Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and consensus statements

Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and... Background: Hyponatremia is a common electrolyte disorder. Multiple organizations have published guidance documents to assist clinicians in managing hyponatremia. We aimed to explore the scope, content, and consistency of these documents. Methods: We searched MEDLINE, EMBASE, and websites of guideline organizations and professional societies to September 2014 without language restriction for Clinical Practice Guidelines (defined as any document providing guidance informed by systematic literature review) and Consensus Statements (any other guidance document) developed specifically to guide differential diagnosis or treatment of hyponatremia. Four reviewers appraised guideline quality using the 23-item AGREE II instrument, which rates reporting of the guidance development process across six domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Total scores were calculated as standardized averages by domain. Results: We found ten guidance documents; five clinical practice guidelines and five consensus statements. Overall, quality was mixed: two clinical practice guidelines attained an average score of >50% for all of the domains, three rated the evidence in a systematic way and two graded strength of the recommendations. All five consensus statements received AGREE scores below 60% for each of the specific domains. The guidance documents varied widely in scope. All dealt with therapy and seven included recommendations on diagnosis, using serum osmolality to confirm hypotonic hyponatremia, and volume status, urinary sodium concentration, and urinary osmolality for further classification of the hyponatremia. They differed, however, in classification thresholds, what additional tests to consider, and when to initiate diagnostic work-up. Eight guidance documents advocated hypertonic NaCl in severely symptomatic, acute onset (<48 h) hyponatremia. In chronic (>48 h) or asymptomatic cases, recommended treatments were NaCl 0.9%, fluid restriction, and cause-specific therapy for hypovolemic, euvolemic, and hypervolemic hyponatremia, respectively. Eight guidance documents recommended limits for speed of increase of sodium concentration, but these varied between 8 and 12 mmol/L per 24 h. Inconsistencies also existed in the recommended dose of NaCl, its initial infusion speed, and which second line interventions to consider. Conclusions: Current guidance documents on the assessment and treatment of hyponatremia vary in methodological rigor and recommendations are not always consistent. Keywords: Clinical practice guideline, Hyponatremia, Systematic review * Correspondence: evi.nagler@ugent.be European Renal Best Practice (ERBP), guidance body of the European Renal Association ? European Dialysis and Transplant Association (ERA-EDTA), De Pintelaan 185, Ghent 9000, Belgium Renal Division, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium Full list of author information is available at the end of the article ? 2014 Nagler et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nagler et al. BMC Medicine 2014, 12:231 Page 2 of 16 http://www.biomedcentral.com/1741-7015/12/231 Background to assist clinicians in the management of hyponatremia. Hyponatremia is the most common electrolyte disorder in To be reliable, these recommendations must be based clinical medicine; it represents an excess of water relative on a systematic review of the evidence, and have a trans- to total body solute [1]. Hyponatremia usually results from parent and multidisciplinary development process [9]. the intake and subsequent retention of electrolyte-free Inconsistencies between recommendations may arise water in response to true hypovolemia due to gastro- from failing to meet development standards and can intestinal solute loss or malnutrition; decreased effective only add to unwarranted variability in management. In circulating volume due to heart failure or liver cirrhosis; this study, we aimed to explore the scope, content, and or non-osmotic vasopressin activity due to malignancies, consistency of the existing guidance documents on the infections, medications, pain, or stress [2]. When defined diagnosis and management of hyponatremia in adults as a serum sodium concentration below 135 mmol/L, and children. hyponatremia occurs in up to 8% of the general popula- tion and in up to 60% of hospitalized patients [2,3]. Acute Methods profound hyponatremia can cause brain edema, but also Criteria for selection of studies chronic mild hyponatremia is associated with poor health We included evidence-based clinical practice guidelines outcomes. Even when comorbid conditions are taken and consensus statements on the diagnosis and treatment into account, people with a mildly decreased serum of hyponatremia. We defined clinical practice guidelines sodium concentration have a 30% higher risk of death and as statements that included recommendations intended to are hospitalized 14% longer relative to those without optimize patient care informed by a systematic review of hyponatremia [2,4]. evidence and an assessment of the benefits and harms Despite the frequency and severity of some of the of alternative care options [9]. We defined consensus associated complications, research suggests hyponatre- statements as documents containing clinically relevant mia is often neglected by clinicians [5]. If acquired in suggestions or recommendations based on the col- hospital, it may take days before the electrolyte disorder lective opinion of an expert panel [9]. We included all is investigated, potentially allowing a further decrease in publications independent of language. We excluded serum sodium concentration and exposing patients to guidelines related to the prevention of hyponatremia the dangers of profound hyponatremia. When efforts are as well as guidelines relevant to conditions associated made to explore the underlying cause, clinicians use widely with hyponatremia if they were not specifically designed different strategies for differential diagnosis, testing is often to address hyponatremia. Hence, we excluded guidelines inadequate and misclassification of the hyponatremia fre- targeting treatment of heart failure, cirrhosis, and cancer quently occurs [6,7]. unless they were developed with a focus on hyponatremia Hyponatremia may be managed clinically by different as a complication. Finally, we also excluded draft unpub- specialists, such as endocrinologists, nephrologists, geri- lished guidelines, conference or discussion papers, personal atricians, or intensivists, and, accordingly, management opinions, and obsolete guidelines replaced by updated rec- strategies often vary [5]. Although probably related to ommendations from the same organization. variation in awareness, differences in expert opinion on whom and how to treat only add to the confusion over optimal management. For instance, although experts agree Search methods for guidelines and consensus statements that acute symptomatic hyponatremia should be treated We searched MEDLINE (1946 to September Week 1, with hypertonic saline, the optimal concentrations and 2014) and EMBASE (1980 to September 2014), combining methods for determining initial infusion speeds are vocabulary terms and text words for hyponatremia with debated [1]. In addition, the risk of osmotic demyelination terms related to clinical practice guidelines and consensus syndrome after rapid correction of hyponatremia has statements. We also searched guideline databases and fuelled intense debate among experts on whether compli- websites of organizations as well as of selected profes- cations of untreated hyponatremia or complications of sional specialist societies in nephrology, endocrinology, treatment pose the greatest risk [8]. As different specialist and intensive care medicine. A list of the databases and physicians deal with hyponatremia, consultation of differ- websites along with the full search strategies are outlined ent information and guidance sources may add to the in Additional file 1. EN and JV independently screened variability in treatment seen in clinical practice today. the titles and abstracts and discarded those that did not Clinical practice guidelines and consensus statements meet the inclusion criteria. Full texts for potentially provide recommendations to help evidence-based prac- relevant guidelines or consensus statements were retrieved tice by suggesting the most appropriate diagnostic tests and examined for eligibility. Both the initial screening and and the most appropriate treatments. Over the years, subsequent full-paper assessment stage were completed multiple organizations have developed recommendations using Early Review Organizing Software [10]. Nagler et al. BMC Medicine 2014, 12:231 Page 3 of 16 http://www.biomedcentral.com/1741-7015/12/231 Data collection process and data items domains covered by the guidelines. These were cross- We developed a draft data extraction form which was tabulated with the guidelines and recommendations were piloted and modified as necessary. The extracted data inserted into the corresponding cell. For each domain, we included document characteristics (e.g., year of publi- compared guideline recommendations to identify similar- cation, country/region, development team, funding ities and discrepancies. Consistent with the scope of this organization), recommendations related to the diagno- review, we only tabulated the information on diagnosis sis and assessment of hyponatremia, and recommen- and treatment of hyponatremia. dations related to the treatment of hyponatremia. EN and JV extracted all data using the standardized data Results extraction form (Additional file 2) and resolved dis- Search results crepancies by consensus. We identified 1,402 citations, of which we excluded 1,367 after screening titles and abstracts because they did not Appraisal of guidelines and consensus statements meet our eligibility criteria (Figure 1). We assessed the full Four reviewers independently assessed methodological text of the remaining 39 citations and excluded 29 because quality using the Appraisal of Guidelines for Research and they were not related to the diagnosis or treatment of Evaluation (AGREE II) instrument [11]. AGREE II is an hyponatremia, were not clinical practice guidelines or con- internationally validated, rigorously developed 23-item tool sensus statements, or were guidelines replaced by an used to evaluate six domains of guideline development: updated version (Additional file 4). Ultimately, we included scope and purpose, stakeholder involvement, rigor of de- five clinical practice guidelines [16-20] and five consensus velopment, clarity of presentation, applicability, and editor- statements [21-25]. Six of these documents were retrieved ial independence [12] (Additional file 3). The AGREE tool through searching the medical databases [18-20,23-25], the has also been used to assess consensus statements [13,14]. other four through the search of guideline databases and The reviewers rated each item on a Likert scale from 1 professional society websites [16,17,21,22]. (? Strongly Disagree?)to 7 (? Strongly Agree? ). We calculated Table 1 shows the general characteristics of the included a total score for each domain by summing up all the scores clinical practice guidelines and consensus statements. Eight of the individual items in a domain for each reviewer national or regional organizations from the Netherlands and then standardizing this total as a percentage of the [16], United Kingdom [17], Northern Ireland [22], Spain maximum possible score for that domain, calculated as [23,25], United States [18,19], Australia [21], and two inter- follows [12]: national groups [20,24] published these guidance docu- ments between 2004 and 2014. One document specifically Obtained score − Minimum possible score covered children [21], the others primarily targeted adults. 