1. APPROACH TO HYPERNATREMIABY
DR.SUDHA RANI

2. MODERATOR
DR. B.S.K.PRUSTY

3. Step-by-step diagnostic approach
Hypernatremia is defined as plasma sodium concentration of >145 mEq/L. A thorough physical exam should be completed, including evaluation of volume status, mental status, and neurologic assessment.

4. Symptoms and signs of hypernatremia
usually involve CNS manifestations and include irritability, restlessness, lethargy, muscle twitching, spasticity, and hyperreflexia, which are all due to a decreased water content in the brain. [
Severe hypernatremia (plasma sodium concentration >158 mEq/L) may present with serious signs and symptoms, such as hyperthermia, delirium, seizures, and coma

5. etiology
History
Age and mobility of the patient may be helpful in determining the etiology
Lack of access to water is a consideration in infants, disabled people, people with impaired mental status, postoperative patients, and intubated patients in the ICU.
A full medical history ,the presence of any chronic conditions excluded, particularly severe uncontrolled diabetes mellitus (may lead to hyperglycemia resulting in glycosuria, hypernatremia, and hyperosmolar hyperglycemic state)

6. Cushing syndrome, primary aldosteronism, underlying kidney disorder (e
Cushing syndrome, primary aldosteronism, underlying kidney disorder (e.g., sickle cell disease, obstructive uropathy, and reflux nephropathy), or Crohn disease (may have underlying enteric fistulae).
history of diarrhea or loose stools is present, the patient should be asked about the use of any laxative or bowel cleansing agent (e.g., lactulose or sorbitol)

7. In addition, the presence of any conditions (tropical sprue, pancreatitis, and lactose intolerance) causing possible carbohydrate malabsorption, including a history of bowel surgery, should be excluded.
Symptoms of viral gastroenteritis should be elicited (nausea, vomiting, and abdominal pain in addition to diarrhea)
A complete medication history : Drugs such as colchicine, gentamicin, lithium, rifampin, and propoxyphene may induce nephrogenic diabetes insipidus. In addition, loop diuretics (e.g., furosemide and torsemide) and intravenous mannitol can cause an osmotic diuresis resulting in hypernatremia.

8. A history of traumatic brain injury or any other insult to the brain (vascular syndromes, infections, tumors, or aggressive neurosurgery for craniopharyngioma, Rathke cleft cyst, or other hypothalamic tumor) may be suggestive of central diabetes insipidus.
On rare occasions, the presence of a brain tumor or vascular occlusion in the brain may cause primary hypodipsia, which presents with hypernatremic volume depletion.

9. Increased body temperature and exposure to the elements should also be considered. Prolonged exposure to heat, fever, excessive sweating, exercise, and severe cutaneous burns result in insensible water loss due to evaporation from the skin and may cause hypernatremia.

10. A history of recurrent urinary tract infections and pneumaturia, enterovesical fistula ,enterovaginal fistula . enterocutaneous fistula, cologastric fistula.

11. Iatrogenic causes : inadvertent administration of hypertonic sodium chloride or sodium bicarbonate, or even the use of isotonic saline in a patient with an osmotic diuresis.
High-protein diets, including high-protein tube feeds, lead to increased urea production and consequently osmotic diuresis, increasing the risk of hypernatremia.

12. pathophysiology
Pathogenesis of hypernatremia.: The renal concentrating mechanism is the first line of defense against water depletion and hyperosmolality. When renal concentration is impaired, thirst becomes a very effective mechanism for preventing further increases in serum osmolality. Hypernatremia results from disturbances in the renal concentrating mechanism. This occurs in interstitial renal disease, with administration of loop and osmotic diuretics, and with protein malnutrition, in which less urea is available to generate the medullary interstitial tonicity. Hypernatremia usually occurs only when hypotonic fluid losses occur in combination with a disturbance in water intake, typically in elders with altered consciousness, in infants with inadequate access to water, and, rarely, with primary disturbances of thirst , GFR—glomerular filtration rate; ADH—antidiuretic hormone; DI—diabetes insipidus.

