QJM Advance Access originally published online on June 13, 2005
QJM 2005 98(7):529-540; doi:10.1093/qjmed/hci081
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Commentary |
Diagnostic approach to a patient with hyponatraemia: traditional versus physiology-based options
From the 1Department of Internal Medicine, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands, and 2Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Canada
Address correspondence to Dr R. Zietse, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. email: r.zietse{at}erasmusmc.nl
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Summary |
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 Top Summary IntroductionMethodsCasesResultsDiscussionConcluding remarksReferences |
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The usual diagnostic approach to a patient with hyponatraemia is based on the clinical assessment of the extracellular fluid (ECF) volume, and laboratory parameters such as plasma osmolality, urine osmolality and/or urine sodium concentration. Several clinical diagnostic algorithms (CDA) applying these diagnostic parameters are available to the clinician. However, the accuracy and utility of these CDAs has never been tested. Therefore, we performed a survey in which 46 physicians were asked to apply all existing, unique CDAs for hyponatraemia to four selected cases of hyponatraemia. The results of this survey showed that, on average, the CDAs enabled only 10% of physicians to reach a correct diagnosis. Several weaknesses were identified in the CDAs, including a failure to consider acute hyponatraemia, the belief that a modest degree of ECF contraction can be detected by physical examination supported by routine laboratory data, and a tendency to diagnose the syndrome of inappropriate secretion of antidiuretic hormone prior to excluding other causes of hyponatraemia. We conclude that the typical architecture of CDAs for hyponatraemia represents a hierarchical order of isolated clinical and/or laboratory parameters, and that they do not take into account the pathophysiological context, the mechanism by which hyponatraemia developed and the clinical dangers of hyponatraemia. These restrictions are important for physicians confronted with hyponatraemic patients and may require them to choose different approaches. We therefore conclude this review with the presentation of a more physiology-based approach to hyponatraemia, which seeks to overcome some of the limitations of the existing CDAs.
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Introduction |
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TopSummaryIntroductionMethodsCasesResultsDiscussionConcluding remarksReferences |
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There are two different, but not mutually exclusive, ways to arrive at a clinical diagnosis in a patient with hyponatraemia and to design appropriate therapy.1 The first, which we shall call the traditional approach, uses a combination of clinical and laboratory parameters, and often relies on the use of clinical diagnostic algorithms (CDA). The second, which we shall call the physiology-based approach, emphasizes the underlying mechanisms that might have led to the development of hyponatraemia. It applies simple principles of physiology at the bedside, and relies on deductive reasoning and a quantitative analysis.1,2
Our objective is to compare these two approaches by conducting a survey where physicians were asked to apply ten different CDAs for hyponatraemia in four selected cases. The outcome was compared to a physiology-based approach.
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Methods |
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Literature review
Published CDAs were identified from a literature search using ‘hyponatraemia’ (Medical Subject Heading) limited to review articles published in the English language between January 1998 and August 2004. The search yielded 218 articles, of which 11 were review articles that included a CDA with an approach to the patient with hyponatraemia.3–13 We also collected eight CDAs from textbooks of general internal medicine, nephrology and endocrinology.14–21 Eliminating identical and overlapping CDAs, these 19 CDAs were reduced to 10 (Table 1).
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The parameters to evaluate included a clinical assessment of the extracellular fluid (ECF) volume (8/10), fluid challenge tests (1/10), and whether 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) (5/10), and the fractional excretion of urea and urate (1/10) were assessed (Table 1).3–21
Survey
Four challenging cases where hyponatraemia was a central diagnostic issue were selected.22–25 To determine the value of each CDA in the differential diagnosis of hyponatraemia, 60 surveys containing the four cases and the ten CDAs were sent to physicians from five different countries (Canada, the Netherlands, South-Africa, Taiwan, USA); 46 surveys (from 27 residents, 6 fellows, and 13 staff physicians in internal medicine specialties) were available for complete analysis (77%). The reason that we chose the survey as our method of analysis is that it provides a reasonable way to evaluate the current diagnostic approaches to hyponatraemia.