100% Maximum possible score − Minimum possible score Six groups reported undertaking a systematic review and appraisal of the evidence [16-20,24]. Only three were ex- The minimum possible score for each domain equaled plicit about the level of evidence that underpinned their the number of questions multiplied by the number of recommendations [16,18,20], and only two graded the reviewers, multiplied by 1 (strongly disagree). The max- strength of the guidance recommendations themselves imum score for a domain equaled the number of ques- [18,20]. Five guidance documents covered hyponatremia tions multiplied by the number of reviewers, multiplied broadly; one specifically covered it in the setting of pri- by 7 (strongly agree). To ensure standardization of each mary care, one in liver cirrhosis, one in neurosurgery, and reviewer? s approach, all reviewers completed the online one in exercise-associated hyponatremia. Three included training tutorial [15] before starting the project. treatment only [23-25], the seven others covered diagnosis In a consensus meeting among the reviewers, we dis- as well [16-22]. Two groups reported funding by a govern- cussed every item for which scores differed by more than mental institution [16,22], one by the professional soci- 1 point (e.g., 1 versus 3) on the original 7-point scale. eties they represented [20]; the others did not report their Reviewers in turn explained the rationale for their score funding sources [17-19,21,23-25]. and had the opportunity to revise their score when they considered this appropriate. We audiotaped the consensus Appraisal of guidelines and consensus statements meeting to reliably record the underlying reasons for Figure 2 shows the standardized domain scores for each changing scores. guideline for each of the six quality domains assessed with the AGREE II tool (See Additional file 5 for mean Synthesis of guideline recommendations individual scores per item across reviewers). The overall We conducted a textual descriptive synthesis to analyze the quality of reporting of the guideline development process scope, content, and consistency of the included recommen- as assessed by AGREE varied widely both between guid- dations. EN inductively coded the text manually to identify ance documents across domains and within guidance Nagler et al. BMC Medicine 2014, 12:231 Page 4 of 16 http://www.biomedcentral.com/1741-7015/12/231 Figure 1 Flow diagram of the identification process for clinical practice guidelines and consensus statements on hyponatremia. documents between domains. Overall, guideline devel- within one point of each other. Major reasons for chan- opers reported the details of the guideline development ging an entry were a change of own opinion after clarifi- process only to a limited extent. Most had average scores cation of the opinion of other reviewers during the below 50% in four to six of the six AGREE II domains group discussion (180/920 entries; 20% entries); aiming [17,19,21-25], only two received an average >50% on all for consistency between entries given same available data six [16,20]. (39/920; 4%); re-evaluation of the score in light of a Guidelines received the highest scores for scope and noted comment during the appraisal process (30/920; purpose (median 62%; range 28% to 92%) and clarity of 3%); correction for available data that were overlooked presentation (median 47%; range 27% to 75%), and low- during the initial appraisal (22/920; 2%); misinterpret- est scores for applicability (median 19%; range 10% to ation of the question during the initial appraisal (6/920; 68%) and editorial independence (median 19%; range 2% 0.7%); adjusting for arbitrary scoring of items that were to 79%). felt to be inapplicable for some reason (3/920; 0.3%); Initial appraisal results differed more than one point adjusting for inconsistent approach to deal with the on the Likert scale between two or more reviewers for assumption that a criterion was fulfilled even if this was 143/230 items (62%). The majority of discrepancies were not clearly mentioned (4/920; 0.4%); and data entry error found in the domain ? Clarity of Presentation?, with 90% (3/920, 0.3%). Overall, this resulted in 29/60 (48%) of of items differing more than one point. Group discussion standardized domain scores being downgraded by a max- resulted in 287/920 (31%) of individual entries being imum of 10% and 10/60 (17%) of standardized domain changed. Finally, no scores differed more than two scores being upgraded with a maximum of 10%; the points and for 82% of items, scores were the same or remaining 35% remained unchanged. Nagler et al. BMC Medicine 2014, 12:231 Page 5 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 1 Characteristics of included guidelines and consensus statements Developer Year Country Funding Target Target Guideline Guideline Guideline Methods Evidence source population users writers review update support base Europe NIV 2012 Netherlands Government Adults with Clinicians, Multidisciplinary Dutch Association In case of PROVA ? company Systematic funding hyponatremia Internists internists, of Internists (NIV), breakthrough specialized in literature epidemiologist expert peer review changes in Evidence Based review diagnosis or Guideline treatment Development NHS 2011 UK NS Adults with Primary care NS NS Planned NS Systematic hyponatremia in professionals in 2015 literature primary care within NHS review GAIN* 2010 Northern Government Adults with NS Multidisciplinary NS 3 years NS NS Ireland funding hyponatremia anesthetists, clinical chemist, nephrologist AEEH* 2003- Spain NS Patients with cirrhosis NS Gastroenterologists NS NS NS NS EHN* 2013 Spain NS Hospitalized patients NS Multidisciplinary NS NS NS Consensus with SIADH endocrinologists, statements nephrologists, internists, hospital pharmacist ERBP/ESE/ 2014 Europe Unrestricted Adults with Health care Multidisciplinary External review by 5 years or ERBP methods Systematic ESICM grant from hyponatremia professionals nephrologists, KHA-CARI, ESA, and earlier in support team literature participating dealing with endocrinologists, members ERA-EDTA case of new review societies hyponatremia general internists, evidence critical care physicians requiring changes North America UF 2008- USA NS Neurosurgery patients NS Multidisciplinary NS NS NS Systematic 2009 with hyponatremia neurosurgeons, nurse literature practitioners, nephrologists, review critical care physician, endocrinologist, pharmacist, nurses HEP 2013 USA Funding Patients with NS Endocrinologist, NS NS NS Systematic Unrestricted hyponatremia nephrologists literature educational review grant from pharmaceutical company Australia RCHM* 2012 Australia NS Children NS NS External review 12 to NS NS within the hospital 24 months where appropriate? Nagler et al. BMC Medicine 2014, 12:231 Page 6 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 1 Characteristics of included guidelines and consensus statements (Continued) International EAH- ICD* 2007 USA, Canada, No commercial People with Medical Multidisciplinary NS NS NS Systematic UK, Switzer-land, sponsorship? exercise-associated personnel, endocrinologist, literature Canada, South hyponatremia athletes, epidemiologist, review Africa, New greater public nephrologists, Zealand, Australia emergency medicine physician, general practitioner, internist, sports physicians, exercise physiologists NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]; [Na], Serum sodium concentration; NS, Not stated; KHA-CARI, Kidney Health Australia, Caring for Australasians with Renal Impairment; ESA, Endocrine Society of Australia; ERA-EDTA, European Renal Association; European Dialysis and Transplant Association; *Classified as consensus statement. Nagler et al. BMC Medicine 2014, 12:231 Page 7 of 16 http://www.biomedcentral.com/1741-7015/12/231 Figure 2 Guideline assessment according to the appraisal of guideline for research and evaluation (AGREE II) instrument. NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa? ola para el Estudio del H?gado [23]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [15]; *Classified as consensus statement. Note: items were originally scored on a Likert scale of 1 [Strongly Disagree] to 7 [Strongly Agree]. The numerical scores presented for each domain are a summary of individual item scores by each reviewer. Synthesis of recommendations Guidance documents differed somewhat in their recom- The included guidance documents addressed three major mended threshold for starting diagnostic assessment. Six themes: diagnosis, treatment, and speed of correction. recommended starting diagnostic assessment when the serum sodium concentration dropped below 135 mmol/L [17,19-23] and to confirm hypotonicity through a measured Approaches to diagnostic strategies for hyponatremia serum or plasma osmolality <275 to 285 mOsm/kg Seven guidance documents covered diagnosis and differen- [16-20,22]. Two others set lower thresholds of serum so- tial diagnosis of hyponatremia [16-22]. Table 2 shows the dium concentration at <131 mmol/L [18] and <130 mmol/L key recommendations. The key areas addressed included [23]. Six guidance documents advised classifying hypotonic the threshold for initiating diagnostic workup, confirmation hyponatremia into categories of hypovolemia, euvolemia, and classification of hypotonic hyponatremia, and identifi- and hypervolemia to aid differential diagnosis and guide cation of the underlying disorder. treatment [16-22]. Most guidance documents recom- Nagler et al. BMC Medicine 2014, 12:231 Page 8 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 2 Summary of recommendations for approaches to diagnosis of hyponatremia by included guidance documents Guideline Organization/Society Criteria/Categories NIV [16] NHS [17]GAIN[22] AEEH [23] EHN [25] ERBP/ESE/ UF [18] HEP [19] RCHM [21]EAH-ICD ESICM [20] [24] Threshold workup [Na] <135 mmol/L <135 mmol/L <135 mmol/L <130 mmol/L <135 mmol/L <135 mmol/L <131 mmol/L <135 mmol/L <135 mmol/L Confirming hypotonic Serum osmolality Plasma osmolality Serum osmolality Plasma osmolality Serum osmolality Serum osmolality Plasma osmolality Serum hyponatremia <275 mOsm/kg <280 mOsm/kg <275 mOsm/kg <275 mOsm/kg <275 mOsm/kg <285 mOsm/kg <280 mOsm/kg osmolality threshold not stated How to classify hypotonic hyponatremia to aid identification of underlying cause Volume status/ Clinical Physical Physical Physical Physical Physical Physical To assess hydration state/ evaluation examination/clinical examination/clinical examination/ examination/ examination/ examination/ but method extracellular fluid signs of dehydration signs of dehydration clinical signs of clinical signs of laboratory laboratory not stated status or edema or edema low circulating dehydration measurements measurements volume or edema Urinary [Na]/Threshold 30 mmol/L Spot urine: 15 mmol/L 40 mmol/L 30 mmol/L 25 mmol/L Spot urine: No threshold 20? 30 mmol/L 20? 30 mmol/L stated Urinary osmolality/ 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg No threshold Threshold stated How to identify the underlying disorder History Medications Medications Diuretic use Fluid intake Recently prescribed intravenous fluids Nocturnal polyuria Vomiting/diarrhea Lab tests Serum potassium ++ + concentration Serum chloride + + concentration Serum urea +/? + +/? +/? + concentration Serum creatinine ++ +/? +/? + concentration Serum glucose ++ +/? ++ concentration Nagler et al. BMC Medicine 2014, 12:231 Page 9 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 2 Summary of recommendations for approaches to diagnosis of hyponatremia by included guidance documents (Continued) Urinary potassium + + concentration Renal tests + Liver tests + +/? Urinary protein +/? Thyroid function +/? +/? +/? +/? tests Adrenal function +/? +/? +/? +/? tests Serum protein +/? electrophoresis Urine protein +/? electrophoresis Fractional sodium +/? excretion Serum uric acid +/? +/? ++/? concentration Fractional uric acid +/? concentration Fractional excretion +/? urea Urinary chloride +/? ++/? concentration Molar weight urine +/? Serum bicarbonate +/? concentration Hematocrit +/? [Na], Serum sodium concentration; +, always; +/? , If clinically indicated/sometimes useful. NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]. Nagler et al. BMC Medicine 2014, 12:231 Page 10 of 16 http://www.biomedcentral.com/1741-7015/12/231 mended a clinical assessment of hydration status and a whereas one advised to consider stopping diuretics [23]. urinary sodium concentration as well as a urinary osmo- One guideline additionally proposed demeclocycline and lality measurement, although specific criteria, thresholds, two proposed vasopressin receptor antagonists as a second- and algorithms differed. line treatment for refractory hyponatremia [17,19], whereas Most guidance documents proposed additional labora- one guideline specifically recommended against both deme- tory tests that could be of value to identify the underlying clocycline and vasopressin receptor antagonists [20]. disorder, but they varied substantially regarding which tests to use in what situation and which reference values Targets and limits of speed of correction to use. Only two explicitly recommended taking a history Table 4 shows the key recommendations. The key areas of drug intake and symptoms as part of the assessment include targets and limits for increase in serum sodium [17,22]. Four presented an algorithm to guide differential concentration. diagnosis [16,18,20,22]. Seven guidance documents provided targets or aims for the increase in serum sodium concentration in case of Approaches to treatment for hyponatremia symptomatic and/or acute hyponatremia [16,17,19-22,25]. Table 3 shows the recommendations for the medical man- Seven guidance documents provided limits for the agement of hyponatremia. Guidance documents distin- increase in serum sodium concentration that should guished treatment scenarios based on whether patients not be surpassed [16-22,25]. Five did so independent of had severe symptoms [17-22,24,25] or whether the hypo- symptoms [16,18,20,22,25]. Limits usually varied between natremia was acute (48 h) or chronic [16]. All but one 8 to 12 mmol/L during the first 24 hours [16-22,25] and discussed treatment in the setting of severe symptoms and 18 mmol/L during the first 48 hours [16,17,19,20,25], recommended infusion of hypertonic saline, usually speci- irrespective of whether hyponatremia was acute or fied as having a concentration of 3% [17,19-21,24,25]. One chronic [16,17,20,25]. Three guidance documents set a suggested using a formula to guide the infusion speed of a stricter limit of <8 mmol/L during the first 24 hours in continuous infusion [16], five others recommended giving cases where the patient was believed to be high risk for a fixed dose [19,20,22,24,25], or a dose adjusted to body developing osmotic demyelination syndrome [16,19,25]. weight [21,25] with repeated serum sodium concentration Four discussed what to do in case of overcorrection, i.e., measurements to check progression [16,20-22,25]. to stop current treatment and to consider re-lowering Patients without symptoms of hyponatremia were serum sodium concentration by starting hypotonic infu- assumed to have chronic onset hyponatremia, and sion and administering 1 to 4 μg desmopressin every 6 to treatment suggestions were mostly dependent on the 8 hours [16,19,20,25]. classification hypovolemic, euvolemic, or hypervolemic. Only three guidance documents specifically advised treat- Discussion ing the underlying condition [19,22]. Seven suggested We found five clinical practice guidelines and five con- 0.9% saline in hypovolemia [16-22], with infusion speeds sensus statements covering the diagnostic approach to calculated with Adrogu?