Hyponatremia

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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.
  2003351495-1499.

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• Important cause of mortality
• Mortality more if hyponatremia develops after
  hospitalisation
• Increased duration of hospital stay
• Increased mortality continues even after
  discharge
• Even mild hyponatremia though till now considered
  benign is associated with osteoporosis and
  fractures
• Adrogué HJ. Am J Nephrol. 200525240-249
• Gill ,clin endocrino 2006
• Clayton ,QJM 2006
• European 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 lt 120mEq/L

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symptoms
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Clinical Manifestations

• Hyponatremia not a disease but a manifestation of
  a variety of disorders.
• Clinical symptoms
• hyponatremia itself
• Disease causing hyponatremia
• recognition of hyponatremia incidental.

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Pathogenesis
Acute Low serum Na More Na in brain Water
enters brain cells Cerebral oedema Chronic Adap
tation
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Symptoms depend on magnitude of the hyponatremia
rapidity of its development.
Asymptomatic GI sym Headache Lethargy Confusion O
btundation
S Na gt 125 mmol/L or Gradual onset

Stupor Seizures Coma Rhabdomyolysis Brain stem
compressiom Pulm oedema
Na level lt120mEq/L or Rapid decrease(lt48hr)
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Symptoms signs

• Gait disturbances
• Fractures
• 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
?
Hyperlipidemia Hyperproteinemia
?
?
?
?
Hyperglycemia Mannitol
CHF NS Cirrhosis
CRF
Salt wasting dz RTA Diuretics Cerebral salt
wasting
GI loss 3rd space loss
SIADH GC def Hypothyroid Exercise ind Psychogenic
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Determine if true Hyponatremia?

• IA Pseudohyponatremia/Normal plasma osmolality
• (275-295)
• Hyperlipidemia - ion-specific electrodes avoid
  this
• Hyperproteinemia-Multiple myeloma
• IB Increased plasma osmolality /Translocational/re
  distributive
• (osmo gt 295)
• Hyperglycemia 1.6 mEq/L for every 100 mg/dL
  glucose)
• Mannitol
• II. Hypoosmolal hyponatremia (serum
  osmolalitylt275mOsm/kg)

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How to detect Pseudohypo? check pl osmolality.

• Measured by osmometer
• Calculated Pl osmolality
• 2xNa(mEq/L) serum glucose(mg/dL)/18
  BUN (mg/dL)/2.8
• True hyponatremia Both are equal or lt 10 mosm
  diff Pseudo Calculated OSM lt
  Measured OSM

If osmolality not available check routine
biochemistry
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2 stepcheck volume status
Euvolemic
Hypervolemic
Hypovolemic
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Hypovolemic- Low CVP Responds to NS

• Low urine Na(lt20 mmol/l)

• High urine Na gt20 mmol/l

• Non renal
• Volume Depletion
• GI, lung or skin losses -burns
• Third space sequestration
• CSW
• Excess water intake

• Renal
• Salt wasting nephropathy
• Mineralocorticoid deficiency-high K
• Osmotic diuresis-KB
• Cerebral salt wasting

Step 3 Check renal or non renal Urine Na
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Diuretics

• Loop Diuretics
• Urine excreted 1/2 NS
• Lose gt water than thiazides
• Reason for hypoNa
• Impair generation of medullary hypertonicity

• 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

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Cerebral Salt Wasting

• Causes Head injury, surgery, tumors, Infections
• Signs/symptoms
• Polyuria, Dehydration/hypovolemia/Hypotension
• High urine Na gt 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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Hypervolemic
Euvolemic
Hypovolemic
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Hypervolemic -High CVP Increased total
body water that exceeds the increase in total
body Na

• High urine Na gt20 mmol/l

• Low urine Na lt20 mmol/l

• CHF
• Cirrhosis with ascites
• Nephrotic syndrome

• Advanced renal failure

Step 3 Check 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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Hypervolemic
Euvolemic
Hypovolemic
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Euvolemic Normal CVP

• Normal sodium stores (N ECF) total body excess
  of free water.
• SIADH/Reset osmostat
• Primary polydipsia
• Hypothyroidism
• Glucocorticoid deficiency
• Exercise induced
• Beer potomania
• Post op

Step 3 All have high urine Na U osm lt100 in PP,
BP
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SIADH (Bartters Criteria)60 of all euvolemic
hyponatremia

• F
• Essential criteria
• Hyponatremia
• pl osmlt275
• Euvolemia clinical
• u osmolality gt 200 mOsm/kg
• N renal, cardiac, hepatic, adrenal, pituitary,
  thyroid
• No H/o antidiuretic drugs
• No emotional or physical stress
• Urinary sodium gt 20 mEq/l
• Cr N, N ABG, K handling

• Supplemental features
• uric acidlt4
• BUNlt10
• failure to correct hypoNa after NS infusion
• correction of hypoNa after fluid restriction
• ? S ADH

Step 4 Check urine osmolality K/Cr/ Cr/Urea/uric
acid T3/T4/TSH Cortisol CT as needed
U SP gravity can be used if u osm not possible, U
osm 100 u sp gr 1.005
a
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Disorders associated with SIADH

• CNS-ADH secr
• Encephalitis /Meningitis , trauma
• Brain abscess/Brain tumors
• GBS/Acute intermittent porphyria
• Subarachnoid/subdural hematoma
• Cerebellar and cerebral atrophy
• Cavernous sinus thrombosis
• Neonatal hypoxia
• Hydrocephalus
• Delirium tremens
• CVA, Acute psychosis
• Peripheral neuropathy
• Multiple sclerosis

