Continuing Education Activity

Glucagon is a medication used in the management and treatment of hypoglycemia, as an antidote to beta-blocker and calcium channel blocker overdose, anaphylaxis refractory to epinephrine, and to aid in passing food boluses. It is in the anti-hypoglycemic class of medications. This activity describes the indications, actions, and contraindications for glucagon as a valuable agent in the management of acute hypoglycemia, beta-blocker and calcium channel blocker overdose, refractory anaphylaxis, and esophageal obstruction due to food bolus. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with the indicated conditions.

Objectives:

• Identify the mechanism of action of glucagon.
• Describe the contraindications to glucagon.
• Review the appropriate monitoring and toxicity of glucagon.
• Discuss interprofessional team strategies for improving care coordination and communication to advance effective treatment with glucagon and improve outcomes.

Indications

Glucagon is a polypeptide hormone commonly used in the treatment of severe hypoglycemia with FDA approval for the treatment of severe hypoglycemia and as a diagnostic aid in imaging of the GI tract. Glucagon has several off-label indications, including beta-blocker overdose therapy, calcium channel blocker overdose adjunctive therapy, and medical treatment of esophageal food impaction. Glucagon's indications have continued to develop since its discovery, and research is ongoing for use to treat asthmatic bronchospasm, as a constituent in bi-hormonal artificial pancreases along with more traditional insulin, and the treatment of arrhythmias secondary to cardiac anaphylaxis.[1][2][3]

Severe hypoglycemia is a life-threatening event treated with oral carbohydrate intake, IV glucose, or glucagon by various routes. Glucagon has attractive traits in the diabetic population due to its simplicity of use and safe administration, not requiring patent IV access.  Patients with decreased levels of consciousness cannot safely consume the oral carbohydrates needed to raise their blood sugar without risk of aspiration, and obtaining IV access can be problematic in the diabetic population, which can prevent prompt administration of IV glucose.  IV glucose also runs the risk of severe tissue necrosis in the setting of IV medication extravasation. Glucagon is a reliable method of raising the patient's glucose and relieving severe hypoglycemia long enough for more definitive correction of the patient's glucose levels by mouth, particularly when IV access is unavailable to the provider or has failed.[4]

Glucagon's role in gastrointestinal imaging is to induce bowel and upper gastrointestinal tract hypotonia, which permits more precise visualization for studies and procedures; this is the same mechanism by which it helps esophageal food boluses pass. The primary indicated use is to decrease peristalsis during abdominal vascular procedures such as treatment of esophageal varices and other GI bleeds. Glucagon is also utilized in biopsies, abscess drainage, GI stenting, and gastrostomy tube placement. Previously, radiologists used anticholinergic agents for the same indication but switched to glucagon in the 1970s due to a safer side effect profile.[5][6]

Beta-blocker overdose and calcium channel blocker overdose can be treated with high-dose glucagon infusion in addition to beta-agonists such as epinephrine, because of the logistical difficulties associated with obtaining large amounts of glucagon needed for infusion, the recommendation that high dose insulin euglycaemic therapy (HIET) and catecholamine therapy be optimized before adding glucagon infusion unless readily available in adequate quantities. Calcium channel blocker overdose can also receive treatment with glucagon; in this instance, glucagon is a second line therapy behind calcium, epinephrine, and high dose insulin and dextrose.[7][8]

Mechanism of Action

Glucagon binds G-coupled surface receptors found throughout the body in varying concentrations; binding to the glucagon receptors in the liver, GI tract, heart, pancreas, fat, adrenal glands, and kidneys activate adenylate cyclase which in turn raises cAMP levels. cAMP stimulates glycogenolysis and glucogenesis, resulting in the release of glucose, primarily from liver glycogen stores. The extrahepatic effects of glucagon are also mediated by adenylate cyclase, including relaxation of GI smooth muscle and positive inotropic effects.[9][10]

Administration

Glucagon can be administered IV as a bolus or infusion, IM, subcutaneously, and intranasally. Glucagon is available as a dehydrated powder termed a "Glucagon Emergency Kit," which is reconstituted with supplied sterile water or as a purpose formulated intranasal spray. Similar to epinephrine auto-injectors, a pre-filled glucagon injector has received approval, which injects into the patient's thigh. Healthcare providers will most often encounter the emergency kit formulation necessitating reconstitution before injecting the medication, but the intranasal spray may be encountered with increasing frequency in hypoglycemia kits for layperson use. The intranasal powder requires no preparation, and administration is via a spray into the patient's nose while holding the other nare closed.[11][12][13][14]

