Toxicology case presentation CK Chan, UCH

History F/2. Good past health. Live with parents, elder brother and grandma (70). Taken care by grandma usually. Found drowsy in bed by mother at about 11:30am 20/10/2004. Unwell before sleep last night, vomiting for once. Otherwise no recent illnesses.

Pysical examination GCS 5/15 (E1 V2 M2) BP 124/76, P88, Temp 35.6, RR 24, SaO2 99% in RA. H’stix 1.1mmol/L No external wound / bruising marks Chest / CVS / Abdominal examination unremarkable

Initial treatment D25 30ml (2ml/kg) IV bolus Oxygen by rebreathing mask Blood for spot glucose Regain consciousness after IV dextrose GCS 13/15 (E4 V4 M5)

In-patient progress (1) Grandma has dropped some medications recently (including metformin & daonil), likely taken by the kid while playing around in home the day before presentation. Diagnosed as a case of OHA poisoning Admitted paediatric HDU with D10 60ml/hr.

In-patient progress (2) Glucose infusion continued till D3 due to recurrent hypoglycaemia. Noticed speech delay & developmental delay during hospital stay. Vaccination up to 2 months of life only. Case conference held & established the case as child neglect.

Drug-induced hypoglycaemia Aspirin poisoning (increased glucose utilization) Ethanol (inhibit gluconeogenesis) Sulphonylureas & quinine (increasing insulin release & insulin sensitivity) β-adrenergic antagonist (impair catecholamine mediated glycogenolysis & gluconeogenesis) Insulin

Delayed presentation of hypoglycaemia in sulphonylurea overdose Hypoglycaemia presented late in our case (overnight delay) Possible explanation of this delayed presentation: Effect of glucose homeostasis Long elimination half-life of sulphonylurea Child neglect

Glucose homeostasis Serum glucose levels are maintained by: (1) Gut absorption (post-prandial) (2) Glycogenolysis; & (3) Gluconeogenesis (important after 2-3hr PP) Failure in all 3 mechanism leads to hypoglycaemia (Fasting + depletion of glycogen store + impaired gluconeogenesis)

Gluconeogenesis Important source of glucose during fasting, prevent depletion of glycogen store Fuelled by intermediates of the Krebs cycle. Break down of certain amino acids can enter Krebs cycle & converted to glucose. A reverse of glycolysis. Direction of substrate flow depends on hormone status, ATP/ADP ratio & cytosolic NADH/NAD ratio. Stimulate by glucagon & catecholamines. Inhibit by insulin. Ethanol inhibit gluconeogenesis by altering cytosolic redox ratio (high NADH/NAD ratio, high reducing potential). NADH is accumulated during reduction of ethanol by alcohol dehydrogenase

Duration of action of commonly used sulphonylureas Elimination T1/2 (hrs)Duration of action (hrs) Diabenase (Chlorpropamide)25-60~72 Diamicron (Gliclazide) Daonil (Glibenclamide) Minidiab (Glipizide) Hypoglycaemia can present at any time during the DOA – refractory hypoglycaemia secondary to inadequate treatment / poor oral intake

A poison control center retrospective study including 185 pediatric patients reported to have ingested sulfonylurea revealed that although 96% of the 55 hypoglycemic developed symptoms within 8 hours, 3 patients developed symptoms up to 24 hours later Significance: prolonged observation in asymptomatic overdose. Spiller HA, Krenzelok EP, Anderson BD. Sulfonylurea ingestion in children: Is an 8-hour observation period sufficient? J Pediatr 1998;133:584-5

Treatment of hypoglycaemia Glucose water 10-20g for conscious patient (20-40ml D50 PO) Dextrose: Adult D50 40ml IV; Paed. D25 2-4ml/kg IV Glucagon: 1mg IMI in failed IV line setting (0.5mg if body weight <25kg). Glucagon increases blood glucose by mobilizing glycogen store in liver. Not useful in patient with depleted liver glycogen store (starvation, chronic alcoholism, chronic hypoglycaemia, hormonal deficiencies including cortisol & growth hormone deficiency). Effect in 1 min, half-life 6.6 min. Use in hypoglycaemia must be followed by glucose infusion. Unreliable effect in sulphonylurea overdose (glycogenolysis inhibited).

Specific antidote - Octreotide Octreotide, a long acting analogue of somatostatin Use in refractory hypoglycaemia induced by overdose of sulphonylureas or quinine Act by inhibiting insulin secretion & decreasing insulin sensitivity Peak effect 30min, elimination T1/2 ~90min By IV/SC route, 50ug (1-5ug/kg, max. 50ug) every 6hrs (100ug 1ml ampule $165.36). Duration of treatment depends on the duration of action of offending agent. Dextrose/oral intake still required

Intentional poisoning / Poisoning secondary to child neglect - Alarming features 1. Confusing presentation - ?fabricated 2. Delayed presentation 3. Inappropriate parents ’ reaction 4. Repeated attendance with bizarre presentation (secondary to bizarre poisoning agents) 5. Apparent life threatening event / apnea 6. Too young ( 6) for unintentional ingestion 7. Massive ingestion 8. Intoxication with substances that should not be reached by child (OHA in our case) 9. Multiple substances ingestion 10. Repeated ingestion 11. History of previous trauma Key features of unintentional poisoning: Young child (<6), substances that could be reached by child (e.g.: household products), small amount, single episode, straight forward history.