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Hypoglycemia

      Key Messages
      • It is important to prevent, recognize and treat hypoglycemic episodes secondary to the use of insulin or insulin secretagogues.
      • The goals of treatment for hypoglycemia are to detect and treat a low blood glucose (BG) level promptly by using an intervention that provides the fastest rise in BG to a safe level, to eliminate the risk of injury and to relieve symptoms quickly.
      • It is important to avoid overtreatment, since this can result in rebound hyperglycemia and weight gain.

      Introduction

      Drug-induced hypoglycemia is a major obstacle for individuals trying to achieve glycemic targets. Hypoglycemia can be severe and result in confusion, coma or seizure, requiring the assistance of other individuals. Significant risk of hypoglycemia often necessitates less stringent glycemic goals. Frequency and severity of hypoglycemia negatively impact on quality of life (
      • Alvarez-Guisasola F.
      • Yin D.D.
      • Nocea G.
      • et al.
      Association of hypoglycemic symptoms with patients' rating of their health-related quality of life state: A cross sectional study.
      ) and promote fear of future hypoglycemia (
      • Anderbro T.
      • Amsberg S.
      • Adamson U.
      • et al.
      Fear of hypoglycaemia in adults with Type 1 diabetes.
      ,
      • Belendez M.
      • Hernandez-Mijares A.
      Beliefs about insulin as a predictor of fear of hypoglycaemia.
      ). This fear is associated with reduced self-care and poor glucose control (
      • Barnard K.
      • Thomas S.
      • Royle P.
      • et al.
      Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review.
      ,
      • Di Battista A.M.
      • Hart T.A.
      • Greco L.
      • Gloizer J.
      Type 1 diabetes among adolescents: reduced diabetes self-care caused by social fear and fear of hypoglycemia.
      ,
      • Haugstvedt A.
      • Wentzel-Larsen T.
      • Graue M.
      • et al.
      Fear of hypoglycaemia in mothers and fathers of children with Type 1 diabetes is associated with poor glycaemic control and parental emotional distress: a population-based study.
      ). As such, it is important to prevent, recognize and treat hypoglycemic episodes secondary to the use of insulin or insulin secretagogues (see Pharmacotherapy in Type 1 Diabetes, p. S56, and Pharmacologic Management of Type 2 Diabetes, p. S61, for further discussion of drug-induced hypoglycemia).

      Definition of Hypoglycemia

      Hypoglycemia is defined by 1) the development of autonomic or neuroglycopenic symptoms (Table 1); 2) a low plasma glucose level (<4.0 mmol/L for patients treated with insulin or an insulin secretagogue); and 3) symptoms responding to the administration of carbohydrate (
      • Hepburn D.A.
      Symptoms of hypoglycaemia.
      ). The severity of hypoglycemia is defined by clinical manifestations (Table 2).
      Table 1Symptoms of hypoglycemia
      Neurogenic (autonomic)Neuroglycopenic
      Trembling

      Palpitations

      Sweating

      Anxiety

      Hunger

      Nausea

      Tingling
      Difficulty concentrating

      Confusion

      Weakness

      Drowsiness

      Vision changes

      Difficulty speaking

      Headache

      Dizziness
      Table 2Severity of hypoglycemia
      Mild: Autonomic symptoms are present. The individual is able to self-treat.

      Moderate: Autonomic and neuroglycopenic symptoms are present. The individual is able to self-treat.

      Severe: Individual requires assistance of another person.

      Unconsciousness may occur. PG is typically <2.8 mmol/L.
      PG, plasma glucose.

