Basics
Description
- Oral or parenteral agents that may cause hypoglycemia or other metabolic imbalances
- Hypoglycemic poisoning may be intentional or unintentional (accidental)
Etiology
- Insulin:
- Enhances glucose uptake into cells
- Limits glucose availability to the brain (most sensitive to hypoglycemia)
- Influences potassium redistribution (hypokalemia)
- Sulfonylurea and Meglitinide agents:
- Enhance insulin release from pancreatic β cells, reduce hepatic glucose production, and increase peripheral insulin sensitivity
- Hypoglycemic effect enhanced by:
- Polypharmacy (drug interactions)
- Alcohol use and hepatic dysfunction (poor nutritional stores)
- Renal insufficiency (decreased clearance)
- GLP1 modulators:
- Exenatide is an analog of glucagon-like peptide 1 (GLP1)
- Gliptins (sitagliptin and saxagliptin) inhibit DDP4 which normally inactivates GLP1
- Net effects: Enhanced insulin secretion, delayed gastric emptying, and increased satiety
- Unclear effects on glucose metabolism in overdose (data are lacking at this time)
- Biguanide agents (metformin):
- Antihyperglycemic agents:
- Decrease elevated serum glucose concentrations
- Generally do not cause hypoglycemia in isolation.
- In the presence of insulin, biguanides do the following:
- Increase glucose uptake into cells
- Limit glucose availability to the brain (most sensitive to hypoglycemia)
- Influence potassium redistribution (hypokalemia)
- Decrease GI glucose absorption
- Decrease hepatic gluconeogenesis
- Metabolize glucose to lactate in intestinal cells, which may accumulate and lead to profound lactic acidosis
- Thiazolidinediones:
- In the presence of insulin, thiazolidinediones increase glucose uptake and use and decrease gluconeogenesis
- α-glucosidase inhibitors:
- Lower systemic glucose by decreasing GI absorption of carbohydrates
Diagnosis
Signs and Symptoms
- Insulin or sulfonylureas:
- Overdose causes hypoglycemia
- Symptoms most often occur when glucose <40-60 mg/dL (may occur at higher levels in diabetics)
- Symptoms blunted by β-antagonists
- Facial flushing, diaphoresis, pallor, piloerection
- Hunger, nausea, abdominal cramping
- Labored respirations, apnea
- Headache, blurred vision
- Paresthesias, weakness, incoordination, tremor
- Anxiety, irritability, bizarre behavior, confusion, stupor, coma, seizures
- Palpitations, tachycardia, bradycardia (late)
- Hypertension
- Hypothermia
- Biguanides:
- Toxicity primarily owing to lactic acid accumulation
- Nausea, vomiting, abdominal pain
- Agitation, confusion, lethargy, coma
- Kussmaul respirations
- Hypotension, tachycardia
- Neonatal hypoglycemia may occur after maternal use of sulfonylureas during labor
- Ingestion of 1 sulfonylurea tablet may cause hypoglycemia in a child:
- Death has been reported after ingestion of a single tablet
- Onset of symptomatic hypoglycemia may be delayed up to 8 hr
History
- Diagnosis of diabetes in patient
- Access to diabetic medications:
- If occurring in a medical setting (hospital, nursing home), consider:
- Dosing error
- Malicious intent
Physical Exam
- Vital signs:
- Tachycardia (may be blunted if on β-blockers)
- Neurologic:
- Confusion, obtundation, coma
- Ataxia, other cerebellar signs
Essential Workup
- Diagnosis based on clinical presentation and an accurate history
- Monitor serum glucose concentration
- Monitor vital signs and neurologic status
- Obtain serum electrolytes and lactate for biguanide ingestion
- Obtain liver function tests for thiazolidinedione ingestion
Diagnosis Tests & Interpretation
Lab
- Serum glucose before and after treatment
- Electrolytes:
- Check for hypokalemia
- Anion gap acidosis
- BUN, creatinine:
- May reveal renal insufficiency, causing drug accumulation
- CBC
- Ethanol level
- Lactate level (especially if biguanide medications involved)
- Liver function tests
- Arterial blood gas
- Assays for immunoreactive insulin and C-peptide levels:
- Confirms administration of exogenous insulin if insulin level is high and C-peptide is low in the setting of hypoglycemia
- Do not correlate with severity of clinical symptoms
Imaging
- ECG: Sinus tachycardia, premature ventricular contractions (PVCs), atrial dysrhythmias
- EEG: Diffuse slowing without focal abnormalities
- CT scan: Cerebral edema if prolonged hypoglycemia
- Chest radiograph: Aspiration pneumonia or pulmonary edema
Differential Diagnosis
- Addison disease
- Panhypopituitarism
- Sepsis
- Insulinoma
- Neuroendocrine tumors
- Cirrhosis
- Chronic ethanol abuse
- Ethanol ingestion
- Salicylate ingestion
- β-antagonist ingestion
- Ackee fruit poisoning
Treatment
Pre-Hospital
