Hypoglycemia

Hypoglycemia, or low blood sugar, has a variety of causes, but most often occurs as a result of insulin therapy or other medications in patients with diabetes. Although hypoglycemic symptoms can appear when blood glucose is < 70 mg/dL, its onset depends largely on individual physiological adaptation mechanisms. Hypoglycemia manifests with autonomic symptoms such as hunger, sweating, and tachycardia, as well as neuroglycopenic symptoms such as confusion, behavioral changes, and somnolence. A change in a patient's mental status should prompt immediate fingerstick blood glucose measurement and treatment if needed, as prolonged hypoglycemia can potentially cause acute brain damage. Glucose is the preferred treatment. Patients who are conscious should receive a fast-acting carbohydrate such as glucose tablets, candy, or fruit juice. Intravenous dextrose or intramuscular glucagon is administered to unresponsive patients.

The following is consistent with the 2021 American Diabetes Association guidance. ^[1]

• Hypoglycemia in patients with diabetes: generally described as ≤ 70 mg/dL (≤ 3.9 mmol/L) ^[1][2]
  • Level 1: blood glucose level of 54–70 mg/dL
  • Level 2: blood glucose level < 54 mg/dL
  • Level 3: hypoglycemia episode with altered mental status or physical impairment requiring assistance to treat
• Hypoglycemia in patients without diabetes: blood glucose level < 55 mg/dL with symptoms of hypoglycemia ^[3]
• Whipple triad: helps to confirm the diagnosis of hypoglycemia ^[4][5]
  • Low blood glucose levels
  • Signs or symptoms consistent with hypoglycemia (see “Clinical features”)
  • Relief of symptoms when blood glucose increases after treatment

Diabetic patients ^[5][6]

In patients with diabetes who present with hypoglycemia in the absence of medication changes, consider another underlying condition, e.g., acute infection or decreased drug metabolism or drug excretion secondary to new-onset organ impairment. ^[11]

(Relative) overdose of insulin or a noninsulin drug is by far the most common cause of hypoglycemia.

Consider factitious disorder in patients with access to insulin and other diabetes medications (e.g., healthcare professionals), for whom there is no other obvious explanation for hypoglycemia.

Nondiabetic patients ^[5][6]

Older patients are at risk of developing hypoglycemia regardless of diabetes status, and they are at increased risk of adverse outcomes resulting from hypoglycemic episodes. ^[13]

Threshold for symptoms

• Varies greatly; , but most adults become symptomatic when blood glucose level is less than approx. 50 mg/dL (2.8 mmol/L)
• The threshold at which symptoms may appear in patients with chronic diabetes is especially variable due to hypoglycemia-associated autonomic failure (HAAF). ^[4]
  • Recurrent hypoglycemia → changes in the counterregulatory response (e.g., decreased epinephrine release) → lower glucose threshold needed to trigger symptoms → asymptomatic hypoglycemia
  • For this reason, the initial symptom of hypoglycemia in patients with HAAF is often confusion.
• The threshold can also vary due to medication: Beta blockers can mask signs of hypoglycemia.

Educating patients about hypoglycemia unawareness can help them to recognize the onset of autonomic symptoms and minimize the risk of severe hypoglycemia.

Signs and symptoms

• Neurogenic/autonomic
  • Increased sympathetic activity: tremor, pallor, anxiety, tachycardia, sweating, and palpitations
  • Increased parasympathetic activity: hunger, paresthesias, nausea, and vomiting
• Neuroglycopenic
  • Agitation, confusion, behavioral changes
  • Fatigue
  • Seizure, focal neurological signs
  • Somnolence → obtundation → stupor → coma → death

Beta blockers can mask signs of hypoglycemia.

Hypoglycemia is rare in patients without diabetes and should prompt investigation for an underlying hypoglycemic disorder. ^[5]

In unstable patients with suspected hypoglycemia, obtain POC glucose and treat symptomatic patients without delay.

