Glucagon 2.0

In the pre-hospital setting, Glucagon primarily plays a role in the management of hypoglycemic patients. Emergency Medical Technicians carry Glucagon as an alternative or adjunctive therapy to dextrose administration in these patients. However, this is not the only usage of Glucagon in the field. Many ALS protocols include Glucagon for the treatment of symptomatic bradycardia in patients who have overdosed on β-blockers or are refractory to standard ACLS treatments. As we will find, there are a number of alternative usages of Glucagon which could be considered in the field under online medical direction.

Common Clinical Applications of Glucagon

• Hypoglycemia
• Symptomatic bradycardia secondary to β-blocker overdose
• Symptomatic bradycardia secondary to Ca-channel blocker overdose

Uncommon Clinical Applications of Glucagon

• Steakhouse syndrome
• Refractory anaphylaxis
• Severe asthma (little support)
• Refractory CHF (little support)

Pharmacology

Glucagon is a hormone produced by alpha cells in the islets of Langerhans of the pancreas. The primary effect of Glucagon is to promote the release of stored glucose in the liver and stimulate the release of insulin from the pancreas to promote uptake of glucose into the cells. Additional effects of Glucagon include a cascade of activations resulting in an increase of cyclic-AMP (cAMP). cAMP is an important intracellular messenger, responsible for carrying the signals of epinephrine and glucagon across the cell membrane. cAMP also regulates the flux of Ca2+ through ion channels independent of β-adrenergic receptors. This quality of Glucagon is what is thought to explain the various changes to the cardiovascular system seen after its administration.

In the field, Glucagon is commonly packaged as a powder which is reconstituted with either sterile water or D5W (5% dextrose in water) to give a final concentration of 1 mg in 1 cc. Glucagon can be administered intravenously (IV), intraosseously (IO), intramuscularly (IM), subcutaneously (SQ), or intranasally (IN). Glucagon is assigned to the pregnancy category B, therefore usage during pregnancy should be considered when the benefits outweigh the potential risks. The most common side effects are nausea and vomiting, thought to be associated with the rate of IV administration. When giving high doses of Glucagon, the usage of antiemetics such as ondansetron or promethazine should be considered. Additionally some diluents packaged with Glucagon contain phenol, which in high doses can be toxic. Therefore, reconstitution should be done in sterile water, D5W, or normal saline.

Hypoglycemia

As this article is intended for pre-hospital providers, it is assumed that the usage of Glucagon in hypoglycemia is well understood, therefore this indication will not be explored in depth. However, pre-hospital providers may be surprised to learn that the administration of 2 mg Glucagon intranasally (IN) was shown to be as safe and efficacious as an IM administration of 1 mg. Recently the administration of drugs through the IN route has gained in popularity, the most visible of those being naloxone (Narcan). In 2009, naloxone administration via the IN route was added to the scope of practice for all levels of EMTs in North Carolina, where this author practices.

Given the few side effects and complications associated with the administration of Glucagon, it would be a powerful addition to BLS providers for hypoglycemic patients in which oral glucose is not indicated. Yet the widespread adoption of intranasal Glucagon has not been seen in EMS, even though studies on intranasal Glucagon were conducted as far back as the 1980s. One potential explanation could be the relatively high cost of Glucagon. A casual and unscientific search of Internet distributors shows the average price of 1 mg Glucagon ranges from $70-150 USD. In comparison, naloxone ranges from $18-25 USD for the common pre-hospital packaging. Given the economic troubles in 2009 and 2010, it seems unlikely that the intranasal route will gain traction amongst already cash strapped BLS providers.

Symptomatic Bradycardia

Beyond hyperglycemic effects, Glucagon exerts both positive chronotropic and inotropic effects on the heart through non-adrenergic receptors. Because the cardiovascular actions are orthogonal to β-adrenergic receptors, it should be considered in any symptomatic bradycardia refractory to sympathomimetics or as an adjunct to sympathomimetic therapy. High-dose IV Glucagon has been shown to be effective when there is a known β-blocker or Ca-channel blocker overdose.

