Background While glucose tablets have been advocated for treating symptomatic hypoglycaemia in awake patients, dietary sugars may be more convenient. We performed a systematic review to compare the impact of these treatment options on the relief of symptomatic hypoglycaemia, time to resolution of symptoms, blood glucose levels, complications and hospital length of stay.
Method We searched PubMed, Embase and the Cochrane Library through 28 June 2016 and assessed the quality of evidence using the Grades of Recommendation, Assessment, Development and Evaluation approach. Reference lists from a subset of the resulting articles were mined for additional, potentially eligible papers. We calculated the risk ratio (RR) of each treatment option for the preselected outcomes of interest.
Results Of the 1774 identified papers, four studies met the inclusion criteria; three randomised controlled trials totalling 502 hypoglycaemic events treated with dietary sugars and 223 with glucose tablets and one observational study with 13 events treated with dietary sugars and 9 with glucose tablets. The dietary forms of sugar included sucrose, fructose, orange juice, jelly beans, Mentos, cornstarch hydrolysate, Skittles and milk. In the pooled analysis, patients treated with dietary sugars had a lower resolution of symptoms 15 min after treatment compared with glucose tablets (RR 0.89, 95% CI 0.83 to 0.95).
Conclusions When compared with dietary sugars, glucose tablets result in a higher rate of relief of symptomatic hypoglycaemia 15 min after ingestion and should be considered first, if available, when treating symptomatic hypoglycaemia in awake patients.
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What is already known on this subject?
While both dietary sugars and glucose tablets are available for treating symptomatic hypoglycaemia in awake patients with diabetes, the ideal treatment strategy is unknown.
What might this study add?
Glucose tablets should be considered first, if available, when treating symptomatic hypoglycaemia in awake patients.
Overall, 9% of adults worldwide live with diabetes.1 Patients with diabetes may develop hypoglycaemia as a result of inadequate or delayed carbohydrate intake after their usual insulin or oral medication dose, exercise without adequate carbohydrate intake or in the setting of illness. Hypoglycaemic events range from non-severe (eg, feeling hungry which can be self-managed) to severe (eg, coma where medical providers may be needed). Hypoglycaemic events occur frequently in patients with diabetes; up to 1.7/week for non-severe events and up to 0.9/annually for severe events and may occur more frequently in children.2 ,3 These events impact patients on a personal level and also result in lost work and increased healthcare costs.2 It is estimated that over $100 million is spent annually treating hypoglycaemia in US EDs.4 Other countries, including the UK, have noted frequent episodes of hypoglycaemia in patients with diabetes (11–12 events/100 years), with certain areas, including the Tayside region of Scotland spending over 92 000 pounds annually treating hypoglycaemia.5
Although one of the goals of diabetes care is avoidance of hypoglycaemic events, management plans that aim for blood sugar levels as close as possible to normal mean that hypoglycaemic events may occur. Early recognition with the most appropriate intervention can help treat symptomatic hypoglycaemia and obviate the need for immediate transport for further medical care. Hypoglycaemia is the most common diabetic emergency encountered by Emergency Medical Service (EMS) personnel and can often be managed safely and effectively at the scene.6 ,7 Identifying the ideal treatment regimen could be beneficial to patients, their families and EMS providers. Multiple options exist for managing these conditions in awake patients with symptomatic hypoglycaemia. While both dietary sugars and glucose tablets may be used for the treatment of conscious patients with symptomatic hypoglycaemia, the preferred treatment option remains unclear.
As first-aid treatment may be needed for patients with symptomatic hypoglycaemia, ‘Treatment of Hypoglycaemia’ was included as a new topic in the 2015 International Liaison Committee on Resuscitation's (ILCOR) Consensus on Science and Treatment Recommendation (CoSTR) review process for resuscitation and first aid. We conducted this systematic review as a part of the ILCOR process. The search strategy was designed to address the following PICO (P-Population, I-Intervention, C-Comparison, O-Outcome) question: ‘Among adults and children with symptomatic hypoglycaemia (P), does administration of dietary forms of sugar (I) compared with standard dose (15–20 g) glucose tablets (C) change time to resolution of symptoms, risk of complications (eg, aspiration), blood glucose, hypoglycaemia, hospital length of stay (O)?’ While the findings from the ILCOR CoSTR presented recommendations on the implementation and feasibility of search relating to the PICO, we present the summary of the existing data.
