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• Response to the letter of Dr Oudesluys-Murphy
  Mitchell L Halperin
  Published on: 7 March 2003
• Changes in serum sodium levels during treatment of hyperglycaemia
  Anne Marie Oudesluys-Murphy
  Published on: 17 February 2003

• Published on: 7 March 2003

  Response to the letter of Dr Oudesluys-Murphy

  • Mitchell L Halperin, Physician

  Dear Editor

  We thank Dr Oudesluys-Murphy for her letter in response to our article. In essence, two points were raised.

  I. Can one estimate the deficits of Na+ and water if one applies the formula proposed by Katz [1]]?

  This calculation makes the presumption that one can predict the change in plasma sodium concentration (PNa) when water is drawn out of cells by hyperglycaemia. This assumpti...

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  Dear Editor

  We thank Dr Oudesluys-Murphy for her letter in response to our article. In essence, two points were raised.

  I. Can one estimate the deficits of Na+ and water if one applies the formula proposed by Katz [1]]?

  This calculation makes the presumption that one can predict the change in plasma sodium concentration (PNa) when water is drawn out of cells by hyperglycaemia. This assumption is not correct for a number of reasons (for details, see [2]).
  

  • A. Glucose must be added as a pure solute. Glucose will be retained in the ECF compartment (normal 10 L in a 50-kg person with 30 L of total body water). With the net retention of 600 mmol of glucose without water in the ECF compartment, the PGlu will rise by close to 57 mM if we assume that glucose distribution is only in the ECF compartment because water will shift from cells to the ECF. In more detail, the total number of osmoles in the body was 8550 milliosmoles (285 X 30 L) before the addition of glucose and 9150 milliosmoles after the addition of glucose (8550 + 600). Therefore the new Posm will be 305 mOsm/kg H2O (9150/30 L). The new ECF volume is equal to the total ECF osmoles (2850 + 600) divided by the new osmolality of 305 mOsm/L, or 11.3 L. Therefore 1.3 L of water will be drawn out of cells due to the high PGlu. Bottom line: The new PGlu is 57.5 mM, the new PNa is 124 mM, and the new ECFV is 11.3 L.

  • B. Addition of isosmotic glucose (285 mM) to raise the PGlu by close to 50 mM with all the same assumptions: No water is drawn out of or enters cells because an iso-osmotic solution of glucose was added to the ECF compartment and all added glucose remains in the ECF compartment. When 2.3 L of this glucose solution is in the ECF compartment, the new PGlu is 57 mM, the new PNa is 114 mM because water was retained in the ECF compartment without Na+, and the new ECF volume is 12.3 L. Bottom line: The new PGlu is 57 mM, the new PNa is 114 mM, and the new ECFV is 12.3 L.

    Overall, because the ECF volume was expanded by different amounts in calculations A and B above yet the rise in the PGlu was virtually identical, there is no constant relationship between the PGlu and the ECF volume. Moreover, there was no change in the content of Na in the ECF compartment in these two examples. In contrast, patients presenting with DKA have a contracted ECF volume and a deficit of Na+ when their PGlu is 57 mM.
    Conclusion: If you do not know what the ECF volume is in quantitative terms, you cannot deduce the ECF Na+ content from the PGlu. Accordingly, much as we would like to agree with the suggestion of Dr Oudesluys-Murphy, the facts do not support that view.

  • C. Potassium: Part of the deficit of K+ reflects the shift of K+ out of cells in a 1:1 relationship with a cation (Na+ and H+) of unpredictable amounts. The other major part of K+ loss from the ICF reflects the catabolic state (primarily a loss of K+ with organic phosphate (e.g, from RNA)). Since both of these components are not known with certainty, one cannot use the relationship described by Katz [1] to help in this context.

  • D. Error in the assumption of Katz [1]: The volume of distribution of glucose is larger than the ECF volume even if there is a lack of insulin actions. Our reasoning is that, in cells that do not require insulin for glucose transport such as liver cells, cells of the proximal convoluted tubule, and red blood cells, the concentration of glucose is likely to be equal in their ICF and ECF compartments.[3]

  II. Urea should be included in calculations of effective osmolality. Urea is not an effective osmole across cell membranes when the change in the plasma urea concentration (Purea) is not abrupt.[4] Given the time course for the fall in Purea in patients with DKA, we did not include urea in our calculation of effective osmolality. Therefore we believe that it is more prudent to keep the PGlu + 2 (PNa + PK) relatively constant in the first 12-18-h of therapy. We agree that a gradual decline in the effective Posm should occur with time thereafter.

  References

  (1) Katz MA. Hyperglycemia-induced hyponatremia: Calculation of expected serum sodium depression. N Engl J Med 1973;289:843-4.

  (2) Davids MR, Lin S-H, Edoute Y, Cheema-Dhadli S, Halperin ML. Hyponatraemia and hyperglycaemia during laproscopic surgery. Quart J Med 2002;95:321-30.

  (3) Roscoe JM, Halperin ML, Rolleston FS, Goldstein MB. Hyperglycemia-induced hyponatremia: metabolic considerations in calculation of serum sodium depression. CMA Journal 1975;112:452-3.

