EM@3AM: Hypoglycemia

Author: Stephen Thrasher, MD (TY Intern, NMCP, LT MC USN), Eric Sulava, MD (EM Resident, NMCP, LT MC USN) // Edited by: Brit Long, MD (@long_brit, EM Attending Physician, San Antonio, TX) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Welcome to EM@3AM, an emDOCs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.

A 27-year-old female with a history of insulin-dependent diabetes presents to the ED on a Friday evening somnolent and disoriented.  Her coworkers report she started slurring her speech and became increasingly altered after they met at a bar after work.  They note that they were only at the bar for roughly an hour when the symptoms began, and the patient had only ordered a water at that point.  She had a normal day of work with no signs of illness before the event.

Initial Vital Signs: HR: 106, RR: 21, BP: 146/87, SpO2: 98%, Temp: 96.7F

Exam: Diaphoretic, obtunded female not oriented to person, place, or time. Her GCS is 11 (E3V3M5).  Speech is dysarthric and tangential. PERRLA, cranial nerve reflexes intact. No evidence of trauma.  Abdominal exam demonstrates no TTP or guarding but is notable for scattered ecchymoses.

EKG: Sinus tachycardia; mild QTc prolongation

What do you suspect as the diagnosis? What should your first order be?

Answer:

• Hypoglycemia, likely secondary to insulin-dependent diabetes (formerly type 1 diabetes (DM1))
• Order a point of care blood glucose measurement

Definitions and Epidemiology:

Hypoglycemia Definition:  All episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm

Diabetic Patient: Lower limit of normal is typically defined as a self-monitored glucose level <70mg/dL.

• Common in insulin-dependent diabetes (especially in patients receiving intensive insulin therapy)
  • Averages:
    • 2 episodes of symptomatic hypoglycemia per week
    • 1 episode of severe, at least temporarily disabling, per year
  • Severe = requiring the assistance of another individual
  • Less frequent in non-insulin-dependent diabetes (formerly type 2 diabetes (DM2))
    • Overall event rate for severe hypoglycemia in insulin-treated DM2 is ~30% of that seen in insulin-dependent diabetes
    • Over time the frequency of hypoglycemia in non-insulin-dependent diabetes approaches that of insulin-dependent diabetes
      • Insulin-deficient end of the spectrum of non-insulin-dependent diabetes requires aggressive insulin treatment

Non-Diabetic Patient: Very Uncommon

• Whipple’s Triad guides diagnosis:
  • Signs/symptoms of hypoglycemia
  • Low plasma glucose (<70mg/dL)
  • Resolution of signs/symptoms after plasma glucose raised
• Averages:
  • Frequency of hypoglycemia ~ 36 per 10,000 admissions (nondiabetic, noncritical care hospital admissions)

Causes and Risk Factors:

Diabetic Patient

• Hypoglycemic Agents (Sulfonylureas, Insulin)
• Polypharmacy and other medications
• Missed Meals / Fasting
• Severe illness
• Malnutrition
• Alcohol Ingestion

Non-Diabetic Patient

• Endogenous hyperinsulinism
  • Insulinoma (beta cell tumor)
  • Nesidioblastosis (functional beta cell disorder)
    • Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
    • Post-gastric bypass hypoglycemia
  • Insulin autoimmune hypoglycemia
    • Antibodies directed to endogenous insulin
    • Antibodies directed to the insulin receptor
  • Severe illness (including liver and kidney failure)
    • Sepsis / infection
    • Malaria
    • Adrenal insufficiency
  • Drugs
    • Exogenous Insulin / sulfonylureas use
    • Alcohol
    • Medication Side Effects (low quality evidence)
      • Quinolones, pentamidine, quinine, beta blockers, angiotensin-converting enzyme inhibitors, and IGF-1

Clinical Manifestations:

Symptoms

• Nonspecific autonomic and neuroglycopenic symptoms (respectively):
  • Tremor, palpitations, tachycardia, anxiety/arousal, sweating, hunger, and paresthesias
  • Cognitive impairment, behavioral changes, psychomotor abnormalities, seizure, and coma

Important HPI Questions:

• History of diabetes, family history of diabetes or autoimmune disorders, recent food intake, infectious symptoms, ischemic symptoms, last HgA1C level, average blood sugar levels, and medication regimen
• Must ask concerning inciting factors

Physical Exam:

• Highly variable and non specific
  • Patient appearance: pallor, tremors, diaphoresis
    • Severe hypoglycemia: seizures, altered mental status, behavioral changes, psychomotor abnormalities, focal neurologic deficit
  • Vital signs: tachycardia, tachypnea, hypertension, and hypothermia

