Clinical Medicine, Slides of Clinical Medicine

Download Clinical Medicine and more Slides Clinical Medicine in PDF only on Docsity! Clinical Medicine The Variable Hyponatremic Response to Hyperglycemia S. MARK MORAN, MD, and REX L. JAMISON, MD, Stanford, California Hyperglycemia may lower the plasma sodium concentration. Theoretical analyses have suggested that elevations in glucose concentration produce an invarianthyponatremic response. Wepropose, however, thatchange in plasma sodium concentration in response to hyperglycemia is variable and depends on (1) the distribution of total body water and solute, (2) the relationship between the gain of extracellular glucose and the loss of intracellular solute and (3) the intake and loss of solute and water. These factors are incorporated into a formulation of the relationship between the plasma sodium andglucose concentrations. (Moran SM, Jamison RL: The variable hyponatremic response to hyperglycemia. West J Med 1985 Jan; 142:49-53) Because hyperglycemia may notably reduce plasma so- dium concentration, a clinician often must decide whether the reduction is appropriate for the elevation in glu- cose concentration ofthe plasma. 1-6 More than 20 years ago it was suggested that sodium concentration would decline ap- proximately 2.8 mEq per liter for each 100 mg per dl rise in glucose concentration above 100 mg per dl.1-2 Katz rejected this "classic" figure and suggested that the change in sodium concentration varied linearly with the increment in glucose concentration. He calculated the decrement in sodium concen- tration to be 1.6 mEq per liter per 100 mg per dl rise in glucose concentration.3 This figure and the analysis from which it was derived are widely accepted.4` In assessing the relationship between hyperglycemia and hyponatremia, how- ever, the answers to several questions will largely determine the correct decrement in sodium concentration. What is the distribution of body solute and water? What is the source of the extracellular glucose that produces hyperglycemia? What other conditions apply? Understanding the limitations in- herent in earlier approaches enables us to formulate a more broadly applicable relationship. Classic.Solution The classic analysis included these assumptions: (1) total body water is 60% of body weight and is distributed two thirds as intracellular fluid (ICF) and one third as extracellular fluid (ECF), (2) glucose and sodium are essentially restricted to the extracellular space, (3) water freely crosses cellular membranes, (4) glucose is "added to" the extracellular space, (5) intracellular solute remains constant, (6) extracel- lular, and therefore intracellular, osmolality ultimately re- turns to nonral-that is, an elevated glucose and a coinciden- tally depressed sodium concentration`-3and (7) the classic solution does not specify that the increase in extracellular fluid space that occurs in hyperglycemia must be supplied by a positive water balance. It follows that if osmolality is to remain unaltered and intracellular solute is constant, intracel- lular volume must be static. Because water traverses cellular membranes easily, the fol- lowing relationship obtains: ICF solute (osmole) ECF solute(osmole)(1) ICF volume (liter) ECF volume (liter) For purposes of calculation and to illustrate the classic solu- tion, the following plasma values will be defined as normal for a 70-kg man: sodium, 140 mEq per liter; glucose, 100mg per dl (5.5 mosm per liter); osmolality, 285 mosm per kg. Total body water is 42 liters. The ICF has a volume of 28 liters and contains 7,980 mosm. The ECF has a volume of 14 liters and contains 3,990 mosm. Inserting these values into equation 1, the effect of adding glucose to the extracellular fluid may be expressed as: 7,980mosm _ (3,990 + G) mosm (2) 28 liters (14 + X) liters where G = milliosmoles of added glucose and X = the addi- tional water (in liters) needed to reestablish normal osmo- lality. Solving for X(in liters) in terms ofG (in milliosmoles), X = 0.0035G. From the Division ofNephrology, Department ofMedicine, Stanford University School of Medicine, Stanford, California. Dr Moran is a Fellow in Nephrology. Submitted, revised, January 23, 1984. This work was supported by National Institutes ofHealth grant 5-T32-AM-07357 and a grant from the Marilyn Simpson Trust. Reprint requests to Mark Moran, MD, Division ofNephrology, Room S2 15, Stanford University School ofMedicine, Stanford, CA 94305. JANUARY 1985 - 142 o 1 49 VARIABLE HYPONATREMIC RESPONSE TO HYPERGLYCEMIA ABBREVIATIONS USED IN TEXT ECF=extracellular fluid ICF=intracellular fluid The new sodium concentration, PNa, is PN. = 140 114 - ]mEq/liter.