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Article ContentsJournal Article Goce Spasovski, 1 State University Hospital Skopje, Skopje, Macedonia Correspondence should be addressed to The Editorial office, European Journal of Endocrinology; Email: Search for other works by this author on: Raymond Vanholder,2 Ghent University Hospital, Ghent, Belgium Search for other works by this author on: Bruno Allolio,3 Würzburg University Hospital, Würzburg, Germany Search for other works by this author on: Djillali Annane,4 Raymond Poincaré Hospital, University of Versailles Saint Quentin, Paris, France Search for other works by this author on: Steve Ball,5 Newcastle Hospitals and Newcastle University, Newcastle, UK Search for other works by this author on: Daniel Bichet,6 Sacré-Coeur Hospital, University of Montreal, Montreal, Quebec, Canada Search for other works by this author on: Guy Decaux,7 Erasmus University Hospital, Brussels, Belgium Search for other works by this author on: Wiebke Fenske,3 Würzburg University Hospital, Würzburg, Germany Search for other works by this author on: Ewout J. Hoorn,8 Erasmus Medical Centre, Rotterdam, The Netherlands Search for other works by this author on: Carole Ichai,9 Nice University Hospital, Nice, France Search for other works by this author on: ... Show moreThe guidelines were peer reviewed by the owner societies and by external referees prior to publication. Author Notes
Published: 25 February 2014
Close Navbar Search Filter Microsite Search Term Search AbstractHyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association – European Dialysis and Transplant Association (ERA–EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice. 1. FOREWORDHyponatraemia is a clinical feature in 15–20% of emergency admissions to hospital. It is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Hyponatraemia is therefore both common and important. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia under widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. However, the paucity of well-designed, prospective studies in the field has limited the evidence-base to these approaches. Previous guidance has often been based on experience or practice, without a systematic approach to evaluation and lacking a clear, patient-centred focus. Clinicians using previous guidance may have noted a number of problems:
Together, these factors have limited the utility of previous advice. Two emerging themes require that we revisit the area:
To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association–European Dialysis and Transplant Association (ERA–EDTA), represented by European Renal Best Practice (ERBP), have developed new guidance on the diagnostic approach and treatment of hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice. 2. COMPOSITION OF THE GUIDELINE DEVELOPMENT GROUPA steering committee with representatives of all the three societies convened in October 2010 and decided on the composition of the Guideline Development Group, taking into account the clinical and research expertise of each proposed candidate. Guideline development group co-chairs Goce Spasovski Consultant Nephrologist, State University Hospital Skopje, Skopje, Macedonia. Raymond Vanholder Consultant Nephrologist, Ghent University Hospital, Ghent, Belgium. Work Group Bruno Allolio Consultant Endocrinologist, Würzburg University Hospital, Würzburg, Germany. Djillali Annane Consultant Intensivist, Raymond Poincaré Hospital, University of Versailles Saint Quentin, Paris, France. Steve Ball Consultant Endocrinologist, Newcastle Hospitals and Newcastle University, Newcastle, UK. Daniel Bichet Consultant Nephrologist, Hospital, Montreal, Canada. Guy Decaux Consultant Internal Medicine, Erasmus University Hospital, Brussels, Belgium. Wiebke Fenske Consultant Endocrinologist, Würzburg University Hospital, Würzburg, Germany. Ewout Hoorn Consultant Nephrologist, Erasmus Medical Centre, Rotterdam, The Netherlands. Carole Ichai Consultant Intensivist, Nice University Hospital, Nice, France. Michael Joannidis Consultant Intensivist, Innsbruck University Hospital, Innsbruck, Austria. Alain Soupart Consultant Internal Medicine, Erasmus University Hospital, Brussels, Belgium. Robert Zietse Consultant Nephrologist, Erasmus Medical Centre, Rotterdam, The Netherlands. ERBP methods support team Maria Haller Specialist Registrar Nephrology, KH Elisabethinen Linz, Linz, Austria. Evi Nagler Specialist Registrar Nephrology, Ghent University Hospital, Ghent, Belgium. Wim Van Biesen Consultant Nephrologist, Chair of ERBP, Ghent University Hospital, Belgium. Sabine van der Veer Implementation Specialist, Amsterdam Medical Centre, Amsterdam, The Netherlands. 3. PURPOSE AND SCOPE OF THIS GUIDELINE3.1. Why was this guideline produced?The purpose of this Clinical Practice Guideline was to provide guidance on the diagnosis and treatment of adult individuals with hypotonic hyponatraemia. It was designed to provide information and assist in decision-making related to this topic. It was not intended to define a standard of care and should not be construed as one. It should not be interpreted as prescribing an exclusive course of management. This guideline was developed as a joint venture of three societies representing specialists with a natural interest in hyponatraemia: the ESICM, the ESE and the ERA–EDTA, represented by ERBP. All three societies agreed that there was a need for guidance on diagnostic assessment and therapeutic management of hyponatraemia. A recent systematic review, which included three clinical practice guidelines and five consensus statements, confirmed the lack of high-quality guidelines in this field [1]. The guidance documents scored low to moderate in the six domains of the AGREEII tool – scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability and editorial independence – and the management strategies proposed in the different guidance documents were sometimes contradictory [2]. 3.2. Who is this guideline for?This guideline was meant to support clinical decision-making for any health care professional dealing with hyponatraemia, i.e. general practitioners, internists, surgeons and other physicians dealing with hyponatraemia in both an outpatient and an in-hospital setting. The guideline was also developed for policymakers for informing standards of care and for supporting the decision-making process. 3.3. What is this guideline about?This section defines what this guideline intended to cover and what the guideline developers considered. The scope was determined at a first meeting held in Barcelona in October 2010 with representatives of ESICM, ESE and ERBP present. 3.3.1. PopulationThe guideline covers hyponatraemia in adults through the biochemical analysis of a blood sample. It does not cover hyponatraemia detected in children because the guideline development group judged that hyponatraemia in children represented a specific area of expertise. The guideline also does not cover screening for hyponatraemia. 3.3.2. ConditionsThe guideline specifically covers diagnosis and management of true hypotonic hyponatraemia. It covers the differentiation of hypotonic hyponatraemia from non-hypotonic hyponatraemia but does not deal with the specific diagnostic and therapeutic peculiarities in the setting of pseudohyponatraemia, isotonic or hypertonic hyponatraemia. These situations are not associated with the hypotonic state responsible for the majority of symptoms attributable to true hypotonic hyponatraemia. The guideline covers diagnosis and management of both acute and chronic hypotonic hyponatraemia in case of reduced, normal and increased extracellular fluid volume. It does not cover the diagnosis or treatment of the underlying conditions that can be associated with hypotonic hyponatraemia. 3.3.3. Health care settingThis guideline targets primary, secondary and tertiary settings dealing with diagnostic testing and the management of hyponatraemia in adults. 3.3.4. Clinical managementThis guideline deals with diagnostic tools for improving accuracy of the differential diagnosis of hypotonic hyponatraemia, allowing more specific treatment strategies tailored to the underlying cause and/or pathophysiological mechanism. This guideline covers the treatment for adults with acute or chronic, symptomatic or asymptomatic hypotonic hyponatraemia, regardless of the underlying condition. 4. METHODS FOR GUIDELINE DEVELOPMENT4.1. Establishment of the guideline development groupThe councils of the three participating societies, ESICM, ESE and ERBP, selected the co-chairs of the guideline development group. The co-chairs then assembled the steering committee with representatives of the three societies involved in this joint venture. This steering committee convened in October 2010 and decided on the composition of the guideline development group, taking into account the clinical and research expertise of the proposed candidates. The guideline development group consisted of content experts, which included individuals with expertise in hyponatraemia, endocrinology, general internal medicine, intensive care medicine and clinical nephrology as well as an expert in systematic review methodology. The ERBP methods support team provided methodological input and practical assistance throughout the guideline development process. 4.2. Developing clinical questionsFrom the final scope of the guideline, specific research questions, for which a systematic review would be conducted, were identified. 4.2.1. Diagnosis and differential diagnosis of hypotonic hyponatraemia
4.2.2. Acute and chronic treatment of hypotonic hyponatraemia
4.3. Development of review questionsThe methods support team assisted in developing review questions, i.e. framing the clinical questions into a searchable format. This required careful specification of the patient group (P), the intervention (I), the comparator (C) and the outcomes (O) for intervention questions and the patient group, index tests, reference standard and target condition for questions of diagnostic test accuracy [3]. For each question, the guideline development group agreed on explicit review question criteria including study design features (See Appendices 1, 2 for Detailed Review Questions and PICO tables. See section on Appendix given at the end of this article). 4.4. Assessment of the relative importance of the outcomesFor each intervention question, the guideline development group compiled a list of outcomes, reflecting both benefits and harms of alternative management strategies. The guideline development group ranked the outcomes as critically, highly or moderately important according to their relative importance in the decision-making process. As such, patient-important health outcomes related to hyponatraemia and the treatment for hyponatraemia were considered critical. Owing to its surrogate nature, the outcomes ‘change in serum sodium concentration’ and ‘correction of serum sodium concentration’ were considered less important than the critically and highly important clinical outcomes (Table 1). Table 1. Hierarchy of outcomes.
Table 1. Hierarchy of outcomes.
4.5. Target population perspectivesAn effort was taken to capture the target population's perspectives by adopting two strategies. First, ERBP has a permanent patient representative in its board. Although he was not included in the guideline development group or in the evidence review process, drafts of the guideline document were sent for his review and his comments were taken into account in revising and drafting the final document. Secondly, the guideline underwent public review before publication. The guideline was sent to the council of two different societies for each specialty involved: for ESICM, the Australian and New Zealand Intensive Care Society (ANZICS) and American Society of Critical Care Medicine (SSCM); for ESE, the Endocrine Society of Australia (ESA) and the Endocrine Society (USA); and for ERBP, the Kidney Health Australia–Caring for Australasians with Renal Impairment (KHA–CARI) and the American Society of Nephrology (ASN). Each of these societies was specifically asked to indicate two to three reviewers. Reviewers could use free text to suggest amendments and/or fill in a matrix questionnaire in Microsoft Excel. All members of the ERA–EDTA received an online questionnaire with a standardised answer form in Microsoft Excel. ERA–EDTA members were asked to express to what extent they judged the individual statements were clear and implementable and to what extent they agreed with the content. In addition, a free text field was provided to allow for additional comments. 4.6. Searching for evidence4.6.1. SourcesThe ERBP methods support team searched The Cochrane Database of Systematic Reviews (May 2011), DARE (May 2011), CENTRAL (May 2011) and MEDLINE (1946 to May, week 4, 2011) for questions on both diagnosis and treatment. To identify the limits for the increase in serum sodium concentration above which the risk of osmotic demyelination starts to rise, we searched MEDLINE database from 1997 onwards under the assumption that earlier reports would describe more dramatic increases and would not contribute to helping us set an upper limit. All searches were updated on 10th December 2012. The search strategies combined subject headings and text words for the patient population, index test and target condition for the diagnostic questions and subject headings and text words for the population and intervention for the intervention questions. The detailed search strategies are available in Appendix 3, see section titled Appendix given at the end of this article. Reference lists from included publications were screened to identify additional papers. The methods support team also searched guideline databases and organisations including the National Guideline Clearinghouse, Guidelines International Network, Guidelines Finder, Centre for Reviews and Dissemination, National Institute for Clinical Excellence, and professional societies of Nephrology, Endocrinology and Intensive Care Medicine for guidelines to screen the reference lists. 4.6.2. SelectionFor diagnostic questions, we included every study that compared any of the predefined clinical or biochemical tests with infusion of 2 l 0.9% saline as a reference test or with an expert panel for differentiating hypovolaemic from euvolaemic hyponatraemia. For questions on treatment strategies, we included every study in which one of the predefined medications was evaluated in humans. We excluded case series that reported on benefit if the number of participants was ≤5 but included even individual case reports if they reported an adverse event. No restriction was made based on language. For identifying the limits for the increase in serum sodium concentration above which the risk of osmotic demyelination starts to rise, we included all observational studies reporting cases of osmotic demyelinating syndrome and corresponding serum sodium concentration correction speeds. A member of the ERBP methods support team screened all titles and abstracts to discard the clearly irrelevant ones. All members of the guideline development group completed a second screening. All abstracts that did not meet the inclusion criteria were discarded. Any discrepancies at this stage were resolved by group consensus. The methods support team retrieved full texts of potentially relevant studies and two reviewers examined them for eligibility independently of each other. The reviewer duos always consisted of one content specialist and one methodologist from the ERBP methods support team. Any discrepancies were resolved by consensus. If no consensus could be reached, the disagreement was settled by group arbitrage. 4.6.3. Data extraction and critical appraisal of individual studiesFor each included study, we collected relevant information on design, conduct and relevant results through standardised data extraction forms in Microsoft Excel (2010). As part of an ongoing process of introducing software to facilitate the guideline development process, the ERBP methods support team used two formats for data extraction and collation. For detailed methods, see Appendices 4, 5, see section titled Appendix given at the end of this article. Briefly, we used both a simple spreadsheet format and a more sophisticated version, which incorporated user forms programmed in Visual Basic. For each question, two reviewers extracted all data independently of each other. We produced tables displaying the data extraction of both reviewers. Both reviewers checked all data independently of each other. Any discrepancies were resolved by consensus and if no consensus could be reached, disagreements were resolved by an independent referee. From these tables, we produced merged consensus evidence tables for informing the recommendations. The evidence tables are available in Appendices 6, 7, see section titled Appendix given at the end of this article. Risk of bias of the included studies was evaluated using various validated checklists, as recommended by the Cochrane Collaboration. These were AMSTAR for Systematic Reviews [4], the Cochrane Risk of Bias tool for randomised controlled trials [5], the Newcastle Ottawa scale for cohort and case–control studies [6] and QUADAS for diagnostic test accuracy studies [7]. Data were compiled centrally by the ERBP methods support team. 4.6.4. Evidence profilesThe evidence for outcomes on therapeutic interventions from included systematic reviews and randomised controlled trials was presented using the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group (http://www.gradeworkinggroup.org/). The evidence profiles include details of the quality assessment as well as summary – pooled or unpooled – outcome data, an absolute measure of intervention effect when appropriate and the summary of quality of evidence for each outcome. Evidence profiles were constructed by the methods support team and reviewed and confirmed with the rest of the guideline development group. Evidence profiles were constructed for research questions addressed by at least two randomised controlled trials. If the body of evidence for a particular comparison of interest consisted of only one randomised controlled trial or of solely observational data, the summary tables provided the final level of synthesis. 4.7. Rating the quality of the evidence for each outcome across studiesIn accordance with GRADE, the guideline development group initially categorised the quality of the evidence for each outcome as high if it originated predominantly from randomised controlled trials and low if it originated from observational data. We subsequently downgraded the quality of the evidence one or two levels if results from individual studies were at serious or very serious risk of bias, there were serious inconsistencies in the results across studies, the evidence was indirect, the data were sparse or imprecise or publication bias thought to be likely. If evidence arose from observational data, but effect sizes were large, there was evidence of a dose–response gradient or all plausible confounding would either reduce a demonstrated effect or suggest a spurious effect when results showed no effect, we would upgrade the quality of the evidence (Table 2). Uncontrolled case series and case reports automatically received downgrading from low to very low level of evidence for risk of bias, so that no other reasons for downgrading were marked. By repeating this procedure, we would obtain an overall quality of the evidence for each outcome and each intervention. For list of definitions, see Table 3. Table 2. Method of rating the quality of the evidence. Adapted from Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011 64 401–406 [240].
Table 2. Method of rating the quality of the evidence. Adapted from Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011 64 401–406 [240].
Table 3. Grade for the overall quality of evidence. Adapted from Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ & GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008 336 924–926 [8].
Table 3. Grade for the overall quality of evidence. Adapted from Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ & GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008 336 924–926 [8].
4.8. Formulating statements and grading recommendations4.8.1. RecommendationsAfter the summary tables were produced and evidence profiles had been prepared, revised and approved by the guideline development group, two full-weekend plenary meetings were held in September 2012 and December 2012 to formulate and grade the recommendations. Recommendations can be for or against a certain strategy. The guideline development group drafted the recommendations based on their interpretation of the available evidence. Judgements around four key factors determined the strength of a recommendation: the balance between desirable and undesirable consequences of alternative therapeutic or diagnostic strategies, the quality of the evidence, the variability in values and preferences. We did not conduct formal decision or cost analysis. In accordance to GRADE, we classified the strength of the recommendations as strong, coded ‘1’ or weak, coded ‘2’ (Table 4; Fig. 1) [8]. Individual statements were made and discussed in an attempt to reach group consensus. If we could not reach consensus, we held a formal open vote by show of hands. An arbitrary 80% had to cast a positive vote for a statement to be accepted. Voting results and reasons for disagreement were specified in the rationale. Table 4. Implications of strong and weak recommendations for stakeholders. Adapted from Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, Schünemann HJ & GRADE Working Group. Going from evidence to recommendations. BMJ 2008 336 1049–1051. The additional category ‘Not Graded’ was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counselling and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements but are not meant to be interpreted as being stronger recommendations than level 1 or 2 recommendations.
Table 4. Implications of strong and weak recommendations for stakeholders. Adapted from Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, Schünemann HJ & GRADE Working Group. Going from evidence to recommendations. BMJ 2008 336 1049–1051. The additional category ‘Not Graded’ was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counselling and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements but are not meant to be interpreted as being stronger recommendations than level 1 or 2 recommendations.