Adverse Effects

Nausea is the most frequently encountered adverse effect of glucagon administration, with an incidence as high as 35% in some studies. Hypertension has been described up to 2 hours following administration for GI cases due to the inotropic effects of glucagon. Additionally, severe anaphylactic reactions, including hypotension, rash, and vomiting, have been observed due to the protein structure. Hypersensitivity reactions are rare, and most have occurred in the endoscopic setting with IV administration. Adverse reactions from glucagon administration become more likely with the IV route and when giving higher doses.[14][15]

Less common adverse reactions include rebound hypoglycemia in the setting of insulinoma and worsening hyperglycemia in the setting of pancreatic glucagon secreting tumor. Additionally, the positive inotropic effects of glucagon can precipitate severe hypertension when administered to patients with pheochromocytoma and should be avoided in favor of oral or IV glucose for emergency use and the clonidine suppression test for pheochromocytoma diagnosis.[16]

Contraindications

The only absolute contraindication to glucagon administration is known hypersensitivity to the medication. Most hypersensitivity reactions occur in GI imaging patients.[17]

Relative contraindications include use in neonates or children, which may not have sufficient glycogen stores, patients with known insulinoma, pheochromocytoma, or glucagon secreting tumor, and known lactose allergy (some formulations contain lactose).[18][19][20]

Monitoring

Monitoring following glucagon injection should include blood pressure, heart rate, ECG, serial blood glucose checks, and signs of a hypersensitivity reaction. Monitoring is recommended for up to 2 hours after administration due to the medication's duration of action.

Toxicity

Administering doses of exogenous glucagon over the dose required can predictably result in adverse reactions requiring intervention. However, this is rare in the literature. Insulin antagonizes glucagon, but toxicity should not have treatment with insulin in most circumstances. The transient hyperglycemia associated with glucagon administration is rarely life-threatening, and iatrogenic rebound hypoglycemia has a substantial risk of harm. Treatment should focus on mitigating the hypertensive response to glucagon with alpha-blocking agents and vasodilators. 

Enhancing Healthcare Team Outcomes

Glucagon may be necessary for the treatment of a variety of conditions, as discussed above, with hypoglycemic shock being the most common indication.  The emergent nature of many of these indications necessitates the involvement of an interdisciplinary team lead by various specialty physicians, advised by a pharmacist, administered by nurses and paramedics, and monitored by lab technicians. Without intervention, morbidity, and mortality from hypoglycemic shock and beta-blocker and calcium channel blocker overdoses are substantial.[4] [Level 4] Gastrointestinal imaging benefits from glucagon administration by improving image clarity and has been made safer by the transition from anticholinergics to glucagon.[17][21] [Level 5]

The interprofessional healthcare team can enhance outcomes by coordinating care when nurses, laboratory technicians, and physicians work together to identify at-risk patients that may benefit from glucagon administration, often after failed first-line therapies or when first-line treatment is not immediately available. Pharmacists should be available to provide guidance in deciding to utilize glucagon, and at what dosage, particularly given the high-stress environment in which this medication may be necessary. Pharmacist consultation has demonstrably increased the availability of glucagon to patients taking insulin.[22] [Level 3]

Coordinated care of an interdisciplinary team would include:

• Clinicians ordering and nurses and technicians obtaining blood glucose levels
• Nurses and clinicians monitoring the patient for signs of hypoglycemia, including tachycardia, diaphoresis, tremors, altered mentation, or coma.
• Ensuring the patient has ingested carbs and protein capable of preventing rebound hypoglycemia once capable of protecting their airway.
  • Note:  tachycardia may be absent in beta-blocker and calcium channel blocker overdoses.
• Consulting a pharmacist regarding glucagon infusions in the setting of overdose.[8] [Level 4]
• Consulting with a toxicologist for all glucagon therapy in the setting of overdose. Additionally, engaging a toxicologist if an overdose of glucagon is suspected.

Patients requiring prompt intervention with glucagon resulting from hypoglycemia, overdose, or for imaging can be encountered throughout the hospital system and in the general public. Once acute intervention has stabilized the patient, it is crucial to prevent a relapse of the condition as glucagon's duration of action is likely shorter than the underlying cause of the emergency. Diabetic patients experiencing hypoglycemic shock will likely require hospitalization but should also have a prompt follow-up with their endocrinologist or managing physician shortly after discharge.  For cases suspected to be intentional overdoses, a caseworker and psychiatrist should be brought on the case. A coordinated interdisciplinary approach to patient care is generally necessary to continue improving patient safety and access and is essential in the safe treatment of patients with glucagon.