The American Diabetes Association defines hypoglycemia in diabetes non-numerically as “all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm” (2). Nevertheless, it is essential to identify a level of hypoglycemia that should be avoided due to its immediate and long-term impact on the individual (1). Numerical definitions ( Table 1 ) are based on glucose values detected by self-monitoring blood glucose (SMBG), CGM, or laboratory measurement of plasma (2). Hypoglycemia is symptomatic when the child, adolescent, or parent notices the presence of one or more symptoms and verifies that the blood glucose is <70 mg/dL (3.9 mmol/L).

A hypoglycemic episode can be defined as:

Note that as young children require assistance to correct even mild hypoglycemia, the event requires the caregiver and physician to evaluate whether the child has hypoglycemia-induced cognitive dysfunction.

Mild hypoglycemia is common and asymptomatic events are likely to be underreported, making the exact incidence of hypoglycemia difficult to establish. However, symptomatic hypoglycemia is estimated to occur on average twice a week in >80% of people with diabetes, with countless episodes in a lifetime (5). There has been a significant reduction in the incidence rates of hypoglycemia in international registries over the last two decades (6–8).

In pediatric PWD, severe hypoglycemia is characterized by convulsions, coma, or other neurological symptoms of neuroglycopenia, and it requires therapy with glucagon or IV glucose (17). Risk factors for severe hypoglycemia are age, diabetes duration, glycemic control, type of treatment, unawareness, nighttime episodes, exercise, and previous episodes (10). Other possible risk factors include risky behaviors (alcohol, recreational substances, lack of preparation for sports, infrequent blood glucose monitoring, etc.), as described further below. While younger children are thought to be at higher risk of severe hypoglycemia (24), some studies have not confirmed this association (25–27). Severe hypoglycemia is probably more frequent in adolescents because of the longer duration of disease and higher insulin requirements. Low HbA1c is no longer considered a risk factor for severe hypoglycemia in young PWD since the advent of AID, but a low HbA1c value must always be carefully considered in the clinical context; on the contrary, severe hypoglycemia is followed by a progressive and lasting increase in HbA1c in children and adolescents with T1D (26). People with T1D treated with five or more daily insulin injections were shown to be at reduced risk of severe hypoglycemia compared with subjects on fewer daily injections (24). People with T1D on insulin pumps are at reduced risk of severe hypoglycemia (16), and no episodes of severe hypoglycemia were observed in most hybrid closed-loop (HCL) or advanced hybrid closed-loop (AHCL) trials (18, 19, 28).

Alcohol use is common in adolescents with T1D. Since alcohol intake is more frequent during evening hours and plasma glucose mainly decreases 8-12 hours after ethanol administration (20), the risk of hypoglycemia is higher during subsequent sleep hours. Binge drinking represents one end of the spectrum of alcohol consumption, and it is more frequent in males (21). In the DPV registry of youths and young adults with T1D, alcohol use was associated with worse glycemic control, more severe hypoglycemia, and increased rates of diabetic ketoacidosis (DKA) (22).

Even though the combination of alcohol intake and fasting is assumed to induce hypoglycemia, there are few real-time studies on the topic. Garcia et al. (23) reported that moderate alcohol consumption (0.7 g of alcohol per kg of body weight, given as beer) with a mixed meal does not seem to increase the risk of postprandial hypoglycemia over at least six hours post-ingestion. A systematic review applying GRADE criteria by Tetzschner et al. (29) examined studies of alcohol-induced hypoglycemia in PWD and found that most recommendations on hypoglycemia prevention strategies were based on best clinical practice rather than on objective evidence. Overall, the first advice for subjects with T1D is to take precautions when consuming alcohol: the best prevention for alcohol-induced hypoglycemia is, in fact, an awareness of its hypoglycemic effects, especially when it is drunk without simultaneous ingestion of carbohydrates.