FIGURE 1: Grade system for grading recommendations. Adapted from Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ & GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008 336 924–926. [8] 4.8.2. Ungraded statements and advice for clinical practiceWe decided to use an additional category of ungraded statements for areas where formal evidence was not sought and statements were based on common sense or expert experience alone. They were termed ‘statement’ to differentiate them from graded recommendations and do not hold an indicator for the quality of the evidence. The ungraded statements were generally written as simple declarative statements but were not meant to be stronger than level 1 or 2 recommendations. We also provided additional advice for clinical practice. The advice is not graded and is only for the purpose of improving practical implementation. It contains some elaboration on one of the statements, clarifying how the statement can be implemented in clinical practice. 4.8.3. Optimizing implementationRecommendations often fail to reach implementation in clinical practice partly because of their wording. As part of a research project to evaluate methods for improving guideline development processes, we integrated the GuideLine Implementability Appraisal (GLIA) instrument to optimise the wording of the recommendations [9]. The tool primarily enables structured evaluation of factors such as executability (is it clear from the statement exactly what to do) and decidability (exactly under what conditions) of preliminary recommendations. In addition, the tool is designed to highlight other problems possibly hindering implementation, e.g. recommendations being inconsistent with clinicians' existing beliefs or patients' expectations. The appraisal was done by a panel of target guideline users external to the guideline development group. Comments and remarks were communicated to the guideline development group and used to help refine the recommendations. 4.9. Writing rationaleWe collated recommendations and ungraded statements for each of the clinical questions in separate sections structured according to a specific format. Each question resulted in one or more specific boxed statements. Within each recommendation, the strength was indicated as level 1 or 2 and the quality of the supporting evidence as A, B, C or D as prescribed by the GRADE methodology (Table 4). These statements are followed by advice for clinical practice where relevant and the rationale. The rationale contains a brief section on ‘why this question’ with relevant background and justification of the topic, followed by a short narrative review of the evidence in ‘what did we find’ and finally a justification of how the evidence translated in the recommendations made in ‘how did we translate the evidence into the statement’. When areas of uncertainty were identified, the guideline development group considered making suggestions for future research based on the importance to patients or the population and on ethical and technical feasibility. 4.10. Internal and external review4.10.1. Internal reviewA first draft of the guideline was sent to a selected group of internal reviewers. Each society nominated experts in hyponatraemia and/or members of their governance body. Internal reviewers were asked to complete a grid-based evaluation of overall appreciation of each individual statement, using a score between 1 and 5. These scores were averaged and colour-coded between red [1] and green [5] to help visualise any problematic part. In addition, internal reviewers were asked to comment on the statements and the rationale within free text fields limited to 225 characters. All these comments and suggestions were discussed during an additional meeting of the guideline development group in June 2013. For each comment or suggestion, the guideline development group evaluated whether it was needed to adapt the statement, again taking into account the balance between desirable and undesirable consequences of the alternative management strategies, the quality of the evidence and the variability in values and preferences. 4.10.2. External reviewThe guideline was sent to the ESA and KHA–CARI for review. Reviewers could use free text to suggest amendments and/or fill in a matrix questionnaire in Microsoft Excel. In addition, all members of the ERA–EDTA received an online questionnaire with a standardised answer form in Microsoft Excel. ERA–EDTA members were asked to express to what extent they believed the individual statements were clear, implementable and to what extent they agreed with the content on a scale from 1 to 5. In addition, a free text field was provided to allow for additional comments. All these valid comments and suggestions were discussed with the guideline development group through e-mail and during a final meeting of the co-chairs of the guideline development group, the methods support team and the chair of ERBP. 4.11. Timeline and procedure for updating the guidelineIt was decided to update the guideline at least every 5 years. New evidence requiring additional recommendations or changes to existing statements could instigate an earlier update. At least every 5 years, the ERBP methods support team will update its literature searches. Relevant studies will be identified and their data will be extracted using the same procedure as for the initial guideline. During a 1-day meeting, the guideline development group will decide whether or not the original statements require updating. An updated version of the guideline will be published online accompanied by a position statement in the journals of the three societies describing the changes made. During the 5-year interval, the guideline development group co-chairs will notify the ERBP chair of new information that may justify changes to the existing guideline. Together, they will consult at least one guideline development group member representing each of the collaborating societies. If they decide that an update is needed, an updated version of the guideline will be produced using the same procedures as for the initial guideline. 5. PATHOPHYSIOLOGY OF HYPONATRAEMIA5.1. IntroductionHyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It occurs in up to 30% of hospitalised patients and can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening [10, 11]. Because hyponatraemia can result from a varied spectrum of conditions, based on different mechanisms, we believed that it would be useful to include an introductory section that outlines some of the pathophysiological principles encountered in hyponatraemia. It was not intended to be a detailed reference section. It was only meant to clarify some of the important concepts to enhance understanding of the rationale of the statements in the guideline. Hyponatraemia is primarily a disorder of water balance, with a relative excess of body water compared to total body sodium and potassium content. It is usually associated with a disturbance in the hormone that governs water balance, vasopressin (also called antidiuretic hormone). Even in disorders associated with (renal) sodium loss, vasopressin activity is generally required for hyponatraemia to develop. Therefore, after describing common signs and symptoms, we detail the mechanisms involved in vasopressin release. Changes in serum osmolality are primarily determined by changes in the serum concentration of sodium and its associated anions. It is important to differentiate the concepts of total osmolality and effective osmolality or tonicity. Total osmolality is defined as the concentration of all solutes in a given weight of water (mOsm/kg), regardless of whether or not the osmoles can move across biological membranes. Effective osmolality or tonicity refers to the number of osmoles that contribute water movement between the intracellular and extracellular compartment. It is a function of the relative solute permeability properties of the membranes separating the intracellular and extracellular fluid compartments [12]. Only effective solutes create osmotic pressure gradients across cell membranes leading to osmotic movement of water between the intracellular and extracellular fluid compartment. In most cases, hyponatraemia reflects low effective osmolality or hypotonicity, which causes symptoms of cellular oedema. However, hyponatraemia may also (rarely) occur with isotonic or hypertonic serum if the serum contains many additional osmoles, such as glucose or mannitol. Therefore, we discuss not only how hypo-osmolar but also how isosmolar and hyperosmolar states develop. Finally, we review the pathophysiology of distinct clinical disorders that can cause hyponatraemia. We have categorised the causes of hyponatraemia in those associated with a reduced, normal or increased extracellular fluid volume. Although the clinical assessment of volume status is often difficult in practice, the concept of volume status has proven useful because it provides a simple framework to understand the diagnosis and treatment of hypo-osmolar disorders. 5.2. Clinical featuresSymptoms can vary from mild, non-specific to severe and life-threatening (Table 5). Severe symptoms of hyponatraemia are caused by brain oedema and increased intracranial pressure. Brain cells start to swell when water moves from the extracellular to the intracellular compartment because of a difference in effective osmolality between brain and plasma. This usually occurs when hyponatraemia develops rapidly, and the brain has had too little time to adapt to its hypotonic environment. Over time, the brain reduces the number of osmotically active particles within its cells (mostly potassium and organic solutes) in an attempt to restore the brain volume (Fig. 2). This process takes ∼24–48 h, hence the reason for using the 48-h threshold to distinguish acute (<48 h) from chronic (≥48 h) hyponatraemia. Table 5. Classification of symptoms of hyponatraemia. The guideline development group wants to underscore that these symptoms can also be induced by other conditions. Clinical and anamnestic data should be taken into account when assessing the causal relationship between hyponatraemia and a certain symptom (i.e. to assess whether the symptom has been caused by hyponatraemia or hyponatraemia by the underlying condition/symptom). The less pronounced (e.g. mild) the biochemical degree of hyponatraemia, the more caution should be taken when considering that hyponatraemia is the cause of the symptoms. This list is not exhaustive, and all symptoms that can be signs of cerebral oedema should be considered as severe or moderate symptoms that can be caused by hyponatraemia.
Table 5. Classification of symptoms of hyponatraemia. The guideline development group wants to underscore that these symptoms can also be induced by other conditions. Clinical and anamnestic data should be taken into account when assessing the causal relationship between hyponatraemia and a certain symptom (i.e. to assess whether the symptom has been caused by hyponatraemia or hyponatraemia by the underlying condition/symptom). The less pronounced (e.g. mild) the biochemical degree of hyponatraemia, the more caution should be taken when considering that hyponatraemia is the cause of the symptoms. This list is not exhaustive, and all symptoms that can be signs of cerebral oedema should be considered as severe or moderate symptoms that can be caused by hyponatraemia.
FIGURE 2: Adaptation of the brain to hypotonicity. Reproduced with permission from Massachusetts Medical Society, Copyright © 2000 Adrogue HJ & Madias NE. Hyponatremia. New England Journal of Medicine 2000 342 1581–1589. Although the more severe signs of acute hyponatraemia are well established, it is now increasingly clear that even patients with chronic hyponatraemia and no apparent symptoms can have subtle clinical abnormalities when analysed in more detail. Such abnormalities include gait disturbances, falls, concentration and cognitive deficits [13]. In addition, patients with chronic hyponatraemia more often have osteoporosis and more frequently sustain bone fractures than normonatraemic persons [14, 15, 16]. Finally, hyponatraemia is associated with an increased risk of death [17, 18]. Whether these are causal associations or merely symptoms of underlying problems such as heart or liver failure remains unclear [19]. 5.3. Regulation of water intake and homeostasisAs the serum sodium concentration is determined by the amount of extracellular water relative to the amount of sodium, it can be regulated by changing intake or output of water. The major mechanisms responsible for regulating water metabolism are thirst and the pituitary secretion and renal effects of vasopressin. Regulation of body water serves to minimise osmotically induced disruptions in cell volume with adverse effects on multiple cellular functions. Osmoreceptive neurons located in the anterior hypothalamus detect changes in cell stretch due to changes in systemic effective osmolality. A decrease in cell stretch increases the firing rate of osmoreceptive neurons, which leads to both increased thirst and increased release of vasopressin from the pituitary gland. Vasopressin in turn increases the re-absorption of water from the primitive urine in the distal tubules of the nephron, which leads to urine that is more concentrated. To prevent persistent thirst, the threshold for releasing vasopressin is lower than that for triggering thirst (Fig. 3) [12]. FIGURE 3: Osmotic stimulation of vasopressin release. Schematic representation of normal physiological relationships among plasma osmolality, plasma AVP concentrations, urine osmolality and urine volume in man. Note particularly the inverse nature of the relationship between urine osmolality and urine volume, resulting in disproportionate effects of small changes in plasma AVP concentrations on urine volume at lower AVP levels. Reproduced with permission from Elsevier Copyright © 2003 Verbalis JG. Disorders of body water homeostasis. Best Practice & Research. Clinical Endocrinology & Metabolism 2003 17 471–503. 5.3.1. Osmoregulation and vasopressin releaseUnder normal circumstances, osmotic regulation of the release of vasopressin from the posterior pituitary primarily depends on the effective osmolality of the serum. Central osmoreceptors, expressing transient receptor potential vanilloid 1 (TRPV1), and peripheral osmoreceptors, expressing TRPV4, relay the information on osmolality [20, 21]. The stretch-inactivating cationic TRPV1 and TRPV4 channels transduce osmotically evoked changes in cell volume into functionally relevant changes in membrane potential. TRPV1 is an osmotically activated channel expressed in the vasopressin producing magnocellular cells and in the circumventricular organs [22, 23]. Recently, afferent neurons expressing the osmotically activated ion channel TRPV4 (able to detect physiological hypo-osmotic shifts in blood osmolality) have been identified in the thoracic dorsal root ganglia, which innervate hepatic blood vessels [21]. 5.3.2. Baroregulation of vasopressin releaseStretch-sensitive receptors in the left atrium, carotid sinus and aortic arch sense circulating volume. When the circulating volume is increased, afferent neural impulses inhibit the secretion of vasopressin [12]. Conversely, when the volume is decreased, the discharge rate of the stretch receptors slows and vasopressin secretion increases [24]. Reductions in blood pressure as little as 5% increase the serum vasopressin concentration [25]. In addition, there seems to be an exponential association between the serum vasopressin concentration and the percentage decline in mean arterial blood pressure, with faster increases as blood pressure progressively decreases. Because osmoregulated and baroregulated vasopressin secretion are interdependent, renal water excretion can be maintained around a lower set point of osmolality under conditions of moderately decreased circulating volume [26]. As the circulatory hypovolaemia worsens, the serum vasopressin concentration dramatically increases and baroregulation overrides the osmoregulatory system. Osmosensitive neurons are located in the subfornical organ and the organum vasculosum of the lamina terminalis. Because these neurons lie outside the blood–brain barrier, they integrate osmotic information with endocrine signals borne by circulating hormones, such as angiotensin II and atrial natriuretic peptide. The direct angiotensin II effect on osmoregulatory neurons has been termed ‘osmoregulatory gain’ since Zhang et al. [27] have shown that in rats, angiotensin II amplifies osmosensory transduction by enhancing the proportional relationship between osmolality, receptor potential and action potential firing in supra-optic nucleus neurons. Modifications in osmoregulatory gain induced by angiotensin, together with changes in vasopressin secretion induced by baroregulation (see below), may explain why the changes in the slope and threshold of the relationship between serum osmolality and vasopressin secretion are potentiated by hypovolaemia or hypotension and are attenuated by hypervolaemia or hypertension (Fig. 4) [28]. FIGURE 4: Effects of hypovolaemia on osmoreceptor gain. Reproduced with permission from The Endocrine Society Copyright © 1976 Robertson GL & Athar S. The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man. Journal of Clinical Endocrinology and Metabolism 1976 42 613–620. 5.3.3. Unregulated vasopressin releaseThe posterior pituitary is the only organ in which regulated vasopressin release takes place. Under pathological conditions, both pituitary and other cells may also synthesise and secrete vasopressin independent of serum osmolality or circulating volume. Originally, Schwartz & Bartter [29] introduced the term syndrome of inappropriate antidiuretic hormone secretion (SIADH) as an overarching term. We now know that both genetic and pharmacological factors can also increase water permeability in the collecting duct in the absence of vasopressin. Others have previously introduced the term syndrome of inappropriate antidiuresis (SIAD) to cover both situations. We will use it throughout this text. 5.3.4. Renal actions of vasopressinIn order to re-absorb water from the collecting duct, and to concentrate the urine, the collecting duct must become permeable to water. The basolateral membrane is always permeable to water because of aquaporin-3 and aquaporin-4 water channels. Vasopressin regulates the permeability of the apical membrane by insertion of aquaporin-2 water channels through vasopressin-2-receptor activation. The high osmolality of the medulla provides the driving force needed for re-absorption of water from the collecting duct. Thanks to the counter current configuration of the loops of Henle, the kidney is able to create solute gradients from the cortex to the inner medulla. Because of the re-absorption of both sodium and urea from the lumen, the osmolality of the tip of the medulla may reach 1200 mOsm/l in case of water depletion. The medullary osmolality determines maximum urine osmolality and is influenced by vasopressin. 5.4. PseudohyponatraemiaPseudohyponatraemia is a laboratory artefact that occurs when abnormally high concentrations of lipids or proteins in the blood interfere with the accurate measurement of sodium. Pseudohyponatraemia was seen more frequently with flame photometric measurement of serum sodium concentration than it is now with ion-selective electrodes, but despite common opinion to the contrary, it still occurs [30], because all venous blood samples are diluted and a constant distribution between water and the solid phase of serum is assumed when the serum sodium concentration is calculated [30] (Fig. 5). Serum osmolality is measured in an undiluted sample and the result will be within the normal range in case of pseudohyponatraemia. If the measurement of serum osmolality is not available, direct potentiometry using a blood gas analyser will yield the true sodium concentration, as this measures the sodium concentration in an undiluted sample too. FIGURE 5: Pseudohyponatraemia. Normally, serum contains 7% solids by volume. In order to reduce the volume of blood needed for analysis, serum is frequently diluted before the actual measurement is obtained. The same volume of diluent is always used; the degree of dilution is estimated under the assumption that the serum contains 7% solid-phase particles. When the fraction of solid-phase particles is increased, the same amount of diluent results in a greater dilution, unbeknownst to the laboratory personnel (right side of figure). Consequently, the calculation of an ion level with the use of a degree of dilution that is based on the incorrect fraction of solid-phase particles will lead to an underestimate. Reproduced with permission from Massachusetts Medical Society Copyright © 2003 Turchin A, Seifter JL & Seely EW. Clinical problem-solving. Mind the gap. New England Journal of Medicine 2003 349 1465–1469. 