13. i
Pure Water deficit : Inadequate intake (e.g., Poor water access due to debility, Adipsic hypernatremia)
Insensible losses Skin Respiratory tract (mechanical ventilation)
Renal Loss: Diabetes insipidus (Primary Central or Nephrogenic DI, Secondary Central or Nephrogenic DI e.g., head trauma, neoplasm, renal disease, hypercalcemia, hypokalemia, pregnancy, Lithium, Demeclocycline, Methoxyflurane, Foscarnet, Aminoglycosides, Amphotericin B, Cidofovir, Vaptans) Water and Sodium deficit
Extrarenal Loss: Skin (burns, excessive sweating) Gastrointestinal Tract (viral gastroenteritis, osmotic diarrhoea e.g. lactulose, vomiting,
Renal Loss: Loop Diuretics, Osmotic diuresis (Hyperglycemia, Mannitol, High Protein Diet, Tissue catabolism), Renal disease, Post obstructive diuresis, Resolving or polyuric ATN.
Sodium Gain :(Iatrogenic, hyperaldosteronism, Cushing’s syndrome, Sea water intake, Ingestion of salt or baking soda, Hypertonic feeding)
Transient : After seizures or vigorus exercise.

15. Effects of Hypernatremia on the Brain and Adaptive Responses
Within minutes after the development of hypertonicity, loss of water from brain cells causes shrinkage of the brain and an increase in osmolality. Partial restitution of brain volume occurs within a few hours as electrolytes enter the brain cells (rapid adaptation). The normalization of brain volume is completed within several days as a result of the intracellular accumulation of organic osmolytes (slow adaptation). The high osmolality persists despite the normalization of brain volume. Slow correction of the hypertonic state reestablishes normal brain osmolality without inducing cerebral edema, as the dissipation of accumulated electrolytes and organic osmolytes keeps pace with water repletion. In contrast, rapid correction may result in cerebral edema as water uptake by brain cells outpaces the dissipation of accumulated electrolytes and organic osmolytes. Such overly aggressive therapy carries the risk of serious neurologic impairment due to cerebral edema.

18. Regulation of brain cell volume
Acute hypernatremia is associated with a rapid decrease in intracellular water content and brain volume caused by an osmotic shift of free water out of the cells. Within 24 hours, electrolyte uptake into the intracellular compartment results in partial restoration of brain volume. A second phase of adaptation, characterized by an increase in intracellular organic solute content (accumulation of amino acids, polyols, and methylamines), restores brain volume to normal. Some patients complete this adaptive response in less than 48 hours. The accumulation of intracellular solutes bears the risk for cerebral edema during rehydration. The brain cell response to hypernatremia is critical.

19. The normal plasma osmolality (Posm) lies between 275 and 290 mOsm/kg and is primarily determined by the concentration of sodium salts. (Calculated plasma osmolality: 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8). Regulation of the Posm and the plasma sodium concentration is mediated by changes in water intake and water excretion. This occurs via 2 mechanisms:
Urinary concentration (via pituitary secretion and renal effects of theantidiuretic hormone  arginine vasopressin [AVP]) 
Thirst 
In a healthy individual, thirst and AVP release are stimulated by an increase in body fluid osmolality above a certain osmotic threshold, which is approximately mosm /Kg. An increased osmolality draws water from cells into the blood, thus dehydrating specific neurons in the brain that serve as osmoreceptors or “tonicity receptors.” It is postulated that the deformation of the neuron size activates these cells (thus acting like mechanoreceptors). On stimulation, they signal to other parts of the brain to initiate thirst and AVP release, resulting in increased water ingestion and urinary concentration, rapidly correcting the hypernatremic state.

