Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of first aid glucose administration by any route appropriate for use by first aid providers (buccal, sublingual, oral, rectal) for symptomatic hypoglycaemia.
Background
Description of the condition
Hypoglycaemia is common in individuals with diabetes but can also occur in individuals without diabetes due to an imbalance in glucose homeostasis (e.g. poor dietary intake or acute disease) (Ostenson 2014; Sako 2017). Symptoms of hypoglycaemia range from mild (e.g. sweating and hunger) to severe (e.g. seizures and altered mental status). According to the International Diabetes Federation (IDF) there are over 425 million people living with diabetes worldwide, and hypoglycaemia carries a significant burden of disease (IDF 2017). Even mild hypoglycaemic events have a considerable impact on both individuals and society since they can require additional healthcare resources, and individuals with non‐severe hypoglycaemia may experience loss of work time estimated to cost approximately USD 2300 per diabetic patient per year (Geelhoed‐Duijvestijn 2013; Ostenson 2014). Early treatment may consequently result in grossly underreported true rate of hypoglycaemia as prompt action helps to avoid the need for further medical care (Cain 2003; Ostenson 2014).
Description of the intervention
Treatment of mild hypoglycaemia is essential to prevent progression to a life‐threatening condition. It consists of the intake of glucose or dietary sugars to quickly increase the blood sugar level. While multiple protocols are available to healthcare providers, first aid for this condition is often self‐administered or provided by family or friends (Ostenson 2014; Rostykus 2016). While parenteral treatment with glucagon kits is available in some countries, this is typically reserved for use by trained family members in the presence of severe hypoglycaemia and unresponsiveness, or inability to swallow.
A systematic review has suggested oral glucose may be preferred over dietary sugars, such as orange juice, jelly beans, or Mentos® for treatment of less severe hypoglycaemia in people who are responsive, able to swallow, and able to follow commands (Carlson 2017). Current guidelines recommend oral glucose for the treatment of symptomatic hypoglycaemia in conscious people (Singletary 2015; Zideman 2015).
How to best deliver glucose, both in terms of efficacy (e.g. resolution of symptoms and rate of normalisation of blood glucose levels) and safety (e.g. complications including aspiration), is unknown (Singletary 2015; Zideman 2015). Possible administration routes to deliver glucose, and available in first aid situations, include buccal, sublingual, oral, and rectal administration. Buccal administration is defined as the application of glucose to the inner cheek mucosa; sublingual administration as the administration of glucose under the tongue; and both routes do not require swallowing of the glucose.
Adverse effects of the intervention
In addition to aspects of bioavailability described below, various administration routes carry different safety concerns. For example, the oral route requires the individual to have the ability to swallow and may potentially be associated with aspiration if swallowing is impaired (e.g. due to an altered level of consciousness). As such, it is important to help individuals understand the risks and benefits associated with various treatment options.
How the intervention might work
While other routes, such as intravenous or intraosseous administration, are available to professional caregivers these routes are not practical or feasible in many first aid settings and are likely not needed in cases of mild hypoglycaemia. The buccal, sublingual, oral, and rectal routes could potentially be used by both hypoglycaemic individuals and first aid providers managing hypoglycaemia; however their efficacy and safety are unknown. Each of these routes may have various levels and rates of bioavailability which may impact on clinical recovery rates.
In the case of buccal administration, medications or sugars are held inside the cheek and then diffuse through the oral mucosa to directly enter the bloodstream. Compared to oral administration the substance does not pass through the digestive system and has less chance of becoming degraded. Therefore, the drug can potentially act faster; however, the bioavailability of buccal administered medications or sugars is unknown. With sublingual administration, a sugar or medicine diffuses into the blood through the mucous membrane under the tongue. As with buccal administration, it does not pass through the gastrointestinal tract and may be absorbed faster than the oral route. However, the total available area under the tongue for absorption may limit the extent of uptake. While many medications are specifically designed for buccal or sublingual administration, it is unknown which administration route is most effective for glucose.
