Methods of Glucose Administration in First Aid for Hypoglycemia

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Citation

Borra V, Carlson JN, De Buck E, Djärv T, Singletary EM, Zideman D, Bendall J, Berry DC, Cassan P, Chang WT, Charlton NP, Hood NA, Meyran D, Woodin JA, Swain J

Glucose administration routes for first aid in case of symptomatic hypoglycemia.

Consensus on Science and Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) First Aid Task Force, 2018 Aug 27.  Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence process for the production of the Consensus of Science and Treatment Recommendations (CoSTR) started with a systematic review of methods of glucose administration in first aid for hypoglycemia (DeBuck, 2018, PROSPERO CRD42018088637) conducted by Emmy DeBuck of the Centre for Evidence-Based Practice (CEBaP), Belgian Red Cross, Mechelen, Belgium, with involvement of clinical content experts. Evidence for adult and pediatric literature was sought and considered by the First Aid Task Force. An additional search of the scientific literature was performed after the completion of the systematic review and no additional studies were identified for inclusion in this review. 

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults and children with suspected hypoglycemia (out-of-hospital, including healthy volunteers). Neonates are excluded, as we believe the identification of hypoglycemia in this age group is a specialized diagnostic and treatment process well beyond First Aid.

Intervention: Administration of glucose by any enteral route appropriate for use by first aid providers

Comparators: Administration of glucose by another enteral route appropriate for use by first aid providers

Outcomes:

  • Resolution of symptoms (critical) – defined as the reversal of the initial symptoms (dichotomous outcome; yes/no).
  • Time to resolution of symptoms (critical) - defined as the time from the administration of the sugar containing solution until the symptoms resolved (continuous outcome).
  • Blood or plasma glucose concentration at 20 minutes (critical) – defined as the glucose level as measured 20 minutes after the administration of the sugar substrate (continuous outcome) or as evidence of blood or plasma glucose elevation at 20 minutes (dichotomous outcome; yes/no).
  • Resolution of hypoglycemia (Important) – defined as elevation of the blood glucose level to rise above the authors’ threshold for determining hypoglycemia (dichotomous outcome; yes/no).
  • Time to resolution of hypoglycemia (Important) - defined as the time from the administration of the sugar containing solution until the blood glucose concentration rose above the threshold for the authors’ definition of hypoglycemia (continuous outcome).
  • Any adverse event (Important) – any event resulting from the administration as defined by the study authors (e.g. aspiration).
  • Administration delay (Important) – defined as the delay in administering the sugar containing solution as a result of the administration arm (dichotomous outcome; yes/no).

Study Designs: Randomized and nonrandomized clinical trials, observational studies were included. Unpublished studies (e.g., conference abstracts, trial protocols, methods papers) were excluded.

Timeframe: All years and all languages were included provided there was an English abstract from inception to December 22, 2017 with an update performed on July 11, 2018.

Studies were included where either glucose, table sugar (sucrose) or liquid sugar (e.g. corn syrup), was administered by any enteral route appropriate for use by first aid providers (buccal, sublingual, oral). Glucose and sugar formulations could include spray, gel, liquid, paste, syrup or tablet form. Buccal administration was defined as application to the cheek mucosa and sublingual administration as application under the tongue, both without swallowing. 

PROSPERO Registration CRD42018088637

Consensus on Science

Buccal compared with oral administration of glucose

For the critical outcome of plasma glucose concentration at 20 min (mg/dL), we found evidence with very low certainty (downgraded for risk of bias, indirectness and imprecision) from one non-randomized controlled trial enrolling 16 healthy volunteers that showed benefit from oral glucose administration compared with buccal glucose administration (mean difference [MD]; 95% confidence interval [CI]) (MD, -15; 95%CI, -24.20– -5.80 with an assumed within subjects correlation coefficient of 0.1; P < 0.01; MD, -15; 95%CI, -18.07– -11.93 with an assumed within subjects correlation coefficient of 0.9; P < 0.01) (Chlup 2009 205).

For the critical outcome of blood glucose concentration at 20 min (mg/dL), measured as a dichotomous outcome (number of subjects with increased blood glucose at 20 min), we found evidence with very low certainty (downgraded for risk of bias, indirectness and imprecision) from one non-randomized controlled trial enrolling 7 healthy adult volunteers that showed benefit from oral glucose administration compared with buccal glucose administration. None (0/7) of the participants in the buccal administration group showed an increased blood glucose concentration while all (7/7) participants in the oral glucose administration group showed an increased blood glucose concentration (risk ratio [RR]; 95% CI)(RR, 0.00; 95%CI, 0.00– 0.55; P = 0.02) (Gunning 1976 1611). 

We did not identify any evidence to address the critical outcomes of resolution of symptoms and time to resolution of symptoms, and the important outcomes of adverse events, resolution of hypoglycemia, time to resolution of hypoglycemia and administration delay.

