What causes persistent hypoglycemia despite intravenous (IV) glucose administration?

From the Guidelines

Persistent hypoglycemia despite intravenous glucose administration can be caused by several conditions, with excessive insulin administration being a common cause, as noted in the 2024 study by 1. The most common causes of persistent hypoglycemia include:

• Excessive insulin administration (either exogenous or endogenous)
• Severe liver disease
• Adrenal insufficiency
• Certain medications, such as insulin, sulfonylureas (like glipizide or glyburide), and alcohol
• Insulinomas (insulin-secreting tumors)
• Severe sepsis
• Non-islet cell tumors producing insulin-like growth factors If this occurs, immediate management should include continuing glucose administration while investigating the underlying cause.

Key Considerations

• Blood samples should be drawn during hypoglycemic episodes to measure insulin, C-peptide, and sulfonylurea levels, as recommended by 1.
• For suspected insulin overdose, glucagon 1mg IM/IV can temporarily raise blood glucose.
• For adrenal insufficiency, hydrocortisone 100mg IV may be needed. This persistent hypoglycemia occurs because the rate of glucose utilization or removal from the bloodstream exceeds the rate of glucose administration and endogenous production.

Prevention and Treatment

• The liver normally releases glucose through glycogenolysis and gluconeogenesis when blood sugar drops, but this mechanism may be impaired in certain conditions, leading to persistent hypoglycemia despite treatment, as noted in the 2016 study by 1.
• Recent inpatient studies show promise for CGM as an early warning system to alert of impending hypoglycemia, offering an opportunity to mitigate it before it happens, as reported by 1.
• The use of personal CGM and AID devices, such as insulin pumps, is recommended by 1.

From the FDA Drug Label

In patients with insulinoma, administration of glucagon may produce an initial increase in blood glucose; however, Glucagon for Injection administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia Glucagon for Injection is effective in treating hypoglycemia only if sufficient hepatic glycogen is present. Patients in states of starvation, with adrenal insufficiency or chronic hypoglycemia may not have adequate levels of hepatic glycogen for Glucagon for Injection administration to be effective. Glucagon administered to patients with glucagonoma may cause secondary hypoglycemia.

The following can make blood sugar keep dropping even after glucose intravenous administration:

• Insulinoma: administration of glucagon may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia 2
• Lack of hepatic glycogen: patients in states of starvation, with adrenal insufficiency or chronic hypoglycemia may not have adequate levels of hepatic glycogen for Glucagon for Injection administration to be effective 2
• Glucagonoma: glucagon administered to patients with glucagonoma may cause secondary hypoglycemia 2
• Indomethacin: in patients taking indomethacin Glucagon for Injection may lose its ability to raise glucose or may produce hypoglycemia 2

From the Research

Factors Contributing to Persistent Low Blood Sugar

• Impairments in counterregulatory responses and hypoglycemia unawareness can increase the risk of severe hypoglycemia, even after glucose intravenous administration 3
• The use of insulin and/or sulphonylureas can increase the risk of hypoglycaemia 4
• Vulnerable patients with type 2 diabetes (T2D) at dual risk of severe hypoglycaemia and cardiovascular outcomes may experience persistent low blood sugar due to "frailty" 4

Treatment-Related Factors

• Administration of high concentrations of dextrose, such as 50% dextrose (D50), may cause harm and lead to difficulties regulating blood glucose levels (BGLs) post-treatment, potentially resulting in persistent low blood sugar 5
• The use of lower concentrations of dextrose, such as 10% dextrose (D10), may improve symptoms while minimizing harm, but may require longer times to resolve symptoms and may necessitate subsequent doses 5

Patient-Related Factors

• Patients with impaired awareness of hypoglycaemia may be more prone to persistent low blood sugar due to delayed recognition and treatment of hypoglycemic episodes 4
• Physical activity, carbohydrate intake, and insulin doses can impact blood glucose levels and contribute to persistent low blood sugar if not properly managed 4