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DEFINITION

• Low blood sugar (<70 mg/dL,[3.9mmol/l]) during sleep
• Suspected if symptoms occur but low blood glucose not documented, definite if symptoms occur and low blood glucose documented, severe if assistance of another person is needed. 

EPIDEMIOLOGY

• In the Diabetes Control and Complications Trial (DCCT), 43% of all hypoglycemic episodes and 55% of severe episodes occurred during sleep.
• Also in DCCT, severe hypoglycemic episodes were three times more likely in patients on intensive insulin therapy than in those on conventional therapy.
• Common, especially in patients with type 1 diabetes, when blood glucose is most variable (Yale).
• Often episodes occur without symptoms and go unrecognized; majority of episodes in type 1 diabetes occur during late sleep (3am-7 am) (Amin).

DIAGNOSIS

• Risk factors include: slow clearance of insulin or oral antihyperglycemic agents (e.g.: liver or kidney disease); use of intermediate-acting (NPH) insulin at suppertime; missed meal; unplanned exercise; alcohol; infection; decreased gluconeogenic substrate (e.g. from cachexia); long-acting sulfonylureas, insulin, or insulin combined with oral antihyperglycemic agents; history of hypoglycemia, hypoglycemia unawareness, or both; age.
• Most convincingly diagnosed if Whipple's triad documented: symptoms compatible with hypoglycemia, low blood glucose concentration recorded, and resolution of these symptoms after correcting blood glucose.

SIGNS AND SYMPTOMS

• Signs: pallor and diaphoresis; increased heart rate and systolic blood pressure; hypothermia; in severe episodes, unarousable, transient focal neurological deficits (e.g. diplopia, hemiparesis), or seizures. Partner may note altered breathing, irritable sleep.
• Symptoms: episodes range from asymptomatic to severe; can, rarely, be fatal. Patients often awaken due to bad dreams, sweating.
• Neurogenic symptoms: adrenergic (catecholamine mediated)- tremulousness, palpitations, and anxiety/arousal; cholinergic - sweating, hunger, and paresthesias
• May be asymptomatic, due to hypoglycemia unawareness, or because cognition is suppressed during sleep.

CLINICAL TREATMENT

• Key to treatment is early recognition.
• DO NOT ADMINISTER ANYTHING BY MOUTH (SUCH AS JUICE) IF THE PATIENT CANNOT SIT UP AND EAT/DRINK. THIS MAY CAUSE ASPIRATION.
• In awake individual, prefer 15-20 grams of fast-acting carbohydrate (eg, glucose-containing drink, cookies, candy, glucose tablets).
• Repeat self-monitored blood glucose in 15-20 min if symptoms not improved or the monitored blood glucose remains low.
• Since glycemic response to oral glucose is transient ( <2 h), eat snack or meal shortly after plasma glucose concentration is raised.
• Avoid foods high in fat, which delay glucose absorption.
• Intramuscular glucagon (1 mg) administration (may be administered by a non-professional) or intravenous glucose (25 cc of 50% dextrose, administered by a health care professional) is required if the patient is unable to sit up and drink liquid.
• Nausea and vomiting are common side effects of glucagon.
• For hospitalized patients, document absence of nocturnal hypoglycemia before patient discharged.

FOLLOW UP

• Change treatment regimen in order to prevent subsequent episodes of nocturnal hypoglycemia, reducing nighttime dose of insulin or oral hypoglycemic agent, or instituting a small bedtime snack.
• Provide education to patient and family about risks and risk-reduction strategies.
• Plan meals and exercise carefully.
• Avoid NPH insulin at suppertime, or short/fast-acting insulin at bedtime, as insulin levels will peak during sleep.
• Use fast-acting insulin analogs (instead of regular insulin) at dinnertime
• If insulin administered at bedtime, long-acting insulin preferred
• Try moving long-acting insulin analog to morning, instead of bedtime, if nocturnal hypoglycemia persists.
• Avoid excess alcohol intake.
• Carefully and consistently perform self monitoring blood glucose (SMBG), including in middle of night to avoid nocturnal hypoglycemia.
• Reinforce that a change in routine (e.g. change in time zone, holidays, vacation) may increase risk for nocturnal hypoglycemia.
• Continuous glucose monitoring may be useful for patients with hypoglycemic unawareness and frequent nocturnal hypoglycemia.

EXPERT COMMENTS

• Nocturnal hypoglycemia remains significant barrier to intensive therapy needed to avoid long-term complications of diabetes.
• Though rarely fatal, it accounted for half of all unexpected deaths of people with type 1 diabetes in a study from the United Kingdom (Tattersall). Should therefore be taken seriously.
• Frequent episodes of nocturnal hypoglycemia can exacerbate hypoglycemia unawareness.
• Choosing a more carefully fine-tuned insulin regimen or use of an insulin pump can lower nocturnal hypoglycemia risk without compromising glycemic control.
• Though often called the "Somogyi phenomenon", nocturnal hypoglycemia is not a cause of morning or subsequent day hyperglycemia (unless over treated) (Tordjiman, Hirsch).
• A common vicious cycle, however, is to become hypoglycemic at night, over-treat the hypoglycemia, and start the day hyperglycemic. 

REFERENCES