Pharmacological interventions for treating acute hyperkalaemia in adults

  • Protocol
  • Intervention

Authors


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 pharmacological treatments used in the management of acute hyperkalaemia in adults. This review will evaluate the therapies that reduce serum potassium as well as those that prevent complications of hyperkalaemia.

Background

Description of the condition

Hyperkalaemia is defined as an excess concentration of potassium ions in the extracellular fluid compartment. Acute hyperkalaemia, as opposed to chronic hyperkalaemia, occurs over hours to days, and depending on the degree of hyperkalaemia requires rapid treatment. Hyperkalemia occurs in both outpatients and hospitalised patients, often due to kidney failure, drugs or disorders that inhibit the renin-angiotensin-aldosterone axis, insulin deficiency or direct tissue trauma. Patients with hyperkalaemia may experience muscle weakness, fatigue, distal paraesthesias and respiratory depression (Freeman 1993). The most feared consequence of hyperkalaemia is cardiac arrhythmias. Electrocardiogram (ECG) changes include peaked T waves, QRS widening and diminished P waves. Severe hyperkalaemia may lead to a sine wave ECG pattern, ventricular tachycardia, ventricular fibrillation and death (Browning 1981).

Description of the intervention

A number of different pharmacologic interventions are used to treat patients with hyperkalaemia. Intravenous (IV) calcium salts are believed to stabilise the cardiac membrane, thereby reducing the risk of fatal arrhythmias even in the absence of any effect on serum potassium levels (Greenberg 1998Schwartz 1978). IV bicarbonate lowers the serum hydrogen ion concentration, thereby promoting an intracellular shift of potassium ions in exchange for hydrogen ions. Beta-2 agonists and insulin enhance the activity of the Na-K-ATPase pump in skeletal muscle and drive potassium intracellularly (Williams 1985Zierler 1987). Diuretics can enhance the loss of potassium from the kidneys. Cation exchange resins are also thought to bind potassium in the intestinal tract and remove it from the body via faecal excretion (Berlyne 1966Johnson 1976).

The evidence for renal replacement therapy (RRT) will not be discussed in detail in this review. Dialysis is known to be effective in both acute and chronic hyperkalaemia in patients with kidney failure. In an acute situation, the decision to use dialysis depends on the severity and aetiology of the hyperkalaemia, the safety and effectiveness of alternate therapies, as well as availability of dialysis (Evans 2005; Putcha 2007). Pharmacological interventions are used in patients with hyperkalaemia to either prevent the need for dialysis or to prevent complications until dialysis can be performed. In this review, the need for dialysis will be treated as an outcome rather than a treatment (Carvalhana 2006).

Although the evidence for RRT is outside the scope of this review, it is worth noting that dialysis is generally considered the definitive treatment for hyperkalaemia. Conventional haemodialysis causes the most rapid decrease in serum potassium levels. Other forms of dialysis (peritoneal dialysis, continuous venovenous haemofiltration or continuous venovenous haemodialysis) are also effective. The amount of potassium removed during dialysis depends on dialysis duration, dialysate potassium concentration, dialyser membrane, and patient characteristics such as baseline serum potassium (Evans 2005).

Why it is important to do this review

Hyperkalaemia is a commonly encountered, potentially life-threatening clinical event that requires prompt and effective treatment to prevent serious complications. This review will summarise and synthesise the literature published on the pharmacological management of hyperkalaemia to help clinicians best treat their patients. This review is a derivative of a Cochrane systematic literature review first published in 2005 (Clase 2005), but has narrowed the focus to the effectiveness and safety of the pharmacological management of hyperkalaemia in adults.

Objectives

This review aims to look at the benefits and harms of pharmacological treatments used in the management of acute hyperkalaemia in adults. This review will evaluate the therapies that reduce serum potassium as well as those that prevent complications of hyperkalaemia.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (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 any pharmacological intervention for management of acute hyperkalaemia in adults with be included. Non-standard study designs such as cross-over trials will also be included in the review.

Types of participants

Inclusion criteria

The study population of this review is adults (18 years and over) with acute hyperkalaemia receiving pharmacological therapy to reduce serum potassium or to prevent arrhythmias. Hyperkalaemia is defined as serum potassium concentration ≥ 4.9 mmol/L. Studies will be included when it is clear that the majority of study participants meet this definition. Patients with a variety of causes of hyperkalaemia, including both acute and chronic kidney failure, will be included in the study.

Exclusion criteria

Patients with artificially induced hyperkalaemia will be excluded from this review.

Types of interventions

All pharmacological therapies used in the short-term management of hyperkalaemia will be considered, including interventions used to reduce serum potassium as well as therapies used to prevent arrhythmias.

Studies where interventions are compared with placebo or another pharmacological therapy will be included. Studies comparing a pharmacological intervention with dialysis will not be included. Studies will be included regardless of the route of administration or dose of the pharmacological therapy. For the initial analysis, all studies of a particular pharmacological therapy, regardless of dose or route of administration, will be analysed together.

The source of a blood sample for potassium measurement (venous or arterial) can introduce additional variation (Johnston 2005). Ideally, all studies will report potassium measurements from the same source, but if this is not the case, potassium levels will be preferentially used from whichever source is more common.

