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      Chapter 3 Hypoglycemia

      Linda Gonder-Frederick, PhD, Daniel J. Cox, PhD, ABPP,

      Harsimran Singh, PhD, and Jaclyn A. Shepard, PsyD

       The Problem of Hypoglycemia: Definitions and Prevalence

      Hypoglycemic episodes, the most common acute complication of diabetes, are almost unavoidable, especially for patients using insulin. Hypoglycemia can be defined both biologically and symptomatically. The biological definition, based on blood glucose (BG) levels, is any reading <3.9 mmol/l (70 mg/dl) (Workgroup on Hypoglycemia, American Diabetes Association [ADA] 2005). This, however, treats all BG levels <70 as symptomatically equal, which is misleading. Symptomatically, hypoglycemia is defined in terms of its impact on the central nervous system. The Diabetes Control and Complications Trial (DCCT) defined three levels of hypoglycemia: mild, moderate, and severe (DCCT Research Group 1997). Mild hypoglycemia is characterized by symptoms caused by counterregulatory hormones and mild neuroglycopenia that do not significantly disrupt cognitive-motor functioning and are quickly alleviated by consuming carbohydrates. Moderate hypoglycemia can disrupt routine functioning, but the individual maintains the executive capacity to recognize symptoms and initiate treatment.

      When mild or moderate episodes are not recognized or treated in a timely manner, severe hypoglycemia (SH) can occur. With SH, extreme neuroglycopenia precludes the ability to self-treat due to cognitive impairment, unconsciousness, or seizure. Episodes of SH are inherently dangerous, especially when no one else is present to provide emergency assistance or when the individual is engaging in potentially dangerous activities such as driving a vehicle (Cox 2006b). Mortality due to SH, albeit uncommon, does occur, accounting for an estimated 2 to 4% of deaths in individuals with type 1 diabetes (T1D) (Swade 1997, Allen 2003, Dagogo-Jack 2004, Friedrich 2004, Cox 2006b). Some of these mortalities are associated with nocturnal hypoglycemia, which can lead to what has been called the “dead in bed” phenomenon (Sovik 1999).

      There are no definitive statistics on the frequency of hypoglycemia, but it has been estimated that individuals with T1D have an average of two episodes per week, most of these mild or moderate (Allen 2001, Cryer 2003). For SH, estimates of prevalence vary widely across studies. In the DCCT, SH occurred at least once per year in 65% of patients on intensive insulin regimens, with an average of 61.2 episodes per 100 patient years (DCCT Research Group 1997). Other prospective studies have reported frequencies ranging from 4.8 to 19 episodes per 100 patient years (Bognetti 1997, Davis 1997, Allen 2001, Rewers 2002, Leese 2003). However, prevalence rates do not accurately reflect the fact that the majority of episodes are concentrated in a minority subgroup of patients who have frequent and recurrent SH (Cox 1999, Honkasalo 2011). This is true not only for adults, but also for children, where 80 to 100% of episodes occur in 20 to 33% of patients (Bognetti 1997, Rewers 2002). The occurrence of SH is also not evenly distributed across times of day, with 50% or more episodes occurring at night in both children and adults (DCCT Research Group 1991, Bognetti 1997, Davis 1997).

      In type 2 diabetes (T2D), some studies have reported a much lower frequency of hypoglycemia, especially when patients on all treatment regimens, including dietary therapy alone and low-dose oral medications, are included in the study (Katakura 2003). Hypoglycemia is less common during the initial years following diagnosis of T2D, presumably due to intact counterregulatory hormone mechanisms (Cryer 2003, Henderson 2003, Zammitt 2005). However, it seems that after insulin use begins, the frequency of hypoglycemia, including SH, is equivalent in T1D and T2D (Holstein 2003, Leese 2003). The use of oral sulfonylureas also greatly increases hypoglycemia in patients with T2D (Chelliah 2004, Steppel 2004, Zammit 2005).

