Doctor123.org

Hypoglycemic Agent Poisoning, Emergency Medicine

Basics

Description

- 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

- 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

- Diagnosis of diabetes in patient - Access to diabetic medications: - If occurring in a medical setting (hospital, nursing home), consider: - Dosing error - Malicious intent

- ABCs: - Airway control essential - Administer supplemental oxygen - IV access - Cardiac monitor and pulse oximetry

- 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

- 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

- Sulfonylureas can have markedly prolonged half-lives and long elimination times: - Delayed hypoglycemia and refractory hypoglycemia are common - Admit for observation, at a minimum

  • 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 cellsLimits 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 sensitivityHypoglycemic 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 GLP1Net effects: Enhanced insulin secretion, delayed gastric emptying, and increased satietyUnclear effects on glucose metabolism in overdose (data are lacking at this time)
  • Biguanide agents (metformin):Antihyperglycemic agents:Decrease elevated serum glucose concentrationsGenerally do not cause hypoglycemia in isolation.In the presence of insulin, biguanides do the following:Increase glucose uptake into cellsLimit glucose availability to the brain (most sensitive to hypoglycemia)Influence potassium redistribution (hypokalemia)Decrease GI glucose absorptionDecrease hepatic gluconeogenesisMetabolize 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
  • О±-glucosidase inhibitors:Lower systemic glucose by decreasing GI absorption of carbohydrates

Diagnosis

Signs and Symptoms

  • Insulin or sulfonylureas:Overdose causes hypoglycemiaSymptoms most often occur when glucose <40-60 mg/dL (may occur at higher levels in diabetics)Symptoms blunted by β-antagonistsFacial flushing, diaphoresis, pallor, piloerectionHunger, nausea, abdominal crampingLabored respirations, apneaHeadache, blurred visionParesthesias, weakness, incoordination, tremorAnxiety, irritability, bizarre behavior, confusion, stupor, coma, seizuresPalpitations, tachycardia, bradycardia (late)HypertensionHypothermia
  • Biguanides:Toxicity primarily owing to lactic acid accumulationNausea, vomiting, abdominal painAgitation, confusion, lethargy, comaKussmaul respirationsHypotension, 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 errorMalicious intent

Physical Exam

  • Vital signs:Tachycardia (may be blunted if on β-blockers)
  • Neurologic:Confusion, obtundation, comaAtaxia, 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 hypokalemiaAnion 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 hypoglycemiaDo 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 пїЅ

Initial Stabilization/Therapy

  • ABCs:Airway control essentialAdminister supplemental oxygenIV accessCardiac 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 hyperglycemiaFood (if mental status improves or normalizes)
  • Neuroglycopenia:May persist shortly after serum glucose correctedPersistent 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 bolusPressor support with dopamine or norepinephrine as needed:Pressors may increase lactate productionUse 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:OctreotideDiazoxide (watch for hypotension)
  • Early hemodialysis may be beneficial in cases of biguanide-induced lactic acidosis:Corrects acid-base abnormalitiesEnhances 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 Ојg 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 intakeEnsure 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 пїЅ

Pearls and Pitfalls

  • Sulfonylureas can have markedly prolonged half-lives and long elimination times:Delayed hypoglycemia and refractory hypoglycemia are commonAdmit 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 biguanidesCan induce metformin-associated lactic acidosis

Additional Reading

  • Bosse пїЅGM. Chapter 48. Antidiabetics and hypoglycemics. In: Hoffman пїЅRS, Nelson пїЅLS, Goldfrank пїЅLR, et al., eds. Goldfranks Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011.
  • Dougherty пїЅPP, Klein-Schwartz пїЅW. Octreotide's role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol. 2010;6(2):199-206.
  • Glatstein пїЅM, Scolnik пїЅD, Bentur пїЅY. Octreotide for the treatment of sulfonylurea poisoning. Clin Toxicol (Phila). 2012;50(9):795-804.
  • Kopek пїЅKT, Kowalski пїЅMJ. Metformin-associated lactic acidosis (MALA): Case files of the Einstein Medical Center medical toxicology fellowship. J Med Toxicol. 2013;9(1):61-66.
  • Kruse пїЅJA. Metformin-associated lactic acidosis. J Emerg Med. 2001;20(3):267-272.
  • Little пїЅGL, Boniface пїЅKS. Are one or two dangerous? Sulfonylurea exposure in toddlers. J Emerg Med. 2005;28(3):305-310.
  • Rowden пїЅAK, Fasano пїЅCJ. Emergency management of oral hypoglycemic drug toxicity. Emerg Med Clin North Am. 2007;25:347-356.

See Also (Topic, Algorithm, Electronic Media Element)

Hypoglycemia пїЅ

Codes

ICD9

962.3 Poisoning by insulins and antidiabetic agents пїЅ

ICD10

T38.3X1A Poisoning by insulin and oral hypoglycemic drugs, acc, init пїЅ

SNOMED

  • 212545006 Poisoning by antidiabetic agent (disorder)
  • 21445009 Poisoning by oral sulfonylurea derivative (disorder)