvolemic hyponatremia

Water restriction Free water restriction ,¾ maintenance (1 L/d)

Clozapine -schizophrenic patients with compulsive water drinking

Pharmacological agents (Long-term)Demeclocycline 300 - 600 mg bdUrea 15-60 gm/dLithiumV2 receptor antagonist- Aquaretics

AVP Receptor antagonists

– •

Mechanism of actionBind to the V2 receptors in renal

collecting tubules/ducts Vasopressin antagonist Uses Euvolemic/ hypervolemic hypo

Na+; Contraindicated in hypovolemia

Chronic hyponatremia not in acute hyponatremia or in

patients with sNa < 115 mmol/L as slow aquaresis Adverse effects: Thirst ; dry mouth

SALT NEJM 2006

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Vasopressin Receptor Location & Functions (KI 2006)

Vasopressin Receptor Antagonists

Tol-vaptan*

Lixi-Vaptan Sata-vaptan

Coni-vaptan

Receptor V2 V2 V2 V1a/V2

Route of administration

Oral Oral Oral IV

Urine Volume

UOSM

24 h Na excretion

No ∆ No ∆ low Dose

High Dose

No ∆ No ∆

*SALT I and SALT II Trials.

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CI

Concomitant use of vaptan and potent CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, ritonavir, or indinavir is contraindicated

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Central Pontine MyelinolysisOsmotic demyelination

Pathogenesis• rapid correction / overcorrection of ch hyponatremia.  • hypoxic encephalopathy / complication of therapy

Prevention• Adequate oxygenation• Gradual increase in serum sodium level to 120-125 mEq/L.

Symptoms • Dysarthria, dysphagia, seizures, altered mental status,

quadriparesis, hypotension ,locked in syndrome, extrapontine

• Begin 1-3 days after correction of S Na• Irreversible , devastating • MRI diagnostic < 24 h

Risk factors- Hypokalemia, females,alcoholism, liver transplant

Treatment- Relowering S Na - hypotonic fluids, Desmopressin

SUMMARISING……

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Hyponatremia

Low<275True

High>295HyperglycemiaMannitol

N 275-295HyperlipidemiaHyperproteinemia

Volume

SIADHGC defHypothyroidExercise indPsychogenic

< 20 mmol/lExtrarenalCHFNSCirrhosis

>20 mmol/lRenalCRF

Urine Na

Extra renalGI loss3rd space loss

RenalSalt wasting dzDiureticsCerebral salt wasting

Urine Na

Hypovolemic Euvolemia High

S osmolality

Urine Osm, S Cr,Ur,TSH

Hyponatremia

AsymptomaticSymptomatic

Long term managementHypertonic saline

Acute <48 hrs

No immediateCorrection neededEmergency

Go slow

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Take home message

Hyponatremia –a common, life theatening problem

Step wise evaluation importantInappropriate treatment – Worse

than disease

Practising is the best way of learning!!!

Manisha Sahay

Manisha sahay

Hope some pieces of puzzle are in place !!

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