The first consideration for EMTs when using Glucagon for a patient with suspected β-blocker or Ca-channel blocker overdose is the extreme dosage to be administered. A loading dose of 2-10 mg is cited by the literature, followed by 1-5 mg/hr maintenance infusions titrated to effect if hypotension and bradycardia persist. The service at which the author works only carries two 1 mg Glucagon kits per ambulance, which is relatively common amongst ALS providers. Therefore, a second unit or ALS QRV should be requested for an intercept to supply additional Glucagon kits. This logistical concern obviates any on-scene treatment with Glucagon for symptomatic bradycardia, and should not delay safe and expeditious transport.

Steakhouse Syndrome

Steakhouse syndrome, otherwise known as an esophageal food bolus obstruction, is a medical emergency occurring when a foreign body becomes stuck in the esophagus either due to spasms, strictures, or rings. Standard treatment includes endoscopy, digestive enzymes (such as papain), or Glucagon. An interesting property of Glucagon is that it can overcome smooth muscle spasms of the lower esophagus and lower esophageal sphincter pressures. Glucagon has been used in various radiological studies since the 1970s and its hypotonic effects on the esophagus are well documented.

Usage in the ED began formalization in the 1990s with studies on determining an effective treatment protocol. The most common protocol begins with fluoroscopy studies to determine the extent of the obstruction. Next, the patient is laid supine and 1 mg of Glucagon is given over 1 minute via IV push (to lessen the chance of nausea and vomiting). Finally, the patient is sat upright and encouraged to drink 200 cc of water and an effervescent solution. The combination of Glucagon’s spasmolytic effects, the hydrostatic pressure of the column of water, and the esophageal dilation secondary to the effervescence is very successful at passing obstructions.

In the field, patients will present with an inability to swallow, excessive salivation, drooling, and will probably be distressed. If prompt medical attention is not sought, aspiration, esophageal rupture or perforation may occur. A trial of 1 mg Glucagon slow IVP under medical direction may be an effective means of terminating any spasms and passing the obstruction. Glucagon could also be considered in the case of a recent clearing of a foreign body airway or esophageal obstruction with excessive coughing or spasms. Unfortunately the use of Glucagon in the field to treat true esophageal food bolus obstructions is limited by an inability to conduct radiological studies, so unless transport times are long or the EMS system rural, safe and expeditious transport should not be delayed.

Refractory Anaphylaxis

Prompt recognition and management of anaphylactic shock is constantly stressed in EMS education as it is both rapidly fatal and reversible. Treatment protocols include epinephrine, antihistamines, corticosteroids, inhaled β2-agonists, and aggressive fluid resuscitation. However, in certain patient populations the use of epinephrine may not be desired or outright contraindicated. Additionally, some patients may just not respond to β-adrenergic stimulation. Due to its orthogonal cardiovascular mechanism of action, Glucagon is an appropriate choice as supplemental treatment in these patients.

In the field, dosages for Glucagon in refractory anaphylaxis should begin at 1 mg IV every 5 minutes as needed. If the patient has a known β-blockade or is refractory to epinephrine, doses as high as 3-5 mg may be required. If hypotension continues in spite of aggressive fluid resuscitation, a maintenance infusion of 1-5 mg/hr should be started, titrated to effect. As discussed in β-blocker overdoses, most ALS units do not carry enough Glucagon for prolonged treatment and additional units should be requested for an intercept. As before, safe and expeditious transport to an ED should not be delayed for treatment with Glucagon.

Severe Asthma

Treatment of asthma in the field is relatively straightforward, involving nebulized β2-agonists and parasympatholytics, IM sympathomimetics, and IV corticosteroids. However, if a patient has a β-blockade or is in status asthmaticus, the condition may be so severe that standard treatments are not effective on their own. Studies were conducted in the late 1980s and early 1990s on the use of IV and nebulized Glucagon for the adjunctive treatment of bronchospasm. They showed that the smooth muscle relaxation of Glucagon, which is independent of β-adrenergic pathways, provides some clinical benefit when compared against using β2-agonists alone. Current clinical guidelines for the management of asthma note that "last ditch" treatments such as magnesium sulfate or Glucagon have little support in the literature and may even be harmful. However, Glucagon has been shown to be safe even if the additive benefit is negligible.

