Goce SpasovskiRaymond VanholderBruno AllolioDjillali AnnaneSteve BallDaniel BichetGuy DecauxWiebke FenskeEwout HoornCarole IchaiMichael JoannidisAlain SoupartRobert ZietseMaria HallerSabine van der VeerWim Van BiesenEvi Nagler

Clinical practice guideline on diagnosisand treatment of hyponatraemia

Received: 31 December 2013Accepted: 3 January 2014Published online: 22 February 2014 Springer-Verlag Berlin Heidelberg andESICM 2014

Electronic supplementary materialThe online version of this article(doi:10.1007/s00134-014-3210-2) containssupplementary material.

G. SpasovskiState University Hospital Skopje, Skopje,Macedonia

R. Vanholder W. Van Biesen ())Ghent University Hospital, Ghent, Belgiume-mail: Wim.VanBiesen@UGent.be

B. Allolio W. FenskeWurzburg University Hospital, Wurzburg,Germany

D. AnnaneRaymond Poincare Hospital, University ofVersailles Saint Quentin, Paris, France

S. BallNewcastle Hospitals and NewcastleUniversity, Newcastle, UK

D. BichetConsultant Nephrologist, Sacre-CoeurHospital, University of Montreal, Montreal,Canada

G. Decaux A. SoupartErasmus University Hospital, Brussels,Belgium

E. Hoorn R. ZietseErasmus Medical Centre, Rotterdam,The Netherlands

C. IchaiNice University Hospital, Nice, France

M. JoannidisInnsbruck University Hospital, Innsbruck,Austria

M. Haller S. van der Veer E. NaglerERBP Methods Support Team, GhentUniversity Hospital, Ghent, Belgium

M. HallerKH Elisabethinen Linz, Linz, Austria

S. van der VeerCentre for informatics, Amsterdam MedicalCentre, Amsterdam, The Netherlands

Abstract Hyponatraemia, defined asa serum sodium concentration\135 mmol/L, is the most commondisorder of body fluid and electrolytebalance encountered in clinical prac-tice. Hyponatraemia is present in1520 % of emergency admissions tohospital and occurs in up to 20 % ofcritically ill patients. Symptomatologymay vary from subtle to severe or evenlife threatening. Despite this, the man-agement of patients remainsproblematic. Against this background,the European Society of Intensive CareMedicine, the European Society ofEndocrinology and the European RenalAssociationEuropean Dialysis andTransplant Association, represented byEuropean Renal Best Practice havedeveloped a Clinical Practice Guide-line on the diagnostic approach andtreatment of hyponatraemia as a jointventure of three societies representingspecialists with a natural interest inhyponatraemia.

Keywords Hyponatraemia Hypotonic Guideline Diagnosis Management

Intensive Care Med (2014) 40:320331DOI 10.1007/s00134-014-3210-2 GUIDELINES

1 Introduction and methodology

Hyponatraemia, defined as a serum sodium concentration\135 mmol/L, is the most common disorder of body fluidand electrolyte balance encountered in clinical practice.Hyponatraemia is present in 1520 % of emergencyadmissions to hospital and occurs in up to 20 % of criti-cally ill patients [1]. It can lead to a wide spectrum ofclinical symptoms, from subtle to severe or even lifethreatening [2, 3] and is associated with increased mortality,morbidity and length of hospital stay in patients presentingwith a range of conditions. Despite this, the management ofpatients remains problematic. The prevalence of hypona-traemia in widely different conditions and the fact thathyponatraemia is managed by clinicians with a broad varietyof backgrounds, has fostered diverse institution- and speci-ality-based approaches to diagnosis and treatment.

Against this background, the European Society ofIntensive Care Medicine (ESICM), the European Societyof Endocrinology (ESE) and the European Renal Asso-ciationEuropean Dialysis and Transplant Association(ERAEDTA), represented by European Renal BestPractice (ERBP) have developed this Clinical PracticeGuideline on the diagnostic approach and treatment ofhyponatraemia as a joint venture of three societies rep-resenting specialists with a natural interest inhyponatraemia. In addition to a rigorous approach tomethodology and evaluation, we were keen to ensure thedocument focused on patient-important outcomes and hadutility for clinicians involved in every-day practice.