-Madias [22], until restoration of and treatment of hyponatremia. Although most used blood pressure [17,19] or until nasogastric rehydration serum osmolality, volume status, urinary sodium, and could start [21]. urinary osmolality to guide differential diagnosis, they For euvolemic asymptomatic hyponatremia, the majority differed in classification thresholds, what additional tests recommended fluid restriction as the first-line treatment to consider, and when to initiate diagnostic work-up. [16-25]. Five guidance documents proposed a number of Most advocated hypertonic NaCl in severely symptom- other interventions as second-line treatments including atic, acute onset hyponatremia and NaCl 0.9%, fluid loop diuretics [16,18,20,25], demeclocycline [16-19], urea restriction, and cause-specific therapy for hypovolemic, [16,19,20,25], vasopressin receptor antagonists [16,17,25], euvolemic, and hypervolemic hyponatremia, respectively. or lithium [18]. One guideline specifically recommended However, they somewhat differed in the limits for speed against vasopressin receptor antagonists in case of a serum of increase in serum sodium concentration and which sodium concentration <125 mmol/L [20]. specific medications to use. The reasons for offering For hypervolemic asymptomatic hyponatremia, seven different recommendations are undoubtedly multifac- guidance documents recommended fluid restriction as torial. They may in part be explained by the fact that the first-line treatment [16,17,19-23] (Table 3). Three guid- recommendations were issued by organizations differing ance documents advocated concomitant salt restriction, in context and scope. It is also very likely that some without clear dose recommendations [17,19,22], and one to variability in guidance arose through limitations in the avoid hypotonic infusion solution [21]. Three additionally evidence available for guideline developers to base their proposed loop diuretics [16,17,19] and three others gener- recommendations on [8]. In the most recent guideline ally stated to treat the underlying disease [17,20,22], on diagnosis and treatment of hyponatremia, 98% of the Nagler et al. BMC Medicine 2014, 12:231 Page 11 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 3 Summary of recommendations for approaches to treatments for hyponatremia by included guidance documents Guideline Organization/Societies Criteria/ NIV [16] NHS [17]GAIN[22] AEEH [23] EHN [25] ERBP/ESE/ UF [18] HEP [19] RCHM [21] EAH-ICD categories ESICM [20] [24] Symptoms Acute Onset NaCl >1% NaCl 3% NaCl 2.7% NaCl 3% 100 mL/ NaCl 3% 150 mL/ NaCl >1% NaCl 3% 100 mL/ NaCl 3% NaCl 3% (<48 h) Infusion speed 200 mL over 10 min up to 20 min up to 4? 10 min up to 4 mL/kg 100 mL may be guided by 30 min 3? or infused at 3? or infused at over 30 min bolus Adrogu?-Madias 0.5? 2mL/kg/h 0.5? 2mL/kg/h Hypovolemia NaCl 0.9% until blood pressure restored Euvolemia Fluid restriction No hypotonic fluids Stop offending drugs Stop hypotonic fluids Hypervolemia Furosemide Furosemide Chronic onset NaCl >1% Infusion NaCl 3% Only if severe NaCl 3% 100 mL/ NaCl 3% 150 mL/ NaCl >1% NaCl 3% 100 mL/ (>48 h) speed calculation symptoms NaCl 2.7% 10 min up to 20 min up to 4? 10 min up to 3? may be guided by 200 mL over 30 min 3? or infused at or infused at Adrogu?-Madias infusion speed by 0.5? 2mL/kg/h 0.5-2 mL/kg/h may be guided Adrogu?-Madias Hypovolemia NaCl 0.9% 1 L over NaCl 0.9% until 2? 4 h infusion speed blood pressure may be guided by restored Adrogu?-Madias Euvolemia Fluid restriction Stop offending medications Stop hypotonic fluids Hypervolemia Fluid restriction Furosemide Salt restriction No symptoms Acute onset NaCl >1% Treat underlying Stop offending fluids Treat underlying (<48 h) Infusion speed by condition and medications, condition Adrogu?-Madias treat underlying Nagler et al. BMC Medicine 2014, 12:231 Page 12 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 3 Summary of recommendations for approaches to treatments for hyponatremia by included guidance documents (Continued) condition NaCl 3% 150 mL/20 min Chronic Treat underlying Treat underlying Stop non-essential Treat underlying onset (>48 h) condition condition fluids Stop offending condition medications Treat underlying condition Hypovolemia NaCl 0.9% NaCl 0.9% until NaCl 0.9% NaCl 0.9% or NaCl 0.9% NaCl 0.9% until Nasogastric blood pressure infusion speed balanced crystalloid blood pressure rehydration restored may be guided by 0.5? 1mL/kg/h restored Adrogu?-Madias NaCl tablets No VPA NaCl 0.9% Euvolemia Fluid restriction, Fluid restriction, Fluid restriction Fluid restriction Fluid restriction Fluid restriction Fluid restriction Fluid restriction, dose dependent 500? 1,000 mL/d <500? 1,000 mL/d 500 mL below no hypotonic on serum and average daily fluids urinary electrolytes urine output No salt Salt restriction Salt 5? 8 g/d No salt restriction restriction Loop diuretics Furosemide Loop diuretics, Diuretics 20? 60 mg/d + low dose + oral NaCl oral NaCl Demeclocycline Demeclocycline No demeclocycline Demeclocycline Demeclocycline, 600? 1,200 mg/d Urea Urea 30 g/d Urea, 0.25? 0.5 g/kg/d Urea Urea, 15? 60 g/d Vasopressin Vasopressin Tolvaptan No vasopressin receptor receptor antagonist 15? 60 mg/d receptor antagonists antagonist Hypervolemia Treat underlying condition Fluid restriction, Fluid restriction Fluid restriction Fluid restriction Fluid restriction Fluid restriction, Fluid restriction dose dependent <1,000 mL/d <insensible losses + on serum and urine output urinary electrolytes Loop diuretics Salt restriction Salt restriction No NaCl >0.9% Salt restriction Demeclocycline Stop No demeclocycline Possibly vasopressin diuretics receptor antagonist Vasopressin No vasopressin receptor receptor antagonist antagonist NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]. Nagler et al. BMC Medicine 2014, 12:231 Page 13 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 4 Summary of recommendations for targets and limits for speed of correction of hyponatremia by included guidance documents Guideline Organization/Societies Criteria/ NIV NHS GAIN AEEH EHN ERBP/ESE/ESICM UF HEP RCHM EAH- categories ICD [16][17][22][23][25][20][18][19][21][24] Targets [Na] increase Symptoms Independent If symptoms If symptoms If symptoms If symptoms If symptoms Until seizures resolve of symptoms or [Na] >125 mmol/L Acute onset 1? 2 mmol/L/h Until [Na] 1? 2 mmol/L/h 1? 6 mmol/L first 2 h 5 mmol/L first h 4? 6 mmol/L Independent of onset (<48 h) initially >120 mmol/L first 2? 3h urgently independent of onset Chronic onset 0.5? 1 mmol/ 1? 6 mmol/L first 2 h 5 mmol/L first h If seizures or coma (>48 h) L/h first 2? 3h 4? 6 mmol/L urgently, otherwise 4? 6 mmol/L per 24 h Limits [Na] increase Symptoms Independent If no symptoms Independent Independent of Independent Independent If no symptoms Symptom dependent of symptoms of symptoms symptoms of symptoms of symptoms Acute onset If no risk of ODS ≤8? 12 mmol/L per <12 mmol/L If no risk of ODS ≤10 mmol/L first ≤10 mmol/L No limits ≤8 mmol/L per 24 h (<48 h) ≤10 mmol/L per 24 h ≤18 mmol/L per per 24 h ≤10 mmol/L per 24 h 24 h ≤8 mmol/L per 24 h after seizures resolve, 24 h ≤18 mmol/L 48 h ≤18 mmol/L per 48 h every 24 h thereafter Independent of onset per 48 h If risk of If risk of ODS <8 mmol/L ODS <8 mmol/L per 24 h per 24 h Chronic onset <8 mmol/L ≤8? 12 mmol/L <12 mmol/L <8? 12 mmol/L ≤10 mmol/L first ≤10 mmol/L <8? 12 mmol/L (>48 h) per 24 h per 24 h ≤18 mmol/L per 24 h per 24 h <18 mmol/L 24 h ≤8 mmol/L per 24 h per 24 h <18 mmol/L per 48 h per 48 h every 24 h thereafter per 48 h [Na] ? Serum sodium concentration. NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]. Nagler et al. BMC Medicine 2014, 12:231 Page 14 of 16 http://www.biomedcentral.com/1741-7015/12/231 graded recommendations were based on very low and hyponatremia, such as fluid restriction, may affect quality low level of evidence, while none were based on a high of life and patient preference should influence the ultimate level of evidence. The lack of high quality evidence may recommendations. have increased the part opinion had to play in framing Low scores for applicability mostly reflect the absence the recommendations. In addition, the evidence that of describing barriers to guideline implementation and was available may have been interpreted differently failure to provide tools for putting the recommendations dependent on the importance for decision making given into practice. In part, guidelines are designed to deal with to certain outcomes (e.g., serum sodium concentration). the challenges of increasing knowledge and time-pressure. Finally, differences in personal experience due to differ- They are designed to help make decisions at the point ing availability of medications may partly explain pos- of care. However, being often lengthy publications with- sible differences in perception of uncertainties around out layered presentation of information, it is likely that drug safety. the majority of the guidance documents may not reach However, it is also possible that discrepancies between their target audience or stimulate implementation. Four guidance documents may in part be explained by differ- guidance documents provided algorithms for diagnosis ences in underlying methods of development. Quality, or treatment [16,18,20,25]; although these are likely to as assessed by AGREE II, was suboptimal at best, with increase the utility of a guideline, it is unclear to what only two documents obtaining a score >50% for each of extent they truly improve implementation of the recom- the six quality domains [16,20]. The findings suggest mendations. How to best communicate evidence-based that several aspects related to methodological rigor of recommendations to the relevant stakeholders is a recent development, stakeholder involvement, applicability, and but active area of research lead by the DECIDE consor- editorial independence could be improved, possibly im- tium [28]. With results of their research expected, guide- proving consistency in provided guidance. This is in line line developers will have additional targets for improving with the findings of a recent overview of 42 appraisal the applicability in the future. studies including a total of 626 clinical practice guidelines To our knowledge, this is the first attempt to systemat- across several clinical disciplines [26]. For guidelines to ically synthesize and appraise clinical guidelines on the be trustworthy, they must be i) founded on high quality diagnosis and treatment of hyponatremia In accordance systematic reviews, ii) include the relevant stakeholders, with the Prisma statement, we conducted a comprehensive and iii) be applicable in clinical practice [9]. literature search and searched an additional 337 web- Only half of the guidance groups stated they had con- sites of specialist societies and guideline organizations ducted a systematic review of the evidence. Save one, the [29] (Additional file 6). We used AGREE II, a validated and reviewswould nothavemet theInstitute of Medicine?scri- reliable instrument, and an adequate number of reviewers teria for reporting high-quality systematic reviews [20,27], to individually appraise the guidance documents [30]. On because key methods for finding and assessing individual top of the individual appraisals, we included an attempt studies as well as synthesizing the body of evidence were to resolve major discrepancies and increase consistency not described. Conducting high-quality systematic reviews by introducing an audiotaped group consensus meeting. requires specific methodological expertise and support During this meeting, reviewers could explain and motivate which may not be available to most groups [27]. One their scores and adapt them if they wanted to. This mostly solution might be to harmonize effort across organiza- resulted only in modest downgrading of domain scores tions, thus focusing resources, allowing higher quality by 1% to 10%. Most of the changes happened because reviews and reducing duplication and possibly inconsist- reviewers felt they had scored inconsistently for a same ency between guidelines. rationale, or because they missed information during Six groups included healthcare professionals from dif- the initial appraisal that was in fact available in the document. Although the scores did not change substan- ferent specialties [16,18,20,22,24,25]. Multidisciplinary contribution serves to broaden the approach to health-care tially, the group felt the discussion further highlighted problems, increase the completeness of evidence-finding the qualitative differences between the guidance docu- ments. In addition, even the reviewers with large devia- strategies, and help to identify hurdles to implementation. When reflecting on approaches to hyponatremia, bringing tions from the mean in their initial scores felt they agreed together several disciplines mirrors the clinical reality with the conclusion. It means that final average scores were truly a product of consensus rather than a mathem- of multiple specialty areas dealing with the same prob- lem but looking at it from a different angle. Only one atical calculation, as proposed in the original AGREE of the development groups