5.5. Reset osmostatIn reset osmostat, there is a change in the set point as well as in the slope of the osmoregulation curve [12]. The response to changes in osmolality remains intact. We see this phenomenon, for example, in pregnancy where the serum sodium concentration may mildly decrease 4–5 mmol/l. 5.6. Non-hypotonic hyponatraemia5.6.1. Isotonic hyponatraemiaIn the majority of patients that present with hyponatraemia, the serum is hypotonic, i.e. both the sodium concentration and the effective osmolality are low. Sometimes, the serum contains additional osmoles that increase effective osmolality and reduce the serum sodium concentration by attracting water from the intracellular compartment. Examples of such osmoles include glucose (hyperglycaemia due to uncontrolled diabetes mellitus), mannitol and glycine (absorption of irrigation fluids during urological or gynaecological surgery) [31, 32, 33]. The resulting ‘translocational’ hyponatraemia is often wrongly considered a form of pseudohyponatraemia. However, as described earlier, in pseudohyponatraemia, serum osmolality is normal and no shifts of water occur. 5.6.2. Hypertonic hyponatraemiaIn hyperglycaemia-induced hyponatraemia, hyponatraemia is caused by dilution due to hyperosmolality. It is important to make the distinction between measured osmolality and effective osmolality [34]. Effective osmolality may be calculated with the following equations: Effective osmolality (mmol/kg H2O) = 2 × (serum Na (mmol/l) + serum K (mmol))+ serum glycaemia (mg/dl)/18 Effective osmolality (mmol/kg H2O) = 2 × (serum Na (mmol/l)+ serum K (mmol/l)) + serum glycaemia (mmol/l) This includes only osmoles that are restricted to the extracellular fluid volume. As water returns to the intracellular space during treatment of hyperglycaemia, serum sodium concentration should increase, thus resulting in a constant effective osmolality. If it does not, brain oedema may ensue due to an overly rapid drop in effective osmolality [35]. 5.6.3. Ineffective osmolesHigh urea concentrations in kidney disease may also increase measured osmolality. However, urea is not an effective osmole because it readily passes across the cellular membrane. It does not change effective osmolality, does not attract water to the extracellular fluid compartment and does not cause hyponatraemia [36]. 5.7. Hypotonic hyponatraemia with decreased extracellular fluid volumeDepletion of circulating volume, with or without deficit of total body sodium, can markedly increase the secretion of vasopressin leading to water retention despite hypotonicity. Although the vasopressin release in this case is inappropriate from an osmoregulatory point of view, it happens in order to preserve intravascular volume and can be considered appropriate from a circulatory point of view. 5.7.1. Non-renal sodium loss5.7.1.1. Gastrointestinal sodium lossVolume depletion can occur if the body loses sodium through its gastrointestinal tract. In case of severe diarrhoea, the kidneys respond by preserving sodium and urine sodium concentrations are very low. In case of vomiting, metabolic alkalosis causes renal sodium loss as sodium accompanies bicarbonate in the urine despite activation of the renin–angiotensin system. By contrast, in patients with diarrhoea, chloride accompanies ammonium excreted by the kidneys in an effort to prevent metabolic acidosis. 5.7.1.2. Transdermal sodium lossThe body can lose substantial amounts of sodium transdermally due to heavy sweating. This may be caused by impaired re-absorption of sodium in the sweat duct as in cystic fibrosis or by an impaired natural barrier function due to extensive skin burns. It results in increased vulnerability to sodium depletion and volume depletion. The amount of sodium that is lost in sweat varies markedly between healthy individuals, but to date, no link has been found between the sodium concentration in sweat and cystic fibrosis-causing mutations of the cystic fibrosis transmembrane conductance regulator gene [37]. 5.7.2. Renal sodium loss5.7.2.1. DiureticsUrinary sodium loss can cause volume depletion and, if sufficiently severe, trigger vasopressin release. Diuretics and especially thiazides are frequently implicated as a cause of hyponatraemia. The traditional explanation is that renal sodium loss leads to volume contraction with subsequent release of vasopressin. However, this would require a substantial loss of sodium and body weight, while patients with thiazide-induced hyponatraemia often have increased body weight [38]. It might be reasonable to assume that thiazides directly induce the release of vasopressin or increase the response of the collecting duct to circulatory vasopressin. In any case, there appears to be an individual susceptibility to these effects, as hyponatraemia only occurs in certain patients and usually reoccurs if thiazides are reintroduced [38]. Despite the potential for causing more urinary sodium loss, loop diuretics only rarely cause hyponatraemia because they reduce osmolality in the renal medulla and thus limit the kidney's ability to concentrate urine [39]. 5.7.2.2. Primary adrenal insufficiencyIn primary adrenal insufficiency, hypoaldosteronism causes renal sodium loss, contracted extracellular fluid volume and hyponatraemia. Although primary adrenal insufficiency usually presents in combination with other clinical symptoms and biochemical abnormalities, hyponatraemia can be its first and only sign [40]. 5.7.2.3. Cerebral salt wastingRenal sodium loss has been documented in patients with intracranial disorders such as subarachnoid bleeding. This renal salt wasting has been rather confusingly named ‘cerebral’ salt wasting, and increased levels of brain natriuretic peptide have been implicated in its pathogenesis [41]. Because diagnosis may be difficult, and both inappropriate antidiuresis and secondary adrenal insufficiency are actually more common in this clinical setting, cerebral salt wasting may be over diagnosed [42]. Nevertheless, the recognition of cerebral salt wasting is important because its treatment requires volume resuscitation rather than water restriction. 5.7.2.4. Kidney diseaseRenal salt wasting can also occur in kidney dysfunction. The so-called salt-losing nephropathies, such as tubulopathy after chemotherapy or in analgesic nephropathy, medullary cystic kidney disease and certain pharmacological compounds can inhibit the kidney's ability to re-absorb appropriate amounts of sodium [43]. 5.7.3. Third spacingBowel obstruction, pancreatitis, sepsis or muscle trauma may markedly reduce effective circulating blood volume through fluid leakage from blood vessels. This causes baroreceptor activation and vasopressin release, which may result in hyponatraemia. Infusion of hypotonic fluids in this case may worsen hyponatraemia. 5.8. Hypotonic hyponatraemia with normal extracellular fluid volumeEuvolaemic hyponatraemia is caused by an absolute increase in body water, which results from an excessive fluid intake in the presence of an impaired free water excretion, either due to inappropriate release of vasopressin or due to a low intake of solutes. 5.8.1. Syndrome of inappropriate antidiuresisThe vasopressin secretion in SIADH is inappropriate because it occurs independently from effective serum osmolality or circulating volume. It may result from increased release by the pituitary gland or from ectopic production. Inappropriate antidiuresis may also result from increased activity of vasopressin in the collecting duct or from a gain-of-function mutation in its type 2 receptor [44]. Throughout this text, we will use the terminology ‘SIAD’ as an overarching term because management principles are the same for both conditions and any distinction is merely academic and out of the scope of this document [45]. In SIAD, antidiuresis causes progressive hyponatraemia until the expression of vasopressin V2 receptors and aquaporin-2 water channels is down-regulated, a process appropriately called ‘vasopressin escape’ [46]. Because of the vasopressin activity, urine osmolality will be inappropriately high (usually >100 mOsm/l) and this is one of the criteria required for a diagnosis of SIAD. The criteria are largely the same as originally proposed by Bartter & Schwartz [29]. Importantly, SIAD remains a diagnosis of exclusion (Table 6). Table 6. Diagnostic criteria for the syndrome of inappropriate antidiuresis. Adapted from Schwartz WB, Bennett W, Curelop S & Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. American Journal of Medicine 1957 23 529–542 [29] and Janicic N & Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinology and Metabolism Clinics of North America 2003 32 459–481, vii [242].
Table 6. Diagnostic criteria for the syndrome of inappropriate antidiuresis. Adapted from Schwartz WB, Bennett W, Curelop S & Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. American Journal of Medicine 1957 23 529–542 [29] and Janicic N & Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinology and Metabolism Clinics of North America 2003 32 459–481, vii [242].
General anaesthesia, nausea, pain, stress and a variety of drugs are non-specific but potent stimuli for the secretion of vasopressin and a frequent cause of SIAD in hospitalised patients. The use of prescribed or illicit drugs may result in either increased vasopressin release or increased effects of vasopressin in the collecting duct. The most frequent causes of increased inappropriate secretion of vasopressin include cancers (e.g. small cell carcinoma of the lung) and diseases of the lung (e.g. pneumonia) or central nervous system (e.g. subarachnoid haemorrhage) (Table 7). Recently, several genetic disorders causing SIAD have been identified. Among them are polymorphisms resulting in a loss-of-function of TRPV4, a gene that encodes for an osmosensitive calcium channel expressed in osmosensing neurons [47]. Another is a gain-of-function mutation in the vasopressin 2 receptor, resulting in a constitutively activated receptor causing increased water re-absorption and chronic hyponatraemia [44]. Table 7. Causes of the syndrome of inappropriate antidiuresis. Adapted from Liamis G, et al. American Journal of Kidney Diseases 2008 52 144–153 [247].
AIDS, acquired immunodeficiency syndrome; MOAI, monoamine oxidase inhibitors; MDMA, 3,4-methylenedioxymethamphetamine; NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors. Table 7. Causes of the syndrome of inappropriate antidiuresis. Adapted from Liamis G, et al. American Journal of Kidney Diseases 2008 52 144–153 [247].
AIDS, acquired immunodeficiency syndrome; MOAI, monoamine oxidase inhibitors; MDMA, 3,4-methylenedioxymethamphetamine; NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors. 5.8.2. Secondary adrenal insufficiencyThe production of aldosterone is less impaired in secondary than in primary adrenal insufficiency and renal sodium loss does not contribute to the development of hyponatraemia. Secondary adrenal insufficiency is caused by reduced or absent secretion of adrenocorticotrophic hormone, resulting in hypocortisolism. Under normal circumstances, cortisol suppresses both production of corticotrophin-releasing hormone and vasopressin in the hypothalamus. In secondary adrenal insufficiency, persistently low concentrations of cortisol fail to suppress vasopressin and hyponatraemia results from impaired free water excretion, as it does in SIAD [48]. 5.8.3. HypothyroidismAlthough included in many diagnostic algorithms, hypothyroidism very rarely causes hyponatraemia [49]. In 2006, Warner et al. [50] observed that serum sodium concentration decreased by 0.14 mmol/l for every 10 mU/l rise in thyroid-stimulating hormone, indicating that only severe cases of clinically manifest hypothyroidism resulted in clinically important hyponatraemia. Development of hyponatraemia may be related to myxoedema, resulting from a reduction in cardiac output and glomerular filtration rate [51]. 5.8.4. High water and low solute intakeUnder conditions of high water and low solute intake, the excess water intake is primarily responsible for hyponatraemia. Vasopressin activity is absent, which is reflected by an appropriately low urine osmolality, usually <100 mOsm/kg. Patients with primary polydipsia drink more than what the kidneys can eliminate. Primary polydipsia may occur in combination with psychiatric disorders such as schizophrenia. Although excess water intake contributes most to hyponatraemia, renal loss of solutes and an acquired impairment in free water excretion may also occur [52]. The amount of water that the kidneys can remove on a daily basis depends on solute excretion and hence solute intake. Depending on the kidney's ability to dilute urine, 50–100 mmol of solutes, such as urea and salts, are required to remove 1 l of fluid. If solute intake is low relative to water intake, the number of available osmoles can be insufficient to remove the amount of water ingested. This is seen in patients with anorexia (nervosa), beer potomania and so-called ‘tea and toast’ hyponatraemia [53]. 5.9. Hypotonic hyponatraemia with increased extracellular fluid volume5.9.1. Kidney diseaseWhen glomerular filtration rate deteriorates, or when there is tubular injury or scarring, the ability to dilute urine and excrete free water decreases. In advanced kidney disease, urine osmolality is usually close to serum osmolality (isosthenuria). Free water removal is no longer regulated by vasopressin but is determined by the number of osmoles excreted in the urine (i.e. solute intake). Consequently, hyponatraemia can readily develop if patients do not adhere to fluid restriction. In addition, in patients treated with peritoneal dialysis, the use of icodextrin-based dialysis solutions can cause clinically relevant hyponatraemia [54]. 5.9.2. Heart failureApproximately 20–30% of patients with chronic heart failure New York Heart Association (NYHA) classes III and IV have hyponatraemia [55]. It is associated with more severe heart failure and an increased risk of death, independent of other comorbid conditions [55, 56]. Whether this reflects (unacknowledged) disease severity or has a causal effect remains unclear. Although renal sodium retention tends to increase the extracellular volume, the effective circulating blood volume is generally reduced due to impaired cardiac output. Baroreceptor-mediated neurohumoral activation commonly results in increased secretion of vasopressin by the pituitary. Simultaneous activation of the renin–angiotensin system and increased release of vasopressin reduces urinary sodium excretion and increases urine osmolality. Although simultaneous use of diuretics may contribute to the development of hyponatraemia, loop diuretics have less potential for causing hyponatraemia than thiazides. 5.9.3. Liver failureAlso in liver failure, hyponatraemia is associated with poorer survival [57]. Whether this reflects disease severity or has a direct contributory effect remains unclear [58]. Systemic vasodilation and arteriovenous shunting of blood may reduce the effective arterial blood volume. As in heart failure, this reduction can lead to neurohumoral activation and water retention due to baroreceptor-mediated vasopressin release. In addition, mineralocorticoid receptor blockers such as spironolactone, which either alone or in combination with loop diuretics, are frequently used to reduce sodium retention in liver failure, can contribute to hyponatraemia [59]. 5.9.4. Nephrotic syndromeIn nephrotic syndrome, blood volume may be decreased due to the lower serum oncotic pressure (under-fill hypothesis). If this happens, stimulation of vasopressin secretion can cause patients to develop hyponatraemia. The tendency for water retention is generally balanced by intense sodium retention, but the increased renal re-absorption of sodium usually necessitates a considerable dose of diuretics. The combination of increased vasopressin release and diuretic use may promote moderate hyponatraemia, especially in children with low blood pressure [60]. 6. DIAGNOSIS OF HYPONATRAEMIA6.1. Classification of hyponatraemia6.1.1. Definition of hyponatraemia based on biochemical severity6.1.1.1. We define ‘mild’ hyponatraemia as a biochemical finding of a serum sodium concentration between 130 and 135 mmol/l as measured by ion-specific electrode. 6.1.1.2. We define ‘moderate’ hyponatraemia as a biochemical finding of a serum sodium concentration between 125 and 129 mmol/l as measured by ion-specific electrode. 6.1.1.3. We define ‘profound’ hyponatraemia as a biochemical finding of a serum sodium concentration <125 mmol/l as measured by ion-specific electrode. 6.1.2. Definition of hyponatraemia based on time of development6.1.2.1. We define ‘acute’ hyponatraemia as hyponatraemia that is documented to exist <48 h. 6.1.2.2. We define ‘chronic’ hyponatraemia as hyponatraemia that is documented to exist for at least 48 h. 6.1.2.3. If hyponatraemia cannot be classified, we consider it being chronic, unless there is clinical or anamnestic evidence of the contrary (Table 8). Table 8. Drugs and conditions associated with acute hyponatraemia (<48 h).
Table 8. Drugs and conditions associated with acute hyponatraemia (<48 h).
6.1.3. Definition of hyponatraemia based on symptoms6.1.3.1. We define ‘moderately symptomatic’ hyponatraemia as any biochemical degree of hyponatraemia in the presence of moderately severe symptoms of hyponatraemia (Table 5). 6.1.3.2. We define ‘severely symptomatic’ hyponatraemia as any biochemical degree of hyponatraemia in the presence of severe symptoms of hyponatraemia (Table 5). Rationale
Table 9. Association between serum glucose concentration, measured serum sodium and corrected serum sodium concentration. Calculated using equation from Hillier TA, Abbott RD & Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. American Journal of Medicine 1999 106 399–403 [31].
Table 9. Association between serum glucose concentration, measured serum sodium and corrected serum sodium concentration. Calculated using equation from Hillier TA, Abbott RD & Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. American Journal of Medicine 1999 106 399–403 [31].
Questions for future research
6.2. Confirming hypotonic and excluding non-hypotonic hyponatraemia6.2.1.1. We recommend excluding hyperglycaemic hyponatraemia by measuring the serum glucose concentration and correcting the measured serum sodium concentration for the serum glucose concentration if the latter is increased (1D). 6.2.1.2. Hyponatraemia with a measured osmolality <275 mOsm/kg always reflects hypotonic hyponatraemia (not graded). 6.2.1.3. Accept as ‘hypotonic hyponatraemia’ a hyponatraemia without evidence for causes of non-hypotonic hyponatraemia as listed in Table 10 (not graded). Table 10. Causes of non-hypotonic hyponatraemia.
Table 10. Causes of non-hypotonic hyponatraemia.
Advice for clinical practice Estimates of the serum sodium concentration corrected for the presence of hyperglycaemia can be obtained from the following equations [31]: $$\eqalign{& {\rm Corrected}\,{\rm serum\, (Na}^{\rm+} {\rm )} \cr & \quad {\rm=measured}\,{\rm (Na}^{\rm+} {\rm )+2}{\rm .4} \cr & \quad \quad \times \displaystyle{{({\rm glucose\,(mg/dl) - 100\,(mg/dl)})} \over {100\,{\rm mg/dl}}}}$$ $$\eqalign{& {\rm Corrected\, (Na}^{\rm+} {\rm )} \cr & \quad {\rm=measured}\,{\rm (Na}^{\rm+} {\rm )+2}{\rm .4} \cr & \quad \quad \times \displaystyle{{({\rm glucose\,(mg/dl) - 5}{\rm .5\,(mmol/l)})} \over {{\rm 5}{\rm .5}\,{\rm mmol/l}}}}$$ Na+, serum sodium concentration; glucose, serum glucose concentration. This translates into adding 2.4 mmol/l to the measured serum sodium concentration for every 5.5 mmol/l (100 mg/dl) incremental rise in serum glucose concentration above a standard serum glucose concentration of 5.5 mmol/l (100 mg/dl). Alternatively, the estimated value of the corrected serum sodium concentration across a range of serum glucose concentrations can be obtained from Table 9. Rationale
Questions for future research
6.3. Which parameters to be used for differentiating causes of hypotonic hyponatraemia?6.3.1.1. We recommend interpreting urine osmolality of a spot urine sample as a first step (1D). 6.3.1.2. If urine osmolality is ≤100 mOsm/kg, we recommend accepting relative excess water intake as a cause of the hypotonic hyponatraemia (1D). 6.3.1.3. If urine osmolality is >100 mOsm/kg, we recommend interpreting the urine sodium concentration on a spot urine sample taken simultaneously with a blood sample (1D). 6.3.1.4. If urine sodium concentration is ≤30 mmol/l, we suggest accepting low effective arterial volume as a cause of the hypotonic hyponatraemia (2D). 6.3.1.5. If urine sodium concentration is >30 mmol/l, we suggest assessing extracellular fluid status and use of diuretics to further differentiate likely causes of hyponatraemia (2D). 6.3.1.6. We suggest against measuring vasopressin for confirming the diagnosis of SIADH (2D). Advice for clinical practice
Rationale
Table 11. Differences between SIADH and cerebral salt wasting. Adapted from Sherlock M, O'Sullivan E, Agha A, Behan LA, Rawluk D, Brennan P, Tormey W & Thompson CJ. The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clinical Endocrinology 2006 64 250–254 [42].
