Body compartment volumes and composition after giving a vasopressin antagonist: changes are revealed by a tonicity balance

(Section Editor: K. Kühn)

Mogamat Razeen Davids1, Yeouda Edoute2, Jean-Pierre Mallie3, Daniel G. Bichet4 and Mitchell L. Halperin5,

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 1Go). 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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Fig. 1. Balances in the index case. The solid rectangle represents total body composition in Na++K+ and water terms. The PNa of 120 mmol/l at the start of the period is shown above each rectangle and the PNa at the end of the period (128 mmol/l) is shown at the bottom of each rectangle. An electrolyte-free water balance is shown in the top portion of the figure while a tonicity balance is shown in its bottom portion. Mass balances are shown in dashed boxes inside the total body rectangle.

 

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 2Go). 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 clear—create 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 2Go). 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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Fig. 2. Body fluid compartment volumes and compositions before drug administration: goals of therapy. The solid rectangle represents the body with its ICF (20 liters) and ECF (10 liters) compartment volumes. The ICF is expanded by 15% (100x(140–120)/140) or by 3 litres of water while the ECF volume is normal (physical examination). Hence the ECF compartment has a deficit of 200 mmol of Na+ ((140–120 mmol/l)x10 litres). Hence there are two goals of therapy, cause a deficit of 3 litres of electrolyte-free water from the ICF compartment (A) and create a 200 mmol positive balance for Na+ in the ECF compartment (B).

 

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 3Go). 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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Fig. 3. Calculation of electrolyte-free water. The 4 litres of urine output are divided into a 2-litre portion of fluid with a concentration of Na++K+ that is identical to the plasma of the patient (120 mmol/l) and the remaining 2-litre volume is electrolyte-free water (EFW).

 
We shall now illustrate that balances of water and electrolytes should be considered separately—a tonicity balance (Figure 1Go, lower panel) [11]. Because the input and output volumes were both 4 litres, water balance was zero. Therefore a water deficit cannot be the reason for the observed rise in PNa. When Na+ (+K+) balance was examined, input was 480 mmoles (4 litresx120 mmol/l) and output was 240 mmoles (4 litresx60 mmol/l), yielding a positive balance of 240 mmoles of Na+ (K+ balance was zero). This should also cause a rise in PNa of 7.3 mmol/l (240 mmol/33 litres total body water), which is close to what was observed.

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 balance—considering inputs as well—the 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 4Go). 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 fall—there 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 5Go) 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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Fig. 4. Balances in the hypothetical alteration of the case. For details, see legend to Figure 1Go. The only difference from the index case is that the input now is 4 litres of electrolyte-free water (EFW) instead of isotonic (to the patient) saline.

 


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Fig. 5. Body fluid compartment volumes and compositions in the hypothetical example. An electrolyte-free water balance calculation (part A) is shown in the top portion of the figure and a tonicity balance (part B) is shown in the bottom portion of the figure. Although the ICF volume and the PNa are identical in both approaches, the ECF volume and its Na+ content are both higher when an EFW balance was the method of calculation and do not reflect the actual values as shown by the tonicity balance calculation.

 

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

(1) One cannot infer why the PNa rises or falls from an examination of output alone.
(2) Separate balances for Na+ plus K+ and for water (a tonicity balance) are needed to indicate why the change in PNa occurs and what the therapy should be.

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 Back

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