      Complications of Severe Hypoglycemia

      Short-term risks of hypoglycemia include the dangerous situations that can arise while an individual is hypoglycemic, whether at home or at work (e.g. driving, operating machinery). In addition, prolonged coma is sometimes associated with transient neurological symptoms, such as paresis, convulsions and encephalopathy. The potential long-term complications of severe hypoglycemia are mild intellectual impairment and permanent neurologic sequelae, such as hemiparesis and pontine dysfunction. The latter are rare and have been reported only in case studies.
      Recurrent hypoglycemia may impair the individual's ability to sense subsequent hypoglycemia (
      • Davis S.N.
      • Mann S.
      • Briscoe V.J.
      • et al.
      Effects of intensive therapy and antecedent hypoglycemia on counterregulatory responses to hypoglycemia in type 2 diabetes.
      ,
      • Tsalikian E.
      • Tamborlane W.
      • Xing D.
      • et al.
      Diabetes Research in Children Network (DirecNet) Study Group
      Blunted counterregulatory hormone responses to hypoglycemia in young children and adolescents with well-controlled type 1 diabetes.
      ). The neurohormonal counterregulatory responses to hypoglycemia may become blunted; however, this is potentially reversible (see Pharmacotherapy in Type 1 Diabetes, p. S56).
      Retrospective studies have suggested a link between frequent severe hypoglycemia (≥5 episodes since diagnosis) and a decrease in intellectual performance. These changes were small but, depending on an individual’s occupation, could be clinically meaningful. Prospective studies in type 1 diabetes have not found an association between intensive insulin therapy and cognitive function (
      The Diabetes Control and Complications Trial Research Group
      Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial.
      ,
      • Reichard P.
      • Pihl M.
      Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study.
      ,
      • Jacobson A.M.
      • Musen G.
      • Ryan C.M.
      • et al.
      Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group
      Long-term effect of diabetes and its treatment on cognitive function.
      ). A meta-analysis concluded that lowered cognitive performance in people with type 1 diabetes appeared to be associated with the presence of microvascular complications but not with the occurrence of severe hypoglycemic episodes or with poor metabolic control (
      • Brands A.M.
      • Biessels G.J.
      • de Haan E.H.
      • et al.
      The effects of type1 diabetes on cognitive performance: a meta-analysis.
      ). Unlike patients with type 1 diabetes, those with type 2 diabetes and previous severe hypoglycemia requiring presentation to the hospital have increased risk of subsequent dementia (
      • Whitmer R.A.
      • Karter A.J.
      • Yaffe K.
      • et al.
      Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
      ).
      In patients with type 2 diabetes and established, or very high risk for, cardiovascular disease, symptomatic hypoglycemia (<2.8 mmol/L) is associated with increased mortality (
      • Bonds D.E.
      • Miller M.E.
      • Bergenstal R.M.
      • et al.
      The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.
      ). The mechanism for this increase is not certain; however, acute hypoglycemia is proinflammatory (
      • Wright R.J.
      • Newby D.E.
      • Stirling D.
      • et al.
      Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.
      ) and may affect cardiac conduction (depolarization, QT prolongation). This effect, however, may be related to sympathetic tone rather than glucose per se (
      • Koivikko M.L.
      • Karsikas M.
      • Salmela P.I.
      • et al.
      Effects of controlled hypoglycaemia on cardiac repolarisation in patients with type 1 diabetes.
      ,
      • Kubiak T.
      • Wittig A.
      • Koll C.
      • et al.
      Continuous glucose monitoring reveals associations of glucose levels with QT interval length.
      ).
      The major risk factors for severe hypoglycemia in patients with type 1 diabetes include prior episode of severe hypoglycemia (
      The Diabetes Control and Complications Trial Research Group
      Adverse events and their association with treatment regimens in the Diabetes Control and Complications Trial.
      ,
      The Diabetes Control and Complications Trial Research Group
      Hypoglycemia in the Diabetes Control and Complications Trial.
      ,
      • Mühlhauser I.
      • Overmann H.
      • Bender R.
      • et al.
      Risk factors of severe hypoglycaemia in adult patients with type I diabetes: a prospective population based study.
      ), current low glycated hemoglobin (A1C) (<6.0%) (
      The Diabetes Control and Complications Trial Research Group
      Hypoglycemia in the Diabetes Control and Complications Trial.
      ,
      The DCCT Research Group
      Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial.
      ,
      • Davis E.A.
      • Keating B.
      • Byrne G.C.
      • et al.
      Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM.
      ,
      • Egger M.
      • Davey Smith G.
      • Stettler C.
      • et al.
      Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis.
      ), hypoglycemia unawareness (
      • Gold A.E.
      • MacLeod K.M.
      • Frier B.M.
      Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia.
      ), long duration of diabetes (
      • Davis E.A.
      • Keating B.
      • Byrne G.C.
      • et al.
      Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM.
      ,
      • Mokan M.
      • Mitrakou A.
      • Veneman T.
      • et al.
      Hypoglycemia unawareness in IDDM.
      ), autonomic neuropathy (
      • Meyer C.
      • Grossmann R.
      • Mitrakou A.
      • et al.
      Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients.
      ), adolescence (
      Diabetes Control and Complications Trial Research Group
      Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial.
      ) and preschool-age children unable to detect and/or treat mild hypoglycemia on their own. Risk factors for hypoglycemia in patients with type 2 diabetes include advancing age (
      • Miller M.E.
      • Bonds D.E.
      • Gerstein H.C.
      • et al.
      The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study.
      ), severe cognitive impairment (
      • de Galan B.E.
      • Zoungas S.
      • Chalmers J.
      • et al.
      Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.
      ), poor health literacy (
      • Sarkar U.
      • Karter A.J.
      • Liu J.Y.
      • et al.
      Hypoglycemia is more common among type 2 diabetes patients with limited health literacy: the Diabetes Study of Northern California (DISTANCE).
      ), food insecurity (
      • Seligman H.K.
      • Davis T.C.
      • Schillinger D.
      • Wolf M.S.
      Food insecurity is associated with hypoglycemia and poor diabetes self-management in a low-income sample with diabetes.
      ), increased A1C (
      • Miller M.E.
      • Bonds D.E.
      • Gerstein H.C.
      • et al.
      The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study.
      ,
      • Davis T.M.
      • Brown S.G.
      • Jacobs I.G.
      • et al.
      Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.
      ), hypoglycemia unawareness (
      • Schopman J.E.
      • Geddes J.
      • Frier B.M.
      Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes.
      ), duration of insulin therapy, renal impairment and neuropathy (
      • Davis T.M.
      • Brown S.G.
      • Jacobs I.G.
      • et al.
      Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.
      ). In patients with type 2 diabetes and established cardiovascular disease (CVD) or age >54 years and 2 CVD risk factors, the risk of hypoglycemia is also increased by female gender (
      • Miller M.E.
      • Bonds D.E.
      • Gerstein H.C.
      • et al.
      The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study.
      ). Patients at high risk for severe hypoglycemia should be informed of their risk and counselled, along with their significant others, on preventing and treating hypoglycemia (including use of glucagon), preventing driving and industrial accidents through self-monitoring of blood glucose (BG) and taking appropriate precautions prior to the activity, and documenting BG readings taken during sleeping hours. Individuals may need to have their insulin regimen adjusted appropriately to lower their risk. Risk factors for severe hypoglycemia are listed in Table 3.
      Table 3Risk factors for severe hypoglycemia
      • Prior episode of severe hypoglycemia
      • Current low A1C (<6.0%)
      • Hypoglycemia unawareness
      • Long duration of insulin therapy
      • Autonomic neuropathy
      • Low economic status
      • Food insecurity
      • Low health literacy
      • Cognitive impairment
      • Adolescence
      • Preschool-age children unable to detect and/or treat mild hypoglycemia on their own
      A1C, glycated hemoglobin.

