HYPERNATREMIA/HYPONATREMIA

Transcription

1 The following is material that is not all Dr. Ciorciari's original thoughts and not fully referenced to give credit to all information cited. Further this is not considered an authoritative source but suggestions and perspectives that may aid in guiding your art of medicine. 01/22/13 1

2 The atomic weight of sodium is 23. The atomic weight of chloride is The valance is one. For normal saline, there are 9000 mg in a liter. Divide that by 58.5 (the AW of both sodium and chloride) and you get close to 154 (which is the amount of meq per liter; for sodium, potassium and chloride, the mosm equals the meq). One mosm of a divalent ion (calcium) is equal to 2 meq. An osmole is 1 mole of osmotically active particles or one mole of solute present in solution. A mole of any atoms has a mass in grams equal to the atomic weight of the element. A mosm is equal to 1/1000 of an osmole. Blood plasma comprises 90% water and 10 % cellular material. Normal sodium plasma levels average 140 meq/l, which is the amount of sodium found in the liquid portion of plasma. To get a true concentration of sodium in a crystalloid solution, the 10% cellular component needs to be accounted for. This means that the normal sodium level of 140 meq/l must be increased by 10% or 14 meq, for a total of 154 meq/l, which is the level of sodium found in normal saline. Remember that one liter of normal saline has 3.5 grams of sodium in it. If total body water changes without an accompanying change in the total body solute, plasma osmolality changes, and hyponatremia or hypernatremia results. Disturbances of the plasma sodium concentration are therefore the result of alterations in water homeostasis. In contrast, disturbances of sodium homeostasis primarily affect extracellular fluid volume and may result in hypovolemia or hypervolemia. Although water homeostasis and sodium balance are independently regulated, there are strong interactions. Alterations in sodium balance, although not a direct cause hypernatremia or hyponatremia, modulate water homeostasis and may contribute to the development of these disturbances. Because sodium is a functionally impermeable solute, it contributes to tonicity and induces the movement of water across cell membranes. Therefore, hypernatremia invariably denotes hypertonic hyperosmolality and always causes cellular dehydration, at least transiently. Regulation of Water Homeostasis: Thirst, ADH, and aldosterone. When the osmolarity is equal or above , osmoreceptors in the organum vasculosum of the lamina terminalis (OVLT) in the anterior wall of the third ventricle (Thrasher, Am J Physiol, 1987) are activated, which leads to thirst. In response to increases in osmolality above this threshold, thirst increases linearly. Thirst is also stimulated by hypovolemia (thirst is not stimulated unless the change in volume exceeds 10%) and hypotension. When the osmolarity is at or above , ADH (also in the hypothalamus) is transported in to the posterior pituitary (affects the permeability of the collecting duct; hypotonicity leads to dilute urine excretion, hypertonicity leads to concentrated urine excretion). ADH is also released when there is a decrease in blood volume, blood 01/22/13 2

3 pressure (through the carotid sinus; these do not occur until the effective arterial volume is decreased by 8-10% (Dunn, J Clin Invest, 1973, studied in the rat), SIADH, oral hypoglycemics, narcotics, nicotine, pneumonia, asthma, pain, nausea, Tegretol (Dilantin and ETOH are inhibitors). Aldosterone: renin angiotensin aldosterone. Release is proportional to the serum potassium as well as a decrease in the extracellular fluid. Renal water excretion provides the main defense against water depletion; however, renal water conservation alone is insufficient to defend against dehydration and hypertonicity. The ultimate defense against hypernatremia is the stimulation of thirst. Individuals with normal kidney function can eliminate up to of free water daily (Noakes TD, S Afr Med J, 2001) Hypernatremia Hypernatremia is defined as a rise in the serum sodium concentration of 145 mmol per liter. The primary deficit in hypernatremia is impaired water intake (in hyponatremia, it is usually a defect in renal water handling). Hypertonicity: Is defined as increases solutes in extracellular fluid (ECF) that do not readily cross cell membranes (eg, sodium, mannitol, glucose). Cells tend to lose water and shrink in a hypertonic environment. Hyperosmolarity: Is defined as an increase in dissolved solutes. These solutes may freely cross cell membranes (eg, urea, alcohol) or they may not (glucose). Hyperosmolarity may be present without hypertonicity. If this is so, cell shrinkage will not occur. To review: The calculation of osmolarity: 2(Na) + glucose/18 + BUN/2.8. Other unmeasured solutes that can contribute to the osmolarity include: methanol (3.2), ethanol (4.6), ethylene glycol (6.2), acetone (6.0), and isopropyl alcohol (6.0). The number in the parenthesis is the molecular weight divided by 10. Dividing the osmolar gap by this number will give you the approximate concentration of the solute in mg/dl. Note the difference between: Osmolality: osmoles per kilogram of water Osmolarity: osmoles per liter of solution The osmotic pressure depends not on the mass or weight of a substance in solution, but on the number of molecules or ions. One mole of any substance which does not dissociate into ions or forms only one ion in solution = 1 osmole. For example: 180 g of glucose or 60 g of urea in 1 liter will be 1 osmole. 01/22/13 3