Initial management ^{[2][5][14][15]}

The following interventions are typically performed simultaneously in clinical practice.

• ABCDE survey
  • Consider airway protection in patients with signs of airway compromise (e.g., reduced GCS) and provide respiratory support, e.g., oxygen therapy, as needed.
  • Obtain IV access and initiate immediate hemodynamic support if necessary.
  • Check POC glucose routinely for patients with unexplained altered mental status or other clinical features of hypoglycemia.
• Administer dextrose: See “Treatment of hypoglycemia” for details.
  • Altered mental status: 50% dextrose IV bolus OR IM glucagon if no IV access is available
  • Alert and oriented patients: Give oral glucose.
• Initial clinical and diagnostic evaluation ^[2][14][16]
  • Obtain routine blood tests (e.g., CBC, BMP, LFTs) and consider septic workup.
  • Screen for conditions predisposing to hypoglycemia and drugs that cause hypoglycemia.
  • See “Diagnostics” for further investigations (e.g., if the diagnosis is uncertain, workup of nondiabetic hypoglycemic disorders).

Treat suspected severe hypoglycemia immediately, without waiting for the results of blood glucose testing!

Subsequent management

• Monitoring
  • Recheck POC glucose after 15 minutes and monitor every 30 minutes for the first 2 hours to check for rebound hypoglycemia. ^[11][14]
  • Observe patients with known or suspected ingestion of hypoglycemic agents for 24 hours. ^[2]
• Maintenance therapy: Maintain serum glucose level > 100 mg/dL. ^[11]
  • Oral intake of long-acting carbohydrates if the patient is conscious and able to tolerate oral intake
  • Consider dextrose infusions (D5NS or 10% dextrose in 0.9% saline) to maintain euglycemia in patients with recurrent or refractory hypoglycemia.
• Supportive care
  • Identify and treat the underlying cause.
  • Consider seizure and aspiration precautions.
  • Consider adjunctive treatment of hypoglycemia, e.g., thiamine, octreotide, as needed.

If there is an inadequate response to parenteral glucose treatment, consider other causes of hypoglycemia, e.g., sepsis, toxin ingestion, hepatic failure, or adrenal insufficiency.

Disposition ^[2][11][14]

Disposition is variable and depends on multiple factors, e.g., the response to treatment, presence of comorbidities, the cause of hypoglycemia, and other patient factors such as social determinants of health. Follow local protocols and consult a specialist when available.

• Admission
  • Consider ICU admission with hourly glucose monitoring if hypoglycemia is refractory.
  • Consider ward admission for patients with any of the following:
    • Hypoglycemia secondary to sulfonylurea and long-acting insulin overdose
    • Neuroglycopenic symptoms that do not rapidly improve with glucose treatment
    • Outpatient workup to diagnose the underlying cause of hypoglycemia in nondiabetic patients is not feasible.
    • Inability to tolerate oral food or liquid intake
    • Intentional overdose with insulin or sulfonylurea
• Discharge (after an uneventful 4-hour monitoring period)
  • Consider discharge home for reliable patients who have social support and any of the following clinical syndromes:
    • Type 1 diabetes mellitus with a short episode of hypoglycemia
    • An isolated episode of unintentional hypoglycemia
  • Discharge planning
    • Educate patients on prescribed medications, self-monitoring, patient safety measures , and reasons to return to seek care, e.g., recurrent symptoms of hypoglycemia. ^[17]
    • Ensure follow-up with primary care provider or clinical diabetes specialist as needed.

Approach

• Confirm low blood glucose (via fingerstick or BMP) and check for Whipple triad.
• Investigate any acute illness as a cause (e.g., infection, sepsis, burns).
• Review medications (see “Drugs that cause hypoglycemia”).
• Perform diagnostic workup based on the leading differential diagnosis and whether the patient has diabetes.

