Author: Nicole Anthony, MD
Peer Reviewer: Trevor Cerbini, MD
In Part 1 of our 2-part series on hypoglycemia, Erroneous Blood Glucose Readings and Where To Find Them, we introduced the vignette of a patient in a shock state whose peripheral fingerstick reading would not respond to repeated dextrose administration. Now, I’d like to present a different scenario.
While working in the critical care area of the ED, you are asked to evaluate a patient in triage. The patient was brought in by EMS for altered mental status. His fingerstick in the field was 40 mg/dL, and his confusion resolved with 2 amps D50W. He’s now sitting comfortably in front of you with normal vitals, awaiting your assessment. It’s time to decide if he needs to stay in the acute care area or if he can be cleared to the main ED (where he might sit for hours before seeing another provider).
Unfortunately for you, he only speaks Taiwanese. The interpreter service keeps you on hold for a very long time before asking for a callback number while they search for a Taiwanese interpreter. You have no way of determining a medical history. Does he stay or does he go pending a normal repeat fingerstick?
Etiology
Determining the etiology of hypoglycemia is more than just an academic exercise. Although acute hypoglycemia is initially managed the same regardless of etiology, understanding the cause will clarify the disposition for the patient and can, on one end of the spectrum, entail ICU admission for hourly glucose monitoring or, in the right setting, allow the patient to be discharged home with close follow-up.
It can be useful to think of the mechanisms as hyper- vs hypo-insulinemic states. This is generally a comment on whether the pathway leads to increased availability of insulin or sensitivity to insulin (hyper-insulinemic) vs decreased availability of insulin or sensitivity to insulin (hypo-insulinemic).
Aside from insulin production, the body also relies on two other processes to maintain blood glucose levels: gluconeogenesis and glycogenolysis. Gluconeogenesis, which occurs primarily in the liver and to a lesser extent, the kidneys, is the creation of glucose from substrates. Glycogenolysis, which occurs primarily in the liver and the muscle, is the breakdown of glycogen to produce glucose.
Medication Misdosing
Insulin state: Hyper-insulinemic (↑ availability)
Gluconeogenesis: Normal
Glycogenolysis: Normal
By far, this is the most common cause and, perhaps, the easiest to assess for. However, there is usually a trigger that leads the patient to become hypoglycemic on their usual insulin regimen. If the trigger isn’t identified and corrected, there is a high risk of hypoglycemia recurring.
Targeted therapy: In the case of hypoglycemia due to sulfonylurea use, you can consider octreotide. Sulfonylureas stimulate the islet cells to release insulin while octreotide suppresses insulin release by mimicking somatostatin.
Pearls:
– Ask the patient how frequently hypoglycemic episodes occur.
– Have the patient demonstrate exactly how they administer their insulin. Do they usually wear glasses (but perhaps didn’t this time)? Are they borrowing someone else’s insulin pen?
– Consider checking renal function as worsening CKD (high prevalence in diabetics) might be a contributing factor.
Adrenal Insufficiency
Insulin state: Hypo-insulinemic (↑ resistance)
Gluconeogenesis: Impaired
Glycogenolysis: Impaired
Cortisol stimulates insulin-resistance, gluconeogenesis, and glycogenolysis. When there is a stress response in the body, cortisol is responsible for making glucose more available. Low cortisol is associated with greater insulin sensitivity and impaired mobilization of glycogen stores – glucose is less available to the body for use. Common causes of adrenal insufficiency include long-term steroid use, pituitary or adrenal tumors, and sepsis.
Figure 1. The effect of cortisol on glucose metabolism.[1]
Glucocorticoids can be considered in the treatment of other mechanisms of persistent hypoglycemia aside from adrenal insufficiency, such as in a massive insulin overdose. As mentioned above, one of the effects of glucocorticoids is to increase insulin-resistance which can make it an attractive adjunct to use with other therapies, such as dextrose drips. Although it should not be the sole treatment, it can decrease the need for dextrose administration and thus decrease the fluid burden.[2]
Hepatic Failure
Insulin state: Hyper-insulinemic (↑ availability)
Gluconeogenesis: Impaired
Glycogenolysis: Impaired
Over 50% of our insulin is metabolized by the liver.[3] Therefore, if hepatic function is impaired, insulin is active for longer, leading to a state of relative hyper-insulinemia.