[( 1 + X) The new glucose concentration, PG, is pG _ G + (5.5) * (14)1 mosm/liter.c L (14+X) The fall in sodium concentration, APN, , iS APNa = [140 - PNaJ mEq/liter. The increment in glucose concentration, APG, is APG = [PG- 5.5] mosm/liter. The relationship between APN. and APG may then be calcu- lated. The sodium concentration is reduced 2.75 mEq per liter per 100 mg per dl increase in glucose concentration. Solution of Katz Katz correctly observed that simple addition of solute to the body would necessarily produce at equilibrium an osmolality greater than normal. A redistribution of body water from intracellular to extracellular fluid space would not suffice to return osmolality to its original value.3 In his analysis, Katz assumes the same conditions as for the classic solution with the following exceptions: (1) it is no longer assumed that osmolality remains normal and (2) intake and output are spe- cifically excluded. Solute as glucose is "added to" the extra- cellular fluid, raising total body solute content. Intracellular water moves to the extracellular compartment until intracel- lular and extracellular osmolality equilibrate at some higher value. Intracellular solute is still assumed to be fixed, how- ever. The relationship is ICF solute (osmole) - ECF solute (osmole) + G (3) ICF volume - Y ECF volume + Y where Y represents the volume of intracellular water moving to the extracellular space, and G is the added glucose. Employing the same normal values as in the classic solution and inserting these into equation 3, Katz's solution may be expressed as 7,980 3,990 + G (4) 28-Y 14+Y Solving for Yin tenns of G, Y= 28G 11,970 + G While sodium concentration declines approximately 1.6 mEq per liter with each 100 mg per dl increase in glucose concen- tration, it is apparent that Y. the volume of intracellular water added to extracellular fluid, cannot vary linearly with the increment in giucose concentration and therefore that APN. cannot vary linearly with APG. General Solution We must identify the source of glucose in the extracellular fluid. This is particularly important in the case of an insulino- penic diabetic patient who has ketoacidosis and is unable to eat, and in whom the plasma glucose is often markedly ele- vated. Glucose is produced intracellularly-it is not "added to" the extracellular fluid from an exogenous source. A va- riety of intracellular substances are consumed or transformed in the production of the glucose that ultimately enters the extracellular space.8 This represents the movement of intra- cellular solute to the extracellular aqueous compartment, and it is incorrect to assume that the quantity of intracellular solute remains fixed. A general analysis of the relationship between glucose concentration and sodium concentration should ac- count for volume changes in both intracellular and extracel- lular solute and water, as well as accommodating the special conditions assumed for both the classic and Katz's solutions. Finally it should be applicable to the clinical setting of dia- betic ketoacidosis where knowledge of the sodium-glucose relationship could be ofgreat benefit. The general expression is (ICF solute - G,) - (ECF solute + G2) where (ICF volume - Y1) (ECF volume + Y2) Y,= water lost from the ICF (in liters), Y,= water gained by the ECF (in liters), Gi= ICF solute loss (in milliosmoles), G,= ECF gain in glucose (in milliosmoles). (If intake and output are excluded, ECF volume gain equals ICF loss, that is, Y1 = Y2; G, does notequal G2, however.) It is more nearly correct to assume in normal humans that 55% of body water (and solute) is intracellular and 45% is extracellular.9 Using this assumption, Katz's solution would have predicted a decline of 1.4 mEq per liter in sodium con- centration for a 100 mg per dl increase in glucose rather than the 1.6 mEq per liter originally calculated. In the 70-kg man used as our example, ICF volume equals 23.1 liters, con- taining 6,584 mosm; ECF volume equals 18.9 liters and con- tains 5,386 mosm. Substituting these values into equation 6, 6,584- GI 5,386 + G2 . (6) 23.1-Y1 18.9+IY2 Equation 1 and equation 3 may be derived as special cases of equation 5. In the classic solution, ICF solute and water are assumed to be constant-that is, G,= 0 and Y,= 0. Applying these values to equation 5 and allowing for the difference in body fluid distribution, equation 2 is derived from equation 5. Katz assumed that there is no intracellular solute loss, or G,= 0. However, in Katz's solution, water was allowed to shift from the intracellular compartment, Y1 # 0. Because intake and output are excluded as factors in Katz's solution, Y1 = Y2. Applying these conditions to equation 5 while using Katz's assumed body fluid distribution, equation 3 is derived from equation 5. Osmotic Equivalence of Glucose Precursors In the absence of glucose intake, extracellular glucose is produced from gluconeogenesis or glycogenolysis.810' I The major precursors of glucose are amino acids (derived from proteolysis and transamination); lactate and pyruvate (pri- marily from glycolysis); and glycerol (from lipolysis).8'10-12 Acetone may also be a precursor of glucose. 13 Although pro- teins and glycogen are large molecules, their osmotic activity cannot safely be neglected.814 Some (obligate) intracellular water is retained by the osmotic activity of glycogen or pro- tein. One gram of glycogen obligates osmotically approxi- mately 1.6 grams of water.814 Assume that 1 gram of gly- cogen per 1.6 grams of water is isosmotic-that is, 1 gram of glycogen per 1.6 grams of H20 is "osmotically equivalent" THE WESTERN JOURNAL OF MEDICINE50