Interventions for chronic non-hypovolaemic hypotonic hyponatraemia

  • Protocol
  • Intervention

Authors

  • Evi V Nagler,

    Corresponding author
    1. University Hospital Ghent, Renal Division, Department of Internal Medicine, Ghent, Belgium
    2. European Renal Best Practice (ERBP), guidance issuing body of the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), Ghent, Belgium
    Search for more papers by this author
  • Maria C Haller,

    1. European Renal Best Practice (ERBP), guidance issuing body of the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), Ghent, Belgium
    2. Krankenhaus Elisabethinen Linz, Department for Internal Medicine III, Nephrology & Hypertension Diseases, Transplantation Medicine & Rheumatology, Linz, Austria
    Search for more papers by this author
  • Wim Van Biesen,

    1. University Hospital Ghent, Renal Division, Department of Internal Medicine, Ghent, Belgium
    2. guidance issuing body of the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), European Renal Best Practice (ERBP), Ghent, Belgium
    Search for more papers by this author
  • Raymond Vanholder,

    1. University Hospital Ghent, Renal Division, Department of Internal Medicine, Ghent, Belgium
    2. European Renal Best Practice (ERBP), guidance issuing body of the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), Ghent, Belgium
    Search for more papers by this author
  • Jonathan C Craig,

    1. The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia
    2. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
    Search for more papers by this author
  • Angela C Webster

    1. The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia
    2. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
    3. The University of Sydney at Westmead, Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead, NSW, Australia
    Search for more papers by this author

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

This review aims to look at the benefits and harms of interventions for chronic non-hypovolaemic hypotonic hyponatraemia when compared with placebo, no treatment or head-to-head.

The review aims to determine if benefits and harms vary in absolute or relative terms dependent on the specific compound within a drug class, on the dosage used, or the underlying disorder causing the hyponatraemia.

Background

Description of the condition

Hypotonic hyponatraemia is a common condition, occurring in up to 60% of people admitted to hospitals, depending on the definition of hyponatraemia, the types of patients who are studied and the healthcare facility to which these patients are admitted (Upadhyay 2009). Hypotonic hyponatraemia is usually defined as a serum sodium concentration < 135 mmol/L with an osmolality < 285 mOsm/kg (Reynolds 2006). It develops when the body retains an excess of water relative to the amount of sodium. It can be caused by intrinsic kidney disease but usually results from incomplete suppression of vasopressin activity despite decreased tonicity of the plasma. In situations of decreased circulating blood volume, vasopressin release is increased in a physiologic response to maintain haemodynamic homeostasis. This occurs both with true volume depletion and with reduced effective arterial circulating volume, as seen in heart failure, liver cirrhosis or nephrotic syndrome. In the syndrome of inappropriate antidiuretic hormone secretion, the increased release of vasopressin is non-haemodynamic and can have multiple causes including ectopic production of vasopressin by a variety of tumours (Verbalis 2007).

When plasma tonicity is low, water tends to enter the cells and causes them to swell. If blood sodium concentrations drop rapidly (within a 48 hour period), the swelling of brain cells may lead to brain oedema, brain stem herniation and eventually even death. Fortunately, when blood sodium concentrations drop more gradually, brain cells adapt to their hypo-osmolar surroundings and prevent swelling by the transport of solutes from the intracellular to the extracellular compartments. As a consequence, immediate symptoms attributable to chronic hyponatraemia are usually less severe (Reynolds 2006). Nevertheless, people with chronic hyponatraemia have reduced attention and less stable gait than those without hyponatraemia (Renneboog 2006). They fall more often and have increased risk of osteoporosis and bone fractures (Arampatzis 2013; Hoorn 2011; Kinsella 2010; Renneboog 2006; Verbalis 2010). Finally, they stay in hospital longer and have an increased risk of death, even when sodium concentrations are only mildly decreased and underlying or comorbid conditions are taken into account (Wald 2010).

Description of the intervention

It is accepted that acute hyponatraemia requires an immediate increase in serum sodium concentration to prevent severe neurologic complications (Ellison 2007). What to do with chronic hyponatraemia is less clear. Firstly, chronic hypotonic hyponatraemia has been treated under the assumption that increasing the sodium concentration improves important health outcomes; that patients live longer, feel better and are hospitalised less frequently. Although several observational studies have indicated an association between hyponatraemia and undesirable outcomes, it is still unclear whether treatment improves them (Upadhyay 2009; Wald 2010). Secondly, once brain cells have adapted to their hypo-osmolar environment, they become vulnerable to osmotic demyelination. Although rare, osmotic demyelination is a devastating neurologic complication that may occur when the myelin sheath around pontine and extrapontine neurons breaks down after increases in serum sodium concentration exceed 8 to 12 mmol/L/24 h and 20 mmol/L/48 h (Adrogue 2012; Ellison 2007; Reynolds 2006). Treatment for chronic hyponatraemia must balance the uncertain benefit of increasing the sodium concentration against this risk of overly rapid correction.

