1 WHAT IS NEW OR DIFFERENT?

2 EXECUTIVE SUMMARY AND RECOMMENDATIONS

3 INTRODUCTION

Hypoglycemia is a common occurrence in the management of T1D. It interferes with daily activities and poses a constant perceived threat to the individual and their families. It is a recognized limiting factor in achieving optimal glycemia¹ with an impact on quality of life.² Minimizing hypoglycemia is an important objective of diabetes management that can be addressed by acknowledging the problem, evaluating the risk factors and applying the principles of intensive glycemic management.³ Therefore, it is vital to address this important clinical concern during diabetes education and institute appropriate management. The last two decades have experienced a paradigm shift in diabetes management through the availability of improved insulin analogues, insulin pump therapy and advent of CGM with algorithms incorporated in sensor-augmented pump therapy (SAP) to reduce and prevent hypoglycemia. There is increasing evidence to suggest that the time spent in hypoglycemia^4-6 and the rates of severe hypoglycemia have declined in recent years in developed countries with newer intensive therapies.^7-11 Unfortunately, hypoglycemia continues to be a problem in countries with limited resources, where many children are treated with insulin injections, with minimal access to technology and resources.

4 DEFINITION AND INCIDENCE

5 MORBIDITY AND MORTALITY WITH HYPOGLYCEMIA

6 SIGNS AND SYMPTOMS

Hypoglycemia is often accompanied by signs and symptoms of autonomic (adrenergic) activation and/or neurological dysfunction from glucose deprivation in the brain (neuroglycopenia),⁸¹ as shown in Table 2. As the blood glucose concentration falls, initial symptoms result from activation of the autonomic nervous system and include shakiness, sweating, pallor, and palpitations. In healthy individuals without diabetes, these symptoms occur at a blood glucose level of ~3.9 mmol/L in children and 3.2 mmol/L in adults.⁸² However, this threshold in individuals with diabetes will depend on their glycemic levels^83-86 with an adaptive shift of the glycemic threshold for symptom onset to a higher glucose level with chronic hyperglycemia and lower glucose level with chronic hypoglycemia. Neuroglycopenic symptoms result from brain glucose deprivation and include headache, difficulty concentrating, blurred vision, difficulty hearing, slurred speech, and confusion. Behavioral changes such as irritability, agitation, quietness, stubbornness, and tantrums may be the prominent symptoms particularly for the preschool child, and may result from a combination of neuroglycopenic and autonomic responses.⁸⁷ In this younger age group, observed signs are more important, and at all ages there is a difference between reported and observed symptoms or signs. The dominant symptoms of hypoglycemia tend to differ depending on age, with neuroglycopenia more common than autonomic symptoms in the young.⁸⁸

Physiological responses in children and adolescents

It is well recognized that although many physiological responses are similar across the age groups, there can be significant developmental and age-related differences in children and adolescents. The DCCT reported a higher rate of severe hypoglycemia in adolescents as compared to adults; 86 versus 57 events requiring assistance per 100 patient-years²⁰ despite higher HbA1c in adolescents. Several physiological and behavioral mechanisms may contribute to this difference. Firstly, there are behavioral factors such as variable engagement with diabetes care which are associated with sub-optimal glycemia in adolescents.⁸⁹ Secondly, during puberty, adolescents with or without T1D are more insulin resistant than adults.⁹⁰ Adolescents also have quantitative differences in counter regulatory hormone responses. In healthy individuals without diabetes, hypoglycemia symptoms occur at a blood glucose level of ~3.9 mmol/L in adolescents and 3.2 mmol/L in adults⁸² In adolescents with suboptimal glycemia, this glucose level may be higher, reported at 4.9 mmol/L in one study.⁸² Intensively treated young adults with T1D counter-regulate and experience hypoglycemia symptoms at a lower glucose level than those on treatment with twice daily injections.⁸⁵ To date, nearly all studies have been conducted in adolescents and young adults primarily due to difficulty in studying a younger age group. As a result, little is known about responses in pre-adolescents as to whether younger children demonstrate a similar or different response to hypoglycemia although there is evidence that a developing brain is more susceptible to the influence of glycemic excursions.⁹¹

