1 Nephrology Unit, University of Stellenbosch, Cape Town, South Africa, 2 Internal Medicine C, Rambam Medical Center, Haifa, Israel, 3 Renal Division, Hôpital d'Enfants, CHU-Nancy, France, 4 Hopital Sacre Coeur, Montreal, Quebec, Canada and 5 Renal Division, St Michael's Hospital, University of Toronto, Toronto, Canada
Keywords: antidiuretic hormone; effective osmolality; electrolyte-free water; extracellular fluid; hypernatraemia; hyponatraemia; intracellular fluid; water
Introduction
Hyponatraemia, the most common electrolyte abnormality in hospitalized patients, is associated with an increased mortality rate [1]. This unfavourable outcome probably reflects the severity of the underlying condition unless hyponatraemia was acute and caused brain cell swelling or there was osmotic demyelination induced by overly rapid correction of hyponatraemia [2].
In acute care settings, nephrologists are often asked to explain why there was a sudden rise or fall in the plasma sodium (Na+) concentration (PNa), what this change in PNa implies for the patient, and how this electrolyte disorder should be managed. The traditional approach views the problem in terms of changes in the excretion of electrolyte-free water [3]. We shall illustrate in this teaching exercise that this is not adequate for clinical decision-making. Accordingly, our purpose is to provide a simple and reliable alternative to define the basis for a change in PNa and to deduce its impact on body fluid compartment volumes and composition because this information is essential to design proper therapy.
For the PNa to change, the content of Na+ and/or water in the extracellular fluid (ECF) compartment must be altered. Two other factors must be considered when assessing the basis for a change in PNa. First, balance for Na+ plus potassium (K+) rather than just Na+ must be calculated [4]. Second, one must be certain that there was not a shift of water across cell membranes due to a gain of particles restricted to the ECF compartment (e.g. glucose [5]) or in the intracellular fluid (ICF) compartment (e.g. during a seizure [6]).
Changes in balance of water and Na++K+ should be related to total body water to determine their quantitative impact on the PNa [7]. Thus, for every mmol of Na++K+ positive or negative balance per litre of total body water, the change in PNa should be 1 mmol/l. When there is a positive or negative balance of 1 litre of water, the PNa should change by the formula, PNax(1 litre/total body water). The initial body weight and an estimate of body composition are used to deduce total body water in all calculations [8].
Index case
Only the features relevant to a change in the PNa are provided because our objective is to focus on specific teaching points.
A 54-year-old woman (weight 60 kg) had chronic hyponatraemia (120 mmol/l) due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). She did not have a stimulus for the release of ADH based on tonicity or a decrease in her effective blood volume. Renal, adrenal, and thyroid diseases were ruled out. Her underlying lesion was carcinoma of the lung. There were no relevant findings on physical examination; the clinical impression was that her ECF volume was normal. To raise her PNa, she was given a vasopressin antagonist (conivaptan hydrochloride was kindly supplied by Parke-Davis Pharmaceutical Research for investigational use). This drug caused her to excrete 4 litres of hypotonic urine (Na++K+=60 mmol/l) over 48 h (Figure 1). Her PNa increased to 128 mmol/l during this period. She excreted all the K+ that she ingested in this 48-h period.
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Comments
The major issues will be addressed by considering four questions.
Question 1: What changes occurred in body fluid compartments when her PNa fell from 140 to 120 mmol/l?
It is important to deduce the impact of chronic hyponatraemia on body fluid compartment volumes and electrolyte content because the objectives of treatment are to restore these compartments to their normal composition (Figure 2). The analysis is performed in three stages. First, body compartment volumes and compositions are defined before hyponatraemia developed. Because of her age, gender, and adiposity, her total body water was assumed to be 50% of weight or 30 litres. Hence her ICF volume would have been 20 litres and her ECF volume would have been 10 litres [9]. Second, because her PNa declined by close to 15% to 120 mmol/l, her ICF volume should be expanded by approximately 15% (gain of 3 litres) [10]. Third, because her PNa declined by 20 mmol/l and her ECF volume was unchanged (10 litres), she had a deficit of 200 mmol of Na+ in her ECF compartment. Therefore the goals of therapy would be clearcreate a negative water balance of 3 litres of water to return her ICF volume to its original 20 litres and to create a positive balance of 200 mmol of Na+ to return her ECF composition to normal (Figure 2
). The order in which these two therapies are instituted could be important. To avoid over-expanding her ECF volume, a water diuresis was induced initially using a V2 specific vasopressin antagonist. The second phase of therapy was to replace the Na+ deficit.