How the intervention might work

Whatever the underlying cause, hyponatraemia usually results from urine being insufficiently dilute to maintain serum osmolality within the normal range (Adrogue 2000). Several treatment strategies can be used to try and overcome this (Adrogue 2012; Ellison 2007; Verbalis 2007).

  1. Restriction of fluid intake aims to decrease the amount of free water needing excretion.

  2. Urea and mannitol improve electrolyte-free water clearance by increasing urine osmolarity and creating osmotic diuresis (Lindner 2012).

  3. Loop diuretics, such as furosemide, bumetanide and ethacrynic acid, impair free-water absorption in the collecting duct by reducing the hypertonicity of the renal medulla.

  4. Corticosteroids with a mineralocorticoid effect increase renal sodium retention by active reabsorption of sodium in the principal cells of the cortical collecting tubule.

  5. Demeclocycline, lithium, phenytoin and vasopressin receptor antagonists act by pharmacologically inhibiting the effect of antidiuretic hormone on the principal cells of the collecting duct, thereby limiting insertion of water channels in the luminal membrane and thus preventing free water reabsorption. 

As hyponatraemia with true volume depletion is treated by restoring volume with water and salt, it will not be covered in this review.

Why it is important to do this review

The benefits and harms of treatments for chronic non-hypovolaemic hypotonic hyponatraemia have not been formally evaluated in a systematic review. Two systematic reviews have explored the efficacy and safety of vasopressin receptor antagonists (e.g. conivaptan, lixivaptan, satavaptan, tolvaptan) versus placebo, no treatment or fluid restriction (Jaber 2011; Rozen-Zvi 2010), but to our knowledge there has been no attempt to compare them with any other intervention or to compare any of the other interventions versus placebo or against one another.

Both systematic reviews have found an early increase in serum sodium concentration, but no improvement in outcomes important to patients. Indeed, most randomised controlled trials (RCTs) have evaluated short-term and surrogate outcomes only, making it difficult to adequately asses any expected benefit in the long-term. Since the most recent systematic review was published, at least three additional RCTs comparing vasopressin receptor antagonists versus placebo have been completed, increasing the total sample size by at least 60%. Although outcomes are still mostly surrogate and short-term, the largest study was terminated early due to a numeric imbalance in the number of early deaths in the experimental group (FDA 2012). We believe it justifies reanalysis including in-depth investigation of possible heterogeneity at this point.

Objectives

This review aims to look at the benefits and harms of interventions for chronic non-hypovolaemic hypotonic hyponatraemia when compared with placebo, no treatment or head-to-head.

The review aims to determine if benefits and harms vary in absolute or relative terms dependent on the specific compound within a drug class, on the dosage used, or the underlying disorder causing the hyponatraemia.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at interventions for chronic, non-hypovolaemic hypotonic hyponatraemia.

We will also include data for hyponatraemia subgroups within studies with broader inclusion criteria (e.g. people with chronic heart failure or people with cirrhosis with or without hyponatraemia) which report outcomes for participants with hyponatraemia, or where we can obtain these subgroup data from the study authors.

Types of participants

Inclusion criteria
  • Adults and children beyond the neonatal period (the interval from birth to 28 days of age)

  • Chronic, hypotonic hyponatraemia: presence of hyponatraemia > 48 hours, serum osmolality < 285 mOsm/kg and serum sodium concentration < 135 mmol/L, or as defined by authors)

  • Hyponatraemia not requiring immediate treatment

  • Hyponatraemia due to:

    • decreased effective circulating volume in the setting of heart failure, liver cirrhosis or nephrotic syndrome;

    • inappropriate antidiuresis, associated with any underlying condition (includes syndrome of inappropriate antidiuretic hormone secretion and nephrogenic syndrome of inappropriate antidiuresis); or

    • impaired renal dilutional capacity due to kidney disease.

Sodium concentrations can be measured in any type of blood sample (e.g. serum, plasma, whole blood, venous, arterial, capillary) using any measurement method (e.g. flame emission spectrophotometry, direct or indirect reading potentiometry by an ion-selective electrode) in any setting (e.g. central laboratory, local laboratory, point of care device).

