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Risk Factors for Developing Severe Hypoglycemia: History
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Contributor: Tatsuhiko Urakami

Hypoglycemia is an often-observed acute complication in the management of children and adolescents with type 1 diabetes. It causes inappropriate glycemic outcomes and may impair the quality of life in the patients. Severe hypoglycemia with cognitive impairment, such as a convulsion and coma, is a lethal condition and is associated with later-onset cognitive impairment and brain-structural abnormalities, especially in young children. Therefore, reducing the frequency of hypoglycemia and minimizing the occurrence of severe hypoglycemia are critical issues in the management of children and adolescents with type 1 diabetes.

  • hypoglycemia
  • severe hypoglycemia
  • children

1. Introduction

Hypoglycemia is an often-observed acute complication in the management of children and adolescents with type 1 diabetes. It causes inappropriate glycemic outcomes and may impair the quality of life in the patients [1]. Reducing hypoglycemia is an important objective that can be attained by evaluating the risk factors for problematic hypoglycemia and by introducing advanced diabetes technologies to the management of diabetes [2].
Severe hypoglycemia is defined as a condition with serious cognitive dysfunction requiring external help from other persons [3]. Severe hypoglycemia is still a lethal condition and is demonstrated to be the cause of death in 4–10% of pediatric patients with type 1 diabetes [4][5][6]. It may cause permanent brain damage, cognitive impairment and brain-structural abnormalities, especially in young children with type 1 diabetes [7][8][9][10][11][12][13][14]. Table 1 shows changes in the incidence of severe hypoglycemia in children and adolescents with type 1 diabetes over time. A high incidence of severe hypoglycemia was demonstrated by the Diabetes Control and Complications Trial (DCCT) in 1997 [15], i.e., 61.2/100 persons/year in patients with intensive insulin treatment (multiple injections of insulin with basal-bolus regimen) and 18.7/100 persons/year in those with conventional insulin treatment (insulin injections twice a day with a mixture of regular- and intermediate-acting insulin), respectively. High incidence was also reported in the large pediatric cohorts in Australia [16] and Colorado, USA [17] in the early 2000s. However, the incidence markedly declined over time, eventually resulting in below 6.0/100 persons/year [18][19][20][21]. Development in the management of diabetes might contribute to reducing the occurrence of severe hypoglycemia. The advanced diabetes technologies in recent years could enable improved glycemic control by decreasing the risk of severe hypoglycemia [22][23][24]. Such advances include the introduction of new insulin analogs, increased frequency of self-monitoring of blood glucose (SMBG), use of continuous glucose monitoring (CGM) and insulin pump therapy. However, despite these new technologies, severe hypoglycemia is still a fear for pediatric patients with type 1 diabetes, family members and their caregivers [3][25].
Table 1. Incidence of severe hypoglycemia in children and adolescents with type 1 diabetes over time.
Report Year Incidence * Reference No.
DCCT 1984–1993   [15]
Conventional   18.7  
Intensive   61.2  
Bulsara MK 1992 7.8 [16]
  2002 16.6  
Rewers A 1996–2000 19.0 [17]
O’Connell SM 2001 17.3 [18]
  2006 5.8  
Karges B 1995
2012		 20.7
3.6		 [19]
Urakami T 2003–2013 4.0 [20]
Cherubini V 2011–2012 7.7 [21]
* 100 persons/year.

2. Risk Factors for Developing Severe Hypoglycemia

Possible risk factors for developing severe hypoglycemia in children and adolescents with type 1 diabetes are shown in Table 2.
Table 2. Risk factors for developing severe hypoglycemia.
Younger aga
Nocturnal hypoglycemia
Impaired awareness of hypoglycemia
Frequent episodes of hypoglycemia
Glycemic control (Recently, association between glycemic control and the risk of severe hypoglycemia seems to be weakened.)

2.1. Younger Age

Several studies have shown that young children are likely to experience hypoglycemia more frequently and/or more seriously as compared with adults with type 1 diabetes because they have more physical activities, unstable eating habits and irregular lifestyles, and are unable to communicate symptoms of hypoglycemia [26][27][28][29][30]. In addition, they tend to impair counterregulatory hormone responses to subsequent hypoglycemia via autonomic nerve function [29]. Neurological damage caused by severe hypoglycemia is more frequently and/or more seriously observed in young children with type 1 diabetes [12][13].