Physicians were asked to provide a (differential) diagnosis in the first three cases using each CDA. Respondents could also indicate that they could not reach a diagnosis with the available information. Diagnoses were subsequently classified as correct, not correct, or not possible (Table 2). Because Case 4 lacked most of the information required for the CDAs, we chose to present a list of possible diagnoses for this case in multiple-choice format (Table 2). We were also interested in additional information such as the likelihood that hyponatraemia could be life-threatening, and which therapy the physicians would select. Finally, a case-specific question was asked (Table 2).
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Cases |
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Case 1
An 88-year-old man had complained of nausea and vomiting for 4 weeks.22 A cutaneous B-cell lymphoma on his right cheek had been diagnosed 2 months ago. He was not taking medications, and had lost 2 kg in weight over the past several months. Physical examination was not consistent with a contracted ECF volume (normal pulse rate and blood-pressure, no orthostatic changes). Plasma sodium (PNa 125 mmol/l), potassium (PK 4.5 mmol/l), glucose (72 mg/dl; 4.0 mmol/l), creatinine (Pcreat 0.9 mg/dl; 77 µmol/l) and thyroid stimulating hormone (2.3 mIU/l) were measured on admission. His UNa was 100 mmol/l. Plasma pH, plasma cortisol, and Uosm were not measured.
Case 2
A 19-year-old woman had myasthenia gravis.23 Her main complaints were progressive weakness and fatigue over the past 6 months. Her appetite was poor and she had a 3 kg weight loss. In addition to a PNa of 118 mmol/l, she had four other important abnormalities: hyperkalaemia (8.1 mmol/l), hypoglycaemia (45 mg/dl; 2.5 mmol/l), a low ECF volume (blood pressure 60/40 mmHg, heart rate 126 bpm in the absence of blood loss) and a low glomerular filtration rate (GFR) (Pcreat 5.3 mg/dl; 461 µmol/l). During the initial 12 h, she received 4.6 l isotonic saline and excreted 4.5 l urine with a Uosm of 438 mOsm/kg H2O and a UNa + UK of 80 mmol/l.
Case 3
A thin, 34-year-old woman ran several miles per day in a hot environment.24 Because she sweated profusely, and because she thought it a healthy habit, she drank a large unmeasured volume of water per day. She was an ovolactovegetarian and had a restricted salt intake. She did not smoke, consume alcohol, or use illicit drugs or herbs. Her only symptom was polyuria (4–5 l/day). There were no findings on physical examination to indicate that her ECF volume was contracted. The principal lab findings were chronic hyponatraemia (131 mmol/l) with Posm 268 mOsm/kg H2O, Uosm 81 mOsm/kg H2O, and UNa 10 mmol/l. She did not have a high Pcreat (0.9 mg/dl; 80 µmol/l) or plasma urea (5.9 mg/dl; 2.1 mmol/l), or a low PK (4.0 mmol/l). Follow-up studies did not reveal thyroid or adrenal insufficiency, a metabolic disease (e.g. porphyria), or lesions to explain why antidiuretic hormone (ADH) might be released.
Case 4
An 18-year-old female presented to the Emergency Department because she became unwell at a party (reference 25, case adapted for this review). Shortly after arrival, she had a grand mal seizure. In blood drawn immediately after the seizure, her PNa was 130 mmol/l; all other measured values except for her plasma chloride were within the normal range. Body temperature was 40°C; other vital and haemodynamic signs were unremarkable. During the first hour of hospitalization, she did not void and therefore there were no urine data. History from accompanying friends revealed that the patient had taken MDMA (methylenedioxymethamphetamine, ‘Ecstasy’), that she had consumed a considerable volume of water, but no alcohol, and that she had been dancing on a crowded and hot dance floor.
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Results |
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Analysis of cases with the traditional approach
Table 1 depicts the ten CDAs, as well as how often each algorithm led to the correct diagnosis. Table 2 depicts the two most frequently chosen diagnoses in Cases 1, 2 and 3 and how often a diagnosis was considered not possible to make using the available data. When compared to the final diagnoses (Table 3), the results demonstrate that for Cases 1, 2 and 3 a correct diagnosis was made in 11%, 19% and 0%, whereas an incorrect diagnosis was made by 59% (48 + 11), 15% (7 + 8) and 79% (53 + 12 + 14) of the respondents. In addition, 30%, 66% and 21% of the respondents felt that insufficient data were provided to establish a diagnosis in these three cases, respectively (Table 2). Table 2 also shows the respondents' opinion about whether hyponatraemia appeared to be life-threatening, which therapy they would have chosen, and which causes of hyponatraemia in Case 4 were thought to be likely.