7 HYPOGLYCEMIA AWARENESS

In healthy individuals without diabetes, endogenous insulin secretion is shut down and counter regulatory hormones (glucagon, epinephrine, and norepinephrine) are released in response to hypoglycemia.⁹² However, in people with diabetes, there is a progressive loss of glucagon response to insulin-induced hypoglycemia. This has been demonstrated as early as 12 months after diabetes onset and is lost in most people with T1D by 5 years.^{93, 94} Individuals with diabetes are therefore primarily dependent on the epinephrine response to counteract the hypoglycemic effect of insulin. Recurrent episodes of hypoglycemia contribute to the development of defective counter regulatory hormone responses to subsequent reductions in glucose levels and may further exacerbate the problem, whereby “hypoglycemia begets hypoglycemia.”

IAH is a syndrome in which the ability to detect hypoglycemia is diminished or absent, reported in ~25% of adults with T1D.⁹² In children and adolescents, a similarly high prevalence (33%) of IAH was reported in 2002, which declined to 21% in 2015.^{95, 96} Although the prevalence of IAH has decreased, it remains a concern in a substantial proportion of adolescents.

IAH is associated with lowering of glycemic thresholds for the release of counter regulatory hormones and generation of symptoms. A two to threefold reduction in the epinephrine responses contributes to the impaired adrenergic warning symptoms during hypoglycemia.⁹⁷ Clinically, this is manifested as loss of some of the symptoms of hypoglycemia over time. The loss of autonomic symptoms precedes the neuroglycopenic symptoms and individuals are less likely to seek treatment for low blood glucose levels. As the awareness of low blood glucose level is impaired, hypoglycemia is prolonged. These episodes, if unrecognized and prolonged, can lead to seizures.⁹⁸ Individuals with IAH have a sixfold increase in severe hypoglycemic episodes.⁹⁹ This highlights the need to evaluate for IAH as part of clinical management. The identification of IAH is limited by the availability of tools to measure hypoglycemia awareness. It is not practical to measure the adrenergic responses during hypoglycemia to identify IAH and questionnaires have been developed as surrogate measures that can be administered to older children who are able to self-report. The single-question Gold,⁹⁹ the eight-question Clarke¹⁰⁰ and six-question modified Clarke^{95, 96} have been used to screen children with IAH(Appendices A to C). The Clarke questionnaire has higher specificity than Gold in predicting clinically significant hypoglycemia.^{101, 102} Although a score of ≥4 implies IAH on these measures, it is important to acknowledge that IAH is not an “all or none phenomenon” but reflects a continuum in which differing degrees of impaired awareness can occur.

The blood glucose threshold for activation of autonomic signs and symptoms is related to glycemic status, antecedent hypoglycemia, antecedent exercise, and sleep. Tight glycemic management leads to adaptations that impair counter regulatory responses¹⁰³ with a lower glucose level required to elicit an epinephrine response.⁸⁶ An episode of antecedent hypoglycemia may reduce the symptomatic and autonomic response to subsequent hypoglycemia, which in turn further increases the risk of subsequent severe hypoglycemia.¹⁰⁴ Likewise, moderate-intensity exercise also blunts the hormonal response to subsequent hypoglycemia.¹⁰⁵ Most severe episodes of hypoglycemia occur at night as sleep further impairs the counter regulatory hormone responses to hypoglycemia in people with diabetes and in normal subjects.¹⁰⁶ On the other hand, the blood glucose threshold for neuroglycopenia does not appear to vary as much with the level of glycemia or with antecedent hypoglycemia.^{82, 107, 108} The glycemic threshold for cognitive dysfunction may be triggered before autonomic activation and hence are the symptoms associated with IAH.