The ERBP methods support team searched TheCochrane Database of Systematic Reviews (May 2011),DARE (May 2011), CENTRAL (May 2011) and MED-LINE (1946 to May, week 4, 2011) for both questions ondiagnosis and treatment. To identify limits for theincrease in serum sodium concentration above which therisk of osmotic demyelination starts to rise, they searchedMEDLINE from 1997 onwards under the assumption thatearlier reports would describe more dramatic increasesand would not contribute to helping us set an upper limit.

A member of the ERBP methods support team screenedall titles and abstracts to discard the clearly irrelevant ones.All members of the guideline development group completeda second screening. All abstracts that did not meet theinclusion criteria were discarded. Any discrepancies at thisstage were resolved by group consensus. The methods sup-port team retrieved full texts of potentially relevant studiesand two reviewers examined them for eligibility indepen-dently of each other. The reviewer duos always included onecontent specialist and a methodologist of the ERBP methodssupport team. Any discrepancies were resolved by consen-sus. If no consensus could be reached, the disagreement wassettled by group arbitrage. The evidence for outcomes ontherapeutic interventions from included systematic reviewsand randomised controlled trials was presented using the

Grading of Recommendations Assessment, Developmentand Evaluation (GRADE) toolbox developed by the inter-national GRADE working group (http://www.gradeworkinggroup.org/).

The guideline underwent external peer review beforepublication.

This condensed version of the Clinical PracticeGuideline on Diagnosis and Treatment of Hyponatraemiafocuses on recommendations on diagnosis and treatmentof hyponatraemia, the full version of the guidelines,additionally covering conflict of interest, purpose andscope, methods of guideline development and pathophy-siology of hyponatraemia, is available as electronicsupplemental material (ESM).

2 Diagnosis of hyponatraemia

2.1 Classification of hyponatraemia

2.1.1 Definition of hyponatraemia based on biochemicalseverity

We define mild hyponatraemia as a biochemicalfinding of a serum sodium concentration between 130and 135 mmol/L as measured by ion specific electrode.

We define moderate hyponatraemia as a biochemicalfinding of a serum sodium concentration between 125and 129 mmol/L as measured by ion specific electrode.

We define profound hyponatraemia as a biochemicalfinding of a serum sodium concentration\125 mmol/Las measured by ion specific electrode.

2.1.2 Definition of hyponatraemia based on timeof development

We define acute hyponatraemia as hyponatraemia that isdocumented to exist \48 h. We define chronic hyp-onatraemia as hyponatraemia that is documented to existfor at least 48 h. If the hyponatraemia cannot be classified,we consider it being chronic, unless there is clinical oranamnestic evidence of the contrary (Tables 1, 2).

2.1.3 Definition of hyponatraemia based on symptoms

We define moderately symptomatic hyponatraemia asany biochemical degree of hyponatraemia in the pre-sence of moderately severe symptoms of hyponatraemia(Table 1).

We define severely symptomatic hyponatraemia as anybiochemical degree of hyponatraemia in the presence ofsevere symptoms of hyponatraemia (Table 1).

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Why did we choose to set definitions?Hyponatraemia can be classified based on different

parameters. These include serum sodium concentration,rate of development, symptom severity, serum osmolality,and volume status. For this guideline, we wanted theclassification to be consistent and clear so all users wouldhave a correct understanding of the terminology used. Wealso wanted to make the classification directly relevant forpatient management. However, treatment strategies can-not be adequately classified with reference to a singlecriterion. Hence, treatment strategies have been classifiedaccording to combinations of these criteria.

What are these definitions based on?Classification based on serum sodium concentrationAuthors mostly use the terms mild, moderate, and

severe [46]. We have chosen to replace severe byprofound to avoid confusion with the classification based

on symptoms, for which we have reserved the term severe.The definitions of mild, moderate and profound hypona-traemia in published research are variable; especially thethreshold used to define profound hyponatraemia for whichvalues have ranged from 110 to 125 mmol/L [7, 8]. Severalstudies report that when serum sodium concentrations dropbelow 125 mmol/L, symptoms become more common [1, 4,913], and the correction to normonatraemia necessitatescareful monitoring to avoid overly rapid correction [14].

