The Adult Hypoglycemic Patient: Tips for Emergency Department Management

Authors: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident at SAUSHEC, USAF) and Daniel Sessions, MD (Medical Toxicologist, South Texas Poison Center / Associate Program Director at SAUSHEC, USA) // Edited by: Jamie Santistevan, MD (@Jamie_Rae_EMdoc, Admin and Quality Fellow at UW, Madison, WI) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW Medical Center / Parkland Memorial Hospital) 

A 55 year-old female with a previous medical history of hypertension, hyperlipidemia, and diabetes, presents to the emergency department with slurred speech and dysarthria. As you enter the room, an anxious family member hands you a list detailing the following medications: lisinopril, clopidogrel, and glimepiride. VS: HR 110, RR 14, BP 132/88, T 99.3. Accucheck: 48 mg/dL.

A 37 year-old male presents for the evaluation of recurrent nausea and diaphoresis. Review of systems is notable for a recent diagnosis of gout with initiation of indomethacin. The patient reports visiting an urgent care facility 48 hours prior for similar symptoms where he was discharged after consuming a container of orange juice. Current VS: HR 123, RR 16, BP 137/92, T 98.9. Accucheck: 51 mg/dL.

The first case above illustrates a commonly encountered scenario: the diabetic patient with possible sulfonylurea toxicity, but what about the second, our 37 year-old male? What could be causing his hypoglycemia? If there are questions in your mind regarding his evaluation and treatment, read on. We’ll review a number of tip and tricks for addressing your next hypoglycemic patient.

Epidemiology of Hypoglycemia

In 2009, the CDC reported 298,000 emergency department visits by diabetic patients assigned the primary diagnosis of hypoglycemia.¹ A relatively recent study of 33 million Medicare patients identified hypoglycemia as the most common acute metabolic event leading to hospitalization among the diabetic population.² 

Aside: Data regarding emergency department visits for hypoglycemia are maintained by the Centers for Disease Control and Prevention (CDC) as subset of the National Ambulatory Health Care Survey.¹ (Metrics are monitored for patients with a primary ICD code of hypoglycemia and a secondary ICD code of diabetes,¹ therefore little cumulative data exists for emergency department visits for hypoglycemia occurring in non-diabetic patients.

Defining Hypoglycemia

In a diabetic patient, hypoglycemia is defined as a self-monitored (acceptably, self-reported) blood glucose level ≤ 70mg/dL.^2,3

All other patients must have a documented experience of Whipple’s triad for the diagnosis of hypoglycemia to be made³:

• Signs or symptoms consistent with hypoglycemia
• A low plasma glucose
• Resolution of symptoms after plasma glucose concentration is raised

Note: Whipple’s triad was identified by Allen Whipple in 1983, the American surgeon who also coined the Whipple procedure. Experts agree that all patients presenting with severe hypoglycemia (blood glucose ≤ 40mg/dL) should undergo evaluation and treatment, even in the absence of associated signs and symptoms.²

Risk Factors for the Development of Hypoglycemia

Risk factors for the development hypoglycemia have been studied extensively in the diabetic population. An observational cohort study including 917,440 adults (age ≥ 18) conducted from 2005-2011 identified patients filling prescriptions for insulin as having the highest rates of hypoglycemia (10-12 times higher than those on non-secretagogue medications, and 3-5 times higher than those prescribed secretagogues) (p<0.001).⁴

The study also identified severe hypoglycemia (hypoglycemia requiring intervention by medical personnel) as occurring up to eight times more frequently in diabetic patients with multiple medical comorbidities (chronic kidney disease, congestive heart failure, and vascular disease).³

A second study, prospectively following 5,063 United Kingdom diabetes patients (ages 25-65 years) for a duration of six years, identified major hypoglycemic events (reported by patients as either requiring third party assistance or medical attention) as occurring most frequently in individuals administering basal and prandial insulin (5.3% annually), followed by basal insulin (3.8% annually), sulfonylurea therapy (1.2% annually), and metformin therapy (0.3% annually) (p<0.0001).⁵

Malnutrition, alcohol abuse, critical illness, cognitive dysfunction, and polypharmacy have also been linked to recurrent hypoglycemic episodes in the diabetic population.⁶

Quick review of medications:

Non-secretagogues

Insulin

Biguanides (metformin)

Thiazolidinediones (rosiglitazone, pioglitazone, troglitazone)

Alpha-glucosidase inhibitors (acarbose, miglitol)

Incretin mimetics (exenatide, liraglutide)

Dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, saxagliptin, etc.)

