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Commentary: Diagnostic Approach To A Patient With Hyponatraemia: Traditional Versus Physiology-Based Options
Commentary: Diagnostic Approach To A Patient With Hyponatraemia: Traditional Versus Physiology-Based Options
Commentary: Diagnostic Approach To A Patient With Hyponatraemia: Traditional Versus Physiology-Based Options
doi:10.1093/qjmed/hci081
Commentary
Summary
The usual diagnostic approach to a patient with be detected by physical examination supported
hyponatraemia is based on the clinical assessment by routine laboratory data, and a tendency to
of the extracellular fluid (ECF) volume, and labora- diagnose the syndrome of inappropriate secretion
tory parameters such as plasma osmolality, urine of antidiuretic hormone prior to excluding other
osmolality and/or urine sodium concentration. causes of hyponatraemia. We conclude that the
Several clinical diagnostic algorithms (CDA) apply- typical architecture of CDAs for hyponatraemia
ing these diagnostic parameters are available to represents a hierarchical order of isolated clinical
the clinician. However, the accuracy and utility and/or laboratory parameters, and that they do not
of these CDAs has never been tested. Therefore, take into account the pathophysiological context,
we performed a survey in which 46 physicians the mechanism by which hyponatraemia developed
were asked to apply all existing, unique CDAs and the clinical dangers of hyponatraemia. These
for hyponatraemia to four selected cases of restrictions are important for physicians confronted
hyponatraemia. The results of this survey showed with hyponatraemic patients and may require them
that, on average, the CDAs enabled only 10% of to choose different approaches. We therefore
physicians to reach a correct diagnosis. Several conclude this review with the presentation of a
weaknesses were identified in the CDAs, including more physiology-based approach to hyponatraemia,
a failure to consider acute hyponatraemia, the which seeks to overcome some of the limitations of
belief that a modest degree of ECF contraction can the existing CDAs.
Introduction
There are two different, but not mutually relies on the use of clinical diagnostic algorithms
exclusive, ways to arrive at a clinical diagnosis (CDA). The second, which we shall call the
in a patient with hyponatraemia and to design physiology-based approach, emphasizes the
appropriate therapy.1 The first, which we shall underlying mechanisms that might have led to
call the traditional approach, uses a combination the development of hyponatraemia. It applies
of clinical and laboratory parameters, and often simple principles of physiology at the bedside,
Address correspondence to Dr R. Zietse, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
email: r.zietse@erasmusmc.nl
! The Author 2005. Published by Oxford University Press on behalf of the Association of Physicians.
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530 E.J. Hoorn et al.
and relies on deductive reasoning and a quantitative from textbooks of general internal medicine,
analysis.1,2 nephrology and endocrinology.14–21 Eliminating
Our objective is to compare these two identical and overlapping CDAs, these 19 CDAs
approaches by conducting a survey where were reduced to 10 (Table 1).
physicians were asked to apply ten different The parameters to evaluate included a clinical
CDAs for hyponatraemia in four selected cases. assessment of the extracellular fluid (ECF) volume
The outcome was compared to a physiology-based (8/10), fluid challenge tests (1/10), and whether
approach. hyponatraemia was acute (1/10). In the laboratory
data, plasma osmolality (Posm) (4/10), plasma
urate (1/10), renal function (1/10), urine sodium
concentration (UNa) (7/10), urine osmolality (Uosm)
Methods (5/10), and the fractional excretion of urea and urate
Literature review (1/10) were assessed (Table 1).3–21
Table 1 Existing algorithms for hyponatraemia and their accuracy in three illustrative test cases
1 ECF volume 5, 9 6%
2 ECF volume – UNa (20–40) 6, 14, 20, 21 7%
3 ECF volume UNa (20) 3, 19 8%
4 Acuity of hyponatraemia ECF volume 13 6%
5 ECF volume 4, 16 12%
UNa (20)
Uosm (500)
6 Posm 8, 11, 12 9%
Uosm
ECF volume
7 Posm 17 11%
Uosm
UNa
8 Posm (280–295) 15, 18 7%
ECF volume
UNa (10 and 20)
9 Posm (280) 10 9%
Uosm (100)
UNa (20–40)
Fluid challenge tests
FEurea, FEurate, Purate
10 Uosm (100) 7 9%
Renal function
ECF volume
UNa (20)
Ten different clinical diagnostic algorithms for hyponatraemia were identified from the literature review. In a survey in
which 46 physicians participated, it was analysed how often these algorithms led to a correct diagnosis in three illustrative
cases of hyponatraemia (see text for case descriptions). The selected diagnoses are described in Table 2. Posm and Uosm are
in mOsm/kg H2O, Una in mmol/l.