Table 11. Differences between SIADH and cerebral salt wasting. Adapted from Sherlock M, O'Sullivan E, Agha A, Behan LA, Rawluk D, Brennan P, Tormey W & Thompson CJ. The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clinical Endocrinology 2006 64 250–254 [42].
FIGURE 6: Algorithm for the diagnosis of hyponatraemia. Questions for future research
7. TREATMENT OF HYPOTONIC HYPONATRAEMIAHow to use the treatment recommendations The advice provided in this section follows a specific hierarchy as illustrated in Fig. 7. Individual recommendations and statements can only be correctly interpreted and implemented if considered within this structure. This is a consequence of the choice to use different classifications for hyponatraemia, as explained in section 6.1. FIGURE 7: Algorithm for the management of hypotonic hyponatraemia. The guideline development group believed that with severe or moderately severe symptoms, the risk of brain oedema outweighs the risk of osmotic demyelination syndrome. They believed that it justifies urgent treatment in these conditions, irrespective of biochemical degree or timing (acute vs chronic) of hyponatraemia. Conversely, the guideline development group believed that in the absence of severe or moderately severe symptoms, there is time for diagnostic assessment and cause-specific treatment is the most reasonable approach. For a correct interpretation of the algorithm in question, it is crucial to understand that for correctly classifying symptoms as ‘severe’ or ‘moderately severe’, there must be sufficient confidence that the symptoms are caused by hyponatraemia. If hyponatraemia is mild and symptoms are severe or moderately severe (Table 5), the guideline development group advises to only accept causality in exceptional cases. Consequently, generally, sections 7.1, 7.2 and 7.3 are not applicable when hyponatraemia is mild. It is also essential to understand that the guideline development group distinguishes between targets and limits. A target is a goal one is aiming for; it is the change in serum sodium concentration that one wishes and expects to achieve with a particular treatment. By contrast, a limit is a change in serum sodium concentration one does not want to exceed and if surpassed, requires prompt counter-regulating intervention as described in section 7.5. In addition, the reader should bear in mind that the absolute numbers provided as ‘targets’ or ‘limits’ should always be interpreted in the clinical context of the individual patient. 7.1. Hyponatraemia with severe symptoms7.1.1. First-hour management, regardless of whether hyponatraemia is acute or chronic7.1.1.1. We recommend prompt i.v. infusion of 150 ml 3% hypertonic over 20 min (1D). 7.1.1.2. We suggest checking the serum sodium concentration after 20 min while repeating an infusion of 150 ml 3% hypertonic saline for the next 20 min (2D). 7.1.1.3. We suggest repeating therapeutic recommendations 7.1.1.1 and 7.1.1.2 twice or until a target of 5 mmol/l increase in serum sodium concentration is achieved (2D). 7.1.1.4. Manage patients with severely symptomatic hyponatraemia in an environment where close biochemical and clinical monitoring can be provided (not graded). 7.1.2. Follow-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 chronic7.1.2.1. We recommend stopping the infusion of hypertonic saline (1D). 7.1.2.2. We recommend keeping the i.v. line open by infusing the smallest feasible volume of 0.9% saline until cause-specific treatment is started (1D). 7.1.2.3. We recommend starting a diagnosis-specific treatment if available, aiming at least to stabilise sodium concentration (1D). 7.1.2.4. We recommend limiting the increase in serum sodium concentration to a total of 10 mmol/l during the first 24 h and an additional 8 mmol/l during every 24 h thereafter until the serum sodium concentration reaches 130 mmol/l (1D). 7.1.2.5. We suggest checking the serum sodium concentration after 6 and 12 h and daily afterwards until the serum sodium concentration has stabilised under stable treatment (2D). 7.1.3. Follow-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 hyponatraemia is acute or chronic7.1.3.1. We recommend continuing an i.v. infusion of 3% hypertonic saline or equivalent aiming for an additional 1 mmol/l per h increase in serum sodium concentration (1D). 7.1.3.2. We recommend stopping the infusion of 3% hypertonic saline or equivalent when the symptoms improve, the serum sodium concentration increases 10 mmol/l in total or the serum sodium concentration reaches 130 mmol/l, whichever occurs first (1D). 7.1.3.3. We recommend additional diagnostic exploration for other causes of the symptoms than hyponatraemia (1D). 7.1.3.4. We suggest checking the serum sodium concentration every 4 h as long as an i.v. infusion of 3% hypertonic saline or equivalent is continued (2D). Advice for clinical practice $${\rm change}\,{\rm in}\,{\rm serum\, (Na}^{\rm+} {\rm )=}\displaystyle{{{\rm infusate\, (Na}^{\rm+} {\rm ) - serum\,(Na}^{\rm+} {\rm )}} \over {{\rm total}\,{\rm body}\,{\rm water}+1}}$$ $$\eqalign{& \hskip -8pt {\rm change}\,{\rm in}\,{\rm serum\, (Na}^{\rm+} {\rm )} \cr & \quad {\rm=}\displaystyle{{{\rm infusate\, (Na}^{\rm+} {\rm )+infusate\, (K}^{\rm+} {\rm ) - serum\,(Na}^{\rm+} {\rm )}} \over {{\rm total}\,{\rm body}\,{\rm water}+1}}}$$
Na+, sodium concentration (mmol/l); K+, potassium concentration (mmol/l). The numerator in formula 1 is a simplification of the expression in formula 2, with the value yielded by the equation (mmol/l). The estimated total body water (l) is calculated as a fraction of body weight. The fraction is 0.6 in non-elderly men and 0.5 in non-elderly women and 0.5 and 0.45 in elderly men and women respectively. Normally, extracellular and intracellular fluids account for 40 and 60% of total body water respectively. Rationale
Suggestions for future research
7.2. Hyponatraemia with moderately severe symptoms7.2.1.1. We recommend starting prompt diagnostic assessment (1D). 7.2.1.2. Stop, if possible, medications and other factors that can contribute to or provoke hyponatraemia (not graded). 7.2.1.3. We recommend cause-specific treatment (1D). 7.2.1.4. We suggest immediate treatment with a single i.v. infusion of 150 ml 3% hypertonic saline or equivalent over 20 min (2D). 7.2.1.5. We suggest aiming for a 5 mmol/l per 24-h increase in serum sodium concentration (2D). 7.2.1.6. We suggest limiting the increase in serum sodium concentration to 10 mmol/l in the first 24 h and 8 mmol/l during every 24 h thereafter, until a serum sodium concentration of 130 mmol/l is reached (2D). 7.2.1.7. We suggest checking the serum sodium concentration after 1, 6 and 12 h (2D). 7.2.1.8. We suggest additional diagnostic exploration for other causes of the symptoms if the symptoms do not improve with an increase in serum sodium concentration (2D). 7.2.1.9. We suggest considering to manage the patient as in severely symptomatic hyponatraemia if the serum sodium concentration further decreases despite treating the underlying diagnosis (2D). Rationale
Suggestions for future research None. 7.3. Acute hyponatraemia without severe or moderately severe symptoms7.3.1.1. Make sure that the serum sodium concentration has been measured using the same technique used for the previous measurement and that no administrative errors in sample handling have occurred (not graded). 7.3.1.2. If possible, stop fluids, medications and other factors that can contribute to or provoke hyponatraemia (not graded). 7.3.1.3. We recommend starting prompt diagnostic assessment (1D). 7.3.1.4. We recommend cause-specific treatment (1D). 7.3.1.5. If the acute decrease in serum sodium concentration exceeds 10 mmol/l, we suggest a single i.v. infusion of 150 ml 3% hypertonic saline or equivalent over 20 min (2D). 7.3.1.6. We suggest checking the serum sodium concentration after 4 h, using the same technique as used for the previous measurement (2D). Rationale
Suggestions for future research Prospective, large-scale, registration-based data collection to facilitate impact evaluation of the proposed management strategy on end-points of clinical response and overcorrection rate. 7.4. Chronic hyponatraemia without severe or moderately severe symptoms7.4.1. General management7.4.1.1. Stop non-essential fluids, medications and other factors that can contribute to or provoke hyponatraemia (not graded). 7.4.1.2. We recommend cause-specific treatment (1D). 7.4.1.3. In mild hyponatraemia, we suggest against treatment with the sole aim of increasing the serum sodium concentration (2C). 7.4.1.4. In moderate or profound hyponatraemia, we recommend avoiding an increase in serum sodium concentration of >10 mmol/l during the first 24 h and >8 mmol/l during every 24 h thereafter (1D). 7.4.1.5. In moderate or profound hyponatraemia, we suggest checking the serum sodium concentration every 6 h until the serum sodium concentration has stabilised under stable treatment (2D). 7.4.1.6. In case of unresolved hyponatraemia, reconsider the diagnostic algorithm and ask for expert advice (not graded). 7.4.2. Patients with expanded extracellular fluid7.4.2.1. We recommend against a treatment with the sole aim of increasing the serum sodium concentration in mild or moderate hyponatraemia (1C). 7.4.2.2. We suggest fluid restriction to prevent further fluid overload (2D). 7.4.2.3. We recommend against vasopressin receptor antagonists (1C). 7.4.2.4. We recommend against demeclocycline (1D). 7.4.3. Patients with SIAD7.4.3.1. In moderate or profound hyponatraemia, we suggest restricting fluid intake as first-line treatment (2D). 7.4.3.2. In moderate or profound hyponatraemia, we suggest the following can be considered equal second-line treatments: increasing solute intake with 0.25–0.50 g/kg per day of urea or a combination of low-dose loop diuretics and oral sodium chloride (2D). 7.4.3.3. In moderate or profound hyponatraemia, we recommend against lithium or demeclocycline (1D). 7.4.3.4. In moderate hyponatraemia, we do not recommend vasopressin receptor antagonists (1C). 7.4.3.5. In profound hyponatraemia, we recommend against vasopressin receptor antagonists (1C). 7.4.4. Patients with reduced circulating volume7.4.4.1. We recommend restoring extracellular volume with i.v. infusion of 0.9% saline or a balanced crystalloid solution at 0.5–1.0 ml/kg per h (1B). 7.4.4.2. Manage patients with haemodynamic instability in an environment where close biochemical and clinical monitoring can be provided (not graded). 7.4.4.3. In case of haemodynamic instability, the need for rapid fluid resuscitation overrides the risk of an overly rapid increase in serum sodium concentration (not graded). Advice for clinical practice
Rationale
Suggestions for future research More high-quality randomised, head-to-head comparison trial data for all potential treatments using longer term health outcomes such as death, quality of life and cognitive function. 7.5. What to do if hyponatraemia is corrected too rapidly?7.5.1.1. We recommend prompt intervention for re-lowering the serum sodium concentration if it increases >10 mmol/l during the first 24 h or >8 mmol/l in any 24 h thereafter (1D). 7.5.1.2. We recommend discontinuing the ongoing active treatment (1D). 7.5.1.3. We recommend consulting an expert to discuss if it is appropriate to start an infusion of 10 ml/kg body weight of electrolyte-free water (e.g. glucose solutions) over 1 h under strict monitoring of urine output and fluid balance (1D). 7.5.1.4. We recommend consulting an expert to discuss if it is appropriate to add i.v. desmopressin 2 µg, with the understanding that this should not be repeated more frequently than every 8 h (1D). Rationale
Suggestions for future research
8. DECLARATION OF INTERESTWe required all participants in the guideline development group to fill out a detailed ‘Declaration of interest’ including all the current and future conflicts of interest as well as past interest restricted to the 2 years before joining the guideline development process. Because it was judged that excluding every individual with some degree of potential conflict of interest would make assembling a guideline development group impossible, we allowed members of the guideline development group to have past financial and/or intellectual conflicts of interest. We did not attach any consequences to the stated interests, but rather insisted on transparency. All members of the guideline development group were allowed to participate in all the discussions and have equal weight in formulating the statements. All were allowed equal involvement in data extraction and writing the rationales. The declaration of interest forms are available from www.european-renal-best-practice.org/content/Joint-workgroup-hyponatraemia and are updated on a regular basis. 9. FUNDINGThe three participating societies sponsored the production of this guideline. ESE provided an unrestricted grant to cover part of the costs to develop the guideline. The spent amount underwent regular scrutiny by the executive committee of ESE. The ESICM is a scientific society that operates under the leadership of its executive committee and its council. Both structures organise, regulate and control the scientific and educational activities of the society. Statutes and detailed standard operating procedures can be found on the ESICM website (www.esicm.org). ESICM receives funding through membership fees and revenues from its congresses, courses, educational ventures and journals. Activities of ERBP and its methods support team are supervised by an advisory board (see www.european-renal-best-practice.org for details and Declaration of interest). ERBP is an independent part of ERA–EDTA. The council of ERA–EDTA approves and provides the annual budget based on a proposition made by the chair of ERBP. ERA–EDTA receives money and is partly funded by industrial partners, but its council is not involved with and does not interfere with topic choice, question development or any other part of the guideline development process. Neither the societies nor the guideline development group received any funds directly from industry to produce this guideline. AcknowledgementsWe would like to express our sincerest gratitude to Benaya Rozen-Zvi, Dafna Yahav, Mihai Georghiade, Asher Korzets, Leonard Leibovici and Uzi Gafter for sharing the data used in their systematic review on vasopressin receptor antagonists for the treatment of hyponatraemia. We would also like to thank Veerle Liébaut for assisting in conceptualizing and programming the data extraction tool. They would like to acknowledge the members of the Cochrane Renal Group for their methodological advice and support throughout the process: Jonathan Craig, Angela Webster, Narelle Willis, An Jones, Gail Higgins and Ruth Mitchell. A special note of gratitude goes to the people involved in appraising the implementability of preliminary statements: Luis Coentrão, Dave Dongelmans, Bruno Lapauw, Georg Lehner, Alberto Ortiz, Adalbert Schiller, Airin Simon, Vladimir Tesar and Dirk Weisman. The generous gift of their time and dedication was greatly appreciated. We are convinced it contributed to the clarity and ultimately to the overall quality of the guideline. We would like to acknowledge all internal reviewers for taking the time to critically read the drafts of this document and to provide us with their comments: Volker Burst, Peter Gross, Franciszek Kokot, Miles Levy, Paul Marik, Dermot Neely, Jean-Christophe Orban, Yvo Sijpkens, Steven Van Laecke, Jill Vanmassenhove, Bernar Vigué and Jack Wetzels. We strongly believe that it has contributed to the quality of the guideline and has helped maximize its practical value. Finally, we gratefully acknowledge the careful assessment of the draft guideline by external reviewers. The guideline development group considered all the valuable comments made and, where appropriate, we incorporated suggested changes in the final document. Co-publication The guidelines will be co-published in Nephrology Dialysis Transplantation and Intensive Care Medicine. AppendixAppendices are available online at http://ndt.oxfordjournals.org. References1 , , , , , , . Diagnosis and treatment of hyponatraemia: a systematic review of clinical practice guidelines. Nephrology, Dialysis , Transplantation , 2013 , vol. 28 (pg. i385 - i391 ) 2 , , , , , , , , , , et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare , Canadian Medical Association Journal , 2010 , vol. 182 (pg. E839 - E842 ) 3 , , . Asking the right question and finding the right answers , Nephrology , 2010 , vol. 15 (pg. 8 - 11 ) 4 , , , , , , , , , . Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews , BMC Medical Research Methodology , 2007 , vol. 710 5 , , . , . Assessing risk of bias in included studies , Cochrane Handbook for Systematic Reviews of Interventions , 2011 (Ch 8, Version 5.1.0. The Cochrane Collaboration) 6 , , , , , , . The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Department of Epidemiology and Community Medicine, University of Ottawa, Canada. Retrieved from: www.ohri.ca/programs/clinical_epidemiology/oxford.asp 7 , , , . QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies , Annals of Internal Medicine , 2011 , vol. 155 (pg. 529 - 536 ) 8 , , , , , , . GRADE Working Group GRADE: an emerging consensus on rating quality of evidence and strength of recommendations , BMJ , 2008 , vol. 336 (pg. 924 - 926 ) 9 , , , , , , . The GuideLine Implementability Appraisal (GLIA): development of an instrument to identify obstacles to guideline implementation , BMC Medical Informatics and Decision Making , 2005 (pg. 523 - 30 ) 10 , , , . Novel risk factors for hospital-acquired hyponatraemia: a matched case–control study , Clinical Endocrinology , 2007 , vol. 66 (pg. 367 - 372 ) 11 , , . Epidemiology of hyponatremia , Seminars in Nephrology , 2009 , vol. 29 (pg. 227 - 238 ) 12 . Disorders of body water homeostasis. Best Practice & Research , Clinical Endocrinology & Metabolism , 2003 , vol. 17 (pg. 471 - 503 ) 13 , , , , . Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits , American Journal of Medicine , 2006 , vol. 119 (pg. 71.e1 - 71.e8 ) 14 , , , , . Mild hyponatremia and risk of fracture in the ambulatory elderly , QJM: Monthly Journal of the Association of Physicians , 2008 , vol. 101 (pg. 583 - 588 ) 15 , , , , , , , , , . Mild hyponatremia as a risk factor for fractures: the Rotterdam Study , Journal of Bone and Mineral Research , 2011 , vol. 26 (pg. 1822 - 1828 ) 16 , , , , , , . Hyponatremia-induced osteoporosis , Journal of Bone and Mineral Research , 2010 , vol. 25 (pg. 554 - 563 ) 17 , , , , , . Electrolyte disorders in community subjects: prevalence and risk factors , American Journal of Medicine , 2013 , vol. 126 (pg. 256 - 263 ) 18 , , , , . Impact of hospital-associated hyponatremia on selected outcomes , Archives of Internal Medicine , 2010 , vol. 170 (pg. 294 - 302 ) 19 , . Hyponatremia and mortality: moving beyond associations , American Journal of Kidney Diseases , 2013 , vol. 62 (pg. 139 - 149 ) 20 . Central mechanisms of osmosensation and systemic osmoregulation. Nature Reviews , Neuroscience , 2008 , vol. 9 (pg. 519 - 531 ) 21 , , , , , , , , , . The molecular and cellular identity of peripheral osmoreceptors , Neuron , 2011 , vol. 69 (pg. 332 - 344 ) 22 , , , . An N-terminal variant of Trpv1 channel is required for osmosensory transduction , Nature Neuroscience , 2006 , vol. 9 (pg. 93 - 98 ) 23 , . Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality , Journal of Neuroscience , 2006 , vol. 26 (pg. 9069 - 9075 ) 24 . Influence of low- and high-pressure baroreflexes on vasopressin release in humans , Acta Endocrinologica , 1989 , vol. 121 (Suppl 1) (pg. 3 - 27 ) 25 . Posterior pituitary function in health and disease , Clinics in Endocrinology and Metabolism , 1983 , vol. 12 (pg. 747 - 770 ) 26 . Thirst and vasopressin function in normal and disordered states of water balance , Journal of Laboratory and Clinical Medicine , 1983 , vol. 101 (pg. 351 - 371 ) 27 , . Amplification of transducer gain by angiotensin II-mediated enhancement of cortical actin density in osmosensory neurons , Journal of Neuroscience , 2008 , vol. 28 (pg. 9536 - 9544 ) 28 , . The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man , Journal of Clinical Endocrinology and Metabolism , 1976 , vol. 42 (pg. 613 - 620 ) 29 , , , . A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone , American Journal of Medicine , 1957 , vol. 23 (pg. 529 - 542 ) 30 , , . Clinical problem-solving. Mind the gap , New England Journal of Medicine , 2003 , vol. 349 (pg. 1465 - 1469 ) 31 , , . Hyponatremia: evaluating the correction factor for hyperglycemia , American Journal of Medicine , 1999 , vol. 106 (pg. 399 - 403 ) 32 , , , . Hyperosmolality with hyponatremia, caused by inappropriate administration of mannitol , American Journal of Medicine , 1967 , vol. 42 (pg. 648 - 650 ) 33 . Serum osmolality and plasma electrolytes in patients who develop dilutional hyponatremia during transurethral resection , Canadian Journal of Surgery , 1970 , vol. 13 (pg. 116 - 121 ) 34 , , , . Tonicity balance, and not electrolyte-free water calculations, more accurately guides therapy for acute changes in natremia , Intensive Care Medicine , 2001 , vol. 27 (pg. 921 - 924 ) 35 , , , , , , , . Preventing a drop in effective plasma osmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis , Journal of Pediatrics , 2007 , vol. 150 (pg. 467 - 473 ) 36 , . Hyponatremia, hyposmolality, and hypotonicity: tables and fables , Archives of Internal Medicine , 1999 , vol. 159 (pg. 333 - 336 ) 37 , , , , . Low abundance of sweat duct Cl− channel CFTR in both healthy and cystic fibrosis athletes with exceptionally salty sweat during exercise. American Journal of Physiology , Regulatory, Integrative and Comparative Physiology , 2011 , vol. 300 (pg. R605 - R615 ) 38 , , , . Thiazide-induced hyponatremia Reproducibility by single dose rechallenge and an analysis of pathogenesis , Annals of Internal Medicine , 1989 , vol. 110 (pg. 24 - 30 ) 39 , , . Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients , Chest , 1993 , vol. 103 (pg. 601 - 606 ) 40 . Addison's disease in Africa – a teaching hospital experience , Clinical Endocrinology , 1999 , vol. 50 (pg. 115 - 120 ) 41 , , , , , , , , . Secretion of brain natriuretic peptide in patients with aneurysmal subarachnoid haemorrhage , Lancet , 1997 , vol. 349 (pg. 245 - 249 ) 42 , , , , , , , . The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage , Clinical Endocrinology , 2006 , vol. 64 (pg. 250 - 254 ) 43 , , , , , . Cisplatin-induced renal salt wasting syndrome , Southern Medical Journal , 2010 , vol. 103 (pg. 793 - 799 ) 44 , , , , , , , , , . Nephrogenic syndrome of inappropriate antidiuresis , New England Journal of Medicine , 2005 , vol. 352 (pg. 1884 - 1890 ) 45 , . Clinical practice. The syndrome of inappropriate antidiuresis , New England Journal of Medicine , 2007 , vol. 356 (pg. 2064 - 2072 ) 46 . Whole-body volume regulation and escape from antidiuresis , American Journal of Medicine , 2006 , vol. 119 (pg. S21 - S29 ) 47 , , , , , , , , , . A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia , PNAS , 2009 , vol. 106 (pg. 14034 - 14039 ) 48 , . Beyond semantics: defining hyponatremia in secondary adrenal insufficiency , Journal of Endocrinological Investigation , 2006 , vol. 29 (pg. 267 - 269 ) 49 . Disorders of sodium balance: hypothyroidism and hyponatraemia: an old wives' tale? , BMJ , 2006 , vol. 332 pg. 854 50 , , . The effect of newly diagnosed hypothyroidism on serum sodium concentrations: a retrospective study , Clinical Endocrinology , 2006 , vol. 64 (pg. 598 - 599 ) 51 . Hyponatremia in primary myxedema , Annals of Internal Medicine , 1956 , vol. 44 (pg. 376 - 385 ) 52 , , . Solute loss plays a major role in polydipsia-related hyponatraemia of both water drinkers and beer drinkers , QJM: Monthly Journal of the Association of Physicians , 2003 , vol. 96 (pg. 421 - 426 ) 53 , , . “Beer potomania” in non-beer drinkers: effect of low dietary solute intake , American Journal of Kidney Diseases , 1998 , vol. 31 (pg. 1028 - 1031 ) 54 , , . Peritoneal dialysis: new developments and new problems , Diabetic Medicine , 2001 , vol. 18 (pg. 360 - 363 ) 55 , , , , , , , , , . Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry , European Heart Journal , 2007 , vol. 28 (pg. 980 - 988 ) 56 , , , , , , , , , . Hyponatremia and long-term mortality in survivors of acute ST-elevation myocardial infarction , Archives of Internal Medicine , 2006 , vol. 166 (pg. 781 - 786 ) 57 , , , , , , , . Hyponatremia and mortality among patients on the liver-transplant waiting list , New England Journal of Medicine , 2008 , vol. 359 (pg. 1018 - 1026 ) 58 , . Hyponatremia and mortality: how innocent is the bystander? , Clinical Journal of the American Society of Nephrology , 2011 , vol. 6 (pg. 951 - 953 ) 59 , , , , , . Appropriateness and complications of the use of spironolactone in patients treated in a heart failure clinic , European Journal of Internal Medicine , 2011 , vol. 22 (pg. 424 - 427 ) 60 , , , . Hypovolemia and hypovolemic shock in children with nephrotic syndrome , Acta Paediatrica Taiwanica , 2000 , vol. 41 (pg. 179 - 183 ) 61 , , . Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management , Nephrology, Dialysis, Transplantation , 2006 , vol. 21 (pg. 70 - 76 ) 62 , , . Mortality after hospitalization with mild, moderate, and severe hyponatremia , American Journal of Medicine , 2009 , vol. 122 (pg. 857 - 865 ) 63 , , , , . Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes , American Journal of Kidney Diseases , 2012 , vol. 59 (pg. 222 - 228 ) 64 . Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases , Annals of Internal Medicine , 1987 , vol. 107 (pg. 656 - 664 ) 65 , , , , , , . Characteristics and mortality of severe hyponatraemia – a hospital-based study , Clinical Endocrinology , 2006 , vol. 65 (pg. 246 - 249 ) 66 , , . Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes , Medicine , 1976 , vol. 55 (pg. 121 - 129 ) 67 , , . Lesson of the week: acute hyponatraemia in children admitted to hospital: retrospective analysis of factors contributing to its development and resolution , BMJ , 2001 , vol. 322 (pg. 780 - 782 ) 68 , , , , , , , , , . Prognostic consequences of borderline dysnatremia: pay attention to minimal serum sodium change , Critical Care , 2013 , vol. 17 pg. R12 69 , , , , , , . Incidence and prognosis of dysnatremias present on ICU admission , Intensive Care Medicine , 2010 , vol. 36 (pg. 304 - 311 ) 70 , , , , , , . Fluctuations in serum sodium level are associated with an increased risk of death in surgical ICU patients , Critical Care Medicine , 2013 , vol. 41 (pg. 133 - 142 ) 71 , , , , , . The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical – surgical intensive care units , Critical Care , 2008 , vol. 12 pg. R162 72 , . Central pontine myelinolysis , Mayo Clinic Proceedings , 2001 , vol. 76 (pg. 559 - 562 ) 73 . Hyponatremia, convulsions, respiratory arrest permanent brain damage after elective surgery in healthy women , New England Journal of Medicine , 1986 , vol. 314 (pg. 1529 - 1535 ) 74 , , . Postoperative hyponatremic encephalopathy in menstruant women , Annals of Internal Medicine , 1992 , vol. 117 (pg. 891 - 897 ) 75 , , , , . Predictors of outcome in hospitalized patients with severe hyponatremia , Journal of the National Medical Association , 2003 , vol. 95 (pg. 335 - 343 ) 76 , , . Hyponatraemia and death or permanent brain damage in healthy children , BMJ , 1992 , vol. 304 (pg. 1218 - 1222 ) 77 , , , . Adaptive responses to sustained volume expansion in hyponatraemic rats , Journal of Endocrinology , 1989 , vol. 122 (pg. 421 - 431 ) 78 , . Hyponatremia causes large sustained reductions in brain content of multiple organic osmolytes in rats , Brain Research , 1991 , vol. 567 (pg. 274 - 282 ) 79 , . Brain volume regulation in response to hypo-osmolality and its correction , American Journal of Medicine , 2006 , vol. 119 (pg. S12 - S16 ) 80 , , , . Volume regulatory loss of Na, Cl, and K from rat brain during acute hyponatremia , American Journal of Physiology , 1987 , vol. 252 (pg. F661 - F669 ) 81 , , . Brain dehydration and neurologic deterioration after rapid correction of hyponatremia , Kidney International , 1989 , vol. 35 (pg. 69 - 75 ) 82 , . Neurological and neuropathological sequelae of correction of chronic hyponatremia , Kidney International , 1991 , vol. 39 (pg. 1274 - 1282 ) 83 , , , . Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study , Journal of Clinical Investigation , 1995 , vol. 95 (pg. 788 - 793 ) 84 , . Hyponatremia revisited: translating physiology to practice. Nephron , Physiology , 2008 , vol. 108 (pg. 46 - 59 ) 85 , , , , . Biochemical and etiological characteristics of acute hyponatremia in the emergency department , Journal of Emergency Medicine , 2005 , vol. 29 (pg. 369 - 374 ) 86 . Treating hyponatremia: why haste makes waste , Southern Medical Journal , 1994 , vol. 87 (pg. 1283 - 1287 ) 87 , . Hyponatremia , New England Journal of Medicine , 2000 , vol. 342 (pg. 1581 - 1589 ) 88 , , . Diagnostic approach to a patient with hyponatraemia: traditional versus physiology-based options , QJM: Monthly Journal of the Association of Physicians , 2005 , vol. 98 (pg. 529 - 540 ) 89 , , , . Clinical assessment of extracellular fluid volume in hyponatremia , American Journal of Medicine , 1987 , vol. 83 (pg. 905 - 908 ) 90 , , . The rational clinical examination. Is this patient hypovolemic? , Journal of the American Medical Association , 1999 , vol. 281 (pg. 1022 - 1029 ) 91 , . Body fluid dynamics: back to the future , Journal of the American Society of Nephrology , 2011 , vol. 22 (pg. 2166 - 2181 ) 92 , , , , . Posttransurethral prostatic resection hyponatremic syndrome: case report and review of the literature , American Journal of Kidney Diseases , 1984 , vol. 4 (pg. 80 - 84 ) 93 , , , , . Hyperammonemia after transurethral resection of the prostate: a report of 2 cases , Journal of Urology , 1984 , vol. 132 (pg. 995 - 997 ) 94 , , , , . Fatal cerebral oedema in adult diabetic ketoacidosis , Netherlands Journal of Medicine , 2010 , vol. 68 (pg. 35 - 37 ) 95 , , , , . Pseudohyponatremia in multiple myeloma , Klinische Wochenschrift , 1980 , vol. 58 (pg. 875 - 880 ) 96 , , . Intravenous immune globulin and pseudohyponatremia , New England Journal of Medicine , 1998 , vol. 339 pg. 632 97 , , , , , . Milky plasma, diabetes, and severe hyponatremia , Kidney International , 2009 , vol. 75 pg. 996 98 , , . Direct ion-selective electrode method is useful in diagnosis of pseudohyponatremia , Journal of Emergency Medicine , 2012 , vol. 43 (pg. 348 - 349 ) 99 , , , . Sodium measurements in multiple myeloma: two techniques compared , Clinical Chemistry , 1982 , vol. 28 (pg. 2383 - 2386 ) 100 , , , . Sodium measurement: effects of differing sampling and analytical methods , Annals of Clinical Biochemistry , 2006 , vol. 43 (pg. 488 - 493 ) 101 , . Sodium , Lancet , 1998 , vol. 352 (pg. 220 - 228 ) 102 , , . Hyponatraemia , Clinical Endocrinology , 2000 , vol. 52 (pg. 667 - 678 ) 103 , , , , , . Combined fractional excretion of sodium and urea better predicts response to saline in hyponatremia than do usual clinical and biochemical parameters , American Journal of Medicine , 1995 , vol. 99 (pg. 348 - 355 ) 104 , , , , . Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study , American Journal of Medicine , 2010 , vol. 123 (pg. 652 - 657 ) 105 , , , , . Hyponatremia in psychogenic polydipsia , Archives of Internal Medicine , 1980 , vol. 140 (pg. 1639 - 1642 ) 106 , , , , , . The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer , Journal of Clinical Oncology , 1986 , vol. 4 (pg. 1191 - 1198 ) 107 , , , , , , . Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics , Journal of Clinical Endocrinology and Metabolism , 2008 , vol. 93 (pg. 2991 - 2997 ) 108 , . Utility and limitations of biochemical parameters in the evaluation of hyponatremia in the elderly , International Urology and Nephrology , 2001 , vol. 32 (pg. 475 - 493 ) 109 , . Diagnostic value of urine sodium concentration in hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion versus hypovolemia , Hawaii Medical Journal , 2010 , vol. 69 (pg. 264 - 267 ) 110 , , , , , . Copeptin in the differential diagnosis of hyponatremia , Journal of Clinical Endocrinology and Metabolism , 2009 , vol. 94 (pg. 123 - 129 ) 111 , , , . Thiazide-induced syndrome of inappropriate secretion of antidiuretic hormone. Time course of resolution , Journal of the American Medical Association , 1981 , vol. 246 (pg. 1235 - 1236 ) 112 . Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy , New England Journal of Medicine , 1988 , vol. 319 (pg. 1127 - 1134 ) 113 , . Beer potomania: an unusual cause of symptomatic hyponatremia , Annals of Emergency Medicine , 1986 , vol. 15 (pg. 745 - 747 ) 114 . Hyponatremia in adrenal insufficiency: review of pathogenetic mechanisms , Southern Medical Journal , 1982 , vol. 75 (pg. 581 - 585 ) 115 , . Adrenal insufficiency , Lancet , 2003 , vol. 361 (pg. 1881 - 1893 ) 116 , , , . Quiz page November: an unusual case of acute hyponatremia and normal anion gap metabolic acidosis , American Journal of Kidney Diseases , 2012 , vol. 60 (pg. xxxiii - xxxvi ) 117 , , . Misinterpretation of serum cortisol in a patient with hyponatraemia , BMJ , 2004 , vol. 328 (pg. 215 - 216 ) 118 , , , , . Severe hyponatremia with high urine sodium and osmolality , Clinical Chemistry , 2009 , vol. 55 (pg. 1905 - 1908 ) 119 , . Treatment of hyponatraemic seizures with intravenous 29.2% saline , BMJ , 1986 , vol. 292 (pg. 168 - 170 ) 120 , , . Rapid correction of severe hyponatremia with intravenous hypertonic saline solution , American Journal of Medicine , 1982 , vol. 72 (pg. 43 - 48 ) 121 , , , . Performance characteristics of a sliding-scale hypertonic saline infusion protocol for the treatment of acute neurologic hyponatremia , Neurocritical Care , 2009 , vol. 11 (pg. 228 - 234 ) 122 , , , , , . Hypertonic saline for hyponatremia: risk of inadvertent overcorrection , Clinical Journal of the American Society of Nephrology , 2007 , vol. 2 (pg. 1110 - 1117 ) 123 , , . Treatment of dilutional hyponatremia in congestive heart failure , Acta Medica Scandinavica , 1980 , vol. 207 (pg. 279 - 281 ) 124 , . Treating the syndrome of inappropriate ADH secretion with isotonic saline , QJM: Monthly Journal of the Association of Physicians , 1998 , vol. 91 (pg. 749 - 753 ) 125 , , , . Quantitative treatment of the hyponatremia of cirrhosis , Digestive and Liver Disease , 2005 , vol. 37 (pg. 176 - 180 ) 126
