Hypo/Hyperosmolar States

Hypo/Hyperosmolar States

Objectives Renal physiology Hypoosmolar state More renal physiology!
Plasma osmolality vs effective osmolality Hypoosmolar state Hyponatremia (in most instances represents a hypoosmolar state BUT not always!) More renal physiology! Regulation of antidiuretic hormone (ADH) Hyperosmolar states Hypernatremia Ingestions

Total Body Water (TBW) ~60% of lean body weight in men and ~50% in women Distribution intracellular compartment (60% of TBW) extracellular compartment (40% of TBW) Osmotic forces are the primary determinants of the distribution of water between compartments Water flows from the compartment of low osmolality to that of high osmolality until the osmotic pressures are equalized

Osmotic Forces Each compartment has one major solute that is restricted within its compartment and thus acts to hold water within that space Na+ salts are the main extracellular osmoles K+ salts are the main intracellular osmoles In contrast, urea rapidly crosses cell membranes and equilibrates throughout the TBW and thus does not affect the distribution of water between the intracellular and extracellular spaces.

Osmolality vs Effective Osmolality
Osmolality: total number of particles in an aqueous solution (mosmol/kg H2O) Normal Posm = mosmol/kg Effective osmolality (tonicity): those particles that can exert osmotic force across membranes, via movement of water into or out of cells Examples: Na+, glucose, mannitol Normal effective Posm = mosmol/kg

Plasma Osmolality Na+, glucose and BUN are major determinants of plasma osmolality Posm = 2 x plasma [Na+] + [Glucose]/18 + [BUN]/2.8 More important clinically to consider effective osmolality than “total’’ osmolality Effective osmoles (Na+ , glucose) exert water shifts unlike urea (as well as ethanol) 1. two reflects the osmotic contribution of the anion accompanying Na+ and 18 and 2.8 represent the conversion of the plasma glucose concentration and the BUN from units of milligrams per deciliter (mg/dL) into millimoles per liter (mmol/L). Under normal conditions, glucose and urea contribute less than 10 mosmol/kg, and the plasma Na+ concentration is the main determinant of the Posm (Posm ~ 2 x plasma [Na+]) 2. (UpToDate Chapter 1B: Units of solute measurement) The osmotic pressure generated by a solution is proportional to the number of particles per unit volume of solvent, not to the type, valence, or weight of the particles. The unit of measurement of osmotic pressure is the osmole. One osmole (osmol) is defined as one gram molecular weight (1 mol) of any nondissociable substance (such as glucose) and contains 6.02 x 1023 particles. In the relatively dilute fluids in the body, the osmotic pressure is measured in milliosmoles (one-thousandth of an osmole) per kilogram of water (mosmol/kg). Since most solutes are measured in the laboratory in units of millimoles per liter, milligrams per deciliter, or milliequivalents per liter, the following formulas must be used to convert into mosmol/kg: mosmol/kg = n x mmol/L or, from Eqs. (1) and (2), (Eq. 4) mosmol/kg = (n x mg/dL x 10) ÷ mol wt (Eq. 5) mosmol/kg = (n x meq/L) ÷ valence where n is the number of dissociable particles per molecule. When n = 1, as for Na+, Cl-, Ca2+, urea, and glucose, 1 mmol/L will generate a potential osmotic pressure of 1 mosmol/kg. If, however, a compound dissociates into two or more particles, 1 mmol/L will generate an osmotic pressure greater than 1 mosmol/kg. 3. (UpToDate Chapter 7A: Exchange of water between the cells and ECF) The osmotic contributions of glucose and urea, both of which are measured in milligrams per deciliter, can be calculated from Eq. (1): (Eq. 1) mosmol/kg = (mg/dL x 10) ÷ mol wt The molecular weight of glucose is 180 and that of the two nitrogen atoms in urea (since urea is measured as the blood urea nitrogen or BUN) is 28. Therefore, the Posm can be estimated from: (Eq. [Na+] ) + ([glucose]/18) + (BUN/2.8) The effective plasma (and extracellular fluid) osmolality is determined by those osmoles that act to hold water within the extracellular space. Since urea is an ineffective osmole: (Eq. 3) Effective [Na+] ) + ([glucose]/18) The normal values for these parameters are: Plasma [Na+] = meq/L [Glucose] = mg/dL, fasting BUN = 10-20 mg/dL Posm = mosmol/kg Effective Posm = mosmol/kg Under normal circumstances, glucose accounts for only 5 mosmol/kg, and Eq. (3) can be simplified to: (Eq. 4) Effective [Na+] Thus, in most conditions, the plasma Na+ concentration is a reflection of the Posm, a finding consistent with the fact that Na+ salts are the principal extracellular osmoles.

Comprehensive Clinical Nephrology, 4th Edition

Take Home Messages Increase in effective ECF osmolality results in cellular dehydration Decrease in effective ECF osmolality results in cellular overhydration Flow of water in and out of brain cells is primarily responsible for clinical CNS manifestations Water shifts do not occur and symptoms of hyperosmolality are absent when the effective osmolality is not increased (ie in patients with uremia)

Take Home Messages Plasma [Na+] is a function of the ratio of the amounts of solute and water present and does not necessarily correlate with volume, which is a function of the total amount of Na+ and water present

Hypotonic Hyponatremia
Hypovolemic ↓ [Na+] = ↓↓TBNa/↓TBW Euvolemic ↓ [Na+] = ↔ TBNa/↑TBW Hypervolemic ↓ [Na+] = ↑TBNa/↑↑TBW

Plasma Osmolality Does hyponatremia represent low plasma osmolality in all cases? NO

Plasma Osmolality Example
Serum Na+ = 125 mEq/L BUN = 140 mg/dL Blood glucose = 90 mg/dL Calculated and measured osmolality = 305 mOsm/kg Posm = 2 x / /2.8 In this case, hyponatremia is associated with an elevated plasma osmolality Effective osmolality = 255 mOsm/kg (calculation excludes BUN) thus this patient may have symptoms of hypotonicity despite an elevated plasma osmolality

Plasma Osmolality Example:
Serum Na+ = 133 mEq/L BUN = 11 mg/dL Blood glucose = 500 mg/dL Effective osmolality = 294 mOsm/kg (2 x /18) Hyponatremia is not always associated with hypoosmolality ; thus direct therapeutic intervention for hyponatremia may not be required (in this example, need to treat underlying hyperglycemia)

Plasma Osmolality Does plasma hypoosmolality always represent hyponatremia? YES Most of the plasma osmoles are Na+ salts, with lesser contributions from other ions, glucose and urea Osmotic effect of the plasma ions (Posm) can be estimated from 2 x plasma [Na+]

Plasma Osmolality Do ineffective osmoles (urea, ethanol, ethylene glycol, methanol) cause hyponatremia? These osmoles readily move between fluid compartments without causing water shifts. NO Remember these osmoles readily move between fluid compartments without causing water shifts

Plasma Osmolality Do effective osmoles (glucose, mannitol) cause hyponatremia? These osmoles shift water out of the cells Yes These osmoles shift water out of the cells

Clinical Examples of Hyponatremia
Plasma Na+ = 120 mEq/L Blood glucose = 90 mg/dL BUN = 14 mg/dL Meas Posm = 250 mosmol/kg Hypotonic hyponatremia: identify some clinical conditions…  risk of cerebral edema

Plasma Na+ = 120 mEq/L Blood glucose = 90 mg/dL BUN = 14 mg/dL Meas Posm = 290 mosmol/kg UpToDate: Dilutional hyponatremia, similar to that induced by hyperglycemia or the administration of hypertonic mannitol, is a potential complication of IVIG therapy [72]. (See "Complications of mannitol therapy".) IVIG is often administered in a 10 percent maltose solution. Maltose is normally metabolized by maltase in the proximal tubule. In patients with renal failure, however, maltose can accumulate in the extracellular fluid, raising the plasma osmolality and lowering the plasma sodium concentration by dilution as water moves out of the cells down the favorable osmotic gradient. Maltose accumulation can also lead to an osmolal gap, as the measured plasma osmolality is greater than that estimated from the contributions of sodium, potassium, glucose, and urea. Affected patients are not at risk for symptoms of hyponatremia, since the plasma osmolality is modestly increased, not reduced. Pseudonatremia can also be seen due to IVIG administration. This phenomenon is due to the protein load, which increases the non-aqueous phase of plasma. Because the concentration of sodium is physiologically regulated in the aqueous phase, but the laboratory sodium determination uses the total plasma volume of the sample, an artifactual dilution of sodium results [73]. Pseudohyponatremia ( lipids, protein) No risk of cerebral edema

Plasma Na+ = 120 mEq/L Blood glucose = 1350 mg/dL BUN = 14 mg/dL Meas Posm = 320 mosmol/kg Hyponatremia caused by hyperglycemia No risk of cerebral edema

Plasma Na+ = 120 mEq/L Blood glucose = 90 mg/dL BUN = 14 mg/dL Calc Posm = 250 mosmol/kg Meas Posm = 325 mosmol/kg Osmolar gap = 75 mosmol/kg Effective osmolality = 320mosmol/kg Dilutional hyponatremia caused by mannitol, which results in an elevated osmolar gap No risk of cerebral edema