20. Workup
Diagnosis of hypernatremia is based on an elevated serum sodium concentration (Na+ >145 mEq/L). It is necessary to obtain the following 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)

21. The first step in the diagnostic approach is to estimate the volume status (intravascular volume) of the hypernatremic patient. The associated volume contraction may be mirrored in a low urine Na+ (usually < 10 mEq/L).
In the hypovolemic patient, a hypertonic urine with a UNa+ < 10 mEq/L will point towards extrarenal fluid losses (GI, dermal), whereas an isotonic or hypotonic urine with a UNa+ >20 mEq/L indicates renal fluid loss (diuretics, osmotic diuresis, intrinsic renal disease).

22. In the euvolemic patient with preserved intravascular volume, hypernatremia is most likely due to pure-water losses. In the presence of hypernatremia, urine osmolality normally should be maximally concentrated (>800 mOsm/kg H2 O). Measurement of the urine osmolality will allow differentiation of the following:
Nonrenal causes with appropriately high urine osmolality - Isolated hypodipsia, increased insensible losses
Renal water loss indicated by inappropriately low urine osmolality - Diabetes insipidus (often U osm < 300 mOsm/kg H 2 O [central, nephrogenic, partial, gestational diabetes insipidus])

23. Symptoms and Signs
The major symptom of hypernatremia is thirst. The absence of thirst in conscious patients with hypernatremia suggests an impaired thirst mechanism. Patients with difficulty communicating may be unable to express thirst or obtain access to water.
The major signs of hypernatremia result from CNS dysfunction due to brain cell shrinkage. Confusion, neuromuscular excitability, hyperreflexia, seizures, or coma may result. Cerebrovascular damage with subcortical or subarachnoid hemorrhage and venous thromboses are common among patients who died of severe hypernatremia.

24. In chronic hypernatremia, osmotically active substances occur in CNS cells (idiogenic osmoles) and increase intracellular osmolality. Therefore, the degree of brain cell dehydration and resultant CNS symptoms are less severe in chronic than in acute hypernatremia.
When hypernatremia occurs with abnormal total body Na, the typical symptoms of volume depletion or overload are present . Patients with renal concentrating defects typically excrete a large volume of hypotonic urine. When losses are extrarenal, the route of water loss is often evident (eg, vomiting, diarrhea, excessive sweating), and the urinary Na concentration is low.

25. Baseline laboratory investigations
A plasma sodium concentration of >145 mEq/L confirms the presence of hypernatremia.
Serum sodium levels of 150 to 170 mEq/L usually indicate volume depletion and the causes thereof.
Serum sodium of >170 mEq/L is usually associated with diabetes insipidus (nephrogenic or central).
Serum sodium of >190 mEq/L is usually a result of exogenous sodium gain

26. Measurement of the urine osmolality will allow differentiation of the following:
Nonrenal causes with appropriately high urine osmolality - Isolated hypodipsia, increased insensible losses
Renal water loss indicated by inappropriately low urine osmolality - Diabetes insipidus (often U osm < 300 mOsm/kg H 2 O [central, nephrogenic, partial, gestational diabetes insipidus])

27. To distinguish between central and nephrogenic diabetes insipidus, first obtain a plasma AVP level and then determine the response of the urine osmolality to a dose of AVP (or preferably, the V2-receptor agonist DDAVP). Generally, an increase in urine osmolality of greater than 50% reliably indicates central diabetes insipidus, while an increase of less than 10% indicates nephrogenic diabetes insipidus; responses between 10% and 50% are indeterminate. Hyperosmolar patients with an elevated AVP level have nephrogenic diabetes insipidus; those with central diabetes insipidus will have inadequately low AVP level.

28. 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)

29. Calculating the free-water clearance (cH2 O), which measures the amount of solute-free water excreted by the kidney, is usesful. However, 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 O = Vurine [1-(UOsm/SOsm)]; cH2 Oe = Vurine [1-(UNa +UK)/SNa]

30. Imaging Studies
A magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain may be helpful in cases of central diabetes insipidus eventuating from head trauma or infiltrative lesions.

31. Medical Care The goals of management in hypernatremia are as follows :
Recognition of the symptoms, when present
Identification of the underlying cause(s)
Correction of volume disturbances
Correction of hypertonicity
The rate of sodium correction depends on how acutely the hypernatremia developed and on the severity of symptoms.