       The Impact of Hypoglycemia on Physical and motional Well-Being

      The practical implications of hypoglycemia can range from patients’ personal lives to their working and social relationships, with potential negative consequences for their overall quality of life (Cryer 2004, Frier 2008, Singh 2010). Episodes of hypoglycemia are typically associated with negative consequences, including unpleasant symptoms, potential embarrassment, and inconvenience (Gonder-Frederick 1997a, Cox 2002, Jørgensen 2003). Scientific studies of the prevalence of physical injury due to SH are somewhat rare (Graveling 2010, Griffith 2011); however, clinical experience indicates that this is not uncommon. Recent retrospective and prospective surveys have demonstrated that a subgroup of patients is at a higher risk for hypoglycemia-related driving mishaps and automobile accidents (Cox 2003, Sommerfield 2003, Cox 2006b).

      In people with T1D, acute hypoglycemia may produce impairment in various cognitive domains, including immediate and visual memory, delayed memory, prospective memory, and visual-motor and spatial skills (Holmes 1984, Wirsén 1992, Draelos 1995, Ewing 1998, Sommerfield 2003, Amiel 2009). There has been concern that frequent episodes of SH may also have long-term negative effects on the brain and cognitive function; however, research in this area has produced mixed results (Wredling 1990, Perros 1997, Deary 2003, Hershey 2003, DCCT Research Group 2007). These equivocal findings may be in part due to sample differences in the age of diabetes onset. Studies examining associations between SH and its impact on cognitive functioning and other development processes have shown that SH may have a more damaging effect on the developing brain in young children with T1D than in older children or adults. Children and adolescents diagnosed with T1D before the age of 5 or 6 years exhibit poorer cognitive function compared with those diagnosed later in life (Ryan 1985, Ryan 1988, Bjørgaas 1996; also see Chapter 5). For older people with T2D, there is increasing evidence to suggest that occurrence of SH is associated with a greater subsequent risk of dementia (Whitmer 2009), but this may be a result of a combination of factors, including chronic hyperglycemia and hypoglycemia (Strachan 2011).

      Recurrent hypoglycemia and SH can also have negative impact on psychosocial functioning, health status, and overall quality of life in both individuals with diabetes and their significant others (Gold 1994, Gonder-Frederick 1997a, Davis 2005, Leiter 2005, Nordfeldt 2005a, Laiteerapong 2011, Pettersson 2011, Williams 2011). In adults with diabetes, there is evidence that ongoing problems with SH are associated with chronic mood changes, reduced happiness and energy levels, and feelings of helplessness, anxiety, and depression, and they can be a risk factor for affective disorders (Gold 1997, Strachan 2000, Hermanns 2003, Hermanns 2005). Treatment and management of SH can also pose a significant economic burden for patients and the health care system in terms of health care expenses and indirect costs due to decreased productivity (DCCT Research Group 1995, Lundkvist 2005, Reviriego 2008).

      Unpleasant symptoms and experiences related to hypoglycemia can cause considerable anxiety in patients with diabetes and their significant others, which may lead to fear of hypoglycemia (FOH) (Myers 2007, Wild 2007, Gonder-Frederick 2011). High levels of FOH can impair quality of life in families of children with T1D (Nordfeldt 2005b, Jaser 2009, Haugstvedt 2010), and parents can exhibit particularly high levels of fear when their children have experienced seizures or comas (Clarke 1998). High FOH may adversely impact glycemic control in children with T1D, as parents may encourage higher BG levels than clinically desirable to avoid future occurrences (Barnard 2010; also see Chapter 14). In spouses and partners of patients who experience recurrent SH, there are not only higher levels of FOH but also more sleep disturbances (due to anxiety about nocturnal hypoglycemia) and reported marital conflict (Gonder-Frederick 1997a, Stahl 1998, Jørgensen 2003). Although numerous studies have investigated FOH, it has been difficult to empirically document its impact on diabetes management (Wild 2007). However, there is some scientific evidence, and much clinical evidence,

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