The cause of IAH is not well understood. “Hypoglycemia-associated autonomic failure” resulting from a failure of centrally-mediated counter regulation is one of the proposed mechanisms¹⁰⁹ although the term may be misleading as the autonomic system does not fail. Rather, recurrent hypoglycemia causes a process of adaptation referred to as habituation; that is, IAH may represent a habituated response to hypoglycemia.^{110, 111} A habituated response can also be temporarily reversed by the introduction of a novel (heterotypic) stimulus (dishabituation). Preliminary results of a recent study demonstrated that a single burst of high-intensity exercise restored counter regulatory responses to hypoglycemia induced the following day in a rodent model¹¹² and in people with T1D and IAH.¹¹³

IAH can be reversed by avoiding hypoglycemia for two to three weeks¹¹⁴ but this may be difficult to accomplish and, until recently, has not been practical in a clinical setting with current therapies. Therapeutic options are limited although some individuals benefit from structured education.¹¹⁵ Technological advances could potentially have a role to play with the use of CGM,¹¹⁶ SAPT with low glucose suspend functions^{4, 117} or hybrid closed loop systems.¹¹⁸

8 RISK FACTORS FOR HYPOGLYCEMIA

Risk factors for hypoglycemia can be classified as modifiable and non-modifiable; most are modifiable. Younger age (due to the inability to communicate symptoms) and prolonged diabetes duration (due to its association with IAH) increase the risk of hypoglycemia. A higher risk of hypoglycemia has also been reported with limited access to private insurance and lack of nationalized schemes to access technology.²² The main risk factor for hypoglycemia is a mismatch between administered insulin and consumed food. Insulin excess could result from increased doses due to poor understanding of insulin type and action, accidental delivery, reduced food intake or missed meals, and in situations where glucose utilization is increased (during exercise) or endogenous glucose production is decreased (after alcohol intake).

Recurrent hypoglycemia

Majority of children with T1D who experience severe hypoglycemia have isolated events; however, a few experience recurrent episodes. After an episode of severe hypoglycemia, the risk of recurrent severe hypoglycemia remains higher up to 4 years compared with children who have never experienced severe hypoglycemia.⁷³ When hypoglycemia is recurrent, it is important to exclude IAH and rule out coexisting autoimmune disorders like subclinical hypothyroidism,¹¹⁹ celiac disease,¹²⁰ and Addison's disease.^{121, 122} Rarely, surreptitious self-administration of insulin causes repeated and unexplained severe hypoglycemia and should be considered as a sign of psychological distress^{123, 124} with underlying risk factors such as eating disorders (anorexia and bulimia) and depression. The clinical factors associated with an increased risk of hypoglycemia are shown in Table 3.

Exercise

The glucose response to exercise is affected by many factors including the duration, intensity and type of exercise, the time of day when exercise is performed, plasma glucose, and insulin levels, and the availability of supplemental and stored carbohydrates.¹²⁵ The risk of hypoglycemia is increased during moderate-intensity exercise, immediately after as well as 7 to 11 h after exercise.¹²⁶ The pathophysiology of post-exercise-induced hypoglycemia is multifactorial, and includes increased insulin absorption, increased insulin sensitivity, increased peripheral glucose utilization with depletion of glycogen stores and exercise-induced counter regulatory hormone deficits. Furthermore, children on fixed insulin doses are at “triple jeopardy” for hypoglycemia on nights following exercise related to: increased peripheral glucose utilization with exercise, impaired counter regulatory hormone responses during sleep, and unchanged insulin concentrations related to the treatment regimen.¹²⁷ Treatment guidelines to help individuals exercise safely are updated in this edition of the ISPAD guidelines (See ISPAD 2022 Consensus Guidelines Chapter 14 for Exercise in Children and Adolescents with Diabetes).

Alcohol

Alcohol inhibits gluconeogenesis¹²⁸ and hypoglycemia may occur if there is an inadequate intake of carbohydrates. Furthermore, the symptoms of hypoglycemia may be masked by the intoxicating effects of alcohol. Even moderate consumption of ethanol may reduce hypoglycemia awareness and impair the counter regulatory response to insulin-induced hypoglycemia.¹²⁹ Apart from the acute effects, moderate consumption of alcohol in the evening is associated with reduced nocturnal growth hormone secretion and may increase the risk of hypoglycemia on the subsequent morning.¹³⁰ Although an increase in insulin sensitivity with alcohol intake has been postulated, this remains inconclusive.¹³¹

