Hypoglycaemic agent toxicity

Insulin

• Risk assessment
  • Hypoglycaemia may last days
  • Severity and duration of hypoglycaemia is unpredictable and correlates poorly with dose injected
  • Poor outcome in delayed presentation. Excellent prognosis with early effective glucose replenishment
• Toxic mechanism
  • Stimulates transfer of glucose, potassium, phosphate and magnesium into cells
  • Promotes storage of glycogen, protein and triglycerides
• Toxicokinetics
  • In overdose, duration of action extends to days and does NOT depend on type of insulin injected
  • Determined by slow and erratic absorption from subcutaneous adipost tissue + prolonged clearance of absorbed insulin
  • Endogenous insulin degraded by liver (60%) and kidneys (40%)

• Clinical features
  • Within 2 hours
  • Autonomic: Nausea, vomiting, diaphoresis, tachycardia, palpitations
  • CNS: Agitation, tremor, confusion, visual disturbance, seizures, hemiplegia, coma
  • Usually >3 days
• Investigations
  • If symptomatic, q30min until normal for 4 hours
  • 2 hourly if asymptomatic until normal for 4 hours then q4h
  • Monitor K, Mg, Phos
  • Insulin + C-peptide levels only if ruling out endogenous hyperinsulinaemic state
  • Target BSL 4-8

•   Dextrose
  • Adult 50mL 50% dextrose IV if <4
  • Child 2mL/kg 10% dextrose IV
  • Commence 10% infusion at 100mL/hr and monitor BSL frequently until stabilised
  • Any further hypoglycaemic episodes are treated with bolus dosing as above
  • If >250mL/hr of 10% dextrose required à Transition to 50% via CVL
• Feed when able with complex carbohydrates
• HypoK
  • If oral – Potassium chloride 14-16mmol (0.25mmol/kg) q2h PO PRN
  • If IV – Potassium chloride 10-20mmol/L IV q2h PRN

• Disposition
  • If asymptomatic and normal BSL at 6 hours, discharge
• Handy tips
  • Insert CVL early for high concentration infusions
  • Diabetic patients may require higher glucose infusion rates as have impaired counter-regulatory hormonal responses to hypoglycaemia
  • Withdrawal of glucose infusion should be gradual and NOT occur at night
  • Monitor patients for 4-6 hours following cessation of glucose infusion
  • Excessively prolonged glucose infusions in non-diabetic patients can cause a hyperinsulinaemic state and difficulty down-titrating infusions
  • Glucagon IS NOT indicated in the hospital management of hypoglycaemia (??)

Metformin

• Lactic acidosis in a patient on therapeutic metformin usually occurs in the context of acute renal failure or severe sepsis and has a mortality >50%
• Acute overdose >10g is thought to be threshold of severe lactic acidosis
  • Although adults with normal renal function can usually tolerate up to 20g 
• Children: Unintentional ingestion up to 1700mg is benign
• Toxic mechanism
  • Inhibition of the mitochondrial transport chain complex-I leading to NADH build-up and subsequent conversion of pyruvate to lactate
  • Inhibits gluconeogenesis, reduces hepatic glucose output and stimulates peripheral glucose uptake
  • Alters intracellular redox potential and increases cellular lactic acid production (see above) + inhibits hepatic uptake of lactic acid
• Toxicokinetics
  • Rapidly and well absorbed. Peak levels at 2 hours
  • Not metabolised and excreted unchanged in urine
  • Elimination half-life is 4-8 hours if normal kidney fx
  • Half-life up to 17.6 hours in renal impairment
• Definitions
  • MILA: Metformin-induced lactic acidosis
    • High levels of metformin are the primary cause of illness
    • Acute metformin overdose
    • Subacute accumulation of metformin due to renal failure
      • Marked lactic acidosis but fairly preserved haemodynamics
  • MALA: Metformin-associated lactic acidosis
    • Acute life-threatening illness in patient who happens to be on metformin
    • Renal insufficiency, higher doses of metformin and alcoholism increase this risk
  • MULA: Metformin-unrelated lactic acidosis
    • Clinically impossible to differentiate from MALA
• Clinical features
  • Acute overdose usually asymptomatic
  • Lactic acidosis, if it develops, manifests hours later with altered LOC, nausea, vomiting, diarrhoea, dyspnoea, tachypnoea, cool peripheries, hypotension
  • Can progress to coma and death
  • Hypoglycaemia is usually absent or minor
• Check lactate in any unwell patient on metformin
• Management
  • Supportive cares, replace glucose if needed, fluids, sodium bicarbonate to control severe acidosis and treat hyperkalaemia while awaiting haemodialysis