Why it is important to do this review
To help guide first aid care, the International Liaison Committee on Resuscitation (ILCOR) uses a continuous evidence evaluation process for resuscitation and relevant first aid topics culminating in the production of a consensus on science with treatment recommendations (CoSTR). Whilst previous work by ILCOR has helped to establish the role of oral glucose (i.e. tablets) over dietary sugars, the optimal enteral route for glucose administration is currently unknown (Carlson 2017; Singletary 2015; Zideman 2015). A Cochrane Review studied the use of oral dextrose gel massaged into the buccal mucosa for the treatment of hypoglycaemia in newborn infants, and showed positive effects towards outcomes as “separation from the mother” and “completing breast‐feeding”. However, we excluded this target group from this Cochrane Review, since the setting of treatment of newborns is less relevant to first aid (Weston 2016). We will conduct this review in cooperation with the ILCOR First Aid Task Force. The aim of this systematic review is to answer the following research question: among adults and children with suspected hypoglycaemia, does administration of glucose by any route appropriate for use by first aid providers compared to administration of glucose by another route appropriate for use by first aid providers change resolution of symptoms, blood glucose concentration, resolution of hypoglycaemia, delay in treatment, or adverse events?
Objectives
To assess the effects of first aid glucose administration by any route appropriate for use by first aid providers (buccal, sublingual, oral, rectal) for symptomatic hypoglycaemia.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) and non‐RCTs. We will exclude observational studies and unpublished studies (e.g. conference abstracts).
Types of participants
We will include studies with adults and children with documented or suspected hypoglycaemia. Participants could be healthy volunteers or diabetic people with hypoglycaemia.
Types of interventions
We plan to investigate the following comparisons of intervention versus control/comparator.
Intervention
We will include studies where glucose (in the form of glucose or dextrose spray, gel, liquids, syrup or tablets, liquid sugar (e.g. corn syrup), or table sugar (sucrose) in different forms (solid or liquid)), is administered by any route appropriate for use by first aid providers (buccal, sublingual, oral, rectal). Buccal administration is defined as application to the cheek mucosa; sublingual administration as application under the tongue; both without intentional swallowing of glucose.
Comparisons
For the comparison, we will include studies where the same sugar compound in the comparison group was administered by a different route of administration (buccal, sublingual, oral, rectal) than the intervention group.
Concomitant interventions must be the same in both the intervention and comparator groups to establish fair comparisons.
If a study includes multiple arms, we will include any study arm that meets the review inclusion criteria.
Minimum duration of intervention
Since glucose administration is a first aid intervention with a quick response, this intervention is administered only one single time and no minimum duration of the intervention will be defined.
Minimum duration of follow‐up
Minimal duration of follow‐up will be 20 minutes.
We will define any follow‐up period going beyond the original time frame for the primary outcome measure as specified in the power calculation of the studies' protocol as an extended follow‐up period (also called ‘open‐label extension study') (Buch 2011; Megan 2012).
Summary of specific exclusion criteria
We will exclude studies of the following category of participants or interventions.
Neonates, as we consider that the presentation of hypoglycaemia in this population differs from adults and children, requiring skills beyond typical first aid.
Intravenous administration of glucose.
Administration of sugars that are not readily available to a first aid provider (e.g. fructose or a specific mixture of different sugars)
Administration of sugar‐containing foods and beverages such as candies, juice, or confectionaries as these have been analysed in a recent systematic review (Carlson 2017).
Types of outcome measures
We will not exclude a study if it fails to report one or several of our primary or secondary outcome measures. If none of our primary or secondary outcomes is reported in the study, we will not include the study but will provide some basic information in the ‘Characteristics of awaiting classification' table.
We will investigate the following outcomes using the methods and time points specified below.
Primary outcomes
Resolution of symptoms.
Time to resolution of symptoms.
Blood or plasma glucose concentration at 20 minutes.
Secondary outcomes
Resolution of hypoglycaemia.
Time to resolution of hypoglycaemia.
Adverse events.
Treatment delay.
Method and timing of outcome measurement
Resolution of symptoms: defined as the reversal of the initial symptoms.
Time to resolution of symptoms: defined as the time from the administration of the glucose containing solution until the symptoms resolved.
Blood or plasma glucose concentration at 20 minutes: defined as the glucose level measured 20 minutes after the administration of the glucose substrate.
Resolution of hypoglycaemia: defined as a rise in the blood or plasma glucose level ≥ 90 mg/dL or a rise in blood or plasma glucose within 20 minutes.
Time to resolution of hypoglycaemia: defined as the time from the administration of the glucose substrate to the time for the blood or plasma glucose concentration to rise above the threshold for hypoglycaemia.
Adverse events: defined as any event resulting from the treatment as defined by the study authors (for example, aspiration).