• Pulmonary
• Pulmonary abscess
• Tuberculosis
• Aspergillosis
• Positive-pressure breathing
• Asthma
• Pneumothorax
• Cystic fibrosis
• Lung cancers

Cancers Small cell carcinoma of the
lung Carcinoma of the duodenum Carcinoma of the
pancreas Thymoma Lymphoma Ewings
sarcoma Mesothelioma Carcinoma of the
bladder Prostatic carcinoma Olfactory
neuroblastoma
PULMONARY
CANCERS
CNS
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SIADH CSW
CNS problem yes yes
Urine Na High (renal) High (renal)
Urine osm High gt100 mosm/kg lt 100 mosm/kg
Urine Output decreased polyuric
CVP High (Euvolemic) Low (Hypovolemic)
BUN N or ?BUN ?BUN
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DRUGS

• Antidiuretic hormones
• Vasopressin,oxytocin
• Diuretics
• Thiazides,furosemide,
• CNS-active drugs
• Vincristine,carbamazepine,
• Psychotropic drugs
• Inhibitors of prostaglandin
• Chlorpropamide, Salicylates,
• Acetaminophen, NSAIDS,COX 2 I
• Others
• Clofibrate,Cyclophosphamide,
• Somatostatin

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Primary Polydipsia

• Psychiatric disorder, ? thirst with
  antipsychotics
• Hypothalamic lesions
• No hyponatremia unless intake gt10-15 L/d, or
  acute 3-4 L water load
• Urine osm below 100
• Rx 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 hyponatremia
• No 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 gt4 l
• Beer protomania- daily solute excretion lt 250
  mosmol /kg, hence maximum urine output can be lt4
  L day ,if more water ingested -hyponatremia
• Urine appears dilute (osm oflt 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 gtout
• Treatment
• Limit water to 400-800 ml/h drink only when
  thirsty
• No role of NS, 3 Nacl if severe
• 
  JCEM
  2008932072-78

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Investigations

• History volume status
• Serum Osmolality
• Urine Osmolality/sp gr
• Urine Na
• S Cr/urea/K
• T3/T4/TSH
• CXR
• CT Scan

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Hyponatremia
Step1 S osmolality
N 275-295 Hyperlipidemia Hyperproteinemia
Lowlt275 True
Highgt295 Hyperglycemia Mannitol
Step 2 Volume
High
Hypovolemic
Euvolemia
Step3 Urine Na
Step 3 Urine Na
Step 4 U Osm/TSH/GC
lt 20 mmol/l CHF NS Cirrhosis
gt20 mmol/l CRF
Renal Salt wasting dz RTA Diuretics Cerebral salt
wasting
Extra renal GI loss 3rd space loss
SIADH GC def Hypothyroid Exercise ind Psychogenic
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Treatment Euvolemic Hyponatremia
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Hyponatremia
Asymptomatic
Symptomatic
Chronic
Acute lt48 hrs
Chronicgt48 hrs
Some immediate correction Hypertonic saline
Furosemide Change to water restriction Frequent
serum urine electrolytes Do not exceed 12
meq/l/d
No immediate Correction needed
Emergency Hypertonic saline furosemide
Long term management Treat etiology Water
restriction Demeclocycline Urea V2 receptor
antagonist
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

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Acute/Severe/symptomatic hyponatremia
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• Rate of correction of
  hyponatremia
• Acute
• severe (S Na lt115mmol/L)
• symptomatic
• Hypertonic (3 NaCl)
• 0.5 mmol/l/hr or 12 mmol/l/day
• Stop
• if convulsions subside
• if 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

• Ringers 130 mEq/L
• 0.45NS 77 mEq/L
• 3 NaCl- 513 meq/L
• 0.9 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 kg
• 50X 0.6x6 0.23 litre or 230 ml
• 513X1.5
• 230 ml in 12 hours
• 19 ml/hr

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Symptomatic/chronichyponatremiaGradual
correction
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Chronic symptomaticgt48 hrs

• 3 NaCL
• lt 0.5 to 1.0mmol/L per h
• (lt10 to 12mmol/L over first 24h)
• Water restriction
• Chronic asymptomatic gt 48 hours
• No immediate correction
• Water 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 bd
• Urea 15-60 gm/d
• Lithium
• V2 receptor antagonist- Aquaretics

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AVP Receptor antagonists

• Mechanism of action
• Bind 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 lt 115 mmol/L
• as slow aquaresis
• Adverse effects
• Thirst dry mouth

SALT NEJM 2006
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Vasopressin Receptor Location Functions (KI
2006)
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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 lt 24 h
• Risk factors- Hypokalemia, females,alcoholism,
  liver transplant
• Treatment- Relowering S Na - hypotonic fluids,
  Desmopressin

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Summarising
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Hyponatremia
S osmolality
N 275-295 Hyperlipidemia Hyperproteinemia
Lowlt275 True
Highgt295 Hyperglycemia Mannitol
Volume
High
Hypovolemic
Euvolemia
Urine Na
Urine Na
lt 20 mmol/l Extrarenal CHF NS Cirrhosis
Urine Osm, S Cr,Ur,TSH
gt20 mmol/l Renal CRF
Renal Salt wasting dz Diuretics Cerebral salt
wasting
Extra renal GI loss 3rd space loss
SIADH GC def Hypothyroid Exercise ind Psychogenic
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Hyponatremia
Asymptomatic
Symptomatic
Acute lt48 hrs
No immediate Correction needed
Emergency
Long term management
Hypertonic saline
Go slow
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Take home message

• Hyponatremia a common, life theatening problem
• Step wise evaluation important
• Inappropriate treatment Worse than disease
• Practising is the best way of learning!!!

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Hope some pieces of puzzle are in place !!