Biochemistry and Clinical Toxicology

1. Biochemistry andClinical Toxicology Mike Hallworth Royal Shrewsbury Hospital

2. Poisoning - epidemiology Incidence approx. 3 per thousand pa Approx. 100 000 hospital admissions pa <5% unconscious <0.5% die

3. Most frequent enquiries to Toxbase [relative to paracetamol] Paracetamol 1.00 Diazepam 0.30 Aspirin 0.28 Ibuprofen 0.26 Zopiclone 0.25 Ecstasy 0.23 Amitriptyline 0.20 Dothiepin 0.20 Temazepam 0.18 Coproxamol 0.17

4. Commonest poisons on admission to hospital(Watson and Proudfoot, 2002) Paracetamol 60% Ethanol 35% Salicylate 30% Carbon monoxide 25% Tricyclics & phenothiazines 12% Others 30%

5. Laboratory support for drug-related emergencies: standard laboratory tests specific drug concentrations drug screens

6. Standard laboratory tests Arterial blood gases Ventilation problems Acid-base disturbances Urea & electrolytes (incl Cl, HCO3, creat) Hyper/hypo kalaemia Anion gap Osmolality Alcohols Calcium, albumin, Mg Oxalate/fluorides

7. Standard laboratory tests ii Glucose Differential diagnosis of coma Hypoglycaemic agents/EtOH/salicylates LFTs Paracetamol Iron salts Halogenated hydrocarbons

8. Standard laboratory tests iii Creatine kinase Rhabdomyolysis FBC/INR Paracetamol Urine tests Colour Hb, (myoglobin) Crystals

9. Emergency measurement of plasma drug concentrations assessing severity of poisoning if this is not possible clinically determining need for specific treatment monitoring efficacy of treatment guiding therapy in severely ill patients in rapidly changing circumstances

10. Toxicological testing in overdose 1. Toxicity predictable based on serum levels. Drug-specific therapy can be instituted when levels dictate: Salicylate Theophylline Lithium Digoxin Paracetamol Methanol Ethylene glycol 2. Toxicity correlates with serum level, but supportive care only required: Ethanol Barbiturates Phenytoin

11. Toxicological testing in overdose 3. Toxicity and requirement for specific treatment depend on clinical parameters - testing only confirms: Tricyclics Narcotics (naloxone) Cyanide Organophosphates Benzodiazepines (flumazenil) 4. Toxicity poor correlation with serum level - supportive care only required: Neuroleptics Cocaine Hallucinogens Phenylpropanolamine Amphetamine Phencyclidine (Mahoney, 1990)

12. Reducing absorption ((emesis)) (lavage) ORAL CHARCOAL

13. Increasing elimination (forced diuresis) Urine alkalinization Dialysis Charcoal/resin haemoperfusion Multiple-dose oral charcoal

14. Specific antidotes Paracetamol: N-acetylcysteine Methionine Methanol/ ethylene glycol: Ethanol, fomepizole Opiates : Naloxone Metals: Chelators (DFO, EDTA, etc)

15. Laboratory analyses for poisoned patients:joint position paper National Poisons Information Service and the Association of Clinical Biochemists Ann Clin Biochem 2002; 39: 328-339

16. Concentration measurements required at any time:(NPIS/ACB, 2002) Salicylate Paracetamol Iron Lithium Theophylline Ethanol CoHb, MetHb Digoxin Paraquat (qual)

17. Specialist assays that may be required urgently(ACB/NPIS, 2002) Methanol Ethylene glycol Phenytoin Carbamazepine Phenobarbital Methotrexate Paraquat (quant. plasma) AChE As Hg Pb Thyroxine Unknown screen

18. Drug screens Usually of very limited value

19. Mahoney et al., 1990 - Boston, USA Impact of qualitative toxic screening in management of suspected OD 176 cases of drug OD 164 screened by: GC, HPLC x3, acid GCMS, basic GCMS