Nocturnal hypoglycemia

The Juvenile Diabetes Research Foundation (JDRF) CGM study group in 2010 described frequent prolonged nocturnal hypoglycemia on 8.5% of nights in both children and adults but more prolonged episodes in children.¹³² In this study, the mean time spent in nocturnal hypoglycemia (<60 mg/dl) was 81 min. Almost half of these episodes were undetected by caregivers or individuals with diabetes.^{133, 134} The counterregulatory responses to hypoglycemia are attenuated during sleep^{106, 135, 136} and individuals with T1D are much less likely to be awakened by hypoglycemia than individuals without diabetes.¹⁰⁶ This is significant as prolonged nocturnal hypoglycemia can lead to seizures.⁹⁸ Nocturnal hypoglycemia should be suspected if pre-breakfast glucose is low, and/or the individual experiences confusion, nightmares or seizures during the night, or if impaired thinking, lethargy, altered mood, or headaches are reported on waking.¹³⁷ It is recommended to monitor overnight glucose levels, particularly if there is an additional risk factor that may predispose to nocturnal hypoglycemia. Younger age, lower HbA1c levels, antecedent exercise, and hypoglycemia are associated with a greater frequency of nocturnal hypoglycemia.¹³⁸

Studies of overnight hypoglycemia in children have been unable to identify a glucose value that reliably predicts a low risk of hypoglycemia. In a study using CGM to detect nocturnal hypoglycemia, there was a twofold increase, 45% versus 22%, in the incidence of hypoglycemia with a bedtime glucose ≤5.5 mmol/L (100 mg/dl).¹³⁹ Similarly, the fasting glucose levels were significantly lower (6.6 mmol/L; 118 mg/dl) in those with than those without hypoglycemia (9.9 mmol/L; 179 mg/dl).¹⁴⁰ In contrast, in children on twice daily soluble and isophane (NPH) insulin therapy, hypoglycemia was partially predicted by a midnight glucose of <7.2 mmol/L (130 mg/dl).¹⁴¹

To reduce nocturnal hypoglycemia, a carbohydrate snack before bed for children on insulin injections was recommended based on studies using intermediate-acting insulins with peak action 4–12 h and duration 16–24 h.¹⁴² However, use of long-acting insulin analogues such as glargine and detemir, due to their less pronounced peak effect, have reduced overnight hypoglycemia.¹⁴³ Hence, extra snacks may be unnecessary¹⁴⁴ and enforcing pre-bed meals may contribute to nocturnal hyperglycemia and add unnecessary calories contributing to weight gain. The recommendation for inclusion of pre-bed snacks is not mandatory and should be individually tailored.¹⁴⁴ Newer insulin analogues, like the ultralong-acting basal insulin degludec, have the potential to provide similar glycemia while reducing nocturnal hypoglycemia risk.¹⁴⁵

Nocturnal hypoglycemia is less frequent with pump therapy and there has been a further decline with use of pumps that incorporate control algorithms that suspend basal insulin with sensor-detected,¹⁴⁶ sensor-predicted hypoglycemia⁴ and hybrid closed loop systems.

9 HYPOGLYCEMIA TREATMENT

Diabetes education should focus on recognition of precipitants and risk factors for hypoglycemia, the ability to detect subtle symptoms, the importance of confirming low glucose levels by monitoring, appropriate hypoglycemia treatment and approaches to prevent future events. Figure 1 outlines the management of hypoglycemia.

