SIADH v/s Diabetes Insipidus .pptx

Differential for Hypernatremia with polyuria

1. SIADH & Diabetes Insipidus -Dr Mahesh Mahajan Senior Resident Department of Neurosurgery G.B.P.H New Delhi

2. Physiology Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the pl asma membrane, leaving the plasma membrane watertight again

3. Diabetes Insipidus (DI) Decreased secretion or action of AVP usually manifests as diabetes insipidus, a syndrome characterized by the production of abnormally large volumes of dilute urine. Diagnostic criteria- Plasma hyperosmolality greater than 300 mosm /l ( 275 to 295 mOsm /kg) U rine hypo-osmolality less than 2 00 mosm /l( 50 to 850 mOsm /kg) Urine specific gravity less than 1.005 ( 1.010 to 1.030) P olyuria (urinary volume greater than 4 mL/kg/hr  to 5 mL/kg/hr for two consecutive hours after surgery .

4. Clinical manifestations- Being extremely thirsty Producing large amounts of pale urine Frequently needing to get up to urinate during the night Preferring cold drinks Bed-wetting Trouble sleeping Vomiting Constipation Weight loss

5. Types Of DI Primary DI- Peripheral/Nephrogenic DI -Due to peripheral resistance to AVP Central DI/ Pitutary DI- A) Congenital B) Acquired/Surgical- The surgically induced forms of pituitary DI usually appear within 24 hours and then go through a 2- to 3-week interim period of inappropriate antidiuresis, after which they may or may not recur C) Genetic Autosomal Domianant- autosomal dominant mode and is caused by diverse mutations in the coding region of the AVP– neurophysin II (or AVP-NPII ) gene Mutations of the WFS 1 gene responsible for Wolfram’s syndrome [diabetes insipidus, diabetes mellitus, optic atrophy, and neural deafness (DIDMOAD)]

6. Secondary DI(Dipsogenic DI)- Secondary deficiencies of AVP result from inhibition of secretion by excessive intake of fluids. They are referred to as primary polydipsia and can be divided into three subgroup Dipsogenic DI -is characterized by inappropriate thirst caused by a reduction in the set of the osmoregulatory mechanism. It sometimes occurs in association with multifocal diseases of the brain such as neurosarcoid , tuberculous meningitis, and multiple sclerosis but is often idiopathic. Psychogenic polydipsia - is not associated with thirst, and the polydipsia seems to be a feature of psychosis or obsessive compulsive disorder. Iatrogenic polydipsia - results from recommendations to increase fluid intake for its presumed health benefits.

7. Causes of DI Central DI- Head trauma Pitutary surgery Neoplasms-Pituitary macroadenoma, Craniopharyngioma, Meningioma. Cavernous ICA aneurysm Other- Schizophrenia ,OCD, Tubercular meningitis, Multiple sclerosis Nephrogenic DI-Congenital/Drugs- Lithium Demiclocycin Amphoterecin B Aminoglycosides Rifampicin Metabolic - Hypercalemia , Hypokalamaia

8. Miller Moses Test The water deprivation test ( Miller-Moses test), a semiquantitative test to ensure adequate dehydration and maximal stimulation of ADH for diagnosis. Procedure- With mild polyuria, water deprivation can begin the night before the test. With severe polyuria, water restriction is carried out during the day for 7 hrs to allow close observation. U rinary osmolality and body weight are measured hourly. When 2 sequential urinary osmolalities vary by less than 30 mOsm /kg or when the weight decreases by more than 3%, 5 U of aqueous ADH(0.3 microgram/kg) are administered subcutaneously. A final urine specimen is obtained 60 minutes later for osmolality measurement. Results- In healthy individuals, water deprivation leads to a urinary osmolality that is 2-4 times greater than plasma osmolality. Administration of ADH produces an increase of less than 9% in urinary osmolality. The time required to achieve maximal urinary concentration ranges from 4-18 hours. In central and nephrogenic DI, urinary osmolality will be less than 300 mOsm /kg after water deprivation. After the administration of ADH, the osmolality will rise to more than 750 mOsm /kg in central DI but will not rise at all in nephrogenic DI. In primary polydipsia, urinary osmolality be above 750 mOsm /kg after water deprivation.

