1. HYPONATREMIA Dr. M. A. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin

2. HYPONATREMIA  Hyponatremia is commonly defined as a serum sodium concentration below 135 meq/L but can vary to a small degree in different clinical laboratories.  The dilutional fall in serum sodium is in most patients associated with a proportional reduction in the serum osmolality (i.e., to a level below 275 mosmol/kg), but there are some exceptions  Hyponatremia represents a relative excess of water in relation to sodium. It can be induced:  Marked increase in water intake (primary polydipsia)  Impaired water excretion from advanced renal failure  Persistent release of antidiuretic hormone (ADH).

3. Disorders in which ADH levels are elevated or appropriately suppressed Effective circulating volume depletion True volume depletion Heart failure Cirrhosis Thiazide diuretics Inappropriate ADH secretion Hormonal changes Adrenal insufficiency Hypothyroidism Pregnancy ADH levels appropriately suppressed Advanced renal failure Primary polydipsia Beer drinker's potomania Hyponatremia with elevated or normal plasma osmolality High plasma osmolality (effective osmols) Hyperglycemia Mannitol High plasma osmolality (ineffective osmols) Renal failure Alcohol intoxication Normal plasma osmolality Pseudohyponatremia (laboratory artifact) High triglycerides Cholestatic and obstructive jaundice (lipoprotein X) Multiple myeloma Absorption of irrigant solutions Glycine Mannitol Sorbitol

4. Acute hyponatremia: Developed within the previous 24 hours Hyperacute hyponatremia Developed over just a few hours due to a marked increase in water intake (self-induced water intoxication, as may be seen in marathon runners, psychotic patients, and users of ecstasy Sub-acute : Developed within the previous 24 to 48 hours. Chronic hyponatremia: Present for more than 48 hours, or if the duration is unknown (such as in patients who develop hyponatremia at home). Mild to moderate and sever hyponatremia: Mild: Serum Na concentration 130 - 135 meq/L; Moderate: Serum Na concentration 121 - 129 meq/L. Severe: Serum sodium of 120 meq/L or less.

5. EVALUATION — The diagnostic approach consists of a directed history and physical examination, appropriate laboratory tests.  A history of fluid loss (e.g., vomiting, diarrhea, diuretic therapy) and, on examination, signs of volume depletion, such as decreased skin turgor, a low jugular venous pressure or orthostatic or persistent hypotension.  A history of low protein intake and/or high fluid intake.  A history consistent with one of the causes of SIADH.  Use of medications associated with hyponatremia.  Signs of peripheral edema and/or ascites, which can be due to heart failure, cirrhosis, or renal failure.  Symptoms and signs suggestive of adrenal insufficiency or hypothyroidism.

6.  Absent symptoms – Patients are frequently asymptomatic, if the hyponatremia is chronic and of mild or moderate severity (i.e., serum sodium >120 meq/L). However, such patients may have subclinical impairments in mentation and gait.  Mild to moderate symptoms –Relatively nonspecific and include headache, nausea, vomiting, fatigue, gait disturbances, and confusion in patients with chronic hyponatremia (i.e., >48 hours duration).  In patients with more acute hyponatremia, such symptoms should be considered ominous and may evolve without warning to seizures, respiratory arrest, and herniation.  Severe symptoms – Severe symptoms of hyponatremia include seizures, obtundation, coma, and respiratory arrest. Symptoms : Hyponatremia

7. Signs & Symptoms  More profound when the decrease in sodium is very large or occurs rapidly (i.e. over hours)  Generally asymptomatic if Na+ level >125  Symptoms include: – Headache – Nausea, vomiting – Muscle cramps – Disorientation, depressed reflexes, lethargy, restlessness – Seizure, coma, permanent brain damage, respiratory arrest, brainstem herniation & death

8. Approach to Hyponatremia  1 st assess volume status Is the patient volume overloaded, depleted, or euvolemic?  2 nd assess osmolality (hyper, iso, or hypo) Is the blood concentrated? For hypotonic hyponatremia, continue to 3 rd step:  3 rd assess urinary sodium excretion and FeNa % Is the urine concentrated? *Remember VOU – volume status, osmolality, and urine studies