reported considering patients? protocol. We believe that a consensus meeting is valuable views and experiences, but even then did so to a limited in any guideline appraisal process, and particularly useful extent [20]. Decisions on clinical care should factor in if reviewer groups have the intention to select a guideline patient values and preferences. Interventions for chronic for local use. Nagler et al. BMC Medicine 2014, 12:231 Page 15 of 16 http://www.biomedcentral.com/1741-7015/12/231 This study has its limitations. We based our assessment Additional file 3: Table S3. Structure and content of the AGREE on what guideline organizations actually reported. Report- instrument. ing by guideline developers may not wholly reflect what Additional file 4: Table S4. Table of excluded studies. occurred in practice with respect to the AGREE criteria, Additional file 5: Table S5. Mean scores across reviewers for the individual AGREE II domain items. and we did not seek additional clarification. However, Additional file 6: PRISMA checklist. contacting guideline developers is not standard practice when using AGREE as the instrument specifically aims to provide a framework for assessing the quality of reporting Abbreviation AGREE II: Appraisal of guidelines for research and evaluation II. of recommendations. We aimed to summarize the existing recommendations on diagnosis and treatment of hypona- Competing interests tremia as formulated by other guideline development Evi Nagler is a member of the Methods Support Team of European Renal groups and to evaluate the quality of the guideline devel- Best Practice (ERBP). She is also one of the authors of the Clinical Practice Guideline on the diagnosis and treatment of hyponatremia, developed in a opment process. We did not aim to summarize or critic- joint venture with the European Society of Endocrinology and the European ally appraise the evidence base itself. Consequently, it is Society of Intensive Care Medicine and one of the guidelines included in the difficult to assess to what extent differences between guid- current review. Jill Vanmassenhove has no relevant disclosures. Sabine van der Veer is a member of the Methods Support Team of European Renal Best ance documents stem from differences in development Practice (ERBP). She is also one of the authors of the Clinical Practice procedures rather than important limitations in the evi- Guideline on the diagnosis and treatment of hyponatremia, developed in a dence base that underpin individual recommendations. joint venture with the European Society of Endocrinology and the European Society of Intensive Care Medicine and one of the guidelines included in the Secondly, the purpose of using the AGREE instrument current review. Ionut Nistor is a member of the Methods Support Team of was not to accuse guideline development groups of being ERBP. Wim Van Biesen is the Chair of ERBP, he is also one of the authors of biased, but rather to highlight both strengths and weak- the Clinical Practice Guideline on the diagnosis and treatment of hyponatremia, developed in a joint venture with the European Society of nesses of existing guidance to suggest on how we could Endocrinology and the European Society of Intensive Care Medicine and one make improvements in the future. of the guidelines included in the current review. Angela Webster has no Calculation of summary scores for each domain across relevant disclosures. Raymond Vanholder is member of ERBP, he is also one of the authors of the Clinical Practice Guideline on the diagnosis and reviewers required summing up all the scores of the in- treatment of hyponatremia, developed in a joint venture with the European dividual items in a domain for each reviewer and then Society of Endocrinology and the European Society of Intensive Care standardizing this total as a percentage of the maximum Medicine and one of the guidelines included in the current review. possible score for that domain. In doing so, the originally Authors? contributions semi-qualitative Likert scale was converted to a quantita- EN designed and conducted the systematic review, conducted the systematic tive score. This may have introduced numeric differences search, selected and critically appraised the studies, collected the data, and between the guidance documents that were beyond the wrote and revised the manuscript. JV selected and critically appraised the studies, collected the data, and revised the manuscript. SVDV critically appraised discriminatory ability of the tool and possibly negligible in the studies. IN conducted the systematic search and critically appraised the practice. Finally, we acknowledge that four of the authors studies. WVB designed the systematic review, critically appraised the studies, of this paper also authored one of the guidelines included and wrote and revised the manuscript. AW designed the systematic review and wrote and revised the manuscript. RV designed the systematic review and in this review. Although we aimed to judge all guidance wrote and revised the manuscript. All authors read and approved the documents fairly against the criteria outlined by the final manuscript. AGREE instrument, we cannot rule out that a subcon- scious intellectual competing interest unduly influenced Acknowledgements the scoring. Evi Nagler, Sabine van der Veer, and Ionut Nistor are fellows of the Methods Support Team of European Renal Best Practice (ERBP), supported by a grant of the European Renal Association- European Dialysis Transplantation Association (ERA-EDTA). Conclusions Author details Current guidelines on the assessment and treatment of European Renal Best Practice (ERBP), guidance body of the European Renal hyponatremia often fail to meet methodological criteria Association ? European Dialysis and Transplant Association (ERA-EDTA), De for development and reporting as described by AGREE II. Pintelaan 185, Ghent 9000, Belgium. Renal Division, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium. Despite many similarities, recommendations are some- Centre for Kidney Research, The Children? s Hospital at Westmead, Locked times inconsistent, but to what extent this is attributable Bag 4001, Westmead 2145, NSW, Australia. Department of Medical to the underlying development process remains unclear. Informatics, Academic Medical Center, Postbus 22660, Amsterdam 1100DD, the Netherlands. Nephrology Department, Gr. T. Popa University of Medicine and Pharmacy, Strada Universit?tii 16, Iasi 700115, Romania. Sydney School of Public Health, Edward Ford Building (A27), The University of Sydney, NSW Additional files 7 2006, Australia. Centre for Transplant and Renal Research, The University of Sydney at Westmead Hospital, Westmead 2145, NSW, Australia. Additional file 1: Table S1. Search strategies. Received: 20 April 2014 Accepted: 7 November 2014 Additional file 2: Table S2. Data extraction template. Nagler et al. BMC Medicine 2014, 12:231 Page 16 of 16 http://www.biomedcentral.com/1741-7015/12/231 References Speedy DB, Stuempfle KJ, Verbalis JG, Weschler LB, Wharam P: Statement of 1. Ellison DH, Berl T: Clinical practice. The syndrome of inappropriate the Second International Exercise-Associated Hyponatremia Consensus antidiuresis. N Engl J Med 2007, 356:2064? 2072. Development Conference, New Zealand, 2007. Clin J Sport Med 2008, 2. Upadhyay A, Jaber BL, Madias NE: Epidemiology of hyponatremia. 18:111? 121. Semin Nephrol 2009, 29:227? 238. 25. Runkle I, Villabona C, Navarro A, Pose A, Formiga F, Tejedor A, Poch E, 3. Liamis G, Rodenburg EM, Hofman A, Zietse R, Stricker BH, Hoorn EJ: European Hyponatremia N: The treatment of hyponatremia secondary to Electrolyte disorders in community subjects: prevalence and risk factors. the syndrome of inappropriate antidiuretic hormone secretion. Medicina Am J Med 2013, 126:256? 263. Cl?nica 2013, 141:e501? e510. 26. Alonso-Coello P, Irfan A, Sol? I, Gich I, Delgado-Noguera M, Rigau D, Tort S, 4. Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE: Impact of hospital- Bonfill X, Burgers J, Schunemann H: The quality of clinical practice associated hyponatremia on selected outcomes. Arch Intern Med 2010, guidelines over the last two decades: a systematic review of guideline 170:294? 302. appraisal studies. Qual Saf Health Care 2010, 19:e58. 5. Hoorn EJ, Lindemans J, Zietse R: Development of severe hyponatremia in 27. Committee on Standards for Systematic Reviews of Comparative Effectiveness hospitalized patients: treatment-related risk factors and inadequate Research, Board on Health Care Services, Institute of Medicine: In Finding What management. Nephrol Dial Transplant 2006, 21:70? 76. Works in Health Care: Standards for Systematic Reviews. Edited by Eden J, Levit 6. Huda MSB, Boyd A, Skagen K, Wile D, van Heyningen C, Watson I, Wong S, L, Berg A, Morton S. US: The National Academies Press; 2011. Gill G: Investigation and management of severe hyponatremia in a 28. Treweek S, Oxman A, Alderson P, Bossuyt P, Brandt L, Brozek J, Davoli M, hospital setting. Postgrad Med 2006, 82:216? 219. Flottorp S, Harbour R, Hill S, Liberati A, Liira H, Sch?nemann HJ, Rosenbaum S, 7. Fenske W, Maier SKG, Blechschmidt A, Allolio B, Stork S: Utility and Thornton J, Vandvik PO, Alonso-Coello P, DECIDE Consortium: Developing and limitations of the traditional diagnostic approach to hyponatremia: a evaluating communication strategies to support informed decisions and diagnostic study. Am J Med 2010, 123:652? 657. practice based on evidence (DECIDE): protocol and preliminary results. 8. Sterns RH, Nigwekar SU, Hix JK: The treatment of hyponatremia. Implementation Science 2013, 8:6. Semin Nephrol 2009, 29:282? 299. 29. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred Reporting Items for 9. Committee on Standards for Developing Trustworthy Clinical Practice Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Guidelines, Board on Health Care Services, Institute of Medicine: In Clinical Med 2009, 6:e1000097. doi:10.1371/journal.pmed1000097. Practice Guidelines We Can Trust. Edited by Graham R, Mancher M, Wolman 30. Irani S, Rashidian A, Yousefi-Nooraie R, Soltani A: Evaluating clinical practice DM, Greenfield S, Steinberg E. US: The National Academies Press; 2011. guidelines developed for the management of thyroid nodules and 10. Glujovsky D, Bardach A, Garc?a Mart? S, Comand? D, Ciapponi A: EROS: a thyroid cancers and assessing the reliability and validity of the AGREE new software for early stage of systematic reviews. Value Health 2011, instrument. J Eval Clin Pract 2011, 17:729? 736. 14:A564. 11. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, doi:10.1186/s12916-014-0231-1 Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L, Cite this article as: Nagler et al.: Diagnosis and treatment of hyponatremia: AGREE Next Steps Consortium: AGREE II: Advancing guideline development, a systematic review of clinical practice guidelines and consensus statements. reporting and evaluation in healthcare. Can Med Ass J 2010, 182:E839? E842. BMC Medicine 2014 12:231. 12. Collaboration AGREE: Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care 2003, 12:18? 23. 13. Tong A, Chapman JR, Wong G, de Bruijn J, Craig JC: Screening and follow-up of living kidney donors: a systematic review of clinical practice guidelines. Transplantation 2011, 92:962? 972. 14. Lopez-Olivo MA, Kallen MA, Ortiz Z, Skidmore B, Suarez-Almazor ME: Quality appraisal of clinical practice guidelines and consensus statements on the use of biologic agents in rheumatoid arthritis: a systematic review. Arthritis Rheum 2008, 59:1625? 1638. 15. AGREE: Advancing the science of practice guidelines. [http://www.agreetrust.org/resource-centre/agree-ii-training-tools/] 16. Geers ABM, Tuut MK, Hoorntje SJ, van Saase JLCM, Zietse R: Electrolytstoornissen. NIV: Hoorn EJ; 2012. [http://www.internisten.nl]. Accessed 01 January 2013. 17. Clinical Knowledge Summaries: Prodigy Topic on Hyponatremia. 2011, [http://www.cks.nhs.uk/hyponatremia]. Accessed 02 January 2013. 18. Rahman M, Friedman WA: Hyponatremia in neurosurgical patients: clinical guidelines development. Neurosurgery 2009, 65:925? 935. 19. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ: Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med 2013, 126:S1? S42. 20. 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, Hyponatraemia Guideline Development Submit your next manuscript to BioMed Central Group: Clinical practice guideline on diagnosis and treatment of and take full advantage of: hyponatremia. Nephrol Dial Transplant 2014, 29:i1? i39. 21. Royal Children's Hospital Melbourne Australia: Clinical Practice Guideline ? Convenient online submission on Hyponatremia. [http://www.rch.org.au/clinicalguide/index.cfm]. ? Thorough peer review Accessed 02 January 2013. 22. Hyponatremia in Adults (On or after 16th Birthday). [http://www.gain-ni. ? No space constraints or color ?gure charges org]. Accessed 03 January 2013. ? Immediate publication on acceptance 23. Gines P, Cabrera J, Guevara M, Morillas R, Ruiz del Arbol L, Solae R, Soriano G: Consensus document on the treatment of ascites, dilutional ? Inclusion in PubMed, CAS, Scopus and Google Scholar hyponatremia and hepatorenal syndrome in liver cirrhosis. Gastroenterol ? Research which is freely available for redistribution Hepatol 2004, 27:535? 544. 24. Hew-Butler T, Ayus JC, Kipps C, Maughan RJ, Mettler S, Meeuwisse WH, Submit your manuscript at Page AJ, Reid SA, Rehrer NJ, Roberts WO, Rogers IR, Rosner MH, Siegel AJ, www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Medicine Springer Journals

Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and consensus statements

Loading next page...