Plasma Na+ = 120 mEq/L Blood glucose = 90 mg/dL BUN = 14 mg/dL Calc Posm = 250 mosmol/kg Meas Posm = 300 mosmol/kg Osmolar gap = 50 mosmol/kg Effective osmolality= 245 mosmol/kg Beer Potomania [EtOH] = 50 mmol/L Stat Ref! ACP Medicine Beer potomania Patients who subsist on beer (a practice known as beer potomania) are susceptible to hyponatremia because of their low rates of solute excretion (beer contains little protein or electrolyte). Reduced delivery of the glomerular filtrate to distal diluting sites limits the amount of water that can be excreted. Nonosmotic stimuli to vasopressin secretion caused by nausea or gastrointestinal fluid losses or by treatment with thiazide diuretics are often contributing factors.  risk of cerebral edema

Plasma Na+ = 120 mEq/L Blood glucose = 90 mg/dL BUN = 126 mg/dL Meas Posm = 290 mosmol/kg Effective osmolality = 245 mosmol/kg Hyponatremia caused by renal failure  risk of cerebral edema Note: a normal measured plasma osmolality does not preclude an increased risk of cerebral edema

Laboratory Approach to Hyponatremia
Start with plasma osmolality to exclude pseudohyponatremia (normal Posm) and hypertonic hyponatremia (elevated Posm) When hypotonicity is confirmed, then clinically evaluate the patients’ volume status

Causes of Hyponatremia
Normal plasma osmolality Severe hyperlipidemia (TG > 1500 mg/dL) and hyperproteinemia (total protein > 8 g/dL) Posttransurethral resection of prostate Use of isosmotic but non-Na+ containing flushing solution (glycine) Unlike hyperlipidemia/hyperproteinemia, plasma [Na+] is truly reduced although Posm is normal Current Medical Diagnosis & Treatment, 2009

Urine Osmolality Determine whether H2O excretion is normal or impaired
Uosm > 100 mosmol/kg occurs in majority of hyponatremic patients and indicates impaired H2O excretion Uosm < 100 mosmol/kg indicates that ADH is appropriately suppressed Primary polydipsia Low solute intake Reset osmostat UpToDate: Malnutrition, described primarily in beer drinkers (called beer drinkers potomania), in which dietary solute intake (sodium, potassium, protein) and therefore solute excretion is so low that the rate of water excretion is markedly diminished even though urinary dilution is intact. (See "Causes of hyponatremia", section on 'Low dietary solute intake'.) Reset Osmostat Has normal osmotic responses to Posm but ADH release is not suppressed until Posm falls well below normal (≠ SIADH in which there is nonsuppressible ADH release) Plasma Na concentration is subnormal but remains stable (usually mEq/L) Associated with hypovolemia, psychosis, malnutrition, quadriplegia and pregnancy Therapy for hyponatremia is unnecessary RESET OSMOSTAT — In normal individuals, plasma antidiuretic hormone (ADH, arginine vasopressin) levels are very low when the plasma osmolality is below 280 mosmol /kg, thereby permitting excretion of ingested water, and increase progressively as the plasma osmolality rises above 280 mosmol/kg (figure 2). Hyponatremia due to downward resetting of osmostat is one form of the SIADH [1,32-34]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Patterns of ADH secretion'.) Downward resetting of the osmostat can also occur in hypovolemic states (in which the baroreceptor stimulus to ADH release is superimposed upon osmoreceptor function), quadriplegia (in which effective volume depletion may result from venous pooling in the legs), psychosis, tuberculosis, and chronic malnutrition [1,32]. The serum sodium concentration also falls by about 5 meq/L in normal pregnancy. No therapy is required. (See "Renal and urinary tract physiology in normal pregnancy".) The presence of a reset osmostat should be suspected in any patient with apparent SIADH who has mild hyponatremia (usually between 125 and 135 meq/L) that is stable over many days despite variations in sodium and water intake. The diagnosis can be confirmed clinically by observing the response to a water load (10 to 15 mL/kg given orally or intravenously). Normal subjects and those with a reset osmostat should excrete more than 80 percent of the water load within four hours, while excretion will be impaired in the SIADH [1]. Identification of a reset osmostat is important because the above therapeutic recommendations for the SIADH may not apply [1,32,35]. These patients have mild to moderate asymptomatic hyponatremia in which there is downward resetting of the threshold for both ADH release and thirst. Since osmoreceptor function is normal around the new baseline, attempting to raise the serum sodium concentration will increase ADH levels and make the patient thirsty, a response that is similar to that seen with fluid restriction in normal subjects. Thus, attempting to raise the serum sodium concentration may be unnecessary (given the apparent lack of symptoms and lack of risk of more severe hyponatremia) and likely to be ineffective (due to increased thirst). Treatment should be primarily directed at the underlying disease, such as tuberculosis [36].

Reset Osmostat Normal osmotic responses to Posm but ADH release is not suppressed until Posm falls well below normal (≠ SIADH in which there is nonsuppressible ADH release) Plasma [Na] is subnormal but remains stable (usually mEq/L) Associated with hypovolemia, psychosis, malnutrition, quadriplegia and pregnancy Therapy for hyponatremia is unnecessary

Urine Sodium Concentration
Una < 20 mEq/L Hypovolemia due to extra-renal losses Edematous states in CHF, cirrhosis, nephrotic syndrome Dilutional effect in primary polydipsia due to very high urine output Una > 20 mEq/L Hypovolemia due to renal losses Renal failure SIADH Reset osmostat

Other Labs Plasma uric acid concentration Blood urea nitrogen
Hypouricemia (< 4mg/dL) in SIADH Mild hypervolemia decreases proximal Na+ reabsorption, leading to increased urinary uric acid excretion Blood urea nitrogen BUN may be < 5mg/dL in SIADH Mild hypervolemia leads to urinary urea wasting

Hyponatremia: Case What labs would you order?
62 year old woman noted an unpleasant, sweet taste in her mouth. She otherwise felt well and was taking no medications. Because dysgeusia is a rare manifestation of hyponatremia, her serum sodium level was tested and was 122 mEq/L. What labs would you order?

Hyponatremia: Case (Cont)
Measured Posm 250 mOsm/kg Urine osmolality 635 mOsm/kg Urine sodium 85 mEq/L. Her thyroid function and adrenal function were normal A chest CT showed a mass in the lower lobe of the left lung, which proved to be a small-cell carcinoma

Causes of SIAD N Engl J Med 2007;356:

Diagnosis of SIAD Table 2. Diagnosis of SIAD.
N Engl J Med 2007;356:

Antidiuretic Hormone Primary determinant of free water excretion
Increases water permeability of the luminal membranes of the cortical and medullary collecting tubules, thus promoting water reabsorption (primarily in principal cells)

Mechanism of Action Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed. FIGURE 25-11 Mechanism of action of vasopressin antagonists. The binding of arginine vasopressin (AVP) to V2 receptors stimulates the synthesis of aquaporin (AQP)-2 water channel proteins and promotes their transport to the apical surface. At the cell membrane, aquaporin-2 permits selective free water reabsorption down the medullary osmotic gradient, ultimately decreasing serum osmolarity and increasing fluid balance. V2 antagonists work by preventing AVP from binding to its cognate receptor. cAMP = cyclic adenosine monophosphate; Gs = Gs protein; PKA = protein kinase A. (Modified from deGoma EM, Vagelos RH, et al: Emerging therapies for the management of decompensated heart failure: From bench to bedside. J Am Coll Cardiol 48:2397, 2006). In chemistry and biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates. The process is referred to as phosphorylation. An enzyme that removes phosphate groups is known as a phosphatase. ADH binds to V2 receptors in the basolateral membrane of principal cells Hormone-receptor complex activates the regulatory protein Gs Adenylate cyclase is activated which converts ATP to cyclic AMP cAMP activates protein kinase A PKA phosphorylates Aquaporin 2 in intracellular vesicles AND phosphorylates transciption factors which leads to gene transcription of Aquaporin2 in the nuclei Aquaporin2 are delivered to the apical membrane by microtubules Aquaporin2 at the apical membrane are recycled via endocytosis in coated vesicles Water absorbed is returned to the systemic circulation across the basolateral membrane, which is both water permeable (even in the absence of ADH) and has a much greater surface area than the luminal membrane Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed.

Aquaporins Brenner: Brenner and Rector's The Kidney, 8th ed.
Transmission electron micrograph illustrating immunogold labeling of aquaporin-1 in the descending thin limb (DTL) of a long-looped nephron from rat kidney. Labeling of aquaporin-1 is seen in both the apical and basolateral plasma membrane. BM, basement membrane. (Magnification, ×120,000.) (From Nielsen S, Kwon TH, Christensen BM, et al: Physiology and pathophysiology of renal aquaporins. J Am Soc Nephrol 10:647, 1999.) Brenner: Brenner and Rector's The Kidney, 8th ed.