Treatment delay: defined as the delay in providing care as a result of the treatment arm.
Search methods for identification of studies
Electronic searches
We will search the following sources from the inception of each database to the date of search and will place no restrictions on the language of publication:
Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO).
MEDLINE Ovid SP (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE; from 1946 onwards).
Embase Ovid SP.
CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature).
ClinicalTrials.gov (www.clinicaltrials.gov).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/trialsearch/).
EU Clinical Trials Register.
For detailed search strategies, see Appendix 1. We apply a continuous email alert service for MEDLINE via OvidSP to identify newly published studies using the search strategy detailed in Appendix 1.
Searching other resources
We will try to identify other potentially eligible studies or ancillary publications by searching the reference lists of included studies, systematic reviews, meta‐analyses, and health technology assessment reports. In addition we will contact the authors of included studies to obtain additional information on the retrieved studies and establish whether we may have missed further studies.
We will not use abstracts or conference proceedings for data extraction unless full data are available from study authors because this information source does not fulfil the CONSORT requirements which consist of "an evidence‐based, minimum set of recommendations for reporting randomised trials" (CONSORT 2019; Scherer 2007). We will present information on abstracts or conference proceedings in the ‘Characteristics of studies awaiting classification' table.
Data collection and analysis
Selection of studies
Two review authors (EDB and TD) will independently screen the abstract or title, or both, of every record retrieved by the literature searches to determine which studies we should assess further. We will obtain the full‐text of all potentially relevant records. We will resolve disagreements through consensus or by recourse to a third review author (VB). If we cannot resolve a disagreement, we will categorise the study as a ‘Study awaiting classification' and will contact the study authors for clarification. We will present an adapted PRISMA flow diagram to show the process of study selection (Liberati 2009). We will list all articles excluded after full‐text assessment in a ‘Characteristics of excluded studies' table and will provide the reasons for exclusion.
Data extraction and management
For studies that meet the inclusion criteria of the review, two review authors (EDB and VB) will independently extract information on key participant and intervention characteristics. Two review authors (EDB and VB) will independently extract the following data using a standardised and a piloted data extraction form: general study information (author, year of publication, country of author), study design, study population (number of participants, mean age, patient characteristics if applicable), intervention (dose, details on intervention and administration route), outcome measures and risk of bias.
We will resolve disagreements by discussion or, if required, by consulting a third review author (TD, JNC, EMS, or DAZ).
We will provide information including trial identifier for potentially relevant ongoing trials in the ‘Characteristics of ongoing trials' table and in a joint appendix ‘Matrix of study endpoints (publications and trial documents)'. We will try to find the protocol for each included study and will report in a joint appendix primary, secondary, and other outcomes in comparison with data in publications.
We will seek relevant missing information on the study from the primary study author(s), if required.
Dealing with duplicate and companion publications
In the event of duplicate publications, companion documents, or multiple reports of a primary study, we will maximise the information yield by collating all available data, and we will use the most complete data set aggregated across all known publications. We will list duplicate publications, companion documents, multiple reports of a primary study, and trial documents of included trials (such as trial registry information) as secondary references under the study ID of the included trial. Furthermore, we will list duplicate publications, companion documents, multiple reports of a study, and trial documents of excluded studies (such as trial registry information) as secondary references under the study ID of the excluded study.
Data from clinical trials registers
If data from included studies are available as study results in clinical trials registers, such as ClinicalTrials.gov or similar sources, we will make full use of this information and will extract the data. If there is also a full publication of the study, we will collate and critically appraise all available data. If an included study is marked as a completed trial in a clinical trials register but no additional information (study results, publication, or both) is available, we will add this trial to the ‘Characteristics of studies awaiting classification' table.
Assessment of risk of bias in included studies
Two review authors (EDB and VB) will independently assess the risk of bias for each included study. We will resolve disagreements by consensus or by consulting a third review author (TD). In the case of disagreement, we will consult the remainder of the review author team and will make a judgment based on consensus. If adequate information is unavailable from the publications, trial protocols, or other sources, we will contact the study authors for more details and to request missing data on ‘Risk of bias' items.
For the RCTs, we will use the Cochrane ‘Risk of bias' assessment tool (Higgins 2017), assigning assessments of low, high, or unclear risk of bias (for details, see Appendix 2; Appendix 3). We will evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions, according to the criteria and associated categorisations contained therein (Higgins 2017).