4 The terminology associated with calculated and measured osmotic activity is often confusing and is not consistent in the medical literature. Osmotic concentration determinations are typically expressed as either milliosmoles/ kilogram (mosm/kg) of solvent -- referred to as osmolality, or milliosmoles/liter (mosm/l) of solution -- referred to as osmolarity. The selection of which term to use (osmolality or osmolarity) depends on how the concentration was derived. When derived by an osmometer in clinical laboratories that use a method such as freezing point depression of water (or less commonly, the vapor pressure technique), the concentration is expressed in terms of solvent and is appropriately referred to as osmolality. Bedside calculations of osmotic activity by clinicians (using the patient's laboratory data), however, are usually expressed in terms of solution, and hence the term osmolarity is appropriate. Therefore, when evaluating published literature, the reader must refer to the study methodology to determine which term is appropriate, since the investigators may have converted osmolar units to osmolal units in an attempt to increase the accuracy of calculated values, or they may have used a term such as osmolality to describe both measured and calculated values. The need to account for differences in the units of the calculated and measured osmotic activity values when estimating the gap is another source of confusion. In the clinical setting, the amount of error introduced by not adjusting for the differences in the osmolality and osmolarity units is small and is usually not performed. Therefore, the gap is actually a hybrid value between the measured osmolality, with units of mosm/kg, and the calculated osmolarity, with units of mosm/l, which explains the variable terminology (osmolal gap vs osmolar gap) found in published literature. When the gap is derived in this manner, the issue seems to be less a function of which term is chosen to describe the gap and more related to the consistent use of whatever term is chosen. For example, in a recent article in a critical care journal, the authors subtracted measured and calculated (with adjustment for water content) osmolality values to determine the gap, yet "osmolar gap" was used to describe the resulting gap values in both the article title and [8, 9] text. The term "osmol gap" increasingly has been appearing in published literature and seems to be a useful way of avoiding the sometimes misleading implications of terms such as "osmolal gap" and "osmolar gap." As illustrated, the terminology associated with osmotic activity measurements in the clinical arena and the medical literature is confusing and inconsistent. It is, indeed, apparent that within the discipline of clinical medicine, both clarification, as well as standardization, of the terminology still needs to occur. At this juncture, however, the weight of scientific data appear to support the use of the term "osmol gap" when subtracting values for calculated osmolarity (or estimated osmolality) from measured osmolality. The methodology of articles should explain how the calculated values were derived and the laboratory technique used to measure osmolality. 01/22/13 4

5 Water homeostasis results from the balance between water intake and the combined water loss from renal excretion, respiratory, skin and GI sources. Under normal conditions, water intake and losses are matched. Insensible (skin and respiratory) losses average 0.6 ml/kg/hour or approximately 1 liter/day in adults. Insensible water loss may be increased in burns, fever, tachypnea, exercise, and elevations in body temperature. GI water loss is normally less than ml/day but can increase markedly in the setting of diarrhea, vomiting, NG suctioning, and bilary or pancreatic drainage. Thirst is regulated physiologically, responding to changes in serum tonicity and extracellular volume. Overall, thirst is the major defense against hypertonicity. Hypernatremia represents a deficit of water in relation to the body s sodium stores, which can result from a net water loss or a hypertonic sodium gain. Net water loss accounts for the majority of cases of hypernatremia. It can occur in the absence of a sodium deficit (pure water loss) or in its presence (hypotonic fluid loss). Groups at the highest risk are those with altered mental status, intubated patients, infants and the elderly (thirst or access to water is impaired). Hypernatremia in infants usually results from diarrhea, whereas in elderly persons it is usually associated with infirmity or febrile illness. Elderly patients generally have few symptoms until the serum sodium concentration exceeds 160. Rapid sodium loading in adults can cause convulsions and coma (Ross, Hypernatremia, Medicine 1969; De Villota, Hyperosmolar crisis following infusion of hypertonic sodium chloride for purposes of therapeutic abortion, Am J Med 1973). With hypernatremia, brain cells initially shrink from water extraction. Water loss is offset immediately by active transport of electrolytes across the neuronal cell membrane. After one hour of hypernatremia, the neurons begin to generate intracellular organic solutes (amino acids, trimethylamines, and myoinositol) that protect the neurons from structural damage and restore cell volume. This, however, leads to ineffective functioning of neurons. This protective mechanism is important to remember when treating a patient with hypernatremia. Otherwise, water replacement may proceed at a rate that does not allow for excretion of accumulated solutes, leading to cerebral edema. Aggressive treatment with hypotonic fluids may cause cerebral edema, which can lead to coma, convulsions and death (3 articles, the last one written in 1969; one paper is an animal study). Brain shrinkage induced by hypernatremia can cause vascular rupture (traction on the dural veins and sinuses), with cerebral bleeding, subarachnoid hemorrhage, and permanent neurologic damage or death. Venous congestion can lead to venous or sinus thrombosis. Arterial stretching can result in subcortical hemorrhages and cerebral infarctions. 01/22/13 5

6 Frequency: Hypernatremia is evidenced in approximately 0.3-1% of hospitalized patients; 60-80% of these patients develop hypernatremia after hospital admission. Mortality/Morbidity: Overall mortality rates are from 40-55%; the highest rates are from individuals who are elderly. Most deaths are due to the underlying disease process, not the hypernatremia. However, delays in treatment (or inadequate treatment), of hypernatremia will increase mortality. Chronic duration (greater than 2 days carries a higher mortality). History: Signs and symptoms of hypernatremia largely reflect CNS dysfunction and are prominent when an increase in the serum sodium concentration is large or occurs rapidly. Can include thirst (may be present initially), restlessness, irritability, disorientation, dry mouth, fever. Physical: Hyperpyrexia, hyperventilation, flushed skin, oliguria, hyperreflexia, muscle twitching, spasticity, depressed mental status, delirium, seizures, coma. Infant findings: Hyperpnea, muscle weakness, restlessness, a characteristic high-pitched cry, insomnia, lethargy, coma. Convulsions are typically absent except in cases of inadvertent sodium loading or aggressive rehydration. Hypovolemic Hypernatremia: Extrarenal losses: Diarrhea Vomiting NG drainage Enterocutaneous fistula Use of osmotic cathartic agent (eg, lactulose) Significant Burns Renal losses: Osmotic diuresis Diuretics Postobstruction diuresis Intrinsic renal disease Polyuric phase of ATN Hypervolemic Hypernatremia: Hypertonic saline Sodium Bicarbonate administration Accidental salt ingestion Cushing syndrome Primary hyperaldosteronism Ingestion of sea water Hypertonic saline enemas Hypertonic dialysis 01/22/13 6