Osmoreceptor Control Osmoreceptors are specialized neurons in the anterolateral hypothalamus The plasma [Na+] is the primary osmotic determinant of ADH release Osmoreceptors are extremely sensitive and respond to changes in plasma osmolality of as low as 1% Stimulation of ADH occurs when osmoreceptor cells shrink in response to increased plasma osmolality from effective osmoles (Na+, hyperglycemia, mannitol)

Osmotic threshold In humans, the osmotic threshold for ADH release is about 280 to 290 mosmol/kg (graph 1) [38,39]. Below this level, there is little if any circulating ADH and the urine should be maximally dilute with an osmolality below 100 mosmol/kg. Above the osmotic threshold, there is a progressive and relatively linear rise in ADH secretion. This system is so efficient that the Posm usually does not vary by more than 1 to 2 percent, despite wide fluctuations in water intake. (2-5 mOsmol/kg)

Baroreceptor Control Afferent stimuli from carotid sinus baroreceptors affect the activity of the vasomotor center in the medulla and subsequently ADH secretion by the cells in the paraventricular nuclei Small changes in pressure or volume have little effect on ADH release

Make sense teleologically!
Reduction of > 10% blood volume leads to exponential increase in ADH release Make sense teleologically!

Control of ADH Secretion
Major stimuli to ADH secretion are hyperosmolality (via osmoreceptors) and effective circulating volume depletion (via baroreceptors) V1 V2 + decreased Posm

Hypernatremia Defined as serum [Na+] > 145 mEq/L
Represents hyperosmolality Results from water loss (skin, respiratory and GI tracts, dilute urine) or Na+ retention Defense against hypernatremia: ADH release Thirst Provides ultimate protection against hypernatremia Should never see an alert adult patient with serum [Na+] > 150 mEq/L who has normal thirst and access to water

As with hyponatremia, patients with hypernatremia fall into three broad categories based on volume status.[15] A diagnostic algorithm is helpful in the evaluation of these patients (Fig. 8.16). Hypovolemia: Hypernatremia Associated with Low Total Body Sodium Patients with hypovolemic hypernatremia sustain losses of both Na+ and water, but with a relatively greater loss of water. On physical examination, there are signs of hypovolemia such as orthostatic hypotension, tachycardia, flat neck veins, poor skin turgor, and sometimes altered mental status. Patients will generally have hypotonic water loss from the kidneys or the gastrointestinal tract; in the latter, the urinary [Na+] will be low. Hypervolemia: Hypernatremia Associated with Increased Total Body Sodium Hypernatremia with increased total body Na+ is the least common form of hypernatremia. It results from the administration of hypertonic solutions such as 3% NaCl given as intra-amniotic instillation for therapeutic abortion and NaHCO3 for the treatment of metabolic acidosis, hyperkalemia, and cardiorespiratory arrest. It may also result from inadvertent dialysis against a dialysate with a high Na+ concentration or from consumption of salt tablets. Therapeutic hypernatremia is also becoming common as hypertonic saline solutions have emerged as a preferable alternative to mannitol for treatment of increased intracranial pressure.[37] Hypernatremia is also increasingly recognized in hypoalbuminemic hospitalized patients with renal failure who are edematous and unable to concentrate their urine. Euvolemia: Hypernatremia Associated with Normal Body Sodium Most patients with hypernatremia secondary to water loss appear euvolemic with normal total body Na+ because loss of water without Na+ does not lead to overt volume contraction. Water loss per se need not result in hypernatremia unless it is unaccompanied by water intake. Because hypodipsia is uncommon, hypernatremia usually develops only in those who have no access to water and the very young and old, in whom there may be an altered perception of thirst. Extrarenal water loss occurs from the skin and respiratory tract in febrile or other hypermetabolic states and is associated with a high urine osmolality because the osmoreceptor-vasopressin-renal response is intact. The urine Na+ concentration varies with the intake. Renal water loss leading to euvolemic hypernatremia results either from a defect in vasopressin production or release (central diabetes insipidus) or from a failure of the collecting duct to respond to the hormone (nephrogenic diabetes insipidus). Defense against the development of hyperosmolality requires the appropriate stimulation of thirst and the ability to respond by drinking water. Polyuric disorders can result from either an increase in Cosm or an increase in Cwater. An increase in Cosm occurs with diuretic use, renal salt wasting, excess salt ingestion, vomiting (bicarbonaturia), alkali administration, and administration of mannitol (as a diuretic, for bladder lavage, or for the treatment of cerebral edema). An increase in Cwater occurs with excess ingestion of water (psychogenic polydipsia) or in abnormalities of the renal concentrating mechanism (diabetes insipidus). Comprehensive Clinical Nephrology, 4th Edition

Diabetes insipidus (DI) is characterized by polyuria and polydipsia and is caused by defects in vasopressin action. Patients with central and nephrogenic DI and primary polydipsia present with polyuria and polydipsia. The differentiation between these entities can be accomplished by clinical evaluation, with measurements of vasopressin levels and the response to a water deprivation test followed by vasopressin administration (Fig. 8.17). Figure 8.17 Water deprivation test. Test procedure: Water intake is restricted until the patient loses 3% to 5% of his or her body weight or until three consecutive hourly determinations of urinary osmolality are within 10% of each other. (Caution must be exercised to ensure that the patient does not become excessively dehydrated.) Aqueous vasopressin (5 U subcutaneously) is given, and urinary osmolality is measured after 60 minutes. The expected responses are given in the table. (From reference 42.) Central Diabetes Insipidus Clinical Features Central DI usually has an abrupt onset. Patients have a constant need to drink, have a predilection for cold water, and commonly have nocturia. By contrast, the compulsive water drinker may give a vague history of the onset and has large variations in water intake and urine output. Nocturia is unusual in compulsive water drinkers. A plasma osmolality of more than 295 mOsm/kg suggests central DI, and a plasma osmolality of less than 270 mOsm/kg suggests compulsive water drinking. Causes Central DI is caused by infection, tumors, granuloma, and trauma affecting the CNS in 50% of the cases; in the other 50%, it is idiopathic (Fig. 8.18). In a survey of 79 children and young adults, central DI was idiopathic in half the cases. The remainder had tumors and Langerhans cell histiocytosis; these patients had an 80% chance for development of anterior pituitary hormone deficiency compared with the patients with idiopathic disease.[38] Autosomal dominant DI is caused by point mutations in a precursor gene for vasopressin that cause “misfolding” of the provasopressin peptide, preventing its release from the hypothalamic and posterior pituitary neurons.[39] Patients present with a mild polyuria and polydipsia in the first year of life. These children have normal physical and mental development. There is a rare autosomal recessive central DI associated with diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome).[40] DI is usually partial and gradual in onset in Wolfram syndrome. It is linked to chromosome 4 and involves abnormalities in mitochondrial DNA. A rare clinical entity is the combination of central DI and deficient thirst. It has been reported in a total of 70 patients in 41 studies.[41] When vasopressin secretion and thirst are both impaired, affected patients are vulnerable to recurrent episodes of hypernatremia. Formerly called essential hypernatremia, the disorder is now called central DI with deficient thirst or adipsic DI. Differential Diagnosis Measurement of circulating vasopressin by radioimmunoassay is preferred to the tedious water deprivation test. Under basal conditions, vasopressin levels are unhelpful because there is a significant overlap among the polyuric disorders. Measurement after a water deprivation test is more useful (see Fig. 8.17). Treatment Central DI is treated with hormone replacement or pharmacologic agents (Fig. 8.19). In acute settings, when renal water losses are extensive, aqueous vasopressin (Pitressin) is useful. It has a short duration of action, allows careful monitoring, and avoids complications such as water intoxication. This drug should be used with caution in patients with underlying coronary artery disease and peripheral vascular disease as it may cause vascular spasm and prolonged vasoconstriction. For chronic central DI, desmopressin acetate is the agent of choice. It has a long half-life and does not have the significant vasoconstrictive effects of aqueous vasopressin. It is administered at the dose of 10 to 20 µg intranasally every 12 to 24 hours. It is tolerated well, safe to use in pregnancy, and resistant to degradation by circulating vasopressinase. Oral desmopressin (0.1 to 0.8 mg every 12 hours) is available as second-line therapy. In patients with partial DI, in addition to desmopressin itself, agents that potentiate the release of vasopressin may be used. These agents include chlorpropamide, clofibrate, and carbamazepine. Comprehensive Clinical Nephrology, 4th Edition