Types of outcome measures

  1. Mortality

  2. Arrhythmias

  3. Dialysis

  4. Serum potassium

  5. ECG changes

  6. Adverse events.

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:

  1. Quarterly 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 contained 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 review articles and relevant studies.

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

Data collection and analysis

Selection of studies

The search methods 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 three authors who will discard studies that are not applicable. Studies and reviews that might include relevant data or information on studies will be retained for consideration. Three authors will independently assess the retrieved abstracts and full texts, if necessary, to determine which studies satisfy the inclusion criteria.

Data extraction and management

Three authors will be involved in the data extraction process. Data extraction will be carried out independently by at least two authors using a standard data extraction form. 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 report with the most complete data will be used in the analyses. Where relevant outcomes are only published in less complete versions, these data will be used. Any discrepancy between published reports will be highlighted. If information about results or study methodology is missing from the original publication, authors will be contacted for additional information.

Assessment of risk of bias in included studies

The following items will be independently assessed by at least 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 (death, arrhythmia, ECG changes), results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (serum potassium), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. Change scores will be used if results are not available as another type and these will be combined with other results using the MD. If studies do not report the within study variance for continuous outcomes, the standard deviation will be imputed using the average standard deviation from other studies. This will only be performed if relatively few studies require imputation of standard deviation.

All studies of a particular pharmacological therapy will be analysed together regardless of route of administration or dose. Subgroup analyses will be subsequently performed to identify any effect of route or dose.

Unit of analysis issues

If cross-over studies are available for inclusion in this review, the paired results will be included in the analysis using the generic inverse-variance method. If studies do not report the necessary data for paired analysis, we will attempt to impute the missing standard deviations. If it is not possible to impute the missing standard deviations, results of the cross-over study will be included in analysis as unpaired data and a sensitivity analysis will be performed to assess the effect of including the data in this manner.

For studies with multiple intervention groups comparing a single pharmacological therapy given by a different route or dose to a control group, we will combine all relevant groups into a single group.

Dealing with missing data

Any further information required from the original author will be requested by written correspondence, and any relevant information obtained in this manner will be included in the review. The number of screened and randomised patients, as well as intention-to-treat, as-treated and per-protocol populations will be carefully evaluated. Attrition rates, including drop-outs, losses to follow-up and withdrawals, will be investigated. We will consider the impact of missing data on study results and critically appraise imputation methods employed by the authors.

Assessment of heterogeneity

We will identify heterogeneity using a Chi² test with N-1 degrees of freedom and an alpha of 0.10. If present, we will quantify the degree of heterogeneity using the I² index with values of 25%, 50% and 75% corresponding to low, medium and high levels of heterogeneity (Higgins 2003).

Assessment of reporting biases

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

Data synthesis

Data will be pooled using the random-effects model. The fixed-effect model will also be used to ensure robustness of the chosen model and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, intervention, study quality). Heterogeneity among studies may be related to patient age, comorbidities, kidney function, and coadministration of medications. Heterogeneity among participants may be related to patient age, kidney function, aetiology of hyperkalaemia, duration of hyperkalaemia, comorbidities, and co-administration of medications. Heterogeneity in treatments may be related to prior therapeutic agent or agents used, time to administration and the agent dose, route of administration and duration of therapy. Adverse effects will be tabulated and assessed using descriptive techniques, because they are likely to vary among the different agents. Where possible, the risk difference will be calculated with a 95% CI for each adverse effect, compared to no treatment or to another agent.

Sensitivity analysis

We will perform sensitivity analyses in order 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, as specified

  • repeating the analysis excluding any very long or large studies to establish how much they influence 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 would like to acknowledge the authors of the previous Cochrane review "Emergency interventions for hyperkalaemia": BA Mahoney, WA Smith, D Lo, K Tsoi, M Tonelli and C Clase (Clase 2005).

We would like to thank the referees for their comments and feedback during the preparation of this protocol.

We would like to thank Dr Gerald Da Roza Faculty who served as the supervisor for Dr Tara Cessford's residency research project.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. MeSH descriptor Hyperkalemia, this term only

  2. (hyperkalemia):ti,ab,kw in Trials

  3. (hyperkalaemia):ti,ab,kw in Trials

  4. (hyperpotassemia):ti,ab,kw in Trials

  5. (#1 OR #2)

MEDLINE
  1. Hyperkalemia/

  2. hyperkalemia$.tw.

  3. hyperkalaemia.tw

  4. hyperpotassemia.tw

  5. or/1-4

EMBASE
  1. hyperkalemia/

  2. hyperkalemia$.tw.

  3. hyperkalaemia.tw

  4. hyperpotassemia.tw

  5. or/1,4

Appendix 2. Risk of bias assessment tool

Potential source of biasAssessment 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

All authors will be involved in each step of the protocol development and review.

  1. Draft the protocol: JB, TC, RT

  2. Study selection: JB, TC, RT

  3. Extract data from studies: JB, TC, RT

  4. Enter data into RevMan: JB, TC, RT

  5. Carry out the analysis: JB, TC, RT

  6. Interpret the analysis: JB, TC, RT

  7. Draft the final review:JB, TC, RT

  8. Disagreement resolution: JB, TC, RT

  9. Update the review:JB, TC, RT

Declarations of interest

All authors have no perceived or actual conflicts of interest to declare.