  (4) Silver SM, Sterns RH, Halperin ML. Brain swelling after dialysis: Old urea or new osmoles. Am J Kidney Dis 1996;28:1-13.

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  Conflict of Interest:
  None declared.

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• Published on: 17 February 2003

  Changes in serum sodium levels during treatment of hyperglycaemia

  • Anne Marie Oudesluys-Murphy, Paediatrician
  • Other Contributors:
    • Petra van Echtelt

  Dear Editor

  We read the paper by Carlotti et al. [1] with great interest.

  They state that fluid and electrolyte management might contribute to the development of cerebral oedema partly because clinicians do not have good data to predict the extent of deficits of sodium, potassium and water. However, there is a simple rule of thumb, formulated by Katz, which may help to calculate these deficits and pr...

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  Dear Editor

  We read the paper by Carlotti et al. [1] with great interest.

  They state that fluid and electrolyte management might contribute to the development of cerebral oedema partly because clinicians do not have good data to predict the extent of deficits of sodium, potassium and water. However, there is a simple rule of thumb, formulated by Katz, which may help to calculate these deficits and predict the changes in sodium levels which accompany changes in glucose levels.[2] Katz has calculated that in assessing the decrease of serum sodium brought about by hyperglycaemia a decrease of 0.29 mmol/l in serum sodium may be expected for every 1.0 mmol/l increment in serum glucose.

  This may be explained as follows: hyperglycaemia causes an osmotic movement of water out of the cells, which leads to hyponatraemia by dilution. Thus, at presentation, the patient with hyperglycaemia is usually severely dehydrated intracellularly. However, the serum sodium is lower than would be expected because of this dilution of the extracellular fluid. In reverse, when the patient is treated with insulin, glucose enters the cells, taking water with it, leading to a relative concentration of the extracellular fluid, and thereby a rise in serum sodium. Thus, at presentation of a patient with hyperglycaemia, the rise in serum sodium during treatment may be predicted and calculated using Katz's formula.[2]

  Carlotti et al. write that the glucose level falls by 5 mmol/l /hour over the initial 6 hours of therapy which means a fall of 30 mmol/l. It may be predicted using Katz’s formula that this fall of glucose of 30 mmol/l will be accompanied by a rise in the sodium level of circa 9 mmol/l. Carlotti et al. calculate serum osmolality as the sum of twice the plasma sodium + glucose which means that with an initial glucose level of 50 mmol/l and sodium level of 140 mmol/l the initial serum osmolality will be 330 mosmol/kg. After 6 hours, when the glucose level is 20 mmol/l, the sodium level will have risen to 149 mmol/l. The serum osmolality is then 318 mosmol/kg. This represents a fall in osmolality of 12 mosm/kg in a period of 6 hours which is 2 mosmol/kg//hour.

  Carlotti et al. also comment on the report of Glaser et al. that the chance of development of cerebral oedema during treatment is increased in children who present with high initial serum urea levels and when there is a lack of an increase in serum sodium levels during treatment.[3] The increased risk of cerebral oedema in patients with a raised urea level may be explained by the fact that the urea level rises in proportion to the degree of dehydration. Thus, the patient with the highest urea level is likely to be the most dehydrated. Urea contributes to the serum osmolality and if the fall in urea is not taken into account the serum osmolality may be allowed to drop too rapidly, thereby increasing the risk of cerebral oedema. Carlotti et al. do not take this into account in their formula for calculation of osmolality. The calculation of serum osmolality as twice the sum of sodium and potassium plus the urea and glucose levels (all in mmol/l) corresponds better with the formally measured osmolality.[4]

  We think that the comment that a smaller increase in serum sodium during treatment may give rise to cerebral oedema could possibly be explained by treatment which is aimed at preventing or lessening the rise in serum sodium by using hypotonic solutions or glucose alone. In this way the serum osmolality will fall rapidly and thereby increase the risk of cerebral oedema.

  We agree with Carlotti et al. that the treatment of hyperglycaemia must proceed slowly without the use of hypotonic solutions or glucose alone. Serum osmolality must be monitored frequently, either by direct measurement or calculation from the sodium, potassium, glucose and urea levels. In this way, the effects of falling urea and glucose levels on the serum osmolality will be seen to be compensated, to a large extent, by the accompanying rise in sodium. Then the osmolality may be allowed to fall slowly and in a controlled fashion at a rate of 1-2 mosmol/kg/ hour thereby reducing the risk of cerebral oedema.

  References

  (1) Carlotti APCP, Bohn D, Halperin ML. Importance of timing of risk factors for cerebral oedema during therapy for diabetic ketoacidosis. Arch Dis Child 2003; 88:170-173.

  (2) Katz MA Hyperglycemia-induced hyponatremia; calculation of expected serum sodium depression. N Eng J Med 1973; 289:843-844.

  (3) Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Eng J Med 2001; 344: 264-9.

  (4) Souhami RL, Moxham J. Textbook of medicine 3rd edition. Edinburgh: Churchill Livingstone, 1997.

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  Conflict of Interest:
  None declared.

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