Acquired Nephrogenic Diabetes Insipidus Acquired nephrogenic DI is more common than and rarely as severe as congenital nephrogenic DI. In these patients, the ability to elaborate a maximal concentration of urine is impaired, but urinary concentrating mechanisms are partially preserved. For this reason, urinary volumes are less than 3 to 4 l/day, which contrasts with the much higher volumes seen in patients with congenital or central DI or compulsive water drinking. The causes and mechanisms of acquired nephrogenic DI are listed in Figure 8.20. Chronic Kidney Disease A defect in urinary concentrating ability may develop in patients with chronic kidney disease of any etiology, but this defect is most prominent in tubulointerstitial diseases, particularly medullary cystic disease. Disruption of inner medullary structures and diminished medullary concentration are thought to play a role; alterations in V2 receptor and AQP2 expression also contribute (see Fig. 8.7). To achieve daily osmolar clearance, an amount of fluid commensurate with the severity of the concentrating defect is necessary in patients who still make urine. Patients should be advised to maintain a fluid intake that matches their urine volume. Electrolyte Disorders Hypokalemia causes a reversible abnormality in urinary concentrating ability. Hypokalemia stimulates water intake and reduces interstitial tonicity, which relates to the decreased Na+-Cl− reabsorption in the TALH. Hypokalemia resulting from diarrhea, chronic diuretic use, and primary aldosteronism also decreases intracellular cyclic adenosine monophosphate accumulation and causes a reduction in vasopressin-sensitive AQP2 expression (see Fig. 8.7). Hypercalcemia also impairs urinary concentrating ability, resulting in mild polydipsia. The pathophysiologic mechanism is multifactorial and includes a reduction in medullary interstitial tonicity caused by decreased vasopressin-stimulated adenylate cyclase in the TALH and a defect in adenylate cyclase activity with decreased AQP2 expression in the collecting duct. Pharmacologic Agents Lithium is the most common cause of nephrogenic DI, occurring in up to 50% of patients receiving long-term lithium therapy. Lithium causes downregulation of AQP2 in the collecting duct; experimentally, it also increases cyclooxygenase 2 (COX-2) expression and urinary prostaglandins, which may contribute to the polyuria.[43] The concentrating defect of lithium may persist even when the drug is discontinued. The epithelial sodium channel, ENaC, is the entrance pathway for lithium into collecting duct principal cells. Amiloride inhibits lithium uptake through ENaC and has been used clinically to treat nephrogenic DI caused by lithium. Aldosterone administration dramatically increases urine production in experimental nephrogenic DI due to lithium[44] (an effect that is associated with decreased expression of AQP2 on luminal membranes of the collecting duct), whereas administration of the mineralocorticoid receptor blocker spironolactone decreased urine output and increased AQP2 expression.[45] It is not yet known if spironolactone is a useful treatment for humans with lithium-induced nephrogenic DI. Other drugs impairing urinary concentrating ability include amphotericin, foscarnet, and demeclocycline, which reduces renal medullary adenylate cyclase activity, thereby decreasing the effect of vasopressin on the collecting ducts. Sickle Cell Anemia Patients with sickle cell disease and trait often have a urinary concentrating defect. In the hypertonic medullary interstitium, the “sickled” red cells cause occlusion of the vasa recta and papillary damage. The resultant medullary ischemia may impair Na+-Cl− transport in the ascending limb and diminish medullary tonicity. Although initially reversible, medullary infarcts occur with long-standing sickle cell disease and the concentrating defects become irreversible. Dietary Abnormalities Extensive water intake or a marked decrease in salt and protein intake leads to impairment of maximal urinary concentrating ability through a reduction in medullary interstitial tonicity. On a low-protein diet with excessive water intake, there is a decrease in vasopressin-stimulated osmotic water permeability that is reversed with feeding. Gestational Diabetes Insipidus In gestational DI, there is an increase in circulating vasopressinase, which is produced by the placenta. Patients are typically unresponsive to vasopressin but respond to desmopressin, which is resistant to vasopressinase. UpToDate Transient DI of pregnancy — Antidiuretic hormone (ADH) increases renal water reabsorption and decreases urine output. This effect is mediated by activation of the V2 receptor in the renal collecting tubules, resulting in enhanced renal water reabsorption and the formation of concentrated urine. Between the eighth week and mid pregnancy, the metabolic clearance of ADH increases four- to six-fold because of an increase in vasopressinase (also known as oxytocinase), which is produced by the placenta. Enzyme activity continues to increase, peaking in the third trimester, remaining high during labor and delivery, and then falling to undetectable levels two to four weeks postpartum. In most pregnant women, plasma concentrations of ADH remain in the normal range, despite increased metabolic clearance, because of a compensatory increase in ADH production by the pituitary gland. As a result, most women do not become polyuric. A small number of pregnant women, however, develop transient DI, which is underdiagnosed because polyuria is often considered normal during pregnancy [33,38-44]. The possibility of this disorder should be considered in women with intense polydipsia and polyuria in the third trimester. The diagnosis is supported by the findings of a high-normal plasma sodium (the plasma sodium concentration in normal pregnancy typically is approximately 5 meq/L lower than in nonpregnant women [34]) in combination with an inappropriately low urine osmolality (ie, below that of plasma) [38-40]. Hypernatremia can occur if water intake is restricted, as in the peripartum period [40,42,45]. If unrecognized and untreated, hypernatremia can result in serious neurologic consequences in both the mother and fetus [45]. It is possible that women with transient DI associated with pregnancy have higher than normal pregnancy-related vasopressinase levels or activity. Women with multiple gestations, because of a larger placental volume, have higher circulating levels of vasopressinase and thus are more likely to experience polyuria. DI related in increased vasopressinase activity resolves postpartum and does not usually recur in subsequent pregnancies. Management — Transient DI of pregnancy can be effectively treated with desmopressin (dDAVP, 5 to 20 mcg intranasally or 2 to 5 mcg subcutaneously every 12 to 24 hours) [40]. Desmopressin is a vasopressin analog that is resistant to degradation by vasopressinase [38,43,46]. No adverse maternal or fetal effects from desmopressin use during pregnancy have been reported [47]. We suggest restriction of water intake to 1000 mL per day during desmopressin therapy to avoid the development of iatrogenic hyponatremia [40]. In the rare patients who develop hypernatremia, simultaneous water administration (either orally or intravenously) is necessary to correct the total body water deficit. The serum sodium concentration should be closely monitored and the rate of correction limited to no more than 12 meq/L per day to avoid cerebral edema from a rapid fall in serum osmolality. (See "Treatment of hypernatremia", section on 'Rate of correction'.) Comprehensive Clinical Nephrology, 4th Edition

Hypernatremia: Case 83 y/o female s/p emergent cholecystectomy for acute cholecystitis with sepsis, 5 days ago. You are called to see her for hypernatremia. She is very weak and ill, and complains of thirst. Her water pitcher is on the bedside table, which is pushed against the wall in her room. PMH: HTN, HLD, OA PE: Ill appearing elderly female. T 101.2, BP 110/68, P 95, Wt 54 kg. Mucous membranes dry. + drainage bag in upper abdomen draining bile. + NG tube. Dressed surgical wound. No edema.

Hypernatremia: Case Meds:
D5 1/2 NS at 100 ml/hour TPN Aztreonam, Flagyl, Vancomycin (all in 0.9% NS) Labs: Na 155; K 4.6; HCO3 32; Cl 110; glucose 95; BUN 45; creatinine 0.8 Drainage bag output 100 ml/day; Urine output is 2.5 liters/day; Urine osmolality 516 mOsm/kg

Etiologies of this patient’s hypernatremia?
Unable to access water Hypotonic fluid losses: NG and biliary drainage Increased insensible losses due to fever Averages ml/day in adults Estimation: 15 ml/kg/day; 15% increase for each 1 ̊C Fever, respiratory infections, burns increase insensible losses ? Mild renal insufficiency results in suboptimal urinary concentration (Uosm 516 mOsm/kg) Hypertonic gains: total parenteral nutrition (hyperosmotic), 0.9% NS used for antibiotics

What’s her free water deficit?
[Na+] [TBW] desired = [Na+] [TBW] actual [140 mEq/L] [TBW] = [155 mEq/L] [0.5 (54kg)] [TBW] desired = 29.9kg Free water deficit= 29.95kg – 27kg= 2.9kg Replace ½ of deficit with free water over 24 hours Lower serum [Na+] no more than 10 mEq/L over 24 hours Also need to take into account daily insensible losses and free water loss via urinary and GI tracts.

Does she have an osmotic diuresis?
Osmotic diuresis: increased urinary water loss induced by the presence of large amounts of nonreabsorbed solute in the tubular lumen (resulting in hypotonic urine) How many osmoles a day is she excreting in her urine? 516 mOsm/Kg x 2.5 liter/day = 1290 mOsm/day An average person excretes about mOsm/day The high urinary osmolar excretion likely accounts for the elevated urine osmolality, due to a high urea concentration from the high protein TPN The high urine [urea] results in an osmotic diuresis

The countercurrent mechanism of the kidneys, which allows urinary concentration and dilution, acts in concert with the hypothalamic osmoreceptors through vasopressin secretion to keep serum [Na+] and tonicity within a very narrow range (Fig. 8.3). A defect in the urine-diluting capacity coupled with excess water intake leads to hyponatremia. A defect in urinary concentrating ability with inadequate water intake leads to hypernatremia. Figure 8.3 Maintenance of plasma osmolality and pathogenesis of dysnatremias. (Modified with permission from reference 5.) Serum [Na+] along with its accompanying anions accounts for nearly all the osmotic activity of the plasma. Calculated serum osmolality is given by 2[Na+] + BUN (mg/dl)/2.8 + glucose (mg/dl)/18, where BUN is blood urea nitrogen. The addition of other solutes to ECF results in an increase in measured osmolality (Fig. 8.4). Solutes that are permeable across cell membranes do not cause water movement and do cause hypertonicity without causing cellular dehydration, for example, in uremia or ethanol intoxication. By comparison, a patient with diabetic ketoacidosis has an increase in plasma glucose, which cannot move freely across cell membranes in the absence of insulin and therefore causes water to move from the cells to the ECF, leading to cellular dehydration and lowering serum [Na+]. This can be viewed as “translocational” at the cellular level, as the serum [Na+] does not reflect change in total body water but rather reflects a movement of water from intracellular to extracellular space. A correction whereby a decrease in serum [Na+] of 1.6 mmol/l for every 100 mg/dl (5.6 mmol/l) of glucose used may somewhat underestimate the impact of glucose to decrease serum sodium concentration. Comprehensive Clinical Nephrology, 4th Edition