Exercise can increase the risk of hypoglycemia via several mechanisms: increased glucose consumption, depletion of glycogen stores, increased insulin sensitivity, and exercise-induced counterregulatory hormone deficits (30). The increased risk of hypoglycemia and FoH are a barrier to exercise for PWD (31). The risk of hypoglycemia is greater with aerobic or endurance exercises than with anaerobic or high-intensity exercises (32). The intensity, duration, and type of physical activity, timing to and site of insulin infusion/injection, carbohydrate intake, glucose profile pre-exercise, type of insulin, insulin treatment (MDI/CSII/AID), hydration status, level of training, and age influence the personal risk of hypoglycemia during exercise (33, 34). The risk of hypoglycemia increases with moderate-intensity exercise, immediately after activity, and 7 to 12 hours after exercise (35).

The risk of hypoglycemia is further increased by the reduced counter-regulatory response induced by exercise itself and during sleep (36). Optimizing the glucose profile is fundamental: the appropriate reduction in insulin (basal and bolus insulins) before and after exercise, adequate intake of carbohydrate (before and after exercise), and monitoring of glucose profiles, recognizing that all glucose sensors are less accurate during exercise and in the hypoglycemic range (35).

Another strategy to minimize exposure to hypoglycemia after exercise is to plan exercise sessions at high intensity: counter-regulatory hormones can, in fact, increase endogenous glucose production and maintain glycemia at a higher range than sessions of moderate-to-intense exercise alone (37).

Nocturnal hypoglycemia has always been scary for PWD and their parents, significantly affecting their sleep quality and, consequently, quality of life (38). New long-acting insulins have significantly reduced the risk of nocturnal hypoglycemia, especially when compared to NPH insulins. More specifically, degludec and U-300 glargine best prevent nocturnal hypoglycemia in children (39). Furthermore, advances in CGM technology and alarm systems have significantly reduced the risk of hypoglycemia at night (40). The use of HCL with low-glucose suspend (LGS) and the possibility of establishing a specific sleep-hours algorithm have significantly diminished the risk of hypoglycemia (41).

In case of unexplained and repeated hypoglycemic episodes (42), celiac disease (43), Addison’s disease (44), hypothyroidism (45), and factitious hypoglycemia (including Munchausen-by-proxy) should be considered. However, the evidence that subclinical hypothyroidism is a cause of repeated hypoglycemia is weak.

In a hospital setting, intravenous glucose must be immediately administered to maximally limit exposure to hypoglycemia. The recommended dose of dextrose (glucose) is 0.2 g/kg; this dose can reverse hypoglycemia without the risk of unintentional osmotic diuresis (2). It is essential to pay attention to the concentration of glucose solution and the infusion rate. Highly concentrated glucose solutions (dextrose 50%) or infusion rates >5 mg/kg/min should be avoided due to the risk of excessive rate of osmotic change and, consequently, the risk of hyperosmolar cerebral injury (46). Moreover, highly concentrated glucose solutions can cause peripheral vein sclerosis, so administering glucose solutions at concentrations greater than 25% dextrose is not recommended. 10% dextrose has been shown to be effective and safe for treating hypoglycemia in a randomized controlled trial (47). The recommended dose of dextrose (0.2 g/kg) equals 2 mL/kg 10% dextrose solution. The maximum dose is 0.5 g/kg of body weight, corresponding to 5 mL/kg. In cases of recurrent hypoglycemia with the inability to take an adequate amount of carbohydrates orally, it is possible to prolong the intravenous infusion of 10% dextrose with a glucose infusion rate of 2-5 mg/kg/min (1.2-3.0 mL/kg/h).

At home and in school, severe hypoglycemia should be immediately treated by administering glucagon. Glucagon can rapidly reverse severe hypoglycemia, except in situations of liver glycogen depletion after prolonged fasting, where intravenous administration of glucose solutions is more effective (48).