, , . Evaluation of a protocol for hypertonic saline administration in acute euvolemic symptomatic hyponatremia: a prospective observational trial , Indian Journal of Critical Care Medicine , 2010 , vol. 14 (pg. 170 - 174 ) 127 , , , , . Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia , American Journal of Kidney Diseases , 2013 , vol. 61 (pg. 571 - 578 ) 128 , . Management of severe hyponatremia: rapid or slow correction? , American Journal of Medicine , 1990 , vol. 88 (pg. 161 - 166 ) 129 , , , . Osmotic demyelination syndrome , BMJ , 2005 , vol. 331 (pg. 829 - 830 ) 130 , . A patient with severe hyponatremia and hypokalemia: osmotic demyelination following potassium repletion , American Journal of Kidney Diseases , 2010 , vol. 55 (pg. 742 - 748 ) 131 , . A trident in the brain, central pontine myelinolysis , Practical Neurology , 2009 , vol. 9 (pg. 231 - 232 ) 132 , , , . Cortical MRI findings associated with rapid correction of hyponatremia , Neurology , 2000 , vol. 55 (pg. 1048 - 1051 ) 133 , , , , . Extrapontine myelinolysis after correction of hyponatremia , Annales Françaises d'Anesthésie-Réanimation , 2006 , vol. 25 (pg. 76 - 77 ) 134 , , , , . Osmotic demyelination syndrome with two-phase movement disorders: case report , Changgeng Yi Xue Za Zhi , 1998 , vol. 21 (pg. 526 - 530 ) 135 , , , , , . “Man-in-the-barrel” syndrome as delayed manifestation of extrapontine and central pontine myelinolysis: beneficial effect of intravenous immunoglobulin , Journal of Neurological Sciences , 2005 , vol. 237 (pg. 103 - 106 ) 136 , , , , . Osmotic myelinolysis following chronic hyponatremia corrected at an overall rate consistent with current recommendations , International Urology and Nephrology , 2005 , vol. 37 (pg. 171 - 173 ) 137 , , . Central pontine myelinolysis following ‘optimal’ rate of correction of hyponatraemia with a good clinical outcome , Annals of Clinical Biochemistry , 2007 , vol. 44 (pg. 488 - 490 ) 138 , , . Central pontine myelinolysis in a previously healthy 4-year-old child with acute rotavirus gastroenteritis , Pediatrics , 1997 , vol. 99 (pg. 738 - 743 ) 139 , , , , . Ocular motor and imaging abnormalities of midbrain dysfunction in osmotic demyelination syndrome , Journal of Neuro-Ophthalmology , 2009 , vol. 29 (pg. 296 - 299 ) 140 , , , , . Best cases from the AFIP: osmotic demyelination syndrome , Radiographics , 2009 , vol. 29 (pg. 933 - 938 ) 141 , . Extrapontine myelinolysis in a patient following correction of hyponatremia , Acta Neurologica Belgica , 2007 , vol. 16 (pg. 188 - 189 ) 142 , , , , , . Late occurrence of severe hyponatremia followed by extrapontine osmotic demyelination syndrome after successful conservative management of postpartum hemorrhage due to placenta accreta by uterine artery embolization , Journal of Maternal–Fetal & Neonatal Medicine , 2010 , vol. 23 (pg. 742 - 746 ) 143 , , , . Severe hyponatraemia secondary to beer potomania complicated by central pontine myelinolysis , International Journal of Clinical Practice , 1998 , vol. 52 (pg. 585 - 587 ) 144 , , , . Central pontine myelinolysis: delayed changes on neuroimaging , Journal of Neuroimaging , 2000 , vol. 10 (pg. 169 - 172 ) 145 , . Myelinolysis after correction of hyponatremia , Annals of Internal Medicine , 1997 , vol. 126 (pg. 57 - 62 ) 146 , . Central pontine myelinolysis and hyponatremia , Clinical case. Revista Medica de Chile , 2001 , vol. 129 (pg. 427 - 432 ) 147 , , , , , . Central and extrapontine myelinolysis in a patient in spite of a careful correction of hyponatremia , Clinical Nephrology , 2001 , vol. 55 (pg. 248 - 253 ) 148 , . Extrapontine myelinolysis after correction of hyponatremia presenting as generalized tonic seizures , American Journal of Emergency Medicine , 2008 , vol. 26 (pg. 632.e635 - 632.e636 ) 149 , , , . Osmotic demyelination syndrome after correction of chronic hyponatremia with normal saline , American Journal of the Medical Sciences , 2002 , vol. 323 (pg. 259 - 262 ) 150 , , , , , . Efficacy of clozapine in a non-schizophrenic patient with psychogenic polydipsia and central pontine myelinolysis , Human Psychopharmacology , 2002 , vol. 17 (pg. 253 - 255 ) 151 , . Extra pontine myelinolysis in a tetraplegic patient: case report , Spinal Cord , 1997 , vol. 35 (pg. 332 - 334 ) 152 , , , , . Extrapontine myelinolysis with parkinsonism after rapid correction of hyponatremia: high cerebrospinal fluid level of homovanillic acid and successful dopaminergic treatment , Journal of Neural Transmission , 1999 , vol. 106 (pg. 949 - 953 ) 153 , , . Central pontine and extrapontine myelinolysis: from epileptic and other manifestations to cognitive prognosis , Journal of Neurology , 2010 , vol. 257 (pg. 1176 - 1180 ) 154 , , , , , , . Confusional syndrome in a patient with severe hyponatremia , Revista Clínica Española , 2008 , vol. 208 (pg. 49 - 51 ) 155 , , , , , . Amelioration of extrapontine myelinolysis and reversible parkinsonism in a patient with asymptomatic hypopituitarism , Internal Medicine , 2005 , vol. 44 (pg. 739 - 742 ) 156 , , , , , , , . Case seminar: a young female with acute hyponatremia and a sellar mass , Endocrine , 2011 , vol. 40 (pg. 325 - 331 )
157 , , , , , . Central pontine and extrapontine myelinolysis despite careful correction of hyponatremia: clinical and neuropathological findings of a case , Neurological Sciences , 2010 , vol. 31 (pg. 227 - 230 ) 158 , , , , . Osmotic myelinolysis with malignant cerebellar edema occurring after DDAVP-induced hyponatremia in a child , Pediatric Neurosurgery , 2010 , vol. 46 (pg. 318 - 323 ) 159 , , , , , . Severe hyponatraemia and central pontine myelinolysis: be careful with other factors! , Annales Françaises d'Anesthésie-Réanimation , 2009 , vol. 28 (pg. 96 - 99 ) 160 . Extrapontine myelinolysis after surgical removal of a pituitary tumour , Acta Neurologica Scandinavica , 1998 , vol. 98 (pg. 213 - 215 ) 161 , , , . Central pontine myelinolysis despite slow sodium rise in a case of severe community-acquired hyponatraemia , Anaesthesia and Intensive Care , 2009 , vol. 37 (pg. 117 - 120 ) 162 , , , . Neuropsychological findings of extrapontine myelinolysis without central pontine myelinolysis , Behavioural Neurology , 2007 , vol. 18 (pg. 131 - 134 ) 163 , , , , , , , , , . Possible case of peripheral osmotic demyelination syndrome , Journal of Neurology, Neurosurgery, and Psychiatry , 2008 , vol. 79 (pg. 331 - 332 ) 164 , , . Central pontine myelinolysis: sequele of hyponatremia during transcervical resection of endometrium , Acta Anaesthesiologica Scandinavica , 2002 , vol. 46 (pg. 914 - 916 ) 165 , , , , . Pontine/extrapontine myelinolysis occurring in the setting of an eating disorder , Neurology , 2005 , vol. 64 (pg. 2156 - 2157 ) 166 , . Osmotic demyelination syndrome following rapid correction of hyponatraemia , Anaesthesia , 2008 , vol. 63 (pg. 92 - 95 ) 167 , , , , , . Hyponatraemia and central pontine myelinolysis after elective colonoscopy , European Journal of Neurology , 2005 , vol. 12 (pg. 322 - 323 ) 168 , , . Parkinsonism after correction of hyponatremia with radiological central pontine myelinolysis and changes in the basal ganglia , Journal of Clinical Neuroscience , 2000 , vol. 7 (pg. 256 - 259 ) 169 , , , , , , , . Acute intermittent porphyria with central pontine myelinolysis and cortical laminar necrosis , Neuroradiology , 1999 , vol. 41 (pg. 835 - 839 ) 170 , , , , . Kluver Bucy syndrome, unusual consequence of excessively rapid correction of severe hyponatremia , Presse Médicale , 2008 , vol. 37 (pg. 975 - 977 ) 171 , , . Pontine and extrapontine osmotic myelinolysis after the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with fluoxetine: case report , Arquivos de Neuro-Psiquiatria , 2007 , vol. 65 (pg. 858 - 864 ) 172 , , . Central myelinolysis in a patient with hyponatraemia , West Indian Medical Journal , 2007 , vol. 56 (pg. 382 - 384 ) 173 , , , , , , . , Annals of Nuclear Medicine , 2009 , vol. 23 (pg. 409 - 412 ) (99m)Tc-TRODAT-1 and [123]I-IBZM SPECT studies in a patient with extrapontine myelinolysis with parkinsonian features 174 , , , , , . Centropontine myelinolysis and extrapontine myelinolysis complicating the quick correction of a hyponatremia , Annales Françaises d'Anesthésie-Réanimation , 2009 , vol. 28 (pg. 714 - 715 ) 175 , , . Central pontine myelinolysis and pregnancy: a case report and review of literature , Revista de Neurología , 2000 , vol. 30 (pg. 1036 - 1040 ) 176 , , . The treatment of hyponatremia , Seminars in Nephrology , 2009 , vol. 29 (pg. 282 - 299 ) 177 , , , , , . Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis , American Journal of Kidney Diseases , 2010 , vol. 56 (pg. 325 - 337 ) 178 , , , , , . Short-term efficacy and safety of vasopressin receptor antagonists for treatment of hyponatremia , American Journal of Medicine , 2011 , vol. 124 (pg. 971 - 979 ) 179 , , , , , , . Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia , Journal of Clinical Endocrinology and Metabolism , 2006 , vol. 91 (pg. 2145 - 2152 ) 180 , , , , . Conivaptan Study Group Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia , American Journal of Nephrology , 2007 , vol. 27 (pg. 447 - 457 ) 181 , , . Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, evaluated in a randomized, controlled trial in patients with euvolemic or hypervolemic hyponatremia , American Journal of the Medical Sciences , 2009 , vol. 337 (pg. 28 - 36 ) Conivaptan Study Group 182 , , , , , , , . Use of Conivaptan (Vaprisol) for hyponatremic neuro-ICU patients , Neurocritical Care , 2010 , vol. 13 (pg. 57 - 61 ) 183 , , , , , . Efficacy and safety of 30-minute infusions of conivaptan in euvolemic and hypervolemic hyponatremia. [Erratum appears in Am J Health Syst Pharm. 2011 Aug 1;68[15]:1374] , American Journal of Health-System Pharmacy , 2011 , vol. 68 (pg. 818 - 827 )
184 , , , , , , . VPA Study Group Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial , Gastroenterology , 2003 , vol. 124 (pg. 933 - 939 )
185 , , , . A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial , Hepatology , 2003 , vol. 37 (pg. 182 - 191 ) 186 , , , , , , , , . HARMONY Study Group Oral lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia , Kidney International , 2012 , vol. 82 pg. 8 187 , , , , , , . LIBRA Study Group Lixivaptan safely and effectively corrects serum concentrations in hospitalized patients with euvolemic hyponatremia , Kidney International , 2012 , vol. 82 pg. 8 189 , , , , , , . Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist , Clinical Journal of the American Society of Nephrology , 2006 , vol. 1 (pg. 1154 - 1160 ) 190 . Long-term satavaptan treatment and drug holiday in patients with SIADH , Journal of the American Society of Nephrology , 2008 , vol. 19 588A 191 , , , , , , HypoCAT Study Investigators .Effects of satavaptan, a selective vasopressin V[2] receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial , Hepatology , 2008 , vol. 48 (pg. 204 - 213 ) 192 . Short- and long-term treatment of dilutional hyponatraemia with satavaptan, a selectve arginine vasopressin V2-receptor antagonist: the DILIPO study , European Journal of Heart Failure , 2011 , vol. 13 (pg. 327 - 336 ) 193 , , , , , , . Tolvaptan Investigators Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial , Circulation , 2003 , vol. 107 (pg. 2690 - 2696 ) 194 , , , , , , , , , . Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial , Journal of the American Medical Association , 2004 , vol. 291 (pg. 1963 - 1971 ) 195 , , , , , , . Tolvaptan Investigators Vasopressin v[2] receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia , American Journal of Cardiology , 2006 , vol. 97 (pg. 1064 - 1067 ) 196 , , , , , , . SALT Investigators Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia , New England Journal of Medicine , 2006 , vol. 355 (pg. 2099 - 2112 ) 197 , , , , , , , , , . Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial , Journal of the American Medical Association , 2007 , vol. 297 (pg. 1319 - 1331 ) 199 , , , , , , , , , . Tolvaptan in patients with autosomal dominant polycystic kidney disease , New England Journal of Medicine , 2012 , vol. 367 (pg. 2407 - 2418 ) 201 , , , , . A double blind, placebo-controlled trial of demeclocycline treatment of polydipsia–hyponatremia in chronically psychotic patients , Biological Psychiatry , 1991 , vol. 30 (pg. 417 - 420 ) 202 , , , . Treatment of euvolemic hyponatremia in the intensive care unit by urea , Critical Care , 2010 , vol. 14 pg. R184 203 , . Urea for long-term treatment of syndrome of inappropriate secretion of antidiuretic hormone , BMJ , 1981 , vol. 283 (pg. 1081 - 1083 ) 204 , , , . Hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Rapid correction with urea, sodium chloride, and water restriction therapy , Journal of the American Medical Association , 1982 , vol. 247 (pg. 471 - 474 ) 205 , . Administration of intravenous urea and normal saline for the treatment of hyponatremia in neurosurgical patients , Journal of Neurosurgery , 1989 , vol. 70 (pg. 201 - 206 ) 206 , , , , , , . Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with urea in critically ill patients , American Journal of Nephrology , 2012 , vol. 35 (pg. 265 - 270 ) 207 , , , , , . The use of demeclocycline in the treatment of patients with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) , Psychiatric Quarterly , 1988 , vol. 59 (pg. 62 - 68 ) 208 , , , . Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline , Annals of Internal Medicine , 1973 , vol. 78 (pg. 870 - 875 ) 209 , , . Lack of efficacy of phenytoin in the syndrome of inappropriate anti-diuretic hormone secretion of neurological origin , Postgraduate Medical Journal , 1989 , vol. 65 (pg. 456 - 458 ) 210 , , , , , , . Fluid restriction does not improve the outcome of acute meningitis , Pediatric Infectious Disease Journal , 1995 , vol. 14 (pg. 495 - 503 ) 211 , , , , , , . Oral urea treatment for polydipsia–hyponatremia syndrome in patients with schizophrenia , Journal of Clinical Psychopharmacology , 2009 , vol. 29 (pg. 499 - 501 ) 212 , , , , . Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH , Clinical Journal of the American Society of Nephrology , 2012 , vol. 7 (pg. 742 - 747 ) 213 , , . Treatment of the polydipsia–hyponatremia syndrome with urea , Journal of Clinical Psychiatry , 2005 , vol. 66 (pg. 1372 - 1375 ) 214 , , , , , . Renal failure associated with demeclocycline in cirrhosis , Annals of Internal Medicine , 1977 , vol. 87 (pg. 195 - 197 ) 215 . Demeclocycline. Treatment for syndrome of inappropriate antidiuretic hormone secretion , Journal of the American Medical Association , 1977 , vol. 237 (pg. 2723 - 2726 ) 216 , , , , , . Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone , New England Journal of Medicine , 1978 , vol. 298 (pg. 173 - 177 ) 217 , . Demeclocycline improves hyponatremia in chronic schizophrenics , Biological Psychiatry , 1985 , vol. 20 (pg. 1149 - 1155 ) 218 , , , . Demeclocycline in the treatment of the syndrome of inappropriate secretion of antidiuretic hormone , Thorax , 1979 , vol. 34 (pg. 324 - 327 ) 219 . Serious hyponatremia in patients with cancer: management with demeclocycline , Cancer , 1981 , vol. 47 (pg. 2908 - 2912 ) 220 , , , , , . Treatment of psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) using lithium and phenytoin , Biological Psychiatry , 1988 , vol. 23 (pg. 25 - 30 ) 221 . Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by long loop diuretics , Nephron , 1983 , vol. 35 (pg. 82 - 88 ) 222 , , , , , , . Demeclocycline-induced phosphate diabetes in a patient with inappropriate ADH secretion and systemic sarcoidosis , Nephron , 1993 , vol. 63 (pg. 226 - 229 ) 223 , , , . Hyponatremia in a cirrhotic suffering from late cutaneous porphyria: a drug to avoid, demeclocycline , La Nouvelle Presse Médicale , 1979 , vol. 8 pg. 210 224 , , . Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with demethylchlortetracycline. Apropos of 2 cases , La Semaine des Hopitaux , 1977 , vol. 53 (pg. 823 - 826 ) 225 , , . Irreversible nephrotoxicity from demeclocycline in the treatment of hyponatremia , Age and Ageing , 2002 , vol. 31 (pg. 151 - 152 ) 226 , , . Renal function during treatment of inappropriate secretion of antidiuretic hormone with demeclocycline , Israel Journal of Medical Sciences , 1978 , vol. 14 (pg. 852 - 857 ) 227 , , , . Demeclocycline-induced phosphate diabetes in patients with inappropriate secretion of antidiuretic hormone , New England Journal of Medicine , 1985 , vol. 313 (pg. 1480 - 1481 ) 228 , , , . Demethylchlortetracycline treatment of cirrhotic ascites with hyponatremia , La Nouvelle Presse Médicale , 1977 , vol. 6 pg. 1066 229 , , . Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients , Journal of the American Medical Association , 1980 , vol. 243 (pg. 2513 - 2515 ) 230 , , . Demeclocycline in the treatment of the syndrome of inappropriate antidiuretic hormone release: with measurement of plasma ADH , Postgraduate Medical Journal , 1978 , vol. 54 (pg. 623 - 627 ) 231 , , , , . Acute pancreatitis caused by demeclocycline , Revista Clínica Española , 1989 , vol. 184 (pg. 392 - 393 ) 232 , , , , , , , , . Effect of demeclocycline on renal function and urinary prostaglandin E2 and kallikrein in hyponatremic cirrhotics , Nephron , 1984 , vol. 36 (pg. 30 - 37 ) 233 , . Therapy with hypertonic saline in combination with anti-convulsants for hyponatremia-induced seizure: a case report and review of the literature , Hawaii Medical Journal , 2002 , vol. 61 (pg. 280 - 281 ) 234 , , , , , . Deleterious effect of prolonged sodium administration and fluid restriction after partial correction of severe hyponatremia , Critical Care Medicine , 1991 , vol. 19 (pg. 305 - 306 ) 235 , , , . Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysms: is fluid restriction harmful? , Annals of Neurology , 1985 , vol. 17 (pg. 137 - 140 ) 236 , , , , , . Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults , Journal of the American Medical Association , 2012 , vol. 308 (pg. 1566 - 1572 ) 237 , , , , , , . Ad-hoc working group of ERBP A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines on Acute Kidney Injury: Part 1: definitions, conservative management and contrast-induced nephropathy , Nephrology, Dialysis, Transplantation , 2012 , vol. 27 (pg. 4263 - 4272 ) 238 Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO Clinical Practice Guideline for Acute Kidney Injury , Kidney International , 2012 , vol. 2 (pg. s1 - s138 ) 239 , , , , , , . DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia , Clinical Journal of the American Society of Nephrology , 2008 , vol. 3 (pg. 331 - 336 ) 240 , , , , , , , , , . GRADE guidelines: 3. Rating the quality of evidence , Journal of Clinical Epidemiology , 2011 , vol. 64 (pg. 401 - 406 ) 241 , , , , , , . GRADE Working Group Going from evidence to recommendations , BMJ , 2008 , vol. 336 (pg. 1049 - 1051 ) 242 , . Evaluation and management of hypo-osmolality in hospitalized patients , Endocrinology and Metabolism Clinics of North America , 2003 , vol. 32 (pg. 459 - 481 ) 243 , , , , , . Acute hyponatremia after cardioplegia by histidine–tryptophane–ketoglutarate – a retrospective study , Journal of Cardiothoracic Surgery , 2012 , vol. 7 pg. 52 244 , , , , . Contrast-induced translocational hyponatremia and hyperkalemia in advanced kidney disease , American Journal of Kidney Diseases , 2004 , vol. 43 (pg. e31 - e35 ) 245 , , . Maltose-induced hyponatremia , Annals of Internal Medicine , 1993 , vol. 118 (pg. 526 - 528 ) 246 , . Pseudohyponatremia in multiple myeloma , Southern Medical Journal , 1993 , vol. 86 (pg. 251 - 252 ) 247 , , . A review of drug-induced hyponatraemia , American Journal of Kidney Diseases , 2008 , vol. 52 (pg. 144 - 153 ) Author notesThe guidelines were peer reviewed by the owner societies and by external referees prior to publication. © European Society of Endocrinology, European Society of Intensive Care Medicine, European Renal Association European Dialysis and Transplant Association (2014). © European Society of Endocrinology, European Society of Intensive Care Medicine, European Renal Association European Dialysis and Transplant Association (2014). Supplementary dataComments6 Comments Response to letter from Otsuka Ltd. 22 June 2014 Wim Van Biesen (with Raymond Vanholder, Hyponatraemia Guideline Development Group) Chair of European Renal Best Practice (ERBP) Group, Ghent University Hospital, Ghent, Belgium This is a response to the letter by Avila (1), which reiterates some of the elements discussed during the many meetings of the Hyponatraemia Guideline Development Group (GDG), which from the start decided to follow an evidence-based, rigorous, and transparent