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Question 2: Does an electrolyte-free water balance explain this increase in PNa?
When an electrolyte-free water balance is calculated [3], all solutions are divided into imaginary volumes of isotonic (to the patient) saline and electrolyte-free water. Therefore her 4-litre urine output defined in electrolyte-free water terms becomes 2 litres of isotonic fluid and 2 litres of electrolyte-free water (Figure 3). Because her input was isotonic saline, she had a negative balance of electrolyte-free water that will increase her PNa by 2 litres/33 litres (the current total body water)x120 mmol/l, or 7.3 mmol/l. This predicted change in PNa is very close to what was observed in our patient. One conclusion might be that the increase in PNa was caused by the net loss of 2 litres of electrolyte-free water. Nevertheless, this conclusion will be shown to be only partially correct when a different form of analysis is performed.
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The difference between the above two methods of calculation is that the tonicity balance explained the degree of change in PNa and the cause for this change whereas the electrolyte-free water balance only predicted the change in PNa without revealing the reason for this change. Therefore the tonicity balance and not the electrolyte-free water balance defines the goals for therapy.
Question 3: What were the changes in volume of the ICF and ECF compartments following this rise in the PNa?
If the patient had a negative balance of 2 litres of water, this would have contracted the ICF and ECF volumes by close to 1.4 and 0.6 litres respectively because water loss is derived from body compartments in proportion to their existing volumes. However, the tonicity balance showed that water balance was in fact zero. Total body water was unchanged while the ICF volume decreased by 1.4 litres (or 6.1%) in response to the 6.1% rise in the PNa. In contrast, because of the positive balance of 240 mmol of Na+, the ECF volume should have increased by 1.4 litres of water that shifted from her ICF compartment. Once again, using an electrolyte-free water balance is misleading by suggesting the presence of a contracted ECF volume when an expanded ECF was actually present.
Question 4: Does the excretion of a dilute urine guarantee that the PNa will rise?
No! Without calculating a tonicity balanceconsidering inputs as wellthe influence of excretion of dilute urine on the PNa cannot be predicted. We demonstrate this with the following hypothetical scenario in which we altered only the input (Figure 4). We gave a hypothetical patient 4 litres of electrolyte-free water instead of 4 litres of isotonic saline and did not change urine volume and composition. A tonicity balance reveals the following; there is zero water balance but a negative balance of 240 mmol Na++K+. This balance would cause a fall in the PNa despite the excretion of a dilute urine with a Na++K+ concentration that is less than the PNa. This loss of Na++K+ will decrease the PNa by 240 mmol/33 litres or 7.3 mmol/l to 113 mmol/l. The use of an electrolyte-free water balance also indicates that the PNa will fallthere is a net gain of 2 litres of electrolyte-free water (4 litres in, 2 litres out) which causes a fall in PNa of 2 litres/33 litresx120 mmol/l or 7.3 mmol/l. It again predicts the magnitude and direction of change in PNa but it cannot shed any light on the reason for this change. If we look at the effects on ICF and ECF volumes (Figure 5
) using a tonicity balance, we find the following. There would be no change in total body water (zero water balance), an increase in ICF volume of approximately 1.4 litres ((7.3 mmol/l/120 mmol/l)x23 litres ICF) and a corresponding 1.4 litre decrease in the ECF volume. Electrolyte-free water balance (+2 litres) suggests that both ICF (1.4 litres) and ECF (0.6 litres) are expanded, which is not the case.
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Concluding remarks
The traditional way to explain the basis for a change in PNa is to describe events in electrolyte-free water terms [3]. This can predict the isolated effects of infusions or excretions on the direction and magnitude of a change in PNa. Calculating an electrolyte-free water balance, however, does not reveal what the changes will be in the ECF compartment volume and composition. It therefore cannot be used to indicate appropriate therapy. In contrast, a tonicity balance is simpler and quicker to perform because one does not need to do the electrolyte-free water calculation. A tonicity balance explains the basis for a change in PNa as well as the expected changes in the volumes and composition of the ECF and ICF compartments. Therefore it defines the goals for therapy.
Teaching points
Notes
Supported by an educational grant from
Correspondence and offprint requests to: M. L. Halperin, MD, FRCP(C), Division of Nephrology, St Michael's Hospital, 38 Shuter Street, Toronto, Ontario, Canada M5B 1A6. Email: mitchell.halperin{at}utoronto.ca
References