20. Mahoney et al., 1990 - Boston, USA 81% screens POSITIVE 19% screens NEGATIVE

21. Mahoney et al., 1990 - Boston, USA Impact of screens on management: Treatment: n % No impact 146 90 Initiated 2 1 theophylline, salicylate Continued 12 7 salicylate x2, lithium x2 paracetamol x2, digoxin x1, Hg x1 Discontinued 4 2 paracetamol x4

22. Mahoney et al., 1990 - Boston, USA Impact of screens on disposition: 35/176 admitted to hospital: 20 because of clinical findings 7 because of clinical findings + drug screen (6 salicylate, 1 imipramine) 8 because of drug screen alone (3 paracetamol, 2 lithium, 1 salicylate, 1 carbamazepine, 1 diphenhydramine)

23. Utility of toxicology screening in paediatric ER (Sugarman; Pediatr Emerg Care 1997; 15: 194-7) Full toxicological screens on 338 children Unexpected results in 7% of screens Management altered as a result of screening results in 3 patients (<1%) All three had abnormal symptoms

24. Urgent drug screens Poisoned patient very ill ? Nature of poison Deteriorating unconscious patient without D

25. �Routine� toxicology Diagnosis of brain death Suitability of organs for Tx Medico-legal (e.g. �date rape�) Forensic

26. Exposure to poisons Toxin Age <5 Age >15 Drugs 50.9% 74.8% Household prods. 20.4% 7.3% Toiletries 7.4% 1.4% Petroleum distill. 5.7% 1.4% Chemicals 6.2% 10.1% (SPIB, 1994)

27. Poisonings other than drugs �Detection of poisonings by substances other than drugs: a neglected art� Badcock NR Ann Clin Biochem 2000; 37: 146-57

28. S.B., 40 years, F On admission (1600, 18.1.97): Na 147, K 4.4, Cl 103, urea 1.5, creat 91 pH 6.73, pO2 51.2 , pCO2 6.2, bicarb 6, glucose 16.9 Anion Gap = 42 mmol/L (12-20) Osmolality: calc: 320, meas: 470 Osmolar Gap = 150 mmol/L

29. Gaps ANION GAP: Raised in: lactic acidosis ketoacidosis salicylate poisoning methanol/ethylene glycol poisoning CRF OSMOLAR GAP Raised with: Unmeasured osmoles: ethanol/methanol (ethylene glycol) mannitol/glycine severe shock high lipid/protein

30. Methanol / ethylene glycol Usually latent period before symptoms (12-72h) Headache Pale, restless Sweating Convulsions Nausea/vomiting Visual symptoms Severe metabolic acidosis Cardiorespiratory failure Crystalluria & renal tubular necrosis (glycol)

32. Diagnosis of methanol poisoning Metabolic acidosis High anion gap High osmole gap Eye signs ? presumptive ?

33. Estimation of alcohol concentration Ethanol (mg/dL) / 4.6 = osmolality i.e. 80 mg/dL = 17 mmol/kg Methanol (mg/dL) / 3.2 = osmolality Ethylene glycol (mg/dL) / 6.2 = osmolality

34. M.McG, age 28, female OD 20 tabs Theo-Dur (husband�s) + 7 cans strong lager Anxious ++, pulse 130-160/reg SWO 1h after ingestion at 11h, Fits ++, pH = 6.9 : xfer to ITU K+ 2.3 mmol/L Theophylline @ 16h = 138 mg/L (760 ?mol/L) Start HD & CHP CK 113,300 U/L, ARF developed (creat = 1355)

35. Key points (i) Laboratory support for drug-related emergencies consists of standard biochemical/haematological tests, measurement of specific substances and drug screens for unknown poisons. Standard laboratory tests are most important for determining immediate management in most patients. Emergency measurement of specific substances is indicated in a small number of cases where specific therapy may be instituted depending on the nature and quantity of the poison ingested.

36. Key points (ii) Laboratories in hospitals dealing with acute admissions need key toxicological analyses available 24/7 Repeated measurement of specific substances may be used to guide therapy. Drug screens rarely of immediate value but may be necessary when the patient is critically ill, or when the patient is ill and not improving, and the diagnosis is uncertain.