      Treatment of Hypoglycemia

      The goals of treatment for hypoglycemia are to detect and treat a low BG level promptly by using an intervention that provides the fastest rise in BG to a safe level, to eliminate the risk of injury and to relieve symptoms quickly. It is also important to avoid overtreatment since this can result in rebound hyperglycemia and weight gain.
      Evidence suggests that 15 g glucose (monosaccharide) is required to produce an increase in BG of approximately 2.1 mmol/L within 20 minutes, with adequate symptom relief for most people (Table 4) (
      • Slama G.
      • Traynard P.Y.
      • Desplanque N.
      • et al.
      The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions.
      ,
      • Wiethop B.V.
      • Cryer P.E.
      Alanine and terbutaline in treatment of hypoglycemia in IDDM.
      ,
      • Brodows R.G.
      • Williams C.
      • Amatruda J.M.
      Treatment of insulin reactions in diabetics.
      ,
      Special problems.
      ,
      Canadian Diabetes Association
      The role of dietary sugars in diabetes mellitus.
      ). This has not been well studied in patients with gastropathy. A 20 g oral glucose dose will produce a BG increment of approximately 3.6 mmol/L at 45 minutes (
      • Wiethop B.V.
      • Cryer P.E.
      Alanine and terbutaline in treatment of hypoglycemia in IDDM.
      ,
      • Brodows R.G.
      • Williams C.
      • Amatruda J.M.
      Treatment of insulin reactions in diabetics.
      ). Other choices, such as milk and orange juice, are slower to increase BG levels and provide symptom relief (
      • Wiethop B.V.
      • Cryer P.E.
      Alanine and terbutaline in treatment of hypoglycemia in IDDM.
      ,
      • Brodows R.G.
      • Williams C.
      • Amatruda J.M.
      Treatment of insulin reactions in diabetics.
      ). Glucose gel is quite slow (<1.0 mmol/L increase at 20 minutes) and must be swallowed to have a significant effect (
      • Slama G.
      • Traynard P.Y.
      • Desplanque N.
      • et al.
      The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions.
      ,
      • Gunning R.R.
      • Garber A.J.
      Bioactivity of instant glucose. Failure of absorption through oral mucosa.
      ). Patients taking an alpha-glucosidase inhibitor (acarbose) must use glucose (dextrose) tablets (
      ) or, if unavailable, milk or honey to treat hypoglycemia. Glucagon 1 mg given subcutaneously or intramuscularly produces a significant increase in BG (from 3.0 to 12.0 mmol/L) within 60 minutes (
      • Cryer P.E.
      • Fisher J.N.
      • Shamoon H.
      ). The effect is impaired in individuals who have consumed more than 2 standard alcoholic drinks in the previous few hours or in those who have advanced hepatic disease (
      ,
      ).
      Table 4Examples of 15 g carbohydrate for treatment of mild to moderate hypoglycemia
      • 15 g glucose in the form of glucose tablets
      • 15 mL (3 teaspoons) or 3 packets of table sugar dissolved in water
      • 175 mL (3/4 cup) of juice or regular soft drink
      • 6 LifeSavers (1 = 2.5 g carbohydrate)
      • 15 mL (1 tablespoon) of honey