Exclusion criteria
  • Children in the neonatal period (the interval from birth to 28 days of age)

  • Isotonic or hypertonic hyponatraemia (osmolality ≥ 285 mOsm/kg)

  • Hyponatraemia due to true (extracellular) volume depletion, such as from third spacing (a shifting of fluid into interstitial spaces), gastrointestinal, or renal sodium loss

  • Hyponatraemia due to secondary adrenal insufficiency or hypothyroidism

  • Hyponatraemia due to primary psychogenic polydipsia

  • Patients treated with any form of dialysis or extracorporeal ultrafiltration.

Types of interventions

We will include studies of any degree of fluid restriction or any drug treatment that has the aim of increasing the sodium concentration. Any dose or route of administration is permitted, and interventions can be compared with placebo, no treatment, a different dose of the same or different interventions, different administration routes of the same or different interventions, or different combinations of interventions.

Treatments will include (but will not be limited to):

  • fluid restriction

  • urea

  • mannitol

  • loop diuretics (furosemide, bumetanide, ethacrynic acid)

  • corticosteroids (hydrocortisone or equivalent, fludrocortisone)

  • demeclocycline

  • lithium

  • phenytoin

  • vasopressin receptor antagonists (conivaptan, mozavaptan, lixivaptan, satavaptan, tolvaptan).

We will exclude studies in which any form of dialysis treatment was given to correct serum sodium concentration.

Types of outcome measures

We will assess outcomes up to one week, up to one, two and six months, and up to one and five years.

Primary outcomes
  • Death (all-cause mortality)

  • Health-related quality of life and specifically symptoms attributed to hyponatraemia by the authors.

Secondary outcomes
  • Length of hospital stay

  • Response defined as increase of ≥ 5 mmol/L or normalisation of serum sodium concentration (≥ 135 to 145 mmol/L, or as defined by the authors)

  • Serum sodium concentration (mmol/L) at end of treatment or change from beginning to end of treatment

  • Outcomes related to over-correction of serum sodium concentration

    • Incidence of hypernatraemia (serum sodium concentration > 145 mmol/L, or as defined by the authors)

    • Rapid increase in serum sodium concentration (increase in serum sodium concentration > 10 mmol/L in 24 h or > 18 mmol/L in 48h, or as defined by the authors)

    • Incidence of osmotic demyelination syndrome, previously known as central pontine and extrapontine myelinolysis (diagnosed clinically, with MRI, or post mortem)

  • Any treatment-specific side effects as defined by authors

    • Acute kidney injury (demeclocycline, mannitol, loop diuretics)

    • Chronic kidney disease (lithium)

    • Hypotension (mannitol, loop diuretics, vasopressin receptor antagonists)

    • Thirst (mannitol, loop diuretics, fluid restriction, vasopressin receptor antagonists)

    • Central nervous system symptoms (phenytoin)

    • Polyuria (mannitol, loop diuretics, vasopressin receptor antagonists)

    • Any other adverse event as reported by triallists

  • Treatment discontinuation or switch.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co-ordinator using search terms relevant to this review.

The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the specialised register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of clinical practice guidelines, review articles and relevant studies.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

  3. Point-of-care sources such as Dynamed and UpToDate as well as US Food and Drug Administration (FDA) and European Medicines Agency (EMA) applications.

Data collection and analysis

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (e.g. death, number of patients with serum sodium concentration increase of ≥ 5 mmol/L, number of patients that develop hypernatraemia, number of patients with rapid increase in serum sodium concentration, number of patients that develop osmotic demyelination syndrome), results will be expressed as risk ratios (RR) with 95% confidence intervals. Where continuous scales of measurement are used to assess the effects of treatment (e.g. length of hospital stay, serum sodium concentration at the end of the study or its change from beginning to the end of treatment), results will be expressed as the mean difference (MD) or as the standardised mean difference (SMD) if different scales have been used.

Unit of analysis issues

  • Cluster RCTs: if cluster studies have been appropriately analysed to account for clustering in the data, direct measures of effect will be extracted if available and used in the meta-analyses using the generic inverse-variance method. If such information is not available, we will use cluster-level data as individual units of analysis, if the necessary data is available.

  • Cross-over studies: we will only use data from the first period if these are available.

  • Studies with multiple treatment groups: we will try to collapse multiple treatment groups into one where appropriate to enable single pair wise comparison (e.g. collapsing three groups of different doses of vasopressin receptor antagonists into one group and include in single pair wise comparison versus placebo) (Higgins 2011).

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing or writing to corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates, for example drop-outs, losses to follow-up and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last-observation-carried-forward) will be critically appraised (Higgins 2011).