Combined oral and buccal compared with oral administration of glucose

For the critical outcome of resolution of symptoms, we identified evidence with low certainty (downgraded for risk of bias and imprecision) from one randomized controlled trial enrolling 41 adult participants with insulin-dependent diabetes that failed to demonstrate a benefit from combined oral and buccal glucose administration compared with oral glucose administration at 20 minutes (RR, 0.36; 95%CI, 0.12–1.14; P = 0.08; 587 fewer per 1,000 treated) following glucose administration (Slama 1990 589).

For the critical outcome of blood glucose concentration at 20 min (mg/dL) we identified low-certainty evidence (downgraded for risk of bias and imprecision) from the same study that failed to demonstrate a benefit from combined oral and buccal glucose administration compared with oral glucose administration (MD, -16; 95%CI, -34.32– -2.32; P = 0.09) (Slama 1990 589).

We did not identify any evidence to address the critical outcome of time to resolution of symptoms, and the important outcomes of adverse events, resolution of hypoglycemia, time to resolution of hypoglycemia and administration delay.

Sublingual compared with oral administration of glucose

For the critical outcome of blood glucose concentration at 20 min (mg/dL), we found evidence with very low certainty (downgraded for risk of bias, indirectness and imprecision) from one randomized trial enrolling 69 children between 1 to 15 years of age with moderate symptoms of hypoglycemia related to acute malaria or respiratory tract infections that showed a benefit favoring sublingual sugar administration (2.5 g of wet sugar under the tongue) compared with oral glucose administration (2.5 g of sugar on the tongue) (MD, 17; 95%CI, 4.38–29.62; P = 0.01) (Barennes 2005 648).

For the important outcome of adverse events, we identified evidence of the rate of adverse events with very low certainty (downgraded for risk of bias, indirectness and imprecision) from the same study, however the RR was not able to be estimated as there were no reported adverse events in either group (Barennes 2005 648).

For the important outcome of resolution of hypoglycemia, defined as “early treatment (administration) failure rate” (the proportion of children with no blood glucose rise at 20 minutes), we found evidence with very low certainty (downgraded for risk of bias, indirectness and imprecision) from the same randomized trial that failed to demonstrate a benefit for sublingual glucose administration compared with oral glucose administration (RR, 0.28; 95%CI, 0.06–1.34; P = 0.11; 192 fewer per 1,000 treated) (Barennes 2005 648).

For the important outcome of resolution of hypoglycemia, defined as “treatment (administration) failure rate” (the proportion of children who did not reach blood glucose concentrations of  ≥ 0.9 g/L within the 80 minute study period), we found evidence with very low certainty (downgraded for risk of bias, indirectness and imprecision) from the same randomized trial that showed a benefit of sublingual sugar administration compared with oral glucose administration (RR, 0.03; 95% CI, 0.00–0.55; P = 0.02; 517 fewer per 1,000 treated) (Barennes 2005 648).

For the important outcome of time to resolution of hypoglycemia (minutes), we found evidence with very low certainty (downgraded for risk of bias, indirectness and imprecision) from the same randomized trial that showed a benefit of sublingual glucose administration compared with oral glucose administration (MD, -51.50; 95%CI, -57.97– -45.03; P < 0.01) (Barennes 2005 648).

We did not identify any evidence to address the critical outcomes of resolution of symptoms and time to resolution of symptoms, and the important outcome of administration delay.

Treatment Recommendations

We recommend the use of oral glucose (swallowed) for individuals with suspected hypoglycemia who are conscious and able to swallow (strong recommendation, very low certainty of evidence).

We suggest against buccal glucose administration compared with oral glucose administration for individuals with suspected hypoglycemia who are conscious and able to swallow (weak recommendation, very low certainty of evidence).

If oral glucose (e.g. tablet) is not immediately available, we suggest a combined oral + buccal glucose (e.g. glucose gel) administration for individuals with suspected hypoglycemia who are conscious and able to swallow (weak recommendation, very low certainty of evidence).

We suggest the use of sublingual glucose administration for suspected hypoglycaemia for children who may be uncooperative with the oral (swallowed) glucose administration route (weak recommendation, very low certainty of evidence). 

Values and Preferences:

A previous review (Carlson 2017 100), examined consumption of dietary sugars compared with glucose tablets and found glucose tablets to be preferred in awake individuals with symptomatic hypoglycemia. The purpose of this review was to evaluate different routes potentially available in a first aid setting (buccal, oral and sublingual), for situations where sugar-containing foods and beverages are not available.

We recognize that the oral route requires the individual to have the ability to swallow. This does not imply that in a standard first aid setting other routes such as buccal or sublingual cannot be used, but suggests that, if given the option, oral glucose should be utilized as a first-line option in awake individuals who are able to swallow. No identified studies compared sublingual and buccal administration.  