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Analysis and comparison with the physiology-based approach
Table 3 summarizes the four cases using a physiology-based approach. It includes the clinical diagnosis, diagnostic pitfalls that were recognized, the physiological principles that were applied and, finally, potential threats to survival.
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Discussion |
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Each case will be analysed in more detail using a physiology-based approach, and this information will be compared to the outcome reached using the traditional approach. We shall organize this section by defining the problem in each case after presenting its outcome (for Cases 1 and 2), and by subsequently asking two questions that are clinically relevant and address the specific challenges of each case.
Case 1: Hyponatraemia without evidence of a contracted ECF volume
Continuation of the case: Because of the lymphoma, normal PK, absence of signs of ECF volume contraction, and a UNa of 100 mmol/l, 48% of the respondents selected the syndrome of inappropriate ADH secretion (SIADH) as the diagnosis (Table 2). The preferred treatment was water-restriction by 65% of the respondents and the authors of the paper.22 With this therapy, hyponatraemia persisted and, unfortunately, the patient died in hospital 2 weeks after admission with haemodynamic collapse. Post-mortem examination revealed adrenal failure (plasma aldosterone 0 pmol/l).22
Definition of the problem: Addison's disease was not suspected and/or excluded because signs of a low ECF volume were not found and hyperkalaemia was absent. Although the symptoms nausea and vomiting may have been suggestive of corticotropic insufficiency,26 they are rather non-specific and can also be symptoms of hyponatraemia.27 Most of the respondents (89%) stated that his hyponatraemia was not potentially life-threatening (Table 2). In conclusion, the two questions that arise from this case are, ‘How reliable is the clinical assessment of the ECF volume?’, and, ‘Why was the PK in the normal range?’
(i) How reliable is the clinical assessment of the ECF volume? All but two CDAs included ECF volume as an important parameter to determine the cause of hyponatraemia, and in 4/10 (40%) it was the first parameter to assess (Table 1). In cases in which a low ECF volume cannot be established by clinical examination, this may lead to the exclusion of causes of hyponatraemia that typically present with a contracted ECF volume such as Addison's disease.
In contrast to the importance the 8 CDAs gave to an evaluation of the ECF volume, the majority of the physicians (65%; 61 + 4) believed that determining ECF by physical examination is not very reliable and should only be supportive in the differentiation of hyponatraemia (Table 2). This opinion is supported by the literature. Several studies have analysed the validity of confirmatory tests for ECF contraction, performed by physical diagnosis,28–32 haemodynamic parameters (blood pressure, central venous pressure, blood volume, plasma volume, cardiac output),33 laboratory analysis (ADH, aldosterone, catecholamines, renin, fractional excretions of Na or urea and total urates),33 and/or urine electrolyte data,34 and all unequivocally showed a low sensitivity and specificity. Therefore, although clinical decision-making is often based on the assumption of ‘dehydration’, the degree of confidence in this impression is not supported by a strong database.
(ii) How can the absence of hyperkalaemia in Addison's disease be explained? Hyperkalaemia is not observed in 1/3 of patients with Addison's disease;35 hence its absence does not exclude this diagnosis. Perhaps normokalaemia reflects a poor intake of K, a deficiency of cortisol with sufficient aldosterone activity remaining to avoid hyperkalaemia, and/or the rate of excretion of K may be unusually high because of a high distal delivery of Na when Na reabsorption in an upstream nephron site was inhibited (aldosterone augments Na reabsorption in the distal convoluted tubule).36,37
Case 2: Excessive renal excretion of sodium
Continuation of the case: There was a presumptive diagnosis of Addison's disease on the basis of her auto-immune disease. As a result of the infusion of isotonic saline, there was a decrease in her PK to 5.1 mmol/l and an increase in her PNa to 129 mmol/l. Unfortunately, this increase in the PNa led to the osmotic demyelination syndrome (ODS) (confirmed by magnetic resonance imaging) and the patient remains in a vegetative state with frequent attacks of myoclonus.