Further workup for hypoglycemia is usually only indicated if all features of the Whipple triad are present. ^[16]

Do not delay treatment of symptomatic hypoglycemia in favor of formally testing for blood glucose levels (see “Management”).

Patients with diabetes ^[4]

• Hypoglycemia in diabetic patients is almost always due to acute illness and/or medications (e.g., insulin) and further workup is generally not indicated.
• Initial workup if no obvious trigger is identified:
  • Routine laboratory studies: CBC, BMP, liver chemistries
  • Septic workup as directed by clinical suspicion: e.g., CXR, urinalysis, blood cultures
  • Consider sulfonylurea and exogenous insulin levels.

Patients without diabetes ^[5]

• Rule out acute illness and medication as a cause.
• Further diagnostic testing should only be pursued if the cause is not evident based on history and examination (and with the guidance of an endocrinologist).
• The goal is to determine if the hypoglycemia is due to hyperinsulinemia (e.g., insulinoma).

Laboratory studies

• The following labs should be obtained during a hypoglycemic episode (or 72-hour fast if no spontaneous hypoglycemic episode is documented):
  • Insulin antibodies
  • Sulfonylurea level (and any other oral antidiabetic agents)
  • β-hydroxybutyrate
  • Proinsulin
  • C-peptide
  • Glucose
  • Insulin
• Glucagon tolerance test (see “Glucagon tolerance test”)
• Consider also: anti-insulin receptor antibodies, IGF-1/IGF-2, cortisol, glucagon, growth hormone

72-hour fast ^[5]

• Procedure: The patient fasts for 72 hours, only drinking noncaloric beverages, and all nonessential medications are discontinued.
  • Measure insulin, C-peptide, and glucose every 4–6 hours.
  • Once blood glucose < 45 mg/dL or < 55 mg/dL with documented Whipple triad, obtain serum studies (see “Laboratory studies” above).
  • After serum studies have been obtained, continue with a glucagon tolerance test and end the fast.
  • This should be done on an inpatient basis and under the guidance of an endocrinologist.
• Limitations
  • Results may be inaccurate if the physiological glucose level is low.
  • Rarely, insulinomas may suppress insulin release in response to hypoglycemia.
  • Insulin levels can be artificially elevated in the presence of circulating anti-insulin antibodies.

The 72-hour fast is only necessary if a spontaneous hypoglycemic episode does not occur.

Glucagon tolerance test

• Procedure
  • After the 72-hour fast has ended, inject glucagon.
  • Measure serum glucose and insulin at baseline, then at 10, 20, and 30 minutes after glucagon injection.
• Normal response: rapid insulin response, up to 100 uU/mL; glucose peak at 20–30 minutes
• Insulinoma patients: exaggerated insulin response (exceeding 160 uU/mL); peak insulin at 15 minutes
• Limitations
  • Unreliable in patients with malnutrition, hepatic disease, and cirrhosis with portocaval anastomosis
  • Medication interference: diazoxide, hydrochlorothiazide, diphenylhydantoin, sulfonylureas, aminophylline
  • Patients with nonislet cell tumors can have insulinoma-like responses.
  • The glucagon tolerance test can induce nausea, vomiting, and hypoglycemia.
  • In 8% of insulinomas, the expected peak is not observed.

Interpreting the results of fasting labs and the glucagon tolerance test ^[4][5]

Nonsuppressed serum insulin concentrations with decreased serum C-peptide and proinsulin concentrations are consistent with exogenous insulin use.