Hypoglycemia can be detected using SMBG or CGM. Newer factory calibrated CGM devices are approved to use sensor glucose data to make diabetes management decisions. However, a fingerpick blood glucose measurement is recommended if there is a suspected mismatch between clinical expectations and the sensor glucose level. Likewise, blood glucose should always be tested if the child is symptomatic or shows signs of hypoglycemia. If the glucose level is <3.9 mmol/L (70 mg/dl), remedial actions to prevent a further drop in glucose is recommended. In adults, 20 g of carbohydrate in the form of glucose tablets raised glucose levels by ~2.5 to 3.6 mmol/L (45–65 mg/dl) at 45 min.^147-149 This was extrapolated to 0.3 g/kg in children, which would be approximately 9 g of glucose for a 30 kg child and 15 g for a 50 kg child. A pediatric study has confirmed that 0.3 g/kg of rapidly acting carbohydrate containing preparations (glucose tablets, orange juice), effectively resolved hypoglycemia in most children and raised median blood glucose by 1–1.3 mmol/L in 10 min and 2–2.1 mmol/L in 15 min without rebound hyperglycemia at the next meal.¹⁵⁰ A similar weight-based approach was also found to be effective in children on insulin pumps.¹⁵¹ In children on insulin pump therapy, it is also recommended that basal insulin delivery is suspended if glucose level is <3 mmol/L. To date no studies have looked at the amount of carbohydrate required to treat hypoglycemia in children who use automated insulin delivery systems that suspend basal insulin delivery when hypoglycemia is predicted or use closed loop systems. The current approach of standard hypoglycemia management can cause rebound hyperglycemia¹⁵²; hence consideration should be given to treat hypoglycemia with less glucose (e.g., 5–10 g)^{152, 153} or approximately half the amount of glucose used for standard treatment.

The choice of carbohydrate source is an important consideration for hypoglycemia treatment. In clinical practice, glucose-containing products are recommended for immediate treatment because of their rapid absorption from the intestine. It is important to review the amount of glucose in the product to ensure adequate treatment is provided. When glucose tablets are not available, dietary sugars can be used. Glucose tablets result in a higher rate of relief of symptomatic hypoglycemia 15 min after ingestion compared with dietary sugars (hard candy, table sugar, jelly beans, fruit juice). If available, glucose-based treatment should be the first choice when treating symptomatic hypoglycemia.¹⁵⁴

Although 15 g of “carbohydrates” are recommended for first-line treatment by ADA,¹⁵⁵ it is essential to note that the dose required for dietary sugars is not established and may be higher than glucose. For example, 40 g of carbohydrate in the form of juice results in approximately the same rise as 20 g in the form of glucose tablets.¹⁴⁷ Likewise, sucrose requires a greater amount to provide the same increase in blood glucose concentration compared to oral glucose.¹⁴⁸ Husband et al reported that glucose- and sucrose-based hypoglycemia treatments resulted in timely resolution of hypoglycemia, although fructose-based treatment (fruit juice) was less effective.¹⁵⁶ Honey and fruit juice have been reported to be more effective than one sugar cube (sucrose) for treatment of hypoglycemia.¹⁵⁷ Honey contains nearly 70% fructose and glucose as main sugars although composition differs depending on the geographical origin which may lead to variability in response. Jelly beans contain glucose syrup and although they cause glucose levels to rise, the resolution of hypoglycemia is slower.¹⁵⁰ If a soft drink is used for treatment, ensure regular and not sugar-free/diet forms is used for treatment.

Dietary sugars are generally discouraged to avoid confusion between “treatment” and “treats” with the potential of hypoglycemia induction to receive these treats. Furthermore, complex carbohydrates, or foods containing fat (chocolate) which delay intestinal absorption and result in slow absorption of glucose should be avoided as the initial treatment of hypoglycemia. Whole milk containing 20 g of carbohydrate (435 ml) causes a minimal response with rise of ~1 mmol/L (18 mg/dl).¹⁴⁷

After treatment, repeat a blood glucose measurement after 15 min.¹⁵⁸ If there is no response or an inadequate response, repeat oral intake as above. It is important to be aware of the physiological time lag with rising and falling sensor glucose levels in children using CGM.¹⁵⁹ The decision to repeat hypoglycemia treatment should not be based on a low sensor glucose level at 15 min unless a finger prick glucose measurement confirms persistent hypoglycemia. Once hypoglycemia is reversed, the child should have the usual meal or snack if due at that time; otherwise, a snack (15 g) of slower-acting carbohydrate, such as bread, milk, biscuits, or fruit should be consumed. However, this is not always required, particularly for those on insulin pump therapy.