      Hypoglycemia and driving

      Individuals with diabetes are a heterogenous group, and the risk of motor vehicle accidents and driving violations may be only slightly increased or markedly increased (relative risk [RR] 1.04 to 3.24) (
      • Kagan A.
      • Hashemi G.
      • Korner-Bitensky N.
      Diabetes and fitness to drive: a systematic review of the evidence with a focus on older drivers.
      ). Factors include age, level of A1C, degree of hypoglycemic awareness, miles driven, presence of complications and many others.
      Advances in treatment, medical technology and self-monitoring have increased the ability of patients with diabetes to control their disease and operate a motor vehicle safely. The fitness of these patients to drive must be assessed on an individual basis. Individuals with diabetes should be encouraged to take an active role in assessing their ability to drive. Patients should have information concerning avoidance, recognition and appropriate therapeutic intervention for hypoglycemia. Drivers with diabetes should be assessed for possible complications, including eye disease, neuropathy (autonomic, sensory, motor), renal disease and cardiovascular disease. In general, a patient is considered fit to drive if he or she is medically fit, is knowledgeable about controlling BG levels and is able to avoid severe hypoglycemic episodes.
      Recommendations
      • 1.
        Mild to moderate hypoglycemia should be treated by the oral ingestion of 15 g carbohydrate, preferably as glucose or sucrose tablets or solution. These are preferable to orange juice and glucose gels [Grade B, Level 2 (
        • Slama G.
        • Traynard P.Y.
        • Desplanque N.
        • et al.
        The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions.
        )]. Patients should retest BG in 15 minutes and re-treat with another 15 g carbohydrate if the BG level remains <4.0 mmol/L [Grade D, Consensus]. Note: This does not apply to children. See Type 1 Diabetes in Children and Adolescents, p. S153, and Type 2 Diabetes in Children and Adolescents, p. S163, for treatment options in children.
      • 2.
        Severe hypoglycemia in a conscious person should be treated by oral ingestion of 20 g carbohydrate, preferably as glucose tablets or equivalent. BG should be retested in 15 minutes and then re-treated with another 15 g glucose if the BG level remains <4.0 mmol/L [Grade D, Consensus].
      • 3.
        Severe hypoglycemia in an unconscious individual
        • a.
          With no IV access: 1 mg glucagon should be given subcutaneously or intramuscularly. Caregivers or support persons should call for emergency services and the episode should be discussed with the diabetes healthcare team as soon as possible [Grade D, Consensus].
        • b.
          With IV access: 10–25 g (20–50 cc of D50W) of glucose should be given intravenously over 1–3 minutes [Grade D, Consensus].
      • 4.
        For individuals at risk of severe hypoglycemia, support persons should be taught how to administer glucagon by injection [Grade D, Consensus].
      • 5.
        Once the hypoglycemia has been reversed, the person should have the usual meal or snack that is due at that time of the day to prevent repeated hypoglycemia. If a meal is >1 hour away, a snack (including 15 g carbohydrate and a protein source) should be consumed [Grade D, Consensus].
      • 6.
        Patients receiving antihyperglycemic agents that may cause hypoglycemia should be counselled about strategies for prevention, recognition and treatment of hypoglycemia related to driving and be made aware of provincial driving regulations [Grade D, Consensus].
      • Abbreviation:
        BG, blood glucose.

      Other Relevant Guidelines

      Related Website

      Begg IS, Yale J-F, Houlden RL, et al. Canadian Diabetes Association’s clinical practice guidelines for diabetes and private and commercial driving. Can J Diabetes. 2003;27:128–140. Available at: http://www.diabetes.ca/files/DrivingGuidelinesBeggJune03.pdf. Accessed April 30, 2012.

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