7 Euvolemic Hypernatremia: Increased insensible water loss DI: The inability to conserve water and maintain an optimum free water level. The kidneys pass large amounts of dilute urine regardless of the body s hydration state, leading to symptoms of extraordinary thirst, copious water intake (up to 2-0 liters a day), dry skin and constipation. Polyuria: more than 3 liters in 24 hours Central DI: deficient vasopressin secretion (causes): Central diabetes insipidus (DI) is characterized by decreased secretion of antidiuretic hormone (ADH), also known as arginine vasopressin (AVP) that results in polyuria and polydipsia by diminishing the patient's ability to concentrate urine. Diminished or absent ADH can be the result of a defect in one or more sites involving the hypothalamic osmoreceptors, supraoptic or paraventricular nuclei, or the supraopticohypophyseal tract. In contrast, lesions of the posterior pituitary rarely cause permanent DI because ADH is produced in the hypothalamus and still can be secreted into the circulation. DI is uncommon, with a prevalence of 1 case per 25,000 people. Pregnancy is associated with an increased risk of DI. Vasopressin: 1. Is a peptide hormone composed of 9 amino acids 2. It is synthesized within the supraoptic and paraventricular nuclei of the hypothalamus. It is transported from the hypothalamus via nerve tracts to the neural lobe of the pituitary, where it is released into the circulation 3. V 1a sites of action: Vascular smooth muscle (causes vasoconstriction), platelets (aggregation), brain (memory), hepatocyte (glycogenolysis), uterine muscle (constriction), adrenal gland (aldosterone and cortisol secretion) 4. V 1b sites of action: anterior pituitary (release of ACTH), brain (beta-endorphin release), pancreas (insulin release) 5. V 2 sites of action: renal collecting ducts (primary, causing free water and sodium resorption), vascular endothelium and vascular smooth muscle (release of vwf and Factor VIII as well as vasodilation) Head trauma, suprasellar or intrasellar tumors, granulomas, histiocytosis, infectious (encephalitis, meningitis, Guillain-Barré syndrome), vascular (cerebral aneurysm, thrombosis, hemorrhage, Sheehan syndrome, CVA), leukemia, lymphoma. Recent literature indicates 30% of cases to be idiopathic, 25% related to malignant or benign tumors of the brain or pituitary (low levels of vasopressin), 16% secondary to head trauma, and 20% following cranial surgery. 01/22/13 7

8 Treatment of central DI: 1. ADH replacement (Pitressin). There is variable duration of activity and local irritation of the nasal mucosa 2. Desmopressin (DDAVP). This is the current drug of choice. For all dosage forms the starting dosage is 10 micrograms at night to relieve nocturia. A morning dose can be added if symptoms continue during the day. 3. Chlorpropramide (Diabenase ): This decreases the clearance of free water, but only if the nuuerohypophysis has some residual secretory capacity. Its antidiuretic effect is likely due to raising the sensitivity of the epithelium of the collecting duct to low concentrations of circulating ADH. 4. Tegretol: reduces the sensitivity of the osmoregulatory system of ADH secretion and simultaneously raises the sensitivity of the collecting duct to the hydro-osmotic action of the hormone 5. Clofibrate: a lipid-lowering agent, stimulates residual ADH production in patients with partial DI. 6. Thiazide diuretics: paradoxically can be used for DI. They exert their effect by decreasing sodium and chloride absorption in the distal tubule, therefore allowing more sodium absorption, and therefore more water absorption, in the proximal tubule Nephrogenic DI (end organ hyporesponsiveness) is characterized by a decrease in the ability to concentrate urine due to a resistance to ADH action in the kidney. Nephrogenic DI can be observed in chronic renal insufficiency, lithium toxicity, hypercalcemia, hypokalemia, and tubulointerstitial (medullary cystic) disease. The rare hereditary form of nephrogenic DI is transmitted as an X-linked genetic defect of the V2 receptor gene. A rare autosomal variant is caused by mutation in the aqua porin gene AQP2, a water-channel exclusively expressed in the collecting ducts of the kidney. Causes of nephrogenic DI: Acquired: Renal diseases: (chronic renal failure, chronic renal medullary disease, pyelonephritis, obstructive uropathy, polycystic kidney disease, renal transplantation), electrolyte disturbances (chronic hypokalemia or chronic hypercalcemia). Potassium depletion is usually associated with the development of polyuria, polydipsia, and a renal concentrating defect that is resistant to ADH. Chronic hypercalcemia may result in interstitial calcification and fibrosis with secondary anatomic disruption of the renal concentrating mechanism, which therefore produces an large amount of urine. Drugs: (amphotericin B (nephrotoxic to the kidney), colchicine (disrupts microtubular function), demeclocycline (an antibiotic of the tetracycline group), 01/22/13 8

