Abstract: 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. 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.

Plain-language summary: We identified four studies. One randomised study (clinical trials where people are randomly allocated to one of two or more treatment groups) compared sublingual glucose administration, in the form of table sugar, with an oral administration in 42 hypoglycaemic children between one and 15 years old. Two non-randomised studies compared buccal glucose administration with oral administration in 23 adult healthy fasting volunteers. One randomised study compared a dextrose gel with oral administration of glucose in 18 people with type 1 diabetes and hypoglycaemia. Providing sugar under the tongue (sublingual) resulted in a greater rise in blood glucose after 20 minutes than giving the sugar orally, but this was in a specific setting including children with hypoglycaemia and symptoms of concomitant malaria or respiratory tract infection. On the other hand, giving glucose by the buccal mucosa route resulted in a lower plasma glucose concentration than with the oral route. For dextrose gel (where uptake of the glucose occurs through a combination of oral swallowing and via the buccal mucosa), no clear benefit was shown compared to oral glucose administration (glucose tablets or glucose solutions). Most studies did not report on time to resolution of symptoms, resolution of hypoglycaemia as defined by blood glucose levels above a certain threshold, time to resolution of hypoglycaemia, adverse events, and treatment delay. The evidence is of very low certainty due to limitations in study design, few studies and small number of participants in the studies, and because half of the studies were performed with healthy volunteers rather than in people with characteristic hypoglycaemia.