Classification based on duration and speed ofdevelopmentPublished research suggests using a threshold of 48 h todistinguish acute from chronic hyponatraemia. Brainoedema seems to occur more frequently when hypona-traemia develops in\48 h [1518]. Experimental studiesalso suggest that the brain needs approximately 48 h toadapt to a hypotonic environment, achieved mainly byextruding sodium, potassium, chloride and organic os-moles from its cells [1921]. Before adaptation, there is arisk of brain oedema, because the lower extracellularosmolality promotes a shift of water into the cells.However, once adaptation is completed, brain cells canagain sustain damage if the serum sodium concentrationincreases too rapidly. Breakdown of the myelin sheathinsulating individual neurons can result in what is calledthe osmotic demyelination syndrome [2225]. Conse-quently, it is important to distinguish between acute andchronic hyponatraemia to assess whether someone is atgreater risk of immediate brain oedema than of osmoticdemyelination [26]. Unfortunately, in clinical practice,the distinction between acute and chronic hyponatraemiais often unclear, particularly for patients presenting to theemergency room. It is often unknown when the serumsodium concentration has started decreasing. If classify-ing hyponatraemia as acute or chronic is not possible, wehave decided to consider the hyponatraemia as beingchronic, unless there are reasons to assume it is acute(Table 10). There is a good reason for this approach.Chronic hyponatraemia is much more common than acutehyponatraemia and should be managed accordingly toavoid osmotic demyelination [27, 28].

Classification based on symptomsWe have divided symptoms of hyponatraemia intomoderately severe and severe. The distinction is basedon selected observations in acute hyponatraemia; thosewho subsequently die more often experience what wedefine as severe symptoms than those who live [15, 16].Moderately severe symptoms caused by brain oedema areless frequently associated with death. Nevertheless, theymay rapidly progress to more severe symptoms associatedwith an adverse outcome.

We have purposefully omitted the category asymp-tomatic as we felt this might create confusion. Patientsare probably never truly asymptomatic in the strictestsense of the word. Very limited and subclinical signs such

Table 1 (Table 5 of the online document): classification ofsymptoms of hyponatraemia

Severity Symptom

Moderately severe Nausea without vomitingConfusionHeadache

Severe VomitingCardio-respiratory distressAbnormal and deep somnolenceSeizuresComa (Glasgow Coma Scale B8)

The guideline development group wants to underscore that thesesymptoms can also be induced by other conditions. Clinical andanamnestic data should be taken into account when assessing thecausal relation between the hyponatraemia and a certain symptom(i.e. to assess whether the symptom has been caused by the hyp-onatraemia or the hyponatraemia by the underlying condition/symptom). The less pronounced (e.g. mild) the biochemical degreeof hyponatraemia, the more caution should be taken when con-sidering that the hyponatraemia is the cause of the symptoms. Thislist is not exhaustive, and all symptoms that can be signs of cerebraloedema should be considered as severe or moderate symptoms thatcan be caused by hyponatraemia

Table 2 (Table 8 of the online document): drugs and conditionsassociated with acute hyponatraemia (\48 h)

Postoperative phasePost-resection of the prostate, post-resection of endoscopic uterine

surgeryPolydipsiaExerciseRecent thiazides prescription3,4-Methyleendioxymethamfetamine (MDMA, XTC)Colonoscopy preparationCyclophosphamide (intravenous)OxytocinRecently started desmopressin therapyRecently started terlipressin, vasopressin

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as mild concentration deficits are seen even with mildhyponatraemia [29].

A classification based on symptoms aims to reflect thedegree of brain oedema and the extent of immediate danger.It allows matching treatment to the immediate risk, withmore aggressive treatment for symptoms that are moresevere. Nevertheless, a classification based only on symp-tom severity has several shortcomings. First, symptoms ofacute and chronic hyponatraemia may overlap [29]. Sec-ond, patients with acute hyponatraemia can present withoutclear symptoms, but go on to develop moderately severe tosevere symptoms within hours [15]. Third, symptoms ofhyponatraemia are nonspecific. Consequently, assessmentof symptoms needs to happen with caution. Clinicians needto be wary that symptoms can be caused by conditions otherthan hyponatraemia; by other conditions in combinationwith hyponatraemia; or by conditions that cause the hyp-onatraemia. In general, one should be particularly carefulwhen attributing moderately severe to severe symptoms tohyponatraemia when the biochemical degree of hypona-traemia is only mild (Table 1).