Children and adolescents with T1D of all ages with severe hypoglycemia can be treated with intramuscular (IM) or subcutaneous (SC) injection of recombinant crystalline glucagon available as a lyophilized (freeze-dried) powder. This formulation needs to be reconstituted to a concentration of 1 mg/mL with sterile water in a series of multiple steps immediately prior to injection. Two commercial glucagon rescue kits are currently available in Italy: GlucaGen^® HypoKit 1 mg (Novo Nordisk^®A/S, Bagsvaerd, Denmark) and Glucagon Emergency Rescue Kit (Baqsimi, formerly Eli Lilly and Company, Indianapolis IN, USA, now Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, CA, USA). The recommended dose of glucagon depends on body weight: adults and children >25 kg should receive 1 mg, whereas children should be treated with 0.5 mg. Nasal glucagon can be used from 4 years of age and above.

In recent years, intranasal (IN) glucagon has been increasingly used due to its easier administration. The IN formulation (Baqsimi™) is composed of glucagon as a powder with beta-cyclodextrin plus dodecylphosphocholine as the promoter for nasal absorption. Clinical trials have demonstrated that administration of IN glucagon is safe and effective for raising blood glucose levels during moderate hypoglycemia episodes under controlled conditions in adults (49) and children (50) with T1D, without being affected by the common cold and concomitant administration of nasal decongestant. Moreover, simulation studies have shown that the administration of nasal glucagon is faster and easier than injectable glucagon (51). The recommended dose of IN glucagon is 3 mg, equal to one puff. A recent meta-analysis demonstrated that intranasal glucagon and subcutaneous (SC)/intramuscular glucagon were equally effective for treating hypoglycemia (52). Moreover, additional real-life evidence has demonstrated the efficacy of IN glucagon in a large cohort of Italian children and adolescents (53). Common side-effects of IM and SC recombinant crystalline glucagon are nausea and vomiting and, in addition to these known side-effects, nasal glucagon may cause headache, upper airway discomfort, or nasal congestion (53).

Mild-to-moderate hypoglycemia should be treated with rapidly absorbed carbohydrates. Subjects should re-test and re-ingest carbohydrates every 15 minutes until they recover from hypoglycemia ( Figure 1 ).

The recommended dose of carbohydrate for children and adolescents is 0.3 g/kg oral glucose, which has been shown to be effective in increasing glucose levels by around 36 mg/dL within 15 minutes of ingestion in children (54). This approach was also found to be effective in children on insulin pumps (55).

Glucose-containing products (e.g., Glucosprint, Fastup, etc) are more effectively and quickly increase glucose levels than sucrose and fructose-containing products (56, 57). Glucose-containing tablets or drinks are currently not reimbursed by the National Health System in Italy, and they are more expensive than non-glucose-containing products. For these reasons, dietary sucrose and fructose-containing products (e.g., candy, sugar cubes, juice) are more frequently recommended in daily clinical practice. Both sucrose and fructose are required in greater amounts to provide the same increase in blood glucose compared with oral glucose (e.g., 20 g in the form of glucose tablets corresponds to 40 g of juice). Moreover, the rise in glycemia after sucrose ingestion is around half as fast as after glucose ingestion and could be even slower with fructose (56).

Parents of toddlers sometimes use honey and milk, but this approach should be discouraged: honey has a fructose content of around 70%, and the total sugar content is highly variable. Milk contains approximately 5 g of carbohydrate in 100 mL, and it causes a minimal rise in glycemia (around 4-5 mg/dL) (58). Complex carbohydrates and foods containing fats (e.g., chocolate) should also be avoided due to delayed intestinal absorption and the slow rise in glucose obtained.

In cases of nausea, vomiting, or food refusal, small doses of subcutaneous glucagon can be administered to restore plasma glucose to normal. Using a standard U-100 insulin syringe, two units (20 μg) for children ≤ 2 years and 1 unit/year for children aged 3-15 years to a maximum dose of 150 μg or 15 units can be administered subcutaneously. If the blood glucose does not increase within 30 minutes, the initial dosage can be repeated. These dosage and treatment protocols are safe and effective in children, including toddlers, and increase glucose by 60-90 mg/dL within 30 minutes of administration (59).