approach (2). The methodology is based on the recommendations of the Institute of Medicine for trustworthy guidelines (3), and this complies with the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria (4, 5). Unfortunately, such methodological strictness does not seem to be characteristic for most of the other hyponatremia guidelines mentioned in the letter. Our guideline (6, 7) is based on the best possible evidence, collected systematically, including meta-analysis when possible. To fulfill the AGREE criterion of stakeholder involvement (5), the GDG consisted of specialists of different fields for whom hyponatremia is relevant (endocrinology, nephrology, and intensive care medicine) and included also methodologists, next to trainees in the specialties mentioned above and patients to enhance the relevance of our document to users and beneficiaries. In addition, the text was submitted for an extensive external review, not only by a multitude of recognized hyponatremia experts of different backgrounds, but also by a web-based evaluation following an email blast to more than 6000 physicians to whom the guidelines were of potential interest. As such, the guideline is not only endorsed by the three societies involved in its production, but also obtained broad general support of the end users for its balanced views and practical value, which in our opinion is one of the major achievements of this initiative. During the review process, many issues were raised by over 700 reviewers, but none of them came up with any of the remarks made by Avila (1). The mere suggestion by itself that the guideline is incorrect and should be replaced by alternative statements, if generated by a highly ranked representative of a company involved in producing a drug that can be used in the treatment of hyponatremia, is therefore at least ethically debatable and may be seen as an insult to all who participated in the development or review of the guideline. AGREE also strongly emphasizes clarity of presentations. Therefore, the e-GLIA tool was used (8, 9) to ensure that all provided statements were unambiguous and clear, and that flowcharts were easy to use. We are convinced that the flowcharts for diagnosis and management are a major educational and didactic advancement in this field. It might be useful to highlight some principles of evidence-based guideline production, which can easily escape the attention or be overlooked by those who are unfamiliar with the procedure. First, a guideline should consider all available evidence, even unpublished, or difficult to find, and obviously also the evidence conflicting with a general opinion or the wish of some of its developers. This is different to opinion-based narrative reviews, such as the international expert panel recommendations by Verbalis et al. (10) suggested by Avila (1) as a reference monograph on the issue, where to the best of our understanding, no methodologies were involved or systematic review procedures followed. Dissecting evidence in different ways until a favorable result pops up, a practice that seems to be proposed as a preference by Avila, is an unacceptable procedure in the context of qualitative evidence-based guidance. Such differences in the inherent quality might explain some differences in the recommendations between the different guidance-providing documents cited by Avila (1). Secondly, guidelines should consider only relevant outcomes when producing their statements. There is little doubt that vaptans do increase serum sodium concentration, especially in patients with syndrome of inappropriate antidiuretic hormone secretion. However, the proof that this is also resulting in a meaningful change in hard, patient-relevant outcomes, such as mortality or even quality of life, is currently lacking. The last decade has seen the emergence of a host of medical interventions that change surrogate markers of disease, but do not result in an improvement of important outcomes; in the nephrology field, herein, we can refer to the erythropoiesis-stimulating agents or the calcimimetics. It is the explicit task of guidelines to point out this type of discrepancy and educate its stakeholders on this topic. For those planning randomized trials, the important take-home message is thus to ascertain that the trial under development considers patient-relevant hard outcomes. If industry wants to take its task toward patients and the society at heart, they should thus consider the trials focusing on hard outcomes that are relevant to patients. For hyponatremia, this would imply delivering proof that increasing serum sodium concentration by a given intervention results in the improvement of patient-relevant outcomes, such as mortality, in the first place. Co-publication This letter will be co-published in the European Journal of Endocrinology and Nephrology Dialysis Transplantation. References 1 Avila M, . The Clinical Practice Guideline on diagnosis and treatment of hyponatraemia: a response from Otsuka Pharmaceutical Europe Ltd . European Journal of Endocrinology 2014 171 L1-L3. 2 Nagler EV, Webster AC, Bolignano D, Haller MC, Nistor I, van der Veer SN, Fouque D, Van Biesen W, . European Renal Best Practice Guideline development methodology: towards the best possible guidelines . Nephrology, Dialysis, Transplantation 2014 29 731-738. 3 Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC, The National Academies Press. 2011. 4 Alonso-Coello P, Irfan A, Sol I, Gich I, Delgado-Noguera M, Rigau D, Tort S, Bonfill X, Burgers J, Schunemann H, . The quality of clinical practice guidelines over the last two decades: a systematic review of guideline appraisal studies . Quality & Safety in Health Care 2010 19 e58. 5 AGREE Collaboration Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project . Quality & Safety in Health Care 2003 12 18-23. 6 Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn E, Ichai C, . Clinical practice guideline on diagnosis and treatment of hyponatraemia . European Journal of Endocrinology 2014 170 G1-G47. 7 Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, . Clinical practice guideline on diagnosis and treatment of hyponatraemia . Nephrology, Dialysis, Transplantation 2014 29 (Suppl 2 ) i1-i39. 8 Shiffman RN, Dixon J, Brandt C, Essaihi A, Hsiao A, Michel G, O'Connell R, . The GuideLine Implementability Appraisal (GLIA): development of an instrument to identify obstacles to guideline implementation . BMC Medical Informatics and Decision Making 2005 5 23. 9 van der Veer SN, Tomson CR, Jager KJ, van Biesen W, . Bridging the gap between what is known and what we do in renal medicine: improving implementability of the European Renal Best Practice guidelines . Nephrology, Dialysis, Transplantation 2014 29 951-957. 10 Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ, . Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations . American Journal of Medicine 2013 126 (10 Suppl 1 ) S1-42. Conflict of Interest:None declared Submitted on 22/06/2014 8:00 PM GMT A response from Otsuka Pharmaceutical Europe Ltd Regional Vice President Medical Europe, Otsuka Pharmaceutical Europe Ltd, Gallions, Wexham Springs, Framewood Road, Wexham SL3 6PJ, UK The publication of the guideline by the European Renal Best Practice (ERBP) group has helped stimulate a debate on this important cause of morbidity and mortality (1, 2), and this joins an ever-growing body of international and national guidelines on hyponatraemia. This includes the international expert panel recommendations by Verbalis et al. (3), and various national recommendations from Spain (4), Sweden (5) and the UK (6). The development of hyponatraemia guidelines in Italy and Norway is also ongoing. Therefore, it seems to be unusual that tolvaptan, the only licensed vasopressin receptor antagonist (vaptan) for hyponatraemia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (1, 2), has been excluded from the European 'Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia' (1, 2). By contrast, most of the recommended treatments are unlicensed for treating the conditions that they are recommended for and do not have the benefit- risk assessment that is signified by licence approval following the regulatory assessment by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) (7, 8). Notably, some of the recommendations of the ERBP guideline are in contrast to those of the other publications mentioned above, particularly in patients with SIADH (1, 2, 3, 4, 5, 6). Unusually, the authors have chosen to analyse four vaptans (tolvaptan, conivaptan, lixivaptan and satavaptan) within the same meta- analysis (9, 10) when only tolvaptan is licensed and approved for use in Europe (1, 2). Moreover, this analysis is based on a heterogeneous population that includes hypervolaemic patients, whereas in Europe tolvaptan is authorised for use only in patients with euvolaemic hyponatraemia secondary to SIADH (1, 2, 9, 10). Although there is a paucity of evidence to support evidence-based recommendations for most available therapies in hyponatraemia (3), the efficacy and safety profile of tolvaptan have been proven in randomised controlled trials (11). Furthermore, since 31 March 2013, pooled exposure data have been made available for the ongoing evaluation of safety from 82 trials, including 6794 subjects worldwide who were exposed to oral doses of tolvaptan, with 425 subjects in trials for hyponatraemia (12). Therefore, it is surprising that the European guideline does not recommend a place for tolvaptan within its licensed indication (1, 2). Based on their review of a meta-analysis consisting predominantly of unlicensed vaptans, the authors concluded that the benefit-risk profile for vaptans seems to be negative. Vaptans, similar to all other treatments for hyponatraemia, can occasionally cause overly rapid correction of hyponatraemia (11). A single case of osmotic demyelination syndrome (13), with a very rare incidence of less than one in 10?000 patients, has been reported with tolvaptan monotherapy to date. The summary of product characteristics for tolvaptan emphasises the importance of close monitoring of serum sodium concentration and titrating the dose to achieve a desired serum sodium concentration in all patients (7). The authors also expressed concern with the hepatotoxicity associated with the use of particularly high doses of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) (1, 2). However, there have been no liver safety signals to date in any other population treated with tolvaptan (hyponatraemia, heart failure or cirrhosis) (14). The long-term safety profile of tolvaptan has been confirmed in the SALTWATER study, with a mean duration of treatment of 1.9 years (15). The vaptan meta-analysis also suggested a signal indicating a possibly increased risk of death for hypervolaemic patients treated with vaptans compared with placebo (1, 2). Moreover, it is important to note that in Europe tolvaptan is not approved in this patient population (1, 2) and there was no increase in mortality when the tolvaptan subgroup was analysed (9, 10). With the rigour afforded to the analyses of the risk-benefit profile for vaptans, it is surprising that the same in-depth analyses do not seem to have been conducted for any treatments the ERBP guideline recommends for SIADH. The authors acknowledge that there are no systematic reviews or randomised controlled trials evaluating the benefits and harms of fluid restriction, urea or loop diuretics (1, 2). Yet the authors' recommendation for first-line treatment with fluid restriction fails to acknowledge that it may be inappropriate for many patient populations (e.g. in patients with cancer where it may delay chemotherapy (16, 17), and it is likely to fail in some patients (e.g. those with high urine osmolality) (3). The guideline recommends second-line treatment with urea or the combination of loop diuretics with oral sodium chloride (NaCl), despite extremely limited efficacy data (1, 2). The authors failed to consider safety data for the use of urea in the studies they quote, for example, one study has shown that urea is associated with a 37% rate of overly rapid correction in patients with severe hyponatraemia (18). In addition, of the four studies mentioned supporting the use of loop diuretics with oral NaCl (19, 20, 21, 22), only one study actually used oral NaCl (n=9), with the remaining studies using NaCl intravenously (19). There is no discussion on the rationale for the inclusion of this combination or any consideration of safety data (1, 2), for example, overly rapid correction was observed in 56-80% of patients in two case series (20, 22), and hypokalaemia developed in 58% of patients in another study (19). Tolvaptan has a proven benefit-risk profile, which is supported by randomised controlled trials and over 4 years of real-world use, and we urge the authors to take a more consistent and measured approach towards evidence-based recommendations. Reply to this letter A response to this letter (23) is being published. Co-publication This letter and the response to it will be co-published in the European Journal of Endocrinology and Nephrology Dialysis Transplantation. References 1 Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn E, Ichai C, . Clinical practice guideline on diagnosis and treatment of hyponatraemia . European Journal of Endocrinology 2014 170 G1-G47. 2 Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, . Clinical practice guideline on diagnosis and treatment of hyponatraemia . Nephrology, Dialysis, Transplantation 2014 29 (Suppl 2 ) i1-i39. 3 Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ, . Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations . American Journal of Medicine 2013 126 S1-S42. 4 Runkle I, Navarro A, Pose A, Villabona C, Formiga F, Tejedor A, Poch E, . El tratamiento de la hiponatremia secundaria al s?ndrome de secreci?n inadecuada de la hormona antidiur?tica . Medicina Cl?nica 2013 141 507.e1-507.e10. 5 Chantzichristos D, Drougge H, Dahm P, Ed?n Engstr?m B, Ekman B, H?ybye C, Manhem P, Olsson T, Rask E, ?hlin B & Johannsson G. V?rdprogram f?r hyponatremi. Gothenburg, Sweden: Svensk F?rening f?r Anestesi och Intensivv?rd & Svenska Endokrinolog F?reningen; 2012. Available at: http://endokrinologforeningen.se/documents/Svenskt%20vardprograQ7m%20for%20hyponatremi_120120.pdf. 6 Grossman A, Thatcher N, Bouloux P, Grant P, Cohen M, Murray R, Rees A, Ayuk J & Cranston I. Expert Panel Guidelines for the Treatment of Hyponatraemia (Draft version, presented at Stratford, UK, February 7th-8th 2013). 7 Otsuka Pharmaceutical Europe Ltd. Samsca (tolvaptan) summary of product characteristics. European Medicines Agency; 2014. 8 Otsuka America Pharmaceutical, Inc. Samsca (tolvaptan) prescribing information 2014. 9 Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, . Clinical practice guideline on diagnosis and treatment of hyponatraemia . Nephrology, Dialysis, Transplantation 2014 29 (10 Suppl 2 ) i1-i39 .Supplementary appendix 6. 10 Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn E, Ichai C, . Clinical practice guideline on diagnosis and treatment of hyponatraemia . European Journal of Endocrinology 2014 170 G1-G47 .Supplementary appendix 6. 11 Verbalis JG, Adler S, Schrier RW, Berl T, Zhao Q, Czerwiec FS, SALT Investigators . Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion . European Journal of Endocrinology 2011 164 725-732. 12 Otsuka Pharmaceutical Europe Ltd. Tolvaptan pooled exposure data. Data on file: Periodic Update Safety Report July 2013. Wexham, Bucks, UK; Otsuka Pharmaceutical Europe Ltd: 2013. 13 Malhotra I, Gopinath S, Janga KC, Greenberg S, Sharma SK, Tarkovsky R, . Unpredictable nature of tolvaptan in treatment of hypervolemichyponatremia: case review on role of vaptans . Case Reports in Endocrinology 2014 doi:10.1155/2014/807054). 14 Otsuka Pharmaceutical Europe Ltd. Tolvaptan liver safety data. Data on file. Wexham, Bucks, UK; Otsuka Pharmaceutical Europe Ltd: 2014 15 Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, Czerwiec FS, SALTWATER Investigators . Oral tolvaptan is safe and effective in chronic hyponatremia . Journal of the American Society of Nephrology 2010 21 705-712. 16 Rosner MH, Dalkin AC, . Electrolyte disorders associated with cancer . Advances in Chronic Kidney Disease 2014 21 7-17. 17 Castillo JJ, Vincent M, Justice E, . Diagnosis and management of hyponatremia in cancer patients . Oncologist 2012 17 756-765. 18 Decaux G, Andres C, Gankam-Kengne F, Soupart A, . Treatment of euvolemic hyponatremia in the intensive care unit by urea . Critical Care 2010 14 R184. 19 Decaux G, . Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by long loop diuretics . Nephron 1983 35 82-88. 20 Forssell G, Nordlander R, Orinius E, . Treatment of dilutional hyponatremia in congestive heart failure . Acta Medica Scandinavica 1980 207 279-281. 21 Castello L, Pirisi M, Sainaghi PP, Bartoli E, . Quantitative treatment of the hyponatremia of cirrhosis . Digestive and Liver Disease 2005 37 176-180. 22 Hantman D, Rossier B, Zohlman R, Schrier R, . Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline . Annals of Internal Medicine 1973 78 870-875. 23 Van Biesen W, Vanholder R, . Clinical Practice Guideline on diagnosis and treatment of hyponatraemia: a response to letter from Otsuka Ltd . European Journal of Endocrinology 2014 171 L5. Conflict of Interest:The author is currently Regional Vice President, Medical Europe for Otsuka Pharmaceutical Europe Ltd. This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Submitted on 22/06/2014 8:00 PM GMT Hypoproteinemia in acutely ill patients masks hyponatremia and its severity; common, often unrecognised with potential to harm patients 14 April 2014 Rousseau Gama (with Elaine Chow) Consultant Chemical Pathologist & Honorary Professor of Laboratory Medicine, Clinical Chemistry, New Cross Hospital, Wolverhampton. UK Sir, The European guidelines on hyponatremia stress the importance of recognising pseudohyponatremia when electrolytes are measured by indirect Ion Selective Electrodes (ISE) [1] but fail to consider the much more common but not widely appreciated pseudonormonatremia in acutely ill patients. It is well-recognised that an increase in dissolved solids as in hyperproteinemia or hyperlipidemia reduces the water fraction of plasma, and indirect ISE measurement of sodium results in pseudohyponatremia [1]. Less well-recognised is that an increase in plasma water fraction as in hypoproteinemia may mask hyponatremia and its severity when plasma sodium is measured by indirect ISE [2,3]. Hypoproteinemia is common in acutely ill patients [4,5]. We have previously reported that indirect ISE, compared to direct ISE, misclassified 19% of acutely ill patients with hyponatremia as being normonatremic and 8% of acutely ill patients with normonatremia as being hypernatremic; no patients had pseudohyponatremia [5]. Clinicians should therefore be aware that 1) Electrolyte results analysed by indirect ISE, as used in major laboratory analysers, are incorrect in the presence of abnormal plasma lipid and protein concentrations. Whereas electrolyte results analysed by direct ISE, as used in Point of Care Analysers (e.g. blood gas analysers with electrolyte measurement), are correct as direct ISE is unaffected by abnormal plasma lipid and protein concentrations. 