Types of studies
We conducted a systematic review of all human studies pertaining to hypoglycaemia treatment with oral agents using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology for evidence evaluation.8 Original research ranging from randomised controlled trials (RCTs) to observational studies was considered for inclusion. There were no restrictions on language or date of publication. The inclusion and exclusion criteria are described in table 1.
Types of participants
We included all human studies comparing any oral form of dietary sugar to glucose tablets. There were no restrictions on participant age.
We conducted a broad, systematic search of the literature to identify all papers relevant to the topic. A professional librarian (CJN) developed search strategies for PubMed, Embase (Elsevier interface) and the Cochrane Library through 5 March 2014 and then again on 28 June 2016. Animal studies, letters, editorials, comments and case reports were excluded from the search (see online supplementary appendix 1 for the complete search strategies). Reference lists from relevant articles were examined to identify additional articles for potential inclusion.
Two authors (JNC and SS-T) screened all titles from the search, accessing abstracts when necessary and identified potentially eligible articles. Three authors (JNC, SS-T and NH) independently examined the resulting abstracts. All articles selected by at least one of the authors were subjected to full-text review. We report the process according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (figure 1).9
The main details for each full-text study were abstracted using a standardised data collection form. These included study year, type of study, number of participants per study arm and outcomes of interest including time to resolution of symptoms, complications, change in blood glucose levels, recurrence of hypoglycaemia and hospital length of stay. The articles were then presented and discussed both between the authors and between ILCOR task force members.
Assessment of risk of bias in included studies
Two authors (JNC and SS-T) independently assessed the risk of bias for each of the four included studies using the Cochrane Risk of Bias tool for RCTs and GRADE criteria for non-RCTs. Disagreements were adjudicated by discussion with a third author (NH) and evaluated on the specific domains based on the type of study (RCT versus non-RCT) (see online supplementary appendix 2).
We identified the following outcomes a priori and abstracted these from the studies when available:
Time to resolution of symptoms—defined as the time from the administration of either dietary sugar or glucose until the symptoms resolved.
Complications—defined as adverse events requiring additional medical care beyond hypoglycaemia treatment (eg, aspiration, seizure, etc).
Blood glucose—defined as the change in blood glucose levels after treatment.
Hypoglycaemia—defined as the persistence of symptoms (yes/no) or recurrence of symptomatic hypoglycaemia >15 min (yes/no) after treatment as previous work has suggested limited response to either dietary sugars or glucose tablets before this time mark.10
Hospital length of stay—defined as the number of days in the hospital if the patients required hospital admission for their symptomatic hypoglycaemia.
Measurement of treatment effect
We used RevMan V.5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) with the Mantel-Haenszel random-effects model to calculate heterogeneity (I2), pooled plots and treatment effect using risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes with 95% CIs.
Assessment of reporting biases
Due to the multiple outcomes and limited number of studies identified, we did not test the effect of small studies in a funnel plot or with Egger's test.11
We pooled data from all studies to evaluate the overall comparison between dietary sugars and glucose tablets. We also pooled data from studies where we believed the studies were clinically homogeneous.
‘Summary of findings’ table
Using the GRADE methodology to assess the quality of the evidence, we created a ‘Summary of findings’ table for the various forms of dietary sugar and the identified outcomes (table 2).
Our initial search yielded 1774 references. After removing duplicate references and those not directly related to our initial clinical question, we selected 34 references for full-text reading of which 4 articles were finally included in our review (figure 1). The included studies consisted of three, non-blinded RCTs3 ,12 ,13 and one observational study10 (table 2). McTavish and Wiltshire3 looked to determine the most effective of four oral treatments for naturally occurring hypoglycaemia in children with type 1 diabetes, using a weight-based protocol, during a diabetes camp. A total of 189 episodes were analysed in 39 children. Treatments were randomly assigned for each episode using a sealed envelope. The study by Husband et al12 reported results from 33 children with type 1 diabetes who each had 15 naturally occurring hypoglycaemic events treated over an average of 3.3 months. Each subject treated five hypoglycaemic events with either glucose, sucrose or fructose, the sugar type allocated in a randomised, crossover design. Slama et al13 studied the response to seven different, randomly assigned carbohydrates in small groups of recently diagnosed type 1 diabetic inpatients, treating an artificially induced hypoglycaemic event. Each group contained only 5–6 patients, reducing the power of the study. The observational study by Brodows et al10 reported on the mean levels of plasma glucose in 13 insulin-dependent inpatients who were given four different types of carbohydrate after an artificially induced hypoglycaemic episode. Twenty-six episodes were studied, again with the numbers in each group being low. The studies, authors, type, sample size and the setting where the study was performed are summarised in table 2. The bias risk was considered individually in each of the included studies (see online supplementary appendix 3).