The amount of carbohydrate required to guide treatment will also depend on the size of the child, type of insulin therapy, active insulin on board, and the timing and intensity of antecedent exercise.^{147, 160} It is important to educate the child/caregiver to consider the factors that led to hypoglycemia.

Severe hypoglycemia

Severe hypoglycemia requires urgent treatment. If the child is unconscious or unable to swallow, hypoglycemia can be safely reversed by administration of glucagon, a potent and effective agent that can be administered intravenously, intranasally, intramuscularly or subcutaneously.¹⁶¹ Table 4 shows a list of the available forms of glucagon.

Recombinant crystalline glucagon is available as a lyophilized (freeze-dried) powder that is mixed with an aqueous diluent to a concentration of 1 mg/ml. Commercially available glucagon rescue kits include GlucaGen® HypoKit 1 mg (Novo Nordisk®A/S, Bagsvaerd, Denmark) and Glucagon Emergency Rescue Kit (Eli Lilly and Company, Indianapolis IN). The recommended glucagon dose is weight based: 1 mg for adults and children >25 kg and 0.5 mg for children <25 kg (according to Novo Nordisk manufacture guidelines) while Eli Lilly uses a weight cut-off of 20 kg. The evidence for these recommendations is unclear.

Glucagon often induces nausea and vomiting on regaining consciousness and hence it is important to continue close observation and glucose monitoring after treatment.¹⁶² The frequency of side effects increases with repeated doses. The efficacy of glucagon depends on having adequate hepatic glycogen. Consequently, glucagon would be predicted to be less efficacious in cases of hypoglycemia associated with prolonged fasting; in these circumstances, parenteral glucose would be the therapy of choice.¹⁶² Currently available preparations require glucagon reconstitution with sterile diluent and therefore parents and caregivers require instruction on how to prepare and administer glucagon. Because glucagon is seldom used, parents and caregivers require regular reviews about when and how to administer glucagon. The need for reinstitution of glucagon powder before use is a known challenge which can delay or prevent glucagon administration. To overcome this barrier, an intranasal single-use glucagon preparation is now available as a needle-free device that delivers glucagon for the treatment of severe hypoglycemia in children¹⁶³ and adults^{164, 165} with T1D. A recent meta-analysis indicated that intranasal glucagon and SC/IM glucagon were equally effective in resolution of hypoglycemia in conscious individuals.¹⁶⁶ Intranasal preparation may cause headache, upper airway discomfort, tearing, or nasal congestion in addition to the typical side effects of glucagon.¹⁶³ A single dose of 3 mg is used in children (≥4 years) and adults with T1D.¹⁶⁷ Administration of nasal glucagon is faster and has a much higher success rate for delivery of the full dose with fewer errors than injectable glucagon.¹⁶⁸ Recently, dasiglucagon has also received regulatory approval.¹⁶⁹ Dasiglucagon, a soluble and stable glucagon analog available as 0.6 mg ready-to-use pen, provided rapid and effective reversal of hypoglycemia in children (≥6 years)¹⁷⁰ and adults¹⁷¹ with T1D; side-effects were comparable to IM glucagon. A premixed SC autoinjector Gvoke HypoPen® (liquid-stable glucagon) is also available for use in children >2 years of age.^{172, 173} The availability of different forms of glucagon varies across different regions of the world and access to these forms of hypoglycemia treatment may be limited in lower resource settings.

In a hospital setting, intravenous glucose or glucagon may be given. Intravenous glucose should be administered by trained personnel over several minutes to reverse hypoglycemia. The recommended dose is 0.2 g/kg of glucose which equates to 2 ml/kg of 10% dextrose with a maximum dose of 0.5 g/kg body (5 ml/kg). As high concentrations cause sclerosis of peripheral veins, the maximum concentration of dextrose that can be administered through a peripheral vein is 25% dextrose. Rapid administration or an excessive concentration (dextrose 50%) can result in a rapid osmotic change with risk of hyperosmolar cerebral injury.¹⁷⁴ 10% dextrose is effective and safe and hence recommended for management.¹⁷⁵ In the event of recurrent hypoglycemia, the child will require additional oral carbohydrates and/or intravenous infusion of 10% dextrose to provide a glucose infusion rate of 2–5 mg/kg/min (1.2–3.0 ml/kg/h). The predisposing events that led to the severe event should be evaluated to prevent future events. Caregivers need to be aware that following a severe hypoglycemic event, the child will be at higher risk of a future event, and alterations to insulin therapy may be appropriate.