2) Hyponatremia and its severity are masked by the hypoproteinemia commonly observed in acutely ill patients when electrolytes are measured in the laboratory. This may lead to the inappropriate diagnosis and management of plasma sodium disorders. We therefore suggest, in acutely ill patients with hypoproteinemia, that POCT Analysers (direct ISE) are used in preference to major laboratory analysers (indirect ISE) as they provide more accurate and consistent electrolyte results minimising the risk of misdiagnosis and mismanagement of plasma sodium disorders in these patients. Elaine Chow BSc MSc MRCP Clinical Research Fellow, Diabetes Centre, Northern General Hospital, Sheffield. UK Rousseau Gama MD FRSC FRCPath FRCP Clinical Chemistry, New Cross Hospital, Wolverhampton. UK References: 1. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn E, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E. Clinical practice guideline on diagnosisand treatment of hyponatraemia. Nephrol Dial Transplant. 2014 Mar 10. [Epub ahead of print] 2. Lang T, Prinsloo P, Broughton AF, Lawson N, Marenah CB. Effect of low protein concentration on serum sodium measurement: pseudohypernatraemia and pseudonormonatraemia! Ann Clin Biochem 2002; 39: 66-7. 3. Dimeski G, Barnett RJ. Effects of total plasma protein concentration on plasma sodium, potassium and chloride measurements by an indirect ion selective electrode measuring system. Crit Care Resusc 2005; 7: 12-5. 4. Marik P. The treatment of hypoalbuminemia in the critically ill patient. Heart Lung 1993; 22: 166-70. 5. Chow E, Fox N, Gama R. The effect of low serum total protein on sodium and potassium measurement by ion-selective electrodes in critically ill patients. Br J Biomed Sci. 2008; 65: 128-31. Conflict of Interest:None declared Submitted on 14/04/2014 8:00 PM GMT Letter to the Editor 14 April 2014 Volker Burst (with Peter Gross) Consultant, Nephrology, University Cologne It is highly appreciated that a group of experts, consisting of endocrinologists, nephrologists, intensivists, and internists, has undertaken the joint effort to put together an interdisciplinary guideline on the management of hyponatremia, a frequent and potentially devastating disorder. This is indeed remarkable because it is the first guideline elaborated on behalf of three distinguished European medical societies, the ERA/EDTA, the ESE, and the ESICM. It is, however, unfortunate, that the guideline was not subject to a public review process or evaluated by an independent expert panel prior to publication. Given the heterogeneity of possible management strategies on one side and the scarcity of robust trial-derived data on the other, it also would have been desirable to try and collect the experiences and perspectives of experts in different countries and to include them in the guideline. With regard to treatment of syndrome of inappropriate ADH secretion (SIADH) without severe symptoms, probably the largest group of patients with chronic hyponatremia, it appears to us that the existing literature was not interpreted well-balanced; the guideline puts much more emphasis on possible side effects than on efficiency of the various therapy options. We clearly agree that fluid restriction should be the first-line treatment in most cases. However, there are circumstances, e.g. high urinary osmolality or tonicity, in which fluid restriction will predictably fail and other options should be considered for initial therapy. The guideline proposes an increase of solute intake, i.e. urea or a combination of low-dose loop diuretics and oral sodium chloride, as second-line option. Both of these options have never been evaluated in a prospective controlled trial and the guideline states: "We identified no systemic reviews or randomised controlled trials evaluating the benefits and harms of urea, demeclocycline, lithium, loop diuretics, phenytoin or fluid restriction." For urea treatment, we found only slightly more than 200 patients in total (either as case reports or in small retrospective series) in a pubmed search. With regard to the potentially detrimental effect of a too rapid increase of serum sodium concentration associated with any kind of active treatment, we only found very limited data for urea. In a retrospective analysis of patients suffering from profound hyponatremia that were treated in an intensive care unit with urea and saline concomitantly, as much as 37% met the definition of overly rapid correction (Decaux et al., Crit Care. 2010;14(5):R184). Data for urea administration as sole treatment are, to our knowledge, lacking and data on oral salt administration together with a loop diuretic are even scarcer. Poor palatability and azotemia in the case of urea treatment and hypokalemia and other putative side-effects of sodium-plus-furosemide therapy make these treatment options not very attractive and are, therefore, not widely in use. We therefore do not agree on this recommendation as second-line treatment. The guideline furthermore does not recommend the use of vaptans in patients with moderate hyponatremia and recommends against the use of vaptans in profound hyponatremia. The guideline explains these recommendations with the lack of proof of a beneficial impact on hard outcome parameters like mortality and emphasizes that the use of vaptans might be associated, although not statistically significant, with an increased mortality in hypervolaemic hyponatremia. To us this is surprising because of several reasons. The only vaptan available in Europe, tolvaptan, is the only approved drug for targeted therapy of SIADH without severe neurologic symptoms. In contrast to the recommended therapies, it is actually the only treatment that has been tested in a placebo-controlled trial. Using this as an argument against its use and advocating other therapies that have never been tested in a proper trial is simply incorrect. Moreover, mortality may not be an adequate outcome parameter (neither can it be tested easily due to ethical reasons). More suitable endpoints (e.g. quality of life etc.) have, at least in part, been analysed in the Salt trials using the SF-12 questionnaire indicating a beneficial impact of tolvaptan. The mentioned putative negative effect on survival in hypervolaemic hyponatremic patients has only been shown for vaptans other than tolvaptan (lixivaptan and satavaptan) which are not approved by the FDA and EMA. It thus seems sensible not to look at the vaptans as a class but rather at individual compounds. Another apparent disadvantage of vaptans according to the guideline is the high rate of overcorrection. However, for tolvaptan an incidence of 10% has been reported which clearly lies below the rate of overcorrection for urea as mentioned above. Furthermore, overcorrection is a potential risk with every active treatment - this only means that adequate monitoring is mandatory. It is therefore not understandable why tolvaptan is completely omitted in the guideline. There is one issue about tolvaptan that has to be taken into account though: its high price. However, economic considerations should not influence the content of a guideline claiming to be objective and based on anything but scientific grounds. The authors of the guideline may argue that the authors of this letter have received honoraria from the company producing tolvaptan and are therefore not objective. However, we like any physician dealing with hyponatremia in a serious way use tolvaptan only very restrictively and only in certain circumstances. Everybody who is experienced with the use of tolvaptan knows that it is a powerful, highly effective tool that definitively has its indications. Recommending against the only approved therapy for the treatment of hyponatremia and recommending inadequately tested and non-approved therapy options instead constitutes a dilemma for the treating physician and might even provoke legal issues. Hence, we strongly recommend to modify the guideline. We absolutely agree with the guideline development group that tolvaptan should not be the first choice in SIADH treatment but it seems unreasonable to completely reject it. The argument regarding possible safety issues is well taken but, given the scarcity of data on effects as well as side effects of other treatment options, do not warrant its relegation. Volker Burst, MD, Klinik II fuer Innere Medizin, Uniklinik Koeln, Kerpener Strasse 62, 50937 Koeln, Germany Peter Gross, MD, Nephrologie, Universitaetsklinikum CG Carus, Fetscherstrasse 74, 01307 Dresden, Germany Conflict of Interest:The authors have received research support for their roles as investigators in hyponatremia trials from Otsuka. They have received fees for expert testimony and review activities, and have served on a speakers' bureau for Otsuka Submitted on 14/04/2014 8:00 PM GMT Treatment of hyponatremia 14 April 2014 Esteban Poch (with I. Runkle, C. Villabona, A. Navarro, A. Pose, F. Formiga, A. Tejedor) Senior Consultant, Servicio Nefrología, Hospital Clínic, Barcelona We read the article by Spasovski et al. on hyponatremia (1) with great interest and hope that, together with the recent guidelines of Verbalis et al. (2), it will serve to make clinicians more aware of the importance of diagnosing and treating hyponatremia. Using evidence in the field of hyponatremia is not an easy task - much of the management of hyponatremia is based on individual articles and expert opinion guidelines. The authors should be congratulated for this attempt. However, it was surprising to see that no attempt at evidence-based analysis was conducted for the treatment of mild to moderate hyponatremia induced by SIADH. Urea is proposed as a treatment for SIADH, without randomized controlled trials to support it. We know very little about possible side effects of urea, except for anecdotal information. In articles published to date, urea is often not effective in achieving eunatremia, yet can induce marked hypernatremia in up to 14% of patients with moderate hyponatremia, with overcorrection in up to 37% of patients with severe hyponatremia (3). Nor does urea seems to be the ideal therapy for patients with SIADH receiving artificial nutrition or chemotherapy. The authors discourage the use of medications with most evidence, vaptans, given the risk for overcorrection of Serum Na (SNa). Conivaptan, satavaptan, lixivatpan and tolvaptan are analyzed together, whereas the analysis that is truly useful for the European clinician is that of tolvaptan, the only one authorized for use in Europe. Tolvaptan has been found to be safe and effective in patients with SIADH (4) in randomized clinical trials, and is one of the treatments of choice for mild/moderate SIADH-induced hyponatremia in recent guidelines (2). Although overcorrection with tolvaptan can occur in 6% of patients (4), no cases of osmotic demyelination have been reported when not used simultaneously with hypertonic saline. We have recently published a protocol for treatment of SIADH that includes measures to "brake" the rise in SNa if necessary when initiating tolvaptan therapy, thus avoiding overcorrection (5). As for the hepatotoxicity the authors refer to, as far as we know, there have been no reported elevations in liver enzymes attributed to the use of tolvaptan in SIADH, perhaps due to the low doses of the medication used in this entity. We believe that tolvaptan has a role to play in the treatment of some patients with SIADH and mild/moderate hyponatremia. 1. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn E, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, NAgler E. Clinical practice Guidline and diagnosis and treatment of hyponatremia. Nephrol Dial Transplant (2014) 0: 1-39 doi: 10.1093/ndt/gfu040 2. Verbalis J, Goldsmith S, Greenberg A, Korzelius C, Schrier R, Sterns R, Thompson C. Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations. Am J Med 2013; 126: (D suppl 1) S1-42. 3. Decaux G, Andres C , Gankam Kengne F, Soupart A. Treatment of euvolemic hyponatremia in the intensive care unit by urea. Crit Care 2010; 14: R18 4. Verbalis J, Adler S, Schrier R, Berl T, Zhao Q, Czerwiec F. Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion. Eur J Endocrinol. 2011; 164(5): 725-732. 5. Runkle I, Villabona C, Navarro A, Pose A, Formiga F, Tejedor A, Poch E. El tratamiento de la hiponatremia secundaria al s?ndrome de secreci?n inadecuada de la hormona antidiur?tica. Med Cl?n 2013; 141(11): 507 e1- 507e10.(English version on web page). Conflict of Interest:Isabelle Runkle has consulted for Otsuka, and given talks sponsored by Otsuka, Amgen and Novarits. Carles Villabona has consulted for Otuska, and given talks sponsored by Otsuka, Ipsen and Novartis. Andr?s Navarro has consulted for Otsuka Antonio Pose has consulted for Otsuka, Boerhinger, MSD, Rvoer and Almirall, and given talks sponsored by Otsuka, Almirall, Boehringer, Novartis, Astra, Bristol, Lilly, Bayer, Sanofi, Lacer and Novo. Francesc Forminga has consulted for Otsuka, and given talks sponsored by Otsuka Alberto Tejedor has consulted for OTsuka and Astra-Zeneca, and given talks sponsored by Otsuka. Esteban Poch has consulted for Otuska, and given talks sponsored by Otsuka. Submitted on 14/04/2014 8:00 PM GMT Drugs induced hyponatremia 2 April 2014 Antonio J Magaldi Professor, Clinical Hospital School of Medicine S?o Paulo University I carefully read the article by Spasovski G et al. (1). It is a very interesting and important article covering this relevant subject and I am sure that it will help clinicians to treat hyponatremia more appropriately and to achieve better results. In item 5 "Pathophysiology of Hyponatremia", the matter is very well discussed and the subitem 5.7.2 "Diuretics" explains thiazide-induced hyponatremia. The traditional explanation postulates that, initially, thiazide causes sodium and water loss by the kidney, producing a decrease in the ECF volume. This effect induces an increase in sodium and water absorption by the proximal tubule decreasing the water delivery to distal tubules and thus decreasing the urinary volume (this effect is known as the paradoxical diuretic effect and is used as a guideline to treat diabetes insipidus). Nevertheless, this effect could be obtained by using other diuretics like furosemide which is much more powerful. However, this effect did not occur showing that this explanation did not result in the real mechanism of the thiazide effect. Recently, our group (2,3) demonstrated that this diuretic, in the absence of vasopressin, increases water absorption in the rat inner medullary collecting duct, as result of its own capacity. This thiazide explains the paradoxical effect and why this diuretic is involved in several cases of hyponatremia. Another article (4) confirms our results, showing that thiazide increases AQP II expression in rats with lithium-induced diabetes insipidus (used to block the effect of vasopressin). Thus, hyponatremia produced by this diuretic is caused neither by the increase of vasopressin release nor by the increase of the vasopressin susceptibility in the IMCD, but, instead, by stimulating AQP II expression. In addition, considering Table 7, some drugs, that are thought to induce an SIADH, fail to do so; that is, they did not increase the vasopressin plasma level. For example, fluoxetine, an SSRIs drug, increases the AQPII expression in the IMCD and does not produce an SIADH, as was demonstrated by our group (5). The same occurs with the anticonvulsant carbamazepine (Nephrol Dial Transplant. 2010 Dec;25:3840-5), with the antidiabetic drug chlorpropamide (Kidney Int. 1991 39:79-86.) and with the MDMA (data in submission). It is necessary to take into account that drug-induced hyponatremia is practically one of the commonest causes of this nosology, as seen in public day clinics as well as in doctors' practices and even in hospitalized patients. In several of them, there is drug-association, many of which involve the use of thiazides. Finally, this guideline is welcome and I am really convinced that it will improve the approach and the treatment of this hydro-electrolyte disorder. Antonio J Magaldi, PhD,MD Clinical Hospital School of Medicine University of S?o Paulo- Brazil References 1-Spasovski G, et al- Clinical practice guideline on diagnosis and treatment of hyponatremia. Nephrol Dial transplant (2014)0:1-39. 2-Cesar KR, Magaldi, AJ- Thiazide induces water absorption in the inner medullary collecting duct of normal and Brattleboro rats.Am J Physiol 1999 Nov;277:F756-60. 3-Magaldi AJ- New insights into the paradoxical effect of thiazides in diabetes insipidus therapy. Nephrol Dial Transplant. 2000 Dec;15:1903-5. Review. 4-Kim Gh et al , Lee JW, Oh YK, Chang HR, Joo KW, Na KY, Earm JH, Knepper MA, Han JS. Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transport, and epithelial sodium channel. J Am Soc Nephrol. 2004 Nov;15:2836-43. 5-Moyses ZP, Nakandakari FK, Magaldi AJ- Fluoxetine effect on kidney water reabsorption.Nephrol Dial Transplant. 2008 Apr;23:1173-8. Conflict of Interest:None declared Submitted on 02/04/2014 8:00 PM GMT I agree to the terms and conditions. You must accept the terms and conditions. Submit a comment Name Affiliations Comment title Comment You have entered an invalid code Thank you for submitting a comment on this article. Your comment will be reviewed and published at the journal's discretion. Please check for further notifications by email. CitationsViewsAltmetricEmail alertsRelated articles in PubMedCiting articles via
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