The four identified studies used multiple forms of dietary sugars including sucrose (including Skittles), fructose, orange juice, Mentos, cornstarch hydrolysate and milk as well as glucose gels and solution compared with glucose tablets. Forest plots for pooled analyses of the various dietary sugars are shown in figure 2. The Forest plots for unpooled analyses (see online supplementary appendices 4 and 5) and GRADE tables (see online supplementary appendix 6) for comparisons between dietary sugars and glucose tablets are included as online supplementary material appendices.
Time to resolution of hypoglycaemic symptoms is a critical outcome for patients with diabetes. None of the four studies revealed a treatment option that would reliably improve the blood glucose to normal within 10–15 min. Regardless of oral carbohydrate used to treat hypoglycaemia, time is required for absorption before the measured blood returns to the normal range and the patient's symptoms improve.
Resolution of hypoglycaemia
Three RCTs3 ,12 ,13 studied the resolution of hypoglycaemia at 15 min. When the results of different dietary sugars, including sucrose, fructose, orange juice, jelly beans, Mentos and milk (502 total events), were pooled and compared against glucose tablets (15–20 g) (223 total events), a higher proportion of patients had a relief of hypoglycaemic symptoms with glucose tablets (RR 0.89, 95% CI 0.83 to 0.96). A small observational study10 including 13 patients receiving dietary sugars and 9 receiving glucose tablets favoured glucose tablets when evaluating for a rise of blood glucose levels of at least 20 mg/dL by 20 min (RR 0.3, 95% CI 0.10 to 0.85).
The analysis of data on specific sugars alone compared with glucose tablets found differences in two subsets: glucose tablets performed better in direct comparison to sucrose dissolved in water (MD in change in blood glucose (mmol/L) after 15 min −0.90, 95% CI −1.78 to −0.02)13 and glucose tablets performed better than fructose (Fruit to Go) in the resolution of hypoglycaemia at 15 min (RR 0.77, 95% CI 0.68 to 0.86).12
Glucose tablets versus other sugars
Sucrose versus glucose tablets
Two RCTs12 ,13 studied the resolution of hypoglycaemia at 15 min. The pooled data on 177 patients receiving sucrose (in the form of Skittles candy or sugar lumps) and 171 patients receiving glucose tablets showed no difference between treatments (RR 0.99, 95% CI 0.91 to 1.07). An RCT13 that studied the mean change in blood glucose (mmol/L) after 15 min in six patients receiving sucrose dissolved in water and six patients receiving glucose tablets showed benefit from glucose administration (MD −0.90, 95% CI −1.78 to −0.02). This study found no difference when comparing sucrose (chewed sugar lumps) to glucose tablets (MD 0.30, 95% CI −0.81 to 1.41).13
Fructose versus glucose tablets
An RCT12 with 165 patient events in each arm compared fructose (Fruit to Go) with glucose tablets, which favoured glucose tablets when measuring the resolution of hypoglycaemia at 15 min (RR 0.77, 95% CI 0.68 to 0.86).
Orange juice (a combination of fructose, glucose and sucrose) versus glucose tablets
The pooled data from two studies3 ,13 of 50 patients receiving orange juice and 58 receiving glucose tablets showed no difference in the resolution of hypoglycaemia at 15 min (RR 0.84, 95% CI 0.69 to 1.02). An observational study10 of eight patients receiving orange juice and nine receiving glucose tablets showed no difference when evaluating blood sugar rise by more than 20 mg/dL at 20 min after treatment (RR 0.48, 95% CI 0.18 to 1.26). An RCT12 with six patients in each arm found that orange juice and glucose tablets resulted in a similar mean change in blood glucose (mmol/L) after 15 min (MD 0.70, 95% CI −1.55 to 0.15).
Jelly beans (58% sucrose, 9% glucose, 7.6% fructose, 2.7% maltose and 22.7% starch) versus glucose tablets
An RCT3 of children with type 1 diabetes compared 45 events treated with jelly beans with 52 events treated with glucose tablets for the resolution of hypoglycaemia at 15 min and found no difference between the two groups (RR 0.85, 95% CI 0.69 to 1.04).
Mentos (71% glucose and 29% oligosaccharides) versus glucose tablets
An RCT3 of type 1 diabetic children compared 48 events treated with Mentos with 52 events treated with glucose tablets for the resolution of hypoglycaemia at 15 min and found no difference between the groups (RR 1.06, 95% CI 0.92 to 1.21).