School personnel should receive an appropriate diabetes education program to identify hypoglycemia signs and symptoms. In the “Hypoglycemia” section of the Diabetes Management Plan, it is essential to define individual signs and glycemic values that define intervention and glucagon use (60). Blood glucose meters should be available in school as a “first aid hypoglycemia management pack” containing glucose, glucose tablets, fast-acting sugar sources, and extra snacks, which should be available in the classroom or the bag of the child or adolescent with T1D.

Although AID systems have been shown to reduce episodes of hypoglycemia (19, 20, 28), they do not completely avoid them. Automated systems can reduce insulin delivery to zero for a period such that, during a hypoglycemia episode, there is usually less active insulin than with traditional insulin pump therapy. However, using these advanced systems, an excess of insulin and consequent hypoglycemia due to human mistakes (for example, a wrong bolus dose) or an unplanned intense physical activity can occur.

Although the traditional oral treatment of mild-to-moderate hypoglycemia in a conscious child involves a correction of 0.3 g/kg of glucose in a PWD using an insulin pump integrated with advanced algorithms, this correction is not always required. It is only necessary in a hypoglycemia alert in symptomatic subjects or within two to three hours of a bolus with excess active insulin. In real life, the current approach is correction with simple sugar/glucose at a dosage of 0.1 g/kg, resulting in 4-8 g of total carbohydrates, but waiting at least 15 minutes before treating to avoid glucose value oscillations. This practical advice arises from two considerations: these systems, in particular AID systems, continue to intervene in the administration of insulin, and subjects are significantly less insulinized than with conventional therapy; therefore, given that the system is reactive to blood sugar, if a sudden increase is detected (hypercorrection), an automatic corrective bolus is delivered that can help propagate new hypoglycemia (61, 62). Moreover, AID systems and sensors in general significantly reduce both severe and mild-to-moderate hypoglycemia episodes (61, 62), especially in the context of a structured educational program (62).

A summary of recommendations for hypoglycemia treatment in children and adolescents using AID systems is shown in Table 4 and Figure 2 .

Since alterations in glucose homeostasis might reduce gray and white matter volume and alter brain metabolism, it is important to note that hyperglycemia more than hypoglycemia can damage the brain. This is particularly interesting in relation to the therapeutic habit of preferring higher blood sugar levels in children with T1D rather than risk unwanted hypoglycemia. In this respect, using an AID system, especially in young children with T1D, can help to prevent both hypo- and hyperglycemia (63).

Interest in the role of hypoglycemia as a cause of long-term morbidity has diminished. Exposure to chronic and repetitive hyperglycemia is now seen as a significant cause of permanent brain damage (64, 65). Transient cognitive dysfunction secondary to an episode of hypoglycemia is followed by a generally complete recovery within one hour of correction of low glucose levels. However, recovery from severe events can take up to 36 hours (66).

Hypoglycemia has been proposed as a possible cause of “death in bed”, which seems to be more frequent in children with T1D than in the healthy population (67). However, it is difficult to demonstrate a causal link between the hypoglycemic event and the cause of death; even the recent ISPAD hypoglycemia guidelines (1) attribute the fatal event mainly to arrhythmic causes, autonomic neuropathy, and genetic predisposition (68–70), not hypoglycemia per se. For these reasons, it is wiser to certify death as a concurrent series of causes that include hypoglycemia.

While the strongest predictor of parental FoH is the experience of a severe hypoglycemic event with their child, fear can occur without previous hypoglycemia (77). FoH may be neither consciously perceived nor explicitly declared. Therefore, clinicians need to suspect and seek it out and have an especially high index of suspicion for “over-compensatory behaviors” (e.g., decreasing in insulin dosage or snacking), “avoidance behaviors” (e.g., limiting physical or social activities), acceptance of persistently high blood glucose levels, excessive daily blood glucose checks, and not implementing “agreed” treatment changes to lower blood glucose levels.