9. Management of Nephrogenic DI The polyuria and polydipsia of nephrogenic DI are not affected by treatment with standard doses of desmopressin. However, treatment with conventional doses of a thiazide diuretic and/or amiloride in conjunction with a low-sodium diet and a prostaglandin synthesis inhibitor (e.g., indomethacin) usually reduces the polyuria and polydipsia by 30–70% and may eliminate them completely in some patients. Stop the culprit drug causing nephrogenic DI

10. Management of Central DI Fluid replacement Replace losses with dextrose and water or an intravenous (IV) fluid that is hypo-osmolar with respect to the patient’s serum Fluid replacement should be provided at a rate no greater than 500-750 mL/h. A good rule of thumb is to reduce serum sodium by 0.5 mmol/L (0.5 mEq /L) every hour(ideally) I n acute hypernatremia, correct the serum sodium at an initial rate of 2-3 mEq /L/h (for 2-3 h) (maximum total, 12 mEq /L/d). Measure serum and urine electrolytes every 1-2 hours Perform serial neurologic examinations and decrease the rate of correction with improvement in symptoms

11. How to calculate water deficit Conventional formula TBW deficit = correction factor × premorbid weight × (1 - 140/Na + ) TBW = weight (kg) x correction factor Correction factors are as follows: Children: 0.6 Nonelderly men: 0.6 Nonelderly women: 0.5 Elderly men: 0.5 Elderly women: 0.45 Adrogué– Madias Formula Change in serum Na +  = ( infusate Na +  - serum Na + ) ÷ (TBW + 1) 5% dextrose in water (D5W): 0 mmol/L 0.2% sodium chloride in 5% dextrose in water (D  5  2NS): 34 mmol/L 0.45% sodium chloride in water (0.45NS): 77 mmol/L Ringer's lactate solution: 130 mmol/L 0.9% sodium chloride in water (0.9NS): 154 mmol/L

12. By Adrogué– Madias Formula An example of the use of the above calculations is as follows: 80-year-old man is admitted in ICU 16 with dry mucous membranes, fever, tachypnea, and a blood pressure of 134/76 mm Hg. His serum sodium concentration is 165 mmol/L. He weighs 70 kg. The man's TBW is calculated by the following: (0.5 × 70) = 35 L To reduce the man's serum sodium, D5W will be used. Thus, the retention of 1 L of D5W will reduce his serum sodium by (0 - 165) ÷ (35 + 1) = -4.6 mmol. The goal is to reduce his serum sodium by no more than 10 mmol/L in a 24-hour period. Thus, (10 ÷ 4.6) = 2.17 L of solution is required. About 1.5 L will be added for obligatory water loss to make a total of up to 3.67 L of D 5  W over 24 hours, or 153 cc/h.

13. By conventional Formula TBW deficit = correction factor × premorbid weight × (1 - 140/Na + ) =0.5x70x(1-140/165) =35x(1-0.8484) =35x0.1516=5.306 Means 5.3 litres of water deficit to be replaced to correct 25 meq of defict for whole body Maximum permissible correction per day is 10meq Hence time required for this correction is 2.5 day Hence fluid to be given in 24 hrs is 5.3/2.5 day=2.16 litres Plus 1.5 litres of insensible losses to be added, therefore 2.16+1.5=3.16 litres in 24 hrs hence 151 cc/ hr

14. Medical Management DDAVP acts selectively at V 2 receptors to increase urine concentration and decrease urine flow in a dose-dependent manner. It is also more resistant to degradation than is AVP and has a three- to fourfold longer duration of action. Desmopressin can be given by IV or SC injection, nasal inhalation, or oral tablet. The doses required to control pituitary DI completely vary widely, depending on the patient and the route of administration. However, they usually range from 1–2 μg qd or bid by injection, 10–20 μg bid or tid by nasal spray, or 100–400 μg bid or tid orally. The onset of action is rapid, ranging from as little as 15 minutes after injection to 60 minutes after nasal and oral administration

15. SIADH(Syndrome of inappropriate Antidiuresis Hormone) Excessive secretion or action of AVP results in the production of decreased volumes of more highly concentrated urine. If not accompanied by a commensurate reduction in fluid intake or an increase in insensible loss, the reduction in urine output results in excess water retention with expansion and dilution of all body fluids . Schwartz Diagnostic criteria 1)Serum sodium less than 135 mosmol /l 2)Serum Osmolality less than 275 mosm /kg 3)Urinary osmolality >100mosm/kg 4)Urinary Na > 40 mmol/l 5)Normal thyroid and adrenal function 6)No hypokalamia and acid base disorder Supporting diagnostic criteria 1)Serum uric acid level <4mg /dl 2)BUN<10 mg/dl 3)FENA >1% 4)Failure to improve /worsening of hyponatremia after correction with normal 0.9% NS 5) Improvenment of Hyponatremia with fluid restriction