Milk versus glucose tablets
An observational study10 on a small number of patients, five given milk and nine given glucose tablets to treat induced hypoglycaemia, looked for a rise of at least 20 mg/dL by 20 min and found no difference between the groups (RR 0.11, 95% CI 0.01 to 1.62).
Glucose gel versus glucose tablets
An RCT13 with six patients in each arm compared glucose gel with glucose tablets in the treatment of induced hypoglycaemia and found no difference in the likelihood of resolution of hypoglycaemia at 15 min between the two groups (RR 0.50, 95% CI 0.14 to 1.77).
Glucose solution versus glucose tablets
An RCT13 with six patients in each arm compared 15 g glucose solution with 15 g glucose tablets in the treatment of induced hypoglycaemia and found no difference in the likelihood of resolution of hypoglycaemia at 15 min between the two groups (RR 1.25, 95% CI 0.64 to 2.44).
Corn hydrosylate versus glucose tablets
An RCT13 compared five patients with induced hypoglycaemia treated with corn hydrosylate with six patients treated with 15 g glucose tablets and found no difference between the two groups in the likelihood of resolution of hypoglycaemia at 15 min (RR 1.20, 95% CI 0.59 to 2.45).
Complications and hospital length of stay, blood glucose and time to resolution of symptoms
None of the four identified studies reported complications beyond recurrent hypoglycaemia (eg, aspiration) or hospital length of stay. None reported blood glucose or time to resolution of symptoms in a manner that could be used to compare dietary sugars to glucose.
Symptomatic hypoglycaemia in patients with diabetes occurs frequently and is often managed by the individual, family or friends.2 While several treatment options are available including multiple forms of dietary sugars, we found that glucose tablets result in the lowest risk of recurrent or persistent hypoglycaemia after administration in awake patients with symptomatic hypoglycaemia. Despite the relatively frequency of hypoglycaemic episodes, there remains limited data examining the ideal form of oral sugar replacement. Although glucose tablets and dietary sugars may be viable treatment options, few studies have examined the most appropriate dose of carbohydrates. While a 15 g tablet is commonly advocated, 20 g tablets or even a weight-based approach, such as 0.3 g/kg, may be more effective in treating hypoglycaemia.14 ,15
Two of the studies included in this review reported response to hypoglycaemia treatment in very small subsets of 3–9 patients.10 ,13 This increases the risk of bias and reduces the power to find statistically significant results. Another factor reducing our ability to analyse results is the variability of the specific carbohydrate content of tested foods and beverages. Orange juice is often diluted with water, and milk can have varying fat content that changes its glycaemic index. We were unable to control the commercial products featured in this review and there may be other confectionary or food products that, if studied, performed equally as well.
There was significant clinical heterogeneity among the included studies limiting our ability to perform a meta-analysis. While we did pool the results of dietary sugars, these were the results from several different sugars (eg, fructose, sucrose, etc) and in different amounts (eg, orange juice with 15 g of carbohydrates vs 40 g). Specific dietary foods performed similar to glucose tablets in many of the individual comparisons but when pooled, food sources underperformed in the treatment of hypoglycaemia compared with glucose tablets.
There was heterogeneity with the types of sugars used in each study, and different populations were examined in various studies. Two of the three RCTs examined dietary sugars and glucose tablets in paediatric patients with diabetes.3 ,12 Identification of hypoglycaemia in paediatric patients can be challenging as young children may have difficulty recognising and communicating their symptoms.16 Also, symptomatic hypoglycaemia may occur at varying levels in children, often below those resulting in symptoms in the adult population, highlighting the differences between managing hypoglycaemia in these two populations.16 This may limit the generalisability of paediatric findings to adults and vice versa.
As nearly 10% of the world's population lives with diabetes, effectively treating symptomatic hypoglycaemia is important as many patients with diabetes experience these episodes regularly.1 ,2 ,5 Non-severe hypoglycaemic events occur frequently (between 0.4 and 1.7 times per week).2 While severe hypoglycaemic events are less frequent (roughly once annually), 49% of cases require additional medical care such as visiting an ED, highlighting the need for early recognition and treatment of symptomatic hypoglycaemia.2 The ED visits are more common with increasing age, with those aged 80 or older having nearly twice the risk of young adults.4
The impact of hypoglycaemic events is also personal. Patients report feeling tired, fatigued, anxious, nervous and less alert even after being treated for symptomatic hypoglycaemia.2 These events can affect a patient's ability to work as 18% of non-severe hypoglycaemic events lead to lost work time.2 Patients with non-severe hypoglycaemic events may be able to self-manage their condition. Patients with severe hypoglycaemic events may still be conscious but require assistance from a third party. Both patients and those assisting patients with symptomatic hypoglycaemia may be unsure of the exact carbohydrate content of the dietary food they are using to treat a hypoglycaemic event. They may elect to use standard 15–20 g glucose tablets, when available, although dietary sugars can still be used if glucose tablets are not available.