 
/lp/springer-journals/diagnosis-and-treatment-of-hyponatremia-a-systematic-review-of-DvenW21nMR

References (38)

Publisher
Springer Journals
Copyright
Copyright © 2014 by Nagler et al.; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Medicine/Public Health, general; Biomedicine general
eISSN
1741-7015
DOI
10.1186/s12916-014-0231-1
pmid
25539784
Publisher site
See Article on Publisher Site

Abstract

Background: Hyponatremia is a common electrolyte disorder. Multiple organizations have published guidance documents to assist clinicians in managing hyponatremia. We aimed to explore the scope, content, and consistency of these documents. Methods: We searched MEDLINE, EMBASE, and websites of guideline organizations and professional societies to September 2014 without language restriction for Clinical Practice Guidelines (defined as any document providing guidance informed by systematic literature review) and Consensus Statements (any other guidance document) developed specifically to guide differential diagnosis or treatment of hyponatremia. Four reviewers appraised guideline quality using the 23-item AGREE II instrument, which rates reporting of the guidance development process across six domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Total scores were calculated as standardized averages by domain. Results: We found ten guidance documents; five clinical practice guidelines and five consensus statements. Overall, quality was mixed: two clinical practice guidelines attained an average score of >50% for all of the domains, three rated the evidence in a systematic way and two graded strength of the recommendations. All five consensus statements received AGREE scores below 60% for each of the specific domains. The guidance documents varied widely in scope. All dealt with therapy and seven included recommendations on diagnosis, using serum osmolality to confirm hypotonic hyponatremia, and volume status, urinary sodium concentration, and urinary osmolality for further classification of the hyponatremia. They differed, however, in classification thresholds, what additional tests to consider, and when to initiate diagnostic work-up. Eight guidance documents advocated hypertonic NaCl in severely symptomatic, acute onset (<48 h) hyponatremia. In chronic (>48 h) or asymptomatic cases, recommended treatments were NaCl 0.9%, fluid restriction, and cause-specific therapy for hypovolemic, euvolemic, and hypervolemic hyponatremia, respectively. Eight guidance documents recommended limits for speed of increase of sodium concentration, but these varied between 8 and 12 mmol/L per 24 h. Inconsistencies also existed in the recommended dose of NaCl, its initial infusion speed, and which second line interventions to consider. Conclusions: Current guidance documents on the assessment and treatment of hyponatremia vary in methodological rigor and recommendations are not always consistent. Keywords: Clinical practice guideline, Hyponatremia, Systematic review * Correspondence: evi.nagler@ugent.be European Renal Best Practice (ERBP), guidance body of the European Renal Association ? European Dialysis and Transplant Association (ERA-EDTA), De Pintelaan 185, Ghent 9000, Belgium Renal Division, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium Full list of author information is available at the end of the article ? 2014 Nagler et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nagler et al. BMC Medicine 2014, 12:231 Page 2 of 16 http://www.biomedcentral.com/1741-7015/12/231 Background to assist clinicians in the management of hyponatremia. Hyponatremia is the most common electrolyte disorder in To be reliable, these recommendations must be based clinical medicine; it represents an excess of water relative on a systematic review of the evidence, and have a trans- to total body solute [1]. Hyponatremia usually results from parent and multidisciplinary development process [9]. the intake and subsequent retention of electrolyte-free Inconsistencies between recommendations may arise water in response to true hypovolemia due to gastro- from failing to meet development standards and can intestinal solute loss or malnutrition; decreased effective only add to unwarranted variability in management. In circulating volume due to heart failure or liver cirrhosis; this study, we aimed to explore the scope, content, and or non-osmotic vasopressin activity due to malignancies, consistency of the existing guidance documents on the infections, medications, pain, or stress [2]. When defined diagnosis and management of hyponatremia in adults as a serum sodium concentration below 135 mmol/L, and children. hyponatremia occurs in up to 8% of the general popula- tion and in up to 60% of hospitalized patients [2,3]. Acute Methods profound hyponatremia can cause brain edema, but also Criteria for selection of studies chronic mild hyponatremia is associated with poor health We included evidence-based clinical practice guidelines outcomes. Even when comorbid conditions are taken and consensus statements on the diagnosis and treatment into account, people with a mildly decreased serum of hyponatremia. We defined clinical practice guidelines sodium concentration have a 30% higher risk of death and as statements that included recommendations intended to are hospitalized 14% longer relative to those without optimize patient care informed by a systematic review of hyponatremia [2,4]. evidence and an assessment of the benefits and harms Despite the frequency and severity of some of the of alternative care options [9]. We defined consensus associated complications, research suggests hyponatre- statements as documents containing clinically relevant mia is often neglected by clinicians [5]. If acquired in suggestions or recommendations based on the col- hospital, it may take days before the electrolyte disorder lective opinion of an expert panel [9]. We included all is investigated, potentially allowing a further decrease in publications independent of language. We excluded serum sodium concentration and exposing patients to guidelines related to the prevention of hyponatremia the dangers of profound hyponatremia. When efforts are as well as guidelines relevant to conditions associated made to explore the underlying cause, clinicians use widely with hyponatremia if they were not specifically designed different strategies for differential diagnosis, testing is often to address hyponatremia. Hence, we excluded guidelines inadequate and misclassification of the hyponatremia fre- targeting treatment of heart failure, cirrhosis, and cancer quently occurs [6,7]. unless they were developed with a focus on hyponatremia Hyponatremia may be managed clinically by different as a complication. Finally, we also excluded draft unpub- specialists, such as endocrinologists, nephrologists, geri- lished guidelines, conference or discussion papers, personal atricians, or intensivists, and, accordingly, management opinions, and obsolete guidelines replaced by updated rec- strategies often vary [5]. Although probably related to ommendations from the same organization. variation in awareness, differences in expert opinion on whom and how to treat only add to the confusion over optimal management. For instance, although experts agree Search methods for guidelines and consensus statements that acute symptomatic hyponatremia should be treated We searched MEDLINE (1946 to September Week 1, with hypertonic saline, the optimal concentrations and 2014) and EMBASE (1980 to September 2014), combining methods for determining initial infusion speeds are vocabulary terms and text words for hyponatremia with debated [1]. In addition, the risk of osmotic demyelination terms related to clinical practice guidelines and consensus syndrome after rapid correction of hyponatremia has statements. We also searched guideline databases and fuelled intense debate among experts on whether compli- websites of organizations as well as of selected profes- cations of untreated hyponatremia or complications of sional specialist societies in nephrology, endocrinology, treatment pose the greatest risk [8]. As different specialist and intensive care medicine. A list of the databases and physicians deal with hyponatremia, consultation of differ- websites along with the full search strategies are outlined ent information and guidance sources may add to the in Additional file 1. EN and JV independently screened variability in treatment seen in clinical practice today. the titles and abstracts and discarded those that did not Clinical practice guidelines and consensus statements meet the inclusion criteria. Full texts for potentially provide recommendations to help evidence-based prac- relevant guidelines or consensus statements were retrieved tice by suggesting the most appropriate diagnostic tests and examined for eligibility. Both the initial screening and and the most appropriate treatments. Over the years, subsequent full-paper assessment stage were completed multiple organizations have developed recommendations using Early Review Organizing Software [10]. Nagler et al. BMC Medicine 2014, 12:231 Page 3 of 16 http://www.biomedcentral.com/1741-7015/12/231 Data collection process and data items domains covered by the guidelines. These were cross- We developed a draft data extraction form which was tabulated with the guidelines and recommendations were piloted and modified as necessary. The extracted data inserted into the corresponding cell. For each domain, we included document characteristics (e.g., year of publi- compared guideline recommendations to identify similar- cation, country/region, development team, funding ities and discrepancies. Consistent with the scope of this organization), recommendations related to the diagno- review, we only tabulated the information on diagnosis sis and assessment of hyponatremia, and recommen- and treatment of hyponatremia. dations related to the treatment of hyponatremia. EN and JV extracted all data using the standardized data Results extraction form (Additional file 2) and resolved dis- Search results crepancies by consensus. We identified 1,402 citations, of which we excluded 1,367 after screening titles and abstracts because they did not Appraisal of guidelines and consensus statements meet our eligibility criteria (Figure 1). We assessed the full Four reviewers independently assessed methodological text of the remaining 39 citations and excluded 29 because quality using the Appraisal of Guidelines for Research and they were not related to the diagnosis or treatment of Evaluation (AGREE II) instrument [11]. AGREE II is an hyponatremia, were not clinical practice guidelines or con- internationally validated, rigorously developed 23-item tool sensus statements, or were guidelines replaced by an used to evaluate six domains of guideline development: updated version (Additional file 4). Ultimately, we included scope and purpose, stakeholder involvement, rigor of de- five clinical practice guidelines [16-20] and five consensus velopment, clarity of presentation, applicability, and editor- statements [21-25]. Six of these documents were retrieved ial independence [12] (Additional file 3). The AGREE tool through searching the medical databases [18-20,23-25], the has also been used to assess consensus statements [13,14]. other four through the search of guideline databases and The reviewers rated each item on a Likert scale from 1 professional society websites [16,17,21,22]. (? Strongly Disagree?)to 7 (? Strongly Agree? ). We calculated Table 1 shows the general characteristics of the included a total score for each domain by summing up all the scores clinical practice guidelines and consensus statements. Eight of the individual items in a domain for each reviewer national or regional organizations from the Netherlands and then standardizing this total as a percentage of the [16], United Kingdom [17], Northern Ireland [22], Spain maximum possible score for that domain, calculated as [23,25], United States [18,19], Australia [21], and two inter- follows [12]: national groups [20,24] published these guidance docu- ments between 2004 and 2014. One document specifically Obtained score − Minimum possible score covered children [21], the others primarily targeted adults. 