Toxic Alcohol Ingestions: Case
A 38-year-old man presented to the emergency department after reportedly ingesting antifreeze. He appeared to be intoxicated and was agitated and combative; chemical sedation was induced. Initial laboratory studies revealed a pH of 7.0, an anion gap of 22 mmol per liter, and an osmolar gap of 79 mOsm. N Engl J Med 2007;356:6

Urine Fluorescence on Wood’s Lamp
Preview Press the Escape key to close Urine Fluorescence in Ethylene Glycol Poisoning McStay, Christopher M; Gordon, Peter E. The New England Journal of Medicine356. 6 (Feb 8, 2007): 611. A 38-year-old man presented to the emergency department after reportedly ingesting antifreeze. He appeared to be intoxicated and was agitated and combative; chemical sedation was induced. Initial laboratory studies revealed a pH of 7.0, an anion gap of 22 mmol per liter, and an osmolar gap of 79 mOsm. It was noted that the patient's urine fluoresced under ultraviolet light (in the basin on the left), as compared with a negative control (in the basin on the right), which shows the purple reflection of the ultraviolet light (arrow). The patient received fomepizole, thiamine, folate, pyridoxine, and bicarbonate; he subsequently underwent hemodialysis. Laboratory studies revealed that his ethylene glycol level had been 222 mg per deciliter when the treatment began. His recovery was uneventful. Fluorescein is a fluorescent dye added to antifreeze preparations to aid in the detection of radiator leaks. In addition to the history and elevated osmolar and anion gaps, the fluorescence of urine under ultraviolet light may aid in the early identification of ethylene glycol poisoning. False negative and false positive results may occur. For example, many containers, such as urine collection bags, may be characterized by native fluorescence. CJASN 2008; 3: Sodium fluorescein is added to some brands of antifreeze at a final concentration of 20 μg/ml (86,87). Examination of urine (collected in containers without intrinsic fluorescence) for visible fluorescence after exposure to ultraviolet light at a wavelength of approximately 360 nm with a Wood's lamp has been used as an additional diagnostic tool (86–89). There are several pitfalls with this test. A number of drugs, food products, toxins, and endogenous compounds can contribute to urine fluorescence, producing false-positive results (86,87,89,90). The urine fluorescence is often short lived because the half-life of sodium fluorescein is 4.25 h (86–89). Not every brand of antifreeze contains fluorescein. Also, the optimal excitation wavelength of fluorescein is approximately 494 nm (86,87). Thus, urine initially considered negative with a Wood's lamp demonstrated fluorescence when studied using a fluorimeter at this wavelength (86–89). Finally, fluorescence is pH dependent and will be minimal or absent at a urine pH ≤4.5 (86,87). Physicians, therefore, should be cautious about either excluding or confirming the diagnosis on the basis of this test, and decision about initiating treatment should never be made on its basis alone. N Engl J Med 2007;356:6

CJASN 2008: 3; Four to 8 h after ingestion of ethylene glycol, calcium oxalate crystals will be present in the urine (38). Crystalluria can persist for as long as 40 h in the absence of renal failure and up to 4 d in its presence (37,38,81). The nature of the crystals can change with time: Within the first 4 to 5 h, envelope-shaped calcium oxalate dihydrate crystals are present; between 5 and 7 h, a mixture of monohydrate and dihydrate crystals are present; and after 7 h, only the needle-shaped monohydrate is present (37,38). Hypocalcemia, which is most profound many hours after ethylene glycol ingestion, is frequent at a time when oxalate crystalluria is prominent

Calcium oxalate dihydrate
Bihydrated calcium oxalate crystals with their typical appearance of a “letter envelope.” There are two types of calcium oxalate crystals. Bihydrated (or weddellite) crystals most often have a bipyramidal appearance (Fig. 4.7B); monohydrated (or whewellite) crystals are ovoid, dumbbell shaped, or biconcave disks (Fig. 4.7C). Both types of calcium oxalate crystals precipitate at pH 5.4 to 6.7. Monohydrated crystals always polarize light, whereas bihydrated crystals usually do not. Comprehensive Clinical Nephrology, 4th Edition

Calcium oxalate monohydrate
Different types of monohydrated calcium oxalate crystals There are two types of calcium oxalate crystals. Bihydrated (or weddellite) crystals most often have a bipyramidal appearance (Fig. 4.7B); monohydrated (or whewellite) crystals are ovoid, dumbbell shaped, or biconcave disks (Fig. 4.7C). Both types of calcium oxalate crystals precipitate at pH 5.4 to 6.7. Monohydrated crystals always polarize light, whereas bihydrated crystals usually do not. Comprehensive Clinical Nephrology, 4th Edition

Needle-shaped monohydrate crystals
(a) The urine sediment with multiple refractile, needle-shaped crystals, which in (b), using a polarizer, shows birefringence (original magnification 40). Kidney International 2008; 73: 1201–1202 The urine sediment with multiple refractile, needle-shaped crystals, which in (b), using a polarizer, shows birefringence (original magnification 40). Two types of calcium oxalate crystals may be seen: needle-shaped monohydrate crystals, which may be misread as hippurate crystals, and envelope-shaped dehydrate crystals. However, it is important to note that the formation of calcium oxalate crystals is not dependent upon the urine’s pH. CJASN 2008: 3; Four to 8 h after ingestion of ethylene glycol, calcium oxalate crystals will be present in the urine (38). Crystalluria can persist for as long as 40 h in the absence of renal failure and up to 4 d in its presence (37,38,81). The nature of the crystals can change with time: Within the first 4 to 5 h, envelope-shaped calcium oxalate dihydrate crystals are present; between 5 and 7 h, a mixture of monohydrate and dihydrate crystals are present; and after 7 h, only the needle-shaped monohydrate is present (37,38). Hypocalcemia, which is most profound many hours after ethylene glycol ingestion, is frequent at a time when oxalate crystalluria is prominent Kidney International 2008; 73: 1201–1202

Osmolar Gap Osmolar gap = measured Posm – calculated Posm
Posm (mOsm/L) = 2 x plasma [Na+] + Glucose (mg/dL)/18 + BUN (mg/dL)/2.8 Measured Posm is usually within 10 mOsm/L of the calculated Posm Elevated osmolar gap: Alcohol ingestions: methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, diethylene glycol (OG > 20 mOsm/L) Diabetic or alcoholic ketoacidosis, lactic acidosis, renal failure (OG < mOsm/L)

Osmolar Gap: Pitfalls The plasma osmolal gap cannot distinguish among various alcohol ingestions Absence of an osmolar gap does NOT exclude an alcohol-related intoxication The plasma osmolal gap increases only in the presence of the parent alcohols. The toxic acid metabolites of methanol and ethylene glycol do not contribute to the calculated osmolal gap. As a result, the plasma osmolar gap is insensitive in late presentations, since most of the parent alcohol has already been metabolized.

Evolution of changes in the serum osmolal and anion gaps during the course of methanol intoxication.
Evolution of changes in the serum osmolal and anion gaps during the course of methanol intoxication. Data from studies of methanol intoxication have revealed that early in the course of the disorder, the serum osmolal gap is the greatest and the serum anion gap the least. As metabolism of the parent alcohol proceeds, the serum osmolal gap and serum anion gap approximate each other. At later stages, the serum osmolal gap may return to baseline, whereas the serum anion gap continues to rise. Although it is presumed that a similar pattern would hold for many of the alcohol intoxications, sufficient data to confirm this are not available. Adapted from reference (23), with permission. CJASN 2008;3:

Metabolic pathways for ethanol, methanol, and ethylene glycol
Metabolic pathways for ethanol, methanol, and ethylene glycol. Although, the metabolites for each alcohol differ, the initial metabolic step facilitated by the enzyme alcohol dehydrogenase (ADH) is an important determinant of generation of these products and serves as an important therapeutic target. Enzymes for only the first two steps of each pathway are shown. The conversion of formate to CO2 and H2O depends on adequate folate concentrations. Pyridoxine promotes the metabolism of glyoxylate to glycine, and thiamine promotes metabolism of glycolic acid to α-hydroxy-β-ketoadipate. ALDH, aldehyde dehydrogenase; FMD, formaldehyde dehydrogenase. CJASN 2008;3:

Metabolic pathways for isopropanol, diethylene glycol, and propylene glycol
Metabolic pathways for isopropanol, diethylene glycol, and propylene glycol. Although the metabolites for each alcohol differ, the initial metabolic step facilitated by the enzyme ADH is an important determinant of generation of these products and serves as an important therapeutic target. Enzymes for only the first two steps of each pathway are shown. UpToDate: Isopropyl alcohol does NOT cause an elevated anion gap acidosis, unlike the toxic alcohols methanol and ethylene glycol. Methanol and ethylene glycol are both primary alcohols, which are oxidized (via alcohol dehydrogenase and then aldehyde dehydrogenase) to carboxylic acids (formic acid in the case of methanol and glycolic, glyoxylic, and oxalic acids in the case of ethylene glycol). These acid metabolites cause the severe toxicity (ie, blindness, renal failure, and death) characteristic of methanol and ethylene glycol poisoning. (See "Methanol and ethylene glycol poisoning".) Isopropyl alcohol is a secondary alcohol; as such, it is metabolized to a ketone (via alcohol dehydrogenase), rather than an aldehyde. Ketones cannot be oxidized to carboxylic acids. As a result, only very limited acidemia can occur; isopropyl alcohol is considerably less toxic than methanol or ethylene glycol. Osmolal gap — The osmolal gap provides important diagnostic information when quantitative serum testing for the toxic alcohols is not readily available. (See "Serum osmolal gap".) By comparing the measured plasma osmolality (determined by freezing point depression) to the calculated osmolarity, the clinician can infer the presence of an osmotically active, electrically neutral substance present at serum concentrations above 10 mmol/L (ie, at least 60 mg/dL of isopropyl alcohol and acetone combined). Both isopropyl alcohol and acetone will raise the osmolal gap [8]. The plasma osmolal gap cannot distinguish among isopropyl alcohol, methanol, and ethylene glycol poisoning, and so cannot be used to exclude ingestion of these more toxic alcohols. (See "Methanol and ethylene glycol poisoning".) Unlike methanol and ethylene glycol poisoning, neither a metabolic acidosis nor an elevated anion gap are expected after isopropyl alcohol ingestion. These findings should prompt the clinician to investigate alternative diagnoses. (See 'Differential diagnosis' above and "Approach to the adult with metabolic acidosis" and "Approach to the child with metabolic acidosis".) Serum and urine ketones — Testing for serum and urine ketones using the nitroprusside reaction will be strongly positive in the presence of acetone. These tests are calibrated for ketonemia due to endogenous metabolism, and are thus very sensitive to the high acetonemia that follows a substantial ingestion of isopropyl alcohol. Low concentrations of serum ketones exclude any significant isopropyl alcohol exposure, provided at least two hours have transpired since ingestion, and alcohol dehydrogenase has not been blocked by coingested ethanol or fomepizole [10]. Some laboratories will measure β-hydroxybutyrate concentrations when “serum ketones” are requested. Acetone is the predominant ketone generated by metabolism of isopropyl alcohol, and serum β-hydroxybutryate concentrations remain low even following large ingestions. CJASN 2008;3:

Disorder Substance(s) Causing Toxicity Clinical and Laboratory Abnormalities Comments Alcoholic (ethanol) ketoacidosis β-hydroxybutyric acid, Acetoacetic acid Metabolic acidosis May be most frequent alcohol-related disorder; mortality low relative to other alcohols; rapidly reversible with fluid administration; increase in SOsm inconsistent Methanol intoxication (windshield wiper fluid, model airplane fuel, antifreeze) Formic acid, Lactic acid, Ketones Metabolic acidosis, hyperosmolality, retinal damage with blindness, putaminal damage with neurologic dysfunction Less frequent than ethylene glycol; hyperosmolality and high anion gap acidosis can be present alone or together; mortality can be high if not treated quickly Ethylene glycol intoxication (antifreeze, runway deicers) Glycolic acid, Calcium oxalate Myocardial and cerebral damage and renal failure; metabolic acidosis, hyperosmolality, hypocalcemia More frequent than methanol intoxication; important cause of intoxications in children; hyperosmolality and high anion gap acidosis can be present alone or together Diethylene glycol intoxication (brake fluid) 2-Hydroxyethoxyacetic acid Neurological damage, renal failure, metabolic acidosis, hyperosmolality Very high mortality possibly related to late recognition and treatment; most commonly results from ingestion in contaminated medications or commercial products; hyperosmolality may be less frequent than with other alcohols Propylene glycol intoxication (solvent for hydralazine, nitroglycerin, lorazepam, diazepam, phenytoin, phenobarbital, digoxin) Lactic acid Metabolic acidosis, hyperosmolality May be most frequent alcohol intoxication in ICU; minimal clinical abnormalities; stopping its administration is sufficient treatment in many cases Isopropanol intoxication (rubbing alcohol) Isopropanol Coma, hypotension, hyperosmolality Hyperosmolality without acidosis; positive nitroprusside reaction CJASN 2008;3: Metabolic acidosis and organ dysfunction primarily result from generation of glycolic and oxalic acid from metabolism of ethylene glycol (13,37,43,79). The accumulation of glycolic acid is the primary cause of metabolic acidosis, but glycolate also impairs cellular respiration, and this effect can contribute to the development of lactic acidosis in some patients (6,37,43). Acute renal failure (ARF), myocardial dysfunction, neurologic function, and possibly pulmonary dysfunction result from deposition of oxalate with calcium in the kidney, heart, brain, and lung (8,13,37). Deposition of calcium oxalate in tissues also produces hypocalcemia, which depresses cardiac function and BP CJASN 2008;3:

Poor Prognostic Factors
Disorder Epidemiology Diagnostic Cluesb Poor Prognostic Factors Methanol intoxication Accidental or intentional ingestion of adulterated alcohol or products with methanol; rare cases of inhalation of methanol Osmolal gap with HAGAc Blood pH <7.1; LA; severe coma; severe hypotension; serum methanol >50 to 100 mg/dl Visual difficulties with optic papillitis Ethylene glycol intoxication Accidental or intentional ingestion of antifreeze, alcohol adulterated with ethylene glycol, or products with ethylene glycol Blood pH <7.1; glycolate level >8 to 10 mmol/L; ARF requiring HD; diagnosis >10 h after ingestion; serum ethylene glycol >50 to 100 mg/dl ARF with osmolal gap Calcium oxalate crystals in urine, monohydrate or dihydrate Diethylene glycol intoxication Ingestion of contaminated medication or products with diethylene glycol Blood pH <7.1; ARF requiring HD; severe coma; ingestion of >1.34 mg/kg body wt Osmolal gap with ARF Osmolal gap with coma Propylene glycol intoxication Intravenous administration of medication with propylene glycol; rare ingestion of products with propylene glycol Osmolal gap with or without LA Severe LA; serum propylene glycol level >400 to 500 mg/dl Isopropanol intoxication Accidental or intentional ingestion of rubbing alcohol Osmolal gap without HAGA Severe LA; hypotension; serum isopropanol level ≥200 to 400 mg/dl Alcoholic ketoacidosis Binge drinking often in alcoholic patients associated with starvation and often vomiting HAGA, trace positive or negative nitroprusside reaction with increase with H2O2; hypoglycemia; osmolal gap Blood pH <7.0; severe comorbid conditions CJASN 2008;3:

Fomepizole has ~500-1000x greater affinity for ADH than ethanol
Although there is little toxicity associated with ethylene glycol itself, it is metabolized by successive oxidations to active metabolites (Figure 1A). One of these metabolites is oxalic acid, which may combine with ionized calcium in plasma to form calcium oxalate. Calcium oxalate precipitates in the renal tubules and is thought to be the cause of ethylene glycol-induced renal injury,56although some studies suggest a role for other metabolites.7The prominent metabolic acidosis is due to circulating glycolic acid.8910 Like ethylene glycol, methanol itself is not responsible for the major adverse effects of its ingestion. Rather, it is metabolized to formaldehyde, which is subsequently oxidized to formic acid (Figure 1B). Formic acid is the cause of the retinal and optic-nerve damage seen in patients who survive serious methanol poisoning.1112Although the primary site of metabolism of methanol is the liver, some metabolism appears to occur in the retina as well, and local retinal conversion to formic acid may be a factor in the retinal toxicity of methanol.1314 The metabolism of both ethylene glycol and methanol occurs primarily through the hepatic enzyme alcohol dehydrogenase (Figure 1A). Ethanol, which is a competitive substrate for alcohol dehydrogenase, can be administered to inhibit the metabolism of ethylene glycol or methanol, followed by hemodialysis to remove both the parent compound and its metabolites However, ethanol has erratic pharmacokinetics181920and can cause changes in mental status,20hypoglycemia,1819and pancreatitis.19 Fomepizole (4-methylpyrazole) is a competitive inhibitor of alcohol dehydrogenase that prevents the formation of metabolites of ethylene glycol8and methanol.21It is most effective when given early, before significant quantities of metabolites are formed. Given the efficacy of inhibition of alcohol dehydrogenase by fomepizole,82122the prognosis is primarily dependent on the time from ingestion to the initiation of therapy and the amount of the toxic metabolite that has accumulated, rather than the plasma concentration of the parent compound at the time that fomepizole is administered. 821Fomepizole was approved in the United States for the treatment of ethylene glycol poisoning in 1997; in 2000, an indication for methanol toxicity was added. N Engl J Med 2009;360:

General Principles in the Treatment of Alcohol Intoxications
Gastric lavage, induced emesis, or use of activated charcoal to remove alcohol from gastrointestinal tract needs to be initiated within 30 to 60 min after ingestion of alcohol Administration of ethanol or fomepizole to delay or prevent generation of toxic metabolites needs to be initiated while sufficient alcohol remains unmetabolized measurement of blood alcohol concentrations and/or serum osmolality can be helpful Dialysisb (hemodialysis > continuous renal replacement therapy > peritoneal dialysis) helpful in removing unmetabolized alcohol and possibly toxic metabolites and delivering base to patient to ameliorate metabolic acidosis