Imaging

• Indications: labs consistent with endogenous hyperinsulinism (e.g., insulinoma) ^[18]
• Usually, combined imaging is required to confirm the diagnosis of insulinoma (CT scan and MRI )

The differential diagnosis of hypoglycemia is broad because of nonspecific symptoms, and the condition may be diagnosed incorrectly as a neurological, psychiatric, or cardiovascular disorder. ^[11]

• Differential diagnoses for hypoglycemia with altered mental status
  • Primary CNS: stroke, TIA, seizure disorder, tumor, cerebral edema, TBI, dementia
  • Psychiatric: depression, anxiety, psychosis, delirium
  • Metabolic/autoregulatory: hypoxia, endocrine derangements, electrolyte abnormalities, shock
  • Infectious: sepsis, meningitis, encephalitis
  • Pharmacological or toxin-related
    • Medication side effects
    • Substance intoxication
    • Withdrawal (see “Overview of substance intoxication and withdrawal”)
    • Poisoning
• Differential diagnoses for hypoglycemia with increased sympathetic activity (e.g., tachycardia)
  • Cardiac: arrhythmia, ischemia
  • Pulmonary: pulmonary embolism, pneumothorax
  • Psychiatric: panic disorder
  • Metabolic/autoregulatory: hyperthyroidism, thyroid storm, dehydration, shock
  • Infectious: active infection, sepsis
  • Pharmacological or toxin-related: cocaine, amphetamine, alcohol intoxication, or withdrawal
  • Pain

Always consider hypoglycemia in the differential diagnosis of altered mental status.

The differential diagnoses listed here are not exhaustive.

Reversing hypoglycemia

Monitor patients regularly for rebound hypoglycemia after treatment.

• Alert and oriented patients
  • Oral glucose 15–20 g ^[14]
  • Fast-acting carbohydrates (e.g., glucose tablets, candy, or fruit juice) ^[14]
• Patients with altered mental status (or impaired oral intake) ^[5]
  • IV dextrose (e.g., D50W): Repeat after 15 minutes if hypoglycemia persists; multiple doses may be required. ^[11][14]
    • Adults: 50% dextrose
    • Children (excluding neonates): 10% dextrose OR 25% dextrose ^[19][20]
  • IM glucagon: if neither oral nor IV routes of administering glucose are feasible ^[14]

For patients with type 1 diabetes presenting with hypoglycemia and using insulin pumps, do not discontinue insulin pumps and treat hypoglycemia as usual. Removing the insulin pump puts patients at risk for diabetic ketoacidosis. ^[11]

Avoid giving orange juice to patients with CKD on a low-potassium diet as it is high in potassium. ^[14]

Adjunctive therapy

• Chronic alcohol dependence and/or malnourishment: Consider IV thiamine. ^[2][15]
• Sulfonylurea toxicity: consider administering octreotide under the guidance of endocrinology to inhibit endogenous insulin release. ^[11]

Treatment of the underlying causes

• Diabetes mellitus: See “Diabetes management” and “Insulin therapy.”
• Other critical illnesses
  • See “Sepsis management.”
  • See “Adrenal crisis.”
  • See “Management of acute liver failure.”
  • See “Myxedema coma.”

• Treat suspected hypoglycemia with oral glucose, IV dextrose, or IM glucagon.
• Confirm hypoglycemia (BMP or POC glucose).
• Recheck glucose after 15 minutes and repeat treatment as needed.
• Start dextrose infusion if hypoglycemia is refractory.
• Check C-peptide and insulin antibodies if there is concern for medication overdose.
• Rule out acute illness as the cause.
• Rule out medications as the cause.
• Consider further diagnostic workup if no clear cause is identified.
• Consider endocrinology consult.
• Consider ICU admission if the patient is critically ill or requires hourly glucose monitoring and a dextrose infusion.

Acute complications of untreated hypoglycemia ^[13][14]

• Cardiac arrhythmias
• Permanent neurological deficits and cognitive impairment
• Coma
• Death

Chronic complications of recurrent hypoglycemia ^[13][14]

These are particularly pronounced in older adults.

• Increased risk of acute vascular events (e.g., stroke, myocardial infarction)
• Increased frailty and impaired cognitive function
• Frequent falls
• Repeated hospitalization

We list the most important complications. The selection is not exhaustive.