A commonly used screening tool for FoH is the Hypoglycemia Fear Survey (HFS), which has been adapted for parents as the Hypoglycemia Fear Survey-Parents (78) and parents of young children as well as adolescents and children themselves (79, 80). The Children’s Hypoglycemia Index (CHI) is another scale that has the added benefit of assessing FoH in specific situations such as only at night or school (80).

Advanced AID systems help to reduce nocturnal hypoglycemia, time spent in hypoglycemia, hyperglycemic episodes, and patient discomfort without increasing the risk of diabetic ketoacidosis or severe hypoglycemia (81). However, studies have not always reported greater satisfaction with treatment and a reduction in FoH with these systems (81). Patients who discontinued CGM showed a worsening of HbA1c levels compared with those who continued with CGM, who had a reduced FoH without improvements in glycemic levels (82). CGM systems with predictive alarms might reduce the time spent in hypoglycemia after physical activity (83), thereby contributing to the propensity for physical activity in PWD. Some believe that improvements in sleep quality and QoL in children and parents using these technologies are attributable to easier night-time control (84). Finally, the use of advanced technologies result in significant improvements in parents’ and children’s sleep quality and in parents’ FoH (85). The advancement and widespread deployment of such technologies has the potential to improve mental and physical health among PWD (86).

It is important to evaluate the psychosocial needs of young people with diabetes and their families when patients start using AID systems and during follow-up (87), establishing realistic expectations about the pros and cons of AID systems (86). Therefore, technological advances must be accompanied by well-timed training and adequate and continuous support (87, 88) and education.

Cognitive behavioral therapy and psychoeducational approaches have been shown to reduce this fear in adults. However, no studies have focused on children and adolescents, although these interventions may benefit older children (89). FoH contributes to the increased frequency of anxiety and depression in PWD and must be evaluated with a structured approach that includes specific screenings. Training must be individualized and take into account that those who have limited access to food due to cost also have limited options for dealing with hypoglycemia (90). A careful evaluation must also consider the coexistence of FoH in disadvantaged families (90).

The opinions of healthcare workers established using Delphi methodology indicated a need for specialized and expert staff (specialized nurses, educators) to train PWD on technologies applied to diabetes (91). Behavioral interventions for family members have shown persistent psychosocial benefits. CGM-focused education with behavioral support probably helps parents of young children with T1D reduce short- and long-term burden and worries (91). Furthermore, a telehealth approach may be helpful in the treatment of FoH (92).

As the most critical risk factor for IAH is recurrent antecedent hypoglycemia, it is reasonable that the most crucial goal should be to reduce the incidence of hypoglycemia. Good metabolic control does not appear to increase the risk of unrecognized hypoglycemia, which is often associated with severe hypoglycemia and FoH (108).

Avoiding hypoglycemia interrupts the vicious cycle that impairs the ability of the adrenal medulla to produce epinephrine (a minor component of the counterregulatory response to hypoglycemia, which is primarily due to sympathetic neural activation) in response to blood glucose levels, restoring hypoglycemia awareness (109).

Technology can also help to restore hypoglycemia awareness; indeed, CGM is associated with a significant reduction in time spent in hypoglycemia episodes. Moreover, stopping insulin infusions when a low blood glucose value is encountered helps to avoid hypoglycemia and to re-start hypoglycemic symptoms. However, an unexpected limitation to restoring hypoglycemia awareness is that adolescents show a high acoustic arousal threshold from sleep (98), so they commonly continue to sleep through an alarm. Structured education on insulin administration, hypoglycemia training, blood glucose targets, and exercise management have also been shown to improve awareness of hypoglycemia (110–112).