For the non‐RCTs we will assess the different items of the ROBINS tool (Sterne 2016). In case of cross‐over studies we will additionally assess the items described in the Cochrane Handbook for Systematic Reviews of Interventions for cross‐over studies (Higgins 2011).
Summary assessment of risk of bias
We will present a ‘Risk of bias' graph and a ‘Risk of bias' summary figure. A study will be overall considered as at high risk of bias if we find that one of the domains within the Cochrane ‘Risk of bias' or ROBINS tool is at high risk of bias.
Measures of treatment effect
We will report dichotomous data as a risk ratio (RR) or an odds ratio (OR) with 95% confidence intervals (CIs). For continuous outcomes measured on the same scale (e.g. glucose concentrations in mg/dL), we will estimate the intervention effect using the mean difference (MD) with 95% CIs. For continuous outcomes that measure the same underlying concept (e.g. health‐related quality of life) but use different measurement scales, we will calculate the standardised mean difference (SMD). We will express time‐to‐event data as a hazard ratio (HR) with 95% CIs.
We will convert all data on glucose concentrations to mg/dL.
Unit of analysis issues
We will take into account the level at which randomisation occurred, such as cross‐over studies, cluster‐randomised trials, and multiple observations for the same outcome. In the case of multi‐arm studies, we will combine groups to create a single pair‐wise comparison. We anticipate identifying studies with paired data (within‐subjects designs), which we will analyse as reported by Elbourne 2002.
Dealing with missing data
If possible, we will obtain missing data from the authors of included studies. Where necessary, we will extract data from graphs from the included studies. Where necessary and if possible, we will impute missing values. We will investigate the impact of imputation on meta‐analyses by performing sensitivity analyses.
Assessment of heterogeneity
In the event of substantial clinical or methodological heterogeneity, we will not report study results as the pooled effect estimate in a meta‐analysis. We will identify heterogeneity (inconsistency) by visually inspecting the forest plots and by using a standard Chi2 test with a significance level of α = 0.1 (Deeks 2017). In view of the low power of this test, we will also consider the I2 statistic, which quantifies inconsistency across studies, to assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003). We will also consider heterogeneity to be significant if the I2 value is greater than 60%.
When we find heterogeneity, we will attempt to determine possible reasons for this by examining individual study and subgroup characteristics.
Assessment of reporting biases
If we include 10 or more studies that investigate a particular outcome, we will use funnel plots to assess small‐study effects. Several explanations may account for funnel plot asymmetry, including true heterogeneity of effect with respect to study size, poor methodological design (and hence bias of small studies), and publication bias (Sterne 2017). Therefore we will interpret the results carefully (Sterne 2011).
Data synthesis
We plan to undertake (or display) a meta‐analysis only if we judge participants, interventions, comparisons, and outcomes to be sufficiently similar to ensure an answer that is clinically meaningful. Unless good evidence shows homogeneous effects across studies of different methodological quality, we will primarily summarise low risk of bias data using a random‐effects model (Wood 2008). Our analyses will be stratified based on administration route (buccal, sublingual, oral, rectal). Since we anticipate variation between studies, we will use the random‐effects model. We will use the Mantel‐Haenszel method for dichotomous outcomes and the Inverse variance method for continuous outcomes. A P value less than 0.05 will be considered significant. We will analyse meta‐analyses involving paired data from within participants designs using R software, version 3.2.5 (R software 2019).
Subgroup analysis and investigation of heterogeneity
We expect the following characteristics to introduce clinical heterogeneity, and we plan to undertake the following subgroup analyses including investigation of interactions (Altman 2003).
Paediatric versus adult individuals.
Individuals with insulin‐dependent and non‐insulin dependent diabetes.
Unconscious versus conscious individuals.
Sensitivity analysis
We plan to perform sensitivity analyses to explore the influence of the following factors (when applicable) on effect sizes by restricting analysis to the following.
Effect of risk of bias, as specified in the Assessment of risk of bias in included studies section.
Effect of an assumed correlation coefficient of 0.1 (low degree of correlation) and 0.9 (high degree of correlation), in case the correlation between the results from the two treatment periods is not known for paired data study designs.
Certainty of the evidence
We will present the overall certainty of the evidence for each outcome specified below, according to the GRADE approach, which takes into account issues related not only to internal validity (risk of bias, inconsistency, imprecision, publication bias) but also to external validity, such as directness of results (Guyatt 2008; Schünemann 2013). Two review authors (EDB and VB) will independently rate the certainty of the evidence for each outcome. We will resolve differences in assessment by discussion or by consulting a third review author (TD).
