Patient Care

Expanding Glucagon Access and Use in the Prehospital Setting

In cases of severe hypoglycemia, an intramuscular injection of glucagon remains the preferred method of treatment.1 Unfortunately, in many states regulatory polices prevent EMT-Basics from being able to administer or carry glucagon, which makes treating such patients experiencing severe hypoglycemia with loss of consciousness far more complicated  and slower than necessary.

In addition to the unavailability of glucagon, many EMTs aren’t permitted to perform blood glucose testing (i.e., fingersticks), which makes the identification and treatment of hypoglycemia even more challenging. Severe hypoglycemic events result in over 100,000 ED visits annually leading to adverse health effects, as well as contributing over $120 million per year in potentially unnecessary healthcare expenditures.2

Although many patients with diabetes and their caregivers will receive training on the use of glucagon, there are still far too many patients and families who don’t have access to glucagon at home.3

By expanding access to glucagon for prehospital providers and families, episodes of severe hypoglycemia can be more easily treated, ultimately resulting in reduced morbidity and mortality.

Physiology of Hypoglycemia

Severe hypoglycemia is defined as an episode in which blood sugar drops dramatically resulting in impaired consciousness limiting an individual’s ability to self-treat, and are a frequent complication of the treatment of diabetes with hypoglycemic agents such as insulin and sulfonylureas.4 Such episodes can be life-threatening and can lead to confusion and disorientation, seizures, loss of consciousness, coma and even death in extreme circumstances.

Those with long-standing diabetes or frequent episodes of hypoglycemia may develop hypoglycemia unawareness with autonomic neuropathy and the loss of the adrenergic response to hypoglycemia, putting them at higher risk for severe episodes of hypoglycemia. These episodes of severe hypoglycemia may develop with patients when they miss or delay a meal, engage in physical exercise, or miscalculate a dose of insulin, among many other conditions.4

When these episodes occur, patients become reliant on the assistance of others to treat it and most often can’t be mitigated with simple oral carbohydrates such as glucose given their impaired consciousness and swallowing abilities.

As a result, glucagon or IV dextrose remains the most effective mechanisms to treat severe hypoglycemia in the prehospital or hospital setting. Given that IV dextrose remains outside of the scope of practice for the majority of families, EMTs or even some nurses, the American Diabetes Association Standards of Medical Care in Diabetes—2018 recommends that, “glucagon should be prescribed for all individuals at increased risk of clinically significant hypoglycemia, defined as blood glucose < 54 mg/dL (3.0 mmol/L), so it’s available should it be needed. Caregivers, school personnel, or family members of these individuals should know where it is and when to administer it. Glucagon administration is not limited to health care professionals.”5

Mechanism of Glucagon Treatment

Glucagon is a hormone made in the pancreas to raise blood sugar by releasing glucose from the liver. Specifically, glucagon causes the liver to break down glycogen, a storage form of glucose and enabling its release into the bloodstream.

Interestingly, in patients with severe liver disease or glycogen storage diseases, glucagon will not be effective given that there is minimal to no glycogen upon which to act. In addition, glucagon causes relaxation of the smooth muscles of the stomach and parts of the intestine, which is thought to lead to the most commonly side experienced effect of nausea. With the sustained release of glucose from the liver, a person suffering from severe hypoglycemia will commonly experience an observable clinical response within 5–10 minutes.

Figure 1: A glucagon kit from Eli Lilly containing a vial of sterile glucagon, attached needle, syringe of sterile diluting agent and instructions for use
Figure 1: A glucagon kit from Eli Lilly containing a vial of sterile glucagon, attached needle, syringe of sterile diluting agent and instructions for use.

Glucagon is administered intramuscularly, currently, the most commonly used glucagon formulation is the Glucagon Emergency Kit manufactured by Eli Lilly. (See Figure 1.) This kit is used by reconstituting a glucagon powder with sterile water and thereafter injecting the contents of this kit into the muscle of the individual with symptoms of severe hypoglycemia.

Although this kit certainly works as intended in settings where the kit is used correctly, human factors research has unfortunately identified low rates of success with the currently available products.6 This likely speaks to the complicated nature of reconstituting glucagon powder in an emergency setting with minimal medical training given to family and caregivers.

Although there are no human factor studies with EMS personnel, it’s reasonable to assume that they would have a higher chance of success with the current formulations. Given the prevalence of severe hypoglycemic episodes and the need for a more user-friendly kit, novel formulations are currently under investigation which may allow glucagon to be delivered subcutaneously or nasally.

Figure 2: Examples of a variety of glucagon pens, mini pens and pumps from Xeris Pharmaceuticals.
Figure 2: Examples of a variety of glucagon pens, mini pens and pumps from Xeris Pharmaceuticals.