2.2. Nocturnal Hypoglycemia

Counterregulatory hormone responses to hypoglycemia attenuate in sleeping time [29][31], and patients with type 1 diabetes are likely to be less awakened by hypoglycemia as compared with healthy control subjects [29]. Several studies have shown the frequency of nocturnal hypoglycemia as 15–25% during the night in children with type 1 diabetes [32][33]. The Juvenile Diabetes Research Foundation (JDRF) continuous glucose monitoring (CGM) study group in 2010 reported frequent and prolonged nocturnal hypoglycemia on 8.5% of nights in both children and adults but more prolonged episodes in children. In this study, the mean time spent in nocturnal hypoglycemia was 81 min [33]. Almost half of these hypoglycemic events were unrecognized by patients themselves, family members and their caregivers [34][35]. Monitoring of overnight glucose levels is recommended, especially if patients have additional risk factors that may predispose them to nocturnal hypoglycemia.

2.3. Impaired Awareness of Hypoglycemia

In healthy people without diabetes, endogenous insulin secretion is closed off, and counterregulatory hormones (glucagon, epinephrine, and norepinephrine) are released in response to hypoglycemia. However, in patients with type 1 diabetes, there is a progressive loss of glucagon response to insulin-induced hypoglycemia. Impaired awareness of hypoglycemia, one of the acquired complications with insulin treatment, can be caused by defective counterregulatory hormone responses to hypoglycemia. It is observed as early as 12 months after the onset of diabetes [36][37]. This condition was observed in approximately a quarter of adults with type 1 diabetes, while in children and adolescents, a similarly high prevalence (33%) was reported in 2002, which decreased to 21% in 2015 [38][39]. Although the prevalence of impaired awareness of hypoglycemia has declined, it remains a concern in a substantial proportion of children and adolescents with type 1 diabetes. Patients with impaired awareness of hypoglycemia showed a six-fold increase in the frequency of severe hypoglycemia [40]; therefore, it should be necessary to evaluate this condition as a part of clinical management. Impaired awareness of hypoglycemia can be reversed by avoiding the occurrence of hypoglycemia for 2 to 3 weeks [41]; however, this may be difficult to accomplish with current insulin treatment.

2.4. Frequent Episodes of Hypoglycemia

The majority of children with type 1 diabetes experience isolated episodes of severe hypoglycemia; however, some experience recurrent episodes of severe hypoglycemia. Frequent episodes of hypoglycemia contribute to defective counterregulatory hormone responses to a subsequent decline in glucose levels. Therefore, prior episodes of frequent hypoglycemia may play an important role in developing subsequent severe hypoglycemia [3]. After an episode of severe hypoglycemia, the risk of recurrent severe hypoglycemia remains higher for up to 4 years as compared with patients who have never experienced severe hypoglycemia [42]. Defective counterregulatory hormone responses and impaired awareness of hypoglycemia contribute to hypoglycemia-related autonomic nerve failure, resulting in subsequent severe hypoglycemia [43]. Rarely, self-administration of insulin causes repeated and unexplained severe hypoglycemia and should be considered a sign of psychological disorders (Factitious hypoglycemia) [44].

2.5. Glycemic Control

Previous studies reported that strict glycemic control was associated with an increased frequency of severe hypoglycemia, especially in young children with type 1 diabetes [15][16][21]. The DCCT demonstrated that there was a threefold increased risk of severe hypoglycemia in individuals requiring intensive management with lower HbA1c levels as compared with those treated conventionally [15]. However, recent studies have demonstrated that the association between glycemic control and the risk of severe hypoglycemia seems to be weakened accompanied by an improvement in diabetes management with a decreased risk of severe hypoglycemia [16][18][21][22][23][45][46]. In the Type 1 Diabetes Exchange (T1D Exchange) and the Diabetes-Patienten-Verlaufsdokumentation (DPV) registry, there were no increased rates of hypoglycemic coma in those aged less than 6 years with HbA1c levels of below 7.5% (58.5 mmol/moL) as compared with those with higher HbA1c levels [45]. No differences in HbA1c levels were also reported from an Indian study assessing children with or without severe hypoglycemia [46]. The decrease in the frequency of severe hypoglycemia may have resulted from advanced insulin treatment and glucose monitoring and improved hypoglycemia education during the past decades. Low HbA1c levels may be not a predictable indicator for severe hypoglycemia in children and adolescents with type 1 diabetes [22]. Therefore, optimal glycemic control by appropriate diabetes management can be achieved without an increase in the frequency of severe hypoglycemia.

This entry is adapted from the peer-reviewed paper 10.3390/jcm12030781

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