9 gentamicin (impairs cellular response to ADH), lithium, loop diuretics, methoxyflurane). Lithium can cause polyuria and polydipsia in as many as 60% of patient at the strat of treatment and the side effects can last in 20-25% even if the plasma lithium is in therapeutic range. Pregnancy (will disappear 4-6 weeks after pregnancy; the vasopressinase produced by the placenta destroys ADH too rapidly), Multiple myeloma, sickle cell disease, protein starvation Familial Treatment of nephrogenic DI: This does not respon to ADH. It is treated by correcting hypokalemia or hypercalcemia and discontinuing any drugs involved. Thiazide diuretics are used along with modest salt restriction to reduce the delivery of filtrate to the diluting segments of the nephron. They exert their effect by decreasing sodium and chloride absorption in the distal tubule, thereby allowing more sodium absorption and therefore more water absorption in the proximal tubule. One way to differentiate between central and nephrogenic DI: In central DI, the vasopressin level will be low after eight hours of water deprivation. It will not be that way in nephrogenic DI. In DI, the urine osmolality is less than the serum osmolality and the urine sodium is variable. The normal urine osmolarity is close to the serum osmolarity. Insensible water loss is about 800 ml/day, however you gain about ml/day through oxidation. DI is characterized by marked polyurea with excretion of a dilute urine and secondary polydipsia. You should measure serum electrolytes and glucose, urine specific gravity, urinary sodium, simultaneous serum and urine osmolality, and ADH levels. A urine specific gravity of or less and a urine osmolality less than 200 mosm/kg is the hallmark of DI. Random plasma osmolality generally is greater than 287 mosm/kg. (These patients appear euvolemic because most of the free water loss is from the intracellular and interstitial spaces, with < 10% occurring from the intravascular space. Typically, symptoms result if the serum sodium is > Treatment for central DI: Vasopressin: 5U SQ every hours, or 01/22/13 9

10 Desmopressin 5-10 micrograms intranasally or mg PO bid In an emergency, most patients with diabetes insipidus (DI) can drink enough fluid to replace their urine losses. Replace losses with dextrose and water or IV fluid hyposmolar to the patient's serum. Avoid hyperglycemia, volume overload, and a correction of hypernatremia that is too rapid. A good rule of thumb is to reduce serum sodium by 0.5 mmol/l/h. Water deficit may be calculated based on the assumption that body water is approximately 60% of body weight in kilograms. In case of inadequate thirst, desmopressin is the drug of choice. Generally, it can be administered 2-3 times per day. Patients may require hospitalization to establish fluid needs. Frequent electrolyte monitoring is recommended. Pharmaceutical therapy for DI includes subcutaneous, nasal, and oral preparations of vasopressin analogues, as well as chlorpropamide, carbamazepine, clofibrate, thiazides, and indomethacin (limited efficacy). Treatment for nephrogenic DI: HCTZ 25 mg PO bid: Thiazide treatment reduces renal water output (via an increase in proximal sodium reabsorption secondary to increased urinary sodium excretion), but may be counterproductive since it can increase lithium retention and can lead to complications such as hypokalemia and hypercalcemia. Hypokalemia may, in turn, exacerbate the nephrogenic diabetes insipidus. Amiloride: potassium-sparing diuretic Adipsic Hypernatremia: Secondary to decreased thirst. Destruction of the thirst centers of the hypothalamus. Causes include: Vascular (15%): Anterior communicating aneurysm, intrahypothalmic hemorrhage, internal carotid artery ligation Neoplastic (50%): Primary (tumor of the hypothalamus) or metastatic (more commonly breast and lung) Granuloma (20%): Histiocytosis X, sarcoidosis Miscellaneous (15%): Hydrocephalus, ventricular cyst, trauma, idiopathic Lab Studies: Low urine sodium and high urine osmolality are consistent with extrarenal hypotonic fluid losses. Isotonic (or hypotonic) urine (with urine sodium usually above 20 meq/l) can be observed with diuretics, osmotic diuresis, or salt wasting. Isotonic or hypertonic urine (with urine sodium of above 20 meq/l) can be seen when total body sodium is increased (primary hyperaldosteronism, Cushing s, salt ingestion, hypertonic sodium infusion, hypertonic dialysis). 01/22/13 10

11 Management: (As per Adrogue, NEJM, 342:20, 5/2000) In patients with hypernatremia that has developed over a period of hours (eg, accidental sodium loading), rapid correction improves the prognosis without increasing the risk of cerebral edema, because accumulated electrolytes are rapidly extruded from the brain cells. In such patients, reducing the serum sodium concentration by 1 mmol per liter per hour is appropriate (Palevsky, Primer on kidney disease, 2nd Ed., Academic Press, 1998). A slower pace of correction is prudent in patients with hypernatremia of longer (24-48 hours duration) or unknown duration, because the full dissipation of accumulated brain solutes occurs over a period of several days (Hogan, Pediatrics, 1969 and Lien, J Clin Invest, 1990). In such patients, reducing the serum sodium concentration at a maximal rate of 0.5 mmol per liter per hour prevents cerebral edema and convulsions. The article recommends a targeted fall of 10 mmol per liter per day for all patients with hypernatremia except those in whom the disorder has developed over a period of hours. The goal of treatment is to reduce the serum sodium concentration to 145 mmol per liter. Routes of administration: Oral route, feeding tube, IV Fluids: Pure water, 5% Dextrose, 1/4 Normal Saline, Half-Normal Saline The more hypotonic the infusate, the lower the infusion rate required. Because the risk of cerebral edema increases with the volume of infusate, the volume should be restricted to that required to correct hypertonicity. Except in cases of frank circulatory compromise, isotonic saline is unsuitable for managing hypernatremia. Treatment: In patients with hypovolemic hypernatremia, normal saline solution is indicated initially to correct the intravascular volume deficit. When that is accomplished, more hypotonic fluids (eg, 0.45% normal saline) can be used. In patients with hypervolemic hypernatremia, removing the source of salt excess, administering diuretics, and replacing water are important to successful therapy. Patients with euvolemic hypernatremia usually require water replacement alone--either free water orally or an infusion of 5% dextrose in water. Again, frequent monitoring of electrolytes is the key to successful management. Formulas: 1) Estimating the effect of 1 liter of any infusate on the serum sodium: 01/22/13 11