100% Maximum possible score − Minimum possible score Six groups reported undertaking a systematic review and appraisal of the evidence [16-20,24]. Only three were ex- The minimum possible score for each domain equaled plicit about the level of evidence that underpinned their the number of questions multiplied by the number of recommendations [16,18,20], and only two graded the reviewers, multiplied by 1 (strongly disagree). The max- strength of the guidance recommendations themselves imum score for a domain equaled the number of ques- [18,20]. Five guidance documents covered hyponatremia tions multiplied by the number of reviewers, multiplied broadly; one specifically covered it in the setting of pri- by 7 (strongly agree). To ensure standardization of each mary care, one in liver cirrhosis, one in neurosurgery, and reviewer? s approach, all reviewers completed the online one in exercise-associated hyponatremia. Three included training tutorial [15] before starting the project. treatment only [23-25], the seven others covered diagnosis In a consensus meeting among the reviewers, we dis- as well [16-22]. Two groups reported funding by a govern- cussed every item for which scores differed by more than mental institution [16,22], one by the professional soci- 1 point (e.g., 1 versus 3) on the original 7-point scale. eties they represented [20]; the others did not report their Reviewers in turn explained the rationale for their score funding sources [17-19,21,23-25]. and had the opportunity to revise their score when they considered this appropriate. We audiotaped the consensus Appraisal of guidelines and consensus statements meeting to reliably record the underlying reasons for Figure 2 shows the standardized domain scores for each changing scores. guideline for each of the six quality domains assessed with the AGREE II tool (See Additional file 5 for mean Synthesis of guideline recommendations individual scores per item across reviewers). The overall We conducted a textual descriptive synthesis to analyze the quality of reporting of the guideline development process scope, content, and consistency of the included recommen- as assessed by AGREE varied widely both between guid- dations. EN inductively coded the text manually to identify ance documents across domains and within guidance Nagler et al. BMC Medicine 2014, 12:231 Page 4 of 16 http://www.biomedcentral.com/1741-7015/12/231 Figure 1 Flow diagram of the identification process for clinical practice guidelines and consensus statements on hyponatremia. documents between domains. Overall, guideline devel- within one point of each other. Major reasons for chan- opers reported the details of the guideline development ging an entry were a change of own opinion after clarifi- process only to a limited extent. Most had average scores cation of the opinion of other reviewers during the below 50% in four to six of the six AGREE II domains group discussion (180/920 entries; 20% entries); aiming [17,19,21-25], only two received an average >50% on all for consistency between entries given same available data six [16,20]. (39/920; 4%); re-evaluation of the score in light of a Guidelines received the highest scores for scope and noted comment during the appraisal process (30/920; purpose (median 62%; range 28% to 92%) and clarity of 3%); correction for available data that were overlooked presentation (median 47%; range 27% to 75%), and low- during the initial appraisal (22/920; 2%); misinterpret- est scores for applicability (median 19%; range 10% to ation of the question during the initial appraisal (6/920; 68%) and editorial independence (median 19%; range 2% 0.7%); adjusting for arbitrary scoring of items that were to 79%). felt to be inapplicable for some reason (3/920; 0.3%); Initial appraisal results differed more than one point adjusting for inconsistent approach to deal with the on the Likert scale between two or more reviewers for assumption that a criterion was fulfilled even if this was 143/230 items (62%). The majority of discrepancies were not clearly mentioned (4/920; 0.4%); and data entry error found in the domain ? Clarity of Presentation?, with 90% (3/920, 0.3%). Overall, this resulted in 29/60 (48%) of of items differing more than one point. Group discussion standardized domain scores being downgraded by a max- resulted in 287/920 (31%) of individual entries being imum of 10% and 10/60 (17%) of standardized domain changed. Finally, no scores differed more than two scores being upgraded with a maximum of 10%; the points and for 82% of items, scores were the same or remaining 35% remained unchanged. Nagler et al. BMC Medicine 2014, 12:231 Page 5 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 1 Characteristics of included guidelines and consensus statements Developer Year Country Funding Target Target Guideline Guideline Guideline Methods Evidence source population users writers review update support base Europe NIV 2012 Netherlands Government Adults with Clinicians, Multidisciplinary Dutch Association In case of PROVA ? company Systematic funding hyponatremia Internists internists, of Internists (NIV), breakthrough specialized in literature epidemiologist expert peer review changes in Evidence Based review diagnosis or Guideline treatment Development NHS 2011 UK NS Adults with Primary care NS NS Planned NS Systematic hyponatremia in professionals in 2015 literature primary care within NHS review GAIN* 2010 Northern Government Adults with NS Multidisciplinary NS 3 years NS NS Ireland funding hyponatremia anesthetists, clinical chemist, nephrologist AEEH* 2003- Spain NS Patients with cirrhosis NS Gastroenterologists NS NS NS NS EHN* 2013 Spain NS Hospitalized patients NS Multidisciplinary NS NS NS Consensus with SIADH endocrinologists, statements nephrologists, internists, hospital pharmacist ERBP/ESE/ 2014 Europe Unrestricted Adults with Health care Multidisciplinary External review by 5 years or ERBP methods Systematic ESICM grant from hyponatremia professionals nephrologists, KHA-CARI, ESA, and earlier in support team literature participating dealing with endocrinologists, members ERA-EDTA case of new review societies hyponatremia general internists, evidence critical care physicians requiring changes North America UF 2008- USA NS Neurosurgery patients NS Multidisciplinary NS NS NS Systematic 2009 with hyponatremia neurosurgeons, nurse literature practitioners, nephrologists, review critical care physician, endocrinologist, pharmacist, nurses HEP 2013 USA Funding Patients with NS Endocrinologist, NS NS NS Systematic Unrestricted hyponatremia nephrologists literature educational review grant from pharmaceutical company Australia RCHM* 2012 Australia NS Children NS NS External review 12 to NS NS within the hospital 24 months where appropriate? Nagler et al. BMC Medicine 2014, 12:231 Page 6 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 1 Characteristics of included guidelines and consensus statements (Continued) International EAH- ICD* 2007 USA, Canada, No commercial People with Medical Multidisciplinary NS NS NS Systematic UK, Switzer-land, sponsorship? exercise-associated personnel, endocrinologist, literature Canada, South hyponatremia athletes, epidemiologist, review Africa, New greater public nephrologists, Zealand, Australia emergency medicine physician, general practitioner, internist, sports physicians, exercise physiologists NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]; [Na], Serum sodium concentration; NS, Not stated; KHA-CARI, Kidney Health Australia, Caring for Australasians with Renal Impairment; ESA, Endocrine Society of Australia; ERA-EDTA, European Renal Association; European Dialysis and Transplant Association; *Classified as consensus statement. Nagler et al. BMC Medicine 2014, 12:231 Page 7 of 16 http://www.biomedcentral.com/1741-7015/12/231 Figure 2 Guideline assessment according to the appraisal of guideline for research and evaluation (AGREE II) instrument. NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa? ola para el Estudio del H?gado [23]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [15]; *Classified as consensus statement. Note: items were originally scored on a Likert scale of 1 [Strongly Disagree] to 7 [Strongly Agree]. The numerical scores presented for each domain are a summary of individual item scores by each reviewer. Synthesis of recommendations Guidance documents differed somewhat in their recom- The included guidance documents addressed three major mended threshold for starting diagnostic assessment. Six themes: diagnosis, treatment, and speed of correction. recommended starting diagnostic assessment when the serum sodium concentration dropped below 135 mmol/L [17,19-23] and to confirm hypotonicity through a measured Approaches to diagnostic strategies for hyponatremia serum or plasma osmolality <275 to 285 mOsm/kg Seven guidance documents covered diagnosis and differen- [16-20,22]. Two others set lower thresholds of serum so- tial diagnosis of hyponatremia [16-22]. Table 2 shows the dium concentration at <131 mmol/L [18] and <130 mmol/L key recommendations. The key areas addressed included [23]. Six guidance documents advised classifying hypotonic the threshold for initiating diagnostic workup, confirmation hyponatremia into categories of hypovolemia, euvolemia, and classification of hypotonic hyponatremia, and identifi- and hypervolemia to aid differential diagnosis and guide cation of the underlying disorder. treatment [16-22]. Most guidance documents recom- Nagler et al. BMC Medicine 2014, 12:231 Page 8 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 2 Summary of recommendations for approaches to diagnosis of hyponatremia by included guidance documents Guideline Organization/Society Criteria/Categories NIV [16] NHS [17]GAIN[22] AEEH [23] EHN [25] ERBP/ESE/ UF [18] HEP [19] RCHM [21]EAH-ICD ESICM [20] [24] Threshold workup [Na] <135 mmol/L <135 mmol/L <135 mmol/L <130 mmol/L <135 mmol/L <135 mmol/L <131 mmol/L <135 mmol/L <135 mmol/L Confirming hypotonic Serum osmolality Plasma osmolality Serum osmolality Plasma osmolality Serum osmolality Serum osmolality Plasma osmolality Serum hyponatremia <275 mOsm/kg <280 mOsm/kg <275 mOsm/kg <275 mOsm/kg <275 mOsm/kg <285 mOsm/kg <280 mOsm/kg osmolality threshold not stated How to classify hypotonic hyponatremia to aid identification of underlying cause Volume status/ Clinical Physical Physical Physical Physical Physical Physical To assess hydration state/ evaluation examination/clinical examination/clinical examination/ examination/ examination/ examination/ but method extracellular fluid signs of dehydration signs of dehydration clinical signs of clinical signs of laboratory laboratory not stated status or edema or edema low circulating dehydration measurements measurements volume or edema Urinary [Na]/Threshold 30 mmol/L Spot urine: 15 mmol/L 40 mmol/L 30 mmol/L 25 mmol/L Spot urine: No threshold 20? 30 mmol/L 20? 30 mmol/L stated Urinary osmolality/ 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg 100 mOsm/kg No threshold Threshold stated How to identify the underlying disorder History Medications Medications Diuretic use Fluid intake Recently prescribed intravenous fluids Nocturnal polyuria Vomiting/diarrhea Lab tests Serum potassium ++ + concentration Serum chloride + + concentration Serum urea +/? + +/? +/? + concentration Serum creatinine ++ +/? +/? + concentration Serum glucose ++ +/? ++ concentration Nagler et al. BMC Medicine 2014, 12:231 Page 9 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 2 Summary of recommendations for approaches to diagnosis of hyponatremia by included guidance documents (Continued) Urinary potassium + + concentration Renal tests + Liver tests + +/? Urinary protein +/? Thyroid function +/? +/? +/? +/? tests Adrenal function +/? +/? +/? +/? tests Serum protein +/? electrophoresis Urine protein +/? electrophoresis Fractional sodium +/? excretion Serum uric acid +/? +/? ++/? concentration Fractional uric acid +/? concentration Fractional excretion +/? urea Urinary chloride +/? ++/? concentration Molar weight urine +/? Serum bicarbonate +/? concentration Hematocrit +/? [Na], Serum sodium concentration; +, always; +/? , If clinically indicated/sometimes useful. NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]. Nagler et al. BMC Medicine 2014, 12:231 Page 10 of 16 http://www.biomedcentral.com/1741-7015/12/231 mended a clinical assessment of hydration status and a whereas one advised to consider stopping diuretics [23]. urinary sodium concentration as well as a urinary osmo- One guideline additionally proposed demeclocycline and lality measurement, although specific criteria, thresholds, two proposed vasopressin receptor antagonists as a second- and algorithms differed. line treatment for refractory hyponatremia [17,19], whereas Most guidance documents proposed additional labora- one guideline specifically recommended against both deme- tory tests that could be of value to identify the underlying clocycline and vasopressin receptor antagonists [20]. disorder, but they varied substantially regarding which tests to use in what situation and which reference values Targets and limits of speed of correction to use. Only two explicitly recommended taking a history Table 4 shows the key recommendations. The key areas of drug intake and symptoms as part of the assessment include targets and limits for increase in serum sodium [17,22]. Four presented an algorithm to guide differential concentration. diagnosis [16,18,20,22]. Seven guidance documents provided targets or aims for the increase in serum sodium concentration in case of Approaches to treatment for hyponatremia symptomatic and/or acute hyponatremia [16,17,19-22,25]. Table 3 shows the recommendations for the medical man- Seven guidance documents provided limits for the agement of hyponatremia. Guidance documents distin- increase in serum sodium concentration that should guished treatment scenarios based on whether patients not be surpassed [16-22,25]. Five did so independent of had severe symptoms [17-22,24,25] or whether the hypo- symptoms [16,18,20,22,25]. Limits usually varied between natremia was acute (48 h) or chronic [16]. All but one 8 to 12 mmol/L during the first 24 hours [16-22,25] and discussed treatment in the setting of severe symptoms and 18 mmol/L during the first 48 hours [16,17,19,20,25], recommended infusion of hypertonic saline, usually speci- irrespective of whether hyponatremia was acute or fied as having a concentration of 3% [17,19-21,24,25]. One chronic [16,17,20,25]. Three guidance documents set a suggested using a formula to guide the infusion speed of a stricter limit of <8 mmol/L during the first 24 hours in continuous infusion [16], five others recommended giving cases where the patient was believed to be high risk for a fixed dose [19,20,22,24,25], or a dose adjusted to body developing osmotic demyelination syndrome [16,19,25]. weight [21,25] with repeated serum sodium concentration Four discussed what to do in case of overcorrection, i.e., measurements to check progression [16,20-22,25]. to stop current treatment and to consider re-lowering Patients without symptoms of hyponatremia were serum sodium concentration by starting hypotonic infu- assumed to have chronic onset hyponatremia, and sion and administering 1 to 4 μg desmopressin every 6 to treatment suggestions were mostly dependent on the 8 hours [16,19,20,25]. classification hypovolemic, euvolemic, or hypervolemic. Only three guidance documents specifically advised treat- Discussion ing the underlying condition [19,22]. Seven suggested We found five clinical practice guidelines and five con- 0.9% saline in hypovolemia [16-22], with infusion speeds sensus statements covering the diagnostic approach to calculated with Adrogu?