Definition of the problem: At first glance, Addison's disease appears to provide a sufficient explanation for the observed hyponatraemia and ECF volume contraction. However, this assumption conflicts with her Na + K excretion rate, which was close to 360 mmol in 12 h (80 mmol/l x 4.5 l) after therapy began. This can be extrapolated to 720 mmol/day (500 µmol/min), a value that is almost 5-fold higher than the usual Na + K excretion rate.38,39 Hence it is prudent to ask, ‘Can low aldosterone levels be the sole explanation for hyponatraemia?’ And, with regard to the development of ODS, ‘How might ODS have been prevented?’
(i) Can hypoaldosteronism explain her deficit of Na? This question can be answered when this patient's renal function is evaluated. Because the GFR should be reduced when the blood pressure is low, the filtered load of Na will be much lower than normal. Moreover, Na reabsorption in nephron segments where aldosterone does not act should be stimulated by the low ECF volume. In quantitative terms, because her PCreat was elevated 6-fold, her GFR should be 
1/6 of normal (20 vs. 120 ml/min). Therefore, her filtered load of Na should be 2360 µmol/min (118 µmol/ml x 20 ml/min) with this GFR. Accordingly, the fractional excretion of Na (FENa) is 25% (500/2360 µmol/min), a value that is much greater than the ‘expected’ 5% of the filtered load of Na. This high FENa suggests that a second ‘renal lesion’ contributed to the excessive excretion of Na.23
The above analysis illustrates that in a case where hyponatraemia is associated with a low ECF volume and impaired renal function, it is useful to calculate the FENa. One CDA introduced the option of evaluating renal function in their strategy,7 but none suggested calculating the FENa (Table 1).
(ii)How might ODS have been prevented? This patient was treated with isotonic saline and 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, rather, it is an upper limit not to be exceeded.2 Moreover, because this patient had chronic hyponatraemia and was catabolic, the risk of ODS was increased.41 Therefore, in cases where there is an ‘acute discovery of chronic hyponatraemia’ the target for the daily rise in the PNa should be much lower, 0–4 mmol/l on the first day.2,23,42
The reasons that her PNa rose so quickly when isotonic saline was infused becomes apparent when a tonicity balance is calculated.43 There was a trivial positive water balance of 4.6–4.5 = 0.1 l. In contrast, there was a large positive Na balance of 330 mmol (4.5 l x 150 – 4.6 l x 80). Prevention of this rapid rise in PNa could have been achieved by matching the tonicity and volume of the infusate to that of the urine (in this case infusing close to half-isotonic saline). This emphasizes the importance of what can be called an intravenous (IV) fluid regimen that remains ‘isotonic to patient’ in balance terms.
Of the respondents, the majority (78%; 61 + 2 + 15) stated that although they would apply a correction rate of 8 mmol/l/day or less, their choices of the type of IV fluid was isotonic (57%) or even hypertonic saline (13%), possibly as a result of the belief that her hyponatraemia was life-threatening (74%, Table 2). This therapy caused too rapid a rise in her PNa and, consequently, the ODS.
Case 3: Hyponatraemia with the ability to have a water diuresis
Definition of the problem: In this case, the first impression is that hyponatraemia is due to the ingestion of large quantities of water. Indeed, most CDAs led to the diagnosis of primary polydipsia (53%, Table 2). However, if this were the case and if kidney function were normal, one would excrete the maximum volume of dilute urine, which is 15 l/day.2 Furthermore, because the Uosm is much lower than the Posm, there appears to be very little ADH action. These considerations lead to the following questions: ‘How can hyponatraemia occur in the context of minimal ADH release?’, and, ‘Which groups of patients are susceptible to this type of hyponatraemia?’