12 Change in serum sodium = infused Na - serum Na total body water + 1 this is the fluid added to the total body water Total body water: The estimated total body water (in liters) is calculated as a fraction of the body weight. The fraction is 0.6 in children, 0.6 and 0.5 in non-elderly men and women, respectively; and 0.5 and 0.45 in elderly men and women, respectively (Found in Fluids, Electrolytes and Acid-Base Disorders, 2nd Ed., 1995) Example: A 58 year old woman with a post-op ileus is undergoing NG suctioning. Her serum sodium is found to be 158, the K is normal; the body weight is 63 kg. Hypernatremia caused by hypotonic fluid loss is diagnosed. The goal: Decrease by 5 mmol per liter over the next 12 hours. Estimated total body water: 0.5 x 63 = 31.5 When using 1/2 normal Saline: = This means that each liter of 1/2 normal saline will decrease the serum sodium by 2.5 mmol. We want a decrease of 5; that means 2 liter are needed; and we want it over 12 hours, that means 2 liters over 12 hours, or 166 ml/hour. However, you still have to add maintenance (which would be around 110ml/hour). Therefore, around 266 ml/hour is needed. 2) Estimating the effect of one liter of any infusate containing sodium and potassium on the serum sodium: Change in serum sodium = (infused Na + infused K) - serum Na total body water + 1 this is the fluid added to the total body water If using 5% Dextrose and water, the glucose level should be monitored because hyperglycemia worsens the hyperosmolarity and can lead to an osmotic diuresis. For those who like to use isotonic saline (as written in the NEJM article): Isotonic saline is unsuitable for correcting hypernatremia. Consider a 50 year old man with a serum sodium concentration of 162 mmol per liter and a body weight of 70 kg (estimated TBW of 42 liters). The retention of one liter of normal saline will decrease the serum sodium by only 0.2 mmol per liter ( /42 + 1). Although the sodium concentration of the infusate is lower than the patient s serum sodium concentration, it is not sufficiently low to alter the hypernatremia substantially. Furthermore, ongoing hypotonic fluid losses might outpace the administration of isotonic saline, aggravating the 01/22/13 12

13 hypernatremia. The sole indication for administering isotonic saline to a patient with hypernatremia is a depletion of extracellular volume that is sufficient to cause substantial hemodynamic compromise. Even in this case, after a limited amount of isotonic saline has been administered to stabilize the patient s circulatory status, a hypotonic fluid should be substituted in order to restore normal hemodynamic values while correcting the hypernatremia. If a hypotonic fluid is not substituted for isotonic saline, the extracellular fluid volume may be overloaded. Hyponatremia It is defined as a decrease in the serum sodium concentration to a level below 136 mmol/liter. Whereas hypernatremia always denotes hypertonicity, hyponatremia can be associated with low, normal or high tonicity. The reported incidence of hyponatremia ranges from 1-4% and is associated with a 7-60 fold increase in mortality. It is not clear, however, weather the excess mortality is directly related to the hyponatremia or whether the hyponatremia is merely a marker for severe underlying disease. First decide if the hyponatremia through the osmolality. If hypotonic, then you need to make assessment of volume status. Normo(Iso)tonic Hyponatremia ( mosm/l): This has been termed pseudohyponatremia. This disturbance is associated with hyperlipidemia or hyperproteinemia. It is actually a laboratory artifact and is dependent upon the method used to measure the sodium concentration. It is rarely seen today because sodium concentration is more commonly measured using direct potentiometry. Hypertonic (Translocational/Factitious) Hyponatremia (> 295 mosm/l): This commonly occurs during hyperglycemia. Other solutes that may produce hypertonic hyponatremia include mannitol, sorbitol, maltose and radiocontrast. In these situations, the hyponatremia per se does not require treatment; however, the underlying hypertonic state must be identified and appropriately treated. Hypotonic (Dilutional) Hyponatremia (< 280 mosm/l): Hypotonic hyponatremia always reflects an inability of the kidney to excrete a sufficient volume of electrolyte-free water to match intake. With the exception of renal failure, these conditions are characterized by high plasma concentrations of vasopressin despite the presence of hypotonicity. Vasopressin is primarily responsible for regulating osmotic homeostatis of body fluids, and it also plays a minor role in volume homeostasis. Vasopressin activation causes a decrease in excretion of free water. Depletion of potassium accompanies many of these disorders and contributes to hyponatremia, since the sodium concentration is determined by the ratio of the exchangeable (i.e., osmotically active) portions of the 01/22/13 13