32. Acute symptomatic hypernatremia, defined as hypernatremia occurring in a documented period of less than 24 hours, should be corrected rapidly
Chronic hypernatremia (>48 h), however, should be corrected more slowly due to the risks of brain edema during treatment.

33. The brain adjusts to and mitigates chronic hypernatremia by increasing the intracellular content of organic osmolytes. If extracellular tonicity is rapidly decreased, water will move into the brain cells, producing cerebral edema, which may lead to herniation, permanent neurologic deficits, and myelinolysis.

34. Treatment recommendations for symptomatic hypernatremia Recommendations are as follows:
Establish documented onset (acute, < 24 h; chronic, >24h)
In 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 .

35. Chronic hypernatremia with no or mild symptoms should be corrected at a rate not to exceed 0.5 mEq/L/h and a total of 8-10 mEq/d (eg, 160 mEq/L to 152 mEq/L in 24 h).
If a volume deficit and hypernatremia are present, intravascular volume should be restored with isotonic sodium chloride prior to free-water administration

36. Estimation of the replacement fluid
Total body water (TBW) refers to the lean body weight of the patient (percentage of TBW decreases in morbidly obese patients.
Adrogué–Madias, are preferred over the conventional equation for water deficit.

37. Formulas used to manage hypernatremia are outlined below.
Equation 1: TBW = weight (kg) x correction factor

38. Correction factors are as follows:
Children: 0.6
Nonelderly men: 0.6
Nonelderly women: 0.5
Elderly men: 0.5
Elderly women: 0.45

39. Equation 2: Change in serum Na+ = (infusate Na+ - serum Na+) ÷ (TBW + 1)
Equation 3: Change in serum Na+ = ([infusate Na+ + infusate K+] – serum Na+) ÷ (TBW + 1)
Equation 2 allows for the estimation of 1 L of any infusate on serum Na+concentration.
Equation 3 allows for the estimation of 1 L of any infusate containing Na+ and K+ on serum Na+

40. Common infusates and their Na+ contents include the following:
5% dextrose in water (D 5 W): 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

41. An example of the use of the above calculations is as follows: An obtunded 80-year-old man is brought to the emergency room with dry mucous membranes, fever, tachypnea, and a blood pressure of 134/75 mm Hg. His serum sodium concentration is 165 mmol/L. He weighs 70 kg. This man is found to have hypernatremia due to insensible water loss.
The man's TBW is calculated by the following:
(0.5 x 70) = 35 L
To reduce the man's serum sodium, D5 W will be used. Thus, the retention of 1 L of D5 W will reduce his serum sodium by ( ) ÷ (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 L will be added for obligatory water loss to make a total of up to 3.67 L of D5 W over 24 hours, or 153 cc/h.

42. Other treatment considerations
If hypernatremia is accompanied by hyperglycemia with diabetes, take care when using a glucose-containing replacement fluid. However, the appropriate use of insulin will help during correction.
In hypervolemic and hypernatremic patients in the ICU who have an impaired renal excretion of sodium and potassium (eg, after renal failure) an addition of a loop diuretic to free water boluses increases renal sodium excretion. Fluid loss during loop diuretic therapy must be restored with the administration of fluid that is hypotonic to the urine

43. Hypernatremia in the setting of volume overload (eg, heart failure and pulmonary edema) may require dialysis for correction.
Although water can be replaced by oral and parenteral routes, an obtunded patient with a large free water deficit likely requires parenteral treatment. If the deficit is small and the patient is alert and oriented, oral correction may be preferred.

44. Once hypernatremia is corrected, efforts are directed at treating the underlying cause of the condition. Such efforts may include free access to water and better control of diabetes mellitus. In addition, correction of hypokalemia and hypercalcemia as etiologies for nephrogenic diabetes insipidus may be required. Vasopressin (AVP, DDAVP) should be used for the treatment of central diabetes insipidus.

45. Surgical Care
Surgical treatment may be required in the setting of severe central nervous system trauma and associated central diabetes insipidus.