Diagnostic approach to hyponatraemia 531
Table 2 Results from survey: algorithm diagnoses and respondents’ analysis of cases
The first column shows the diagnoses selected by the 46 participating physicians in the survey after they had applied the data
of cases 1, 2 and 3 to the algorithms described in Table 1. The two most frequently chosen diagnoses are shown, as well as
how often they felt it was not possible to establish a diagnosis with the data provided. The other columns show the
respondents’ answers to specific questions about the case (see text for details).
532 E.J. Hoorn et al.
paper.22 With this therapy, hyponatraemia persisted with a contracted ECF volume such as Addison’s
and, unfortunately, the patient died in hospital disease.
2 weeks after admission with haemodynamic In contrast to the importance the 8 CDAs gave
collapse. Post-mortem examination revealed to an evaluation of the ECF volume, the majority
adrenal failure (plasma aldosterone 0 pmol/l).22 of the physicians (65%; 61 þ 4) believed that
Definition of the problem: Addison’s disease was determining ECF by physical examination is not
not suspected and/or excluded because signs of a very reliable and should only be supportive in the
low ECF volume were not found and hyperkalaemia differentiation of hyponatraemia (Table 2). This
was absent. Although the symptoms nausea and opinion is supported by the literature. Several
vomiting may have been suggestive of corticotropic studies have analysed the validity of confirmatory
insufficiency,26 they are rather non-specific and tests for ECF contraction, performed by physical
can also be symptoms of hyponatraemia.27 Most of diagnosis,28–32 haemodynamic parameters (blood
the respondents (89%) stated that his hyponatraemia pressure, central venous pressure, blood volume,
was not potentially life-threatening (Table 2). In plasma volume, cardiac output),33 laboratory
conclusion, the two questions that arise from this analysis (ADH, aldosterone, catecholamines, renin,
case are, ‘How reliable is the clinical assessment of fractional excretions of Na or urea and total
the ECF volume?’, and, ‘Why was the PK in the urates),33 and/or urine electrolyte data,34 and all
normal range?’ unequivocally showed a low sensitivity and speci-
(i ) How reliable is the clinical assessment of ficity. Therefore, although clinical decision-making
the ECF volume? All but two CDAs included ECF is often based on the assumption of ‘dehydration‘,
volume as an important parameter to determine the degree of confidence in this impression is not
the cause of hyponatraemia, and in 4/10 (40%) it supported by a strong database.
was the first parameter to assess (Table 1). In cases in (ii ) How can the absence of hyperkalaemia in
which a low ECF volume cannot be established by Addison’s disease be explained? Hyperkalaemia is
clinical examination, this may lead to the exclusion not observed in 1/3 of patients with Addison’s
of causes of hyponatraemia that typically present disease;35 hence its absence does not exclude
534 E.J. Hoorn et al.
this diagnosis. Perhaps normokalaemia reflects a The above analysis illustrates that in a case
poor intake of K, a deficiency of cortisol with where hyponatraemia is associated with a low ECF
sufficient aldosterone activity remaining to avoid volume and impaired renal function, it is useful to
hyperkalaemia, and/or the rate of excretion of K calculate the FENa. One CDA introduced the option
may be unusually high because of a high distal of evaluating renal function in their strategy,7 but
delivery of Na when Na reabsorption in an upstream none suggested calculating the FENa (Table 1).