14 body s sodium and potassium content to total body water. Decreased effective arterial volume: renin release and the formation of angiotensin II. This leads to proximal tubular reabsorption of sodium, decreasing delivery of the solute to distal diluting segments and impairing free water generation. If the decrease in effective volume is of sufficient magnitude, ADH release is also stimulated, further impairing free water excretion. Angiotensin also increases thirst, stimulation water intake. Decreased arterial volume may be the consequence of: 1) Hemorrhage 2) Third-space sequestration (hypervolemic) 3) Sodium depletion 4) Cirrhosis a. Reported in approximately 28% of hospitalized patients with liver disease and 40% of outpatients (Angeli P, Hepatology, 2006) b. In patients with cirrhosis and ascites, splanchnic vasodilatation accounts for the reduction of effective arterial volume and stimulation of vasopressin. c. In patients with cirrhosis and heart failure, vasopressin is primarily under the control of nonosmotic mechanisms (Douglas I, Cleve Clin J Med, 2006) 5) Nephrosis 6) CHF (use water restriction and ACE inhibitor; hypervolemic) a. Studies indicate that hyponatremia occurs in up to 24 % of patients with heart failure (Gheorghiade M, Arch Int Med, 2007) b. Due to increased secretion of vasopressin, because baroreceptors sense hypovolemia c. Vasopressin-mediated inhibition of renal free water excretion leads to increased vascular volume, reduction of sodium and edema (Klein L, Circulation, 2005) 7) Severe Hypoalbuminemia Euvolemic Hyponatremia: 1) Glucocorticoid deficiency: Vasopressin secretion is incompletely suppressed, despite hypoosmolality. Despite relative hypotension, the hyponatremia associated with pure glucocorticoid deficiency is associated with low to normal renin levels and does not correct with saline infusion, indicating that hemodynamic factors do not underlie the disturbance. Glucocorticoid deficiency also has direct effects on renal blood flow and tubular function, which may contribute to the development of hyponatremia. Glucocorticoid replacement results in a prompt water diuresis and resolution of hyponatremia (Oelkers, NEJM, 1989). Can appear like SIADH; look for the hyperkalemia. 2) Hypothyroidism: Associated with non-osmotic vasopressin release and hyponatremia. The defect in water handling corrects with thyroid hormone replacement. Can appear like SIADH. 01/22/13 14

15 3) Diuretic-associated hyponatremia: This syndrome is more common in women than men and can occur as soon as one day after medication (Sonnenblick, Chest, 1993). The causes are multifactorial (inhibit free water generation, induced polydipsia, potassium depletion, variable vasopressin levels). 4) SIADH: Characterized by an inappropriately concentrated urine (> 100 mosm/kg) in the setting of hypotonicity. The diagnosis is one of exclusion. Diagnostic criteria are as follows: a. Hypotonic hyponatremia b. Urine osmolality > 100 mmol/kg c. Absence of extracellular depletion d. Normal thyroid and adrenal function (both increase vasopressin levels) e. Normal cardiac, hepatic and renal function The causes of SIADH (SIAD: Syndrome of Inappropriate Antidiuresis; SIADH is a subset of SAID) include (percentages from Anderson RJ, Ann Int Med, 1985): Postoperative states (30%), active intracranial disease (17%) (head trauma, subdural hematoma, SAH, CVA, meningitis, encephalitis, brain abscess, hydrocephalus, brain tumors, GBS, delirium tremors, MS), cancer (17%) ((bronchogenic, small cell, pancreatic, duodenum, prostate, thymoma, lymphoma, mesothelioma), medications (9%) (opiates, serotonin reuptake inhibitors, Tegretol, chlorpropamide, phenothiazines, TCAs, ACEI, pneumonia (5%) TB empyema. Other causes include pain, nausea and psychosis, tea and toast diet, beer, AIDS, exercise-associated. In patients with SIADH, the release of vasopressin continues despite a plasma osmolality below the osmotic threshold that would normally suppress its release. This results in continued renal reabsorption of free water. Isotonic saline is unsuitable for correcting the hyponatremia of SIADH. If administered, the resulting rise in serum sodium is both small and transient, with the initial salt being excreted in concentrated urine and thereby causing a net retention of water and worsening the hyponatremia (Adrogue, HJ, Intensive Care Med, 1997). Care of SIADH: Restrict free water to ml per day with or without diuretics If you need to give saline, it must have a higher tonicity than urine Demeclocycline: An antibiotic which can induce nephrogenic DI (sometimes used as a treatment) It inhibits the action of ADH on the renal collecting ducts 01/22/13 15