Diagnostics:

• Diabetic Hypoglycemia
  • If not systemically ill and can identify a clear precipitant = no extensive workup
  • If ill appearing, conduct an infectious – cardiopulmonary – neurologic workup as deemed necessary
• Non-Diabetic Hypoglycemia:
  • Additional work-up is variable depending on severity and suspected alternative etiologies
    • Basic Metabolic Panel
    • Liver functionality (hepatic panel, coagulation panel)
    • EtOH Level
    • ECG
  • Infectious Workup
    • Chest x-ray, urinalysis, urine / blood cultures
  • Endocrinologic Workup (not usually done in the ED)
    • Glucose / Insulin
    • C-Peptide (differentiate exogenous vs endogenous insulin)
  • artificial insulin does not contain C-peptide
    • Beta-hydroxybutyrate (BHOB)
  • plasma BHOB concentrations are lower in insulinoma patients
    • Proinsulin
    • Auto-antibodies
    • Cortisol
    • TSH
    • Drug Levels (sulfonylureas, others)

Treatment

Goals

• Return patient to euglycemia without causing hyperglycemia
• Diabetic Patient: >70mg/dL
• Non-Diabetic Patient: >60mg/dL

Mild Hypoglycemia

• If alert, oriented, and able to swallow = oral glucose
  • “Rule of 15” – 15 grams of carbohydrate followed by 15 minute wait, repeat if levels remain low
  • Complex carbs, with protein and fat, are best (the classic ED turkey sandwich, or ice cream)

Severe Hypoglycemia

• Establish IV access – D50 vs D10
  • D50 – 1 amp (50mL, 25g) over 2-3 minutes
    • Risks
  • More likely to cause rebound hypoglycemia
  • May overshoot glycemic target
  • Hypertonicity can cause thrombophlebitis and extravasation with tissue necrosis
    • D10 – 100mL bolus (10g/100mL) – reduces risk of hypoglycemia.
  • If resistant to treatment, consider corticosteroids
  • Unable to establish IV access, then place IO and give glucose
    • Glucagon 5mg IM can be considered, but we have better tools
      • Dependent on glycogen stores which may be depleted in prolonged hypoglycemia, those with poor nutrition, or chronic alcoholics
      • Glucagon’s effectiveness is controversial

Suspected sulfonylurea poisoning

• Activated charcoal (involve poison control)
  • Preferably within 1 hour of ingestion
  • Multiple doses may be needed
• Octreotide 50-150mcg Q6hr (IV, IM, SubQ) initially, followed by SubQ 50 mcg every 6 hours
  • Possible benefit to reduce risk of recurrent hypoglycemia
  • Hyperpolarization of the beta cell results in inhibition of calcium influx, preventing insulin release

Pearls

• Occurs in insulin-dependent diabetes > non-insulin-dependent diabetes late > non-insulin-dependent diabetes early > Non Diabetic
• POC Glucose should be part of initial altered mental status work-up
• Causes: Lifestyle, drugs, alcohol, infection, autoimmune/neoplasm
• D10 vs D50 for severely hypoglycemic patient? Remember D50 can cause rebound hypoglycemia
• Glucagon can be used as a temporizing measure if no IV access
• Sulfonylurea has specific treatment (+/- activated charcoal and octreotide)
• Involve the specialists for further diagnostics and assistance

A 3-month-old girl presents to the emergency department for poor feeding and increased lethargy over the past day. Point-of-care testing is significant for glucose of 40 mg/dL. A nurse is able to place a peripheral IV. Which of the following is the most appropriate initial treatment plan?

