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Toxicology

ORAL HYPOGLYCEMIC OVERDOSE

Jessica Eberhard, Pharm D Candidate 2014

A 15yo female presents to the local hospital of a small remote town in Australia. Some 4 hours ago, following a family dispute, she intentionally ingested all of her father’s diabetic medications. A total of 75 X 5mg (375 mg) glipizide tablets and 29 X 500mg (14.5 g) metformin tablets are unable to be accounted for by her family. Using a risk assessment based approach, the management of sulphonylurea and metformin overdose is discussed.

TOXICOLOGY CASE

On arrival, the patient is vomiting, appears anxious and slightly sweaty.

BP: 110/75 mm HgPulse: 90 bpmRR: 18/minT: 36.8 C (98.24 F)BG: 3.0 mmol/L (54 mg/dL)Glasgow Coma Score: 14/15

PRESENTATION

GENERAL APPROACH TO ACUTE POISONINGS

Establish IV access

Bolus dose of 50 mL of 50% dextrose solution

RESUSCITATION ANTIDOTES

“Hyperglycemia can kill you in 20 years… hypoglycemia can kill you

TODAY.”- Dr. Dugan

5 Factors to consider:1. Agent(s)2. Dose(s)3. Time since ingestion4. Current clinical status5. Patient Factors

RISK ASSESSMENT

Oral hypoglycemic agent used extensively for treating Type-2 DM

Stimulates insulin release from pancreatic beta islet cells

Sustained & profound hypoglycemia is the primary concerning adverse effect of glipizide overdose Potential for delayed hypoglycemia by as much as 18 hours

especially in non-diabetic patients, children, & elderly

Prolonged monitoring of glucose levels is warranted

Seizures can be a presenting symptom in cases of unrecognized SU ingestion

SULFONYLUREAS (SU) - GLIPIZIDE

Action Is antihyperglycemic as opposed to hypoglycemic

Increases cellular insulin sensitivity

Does not cause significant hypoglycemic episodes, even in overdose

Lactic acidosis is the primary concerning adverse effect of metformin overdose Rare – no dose-response relationship exists

Monitor for signs and symptoms

Can be life-threatening if not recognized and treated early

BIGUANIDES - METFORMIN

Absorption of both glipizide & metformin is relatively complete within 1 hour

At 4 hours post-ingestion, gastrointestinal decontamination procedures would likely have minimal impact on subsequent clinical course and managementActivated Charcoal may be an option if ER formulation

DECONTAMINATION

Class Drug t ½ Renal Excretion

Hepatic Excretio

n

Main Adverse Effect

2nd-gen SU Glipizide 16-24 hr 3% 12% Hypo-glycemia (2-4%)

Biguanides

Metformin 1.3-4.5 hr 90% Negligible Lactic acidosis (rare)

AGENTS

Sulfonylurea (glipizide) overdose Dextrose is given to rapidly restore euglycemia

Octreotide is given as soon as possible after dextrose

If octreotide is not available 10% dextrose IV infusion at 100 mL/hr

Metformin overdose Usually causes few problems

Hemodialysis only in severe lactic acidosis to enhance elimination

ANTIDOTES

Attempts to maintain euglycemia by continued infusion of concentrated dextrose is problematic:

Administration of glucose stimulates further insulin release and rebound hypoglycemia

Requires careful monitoring in an intensive care setting

Requires a central line if >20% to avoid peripheral phlebitis caused by hypertonic dextrose solution

A 5-10% infusion is used to maintain euglycemia until octreolide can be sourced and administered

DEXTROSE IV INFUSION

Drug of choice in SU overdoses

A synthetic peptide analog of somatostatin

Binds to G protein-coupled somatostatin-2 receptors in pancreatic beta-cells, resulting in decreased calcium influx and inhibition of insulin secretion

Markedly inhibits insulin releaseIncreases serum glucose concentrationReduces dextrose requirementPrevents recurrent hypoglycemic episodes

OCTREOTIDE

In children, 1-1.5μg/kg SC or IV followed by (2-3) more doses 6 hours apart

In adults, 50μg SC or IV followed by (3) 50μg doses every 6 hours

During octreotide treatment, IV dextrose infusion should be gradually tapered off

OCTREOTIDE

Bolus dose of 50 mL of 50% dextrose

IV infusion of 10% dextrose via peripheral cannula with careful monitoring & hourly bedside blood sugars Rural hospital did not stock octreotide

Royal Flying Doctor Service (RFDS) is enlisted to bring octreotide to the hospital, some 2 hours flying time away

While awaiting the RFDS arrival, the patient has another hypoglycemic episodeAn additional bolus dose of 50% dextrose is givenInfusion rate of 10% dextrose is increased

WHAT HAPPENED TO THE PATIENT?

On arrival of RFDS, a bolus dose of 50μg of octreotide

Flown to the nearest regional base hospital where an octreotide infusion at 25 μg/hr is started

Ongoing management for social & mental health issues

Patient is safely returned to her family & community a few days later

WHAT HAPPENED TO THE PATIENT?

Glatstein M, Scolnik D, Bentur Y. Octreotide for the treatment of sulfonylurea poisoning. Clin Toxicol (Phila) 2012; 50:795.

Soderstrom J, et al. Toxicology case of the month: oral hypoglycaemic overdose. Emerg Med J 2006;23:565-567.

Shannon MW, Borron SW, Burns MJ. Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose . 4 th ed. Philadelphia, PA: Saunders Elsevier; 2007: 1025-1030.

Szlatenyi CS, Capes KF, Wang RY. Delayed hypoglycemia in a child after ingestion of a single glipizide tablet. Ann Emerg Med 1998; 31:773.

REFERENCES