We will use the GRADEpro Guideline Development Tool (GDT) software and will present evidence profile tables as an appendix (GRADEproGDT 2015). We will present results for outcomes as described in the Types of outcome measures section. If meta‐analysis is not possible, we will present the results in a narrative format in the ‘Summary of findings' table. We will justify all decisions to downgrade the certainty of the evidence using footnotes, and we will make comments to aid the reader's understanding of the Cochrane Review when necessary.
‘Summary of findings' table
We will present a summary of the evidence in a ‘Summary of findings' table. This will provide key information about the best estimate of the magnitude of effect, in relative terms and as absolute differences for each relevant comparison of alternative management strategies, numbers of participants and studies addressing each important outcome, and a rating of overall confidence in effect estimates for each outcome. We will create the ‘Summary of findings' table using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017), using Review Manager 5 (RevMan 5) table editor (RevMan 2014).
Acknowledgements
We thank the following people for their valuable support in improving this protocol: the International Liaison Committee on Resuscitation (ILCOR) First Aid Task Force members, Carolyn Ziegler (St. Michael’s Hospital Information Specialist), Peter Morley, Jerry Nolan, and Eddy Lang.
Appendices
Appendix 1. Search strategies
| MEDLINE (Ovid SP) |
| 1 Hypoglycemia/ 2 (Hypoglycemi* or hypoglycaemi*).tw,kf. 3 Healthy Volunteers/ 4 (healthy participant or healthy participants or healthy subject or healthy subjects or healthy volunteer or healthy volunteers or human volunteer or human volunteers or normal volunteer or normal volunteers).tw,kf. 5 healthy people.tw,kf. 6 healthy persons.tw,kf. 7 1 or 2 or 3 or 4 or 5 or 6 8 Glucose/ 9 (glucose or sugar).tw,kf. 10 8 or 9 11 drug administration routes/ or administration, inhalation/ or exp administration, oral/ or Administration, Rectal/ 12 administ*.tw,kf. 13 11 or 12 14 (buccal* or sublingual* or oral* or by mouth or rectal* or tablet* or liquid* or gel or gels or sachet* or spray or sprays or tongue or cheek or swallow* or administration route*).tw,kf. 15 Solutions/ 16 Tablets/ 17 Cheek/ 18 Gels/ 19 14 or 15 or 16 or 17 or 18 20 7 and 10 and 13 and 19 21 limit 20 to (case reports or comment or congresses or editorial or letter) 22 20 not 21 23 22 not (animals/ not humans/) 24 remove duplicates from 23 |
| Cochrane Central Register of Controlled Trials (Cochrane Register of Studies Online) |
| 1 Hypoglycemia/ 2 (Hypoglycemi* or hypoglycaemi*).tw,kf. 3 Healthy Volunteers/ 4 (healthy participant or healthy participants or healthy subject or healthy subjects or healthy volunteer or healthy volunteers or human volunteer or human volunteers or normal volunteer or normal volunteers).tw,kf. 5 healthy people.tw,kf. 6 healthy persons.tw,kf. 7 1 or 2 or 3 or 4 or 5 or 6 8 Glucose/ 9 (glucose or sugar).tw,kf. 10 8 or 9 11 drug administration routes/ or administration, inhalation/ or exp administration, oral/ or Administration, Rectal/ 12 administ*.tw,kf. 13 11 or 12 14 (buccal* or sublingual* or oral* or by mouth or rectal* or tablet* or liquid* or gel or gels or sachet* or spray or sprays or tongue or cheek or swallow* or administration route*).tw,kf. 15 Solutions/ 16 Tablets/ 17 Cheek/ 18 Gels/ 19 14 or 15 or 16 or 17 or 18 20 7 and 10 and 13 and 19 21 remove duplicates from 20 |
| Embase (Ovid SP) |