-Madias [22], until restoration of and treatment of hyponatremia. Although most used blood pressure [17,19] or until nasogastric rehydration serum osmolality, volume status, urinary sodium, and could start [21]. urinary osmolality to guide differential diagnosis, they For euvolemic asymptomatic hyponatremia, the majority differed in classification thresholds, what additional tests recommended fluid restriction as the first-line treatment to consider, and when to initiate diagnostic work-up. [16-25]. Five guidance documents proposed a number of Most advocated hypertonic NaCl in severely symptom- other interventions as second-line treatments including atic, acute onset hyponatremia and NaCl 0.9%, fluid loop diuretics [16,18,20,25], demeclocycline [16-19], urea restriction, and cause-specific therapy for hypovolemic, [16,19,20,25], vasopressin receptor antagonists [16,17,25], euvolemic, and hypervolemic hyponatremia, respectively. or lithium [18]. One guideline specifically recommended However, they somewhat differed in the limits for speed against vasopressin receptor antagonists in case of a serum of increase in serum sodium concentration and which sodium concentration <125 mmol/L [20]. specific medications to use. The reasons for offering For hypervolemic asymptomatic hyponatremia, seven different recommendations are undoubtedly multifac- guidance documents recommended fluid restriction as torial. They may in part be explained by the fact that the first-line treatment [16,17,19-23] (Table 3). Three guid- recommendations were issued by organizations differing ance documents advocated concomitant salt restriction, in context and scope. It is also very likely that some without clear dose recommendations [17,19,22], and one to variability in guidance arose through limitations in the avoid hypotonic infusion solution [21]. Three additionally evidence available for guideline developers to base their proposed loop diuretics [16,17,19] and three others gener- recommendations on [8]. In the most recent guideline ally stated to treat the underlying disease [17,20,22], on diagnosis and treatment of hyponatremia, 98% of the Nagler et al. BMC Medicine 2014, 12:231 Page 11 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 3 Summary of recommendations for approaches to treatments for hyponatremia by included guidance documents Guideline Organization/Societies Criteria/ NIV [16] NHS [17]GAIN[22] AEEH [23] EHN [25] ERBP/ESE/ UF [18] HEP [19] RCHM [21] EAH-ICD categories ESICM [20] [24] Symptoms Acute Onset NaCl >1% NaCl 3% NaCl 2.7% NaCl 3% 100 mL/ NaCl 3% 150 mL/ NaCl >1% NaCl 3% 100 mL/ NaCl 3% NaCl 3% (<48 h) Infusion speed 200 mL over 10 min up to 20 min up to 4? 10 min up to 4 mL/kg 100 mL may be guided by 30 min 3? or infused at 3? or infused at over 30 min bolus Adrogu?-Madias 0.5? 2mL/kg/h 0.5? 2mL/kg/h Hypovolemia NaCl 0.9% until blood pressure restored Euvolemia Fluid restriction No hypotonic fluids Stop offending drugs Stop hypotonic fluids Hypervolemia Furosemide Furosemide Chronic onset NaCl >1% Infusion NaCl 3% Only if severe NaCl 3% 100 mL/ NaCl 3% 150 mL/ NaCl >1% NaCl 3% 100 mL/ (>48 h) speed calculation symptoms NaCl 2.7% 10 min up to 20 min up to 4? 10 min up to 3? may be guided by 200 mL over 30 min 3? or infused at or infused at Adrogu?-Madias infusion speed by 0.5? 2mL/kg/h 0.5-2 mL/kg/h may be guided Adrogu?-Madias Hypovolemia NaCl 0.9% 1 L over NaCl 0.9% until 2? 4 h infusion speed blood pressure may be guided by restored Adrogu?-Madias Euvolemia Fluid restriction Stop offending medications Stop hypotonic fluids Hypervolemia Fluid restriction Furosemide Salt restriction No symptoms Acute onset NaCl >1% Treat underlying Stop offending fluids Treat underlying (<48 h) Infusion speed by condition and medications, condition Adrogu?-Madias treat underlying Nagler et al. BMC Medicine 2014, 12:231 Page 12 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 3 Summary of recommendations for approaches to treatments for hyponatremia by included guidance documents (Continued) condition NaCl 3% 150 mL/20 min Chronic Treat underlying Treat underlying Stop non-essential Treat underlying onset (>48 h) condition condition fluids Stop offending condition medications Treat underlying condition Hypovolemia NaCl 0.9% NaCl 0.9% until NaCl 0.9% NaCl 0.9% or NaCl 0.9% NaCl 0.9% until Nasogastric blood pressure infusion speed balanced crystalloid blood pressure rehydration restored may be guided by 0.5? 1mL/kg/h restored Adrogu?-Madias NaCl tablets No VPA NaCl 0.9% Euvolemia Fluid restriction, Fluid restriction, Fluid restriction Fluid restriction Fluid restriction Fluid restriction Fluid restriction Fluid restriction, dose dependent 500? 1,000 mL/d <500? 1,000 mL/d 500 mL below no hypotonic on serum and average daily fluids urinary electrolytes urine output No salt Salt restriction Salt 5? 8 g/d No salt restriction restriction Loop diuretics Furosemide Loop diuretics, Diuretics 20? 60 mg/d + low dose + oral NaCl oral NaCl Demeclocycline Demeclocycline No demeclocycline Demeclocycline Demeclocycline, 600? 1,200 mg/d Urea Urea 30 g/d Urea, 0.25? 0.5 g/kg/d Urea Urea, 15? 60 g/d Vasopressin Vasopressin Tolvaptan No vasopressin receptor receptor antagonist 15? 60 mg/d receptor antagonists antagonist Hypervolemia Treat underlying condition Fluid restriction, Fluid restriction Fluid restriction Fluid restriction Fluid restriction Fluid restriction, Fluid restriction dose dependent <1,000 mL/d <insensible losses + on serum and urine output urinary electrolytes Loop diuretics Salt restriction Salt restriction No NaCl >0.9% Salt restriction Demeclocycline Stop No demeclocycline Possibly vasopressin diuretics receptor antagonist Vasopressin No vasopressin receptor receptor antagonist antagonist NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]. Nagler et al. BMC Medicine 2014, 12:231 Page 13 of 16 http://www.biomedcentral.com/1741-7015/12/231 Table 4 Summary of recommendations for targets and limits for speed of correction of hyponatremia by included guidance documents Guideline Organization/Societies Criteria/ NIV NHS GAIN AEEH EHN ERBP/ESE/ESICM UF HEP RCHM EAH- categories ICD [16][17][22][23][25][20][18][19][21][24] Targets [Na] increase Symptoms Independent If symptoms If symptoms If symptoms If symptoms If symptoms Until seizures resolve of symptoms or [Na] >125 mmol/L Acute onset 1? 2 mmol/L/h Until [Na] 1? 2 mmol/L/h 1? 6 mmol/L first 2 h 5 mmol/L first h 4? 6 mmol/L Independent of onset (<48 h) initially >120 mmol/L first 2? 3h urgently independent of onset Chronic onset 0.5? 1 mmol/ 1? 6 mmol/L first 2 h 5 mmol/L first h If seizures or coma (>48 h) L/h first 2? 3h 4? 6 mmol/L urgently, otherwise 4? 6 mmol/L per 24 h Limits [Na] increase Symptoms Independent If no symptoms Independent Independent of Independent Independent If no symptoms Symptom dependent of symptoms of symptoms symptoms of symptoms of symptoms Acute onset If no risk of ODS ≤8? 12 mmol/L per <12 mmol/L If no risk of ODS ≤10 mmol/L first ≤10 mmol/L No limits ≤8 mmol/L per 24 h (<48 h) ≤10 mmol/L per 24 h ≤18 mmol/L per per 24 h ≤10 mmol/L per 24 h 24 h ≤8 mmol/L per 24 h after seizures resolve, 24 h ≤18 mmol/L 48 h ≤18 mmol/L per 48 h every 24 h thereafter Independent of onset per 48 h If risk of If risk of ODS <8 mmol/L ODS <8 mmol/L per 24 h per 24 h Chronic onset <8 mmol/L ≤8? 12 mmol/L <12 mmol/L <8? 12 mmol/L ≤10 mmol/L first ≤10 mmol/L <8? 12 mmol/L (>48 h) per 24 h per 24 h ≤18 mmol/L per 24 h per 24 h <18 mmol/L 24 h ≤8 mmol/L per 24 h per 24 h <18 mmol/L per 48 h per 48 h every 24 h thereafter per 48 h [Na] ? Serum sodium concentration. NIV, Nederlandse Internisten Vereniging [16]; NHS, National Health Service [17]; GAIN, Guidelines and Audit Implementation Network [22]; AEEH, La Asociaci?n Espa?ola para el Estudio del H?gado [ 23]; EHN, European Hyponatremia Network [25]; ERBP, European Renal Best Practice; ESE, European Society of Endocrinology; ESICM, European Society of Intensive Care Medicine [20]; UF, University of Florida [18]; HEP, Hyponatremia Expert Panel [19]; RCH Melbourne, the Royal Children? s Hospital Melbourne [21]; EAH-ICD, International Exercise-Associated Hyponatremia Consensus Development Conference [24]. Nagler et al. BMC Medicine 2014, 12:231 Page 14 of 16 http://www.biomedcentral.com/1741-7015/12/231 graded recommendations were based on very low and hyponatremia, such as fluid restriction, may affect quality low level of evidence, while none were based on a high of life and patient preference should influence the ultimate level of evidence. The lack of high quality evidence may recommendations. have increased the part opinion had to play in framing Low scores for applicability mostly reflect the absence the recommendations. In addition, the evidence that of describing barriers to guideline implementation and was available may have been interpreted differently failure to provide tools for putting the recommendations dependent on the importance for decision making given into practice. In part, guidelines are designed to deal with to certain outcomes (e.g., serum sodium concentration). the challenges of increasing knowledge and time-pressure. Finally, differences in personal experience due to differ- They are designed to help make decisions at the point ing availability of medications may partly explain pos- of care. However, being often lengthy publications with- sible differences in perception of uncertainties around out layered presentation of information, it is likely that drug safety. the majority of the guidance documents may not reach However, it is also possible that discrepancies between their target audience or stimulate implementation. Four guidance documents may in part be explained by differ- guidance documents provided algorithms for diagnosis ences in underlying methods of development. Quality, or treatment [16,18,20,25]; although these are likely to as assessed by AGREE II, was suboptimal at best, with increase the utility of a guideline, it is unclear to what only two documents obtaining a score >50% for each of extent they truly improve implementation of the recom- the six quality domains [16,20]. The findings suggest mendations. How to best communicate evidence-based that several aspects related to methodological rigor of recommendations to the relevant stakeholders is a recent development, stakeholder involvement, applicability, and but active area of research lead by the DECIDE consor- editorial independence could be improved, possibly im- tium [28]. With results of their research expected, guide- proving consistency in provided guidance. This is in line line developers will have additional targets for improving with the findings of a recent overview of 42 appraisal the applicability in the future. studies including a total of 626 clinical practice guidelines To our knowledge, this is the first attempt to systemat- across several clinical disciplines [26]. For guidelines to ically synthesize and appraise clinical guidelines on the be trustworthy, they must be i) founded on high quality diagnosis and treatment of hyponatremia In accordance systematic reviews, ii) include the relevant stakeholders, with the Prisma statement, we conducted a comprehensive and iii) be applicable in clinical practice [9]. literature search and searched an additional 337 web- Only half of the guidance groups stated they had con- sites of specialist societies and guideline organizations ducted a systematic review of the evidence. Save one, the [29] (Additional file 6). We used AGREE II, a validated and reviewswould nothavemet theInstitute of Medicine?scri- reliable instrument, and an adequate number of reviewers teria for reporting high-quality systematic reviews [20,27], to individually appraise the guidance documents [30]. On because key methods for finding and assessing individual top of the individual appraisals, we included an attempt studies as well as synthesizing the body of evidence were to resolve major discrepancies and increase consistency not described. Conducting high-quality systematic reviews by introducing an audiotaped group consensus meeting. requires specific methodological expertise and support During this meeting, reviewers could explain and motivate which may not be available to most groups [27]. One their scores and adapt them if they wanted to. This mostly solution might be to harmonize effort across organiza- resulted only in modest downgrading of domain scores tions, thus focusing resources, allowing higher quality by 1% to 10%. Most of the changes happened because reviews and reducing duplication and possibly inconsist- reviewers felt they had scored inconsistently for a same ency between guidelines. rationale, or because they missed information during Six groups included healthcare professionals from dif- the initial appraisal that was in fact available in the document. Although the scores did not change substan- ferent specialties [16,18,20,22,24,25]. Multidisciplinary contribution serves to broaden the approach to health-care tially, the group felt the discussion further highlighted problems, increase the completeness of evidence-finding the qualitative differences between the guidance docu- ments. In addition, even the reviewers with large devia- strategies, and help to identify hurdles to implementation. When reflecting on approaches to hyponatremia, bringing tions from the mean in their initial scores felt they agreed together several disciplines mirrors the clinical reality with the conclusion. It means that final average scores were