(i) How can hyponatraemia occur in the context of minimal release of ADH? Water retention in this setting of minimal ADH release can occur when there is a low delivery of filtrate to the distal nephron.44 To have a low distal volume delivery, there should be a low GFR and/or enhanced reabsorption of filtrate in the proximal convoluted tubule, responses that typically accompany a low intake of sodium chloride.45 Second, there may be a small degree of water permeability in the distal nephron that could be the result of trace levels of ADH—levels that are not detected by conventional assays46 and/or by ADH-insensitive water permeability (called basal water permeability47).
In this patient, there was a very low distal volume delivery as reflected by the low rate of excretion of osmoles. Because urinary osmolality is a composite of both electrolytes (primarily sodium, potassium, and their accompanying anions) and excreted solutes, electrolyte-free water excretion is also dependent on the total rate of solute excretion.24 Therefore, if solute excretion becomes very low, electrolyte-free water will be retained and hyponatraemia may ensue. In this patient, the low rate of solute excretion can be explained by the combination of a low-protein diet (low urea) and a low NaCl intake and/or a large non-renal or former renal NaCl loss. Because isolated groups that eat a diet with little NaCl do not suffer from hyponatraemia,48 a low PNa will not develop solely because of low salt intake, contrary to the comments of 24% of the respondents (Table 2).
(ii) Which groups of patients are likely to develop this type of hyponatraemia? There are three settings where hyponatraemia is associated with a low rate of excretion of electrolyte-free water without having detectable levels of ADH in plasma—called ‘trickle-down hyponatraemia’ by Oh et al.49
First, this can occur in elderly patients who consume tea (electrolyte-free water) and toast (low protein) diets, especially if treated with a thiazide diuretic and a low salt diet for hypertension. Second, it can be observed in patients who wish to control their body weight by diet and exercise, especially if they have a large intake of water. Although exercise causes a large sweat loss, if the diet is particularly low in NaCl, the net effect can result in a very low renal excretion of Na and Cl. The third setting for trickle-down hyponatraemia is beer potomania.50,51 Because dietary carbohydrate, fat and ethanol all have carbon dioxide and water as end-products that are excreted in a 1 : 1 stoichiometry via the lungs,52 they will not usually produce many urinary osmoles because beer is low in protein and NaCl.
In this patient, hyponatraemia was not considered to pose an immediate danger (0%, Table 2). However, this patient could be susceptible to brain swelling if water intake continued, but water loss in sweat (did not run that day) or urine (non-osmotic reason for ADH release) was prevented. In addition, brain damage (ODS) from rapid correction of hyponatraemia could occur, especially if she was malnourished and/or K-depleted.41
Case 4: Acute hyponatraemia in a patient who took ‘Ecstasy’
Definition of the problem: In this case, there appears to be a discrepancy between the measured PNa and the severity of the symptoms. Hence the questions are: ‘Might there be a confounding issue?’, and, ‘Should the emphasis in management be further diagnostic tests or immediate therapy?’
(i) Might there be a confounding issue? Symptoms related to acute hyponatraemia (<48 h) most commonly occur if the PNa is <125 mmol/l.53,54 Nevertheless, the presenting symptom in this case was a seizure, which can raise the PNa acutely by 10–15 mmol/l.55 The mechanism involves the generation of new osmoles that are retained in skeletal muscle cells (which account for 50% of total body water) and cause water to shift from the ECF to the intracellular compartment.55 A similar situation may be seen when severe rhabdomyolysis causes hypernatraemia.2 The PNa should therefore be re-evaluated after the seizure to reveal the steady-state PNa. Almost half of the respondents recognized that the PNa may represent a non-steady-state value (48%, Table 2).
In conclusion, this case illustrates the importance of analysing possible confounding factors in the differential diagnosis of hyponatraemia. The most common examples include ‘pseudohyponatraemia’,56 and situations where an ‘effective’ osmole in the ECF prevents water from moving into the intracellular compartment (e.g. hyperglycaemia, therapy with mannitol, surgery with lavage fluids).2,57,58
(iii) Should the next focus be diagnostic tests or therapy? In the patient with acute symptomatic hyponatraemia, therapeutic considerations dominate over diagnostic ones.59 Once acute, symptomatic hyponatraemia is suspected, it is imperative to infuse hypertonic saline, because irreversible changes in brain function can occur in a very short time.60 A minority of the respondents chose a hypertonic solution (24%, Table 2), although 59% did believe that the hyponatraemia was life-threatening (Table 2). Remarkably, only one recently published algorithm included the distinction of acute vs. chronic hyponatraemia in the diagnostic approach (Table 1),13 despite ample literature on this subject.61–63 This may delay recognizing the dangers of acute hyponatraemia, which should always be the primary focus.