Classification based on serum osmolalityAs this guideline aimed to cover the aspects of diagnosis

and treatment specifically of hypotonic hyponatraemia,we needed to define what distinguishes hypotonic fromnon-hypotonic hyponatraemia. Because this distinction isa necessary first step in the diagnostic evaluation of anyhyponatraemia, we have devoted a separate chapter to thistopic (chapter 8.2). For reasons of completeness, webriefly mention it here. A measured serum osmolality\275 mOsm/kg always indicates hypotonic hyponatra-emia, as effective osmolality can never be higher thantotal or measured osmolality. In contrast, if calculatedosmolality \275 mOsm/kg, the hyponatraemia can behypotonic, isotonic or hypertonic, depending on whichosmotically active agents are present and whether or notthey are incorporated in the formula [30].

Classification based on volume statusPatients with hyponatraemia may be hypovolaemic, eu-volaemic, or hypervolaemic [31]. Many traditionaldiagnostic algorithms start with a clinical assessment ofvolume status [32]. However, it is often not clear if vol-ume status in this context refers to the extracellular fluidvolume, to the effective circulating volume or to the totalbody water. In addition, the sensitivity and specificity ofclinical assessments of volume status are low, potentiallyleading to misclassification early in the diagnostic tree[33, 34]. Therefore, we have used the terms effectivecirculating volume and extracellular fluid volumethroughout the text to reduce ambiguity.

Note of cautionWe wanted the classification of hyponatraemia to beconsistent, easy to use and helpful for both differentialdiagnosis and treatment. Hyponatraemia can be classified

according to different factors, each with advantages andpitfalls depending on the clinical setting and situation. Wehave prioritized the criteria such that we would obtain aclassification that would be clinically relevant and aswidely applicable as possible.

Nevertheless, the user should keep in mind that differ-ential diagnosis of hyponatraemia is difficult and noclassification can be 100 % accurate in every situation. Weemphasize that the different classifications of hyponatra-emia are not mutually exclusive, and that classificationshould always occur with the clinical condition and thepossibility of combined causes of hyponatraemia in mind.

2.2 Confirming hypotonic and excluding non-hypotonic hyponatraemia

We recommend excluding hyperglycaemic hyponatra-emia by measuring the serum glucose concentrationand correcting the measured serum sodium concentra-tion for the serum glucose concentration if the latter isincreased. (1D)

Hyponatraemia with a measured osmolality\275 mOsm/kg always reflects hypotonic hyponatra-emia. (not graded)

Accept as hypotonic hyponatraemia a hyponatraemiawithout evidence for causes of non-hypotonic hyp-onatraemia as listed in Table 3. (not graded)

Advice for clinical practice

Estimates of the serum sodium concentration correctedfor the presence of hyperglycaemia can be obtained fromthe following equations [35]:

Corrected serum Na measured Na 2:4

Glu cos e mg=dl 100 mg=dl100 mg=dl

Corrected Na measured Na 2:4

Glu cos e mmol=L 5:5 mmol=L5:5 mmol=L

where [Na?] is the serum sodium concentration, [Glu-cose] is the serum glucose concentration.

This translates into adding 2.4 mmol/L to the mea-sured serum sodium concentration for every 5.5 mmol/L(100 mg/dL) incremental rise in serum glucose concen-tration above a standard serum glucose concentration of5.5 mmol/L (100 mg/dL).

Alternatively, the estimated value of the correctedserum sodium concentration across a range of serumglucose concentrations can be obtained from (ESMTable 10).

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2.3 Which parameters to use for differentiating causesof hypotonic hyponatraemia? (Fig. 1)

We recommend interpreting urine osmolality of a spoturine sample as a first step. (1D)

If urine osmolality B100 mOsm/kg, we recommendaccepting relative excess water intake as a cause of thehypotonic hyponatraemia. (1D)

If urine osmolality [100 mOsm/kg, we recommendinterpreting the urine sodium concentration on a spoturine sample taken simultaneously with a blood sam-ple. (1D)

If urine sodium concentration B30 mmol/L, we suggestaccepting low effective arterial volume as a cause of thehypotonic hyponatraemia. (2D)

If urine sodium concentration[30 mmol/L, we suggestassessing extracellular fluid status and use of diuretics tofurther differentiate likely causes of the hyponatraemia.(2D)

We suggest against measuring vasopressin for con-firming the diagnosis of SIADH. (2D)

Advice for clinical practice

Correct interpretation of laboratory measurementsrequires contemporaneous collection of blood and urinespecimens.