16 In the setting of normal renal function, hyponatremia secondary to pure water intake is rare because the normal kidney can excrete in excess of 20 liters/day of electrolyte-free water. Hyponatremia secondary to compulsive water drinking, however, occurs in 3-7% of institutionalized psychotic patients (Hurtig, NEJM, 1977; Riggs, Psychosomatics, 1991). Although some of these patients had water intake greater than 20 L/day and presented with polyuria, hyponatremia, and a maximally dilute urine, most cases of hyponatremia in psychiatric patients are associated with some degree of non-osmotic vasopressin release (not fully suppressed) and decreased (not maximally dilute) free water clearance (Smith, Am J Psychiatry,1980; Viewig, J Nerv Mental Dis, 1985; Goldman, NEJM, 1988). 5) Medications such as antidepressants, PPI s anti-seizure medications Clinical Manifestations: Dysfunction of the CNS: Usually when the sodium is less than 125. Headache, nausea, vomiting muscle cramps, lethargy, restlessness, disorientation and depressed reflexes. More severe: seizures, coma, permanent brain damage, respiratory arrest, brain-stem herniation and death. Clinical Approach to the Patient with Hyponatremia: First is to measure the serum osmolality. If the osmolality is high, the presence of an osmotically active solute (glucose) should be sought. If hypotonic hyponatremia is present, the evaluation should start with a physical exam focusing on the volume status. In most cases, the urine is inappropriately concentrated. A low urine osmolarity (< 100 mmol/kg) suggests psychogenic polydipsia or advanced renal failure. With hypovolemic hyponatremia, if the urinary sodium is > 20 meq/l, think of renal losses (diuretics, mineralocorticoid deficiency, salt-losing nephritis, osmotic diuresis, RTA Type II, metabolic alkalosis). If the urine sodium is < 10 meq/l, think extrarenal losses (vomiting, diarrhea, third-spacing, and pancreatitis). It is frequently difficult to distinguish between volume depletion and euvolemic hyponatremia on clinical exam. In these situations, measurement of the urine sodium may be helpful. A low sodium concentration suggests decreased effective arterial volume, whereas in SIADH, the urine sodium is usually greater than 30 mmol/l. A low serum uric acid level is suggestive of SIADH (increased urate excretion), a high level is associated with volume depletion. However, keep in mind that hypovolemic hyponatremia of renal origin may give you a urine sodium > 20 meq/l. 01/22/13 16

17 Hyponatremia in the Alcoholic: 1. Hypovolemia 2. Pseudohyponatremia due to alcohol-induced hypertriglyceridemia 3. Beer potomania 4. Cerebral salt wasting syndrome Treatment: Most of this is taken from Fried LF, Palevsky PM, Hyponatremia and Hypernatremia; Medical Clinics of North America, May 1997) The optimal treatment of hyponatremia is controversial. Some authors have stressed that untreated hyponatremia leads to permanent neurologic damage or death and needs to be treated rapidly; whereas others argue that rapid correction of hyponatremia can lead to central pontine myelinolysis and permanent neurologic dysfunction. The authors' recommendations for treatment are based on the current understanding of the brain's adaptation to hyponatremia. Acutely, in the setting of hyponatremia, there is cell swelling as water enters the intracellular compartment to maintain osmotic equilibrium. Adaptive processes are rapidly activated, which restore the brain volume toward normal. Initially, there is rapid loss of intracellular potassium. Although this reduces brain volume, it does 01/22/13 17

18 not return it to normal, and the loss of electrolytes can impair membrane function and excitability. If hyponatremia persists, there is a loss of organic solutes (e.g., taurine, myoinositol, choline-containing compounds) over a period of hours to days, resulting in restoration of brain volume to normal and preservation of cell function. The degree of brain swelling, and hence symptoms, depends on the rate of development, magnitude, and duration of the hypotonicity. Mild hyponatremia (sodium > 125 mmol/l) is usually asymptomatic. With more severe acute hyponatremia, nausea, headache, confusion, agitation, and incontinence may develop. Seizures, coma, respiratory arrest, and death can occur with profound acute hyponatremia. The symptoms associated with chronic hyponatremia are generally milder: lethargy, confusion, and malaise. Seizures are less common but may also occur. There is a poor correlation between the severity of symptoms and the degree of chronic hyponatremia, reflecting variable degrees of brain adaptation. The following is taken from: Adrogue H. Hyponatremia, NEJM, 2000): Patients who have symptomatic hyponatremia with a concentrated urine (> 200 mosm/kg of water) and clinical euvolemia or hypervolemia require an infusion of hypertonic saline. Hypertonic saline is usually combined with furosemide (20 mg) to limit treatment-induced expansion of extracellular fluid volume. Furosemide-induced diuresis is equivalent to a one-half isotonic saline solution (it aids in the correction of hyponatremia) dermal and respiratory losses also help. Patients with symptomatic hyponatremia and dilute urine ( < 200mOsm/kg) but with less serious symptoms usually require only water restriction and close observation. Severe symptoms (seizure or coma) call for infusion of hypertonic saline). After weighing available evidence and the all-to-real risk of overshooting the mark, the article recommends a targeted rate of 8 mmol/liter on any day of treatment. Remaining within this target, the initial rate of correction can still be 1-2 mmol/liter per hour for several hours in patients with severe symptoms. Use the same formula as in hypernatremia. If you need to give normal saline for the hemodynamically unstable (or hypovolemic patient), keep this in mind. As soon as the patient s extracellular fluid volume nears restoration, the nonosmotic stimulus to vasopressin release will cease, thereby fostering rapid excretion of dilute urine and correction of hyponatremia at an overly rapid pace. Therefore, the prescription is switched to 0.45 percent sodium chloride. The anticipated production of urine with lower sodium concentration than those of the infusate will promote correction of the hyponatremia. Remember: Correction of asymptomatic chronic hyponatremia may be inappropriate or unnecessary, as may occur in cirrhotic patients. 01/22/13 18

