Hyponatremia

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.

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. 2005;25:240-249 Gill ,clin endocrino 2006 Clayton ,QJM 2006 European Jr of Endocrinology,2010 Manisha

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

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. Acute water intoxication of less than 24 hrs often presents with symptoms at Na concentrations beginning at 125 mEq/L. Seizures and coma appear with levels below 115 mEq/L. (e.g., large volumes of hypotonic fluids post-op, initiation of thiazide diuretic therapy) Chronic hyponatremia is often asymptomatic until the Na concentration drops below 115 mEq/L. Treat for symptoms, not for the number.

Pathogenesis Acute Low serum Na More Na in brain Water enters brain cells Cerebral oedema Chronic Adaptation

Brain stem compressiom Symptoms depend on magnitude of the hyponatremia rapidity of its development. Asymptomatic GI sym Headache Lethargy Confusion Obtundation S [Na] > 125 mmol/L or Gradual onset Stupor Seizures Coma Rhabdomyolysis Brain stem compressiom Pulm oedema Na+ level <120mEq/L or Rapid decrease(<48hr)

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 Manisha Sahay

? ? ? ? ? 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

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/redistributive (osmo > 295) Hyperglycemia 1.6 mEq/L for every 100 mg/dL [glucose) Mannitol II. Hypoosmolal hyponatremia (serum osmolality<275mOsm/kg)

How to detect Pseudohypo? check pl osmolality. Measured by osmometer Calculated Pl osmolality = 2x[Na+](mEq/L) + serum glucose(mg/dL)/18 + BUN (mg/dL)/2.8 True hyponatremia :Both are equal or < 10 mosm diff Pseudo : Calculated OSM < Measured OSM If osmolality not available check routine biochemistry

2 step check volume status Euvolemic Hypervolemic Hypovolemic

Hypovolemic- Low CVP Responds to NS Low urine Na(<20 mmol/l) High urine Na >20 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 Manisha Sahay

Diuretics Loop Diuretics Thiazides Urine excreted- NS Lose > 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

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

Treatment Hypovolemic hyponatremia Isotonic saline  Restoration of euvolemia removes the hemodynamic stimulus for AVP release  Excretion of the excess free water

Hypervolemic Euvolemic Hypovolemic

Hypervolemic -High CVP Increased total body water that exceeds the increase in total body Na+ High urine Na >20 mmol/l Low urine Na <20 mmol/l CHF Cirrhosis with ascites Nephrotic syndrome Advanced renal failure Step 3 Check urine Na Manisha Sahayin

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

Hypervolemic Euvolemic Hypovolemic

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 <100 in PP, BP

SIADH (Bartter’s Criteria) 60% of all euvolemic hyponatremia 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<4 BUN<10 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

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 Ewing’s sarcoma Mesothelioma Carcinoma of the bladder Prostatic carcinoma Olfactory neuroblastoma PULMONARY CANCERS CNS

SIADH CSW CVP BUN CNS problem yes Urine Na High (renal) Urine osm High >100 mosm/kg < 100 mosm/kg Urine Output decreased polyuric CVP High (Euvolemic) Low (Hypovolemic) BUN N or ↓BUN ↑BUN

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 Manisha Sahay

Primary Polydipsia Psychiatric disorder,  thirst with antipsychotics ±Hypothalamic lesions No hyponatremia unless intake >10-15 L/d, or acute 3-4 L water load Urine osm below 100 Rx: Restrict free water ;classically rapid correction

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 Manisha Sahay

Beer protomania Low 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

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

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

Hyponatremia Step1 S osmolality N 275-295 Low<275 High>295 Hyperlipidemia Hyperproteinemia Low<275 True High>295 Hyperglycemia Mannitol Step 2 Volume High Hypovolemic Euvolemia Step3 Urine Na Step 3 Urine Na Step 4 U Osm/TSH/GC < 20 mmol/l CHF NS Cirrhosis >20 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

Treatment –Euvolemic Hyponatremia Manisha Sahay

Hyponatremia Asymptomatic Symptomatic Chronic Acute <48 hrs Chronic>48 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

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 Manisha Sahay

severe (S Na+ <115mmol/L) symptomatic Hypertonic (3% NaCl) Rate of correction of hyponatremia Acute severe (S Na+ <115mmol/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

Fluids for correction Ringer’s = 130 mEq/L 0.45%NS = 77 mEq/L 3% NaCl- 513 meq/L 0.9% NaCl- 154 meq/L

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

Symptomatic/chronic hyponatremia Gradual correction Manisha Sahay

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 hours No immediate correction Manisha Sahay

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

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 < 115 mmol/L as slow aquaresis Adverse effects: Thirst ; dry mouth AVP Receptor antagonists SALT NEJM 2006

Vasopressin Receptor Location & Functions (KI 2006)

Vasopressin Receptor Antagonists Tol-vaptan* Lixi-Vaptan Sata-vaptan Coni-vaptan Receptor V2 V1a/V2 Route of administration Oral IV Urine Volume UOSM 24 h Na excretion No ∆ No ∆ low Dose High Dose *SALT I and SALT II Trials.

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

Central Pontine Myelinolysis Osmotic 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 dsMsh S

Summarising…… Manisha Sahay

Hyponatremia S osmolality N 275-295 Low<275 High>295 Volume High Hyperlipidemia Hyperproteinemia Low<275 True High>295 Hyperglycemia Mannitol Volume High Hypovolemic Euvolemia Urine Na Urine Na Urine Osm, S Cr,Ur,TSH < 20 mmol/l Extrarenal CHF NS Cirrhosis >20 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

Long term management Hypertonic saline Hyponatremia Asymptomatic Acute <48 hrs Emergency No immediate Correction needed Long term management Hypertonic saline Go slow

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!!! Manisha Sahay

Hope some pieces of puzzle are in place !! Manisha Sahay