For practical reasons, urine osmolality and sodiumconcentration are best determined in the same urinesample.

If clinical assessment indicates the volume of extracel-lular fluid is not overtly increased and the urine sodiumconcentration [30 mmol/L, exclude other causes ofhypotonic hyponatraemia before implicating SIAD.Consider using the diagnostic criteria listed in Tables 4,5 and looking for known causes of SIAD.

Consider primary or secondary adrenal insufficiency asan underlying cause of the hypotonic hyponatraemia.

Kidney disease complicates differential diagnosis ofhyponatraemia. Besides possibly contributing to thehyponatraemia, the ability of the kidneys to regulateurine osmolality and urine sodium is often diminished,much like with the use of diuretics. As urine osmolalityand sodium may no longer reflect the effects of theregular hormonal axes regulating water and sodiumhomeostasis, any diagnostic algorithm for hyponatra-emia must be used with caution in patients with kidneydisease.

The water-loading test is generally not helpful fordifferential diagnosis of hypotonic hyponatraemia andmay be dangerous in this setting.

3 Treatment of hypotonic hyponatraemia

How to use the treatment recommendations

The advice provided in this chapter follows a specifichierarchy as illustrated in Fig. 2. Individual recommen-dations and statements can only be correctly interpretedand implemented if considered within this structure.

The guideline development group felt that with severeor moderately severe symptoms, the risk of brain oedemaoutweighs the risk of osmotic demyelination syndrome.They felt it justifies urgent treatment in these conditions,irrespective of biochemical degree or timing (acute versuschronic) of hyponatraemia. Conversely, the guidelinedevelopment group believed that in the absence of severeor moderately severe symptoms, there is time for diag-nostic assessment, and cause-specific treatment is themost reasonable approach.

For a correct interpretation of the algorithm in Fig. 2,it is crucial to understand that for correctly classifying

Table 3 (Table 10 of the online document): causes of non-hypotonic hyponatraemia

Setting Serum osmolality Examples

Presence of effective osmoles that raiseserum osmolality and can cause hyponatraemia

Isotonic or hypertonic Glucose [35]Mannitol [38]Glycine [39]Histidinetryptophaneketoglutarate [40]Hyperosmolar radiocontrast media [41]Maltose [42]

Presence of ineffective osmoles that raise serumosmolality but do not cause hyponatraemia

Isotonic or hyperosmolar Urea [43]Alcohols [43]Ethylene-glycol [43]

Presence of endogenous solutes that causepseudohyponatraemia (laboratory artifact)

Isotonic Triglycerides [44]Cholesterol [44]Protein intravenous immunoglobulins [45]Monoclonal gammapathies [46]

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symptoms as severe or moderately severe, there mustbe sufficient confidence that the symptoms are caused byhyponatraemia. If hyponatraemia is mild and symptomsare severe or moderately severe (Table 5 of the onlinedocument), the guideline development group advises toonly accept causality in exceptional cases. Consequently,generally, chapters 3.1, 3.2, and 3.3 are not applicablewhen hyponatraemia is mild. It is also essential tounderstand that the guideline development group

distinguishes between targets and limits. A target is agoal one is aiming for; it is the change in serum sodiumconcentration that one wishes and expects to achievewith a particular treatment. In contrast, a limit is achange in serum sodium concentration one does notwant to exceed and if surpassed, requires prompt coun-ter-regulating intervention as described in chapter 9.5(ESM). In addition, the reader should bear in mind thatthe absolute numbers provided as targets or limits

7

Fig. 1 (Fig. 6 of the onlinedocument): algorithm for thediagnosis of hyponatraemia

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should always be interpreted in the clinical context ofthe individual patient.