Assessment of heterogeneity

Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers. Although the underlying conditions causing hyponatraemia are very different, the mechanism by which hyponatraemia develops is similar in that vasopressin activity plays a role in most forms of the disorder. We believe it justifies pooled analysis across subgroups of participants with different underlying conditions.

Subgroup analysis and investigation of heterogeneity

We will use stratified meta-analysis and where appropriate meta-regression to explore important clinical differences among the studies that may alter the magnitude of the treatment effect.

Heterogeneity among participants could be related to:

  • Serum sodium concentration at baseline (no predefined categories)

  • Underlying condition causing the hyponatraemia: inappropriate antidiuresis, where vasopressin activity is inappropriate, versus impaired renal dilutional capacity due to kidney disease versus heart failure, liver cirrhosis and nephrotic syndrome, in which case the vasopressin release is a physiologic response to maintain effective circulating volume. Hence it can be hypothesized that treatments aiming to counteract the increased vasopressin activity may have different effects depending on the reason for the increase.

Heterogeneity in treatments could be related to the agent within a drug class (e.g. conivaptan versus lixivaptan), the dose and duration of therapy.

Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared with no treatment or another agent.

Sensitivity analysis

We will perform sensitivity analyses to explore the influence of the following factors on effect size:

  • repeating the analysis excluding unpublished studies

  • repeating the analysis taking account of risk of bias

  • repeating the analysis excluding any very long or large studies to establish how much they dominate the results

  • repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.

Acknowledgements

We wish to acknowledge Ruth Mitchell for her contributions in developing the search strategies, running the searches and collecting the citations. We would like to thank Narelle Willis and Ann Jones for their editorial support in developing this protocol. And finally we would like to thank the referees for their comments and feedback during the preparation of this protocol.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. hyponatr*emi*:ti,ab,kw

  2. "inappropriate ADH syndrome":ti,ab,kw

  3. "inappropriate vasopressin secretion":ti,ab,kw

  4. {or #1-#3}

MEDLINE
  1. Hyponatremia/

  2. Inappropriate ADH Syndrome/

  3. hyponatr?emi*.tw.

  4. inappropriate ADH syndrome.tw.

  5. inappropriate vasopressin secretion.tw.

  6. or/1-5

EMBASE
  1. hyponatremia/

  2. inappropriate vasopressin secretion/

  3. hyponatr?emi*.tw.

  4. inappropriate ADH syndrome.tw.

  5. inappropriate vasopressin secretion.tw.

  6. or/1-5

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

  1. Draft the protocol: EVN, MCH, WVB, RVH, JC, ACW

  2. Study selection: EVN, MCH

  3. Extract data from studies: EVN, MCH

  4. Enter data into RevMan: EVN

  5. Carry out the analysis: EVN, MCH, ACW

  6. Interpret the analysis: EVN, MCH, WVB, RVH, JC, ACW

  7. Draft the final review: EVN, MCH, WVB, RVH, JC, ACW

  8. Disagreement resolution: ACW

  9. Update the review: EVN, MCH, WVB, RVH, JC, ACW

Declarations of interest

Evi V Nagler, Maria C Haller, Wim Van Biesen and Raymond Vanholder are members of European Renal Best Practice (ERBP), the guidance producing body of the European Renal Association/ European Dialysis and Transplant Association (ERA-EDTA). ERBP is currently in the process of developing a clinical practice guideline on diagnosis and treatment of hyponatraemia in a joint venture with the European Society of Endocrinology and the European Society of Intensive Care Medicine. ERBP receives their annual budget from the ERA-EDTA. ERA-EDTA does not interfere with topic choice or any other part of the guideline development process.

Evi V Nagler and Maria C Haller received an ERBP grant to fund their research programs. They have no commercial interests to declare.

Wim Van Biesen has no commercial interests related to the treatment of hyponatraemia or this review.

Raymond Vanholder has acted as consultant for Baxter Healthcare, Bellco and Mitsubishi; as expert advisor for Relitech, Dutch Kidney Foundation, Bellco, Amgen, Mitsubishi, DOPPS, Hoffman Laroche, Fresenius Medical Care; has received research grants from Fresenius Medical Care, Baxter Healthcare, Gambro, Astellas, Hoffman Laroche and Amgen. He has no specific commercial interests related to the treatment of hyponatraemia.

Jonathan C Craig and Angela C. Webster have no intellectual or commercial interests to declare.

Sources of support

Internal sources

  • European Renal Best Practice (ERBP), the guidance issuing body of the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), Not specified.

    Provided a grant that funded this research

External sources

  • No sources of support supplied

Ancillary