Three new formulations have recently been slowly working their way through the approval process. The Xeris G-Pen and the Zealand HypoPal both provide an EpiPen-like experience of injecting a premeasured and pre-mixed amount of glucagon (G-Pen) or dasiglucagon (HypoPal) in settings of severe hypoglycemia. (See Figure 2.) The Locemia solutions nasal spray provides glucagon in a premeasured powder form. (See Figure 3.) All are currently undergoing trials for potential FDA approval and may be available within the next 1–2 years, pending successful outcomes of their studies and approval process.7

Figure 3: Needle-free glucagon nasal powder developed by Locemia Solutions.
Figure 3: Needle-free glucagon nasal powder developed by Locemia Solutions.

Obstacles to Glucagon Access

In our recent study, “Underutilization of Glucagon in a Prehospital Setting” published in the Annals of Internal Medicine, we reviewed state-by-state policies regarding glucagon administration and utilization patterns across EMS agencies as reported in the National EMS Information System database (NEMSIS).3

According to NEMSIS, glucagon was administered in 89,263 cases between 2013 and 2015.  Considering that only a small fraction of cases of hypoglycemia severe enough to warrant ambulance services as reflected in NEMSIS, we believe that glucagon is clearly underutilized in the hospital setting.3

Given that in the majority of cases EMTs are unable to carry or use glucagon, this underutilization isn’t at all surprising. In discussions with various stakeholders throughout the country, one of the key elements, which has consistently presented itself as a challenge, is the belief that EMTs aren’t permitted to administer any sort of injectable medication or perform any invasive procedure.3

Unfortunately, such an approach belies the fact that glucagon emergency kits are routinely provided to families and patients alike without any complications when used in these settings. Furthermore, EMTs are already permitted (in the majority of areas) to use EpiPens as well as naloxone, which has been shown to have significant benefits for rural communities with limited ALS responders.8

It’s our belief that glucagon should be considered a similarly simple to use but lifesaving drug to which all prehospital providers should have access. Although we concur with the use of D50 dextrose in the hospital setting with patients in whom IV access has already been established, in the prehospital setting, IV access isn’t always rapidly obtained or within the scope of practice, thus necessitating access to glucagon for all providers.

The Path Forward

Patients with diabetes frequently rely on prehospital care in cases of severe hypoglycemia. Cases of severe hypoglycemia are almost certainly under-reported, and recent research has suggested that patients self-report episodes of severe hypoglycemia at a rate of approximately 12% annually.9

In order to ensure that these patients receive the highest quality of care, it’s essential to address any problems that may result in reduced access to glucagon. Too many families are unaware that glucagon is an essential component of prehospital care, and too many prehospital providers (e.g., EMTs) are unable to access a lifesaving medication in the prehospital setting.   

Glucagon should be thought of like naloxone—a necessary, easy-to-use drug with minimal side effects that has the potential to save many lives as well as prevent morbidity associated with hypoglycemia. Similarly, blood glucose testing should be viewed in the same way—a necessary component of prehospital assessment that’s safe, effective and reduces morbidity/mortality. Endocrinologists and other care providers should work with EMS medical directors regarding ways to expand access to glucagon and blood glucose testing.

References

1. American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(Suppl 1). Retrieved July 9, 2018, from www.diabetesed.net/wp-content/uploads/2017/12/2018-ADA-Standards-of-Care.pdf.

2. Mitchell BD, He X, Sturdy IM, et al. Glucagon prescription patterns in patients with either type 1 or 2 diabetes with newly prescribed insulin. Endocr Pract. 2016;22(2):123–135.

3. Kahn PA, Wagner NE, Gabbay RA. Underutilization of glucagon in the prehospital setting. Ann Intern Med. 2018;168(8):603–604.

4. Kedia N. Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. Diabetes Metab Syndr Obes. 2011;4:337–346.

5. American Diabetes Association. Glycemic Targets: Standards of Medical Care in Diabetes – 2018. Diabetes Care. 2018;41(Suppl 1):S55–S64.

6. Yale JF, Dulude H, Egeth M, et al. Faster use and fewer failures with needle-free nasal glucagon versus injectable glucagon in severe hypoglycemia rescue: A simulation study.. Diabetes Technol Ther. 2017;19(7):423–432.

7. Glucagon Competitive Landscape. (May 2, 2018.) Close Concerns.  Retrieved July 9, 2018, from www.closeconcerns.com/knowledgebase/r/6ab3da46.

8. Kinsman JM, Robinson K. National systematic legal review of state policies on emergency medical services licensure levels’ authority to administer opioid antagonists. Prehosp Emerg Care. Feb. 27, 2018. [Epub ahead of print.]

9. Karter AJ, Moffet HH, Liu JY, et al. Surveillance of hypoglycemia-limitations of emergency department and hospital utilization data. JAMA Intern Med. 2018;178(7):987–988.