Transport all medications, pills, and pill bottles involved in overdose for identification in ED �
Initial Stabilization/Therapy
- ABCs:
- Airway control essential
- Administer supplemental oxygen
- IV access
- Cardiac monitor and pulse oximetry
- Naloxone, thiamine, D50 (or Accu-Chek) if altered mental status
Ed Treatment/Procedures
- Hypoglycemia:
- D50 bolus, then:
- IV infusion D5W or D10W to maintain euglycemia or mild hyperglycemia
- Food (if mental status improves or normalizes)
- Neuroglycopenia:
- May persist shortly after serum glucose corrected
- Persistent symptoms require further dextrose administration
- Decontamination:
- Consider administration of activated charcoal for recent or large ingestion of oral agent (sulfonylurea or biguanide)
- Provide supportive care
- Hypotension:
- 0.9% NS IV fluid bolus
- Pressor support with dopamine or norepinephrine as needed:
- Pressors may increase lactate production
- Use cautiously with biguanide-induced lactic acidosis
- Administer sodium bicarbonate for biguanide-induced lactic acidosis if pH < 7
- Administer benzodiazepines for seizures
- Inhibit insulin secretion for sulfonylurea overdose with recurrent hypoglycemia with:
- Octreotide
- Diazoxide (watch for hypotension)
- Early hemodialysis may be beneficial in cases of biguanide-induced lactic acidosis:
- Corrects acid-base abnormalities
- Enhances elimination of the drug
Medication
- Activated charcoal: 1 g/kg PO
- Dextrose: 50-100 mL D50 (peds: 2 mL/kg of D25 over 1 min) IV; repeat if necessary
- Diazepam: 5-10 mg (peds: 0.2-0.5 mg/kg) IV q10-15min
- Diazoxide: 200 mg PO or 1-3 mg/kg IV (infant: 8-15 mg/kg/24 h q8-12hPO/IV; child: 3-8 mg/kg/24 h q8h PO/IV)
- Glucagon: 1-2 mg (peds: 0.03-0.1 mg/kg) IM/SC/IV
- Lorazepam: 2-4 mg (peds: 0.03-0.05 mg/kg) IV q10-15min
- Octreotide: 50-100 μg q8-12h SC/IV
- Thiamine (vitamin B1): 100 mg (peds: 50 mg) IV or IM
Follow-Up
Disposition
Admission Criteria
- Hypoglycemia owing to sulfonylurea agents (may require several days of monitoring) or long-acting insulin preparations
- Any patient requiring a constant infusion of dextrose to maintain euglycemia
- Intentional overdose or self-injection of insulin warrants admission for 24 hr glucose monitoring
- All children with accidental ingestion of sulfonylureas
- Metabolic alterations owing to biguanide ingestion or accumulation
Discharge Criteria
- Accidental hypoglycemia owing to short-acting insulin injection in the setting of dietary insufficiency:
- Must be tolerating oral intake
- Ensure return to baseline mental status
- Discharge after glucose correction and a 4 hr period of observation
Issues for Referral
- Patients with unintentional (accidental) poisoning require poison prevention counseling
- Patients with intentional (e.g., suicide) poisoning require psychiatric evaluation
Followup Recommendations
Close primary care follow-up to help monitor blood sugar and adjust medication dosages �
Pearls and Pitfalls
- Sulfonylureas can have markedly prolonged half-lives and long elimination times:
- Delayed hypoglycemia and refractory hypoglycemia are common
- Admit for observation, at a minimum
- Metformin must be held for 48 hr after any study requiring IV contrast media:
- IV contrast can prolong renal clearance of biguanides
- Can induce metformin-associated lactic acidosis
Additional Reading
- Bosse �GM. Chapter 48. Antidiabetics and hypoglycemics. In: Hoffman �RS, Nelson �LS, Goldfrank �LR, et al., eds. Goldfranks Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011.
- Dougherty �PP, Klein-Schwartz �W. Octreotide's role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol. 2010;6(2):199-206.
- Glatstein �M, Scolnik �D, Bentur �Y. Octreotide for the treatment of sulfonylurea poisoning. Clin Toxicol (Phila). 2012;50(9):795-804.
- Kopek �KT, Kowalski �MJ. Metformin-associated lactic acidosis (MALA): Case files of the Einstein Medical Center medical toxicology fellowship. J Med Toxicol. 2013;9(1):61-66.
- Kruse �JA. Metformin-associated lactic acidosis. J Emerg Med. 2001;20(3):267-272.
- Little �GL, Boniface �KS. Are one or two dangerous? Sulfonylurea exposure in toddlers. J Emerg Med. 2005;28(3):305-310.
- Rowden �AK, Fasano �CJ. Emergency management of oral hypoglycemic drug toxicity. Emerg Med Clin North Am. 2007;25:347-356.
See Also (Topic, Algorithm, Electronic Media Element)
Hypoglycemia �
Codes
ICD9
962.3 Poisoning by insulins and antidiabetic agents �
ICD10
T38.3X1A Poisoning by insulin and oral hypoglycemic drugs, acc, init �
SNOMED
- 212545006 Poisoning by antidiabetic agent (disorder)
- 21445009 Poisoning by oral sulfonylurea derivative (disorder)