• Decontamination
  • 50g AC if within 2 hours of ingestion with >10g (or 5 hours if >50g or XR)
  • Can repeat if >5g given absorption potential of 50g
  • WBI if >50g of XR preparation
• Enhanced elimination
  • HD removes lactic acid and metformin
  • Urgently indicated in
    • Unwell patient with lactic acidosis from therapeutic administration
    • Worsening lactic acidosis following acute overdose with clinical instability
  • EXTRIP Guidelines for MALA
    • Recommended in severe metformin poisoning
      • Lactate >20
      • pH <7.0
      • Standard therapy fails
    • Suggested if:
      • Lactate >15
      • pH 7.0-7.1
      • Comorbidities that lower threshold: Impaired kidney function, shock, ALOC, liver failure
• Disposition
  • Observe at least 8 hours if >10g
  • If well with normal bicarb at 8 hours, discharge
• Pitfalls
  • Failure to consider metformin-induced lactic acidosis as diagnosis in unwell patients

Sulfonylureas

• Glibenclamide, gliclazide, glimeprimide, glipizide
• Acute OD: Profound and prolonged hypoglycaemia within 8 hours (or longer if SR)
  • Can also develop hypoglycaemia at therapeutic doses, especially if renal dysfunction
• Risk assessment
  • Just one tablet can cause hypoglycaemia in non-diabetic patient
  • Often prolonged hypoglycaemia with recurrence after initial therapy
  • Children: Single tablet can be fatal and can be delayed up to 18 hours

• Toxic mechanism
  • Stimulate endogenous insulin release by inhibition of K+ efflux from beta-cells
• Toxicokinetics
  • Rapidly and completely absorbed with peak levels at 4-8 hours
  • Vd mostly small
  • Metabolised in liver to inactive and active metabolites
  • Elimination is renal of metabolites. Prolonged in overdose
• Clinical features – Signs of hypoglycaemia

• Management
  • Food if possible (complex carbs)
  • Supportive care + 50mL 50% dextrose IV bolus (2mL/kg 10% dextrose)
  • Maintain BSL 4-8 with glucose boluses until octreotide started
    • Repeated boluses can result in insulin release and rebound hypoglycaemia, hence start octreotide as soon as possible and AVOID glucose boluses once octreotide started
  • Check K
  • Check BSL at least 15 minutely in resus then hourly reducing once stable on octreotide infusion
  • If asymptomatic, q2h BSL until normal for 4 hours, then q4h
  • Decontamination
    • AC if presents within 2 hour or up to 6 hours after MR preparation
  • Enhanced elimination not helpful (unlike metformin)
  • Antidote
    • Octreotide 50mcg bolus IV then 25mcg/hr for 24 hours OR 50mcg (2mcg/kg) SC q8h for at least 24 horus
    • Children 1mcg/kg bolus then 1mcg/kg/hr

• Disposition
  • Children: Bedside BSL monitoring for at least 18 hours and if okay, discharge (some authors suggest 48 hours)
  • Adults: Observe 8 hours (12 hours if SR)
  • Monitor for 12 hours after octreotide/glucose ceased
  • Patients who develop hypoglycaemia on therapeutic doses of sulfonylurea need admission, treatment, checking renal function and re-evaluation of diabetic therapy
• Handy tips
  • Early use of octreotide can avoid CVL and hypertonic dextrose infusions
  • Can give octreotide at same dose SC if IV access not immediately available
  • BSL <4 heralds profound hypoglycaemia even if asymptomatic – TREAT
  • Do not give treatment unless hypoglycaemia actually confirmed as need this to make diagnosis
• Pitfalls
  • Recurrent glucose boluses leads to insulin release and rebound hypoglycaemia
  • Failure to admit therapeutic dosing hypoglycaemia patients for workup
  • Failure to observe paediatric cases for 18 hours

DPP-4 inhibitors

• Sitagliptin, Linagliptin, saxagliptin
• Reduce serum glucose by preventing degradation of glucagon-like peptides GIP and GLP-1
• Glucagon-like peptides are released from gastric endocrine cells in response to nutrient ingestion and induce glucose-dependent insulin secretion
  • May also inhibit glucagon release, reduce hunger, and delayed gastric emptying
  • Glucagon-like peptides are inactivated by dipeptidyl peptidase-4
  • Inhibition of DPP-4 increases the plasma level of glucagon-like peptides and prolongs their effect 

• 86% of cases of overdose showed no clinical effects
• 12% minor effects
• 2% moderate effects (nausea, vomiting, abdominal pain, hypoglycaemia)
• Overall risk of hypoglycaemia is low as function as anti-hyperglycaemic agents primarily
• Single case of prolonged hypoglycaemia presents reason for caution
• Should probably monitor for 12 hours given half-life of sitagliptin and potential for hypoglycaemia

Last Updated on November 22, 2021 by Andrew Crofton