Additionally, gluconeogenesis (the creation of glucose from substrates) and glycogenolysis (the breakdown of glycogen to produce glucose) largely occur in the liver and will also be affected, thus decreasing our body’s ability to adequately respond to a hyperinsulinemic state.
Pearl: Hepatic metastases can be an often overlooked cause of persistent hypoglycemia.
Renal Failure
Insulin state: Hyper-insulinemic (↑ availability)
Gluconeogenesis: Mildly impaired
Glycogenolysis: Normal
Whatever insulin isn’t metabolized by the liver is largely metabolized by the kidneys.[3] Be particularly careful when treating hyperkalemia with insulin as hyperkalemia is often precipitated by some level of renal impairment.
Several retrospective studies report incidences of hypoglycemia in up to 19% of patients following the treatment of hyperkalemia with insulin.[4-7] Absence of known diabetes, lower pre-administration glucose levels, and acute kidney injury (as compared to chronic) were most predictive of subsequent hypoglycemic episodes.[4,5,7]
Pearls: Monitor fingersticks hourly for at least 4-6 hours in all patients when treating hyperkalemia with insulin, regardless of the co-administration of dextrose. Most episodes of hypoglycemia occurred about 2 hours after insulin administration.[5] In addition to the strategies mentioned below, you can also opt to start the patient on a dextrose drip, or the simplest strategy of all, feed them.
Figure 2. Hypoglycemia Risk Reduction Strategy in the Treatment of Hyperkalemia (adapted by EM:RAP)[8]
Sepsis
Insulin state: Variable
Gluconeogenesis: Variable
Glycogenolysis: Variable
The mechanism for hypoglycemia in sepsis is poorly understood but thought to be secondary to organ dysfunction, including adrenal insufficiency, renal failure, and hepatic failure.[9,10] Severe hypoglycemia in sepsis is associated with worse outcomes when compared with euglycemic sepsis, including increased 28-day mortality.[11]
Alcohol binge
Insulin state: Hypo-insulinemic (↑ resistance)
Gluconeogenesis: Impaired
Glycogenolysis: Impaired
There are several mechanisms by which prolonged or binge alcohol use can lead to persistent hypoglycemia This occurs through inhibiting gluconeogenesis and ketosis and relying on glycogen stores which are typically reduced in alcoholic patients.
Alcohol metabolism competes with both gluconeogenesis and ketosis for the cofactor NAD+. This will drive gluconeogenesis preferentially towards the production of lactate instead of pyruvate, and in ketosis, towards the production of beta-hydroxybutyrate instead of acetoacetate, ultimately leading to alcoholic ketoacidosis (AKA). Although AKA tends to present with hypoglycemia, it may not, depending on multiple factors including amount of oral intake, underlying glycogen stores, severity of alcohol binge, and underlying insulin deficiency (from diabetes mellitus, for instance).[12]
The last mechanism for persistent hypoglycemia in alcoholic patients is poor glycogen storage. Alcoholic patients may have hepatic dysfunction, and consequently, impaired glycogen stores.
Initial Management (in all cases of persistent hypoglycemia)
1. Replete orally
If the patient is able to tolerate PO, give them carbohydrate-rich food to eat. Although juice is easy to find, the simple carbohydrates in juice are quickly broken down and lead to a spike in blood sugar often followed by a precipitous drop.
2. Replete intravenously
If the patient is not tolerating PO, consider:
– D50W (1 or 2 amps)
– D10W (100 to 200 mL)
(The higher the osmolality, the more likely to cause phlebitis.)
3. Check a fingerstick after 30 min. If normal, consider q2 hour fingerstick checks until there are several, consecutive normal values.
Meanwhile, start a drip!
- D10W at 75 ml/hr
- D5W at 150 ml/hr
Labs – when to get them?
Unless a patient can give you a clear, satisfactory explanation (such as intentional ingestion, dosing error, or failing to eat after mealtime insulin), consider lab testing tailored to your clinical scenario.