truly a product of consensus rather than a mathem- of multiple specialty areas dealing with the same prob- lem but looking at it from a different angle. Only one atical calculation, as proposed in the original AGREE of the development groups reported considering patients? protocol. We believe that a consensus meeting is valuable views and experiences, but even then did so to a limited in any guideline appraisal process, and particularly useful extent [20]. Decisions on clinical care should factor in if reviewer groups have the intention to select a guideline patient values and preferences. Interventions for chronic for local use. Nagler et al. BMC Medicine 2014, 12:231 Page 15 of 16 http://www.biomedcentral.com/1741-7015/12/231 This study has its limitations. We based our assessment Additional file 3: Table S3. Structure and content of the AGREE on what guideline organizations actually reported. Report- instrument. ing by guideline developers may not wholly reflect what Additional file 4: Table S4. Table of excluded studies. occurred in practice with respect to the AGREE criteria, Additional file 5: Table S5. Mean scores across reviewers for the individual AGREE II domain items. and we did not seek additional clarification. However, Additional file 6: PRISMA checklist. contacting guideline developers is not standard practice when using AGREE as the instrument specifically aims to provide a framework for assessing the quality of reporting Abbreviation AGREE II: Appraisal of guidelines for research and evaluation II. of recommendations. We aimed to summarize the existing recommendations on diagnosis and treatment of hypona- Competing interests tremia as formulated by other guideline development Evi Nagler is a member of the Methods Support Team of European Renal groups and to evaluate the quality of the guideline devel- Best Practice (ERBP). She is also one of the authors of the Clinical Practice Guideline on the diagnosis and treatment of hyponatremia, developed in a opment process. We did not aim to summarize or critic- joint venture with the European Society of Endocrinology and the European ally appraise the evidence base itself. Consequently, it is Society of Intensive Care Medicine and one of the guidelines included in the difficult to assess to what extent differences between guid- current review. Jill Vanmassenhove has no relevant disclosures. Sabine van der Veer is a member of the Methods Support Team of European Renal Best ance documents stem from differences in development Practice (ERBP). She is also one of the authors of the Clinical Practice procedures rather than important limitations in the evi- Guideline on the diagnosis and treatment of hyponatremia, developed in a dence base that underpin individual recommendations. joint venture with the European Society of Endocrinology and the European Society of Intensive Care Medicine and one of the guidelines included in the Secondly, the purpose of using the AGREE instrument current review. Ionut Nistor is a member of the Methods Support Team of was not to accuse guideline development groups of being ERBP. Wim Van Biesen is the Chair of ERBP, he is also one of the authors of biased, but rather to highlight both strengths and weak- the Clinical Practice Guideline on the diagnosis and treatment of hyponatremia, developed in a joint venture with the European Society of nesses of existing guidance to suggest on how we could Endocrinology and the European Society of Intensive Care Medicine and one make improvements in the future. of the guidelines included in the current review. Angela Webster has no Calculation of summary scores for each domain across relevant disclosures. Raymond Vanholder is member of ERBP, he is also one of the authors of the Clinical Practice Guideline on the diagnosis and reviewers required summing up all the scores of the in- treatment of hyponatremia, developed in a joint venture with the European dividual items in a domain for each reviewer and then Society of Endocrinology and the European Society of Intensive Care standardizing this total as a percentage of the maximum Medicine and one of the guidelines included in the current review. possible score for that domain. In doing so, the originally Authors? contributions semi-qualitative Likert scale was converted to a quantita- EN designed and conducted the systematic review, conducted the systematic tive score. This may have introduced numeric differences search, selected and critically appraised the studies, collected the data, and between the guidance documents that were beyond the wrote and revised the manuscript. JV selected and critically appraised the studies, collected the data, and revised the manuscript. SVDV critically appraised discriminatory ability of the tool and possibly negligible in the studies. IN conducted the systematic search and critically appraised the practice. Finally, we acknowledge that four of the authors studies. WVB designed the systematic review, critically appraised the studies, of this paper also authored one of the guidelines included and wrote and revised the manuscript. AW designed the systematic review and wrote and revised the manuscript. RV designed the systematic review and in this review. Although we aimed to judge all guidance wrote and revised the manuscript. All authors read and approved the documents fairly against the criteria outlined by the final manuscript. AGREE instrument, we cannot rule out that a subcon- scious intellectual competing interest unduly influenced Acknowledgements the scoring. Evi Nagler, Sabine van der Veer, and Ionut Nistor are fellows of the Methods Support Team of European Renal Best Practice (ERBP), supported by a grant of the European Renal Association- European Dialysis Transplantation Association (ERA-EDTA). Conclusions Author details Current guidelines on the assessment and treatment of European Renal Best Practice (ERBP), guidance body of the European Renal hyponatremia often fail to meet methodological criteria Association ? European Dialysis and Transplant Association (ERA-EDTA), De for development and reporting as described by AGREE II. Pintelaan 185, Ghent 9000, Belgium. Renal Division, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium. Despite many similarities, recommendations are some- Centre for Kidney Research, The Children? s Hospital at Westmead, Locked times inconsistent, but to what extent this is attributable Bag 4001, Westmead 2145, NSW, Australia. Department of Medical to the underlying development process remains unclear. Informatics, Academic Medical Center, Postbus 22660, Amsterdam 1100DD, the Netherlands. Nephrology Department, Gr. T. Popa University of Medicine and Pharmacy, Strada Universit?tii 16, Iasi 700115, Romania. Sydney School of Public Health, Edward Ford Building (A27), The University of Sydney, NSW Additional files 7 2006, Australia. Centre for Transplant and Renal Research, The University of Sydney at Westmead Hospital, Westmead 2145, NSW, Australia. Additional file 1: Table S1. Search strategies. Received: 20 April 2014 Accepted: 7 November 2014 Additional file 2: Table S2. Data extraction template. Nagler et al. BMC Medicine 2014, 12:231 Page 16 of 16 http://www.biomedcentral.com/1741-7015/12/231 References Speedy DB, Stuempfle KJ, Verbalis JG, Weschler LB, Wharam P: Statement of 1. Ellison DH, Berl T: Clinical practice. The syndrome of inappropriate the Second International Exercise-Associated Hyponatremia Consensus antidiuresis. N Engl J Med 2007, 356:2064? 2072. Development Conference, New Zealand, 2007. Clin J Sport Med 2008, 2. Upadhyay A, Jaber BL, Madias NE: Epidemiology of hyponatremia. 18:111? 121. Semin Nephrol 2009, 29:227? 238. 25. Runkle I, Villabona C, Navarro A, Pose A, Formiga F, Tejedor A, Poch E, 3. Liamis G, Rodenburg EM, Hofman A, Zietse R, Stricker BH, Hoorn EJ: European Hyponatremia N: The treatment of hyponatremia secondary to Electrolyte disorders in community subjects: prevalence and risk factors. the syndrome of inappropriate antidiuretic hormone secretion. Medicina Am J Med 2013, 126:256? 263. Cl?nica 2013, 141:e501? e510. 26. Alonso-Coello P, Irfan A, Sol? I, Gich I, Delgado-Noguera M, Rigau D, Tort S, 4. Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE: Impact of hospital- Bonfill X, Burgers J, Schunemann H: The quality of clinical practice associated hyponatremia on selected outcomes. Arch Intern Med 2010, guidelines over the last two decades: a systematic review of guideline 170:294? 302. appraisal studies. Qual Saf Health Care 2010, 19:e58. 5. Hoorn EJ, Lindemans J, Zietse R: Development of severe hyponatremia in 27. Committee on Standards for Systematic Reviews of Comparative Effectiveness hospitalized patients: treatment-related risk factors and inadequate Research, Board on Health Care Services, Institute of Medicine: In Finding What management. Nephrol Dial Transplant 2006, 21:70? 76. Works in Health Care: Standards for Systematic Reviews. Edited by Eden J, Levit 6. Huda MSB, Boyd A, Skagen K, Wile D, van Heyningen C, Watson I, Wong S, L, Berg A, Morton S. US: The National Academies Press; 2011. Gill G: Investigation and management of severe hyponatremia in a 28. Treweek S, Oxman A, Alderson P, Bossuyt P, Brandt L, Brozek J, Davoli M, hospital setting. Postgrad Med 2006, 82:216? 219. Flottorp S, Harbour R, Hill S, Liberati A, Liira H, Sch?nemann HJ, Rosenbaum S, 7. Fenske W, Maier SKG, Blechschmidt A, Allolio B, Stork S: Utility and Thornton J, Vandvik PO, Alonso-Coello P, DECIDE Consortium: Developing and limitations of the traditional diagnostic approach to hyponatremia: a evaluating communication strategies to support informed decisions and diagnostic study. Am J Med 2010, 123:652? 657. practice based on evidence (DECIDE): protocol and preliminary results. 8. Sterns RH, Nigwekar SU, Hix JK: The treatment of hyponatremia. Implementation Science 2013, 8:6. Semin Nephrol 2009, 29:282? 299. 29. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred Reporting Items for 9. Committee on Standards for Developing Trustworthy Clinical Practice Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Guidelines, Board on Health Care Services, Institute of Medicine: In Clinical Med 2009, 6:e1000097. doi:10.1371/journal.pmed1000097. Practice Guidelines We Can Trust. Edited by Graham R, Mancher M, Wolman 30. Irani S, Rashidian A, Yousefi-Nooraie R, Soltani A: Evaluating clinical practice DM, Greenfield S, Steinberg E. US: The National Academies Press; 2011. guidelines developed for the management of thyroid nodules and 10. Glujovsky D, Bardach A, Garc?a Mart? S, Comand? D, Ciapponi A: EROS: a thyroid cancers and assessing the reliability and validity of the AGREE new software for early stage of systematic reviews. Value Health 2011, instrument. J Eval Clin Pract 2011, 17:729? 736. 14:A564. 11. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, doi:10.1186/s12916-014-0231-1 Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L, Cite this article as: Nagler et al.: Diagnosis and treatment of hyponatremia: AGREE Next Steps Consortium: AGREE II: Advancing guideline development, a systematic review of clinical practice guidelines and consensus statements. reporting and evaluation in healthcare. Can Med Ass J 2010, 182:E839? E842. BMC Medicine 2014 12:231. 12. Collaboration AGREE: Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care 2003, 12:18? 23. 13. Tong A, Chapman JR, Wong G, de Bruijn J, Craig JC: Screening and follow-up of living kidney donors: a systematic review of clinical practice guidelines. Transplantation 2011, 92:962? 972. 14. Lopez-Olivo MA, Kallen MA, Ortiz Z, Skidmore B, Suarez-Almazor ME: Quality appraisal of clinical practice guidelines and consensus statements on the use of biologic agents in rheumatoid arthritis: a systematic review. Arthritis Rheum 2008, 59:1625? 1638. 15. AGREE: Advancing the science of practice guidelines. [http://www.agreetrust.org/resource-centre/agree-ii-training-tools/] 16. Geers ABM, Tuut MK, Hoorntje SJ, van Saase JLCM, Zietse R: Electrolytstoornissen. NIV: Hoorn EJ; 2012. [http://www.internisten.nl]. Accessed 01 January 2013. 17. Clinical Knowledge Summaries: Prodigy Topic on Hyponatremia. 2011, [http://www.cks.nhs.uk/hyponatremia]. Accessed 02 January 2013. 18. Rahman M, Friedman WA: Hyponatremia in neurosurgical patients: clinical guidelines development. Neurosurgery 2009, 65:925? 935. 19. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ: Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med 2013, 126:S1? S42. 20. 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, Hyponatraemia Guideline Development Submit your next manuscript to BioMed Central Group: Clinical practice guideline on diagnosis and treatment of and take full advantage of: hyponatremia. Nephrol Dial Transplant 2014, 29:i1? i39. 21. Royal Children's Hospital Melbourne Australia: Clinical Practice Guideline ? Convenient online submission on Hyponatremia. [http://www.rch.org.au/clinicalguide/index.cfm]. ? Thorough peer review Accessed 02 January 2013. 22. Hyponatremia in Adults (On or after 16th Birthday). [http://www.gain-ni. ? No space constraints or color ?gure charges org]. Accessed 03 January 2013. ? Immediate publication on acceptance 23. Gines P, Cabrera J, Guevara M, Morillas R, Ruiz del Arbol L, Solae R, Soriano G: Consensus document on the treatment of ascites, dilutional ? Inclusion in PubMed, CAS, Scopus and Google Scholar hyponatremia and hepatorenal syndrome in liver cirrhosis. Gastroenterol ? Research which is freely available for redistribution Hepatol 2004, 27:535? 544. 24. Hew-Butler T, Ayus JC, Kipps C, Maughan RJ, Mettler S, Meeuwisse WH, Submit your manuscript at Page AJ, Reid SA, Rehrer NJ, Roberts WO, Rogers IR, Rosner MH, Siegel AJ, www.biomedcentral.com/submit

Journal

BMC MedicineSpringer Journals

Published: Dec 11, 2014

There are no references for this article.