Glucagon is not readily available in countries with limited resources. Sugar or any other powdery substance or thin liquids such as a glucose solution or honey should not be given forcibly to the semi/unconscious child. The child should be put in a lateral position to prevent aspiration and a thick paste of glucose (glucose powder with a few drops of water or crushed table sugar with consistency of thick cake icing) smeared onto the dependent cheek pad; the efficacy of this practice is anecdotal. Although an earlier study in healthy adult volunteers demonstrated poor buccal absorption of glucose,¹⁷⁶ sublingual glucose was found to be a child-friendly method of raising blood glucose in severely ill children with malaria.¹⁷⁷ In situations where there is a danger of aspiration and intravenous access is unavailable, parenteral glucose solutions may be administered via nasogastric tubes.¹⁷⁸

Minidose glucagon

Children with gastrointestinal illness and/or poor oral carbohydrate intake with a blood glucose ≤4.4 mmol/L can benefit from mini-dose glucagon injected by their caregivers to avoid impending hypoglycemia and hospitalizations.^{161, 179} The dose of reconstituted glucagon is administered subcutaneously using a 100 U insulin syringe (1 unit ~10 μg of glucagon) and is age-based: 2 units (20 μg) for children ≤2 years and 1 unit/year for children ≥3–15 years (with a maximum dose of 150 μg or 15 units). If blood glucose fails to rise over the first 30 min, a repeat injection should be given using twice the initial dose. The minidose glucagon regimen resulted in an increase of 3.3–5 mmol/L of glucose (60–90 mg/dl) within 30 min of administration with an average increase of 4.7 mmol/L.¹⁶¹

10 ROLE OF TECHNOLOGY IN REDUCTION OF HYPOGLYCEMIA

The rapid technological advances in diabetes management with stand-alone CGM systems or systems with integrated CGM and insulin pump use have empowered individuals with T1D to further reduce the frequency of hypoglycemia. There are many technological devices available to reduce hypoglycemia; however, the choice of device should be a decision based on a dialogue between the health care professional and the individual with diabetes. More detailed recommendations and guidelines for pump and CGM are covered in ISPAD pump and CGM chapters respectively (See ISPAD 2022 Consensus Guideline Chapter 16 on Diabetes Technologies: Glucose Monitoring and Chapters 17 on Diabetes Technologies: Insulin delivery).

Continuous subcutaneous insulin infusion

Continuous subcutaneous insulin infusion (CSII) use can reduce hypoglycemia. A meta-analysis showed that pump therapy in children may be better than injections in reducing the incidence of severe hypoglycemia.¹⁸⁰ Compared to injection therapy, a lower risk of severe hypoglycemia was associated with CSII in the T1D exchange,¹⁸¹ DPV registry¹⁸² and the International Pediatric SWEET Registry.¹⁸³

Continuous glucose monitoring: Stand-alone systems

Studies have shown a reduction in time spent in hypoglycemia with a concomitant decrease in HbA1c with CGM use in both children and adults.^184-186 There was a trend to reduction in severe hypoglycemia in the DPV and T1D Exchange registry with CGM initiation.^{8, 181} Sensors with predictive alerts can further reduce hypoglycemia.¹⁸⁷ These alerts with real-time glucose monitoring may also contribute to reduced parental FOH.⁷⁹ Intermittently scanned CGM (isCGM) (without alerts) also has the potential to reduce hypoglycemia,¹⁸⁸ however the reduction in hypoglycemia is greater with real-time CGM than with intermittently scanned isCGM¹⁸⁹ and is potentially a better management tool for individuals at high risk of hypoglycemia.