Creatinine – assesses renal function
LFTs – assesses liver function
Beta-hydroxybutyrate – insulin should suppress ketone production, so the presence of ketones would support a hypo-insulinemic state
Disposition
The half-life of most fast-acting insulins (including aspart, lispro, and glulisine) is 4-6 hours. If the patient continues to experience drops in blood sugar past this period, further investigate. If the initial episode of hypoglycemia was due to a basal insulin overdose, you would expect a recurrent episode within 4-6 hours as this is the time it takes to reach a steady state. And finally, even though the hypoglycemic effects of sulfonylureas last 12-24 hours, they peak at 3-5 hours and should similarly lead to recurrent hypoglycemic episodes prior to the 4-hour mark.[13]
As such, consider observation in the ED for 4 hours with possible discharge if all of the following conditions are met:
– Resolution of hypoglycemia with oral intake
– No further episodes of hypoglycemia
– A plausible explanation or provoking factor can be addressed in an outpatient setting
– The patient has good social support
Otherwise, consider hospitalizing the patient for glucose monitoring and further evaluation.
References
1. Late onset diabetes of adults (LADA) masked by co-existed adrenal failure in the context of autoimmune polyglandular syndrome 2 – MedCrave online. Accessed January 24, 2022. https://medcraveonline.com/JDMDC/late-onset-diabetes-of-adults-lada-masked-by-co-existed-adrenal-failure-in-the-context-of-autoimmune-polyglandular-syndrome-2.html
2. Tariq K, Tariq S, Queen AMD. Role of Steroids in Refractory Hypoglycemia Due to An Overdose of 10,000 Units of Insulin Glargine: A Case Report and Literature Review. AACE Clin Case Rep. 2018;4(1):70-74. doi:10.4158/EP171780.CR
3. Duckworth WC, Kitabchi AE. Insulin Metabolism and Degradation*. Endocr Rev. 1981;2(2):210-233. doi:10.1210/edrv-2-2-210
4. Coca A, Valencia AL, Bustamante J, Mendiluce A, Floege J. Hypoglycemia following intravenous insulin plus glucose for hyperkalemia in patients with impaired renal function. PloS One. 2017;12(2):e0172961. doi:10.1371/journal.pone.0172961
5. Apel J, Reutrakul S, Baldwin D. Hypoglycemia in the treatment of hyperkalemia with insulin in patients with end-stage renal disease. Clin Kidney J. 2014;7(3):248-250. doi:10.1093/ckj/sfu026
6. Schafers S, Naunheim R, Vijayan A, Tobin G. Incidence of hypoglycemia following insulin-based acute stabilization of hyperkalemia treatment. J Hosp Med. 2012;7(3):239-242. doi:10.1002/jhm.977
7. Pierce DA, Russell G, Pirkle JL. Incidence of Hypoglycemia in Patients With Low eGFR Treated With Insulin and Dextrose for Hyperkalemia. Ann Pharmacother. 2015;49(12):1322-1326. doi:10.1177/1060028015607559
8. Moussavi K, Fitter S, Gabrielson SW, Koyfman A, Long B. Management of Hyperkalemia With Insulin and Glucose: Pearls for the Emergency Clinician. J Emerg Med. 2019;57(1):36-42. doi:10.1016/j.jemermed.2019.03.043
9. Khardori R, Castillo D. Endocrine and Metabolic Changes During Sepsis. Med Clin North Am. 2012;96(6):1095-1105. doi:10.1016/j.mcna.2012.09.005
10. Miller SI, Wallace RJ, Musher DM, Septimus EJ, Kohl S, Baughn RE. Hypoglycemia as a manifestation of sepsis. Am J Med. 1980;68(5):649-654. doi:10.1016/0002-9343(80)90250-8
11. Mitsuyama Y, Shimizu K, Komukai S, et al. Sepsis-associated hypoglycemia on admission is associated with increased mortality in intensive care unit patients. Acute Med Surg. 2022;9(1):e718. doi:10.1002/ams2.718
12. Tox & Hound – aka AKA. The Tox and the Hound. Published May 14, 2018. Accessed January 16, 2022. https://toxandhound.com/toxhound/aka-aka/
13. Ford W, Self WH, Slovis C, McNaughton CD. Diabetes in the Emergency Department and Hospital: Acute Care of Diabetes Patients. Curr Emerg Hosp Med Rep. 2013;1(1):1-9. doi:10.1007/s40138-012-0007-x
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