| 1 hypoglycemia/ or insulin hypoglycemia/ or nocturnal hypoglycemia/ 2 experimental hypoglycemia/ 3 normal human/ 4 (healthy participant or healthy participants or healthy subject or healthy subjects or healthy volunteer or healthy volunteers or human volunteer or human volunteers or normal volunteer or normal volunteers or healthy people or healthy persons).tw. 5 1 or 2 or 3 or 4 6 glucose/ 7 (glucose or sugar).tw. 8 6 or 7 9 drug administration route/ 10 oral drug administration/ 11 enteral drug administration/ 12 sublingual drug administration/ 13 exp buccal drug administration/ 14 rectal drug administration/ 15 administ*.tw. 16 9 or 10 or 11 or 12 or 13 or 14 or 15 17 (buccal* or sublingual* or oral* or by mouth or rectal* or tablet* or liquid* or gel or gels or sachet* or spray or sprays or tongue or cheek or swallow* or administration route*).tw. 18 cheek/ 19 aerosol/ or drug solution/ or gel/ or lozenge/ or oral drops/ or oral spray/ or paste/ or exp tablet/ 20 17 or 18 or 19 21 5 and 8 and 16 and 20 22 limit 21 to (books or "book review" or chapter or conference abstract or conference paper or "conference review" or editorial or letter or note) 23 21 not 22 24 23 not ((exp animal/ or nonhuman/) not exp human/) 25 remove duplicates from 24 26 limit 25 to embase |
| CINAHL Plus with full text (EBSCOhost Research Databases) |
| S1 (MH "Hypoglycemia") S2 TI ( (Hypoglycemi* or hypoglycaemi*) ) OR AB ( (Hypoglycemi* or hypoglycaemi*) ) S3 TI ( (healthy participant or healthy participants or healthy subject or healthy subjects or healthy volunteer or healthy volunteers or human volunteer or human volunteers or normal volunteer or normal volunteers or healthy people or healthy persons) ) OR AB ( (healthy participant or healthy participants or healthy subject or healthy subjects or healthy volunteer or healthy volunteers or human volunteer or human volunteers or normal volunteer or normal volunteers or healthy people or healthy persons) ) S4 S1 OR S2 OR S3 S5 (MH "Glucose") S6 TI ( glucose or sugar ) OR AB ( glucose or sugar ) S7 S5 OR S6 S8 (MH "Drug Administration Routes") OR (MH "Administration, Oral+") OR (MH "Administration, Rectal") OR (MH "Administration, Inhalation") S9 TI administ* OR AB administ* S10 S8 OR S9 S11 TI ( (buccal* or sublingual* or oral* or by mouth or rectal* or tablet* or liquid* or gel or gels or sachet* or spray or sprays or tongue or cheek or swallow* or administration route*) ) AND AB ( (buccal* or sublingual* or oral* or by mouth or rectal* or tablet* or liquid* or gel or gels or sachet* or spray or sprays or tongue or cheek or swallow* or administration route*) ) S12 (MH "Solutions") OR (MH "Tablets") OR (MH "Aerosols") OR (MH "Gels") S13 (MH "Cheek") S14 (MH "Tongue") S15 S11 OR S12 OR S13 OR S14 S16 S4 AND S7 AND S10 AND S15 |
| ClinicalTrials.gov (standard search) |
| Condition or disease: Hypoglycemia Other terms: Hypoglycaemia Study type: Interventional Studies Intervention/treatment: Glucose |
| World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (standard search) |
| hypoglycemia OR hypoglycaemia |
| EU Clinical Trials Register |
| (hypoglycemia OR hypoglycaemia) AND glucose |
Appendix 2. ‘Risk of bias' assessment
| ‘Risk of bias' domains |
|
Random sequence generation (selection bias due to inadequate generation of a randomised sequence) For each included study, we will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
Allocation concealment (selection bias due to inadequate concealment of allocation prior to assignment) We will describe for each included study the method used to conceal allocation to interventions prior to assignment and we will assess whether intervention allocation could have been foreseen in advance of or during recruitment or changed after assignment.
We will also evaluate study baseline data to incorporate assessment of baseline imbalance into the ‘Risk of bias' judgement for selection bias (Corbett 2014). Chance imbalances may also affect judgements on the risk of attrition bias. In the case of unadjusted analyses, we will distinguish between studies that we rate as being at low risk of bias on the basis of both randomisation methods and baseline similarity, and studies that we judge as being at low risk of bias on the basis of baseline similarity alone (Corbett 2014). We will reclassify judgements of unclear, low, or high risk of selection bias as specified in Appendix 3. Blinding of participants and study personnel (performance bias due to knowledge of the allocated interventions by participants and personnel during the study) We will evaluate the risk of detection bias separately for each outcome (Hróbjartsson 2013). We will note whether endpoints were self‐reported, investigator‐assessed, or adjudicated outcome measures (see below).