3.1 Hyponatraemia with severe symptoms

3.1.1 First hour management, regardlessof whether hyponatraemia is acute or chronic

We recommend prompt intravenous infusion of 150 mL3 % hypertonic saline or equivalent over 20 min. (1D)We suggest checking the serum sodium concentra-tion after 20 min while repeating an infusion of 150 mL3 % hypertonic saline or equivalent over the next 20 min.(2D)We suggest repeating therapeutic recommendations3.1.1.1 and 3.1.1.2 twice or until a target of 5 mmol/Lincrease in serum sodium concentration is achieved. (2D)

Manage patients with severely symptomatic hypona-traemia in an environment where close biochemical andclinical monitoring can be provided. (not graded)

3.1.2 Follow up management in case of improvementof symptoms after a 5 mmol/L increase in serumsodium concentration in the first hour, regardlessof whether hyponatraemia is acute or chronic

We recommend stopping the infusion of hypertonicsaline. (1D)

We recommend keeping the intravenous line open byinfusing the smallest feasible volume of 0.9 % salineuntil cause-specific treatment is started. (1D)

We recommend starting a diagnosis specific treatmentif available, aiming at least to stabilize sodium con-centration. (1D)

We recommend limiting the increase in serum sodiumconcentration to a total of 10 mmol/L during the first24 h and an additional 8 mmol/L during every 24 hthereafter until the serum sodium concentration reaches130 mmol/L. (1D)

We suggest checking the serum sodium concentrationafter 6 and 12 h, and daily afterwards until the serumsodium concentration has stabilised under stabletreatment. (2D)

3.1.3 Follow up management in case of no improvementof symptoms after a 5 mmol/L increase in serumsodium concentration in the first hour, regardlessof whether the hyponatraemia is acute or chronic

We recommend continuing an intravenous infusion of3 % hypertonic saline or equivalent aiming for anadditional 1 mmol/L/h increase in serum sodium con-centration (1D).

We recommend stopping the infusion of 3 % hypertonicsaline or equivalent when the symptoms improve, theserum sodium concentration increases 10 mmol/L in totalor the serum sodium concentration reaches 130 mmol/L,whichever occurs first (1D).

We recommend additional diagnostic exploration forother causes of the symptoms than hyponatraemia (1D).

We suggest checking the serum sodium concentrationevery 4 h as long as an intravenous infusion of 3 %hypertonic saline or equivalent is continued (2D).

Advice for clinical practice

Prompt infusion of hypertonic saline may save lives.However, preparing a 3 % hypertonic saline infusiontakes time and errors may occur in calculating therequired amount of sodium chloride. Therefore, it maybe wise for the pharmacy to store pre-prepared 150 mLbags of 3 % hypertonic saline. It ensures that solutions

Table 4 (Table 6 of the online document): diagnostic criteria forthe syndrome of inappropriate antidiuresis

Essential criteriaEffective serum osmolality \275 mOsm/kgUrine osmolality [100 mOsm/kg at some level of decreased

effective osmolalityClinical euvolaemiaUrine sodium concentration[30 mmol/L with normal dietary salt

and water intakeAbsence of adrenal, thyroid, pituitary or renal insufficiencyNo recent use of diuretic agents

Supplemental criteriaSerum uric acid \0.24 mmol/L (\4 mg/dL)Serum urea \3.6 mmol/L (\21.6 mg/dL)Failure to correct hyponatraemia after 0.9 % saline infusionFractional sodium excretion [0.5 %Fractional urea excretion [55 %Fractional uric acid excretion [12 %Correction of hyponatraemia through fluid restriction

Adapted from Schwartz et al. [36] and Janicic et al. [37]

Table 5 (Table 11 of the online document): differences betweenSIADH and cerebral salt wasting

SIADH Cerebral salt wasting

Serum urea concentration Normallow NormalhighSerum uric acid concentration Low LowUrine volume Normallow HighUrine sodium concentration [30 mmol/

L[[30 mmol/L

Blood pressure Normal Normalorthostatichypotension

Central venous pressure Normal Low

Adapted from Sherlock et al. [47] and Brimioulle et al. [48]

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are prepared under sterile conditions, by either thepharmacist or the manufacturer, and are available forimmediate infusion without having to prepare them onthe spot.

Consider using weight based (2 mL/kg) rather thanthe fixed 150 mL infusion volumes of 3 % hyper-tonic saline in case of obviously deviant bodycomposition.

Do not expect patients with severe symptoms tocompletely recover immediately, as it may take sometime for the brain to fully recover. Be aware thatsometimes it may not be possible to assess animprovement in symptoms, e.g. because the patient is

intubated and sedated. In these cases, we advise tofollow guidance as described under 9.1.2.