Only one study was identified comparing oral with sublingual administration of glucose, in children between 1 and 15 years old with moderate clinical symptoms of acute malaria or moderate respiratory tract infections. The evidence from this study favors sublingual administration in this specific population, however, we cannot be certain if these results can be applied to a wider population. Therefore, the task force suggests the use of oral glucose for individuals with suspected hypoglycemia who are conscious and able to swallow. In some countries where resources are limited, the sublingual route of administration of glucose may be preferable in populations with suspected hypoglycemia and where there is concern for the ability to follow commands and swallow.

A single study evaluated the use of glucose gel placed on the buccal mucosa and then swallowed. Because the gel was observed to adhere to the oral mucosa, the task force elected to consider this as a combined oral + buccal route. The task force recognizes that the findings from this single study are likely unique to glucose gel and may not be extrapolated to other forms of glucose such as sprays or pastes administered buccally and swallowed.

Knowledge Gaps:

No studies were identified that evaluated different administration routes in individuals with altered mental status who are not able to swallow an orally administered form of glucose or sugar. No studies were identified that evaluated outcomes following enteral treatment, such as mortality, hospital discharge or need for hospitalization.

More research is needed to help identify the ideal route and dosage of glucose administration in various first aid settings (e.g. sublingual administration in adult population).   

Additional research is needed on outcomes with use of different forms of sugar such as sprays, pastes, or gels.

Additional research is needed to understand the possible adverse events associated with various routes of glucose administration, both in terms of type and frequency.

References

Barennes H, Valea I, Nagot N, Van de Perre P, Pussard E. Sublingual Sugar Administration as an Alternative to Intravenous Dextrose Administration to Correct Hypoglycemia Among Children in the Tropics. Pediatrics 2005, 116(5):e648-e653

Carlson JN, Schunder-Tatzber S, Neilson CJ, Hood N. Dietary sugars versus glucose tablets for first-aid treatment of symptomatic hypoglycaemia in awake patients with diabetes: a systematic review and meta-analysis. Emerg Med J 2017, 34:100-106

Chlup R, Zapletalova J, Peterson K, Poljakova I, Lenhartova E, Tancred A, Perera R, Smital J. Impact of buccal glucose spray, liquid sugars and dextrose tablets on the evolution of plasma glucose concentration in healthy persons. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009, 153(3):205-209

Gunning RR, Garber AJ. Bioactivity of Instant Glucose. Failure of Absorption through Oral Mucosa. JAMA 1978, 240:1611-1612

Slama G, Traynard P, Desplanque N, Pudar H, Dhunputh I, Letanoux M, Bornet FRJ, Tchobroutsky G. The Search for an Optimized Treatment of Hypoglycemia. Carbohydrates in Tablets, Solution, or Gel for the Correction of Insulin Reactions. Arch Intern Med 1990, 150:589-593

Attachments

Should oral + buccal glucose (glucose gel) compared with oral (swallowed) glucose be administered for hypoglycemia?

Should buccal glucose compared with oral (swallowed) glucose be administered for hypoglycemia?

Should sublingual glucose compared with oral (swallowed) glucose be administered for hypoglycemia?


Discussion

GUEST
Judith Finn
Nice work - well done to all involved. Clearly there is a need for further research to inform the management of hypoglycaemia in "individuals with altered mental status who are not able to swallow an orally administered form of glucose or sugar". However, I was wondering if it would be possible for ILCOR to make an 'expert consensus' recommendation re this ?
Reply
GUEST
David Zideman
Dear Judith Thank you for your comment which the First Aid Task Force has considered carefully. This was a challenging review due to the limited number of studies to include, and the very low level of certainty of evidence. The First Aid Task Force use the accompanying GRADE Evidence to Decision tables and extensive discussion to help create an expert consensus recommendation appropriate for first aid providers caring for individuals with suspected hypoglycaemia (which is often accompanied by some degree of altered mental status) and who are able to swallow and follow commands. We will clarify the use of the Evidence to Decision framework for these recommendations in the Values and Preferences statement. For those individuals who are no longer able to swallow or follow commands, parenteral routes remain preferable, but a recommendation of which treatment or route would be outside the scope of the first aid task force. This will be reflected in the Values and Preferences section.
GUEST
Simon Gould
Considering the treatment recommendations will need to be implemented at the most rudimentary BLS level, the use of tablets (a hard choking block for someone with hypoglycaemic induced dysphagia) and despite oral vs buccal administration being faster (but not necessarily safer), where is the practical and evidence-based swallowing function test that should be central to this recommendation? So far it is subjective for people without clinical experience. Australia changed there guideline with no definitive test procedure, however I would expect ILCOR to be more rigorous in ensuring that mitigating one risk does not create another.
Reply
David Zideman (1 posts)
Dear Simon. Thank you for your comment. The function of the ILCOR task force is to examine the published literature, produce a consensus on science (CoS) using GRADE methodology and then provide a treatment recommendation(TR) based on the consensus on science. We qualify our treatment recommendation with a values and preferences statement where we have further qualified the recommendation on swallowing. As with previous ILCOR CoSTR statements it is for the national councils to interpret the recommendation into local practice.

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