Amylin analogues (pramlintide)

Secretagogues:

Sulfonylureas (glipizide, glyburide, glimepiride, etc.)

Meglitinides (repaglinide, nateglinide)

Signs & Symptoms of Hypoglycemia

Glycemic thresholds for hypoglycemic symptoms in diabetic patients are difficult to define. Patients who have recently experienced a severe hypoglycemic event may not become symptomatic until blood glucose levels are dangerously low.^6-8 On the contrary, patients with poorly controlled blood glucose levels may experience symptoms of hypoglycemia when glucose levels are within normal limits.^6-8 The diabetic patient should be questioned regarding symptoms experienced, recent HgbA1C levels, average blood glucose levels, most recent medication injection/ingestion, and recent food intake.

Signs and symptoms of hypoglycemia in non-diabetic patients are relatively easier to predict. Autonomic symptoms (nervousness, anxiety, tremulousness, sweating, palpitations, shaking, dizziness, hunger) and neuroglycopenic symptoms (confusion, weakness, drowsiness, speech difficulty, incoordination, odd behavior) are commonly encountered at threshold glycemic values illustrated below (Figure 1).^6,9 In severe cases, hypoglycemia may result in seizure, coma, or death.

Figure 1: Responses to Hypoglycemia in the Non-Diabetic Patient⁶

 Treating the Hypoglycemic Adult Patient

You have made your diagnosis of hypoglycemia (a symptomatic diabetic patient or one with a D-stick ≤ 70mg/dL or a non-diabetic who meets Whipple’s triad), what comes next?

Start with a glucose containing solution: D50 or D10

D50 vs. D10 – How do they compare?

Adam Spaulding, Pharm D, did an excellent review on this topic for ALiEM in 2014. The full post can be found at: https://www.aliem.com/2014/d50-vs-d10-severe-hypoglycemia-emergency-department/

Here is the quick skinny¹⁰:

• Be aware that D50 bolus may cause rebound hypoglycemia (excess glucose suppresses gluconeogenesis and glycogenolysis) => do not overlook the need to initiate an infusion of glucose containing fluids.
• D50 may overshoot glycemic targets (on average the administration of 50mL of D50 (25g of dextrose) increases blood glucose to approximately 160mg/dL¹⁰), which has been shown to be detrimental in the critically ill population. (Krinsley, Critical Care Medicine, 2008¹¹: increasing glycemic variability confers an independent risk of mortality; n=3,252, p <0.001).
• D50 is hypertonic (2,500 mOsm/L) and should be given slowly over 2-5 minutes; adverse effects of administration include: thrombophlebitis and extravasation with tissue necrosis.
• The osmolarity of D10 is 500 mOsm/L, thus safer for peripheral administration.
• Administration of a 100mL bolus of D10 (10g of dextrose) has been shown to safely increase blood glucose levels without adverse events or deaths (Study performed by California Contra Costa County EMS system: n=162; median initial blood glucose 38mg/dL, median post treatment blood glucose level 98 mg/dL; 29 patients required a repeat bolus¹²).

Bottom line: If you go with D50 give 1 amp (50mL, 25g) at a time over 2-3 mins. If you chose D10, a 100ml bolus (commonly packaged as 10g/100mL) can be run in with a little pressure over the same amount of time as an amp of D50. Check the patients glucose levels often.

