Background: Hypoglycaemia is a common occurrence in people with diabetes but can also result from an imbalance in glucose homeostasis in the absence of diabetes. The best enteral route for glucose administration for suspected hypoglycaemia in a first aid situation is unknown.

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.

Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL as well as grey literature (records identified in the WHO ICTRP Search Portal, ClinicalTrials.gov and the EU Clinical Trials Register) up to July 2018. We searched reference lists of included studies retrieved by the above searches.

Selection criteria: We included studies involving adults and children with documented or suspected hypoglycaemia as well as healthy volunteers, in which glucose was administered by any enteral route appropriate for use by first-aid providers.

Data collection and analysis: Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated trials for overall certainty of the evidence using the GRADE instrument. We used the Cochrane 'Risk of bias' tool to assess the risk of bias in the randomised controlled trials (RCTs), and the 'risk of bias In non-randomised studies of interventions' (ROBINS-I) tool, in addition to the Cochrane Handbook for Systematic Reviews of Interventions recommendations on cross-over studies, for the non-RCTs. We reported continuous outcomes as mean differences (MD) with 95% confidence intervals (CIs) and dichotomous outcomes as risk ratios (RR) with 95% CIs. All data on glucose concentrations were converted to mg/dL. We contacted authors of included studies to obtain missing data.

Main results: From 6394 references, we included four studies evaluating 77 participants, including two RCTs, studying children and adults with hypoglycaemia, respectively, and two non-RCTs with healthy volunteers. The studies included three different routes of glucose administration (sublingual, buccal and a combination of oral and buccal administration). All studies had a high risk of bias in one or more 'Risk of bias' domain.Glucose administration by the sublingual route, in the form of table sugar under the tongue, resulted in a higher blood glucose concentration after 20 minutes compared with the oral route in the very specific setting of children with hypoglycaemia and symptoms of concomitant malaria or respiratory tract infection (MD 17 mg/dL, 95% CI 4.4 to 29.6; P = 0.008; 1 study; 42 participants; very low-quality evidence). Resolution of hypoglycaemia at 80 minutes may favour sublingual administration (RR 2.10, 95% CI 1.24 to 3.54; P = 0.006; 1 study; 42 participants; very low-certainty evidence), but no substantial difference could be demonstrated at 20 minutes (RR 1.26, 95% CI 0.91 to 1.74; P = 0.16; 1 study; 42 participants; very low-certainty evidence). A decrease in the time to resolution of hypoglycaemia was found in favour of sublingual administration (MD -51.5 min, 95% CI -58 to -45; P < 0.001; 1 study; 42 participants; very low-certainty evidence). No adverse events were reported in either group. No data were available for resolution of symptoms and time to resolution of symptoms, and treatment delay.Glucose administered by the buccal route in one study resulted in a lower plasma glucose concentration after 20 minutes compared with oral administration (MD -14.4 mg/dL, 95% CI -17.5 to -11.4 for an imputed within-participants correlation coefficient of 0.9; P < 0.001; 1 trial; 16 participants; very low-quality evidence). In another study there were fewer participants with increased blood glucose at 20 minutes favouring oral glucose (RR 0.07, 95% CI 0.00 to 0.98; P = 0.05; 1 study; 7 participants; very low-certainty evidence). No data were available for resolution of symptoms and time to resolution of symptoms, resolution of hypoglycaemia and time to resolution of hypoglycaemia, adverse events, and treatment delay.For the combined oral and buccal mucosal route (in the form of a dextrose gel) the MD was -15.3 mg/dL, 95%CI -33.6 to 3; P = 0.09; 1 study; 18 participants; very low-quality evidence . No improvement was identified for either route in the resolution of symptoms at 20 minutes or less following glucose administration (RR 0.36, 95% CI 0.12 to 1.14; P = 0.08; 1 study; 18 participants; very low-certainty evidence). No data were available for time to resolution of symptoms, resolution of hypoglycaemia and time to resolution of hypoglycaemia, adverse events, and treatment delay.

Authors' conclusions: When providing first aid to individuals with hypoglycaemia, oral glucose administration results in a higher blood glucose concentrations after 20 minutes when compared with buccal administration of glucose. A difference in plasma glucose concentration could not be demonstrated, when administering a dextrose gel, defined as "a combined oral and buccal mucosal route" compared to oral administration of a glucose tablet or solution. In the specific population of children with concomitant malaria and respiratory illness, sublingual sugar results in a higher blood glucose concentration after 20 minutes when compared with oral administration.These results need to be interpreted cautiously because our confidence in the body of evidence is very low due to the low number of participants and studies as well as methodological deficiencies in the included studies.

EDB: contracted by the American Heart Association on behalf of ILCOR (International Liason Committee on ResuscitationFirst Aid Task Force) as systematic reviewer to conduct the current systematic review; employee at Belgian Red Cross, providing first aid training to laypeople. None of the declared competing interests did influence any of the steps undertaken for the current systematic review.

VB: employee at Belgian Red Cross, providing first aid training to laypeople. This did not influence any of the steps undertaken for the current systematic review.

JNC: none known.

DAZ: none known.

EMS: volunteer member of the First Aid Task Force for the International Liaison Committee on resuscitation; reimbursed for travel expenses related to reviews performed by this organization.

TD: none known.