A) 10% dextrose at 5 mL/kg IV bolus

B) 25% dextrose at 2 mL/kg IV bolus

C) 5% dextrose at 5 mL/kg IV bolus

D) Glucagon 0.3 mg/kg intramuscularly

Answer: A

Hypoglycemia in neonates and infants should be taken seriously has symptomatic neonatal hypoglycemia is associated with brain injury and poor intellectual performance later in childhood. A high suspicion for hypoglycemia should be maintained as symptoms are nonspecific. Neonates can present with jitteriness, hypotonia, altered mental status, cyanosis, poor feeding, hypothermia, seizures, or coma. Older children may present with tachycardia, tachypnea, diaphoresis, or anxiety. The etiology of hypoglycemia in infants includes decreased oral intake, high ratio of insulin to counter-regulatory hormones including secondary to growth hormone deficiency and adrenal insufficiency, inborn errors of metabolism, and sepsis. Hypoglycemia is diagnosed with rapid bedside glucose testing and treatment should be initiated promptly before other studies are complete. However, when possible, extra tubes of blood should be drawn prior to administration of dextrose for possible further workup by the pediatric endocrinologists. The presence or absence of ketonuria can also help differentiate causes of hypoglycemia. Treatment thresholds for hypoglycemia vary slightly in the first days after birth, but generally are < 45 mg/dL in symptomatic patients and < 35 mg/dL in asymptomatic patients. If the hypoglycemia is thought to be secondary to an inborn error of metabolism, glucose should be maintained above 70 mg/dL. First-line treatment for hypoglycemia is bolus dosing of IV dextrose 0.5 g/kg in any of a number of regimens, with preference for larger volumes of less-concentrated dextrose to reduce venous injury. These regimens can be remembered by the “rule of 50s,” in that the product of the concentration of dextrose and volume per kilogram should equal 50. Neonates and infants should be given 10% dextrose at 5 mL/kg IV bolus, toddlers and children should receive 25% dextrose at 2 mL/kg IV bolus, and adolescents can be given 50% dextrose at 1 mL/kg IV bolus. Maintenance dextrose should the be started with 10% dextrose at 6–8 mL/kg/hr IV. For patients without IV access, glucagon can be given at 0.3 mg/kg intramuscularly. Glucagon is additionally beneficial as it can help determine the etiology of the hypoglycemia. If serum glucose increases with glucagon, there are appropriate hepatic glycogen stores and the problem is likely a hormonal deficiency. A lack of an appropriate increase in serum glucose indicates poor hepatic glycogen stores. Additionally, if there is concern for adrenal insufficiency as the cause of hypoglycemia, hydrocortisone should be given. Lastly, there should be a high index of suspicion for sepsis in hypoglycemic neonates and infants, and broad-spectrum IV antibiotics should be considered in these children if they are ill-appearing or have altered mental status.

25% dextrose at 2 mL/kg IV bolus (B) is an appropriate dose as it meets the “rule of 50s,” however, it is a highly concentrated solution and has a high risk of causing venous injury. Neonates and infants should receive a bolus of 10% dextrose at 5 mL/kg. 5% dextrose at 5 mL/kg IV bolus (C) is too small of a dose and is too dilute to be an effective therapy in this symptomatic hypoglycemic patient. Using the “rule of 50s,” this regimen would only provide half the insulin needed to treat this patient’s hypoglycemia. Additionally, dextrose 5% should not be used for bolus dose treatment of hypoglycemia. It is indicated for maintenance fluids in normoglycemic patients to prevent hypoglycemia, especially while they are being kept NPO in the hospital. Glucagon 0.3 mg/kg intramuscularly (D) can be used to treat hypoglycemia but generally should be reserved for patients without IV access. While there are some benefits to glucagon in that it can be both therapeutic and diagnostic of the etiology of hypoglycemia, IV dextrose remains first-line therapy when IV access is present, as in this patient.

Rosh Review Free Qbank Access

References:

1. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94:709.
2. Cryer PE. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention, 3rd, American Diabetes Association, Alexandria, VA 2016.
3. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50:1140.
4. Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 2005; 22:749.
5. Nirantharakumar K, Marshall T, Hodson J, et al. Hypoglycemia in non-diabetic in-patients: clinical or criminal? PLoS One 2012; 7:e40384.
6. Murad MH, Coto-Yglesias F, Wang AT, et al. Clinical review: Drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab 2009; 94:741.
7. Hepburn DA, Deary IJ, Frier BM, et al. Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care 1991; 14:949.
8. Towler DA, Havlin CE, Craft S, Cryer P. Mechanism of awareness of hypoglycemia. Perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes 1993; 42:1791.
9. Service FJ, O’Brien PC. Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic hypoglycemia. J Clin Endocrinol Metab 2005; 90:4555.
10. Tran D et al. Oral Hypoglycemic Agent Toxicity Treatment & Management. http://emedicine.medscape.com/article/1010629-treatment#showall.

FOAMed:

• https://emcrit.org/ibcc/hypoglycemia/
• http://www.emdocs.net/adult-hypoglycemic-patient-tips-emergency-department-management/
• https://www.aliem.com/2014/12/d50-vs-d10-severe-hypoglycemia-emergency-department/ 
• https://lifeinthefastlane.com/resources/hypoglycemia-ddx/