9. Three laboratory tests provide important initial information in the differential diagnosis of hyponatremia :  Serum osmolality  Urine osmolality  Urine sodium, potassium, and chloride concentrations  Serum osmolality (Sosm), (NR 275 to 290 mosmol/kg) is reduced in most hyponatremic patients.  In some patients Sosm is high or normal.  The three most common causes of hyponatremia with a high or normal Sosm  Marked hyperglycemia  Severe azotemia  Alcohol intoxication Laboratory tests :

10. STEP 1 – (V) Volume Status 1 st assess volume status (extracellular fluid volume) Hypotonic hyponatremia has 3 main etiologies: – Hypovolemic – both H2O and Na decreased (H20 < Na) Consider obvious losses from diarrhea, vomiting, dehydration, malnutrition, etc. – Euvolemic – H20 increased and Na stable Consider SIADH, thyroid disease, primary polydipsia – Hypervolemic – H20 increased and Na increased (H2O > Na) Consider obvious CHF, cirrhosis, renal failure

11. STEP 2 - (O) Osmolality 2 nd assess osmolality hyper, iso, or hypo – Hypotonic hyponatremia = warrants further workup, when there is no obvious fluid overload or depletion Serum Osmolality: Calculated serum osmolality (2 X serum [Na]) + [glucose, in mmol/L] + [urea, in mmol/L] – Hypertonic - >295 hyperglycemia, mannitol, glycerol – Isotonic - 280-295 pseudo-hyponatremia from elevated lipids or protein – Hypotonic - <280 excess fluid intake, low solute intake, renal disease, SIADH, hypothyroidism, adrenal insufficiency, CHF, cirrhosis, etc.

12. STEP 3 – (U) Urine Studies For euvolemic hyponatremia, check urine osmolality – Urine osmolality <100 - excess water intake Primary polydipsia, tap water enemas, post-TURP – Urine osmolality >100 - impaired renal concentration SIADH, hypothyroidism, cortisol deficiency Check urine sodium & calculate FeNa % – A low urine sodium (<10) and low FeNa (<1%) implies the kidneys are appropriately reabsorbing sodium – A high urine sodium (>20) and high FeNa (>1%) implies the kidneys are not functioning properly

13. Diagnosis of the underlying aetiology of the hyponatraemia using this system relies on an accurate assessment of the patient's volume status and measurement of urinary [Na + ]. Urine [Na + ] <20 mmol/LUrine [Na + ] >40 mmol/L Hypovolaemia (dry tongue, decreased CVP, increased urea, increased pulse, decreased BP) Vomiting, diarrhoea, skin losses, burns Diuretics, Addison's, cerebral salt-wasting syndrome, salt-losing nephropathy EuvolaemiaHypothyroidism Any cause + hypotonic fluids SIADH Glucocorticoid deficiency Drugs Hypervolaemia (oedema, ascites, LVF, increased JVP, increased CVP) CCF, cirrhosis Nephrotic syndrome Renal failure, any cause + diuretics BP = blood pressure; CCF = congestive cardiac failure; CVP = central venous pressure; LVF = left ventricular failure; JVP = jugular venous pressure; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.

14. Hyponatremia causes: Hyperglycemia – In patients with marked hyperglycemia, which is almost always a manifestation of uncontrolled diabetes, the increase in serum glucose raises the Sosm, which pulls water out of the cells and lowers the serum sodium concentration Azotemia – In patients with advanced renal failure, the hyponatremia is due to an inability to excrete water resulting from the impairment in renal function. Although this will tend to lower the Sosm, this effect is counterbalanced to a variable degree by the associated elevation in blood urea nitrogen (BUN), resulting in an Sosm that may be normal or elevated. Alcohol intoxication – True hyponatremia is common in patients with alcoholism. The reduction in the Sosm associated with hyponatremia can be offset in some patients by high circulating levels of ethanol.