What if you don’t have IV access? Intra-muscular glucagon (5mg) may be given to raise serum glucose levels. (Keep in mind: the efficacy of glucagon is dependent upon hepatic glycogen stores, thus patients with prolonged hypoglycemia may have minimal response to glucagon therapy secondary to glycogen depletion).^13,14

Following establishment of euglycemia (blood glucose >60mg/dL in a non-diabetic patient, and >70mg/dL in a diabetic patient) and improvement in symptoms, patients who are PO tolerant should be allowed to eat (baring any other concern).

If the patient is PO intolerant, consider initiating an IV dextrose drip (D5W at 75-100 mL/hr).¹³

Special Topic: Hypoglycemia Secondary to Sulfonylurea Therapy

Let’s take a minute to address our first case as this tends to be a board favorite.

When evaluating a patient with hypoglycemia (especially a known diabetic patient), a medication list is invaluable. Hypoglycemia in the context of sulfonylurea use is sufficient to establish a diagnosis of sulfonylurea poisoning.¹³

How do we treat sulfonylurea poisoning? IV dextrose and octreotide. 

Experimental data suggests that octreotide causes a G-protein mediated decrease in calcium influx through voltage-gated channels in pancreatic beta islet cells, thus limiting calcium-dependent exocytosis of insulin.¹⁵

Octreotide may be given IV, IM, or subcutaneously; 50-150mcg should be administered every six hours. Intravenous dosing is preferred in patients with compromised peripheral blood flow.¹⁶ Experts recommend continuation of octreotide therapy for a 24-hour duration with blood glucose monitoring at a minimum of every 4-6 hours.¹⁶ Patients should be monitored for recurrent hypoglycemia for at least 18 hours following the final dose of octreotide.¹⁷

Determining an Appropriate Disposition

The Diabetic Patient

Historically, the majority of well-appearing diabetic patients presenting to the emergency department are safely discharged home with PCM follow-up (approximately 75% of the 298,000 presenting annually.¹) When evaluating a diabetic patient with hypoglycemia the emergency physician must:

Look for signs of insulin excess:

• Question the patient regarding frequency of blood glucose monitoring
• Inquire regarding recent additions to medical therapy, or changes in PO/SubQ dosing

Search for evidence of decreased glucose availability:

• Inquire regarding prolonged exercise/missed meals/diet changes/weight loss
• Inquire regarding alcohol intake (reduces gluconeogenesis, thus depleting hepatic glycogen stores if inadequate food consumption³)

Perform a screening BMP to assess for alterations in medication elimination, such as decreased kidney function, as the etiology of hypoglycemia:

• Renally eliminated non-secretagogues and secretagogues include:
  • Insulin (60% of renal clearance occurs secondary to GFR¹⁸)
  • Metformin (not recommended for therapy if GFR is < 30¹⁹)
  • Glyburide & Glimepiride (not recommended for use if GFR is <60¹⁹)
    • Less commonly prescribed sulfonylureas: acetohexamide, chlorpropamide, tolazamide, and tolbutamide all possess significant renal elimination (see Figure 2)¹⁶
  • Exenatide (not recommended for therapy if GFR is < 30¹⁹)

If the patient is well, he/she can safely monitor his/her blood glucose, and obtained labs are within normal limits, discharge home with close PCM follow-up is appropriate.

The Diabetic Patient with Sulfonylurea Poisoning

Diabetic patients with sulfonylurea poisoning should be hospitalized for frequent blood glucose monitoring (drug half lives and durations of action are prolonged – Figure 2 below). As above, a BMP should be attained to evaluate for renal dysfunction as the etiology of the hypoglycemic episode.

Figure 2: Sulfonylurea Pharmacokinetics (Adapted)¹⁶

The Non-Diabetic Patient

A thorough history and physical exam should be performed on all patients meeting Whipple’s triad, or those presenting with a blood glucose ≤ 40mg/dL.³

If the patient is critically ill, look for clues for of the following etiologies of hypoglycemia^3,20:

• Hepatic, renal, or cardiac failure
• Sepsis
• Cortisol deficiency
• Malnutrition

The majority of these patients will require inpatient evaluation and treatment.