Sensor-augmented pump therapy with low glucose and predictive low glucose suspension

The incorporation of algorithms in sensor-augmented pump therapy further reduces the time spent in hypoglycemia due to suspension of basal insulin delivery with hypoglycemia (Low Glucose Suspension)^{117, 190} and with prediction of hypoglycemia.^{4, 191} Predictive Low Glucose Management (PLGM) systems include the Medtronic PLGM system and Tandem Basal IQ. The Medtronic PLGM system suspends basal insulin when sensor glucose (SG) is at or within 3.9 mmol/L (70 mg/dl) above the patient-set low limit and is predicted to be 1.1 mmol/L (20 mg/dl) above this low limit in 30 min. Following pump suspension and in the absence of user interference, insulin infusion resumes after a maximum suspend period of 2 h or earlier if the auto-resumption parameters are met. Prospective and retrospective studies have shown that PLGM reduces hypoglycemia.^{4-6, 192, 193} Time spent in hypoglycemia <3.5 mmol/L was reduced from 2.8% at baseline to 1.5% during the 6-month study compared with a reduction from 3% to 2.6% with SAPT, representing close to 50% reduction in hypoglycemia.⁴

The Tandem Basal IQ, available with Dexcom G6® CGM and Tandem t:slim X2 pump, uses a linear regression algorithm that relies on the last four SG values to predict SG level in 30 min. It suspends basal insulin when SG is predicted to be 4.4 mmol/L (80 mg/dl) in 30 min or current SG is <3.9 mmol/L (70 mg/dl). Time spent in hypoglycemia <3.9 mmol/L decreased from 3.6% at baseline to 2.6% during the 3-week PLGM period compared with 3.2% with SAPT, representing a 31% relative reduction in hypoglycemia.¹⁹¹ The insulin resumption is more aggressive and hence there was no difference in the mean SG levels in the two groups or in the time spent in hyperglycemia.¹⁹¹

Hybrid closed-loop systems

Automated insulin delivery offers the potential to mitigate the significant glycemic excursions associated with conventional therapy. These systems utilize a control algorithm that automatically and continually increases and decreases the subcutaneous delivery of insulin based on real-time sensor glucose levels. Several systems are available but all may not have national regulatory approvals: Medtronic 670G/770G^{194, 195} and Medtronic 780G¹⁹⁶ with advanced algorithm is approved for use in children 7 years and above, Control IQ (Tandem Inc., San Diego, California)^{197, 198} for 6 years and above and CamAPS FX interoperable app^{118, 199-201} (CamDiab, Cambridge, UK) for 1 year and above. These hybrid closed-loop systems require user input of insulin bolus for meals ± corrections. Both in clinical trials and in observational studies, these systems have consistently shown a reduction in time spent in hypoglycemia while improving time in target glucose range.^{194, 195, 197, 202, 203} Improved glycemic variability, especially overnight, with reduced hypoglycemia has the potential to improve sleep and quality of life in children and their parents.²⁰⁴ Individuals with IAH also have the potential to improve their hypoglycemia awareness with these systems.¹¹⁸ Use of closed loop systems in individuals with IAH showed reduction in hypoglycemia with higher self-reported hypoglycemia scores during controlled hypoglycemia. However, this was not associated with an improvement in counter regulatory hormonal responses which could be due to the relatively short duration (8 weeks) use of the system.¹¹⁸ Advancements in this field are ongoing in the pursuit of a fully automated closed loop system that can further improve glycemic outcomes and reduce the burden of disease in individuals with T1D.

11 SUMMARY

Diabetes management should optimize glycemia with minimal hypoglycemia to positively impact quality of life. Hypoglycemia education and management is fundamental in the care of children with T1D. This guideline provides an evidence-based approach to hypoglycemia management.

AUTHOR CONTRIBUTION

All authors contributed to the content of the chapter, reviewed and approved the final version of the manuscript.

CONFLICT OF INTEREST

Dr Dovc received speaker's honoraria from Abbott, Pfizer, Novo Nordisk, and Eli Lilly and Advisory Board honoraria from Sanofi and Pfizer. Dr Dovc is a member of the European Commission Expert panel for Medical Devices for Endocrinology and Diabetes. Dr Abraham received speaker's honoraria for educational sessions organized by Medtronic Australia and Eli Lilly.