Methanol intoxication
Disorder Treatmentb Methanol intoxication Initiate fomepizole (alcohol if fomepizole not available) and HD with methanol >20 mg/dl, in presence of HAGA with osmolal gap and high suspicion of ingestion. Initiate HD alone if HAGA present and methanol levels <10 mg/dl or no osmolal gap but strong suspicion of ingestion. Give folinic or folic acid. Give base with severe acidosis if patient not undergoing HD. Discontinue treatment when pH normalized and methanol levels <10 to 15 mg/dl or undetectable. If measurement of methanol not available use return of blood pH and serum osmolality to normal as goals of therapy. Ethylene glycol intoxication Initiate fomepizole (alcohol if fomepizole not available) and HD with ethylene glycol levels >20 mg/dl or in presence of HAGA with osmolal gap and high suspicion of ingestion. Initiate HD alone if HAGA present and ethylene glycol level <10 mg/dl or no osmolal gap but strong suspicion of ingestion. Give base with severe acidosis if patient not undergoing HD. Give thiamine and pyridoxine. Discontinue treatment when pH normalized and ethylene glycol levels <10 to 15 mg/dl or undetectable. If measurement of ethylene glycol not available use return of blood pH and serum osmolality to normal as goals of therapy. Diethylene glycol intoxication Initiate HD with osmolal gap, HAGA, and ARF or with high suspicion of ingestion because of cohort of cases ingesting contaminated medication. Administration of fomepizole not approved but recommended in addition to dialysis. Discontinuation of treatment with recovery of renal function, normalization of acid-base parameters and osmolal gap. Propylene glycol intoxication Discontinue medication containing propylene glycol which will be effective alone in most cases. Initiate dialysis and/or fomepizole with severe LA or very high serum concentrations >400 mg/dl and evidence of severe clinical abnormalities. Isopropanol intoxication Supportive therapy usually sufficient. Initiate HD with serum level 200 to 400 mg/dl or in presence of marked hypotension or coma.c Alcoholic ketoacidosis Administer intravenous fluids including dextrose and NaCl; base rarely needed, might be considered with blood pH <6.9 to 7.0; consider administering insulin with marked hyperglycemia

Pseudohyponatremia Measures solute per unit plasma water
Serum [Na+] = 140 mEq/L Serum [Na+] = 130 mEq/L Solids 7% Solids 14% 1 liter plasma HYPERLIPIDEMIA 1 liter plasma Water 93% HYPERPROTEINEMIA Water 86% Na+ 130 mEq in 860 ml Na+ 140 mEq in 930 ml OSMOLALITY Measures solute per unit plasma water 140 mEq/930 ml = 151 mEq/liter = 130 mEq/860 ml