Keep in mind that if hypokalaemia is present, correc-tion of the hypokalaemia will contribute to an increasein serum sodium concentration.

To achieve the 1 mmol/L/h increase advised in 9.1.2.1,the formula of AdrogueMadias [32] may be used, butkeep in mind that the actual increase may exceed thecalculated increase:

Change in serum Na infusate Na serum Na

total body water 1

7

7

7

7

7 7

7

Fig. 2 (Fig. 7 of the onlinedocument): algorithm for themanagement of hypotonichyponatraemia (the numbers inthe yellow boxes refer to theonline full guideline document)

327

Change in serum Na infusate Na infusate K serum Na

total body water 1

where [Na?] is the sodium concentration in mmol/L,[K?] is the potassium concentration in mmol/L. Thenumerator in formula 1 is a simplification of theexpression in formula 2, with the value yielded by theequation in mmol/L. The estimated total body water(in litres) is calculated as a fraction of body weight.The fraction is 0.6 in nonelderly men and 0.5 innonelderly women; and 0.5 and 0.45 in elderly menand women respectively. Normally, extracellular andintracellular fluids account for 40 and 60 % of totalbody water respectively.

3.2 Hyponatraemia with moderately severe symptoms

We recommend starting prompt diagnostic assessment.(1D)

Stop, if possible, medications and other factors thatcan contribute to or provoke the hyponatraemia. (notgraded)

We recommend cause-specific treatment. (1D)

We suggest immediate treatment with a single intrave-nous infusion of 150 mL 3 % hypertonic saline orequivalent over 20 min. (2D)

We suggest aiming for a 5 mmol/L/24 h increase inserum sodium concentration. (2D)

We suggest limiting the increase in serum sodium con-centration to 10 mmol/L in the first 24 h and 8 mmol/Lduring every 24 h thereafter, until a serum sodium con-centration of 130 mmol/L is reached. (2D)

We suggest checking the serum sodium concentrationafter one, 6 and 12 h. (2D)

We suggest additional diagnostic exploration for othercauses of the symptoms if the symptoms do notimprove with an increase in serum sodium concentra-tion. (2D)

We suggest considering to manage the patient as inseverely symptomatic hyponatraemia if the serumsodium concentration further decreases despite treatingthe underlying diagnosis. (2D)

3.3 Acute hyponatraemia without severeor moderately severe symptoms

Make sure that the serum sodium concentration hasbeen measured using the same technique as used forthe previous measurement and that no administrativeerrors in sample handling have occurred. (not graded)

If possible, stop fluids, medications and other factorsthat can contribute to or provoke the hyponatraemia.(not graded)

We recommend starting prompt diagnostic assessment.(1D)

We recommend cause-specific treatment. (1D)

If the acute decrease in serum sodium concentrationexceeds 10 mmol/L, we suggest a single intravenousinfusion of 150 mL 3 % hypertonic saline or equiva-lent over 20 min. (2D)

We suggest checking the serum sodium concentrationafter 4 h, using the same technique as used for theprevious measurement. (2D)

3.4 Chronic hyponatraemia without severeor moderately severe symptoms

3.4.1 General management

Stop non-essential fluids, medications and other factorsthat can contribute to or provoke the hyponatraemia.(not graded)

We recommend cause-specific treatment. (1D)

In mild hyponatraemia, we suggest against treatmentwith the sole aim of increasing the serum sodiumconcentration. (2C)

In moderate or profound hyponatraemia, we recommendavoiding an increase in serum sodium concentration of[10 mmol/L during the first 24 h and[8 mmol/L duringevery 24 h thereafter. (1D)

In moderate or profound hyponatraemia, we suggestchecking the serum sodium concentration every 6 huntil the serum sodium concentration has stabilisedunder stable treatment. (2D)

In case of unresolved hyponatraemia, reconsider thediagnostic algorithm and ask for expert advice. (notgraded)

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3.4.2 Patients with expanded extracellular fluid

We recommend against a treatment with the sole aimof increasing the serum sodium concentration in mildor moderate hyponatraemia. (1C)

We suggest fluid restriction to prevent further fluidoverload. (2D)

We recommend against vasopressin receptor antagonists. (1C)