If the patient is clinically well, look for clues of the following etiologies of hypoglycemia^3,20:

• Accidental, surreptitious, or malicious use of hypoglycemic drugs
  • Insulin and insulin secretagogues
• Medications
  • Pentamidine, quinine, cibenzoline, gatifloxacin, indomethacin
• Alcohol abuse (Note: if suspected, treatment should include thiamine in addition to dextrose)
• Patients post gastric bypass
• Patients with a history of autoimmune pathology (autoimmune hypoglycemia)
• Patients reporting hypoglycemic symptoms within 4 hours of food ingestion (reactive hypoglycemia*)
• Patients reporting soft stools post-prandially with hypoglycemic symptoms (alimentary hypoglycemia**)

*Reactive hypoglycemia: mismatch between insulin secretion and glucose absorption resulting in post-prandial hyperglycemia and subsequent hypoglycemia secondary to excess insulin release.²⁰

**Alimentary hypoglycemia: occurs most commonly in young, thin women with a history of increased GI transit time.²⁰

Patients with accidental or surreptitious use of hypoglycemic drugs may require hospitalization for recurrent hypoglycemia. Given the clinical scenario, the majority of these well-appearing patients will be appropriate for discharge and specialty referral.²⁰

Now, back to our second case, the male recently diagnosed with gout – assuming that our patient had no other clinical clues in his history and physical to suggest an alternative etiology of hypoglycemia, it would be appropriate to discontinue his indomethacin therapy given the concern that it might be causing his hypoglycemic episodes.

The More You Know

Let’s talk a little bit about insulin pumps. As the majority of insulin pumps are now sensor-augmented (programmed to recognize low blood glucose levels, commonly < 6mmol/dL), and halt the delivery of basal/bolus insulin in the setting of hypoglycemia, hypoglycemic episodes secondary to continuous insulin therapy is becoming increasingly rare.^21,22

The majority of patients with insulin pumps have undergone extensive diabetes education and are able to manage hypoglycemic events without assistance with carbohydrate ingestion, and repeat blood glucose monitoring.²² Patient’s experiencing recurrent hypoglycemic episodes are often prescribed outpatient glucagon kits (1mg of glucagon, reconstituted with sterile water) for self/by-stander IM administration, and thus may not present to the emergency room for evaluation and treatment.²³

Although consensus statements regarding the management of insulin pumps in the setting of hypoglycemia are lacking, if a diabetic patient undergoing continuous insulin therapy presents to the ED for hypoglycemia, and the etiology of the hypoglycemia is thought secondary to the insulin pump, it is reasonable to turn off the pump, remove the subcutaneous attachment, and treat the patient with IV dextrose/frequent blood glucose monitoring.

A device representative should subsequently be contacted for trouble-shooting/re-programming.

Key Pearls

• Hypoglycemia may present as alteration in mental status – quickly check a point of care glucose.
• Treat the patient: D50 vs. D10
  • D10 may be more appropriate for the critically ill patient
• Do a thorough H&P and obtain a BMP for hypoglycemic diabetic patients:
  • Evaluate for medication issues, decreased renal function, missed meals, etc.
• Non-diabetics meeting Whipple’s triad or presenting with a blood glucose ≤ 40mg/dL = need a thorough H&P to dictate evaluation and treatment
  • Critically ill (sepsis, CKD, etc) + hypoglycemic = Admit
  • Well + hypoglycemic = Ok for discharge and specialist follow-up if no concern for recurrent hypoglycemia (sulfonylurea ingestions, etc.)
• Insulin pump = unlikely to be the etiology of the patient’s hypoglycemia
  • If suspected pump malfunction => turn off the pump and remove the subcutaneous attachment; manage the patients glucose parenterally
    • Call the device representative