Last literature review version 19
Last literature review version 19.2: May 2011 | This topic last updated: September 14, 2000 (More) INTRODUCTION — The body water is distributed between three major compartments: the intracellular space; the interstitium, which constitutes the extracellular environment of the cells; and the vascular space. Regulation of the intracellular volume, which is essential for normal cellular function, is achieved in part by regulation of the plasma osmolality through changes in water balance. In comparison, maintenance of the plasma volume, which is essential for adequate tissue perfusion, is closely related to the regulation of sodium balance. Sodium and water homeostasis will be reviewed in detail in the following two chapters. It is useful, however, to first discuss the factors involved in the distribution of water across the cell membrane (between the intracellular and extracellular fluids) and across the capillary wall (between the vascular space and interstitium). The concept of osmotic pressure can be easily understood from the simple experiment in this figure (figure 1). Suppose distilled water in a beaker is separated into two compartments by a membrane that is permeable to water but not to solutes, and that glucose is added to the fluid on one side of the membrane. Water molecules exhibit random motion and can diffuse across a membrane by a mechanism similar to that for diffusion of solutes. When solutes are added to water, however, the intermolecular cohesive forces lead to a reduction in the random movement (or activity) of the water molecules [2,3]. Since water moves from an area of high activity to one of low activity, water will flow into the compartment containing glucose. EXCHANGE OF WATER BETWEEN CELLULAR AND EXTRACELLULAR FLUIDS — Osmotic forces are the prime determinant of water distribution in the body. Water can freely cross almost all cell membranes; as a result, the body fluids are in osmotic equilibrium as the osmolalities of the intracellular and extracellular fluids are the same [1]. In theory, this movement of water, called osmosis, should continue indefinitely because the activity of water will always be lower in the glucose compartment. However, since the compartment is rigid, the increase in volume will result in an elevation in hydrostatic pressure, causing the fluid column above the compartment to rise. This hydrostatic pressure tends to push water back into the solute-free compartment. Equilibrium will be reached when the hydrostatic pressure (as measured by the height of the column) is equal to the forces pulling water across the membrane. This hydrostatic pressure which opposes the osmotic movement of water is called the osmotic pressure of the solution. The osmotic pressure that is generated is proportional to the number of particles per unit volume of solvent, not to the type, valence, or weight of the particles. The solute, however, must be unable to cross the cell membrane. Let us now consider what would happen in a beaker, similar to that in this figure (figure 1), if a lipid-soluble and freely diffusible solute such as urea were added to one compartment (figure 2). The added urea will move down a concentration gradient into the solute-free compartment. The new equilibrium state will be characterized by equal urea concentrations in each compartment and not by water movement into the urea compartment. As a result, no osmotic pressure is generated by urea at equilibrium and urea is considered to be an ineffective osmole. Osmotic pressure is important in vivo because it determines the distribution of water between the extracellular and intracellular space. Each of these compartments has one solute that is primarily limited to that compartment and therefore is the major determinant of its osmotic pressure: Na+ salts are the principal extracellular osmoles and act to hold water in the extracellular space; conversely, K+ salts account for almost all the intracellular osmoles (most of the other major cell cation Mg2+ is bound and osmotically inactive) and act to hold water within the cells. Although the cell membrane is permeable to both Na+ and K+, these ions are able to act as effective osmoles because they are restricted to their respective compartments by the Na+-K+-ATPase pump in the cell membrane. The net effect is that the volumes of the extracellular and intracellular fluids are determined by the amount of water present and by the ratio of exchangeable Na+ to exchangeable K+†. †The exchangeable portion is used since about 30 percent of the body Na+ and a smaller fraction of the body K+ are bound in areas such as bone where they are "nonexchangeable" and therefore osmotically inactive. These ions also may be partially bound in intracellular organelles such as the nucleus and lysosomes [4]. Under normal circumstances, the water and electrolyte content in the body is maintained within relatively narrow limits as variations in dietary intake are matched by appropriate changes in urinary excretion. Nevertheless, it is important to understand the potential physiologic effects of alterations in solute or water balance, since these disturbances often occur in the clinical setting. If, for example, the osmolality of one fluid compartment is changed, water will move across the cell membrane to reestablish osmotic equilibrium. How this affects water distribution and solute concentration can be appreciated from the following examples (figure 3). For the sake of simplicity, let us assume that the osmolality of the body fluids is 280 mosmol/kg and is due entirely to 140 meq/L of Na+ salts in the extracellular fluid and to 140 meq/L of K+ salts in the cells, i.e., we are assuming that Na+ and K+ salts dissociate completely into cations and anions. As depicted in part A of the following figure (figure 3), an average 70-kg man might have a total body water (TBW) of 42 liters (or 42 kg) of which 25 liters (60 percent) is intracellular and 17 liters (40 percent) is extracellular. What will happen if 420 meq of NaCl (420 mosmol) without water is added to the extracellular fluid, as shown in this figure (figure 3)? Since the NaCl remains extracellular, there will be an increase in the extracellular fluid osmolality, resulting in water movement out of the cells down an osmotic gradient. The following calculations can be used to estimate the characteristics of the total body water in the new equilibrium state: 3. New total body solute = 11, = 12,180 mosmol 2. Initial extracellular solute = 280 mosmol/kg x 17 kg = 4760 mosmol 1. Initial total body solute = 280 mosmol/kg x 42 kg = 11,760 mosmol 6. New extracellular volume = 5180 mosmol ÷ 290 mosmol/kg = 17.9 kg 5. New extracellular solute = = 5180 mosmol 4. New body water osmolality = 12,180 mosmol ÷ 42 kg = 290 mosmol/kg 7. New intracellular volume = = 24.1 kg Thus, increasing the quantity of extracellular solute results in the movement of 900 mL of water from the cells into the extracellular fluid. The net effect is an increase in the osmolality of both compartments even though the added solute is restricted to the extracellular space. This illustrates why the total body water (50 to 60 percent of lean body weight) must be used when calculating the volume of distribution of changes in plasma osmolality. 8. New extracellular or plasma [Na+] = osmolality ÷ 2 = 145 meq/L A different sequence occurs if 1.5 liters of solute-free water is added to the extracellular fluid, eg, by ingestion. This reduces the extracellular fluid osmolality, creating an osmotic gradient favoring the entry of water into the cells, as in part C of the following figure (figure 3). To estimate the new steady state, steps 1 and 2 are similar to those above: 2. Initial extracellular solute = 4760 mosmol 1. Initial total body solute = 11,760 mosmol 5. New body water osmolality = 11,760 mosmol ÷ 43.5 kg = 270 mosmol/kg 4. New total body water = = 43.5 kg 3. Initial intracellular solute = 11, = 7000 mosmol 6. New extracellular volume = 4760 mosmol ÷ 270 mosmol/kg = 17.6 kg 9. New extracellular or plasma [Na+] = osmolality ÷ 2 = 135 meq/L 8. Ratio of intracellular volume to TBW = 25.9 ÷ 43.5 = 60 percent 7. New intracellular volume = 7000 mosmol ÷ 270 mosmol/kg = 25.9 kg † In this example, it is assumed that the administered water is retained. In normal subjects, however, excess water is excreted so rapidly that there is little change in volume or sodium excretion (see Chap. 11). Increases in extracellular volume and sodium excretion after a water load occur only if there is some defect in water excretion, as with persistent secretion of antidiuretic hormone (see Chap. 23). Since there is no change in the ratio of intracellular to extracellular solute in this example, the fractional composition of the TBW is unchanged (cell water is still 60 percent of TBW). However, the TBW is increased, resulting in expansion and dilution of both compartments†. Finally, if both NaCl and water are given as 1.5 liters of isotonic NaCl, there will be no change in osmolality and consequently no water movement across the cell membrane, as depicted in part D of the following figure (figure 3). Since the administered NaCl remains in the extracellular space, the only effect is a 1.5-liter increase in the extracellular fluid volume. The results of these experiments are summarized in this table (table 1) and illustrate an important and often misunderstood concept, that the plasma Na+ concentration is a measure of concentration and not of volume. In each instance, the extracellular fluid volume is increased, because of an elevation in either the TBW and/or the total exchangeable Na+; despite this uniform change in volume, however, the plasma Na+ concentration is, respectively, increased, decreased, and unchanged. This occurs because the plasma Na+ concentration reflects the ratio of the amounts of solute and water present, not the absolute amount of either solute or water. Thus, there is no necessary correlation between the plasma Na+ concentration and the extracellular fluid volume. These parameters change in a parallel direction when Na+ is administered but in an opposite direction (low plasma Na+ concentration, high extracellular fluid volume) when water retention occurs, as shown in parts b and c of this figure (figure 3). Furthermore, since the extracellular volume is the primary determinant of urinary sodium excretion (see Chap. 8), there is also no relationship between the plasma Na+ concentration and the rate of sodium excretion (table 1). When water is retained, for example, the plasma Na+ concentration falls by dilution but urinary sodium excretion will rise because of the increase in extracellular volume. One final point deserves emphasis in these experiments. The intracellular volume varies inversely with the plasma Na+ concentration, decreasing with hypernatremia and increasing with hyponatremia. These changes are important clinically because the neurologic symptoms associated with acute changes in the plasma Na+ concentration are primarily related to these alterations in cell volume in the brain. (See "Manifestations of hyponatremia and hypernatremia".) RELATION OF PLASMA SODIUM CONCENTRATION TO OSMOLALITY — The osmolality of the plasma (Posm) is equal to the sum of the osmolalities of the individual solutes in the plasma†. Most of the plasma osmoles are Na+ salts, with lesser contributions from other ions, glucose, and urea. The osmotic effect of the plasma ions can usually be estimated from 2 x plasma Na+ concentration. The validity of this approximation results from the interplay of several factors: Ionic interactions in plasma reduce the random movement of NaCl so that it acts osmotically as if it were only 75 percent, not 100 percent, dissociated. As a result, 1 mmol of NaCl behaves as if it dissociates into roughly 1.75 particles (0.75 Na+, 0.75 Cl-, and 0.25 NaCl) * [5] *; thus, the plasma Na+ concentration must be multiplied by 1.75 to estimate the osmotic effect of sodium salts. †A review of the units and the methods used to measure the plasma osmolality can be found elsewhere in the program. (See "Chapter 1B: Units of solute measurement", section on 'Osmotic pressure and osmolality'.) Only 93 percent of the plasma is normally composed of water, with fat and proteins comprising the remaining 7 percent. In most laboratories, the plasma Na+ concentration is measured per liter of plasma. This value must be divided by 0.93 to arrive at the physiologically important Na+ concentration in the plasma water (Na+ being present only in the aqueous phase of plasma). Thus, The remaining 0.12 x plasma Na+ concentration is equal to 17 mosmol/kg (0.12 x 140), which fortuitously is the approximate osmotic pressure generated by K+, Ca2+, and Mg2+ salts. = 1.88 x plasma [Na+] Osmolality of Na+ salts = (1.75 ÷ 0.93) x plasma [Na+] The osmotic contributions of glucose and urea, both of which are measured in milligrams per deciliter, can be calculated from Eq. (1): (Eq. [Na+] ) + ([glucose]/18) + (BUN/2.8) The molecular weight of glucose is 180 and that of the two nitrogen atoms in urea (since urea is measured as the blood urea nitrogen or BUN) is 28. Therefore, the Posm can be estimated from: (Eq. 1) mosmol/kg = (mg/dL x 10) ÷ mol wt (Eq. 3) Effective [Na+] ) + ([glucose]/18) The effective plasma (and extracellular fluid) osmolality is determined by those osmoles that act to hold water within the extracellular space. Since urea is an ineffective osmole: Plasma [Na+] = meq/L [Glucose] = mg/dL, fasting BUN = 10-20 mg/dL Posm = mosmol/kg Effective Posm = mosmol/kg The normal values for these parameters are: Under normal circumstances, glucose accounts for only 5 mosmol/kg, and Eq. (3) can be simplified to: Determinants of the Plasma Sodium Concentration — Since the body fluids are in osmotic equilibrium, Thus, in most conditions, the plasma Na+ concentration is a reflection of the Posm, a finding consistent with the fact that Na+ salts are the principal extracellular osmoles. (Eq. 4) Effective [Na+] = (extracellular solute + intracellular solute) ÷ total body water Effective Posm = effective osmolality of total body water (The multiple 2 is used to account for the osmotic contribution of the anions accompanying Na+ and K+.) If we now combine Eqs. (4) and (5), both of which are formulas for the effective Posm [5] : (Eq. 5) Effective x Ke+) ÷ TBW As described above, exchangeable Na+ (Nae+) salts are the primary effective extracellular solutes, and exchangeable K+ (Ke+) salts are the primary effective intracellular solutes. Therefore, As illustrated in this figure (figure 4), this relationship holds over a wide range of plasma Na+ concentrations in humans. (Eq. 6) Plasma The importance of these variables on the plasma Na+ concentration can be appreciated from the examples in Figure 3. Increasing the Nae+ elevates the plasma Na+ concentration; increasing the TBW decreases the plasma Na+ concentration; and increasing the Nae+ and TBW proportionately has no effect on the plasma Na+ concentration (figure 3). The effect of changes in potassium balance is less apparent but can be important clinically [6,7]. Suppose, for example, that K+ is lost from the extracellular fluid because of diarrhea, leading to a fall in the plasma K+ concentration. This will create a concentration gradient favoring the movement of K+ from the cells into the extracellular fluid. Since large proteins and organic phosphates are the major intracellular anions and cannot easily leave the cells, electroneutrality is preserved by Na+ (and H+) entry into the cells, thereby lowering the plasma Na+ concentration. The major clinical application of these concepts occurs in patients with hyponatremia (low plasma Na+ concentration) or hypernatremia (high plasma Na+ concentration). From the relationships in Eq. 4 and 6, we can see that hyponatremia usually represents hypoosmolality and can be produced by Na+ and K+ loss or, most commonly, by water retention. Excretion of the excess water in the urine is normally a very effective defense against the development of hyponatremia. Thus, a fall in the plasma Na+ concentration is almost always associated with a defect in urinary water excretion, due most often to the presence of antidiuretic hormone. On the other hand, hypernatremia represents hyperosmolality and can be produced by Na+ gain or water loss. The toxicity of hyperkalemia (high plasma K+ concentration) prevents the retention of enough K+ to cause an important elevation in the plasma Na+ concentration. The primary protective mechanism against hypernatremia is the stimulation of thirst, thereby increasing water intake and lowering the plasma Na+ concentration to normal. Thus, hypernatremia generally occurs in infants or comatose adults who cannot express a normal thirst response. Notice that the regulation of the plasma Na+ concentration and therefore the plasma osmolality occurs by changes in water balance. Although it is tempting to assume that maintenance of the plasma Na+ concentration must be related to Na+ balance, this is not the case. Alterations in sodium balance are used to maintain the plasma volume and tissue perfusion, not the plasma Na+ concentration. (See "Chapter 8C: Regulation of renal Na+ excretion".) Too much sodium is manifested as edema and too little sodium results in hypovolemia. This discussion is continued elsewhere. (See "Chapter 7B: Exchange of water between plasma and interstitial fluid".)

Other factors affecting ADH secretion
Nausea Extremely potent stimulus (as much as 500-fold rise in ADH level) Hypoglycemia 3-fold rise in ADH level when plasma glucose decreases by 50% Pregnancy (reset osmostat) Lowers the osmoregulatory threshold for ADH release and thirst Fall in plasma [Na+] by about 5mEq/L May be mediated by ↑release of chorionic gonadotropin which causes systemic vasodilation and fall in BP Multiple drugs (i.e. morphine, nicotine, cyclophosphamide)

Hypo/Hyperosmolar States

Similar presentations

Presentation on theme: "Hypo/Hyperosmolar States"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Hypo/Hyperosmolar States

Similar presentations

Presentation on theme: "Hypo/Hyperosmolar States"— Presentation transcript:

Similar presentations

About project

Feedback