We recommend against demeclocycline. (1D)

3.4.3 Patients with syndrome of inappropriateantidiuresis

In moderate or profound hyponatraemia, we suggestrestricting fluid intake as first- line treatment. (2D)

In moderate or profound hyponatraemia, we suggest thefollowing can be considered equal second line treatments:increasing solute intake with 0.250.50 g/kg/day of ureaor a combination of low dose loop diuretics and oralsodium chloride. (2D)

In moderate or profound hyponatraemia, we recommendagainst lithium or demeclocycline. (1D)

In moderate hyponatraemia, we do not recommendvasopressin receptor antagonists. (1C)

In profound hyponatraemia, we recommend againstvasopressin receptor antagonists. (1C)

3.4.4 Patients with contracted circulating volume

We recommend restoring extracellular volume withintravenous infusion of 0.9 % saline or a balancedcrystalloid solution at 0.51.0 mL/kg/h. (1B)

Manage patients with haemodynamic instability in anenvironment where close biochemical and clinicalmonitoring can be provided. (not graded)

In case of haemodynamic instability, the need for rapidfluid resuscitation overrides the risk of an overly rapidincrease in serum sodium concentration. (not graded)

Advice for clinical practice

A sudden increase in urine output to[100 mL/h signalsincreased risk of overly rapid rise in serum sodiumconcentration. If vasopressin activity is suddenly sup-pressed, as happens when intravascular volume isrestored in hypovolaemia, free water clearance candramatically increase, resulting in serum sodium con-centrations rising more rapidly than expected. If urineoutput suddenly increases, we would advise measuringthe serum sodium concentration every 2 h until it hasstabilised under stable treatment. The implicit advice tomonitor urine output does not imply we advise abladder catheter solely for this purpose. Most patientswill be able to void spontaneously and collect urine foroutput monitoring.

As a means of increasing solute intake, we suggestdaily intake of 0.250.50 g/kg urea can be used. Thebitter taste can be reduced by combining it with sweettasting substances. The pharmacist may be asked toprepare the following as sachets: urea 10 g ? NaHCO32 g ? citric acid 1.5 g ? sucrose 200 mg, to be dis-solved in 50100 mL water. This will result in a morepalatable, slightly sparkling solution.

3.5 What to do in case hyponatraemia is corrected toorapidly?

We recommend prompt intervention for re-loweringthe serum sodium concentration if it increases[10 mmol/L during the first 24 h or [8 mmol/L inany 24 h thereafter. (1D)

We recommend discontinuing the on-going activetreatment. (1D)

We recommend consulting an expert to discuss if it isappropriate to start an infusion of 10 mL/kg body weight ofelectrolyte-free water (e.g. glucose solutions) over 1 h understrict monitoring of urine output and fluid balance. (1D)

We recommend consulting an expert to discuss if it isappropriate to add intravenous desmopressin 2 lg, withthe understanding that this should not be repeated morefrequently than every 8 h. (1D)

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Clinical practice guideline on diagnosis and treatment of hyponatraemiaAbstractIntroduction and methodologyDiagnosis of hyponatraemiaClassification of hyponatraemiaDefinition of hyponatraemia based on biochemical severityDefinition of hyponatraemia based on time of developmentDefinition of hyponatraemia based on symptoms

Confirming hypotonic and excluding non-hypotonic hyponatraemiaWhich parameters to use for differentiating causes of hypotonic hyponatraemia? (Fig. 1)

Treatment of hypotonic hyponatraemiaHyponatraemia with severe symptomsFirst hour management, regardless of whether hyponatraemia is acute or chronicFollow up management in case of improvement of symptoms after a 5 mmol/L increase in serum sodium concentration in the first hour, regardless of whether hyponatraemia is acute or chronicFollow up management in case of no improvement of symptoms after a 5 mmol/L increase in serum sodium concentration in the first hour, regardless of whether the hyponatraemia is acute or chronic

Hyponatraemia with moderately severe symptomsAcute hyponatraemia without severe or moderately severe symptomsChronic hyponatraemia without severe or moderately severe symptomsGeneral managementPatients with expanded extracellular fluidPatients with syndrome of inappropriate antidiuresisPatients with contracted circulating volume

What to do in case hyponatraemia is corrected too rapidly?

References