References / Further Reading

1. Diabetes Public Health Resource. Number of emergency department visits (in thousands) with hypoglycemia as a first-listed diagnosis and diabetes as a secondary diagnosis, adults aged 18 years or older, United States, 2007-2009. Centers for Disease Control and Prevention. Available from: http://www.cdc.gov/diabetes/statistics/hypoglycemia/fig1.htm

2. Lipska K, Ross J, Wang Y, et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011. JAMA Intern Med 2014;174:1116–1124
3. Cyer P, Axelrod L, Grossman A, Heller S, Montori V, et al. Evaluation and management of adult hypoglycemic disorders: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2009; 94(3):709-728.
4. Pathak R, Schroeder E, Sequist E, Zeng C, Lafata J, et al. Severe hypoglycemia requiring medical intervention in a large cohort of adults with diabetes receiving care in U.S. integrated health care delivery systems: 2005-2011. Diabetes Care. 2016; 39(3):363-370.
5. Wright A, Cull C, Macleod K, Holman R. Hypoglycemia in type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complications. 2006. 20(6): 395-401.
6. Yung J, Ko S. Avoiding or coping with severe hypoglycemia in patients with type 2 diabetes. Korean J Intern Med. 2015; 30(1):6-16.
7. Boyle P, Schwartz N, Shah S, Clutter W, Cryer P. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 1988; 318:1487–1492.
8. Dagogo-Jack S, Craft S, Cryer P. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest 1993;91:819–828.
9. Henderson J, Allen K, Deary I, Frier B. Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med 2003;20:1016–1021.
10. Spaulding A. D50 vs D10 for severe hypoglycemia in the emergency department. Academic Life in Emergency Medicine. 2014. Available from: https://www.aliem.com/2014/d50-vs-d10-severe-hypoglycemia-emergency-department/
11. Krinsley J. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008; 36(11):3008-3013.
12. Kiefer M, Hern H, Alter H, et al. Dextrose 10% in the treatment of out-of-hospital hypoglycemia. Prehosp Disaster Med. 2014;29(2):190-4.
13. Bosse GM. Antidiabetic and hypoglycemic agents. In: Goldfrank’s Toxicologic Emergencies, 9th ed, Goldfrank LR, Nelson LS, Lewin NA, et al (Eds), McGraw-Hill, New York 2011. p.714.
14. Spiller H. Management of sulfonylurea ingestions. Pediatr Emerge Care. 1999;15(3):227.
15. Hsu W, Xiang H, Rajan A, Kunze D, Boyd A. Somatostatin inhibits insulin secretion by a g-protein-mediated decreased in Ca2+ entry through voltage-dependent Ca2+ channels. J Biol Chem. 1991;266(2):837.
16. Chu J, Stolbach A. Sulfonylurea agent poisoning. UpToDate. 2016. Available from: https://www.uptodate.com/contents/sulfonylurea-agent-poisoning
17. Fasano C, O’Malley G, Dominici P, et al. Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea-induced hypoglycemia. Ann Emerg Med. 2008;51:400-406.
18. Rabkin R, Ryan M, Duckworth W. The renal metabolism of insulin. Diabetologia.1984 Sep; 27(3):351-357.

19. Ioannidis I. Diabetes treatment in patients with renal disease: is the landscape clear enough. World J Diabetes. 2014. 15(5):651-658.
20. O’Shaughnessey C, Shubrook J. Hypoglycemia in adults. Emergency Medicine Reports. 2012. Available from: https://www.ahcmedia.com/articles/78107-hypoglycemia-in-adults?trendmd-shared=1
21. Bergenstal R, Klonoff D, Garg S, Bode B, Meredith M. et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369;224-232.
22. Grunberger G, Abelseth J, Bailey T, Bode B, Handelsman Y, et al. Consensus statement by the American association of clinical endocrinologists and American college of endocrinology insulin pump management task force. Endocrine Practice. 2014. 20(5):463-489.
23. Kedia N. Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. Diabetes Metab Syndr Obes. 2011;4:337-346.