nephron site was inhibited (aldosterone augments (ii )How might ODS have been prevented? This
Na reabsorption in the distal convoluted patient was treated with isotonic saline and
tubule).36,37 developed ODS—her PNa increased by 11 mmol/l
in 24 h. Although a rate of 12 mmol/l/day is said
to be acceptable,40 it is not a target to be achieved,
Case 2: Excessive renal
rather, it is an upper limit not to be exceeded.2
excretion of sodium Moreover, because this patient had chronic hypo-
Continuation of the case: There was a presumptive natraemia and was catabolic, the risk of ODS was
diagnosis of Addison’s disease on the basis of increased.41 Therefore, in cases where there is an
‘Which groups of patients are susceptible to this produce many urinary osmoles because beer is low
type of hyponatraemia?’ in protein and NaCl.
(i ) How can hyponatraemia occur in the context In this patient, hyponatraemia was not considered
of minimal release of ADH? Water retention in this to pose an immediate danger (0%, Table 2).
setting of minimal ADH release can occur when However, this patient could be susceptible to brain
there is a low delivery of filtrate to the distal swelling if water intake continued, but water loss in
nephron.44 To have a low distal volume delivery, sweat (did not run that day) or urine (non-osmotic
there should be a low GFR and/or enhanced reason for ADH release) was prevented. In addition,
reabsorption of filtrate in the proximal convoluted brain damage (ODS) from rapid correction of
tubule, responses that typically accompany a low hyponatraemia could occur, especially if she was
intake of sodium chloride.45 Second, there may be malnourished and/or K-depleted.41
a small degree of water permeability in the distal
nephron that could be the result of trace levels of Case 4: Acute hyponatraemia in
ADH—levels that are not detected by conventional a patient who took ‘Ecstasy’
assays46 and/or by ADH-insensitive water perme-
Convulsions or coma?
NO YES
Can be both
Can be both
Figure 1. Physiology-based approach to hyponatraemia. Free water clearance ¼ urine output (1 Uosm/Posm). Transtubular
potassium gradient ¼ UK/(Uosm/Posm)/PK. Fractional excretion of sodium ¼ (UNa Pcreat)/(PNa Ucreat). In Step 2, ‘High ADH’
and ‘Low ADH’ refer to pathophysiological considerations in the patient, and do not necessarily imply that the determination
of ADH levels is required clinically; an estimate about ADH levels may also be inferred from (for example) the urine
osmolality.
Diagnostic approach to hyponatraemia 537
Renal Na loss and Diuretic-use: often Yes Low PK - High High UK Diuretic-induced
physiological ADH recent and often Metabolic hyponatraemia
secretion thiazides alkalosis High UHCO3–
Low cardiac output History of heart, No; oedema Low PAlb Low FENa (in renal Hyponatraemia
or low albumin liver or renal is possible failure)72 associated with
disease Metabolic heart, liver or renal
acidosis (in renal failure
failure)
Figure 1. Continued.
the CDAs (Table 2). However, the requirement that connecting it to the clinical situation at hand.
certain values should be available before being able In addition, the unique pathophysiology of
to proceed in the CDA, is in itself a weak point, and hyponatraemia with low circulating levels of ADH
may unnecessarily delay diagnosis and treatment. is presented. The final step of our algorithm was
In our analysis, the most serious error was the failure intentionally organized in a tabular format so that
to rule out acute hyponatraemia as the first step. all causes of hyponatraemia can still be taken into
A second weak point was the mistaken belief that consideration without excluding others (Step 3,
a clinician could detect a mild to modest degree of Figure 1). The philosophy behind this is that relying
ECF volume contraction by physical examination on one single value may be misleading, as expected
supported by routine laboratory data. This was most values may vary depending on the situation. This
evident in Case 1, because it led to an incorrect has been illustrated for urinary values36,68 and for
diagnosis (SIADH) and improper treatment (water diagnostic tests.26 Here, a physiological analysis
restriction) that could have been responsible for using simple formulae can be used simultaneously
the fatal outcome, due to eventual haemodynamic and synergistically with the traditional analysis
collapse.22 Although more laboratory tests may (Figure 1 and Table 3) [2,24, 69–74]. We emphasize
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