In the field, patients presenting with severe asthma or status asthmaticus should be treated aggressively using current protocols. Albuterol, ipratropium, epinephrine, and corticosteroids should all be administered prior to the consideration of "last ditch" treatments such as Glucagon. Dosages for Glucagon in severe asthma vary based on the route of administration; 1-2 mg slow IV push or 2 mg nebulized have been shown to be effective in small studies in addition to aggressive β2-agonist treatment. Do not delay safe and expeditious transport or definitive airway management in a decompensating asthmatic.

Refractory CHF

In a patient with acute Congestive Heart Failure, if they are refractory to inotropes Glucagon can be considered as a potential treatment. Studies conducted in the 1960s and 1970s showed promise for Glucagon as a supportive agent in CHF, but only for NYHA Class I and Class II heart failure. Recent studies, however, do not show strong for a support for Glucagon in CHF, reserving its usage for refractory shock states. Dosages in the field of Glucagon for refractory CHF should be 0.01-0.05 mg/kg IV bolus with a maintenance infusion of 1-3 mg/hr. The paucity of literature in support of Glucagon for CHF relegates this treatment to a last ditch effort with close medical direction.

Conclusion

Glucagon is one of the most common items in an ALS drug box and as the literature shows surprisingly versatile. Beyond its hyperglycemic effects, Glucagon is a positive inotropic and chronotropic agent. This oft overlooked mechanism of action arms pre-hospital providers with new treatments without adding additional medications. While medical control will be required for nearly all of the alternate indications, both rural and urban providers can make more informed treatment choices for their patients especially when the standard treatments fail.

Potential Utility of Glucagon in the Field

• Hypoglycemia: Adults: 1 mg SQ, IM, IV; 2 mg IN. Peds: 0.5 mg SQ, IM, IV; 1 mg IN. Neonates: 50 mcg/kg SQ, IV. (should accompany glucose resuscitation)
• Symptomatic bradycardia secondary to β-blocker overdose: 10 mg IV bolus, 1-5 mg/hr maintenance infusion. (should supplement standard treatment)
• Symptomatic bradycardia secondary to Ca-channel blocker overdose: 2-10 mg IV bolus; consider maintenance infusion. (should supplement standard treatment)
• Steakhouse syndrome: 1 mg SQ, IM, IV, may repeat.
• Refractory anaphylaxis: 1 mg IV q 5 min; consider 3-5 mg IV; consider maintenance infusion. (should supplement standard treatment)
• Severe asthma: 1-2 mg IV; 1-2 mg nebulized. (paucity of literature to support this use)
• Refractory CHF: 0.01-0.05 mg/kg IV bolus, 1-3 mg/hr maintenance infusion. (paucity of literature to support this use)

References

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• Rosenfalck AM, et al: Nasal glucagon in the treatment of hypoglycaemia in type 1 (insulin-dependent) diabetic patients. Diabetes Research and Clinical Practice 1992; 17: 43-50.
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• American Heart Association. Part 7.3: Management of Symptomatic Bradycardia and Tachycardia. Circulation 2005; 112; IV-67-IV-77.
• Stadler J, et al: The "steakhouse syndrome". Primary and definitive diagnosis and therapy. Surg Endosc 1989; 3(4):195-8.
• Glauser J, et al: Intravenous Glucagon in the Management of Esophageal Food Obstruction. JACEP June 1979; 8: 228-231.
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• Gavalas M, Sadana A, Metcalf S: Guidelines for the management of anaphylaxis in the emergency department. J Accid Emerg Med 1998; 15: 96-98.
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• Wilson JE, Nelson RN: Glucagon as a Therapeutic Agent in the Treatment of Asthma. J Emerg Med 1990; 8: 127-130.
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• Marik PE, Varon J, Fromm R: The Management of Acute Severe Asthma. J Emerg Med 2002; 23: 257-268.