Our review has several limitations. We attempted to identify all relevant articles; however, there is potential for missed articles. We adhered to the Assessment of Multiple Systematic Reviews checklist, which is one of the most widely validated tools for conducting systematic reviews.17 Three databases were included in this search. We felt other sources such as registries or other databases (eg, Psycinfo) would be unlikely to contain studies prospectively comparing dietary sugars to glucose tables. We performed a broad literature search, conducted by a highly trained information specialist (CJN) with expertise in systematic reviews, and thorough review of works cited ensured that the likelihood of overlooking relevant articles was minimised. We did not search specific oral hypoglycaemic agents such as sulfonylureas that can cause hypoglycaemia. Further work would be needed to determine how patients on various oral hypoglycaemic agents respond to dietary sugars and glucose tablets. Adverse events were not explicitly delineated in the search strategy. We believe that these adverse events would be reported as outcomes (either primary or secondary) in the studies assessing the response to dietary sugars and glucose tablets.
Multiple forms of dietary studies were identified. As a result, the dosages of carbohydrates were not standardised across studies. There may be other forms of dietary sugars (eg, high-fructose corn syrup drinks, honey, jams, yoghurt, etc) that may be used by patients; however, we were unable to identify any studies that evaluated these sugars. We did not evaluate glucose or sugars administered through other routes such as intramuscular injections, rectal administration or absorbed through the buccal mucosa or sublingually.
Several of our a priori outcomes were not reported in the identified studies. We did not perform a preliminary search identifying outcomes such as hospital length of stay. Although this may have helped to refine our PICO, we did not want to bias our search strategy. These results help to highlight the limited work in this area and may be used to refine future search strategies. Additional work will be needed to determine the impact of dietary sugars on hospital length of stay and complications such as aspiration. We did not evaluate dietary sugars in non-awake patients with symptomatic hypoglycaemia or those with impaired awareness. There is concern over the administration of oral sugars to patients with diabetes with symptomatic hypoglycaemia, if they have an alteration of mental status. These individuals may be unable to follow commands and unable to swallow, putting them at increased risk of aspiration. We felt these patients may require different treatment options beyond dietary sugars and therefore were not included in this analysis. Hypoglycaemia can recur after treatment as noted in the identified studies. These four studies reported the early recurrence of hypoglycaemia after treatment however; previous work suggests that 2–7% of cases of hypoglycaemia treated outside of the hospital may recur within 48 hours.18 Additional work will be needed to examine the incidence of these delayed episodes of hypoglycaemia between patients treated with dietary sugars and glucose tablets.
Glucose tablets result in a greater resolution of hypoglycaemia than dietary sugars in awake, symptomatic, hypoglycaemic patients with diabetes. If available, glucose tablets should be used before dietary forms of sugar for treating symptomatic hypoglycaemia in this population.
This work was part of a larger body of work performed by the 2015 International Liaison Committee on Resuscitation's (ILCOR) Consensus on Science and Treatment Recommendation (CoSTR) review process for resuscitation and first aid. The authors wish to thank Eunice Singletary (American Heart Association) for reviewing this work, David Zideman (European Resuscitation Council) for reviewing this work, Emmy DeBuck (Center for Evidence-Based Practice, Mechelen, Belgium) for her assistance with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) tables and forest plots, Eddy Lang (Department of Emergency Medicine, Cumming School of Medicine, Alberta Health Services, Calgary, Canada) for his assistance with the GRADE methodology and the entire ILCOR first aid task force for their assistance with the review and preparation of this work.
Contributors JNC analysed the data, contributed to the discussion and wrote the manuscript. SS researched the data, contributed to the discussion and reviewed/edited the manuscript. CJN performed the data search, contributed to the discussion and reviewed/edited the manuscript. NH analysed the data, contributed to the discussion and reviewed/edited the manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement As a systematic review, the data from each article are publicly available.
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