Finally, with regard to the pathophysiology of Ecstasy-induced hyponatraemia, different possible mechanisms have been described, including ADH release,64 water intoxication65 and reduced intestinal motility.25
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Concluding remarks |
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For a classification to be useful, it must permit the clinician to reach the correct diagnosis and implement the appropriate therapy. It must also rely on criteria that are valid and available in a timely fashion. Unfortunately, as demonstrated by the selected (and biased) cases, the existing CDAs did not live up to these standards (Table 1). In part, the low accuracy can be explained because many physicians felt it was impossible to establish a diagnosis when they applied the available data to the CDAs (Table 2). However, the requirement that certain values should be available before being able to proceed in the CDA, is in itself a weak point, and may unnecessarily delay diagnosis and treatment. In our analysis, the most serious error was the failure to rule out acute hyponatraemia as the first step. A second weak point was the mistaken belief that a clinician could detect a mild to modest degree of ECF volume contraction by physical examination supported by routine laboratory data. This was most evident in Case 1, because it led to an incorrect diagnosis (SIADH) and improper treatment (water restriction) that could have been responsible for the fatal outcome, due to eventual haemodynamic collapse.22 Although more laboratory tests may have been desirable, this case appears to represent a more common pitfall where the clinical scenario resembles SIADH, which subsequently is not reconsidered and may lead to an adverse outcome.22,26,66,67 Of note, SIADH should be a diagnosis of exclusion, and should only be considered if adrenal, thyroid and pituitary insufficiency are absent.26,66,67 Another problem that merits attention is that the traditional approach often relies on generalizations rather than reliable data. Examples cited were the need to find hyperkalaemia to diagnose Addison's disease55 and to assume a stable PNa under circumstances where water-shifts are likely (e.g. seizures, rhabdomyolysis).2,35 In summary, the typical architecture of the current CDAs represents a hierarchical order of isolated clinical and/or laboratory parameters. They do not take into account the pathophysiological context, the mechanism by which hyponatraemia developed and the clinical dangers of hyponatraemia. These restrictions are important for physicians confronted with hyponatraemic patients and may require them to choose different approaches.
Based on the above, we provide a different type of algorithm that is designed to recognize the dangers of hyponatraemia, and to consider the pathophysiology of hyponatraemia before analysing diagnostic parameters (Figure 1). This ‘physiology-based algorithm’ is separated in three steps. First, a distinction between acute and chronic hyponatraemia is made, and therapy is designed accordingly. If the patient is classified as chronic, but does have symptoms of hyponatraemia, a rapid initial restoration is recommended, because ‘acute on chronic’ hyponatraemia is likely. In contrast, slow correction rates are advised when hyponatraemia is chronic and not symptomatic, especially when there is concomitant hypokalaemia and/or malnutrition, because in those situations the risk of ODS is high.23,41 In the second step, the pathophysiology of hyponatraemia is reviewed, connecting it to the clinical situation at hand. In addition, the unique pathophysiology of hyponatraemia with low circulating levels of ADH is presented. The final step of our algorithm was intentionally organized in a tabular format so that all causes of hyponatraemia can still be taken into consideration without excluding others (Step 3, Figure 1). The philosophy behind this is that relying on one single value may be misleading, as expected values may vary depending on the situation. This has been illustrated for urinary values36,68 and for diagnostic tests.26 Here, a physiological analysis using simple formulae can be used simultaneously and synergistically with the traditional analysis (Figure 1 and Table 3) [2,24, 69–74]. We emphasize that our algorithm is not intended to completely replace the other existing CDAs, but rather, to provide a physiology-based alternative, which seeks to overcome some of the identified limitations of the existing CDA's.
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Acknowledgments |
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We would like to thank Dr R.H. Sterns, Dr M.R. Davids and Dr S.H. Lin for their cooperation with collecting the surveys.
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References |
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