15. Less common causes of hyponatremia with a high or normal Sosm include: Administration of either hypertonic mannitol or maltose or sucrose in conjunction with intravenous immune globulin will cause hyponatremia in patients with renal failure. Irrigant absorption – The absorption of nonconductive glycine, sorbitol, or mannitol irrigation solutions during TURP (called the transurethral resection syndrome) or during hysteroscopy or laparoscopic surgery can lower the serum sodium by increasing the extracellular fluid volume with these sodium free solutions. Pseudohyponatremia – Hyperlipidemia or hyperproteinemia lower the serum sodium concentration (and therefore the calculated Sosm) without changing the measured Sosm. This laboratory artifact is called pseudohyponatremia

16. Emergency therapy  Patients with severe symptoms such as seizures or obtundation.  Patients symptomatic with acute hyponatremia. even if such symptoms are mild.  Patients with hyperacute hyponatremia due to self- induced water intoxication, even if there are no symptoms at the time of initial evaluation.  Symptomatic patients who have either acute postoperative hyponatremia or hyponatremia associated with intracranial pathology. Treatment Hyponatremia Patients with acute or hyper-acute hyponatremia, most patients with severe hyponatremia, and many symptomatic patients with moderate hyponatremia should be treated in the hospital

17. Non-emergency therapy  Asymptomatic patients with acute or sub-acute hyponatremia: Initial treatment with hypertonic saline rather than other therapies.  Patients with severe hyponatremia (i.e., serum sodium ≤120 meq/L) who have either absent or mild to moderate symptoms. initial treatment with hypertonic saline  Patients with moderate hyponatremia who have mild to moderate symptoms. Initial therapy depends in large part upon the underlying etiology. Treatment Hyponatremia Patients with acute or hyper-acute hyponatremia, most patients with severe hyponatremia, and many symptomatic patients with moderate hyponatremia should be treated in the hospital

18.  In all hyponatremic patients the serum sodium initially be increased by 4 to 6 meq/L during the first 24 hours and by less than 9 meq/L over any given 24- hour period.  In patients who require non-emergency therapy, this goal can be achieved slowly.  Patients receiving emergency therapy their serum sodium measured every two hours to ensure increase at the desired rate.  Other patients who are treated for chronic hyponatremia in the hospital should have their serum sodium measured often enough to ensure an appropriate rate of correction and to allow the clinician to react quickly to impending overly rapid correction (e.g., every four hours).  The urine output should also be monitored Treatment

19.  An intravenous bolus of 100 mL of 3% saline is given and repeated if symptoms persist after 10 minutes.  Once symptoms improve, the rate of sodium correction in 24 hours with this regimen should not exceed 6 to 8 mEq/L in 24 hours or 12 to 14 mEq/L in 48 hours.  Check serum sodium every two hours and monitor urine output closely  If the patient is making large volumes of urine, serum sodium may be rising too quickly.  This can be accomplished by giving desmopressin to slow urinary free water loss while simultaneously giving hypotonic fluids. Severe symptomatic hyponatremia

20.  Hypovolemic hyponatremia: Treatment is aimed at correcting volume status  ADH secretion will always choose to preserve volume over osmolarity.  In most cases, normal saline will restore intravascular volume.  Rapid correction of serum Na, so hypotonic solutions (½ NS) should be used.  Once volume is replete, ADH release will cease.  Vaptans should not be used in hypovolemic hyponatremia, or in conjunction with other treatments for hyponatremia. Asymptomatic or mildly symptomatic hyponatremia:

21. Euvolemic Hyponatremia: Typically caused by SIADH- high Uosm (>100 mosm/L) and a high UNa (>30 mEq/L). Free water restriction, and fluid at least 500 mL below a patient’s urine output. If this is ineffective, salt tabs can be given to increase the solute load. Nine grams of salt tabs in 3 divided doses (equivalent to 1 L of NS). Patients with highly concentrated urine (Uosm >500 mosm/L) will not respond to the salt load. In such patients, a loop diuretic can be used to help excrete free water. Asymptomatic or mildly symptomatic hyponatremia

22.  Hypervolemic Hyponatremia: caused by CHF, cirrhosis, or NS.  ADH is in all cases.  In CHF and cirrhosis, the degree of hyponatremia is a marker of disease.  Fluid restriction is the cornerstone of therapy  If the patient’s volume status is not optimized, then loop diuretics may improve hyponatremia through excretion of diluted urine.  In addition, ACEI can improve hyponatremia in CHF by reducing ADH levels and improving cardiac output via after-load reduction.  Recent interest in the use of vasopressin V2 receptor antagonists or “vaptans.”  The latest AHA guidelines for CHF recommend (class IIb) vaptans in patients with “hyponatremia that may be causing cognitive symptoms when standard measures have failed. Asymptomatic or mildly symptomatic hyponatremia