19 . Central pontine myelinolysis (CPM)/osmotic demyelination syndrome: is a rare disorder characterized by spastic quadriparesis, pseudobulbar palsy, swallowing dysfunction, altered mentation, delirium, and mutism. (Karp, Medicine, 1993; Sterns, NEJM, 1986). Brain adaptation (to hyponatremia) is the source of the risk of this condition. Shrinkage of the brain triggers demyelination. On autopsy, there is demyelination in the central pons and extrapontine (thalamus and subcortical area) sites. Although CPM may occur in a number of clinical settings, it is associated with rapid correction of hyponatremia. (Sterns and Karp). CPM exhibits demyelination of neurons within the mid-base of the skull not characterized by inflammation (unlike MS). Damage can be fatal or irreversible. Alcoholism is a strong risk factor for CPM. Women in pregnancy are also at risk. The symptoms can appear one day to weeks after hyponatremia is corrected. Patients with chronically depressed sodium are more susceptible than those with hyponatremia of recent onset. Hepatic failure, potassium depletion, and malnutrition increase the risk of this complication. Adams and colleagues first described CPM in 1959 in alcoholic and malnourished patients. Gupta S, Journal of Critical Illness 12/05: described case of CPM with DKA. The mechanism was unclear. Most reported cases of osmotic demyelination occurred after rates of correction that exceeded 12 mmol/liter/day were used, but isolated cases occurred after correction of only 9-10 mmol per liter in 24 hours or 19 mmol per liter in 48 hours. Initially, improvement of the neurologic symptoms associated with hyponatremia is observed followed by the insidious development of the signs of CPM. The cause of CPM is not known, but the risk of its developing is related to the duration of hypotonicity (time for the brain to lose osmoles), the rate of its correction (to allow time to reacquire lost electrolytes and osmoles), and the overall magnitude of change of the plasma sodium concentration. The treatment of hyponatremia must therefore be individualized, taking into account its magnitude, duration, and associated symptoms as well as its cause. Hypotonicity associated with volume depletion is best treated by volume expansion with normal saline. Once the patient is euvolemic, the stimulus for vasopressin secretion is gone and there is prompt excretion of the retained water. Patients with hyponatremia secondary to nephrotic syndrome, heart failure, and cirrhosis should be treated with water restriction. In the case of heart failure, the hyponatremia may improve with the use of angiotensin converting enzyme inhibitors or other therapy to improve myocardial function. Loop diuretics may also be beneficial in edematous patients because they interfere with urine concentration and promote free water excretion. Patients with psychogenic polydipsia usually correct their hyponatremia spontaneously, if access to continued water ingestion is denied. 01/22/13 19

20 Asymptomatic or minimally symptomatic patients with euvolemic chronic hyponatremia are best managed conservatively with fluid restriction and discontinuation of any medications that interfere with free water excretion. To be effective, fluids need to be restricted to less than free water losses. In patients with maximal urinary concentration, fluid intake must be reduced to less than insensible losses to correct the hyponatremia. Symptomatic chronic hyponatremia requires more rapid correction. There is a general consensus that initial therapy of the symptomatic patient should raise serum sodium concentration by no more than 1 to 2 mmol/l/hour. As soon as clinical improvement has occurred, the rate of correction should be reduced, and the overall increase in the serum sodium concentration should be no more than 12 mmol/l over the first 24 hours. Similar treatment should be instituted for severe acute hyponatremia, even if only relatively minor symptoms are present, because more significant symptoms can emerge suddenly. When rapid correction of hyponatremia is required, hypertonic (3%) saline should be administered at a rate of 1 to 2 ml/kg/hour, with close monitoring of the serum sodium concentration. If volume overload occurs, a loop diuretic should be administered. Normal saline is not an appropriate treatment of SIADH; the sodium infused may be rapidly excreted while the water is retained, worsening the hyponatremia. In all cases, water restriction is an important adjunct. Most cases of SIADH are self-limited (e.g., pneumonia, postsurgical). If the hyponatremia is prolonged and the patient does not tolerate water restriction, demeclocycline may be of benefit. This tetracycline antibiotic, at a dose of 600 to 1200 mg/day, induces nephrogenic diabetes insipidus and is an important adjunct to fluid restriction in patients with chronic SIADH. Side effects of demeclocycline include azotemia, photosensitivity, and nausea, and it is contraindicated in patients with liver disease or renal failure. Samsca (tolvaptan): is an oral selective V 2 receptor agonist and it is used at times for hyponatremia. Watch using this drug with the following (because of CYP3A and P-gp): 1. Ketoconazole: 5-fold increase in tolvaptan exposure 2. Grapefruit juice:.8 fold increase 3. P-gp inhibitors: lower dose of Sansca may be required 4. Rifampin and other CYP3A inductions: Higher dose may be required 5. Digoxin, furosemide, HCTZ, warfarin: no relative impact, however a. Samsca will increase digoxin exposure by about 33% What is the tonicity and osmolality of 5% Glucose? This is a complicated question. Just read the following: A major physiology text (Ganong 16 th ed., 1993) defines tonicity as a term used to describe the osmolality of a solution relative to plasma (as in hypotonic, isotonic or hypertonic). Ganong argues that an infusion of 5% Dextrose is initially isotonic but that when glucose is taken up by and metabolized by the cells, the overall effect is of infusing a hypotonic solution. More correctly, one would say that 5% Dextrose is initially isosmolar with plasma (and this avoids hemolysis). Glucose is a permanent solute in the 01/22/13 20

21 non-diabetic patient and can easily enter cells. When infused, the 5% Dextrose is hypotonic (with reference to the cell membrane) despite being isosmolar. Water does not leave the cells initially (and hemolysis does not occur) because there is no osmolar gradient across the cell membrane. The solution is however hypotonic and when glucose enters the cell water does also. If insulin is not present, this movement of glucose does not occur. In this latter case, the solution is isomolar before infusion and can be considered isotonic after infusion as well. 01/22/13 21