Blinding of outcome assessment (detection bias due to knowledge of the allocated interventions by outcome assessment) We will evaluate the risk of detection bias separately for each outcome (Hróbjartsson 2013). We will note whether endpoints were self‐reported, investigator‐assessed, or adjudicated outcome measures (see below).
Incomplete outcome data (attrition bias due to quantity, nature, or handling of incomplete outcome data) For each included study or each outcome, or both, we will describe the completeness of data, including attrition and exclusions from the analyses. We will state whether the study reported attrition and exclusions, and we will report the number of participants included in the analysis at each stage (compared with the number of randomised participants per intervention/comparator groups). We will also note if the study reported the reasons for attrition or exclusion, and whether missing data were balanced across groups or were related to outcomes. We will consider the implications of missing outcome data per outcome such as high dropout rates (e.g. above 15%) or disparate attrition rates (e.g. difference of 10% or more between study arms).
Selective reporting (reporting bias due to selective outcome reporting) We will assess outcome reporting bias by integrating the results of the appendix ‘Matrix of study endpoints (publications and trial documents)' (Boutron 2014; Jones 2015; Mathieu 2009), with those of the appendix ‘High risk of outcome reporting bias according to the Outcome Reporting Bias In Trials (ORBIT) classification' (Kirkham 2010). This analysis will form the basis for the judgement of selective reporting.
Other bias
|
Appendix 3. Selection bias decisions
| Selection bias decisions for studies that reported unadjusted analyses: comparison of results obtained using method details alone versus results obtained using method details and study baseline informationa | |||
| Reported randomisation and allocation concealment methods | ‘Risk of bias' judgement using methods reporting | Information gained from study characteristics data | ‘Risk of bias' using baseline information and methods reporting |
| Unclear methods | Unclear risk | Baseline imbalances present for important prognostic variable(s) | High risk |
| Groups appear similar at baseline for all important prognostic variables | Low risk | ||
| Limited or no baseline details | Unclear risk | ||
| Would generate a truly random sample, with robust allocation concealment | Low risk | Baseline imbalances present for important prognostic variable(s) | Unclear riskb |
| Groups appear similar at baseline for all important prognostic variables | Low risk | ||
| Limited baseline details, showing balance in some important prognostic variablesc | Low risk | ||
| No baseline details | Unclear risk | ||
| Sequence is not truly randomised or allocation concealment is inadequate | High risk | Baseline imbalances present for important prognostic variable(s) | High risk |
| Groups appear similar at baseline for all important prognostic variables | Low risk | ||
| Limited baseline details, showing balance in some important prognostic variablesc | Unclear risk | ||
| No baseline details | High risk | ||
| aTaken from Corbett 2014; judgements highlighted in bold indicate situations in which the addition of baseline assessments would change the judgement about risk of selection bias compared with using methods reporting alone. bImbalance was identified that appears likely to be due to chance. cDetails for the remaining important prognostic variables are not reported. | |||
Contributions of authors
EDB drafted the protocol. All review authors contributed to, read, and approved the final protocol draft.
Sources of support
Internal sources
No sources of support supplied
External sources
-
American Heart Association, USA.
This systematic review received funding from the American Heart Association on behalf of the International Liaison Committee on Resuscitation (ILCOR). The funder was involved in the ILCOR process, but had no role in this systematic review study design, data collection and analysis, or preparation of the manuscript.
Declarations of interest
EDB: contracted by the First Aid Task Force as systematic reviewer; employee of the Belgian Red Cross, involved in providing first aid training to the general public.
VB: member of the ILCOR First Aid Task Force; employee of the Belgian Red Cross, involved in providing first aid training to the general public.
JNC: member of the ILCOR First Aid Task Force; member of American Red Cross Scientific Advisory Council, First Aid Subcouncil.
DAZ: member and Vice‐Chair of the ILCOR First Aid Task Force.
EMS: member and Chair of the ILCOR First Aid Task Force; member of American Red Cross Scientific Advisory Council, First Aid Subcouncil Chair.
TD: member of the ILCOR First Aid Task Force.
Notes
We based parts of the Methods, as well as Appendix 1, Appendix 2, and Appendix 3 of this Cochrane Protocol, on a standard template established by the Cochrane Metabolic and Edocrine Disorders
Group.
New
References
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