16. Clinical features Confusion Disorientation Delirium Generalized muscle weakness Tremor Hyporeflexia Ataxia Dysarthria Cheyne-Stokes respiration Generalized seizures Coma

17. Differential Diagnosis Pseudohyponatremia- Extreme elevations in plasma lipids or proteins can increase the plasma volume and can reduce the measured plasma Na +  concentration. Hyperglycemia- Elevated glucose levels decrease the measured serum Na +  levels by 1.6 mEq /L for every 100 mg/dL increase in glucose. This results from the osmotic effect of glucose drawing water into the intravascular space Cerebral salt wasting- certain cerebral disorders that can impair the ability of the kidneys to conserve Na + , with resultant salt wasting and polyuria. CSW is defined as the renal loss of Na +  with intracranial disease, which leads to hyponatremia and a decrease in extracellular fluid volume Adrenal insufficiency- Cortisol has a negative feedback effect on ADH and corticotropin-releasing hormone. The absence of cortisol thus removes this inhibitory effect, increasing the release of ADH. Renal disease- With declining renal function, the ability to excrete free water decreases, and the more advanced the reduction in glomerular filtration rate (GFR), the easier it is for patients to become hyponatremic with unrestricted fluid intake

18. Investigations- Serum Na + Plasma osmolality Serum creatinine Blood urea nitrogen Blood glucose Urine osmolality Serum uric acid Serum cortisol Lipid profile Serum proteins Plasma AVP

19. American Expert Panel Managaement Protocol- - Fluid restriction should generally be first-line therapy Consider pharmacologic therapies if serum Na  +  is not corrected after 24-48 hr of fluid restriction or if patient has fall in clinical status(GCS) Patients being treated with vaptans should not be on a fluid restriction initially Second-line treatments include increasing solute intake with 0.25–0.50 g/kg per day of urea or sodium chloride with a combination of low-dose loop diuretics.

20. Fluid restriction Restricting total fluid intake to less than the sum of urinary and insensible losses water derived from food (300–700 mL/d) usually approximates basal insensible losses in adults, total discretionary intake (all liquids) should be at least 500 mL less than urinary output Water intake=Urine output-500 If the symptoms or signs of water intoxication are more severe, the hyponatremia can be corrected more rapidly by supplementing the fluid restriction with IV infusion of hypertonic (3%) saline

21. Hypertonic saline 3% saline should be infused at a rate ≤ 3mL/kg / hr ; the effect should be monitored continuously by STAT measurements of serum sodium at least once every 2 hours; and the infusion should be stopped as soon as serum sodium increases by 12 mmol/L or to 130 mmol/L, whichever comes first. “ Rule of sixes ." The rule states that, "Six a day makes sense for safety; 6 in 6 hours for severe symptoms and stop Central pontine myelinolysis an acute, potentially fatal neurologic syndrome characterized by hypotonic quadriparesis, ataxia, and abnormal movements.

22. AVP Antagonists Nonpeptide AVP antagonists One of them, a combined V 2 /V 1a antagonist ( Conivaptan ), has been approved for short-term in-hospital IV treatment of SIAD and the hyponatremia of congestive heart failure. T olvaptan is a selective oral V2 receptor antagonist also approved for use in hospitalized patients for hypervolemia and euvolemic hyponatremia.   The drug is started at 15 mg once daily and titrated up to 60 mg daily as required, and it is best to avoid fluid restriction during the dose-finding phase.

23. Na +  Deficit ( mEq ) = (Desired Na +  - Measured Na + ) x TBW Three-percent hypertonic saline has 513 mEq /L each of Na + . The volume of hypertonic saline needed to correct that deficit can be calculated as follows: Volume of 3% Saline = (Na +  Deficit)/513 mEq /L Na + Assuming a rate of correction of chronic hyponatremia of 0.5 mEq /L per hour, the amount of time needed to correct a given degree of hyponatremia is as follows: Time Needed for Correction = (Desired Na +  - Measured Na + )/0.5 mEq /L per hour The rate of infusion of hypertonic saline is as follows: Rate = (Volume of 3% Saline)/(Time Needed for Correction) Example- A 20 year male of 60 kg admitted in ICU 16 with serum sodium of 120 meq /L with altered senosirium TBW=60X0.6=36 Sodium deficit=(130-120)=10x36=360meq 513meq in one litre of 3% NS so 360 meq will be present in around 700 ml of 3% NS 700 ml is to be given in 24 hrs So rate of transfusion will be 28 ml/hr.

24. Diuretics Concomitant use of furosemide increases free water excretion relative to Na +  excretion by the kidneys, thus correcting fluid expansion induced by hypertonic sodium chloride solution. Urea is used for the treatment of SIADH refractory to or in patients noncompliant with other therapies or when other therapies are not available. Urea is known to promote diuresis. It decreases brain edema, restores medullary tonicity, and induces Na+ retention Mannitol promotes a rapid free-water diuresis by elevating the osmolarity of the glomerular filtrate, thereby hindering the tubular reabsorption of water. Concomitantly, Na+ and Cl- excretion also increase but to a lesser extent than water excretion

25. Management of chronic SIADH In chronic SIAD, the hyponatremia can be corrected by treatment with Demeclocycline , 150–300 mg PO tid or gid, or fludrocortisone , 0.05–0.2 mg PO bid. The effect of the demeclocycline manifests in 7–14 days and is due to production of a reversible form of nephrogenic DI. Potential side effects include phototoxicity and azotemia. The effect of fludrocortisone also requires 1–2 weeks and is partly due to increased retention.

26. Type I hyponatremia- fluid restriction Infusion of hypertonic saline is contraindicated because it further increases total body sodium and edema and may precipitate cardiovascular decompensation. Antagonists of V 2 receptors indicate that they are almost as effective in type I hyponatremia. In type II hyponatremia- the defect in AVP secretion and water balance usually can be corrected easily and quickly by stopping the loss of sodium and water and/or replacing the deficits by mouth or IV infusion of normal or hypertonic saline ,Fluid restriction and administration of AVP antagonists are contraindicated in type II as they would only aggravate the underlying volume depletion and could result in hemodynamic collapse. Type III Hyponatremia- due to protracted nausea and vomiting or isolated glucocorticoid deficiency (type III), all abnormalities can be corrected quickly and completely by giving an antiemetic or stress doses of hydrocortisone

27. CSWS(Cerebral salt wasting syndrome) First described by Peters et al in 1950, cerebral salt-wasting syndrome is defined by the development of extracellular volume depletion due to a renal sodium transport abnormality in patients with intracranial disease and normal adrenal and thyroid function.   As such, it may be more appropriately termed renal salt wasting. Complications of cerebral salt-wasting syndrome include symptomatic  hyponatremia  and dehydration Symptoms- Orthostatic tachycardia or hypotension Increased capillary refill time Increased skin turgor Dry mucous membranes A sunken anterior fontanelle

28. Another hypothesis involves the release of  natriuretic factors , possibly including brain natriuretic peptide (C-type natriuretic peptide) or urodilatin by the injured brain.The abnormalities in proximal tubular transport may be secondary to a plasma natriuretic factor that reduces proximal and, possibly, distal sodium transport in cerebral salt-wasting syndrome. It may also inhibit the tubular transport of urate, phosphate, and urea in addition to sodium

29. The following lab studies may be indicated in patients with cerebral salt-wasting syndrome: Serum sodium concentration - Patients with untreated cerebral salt-wasting syndrome are often hyponatremic Serum osmolality - If measured serum osmolality exceeds twice the serum sodium concentration and azotemia is not present, suspect hyperglycemia or mannitol as the cause of hyponatremia Urinary output - Urine flow rate is often high in cerebral salt-wasting syndrome; urine flow rate is low in SIADH

30. CSW Vs SIADH Fractional excretion of urate (FEU) may remain elevated even after correction of hyponatremia in patients with cerebral salt-wasting syndrome. This is distinct from SIADH, in which the fractional excretion of urate returns to the reference range once the hyponatremia is corrected.   Urinary sodium concentrations are typically elevated in SIADH and in cerebral salt-wasting syndrome (>40 mEq /L). However, urinary sodium excretion (urinary sodium concentration [ mEq /L] x urinary volume [L/24 h]) is substantially higher than sodium intake in cerebral salt-wasting syndrome but generally equals sodium intake in SIADH. Therefore, net sodium balance (intake minus output) is negative in cerebral salt-wasting syndrome. Fractional excretion of phosphate (FEP) should be determined when evaluating patients with hyponatremia and hypouricemia. Elevated FEP suggests cerebral salt-wasting syndrome as opposed to SIADH

31. Management Management centers on correction of intravascular volume depletion and hyponatremia, as well as on replacement of ongoing urinary sodium loss, usually with intravenous (IV) hypertonic saline solutions.  [ 3 ]  Some clinicians have reported a favorable response to mineralocorticoid therapy in cerebral salt-wasting syndrome. Once the patient is stabilized, enteral salt supplementation can be considered .