Biochemistry andClinical Toxicology

Mike HallworthRoyal Shrewsbury Hospital

ACB North West RegionAutumn Meeting – 18 October 2005

Poisoning - epidemiology

• Incidence approx. 3 per thousand pa

• Approx. 100 000 hospital admissions pa

• <5% unconscious• <0.5% die

Most frequent enquiries to Toxbase [relative to paracetamol]

1. Paracetamol 1.002. Diazepam 0.303. Aspirin 0.284. Ibuprofen 0.265. Zopiclone 0.256. Ecstasy 0.237. Amitriptyline 0.208. Dothiepin 0.209. Temazepam 0.1810. Coproxamol 0.17

(Camidge et al, 2003)

Commonest poisons on admission to hospital

(Watson and Proudfoot, 2002)

• Paracetamol 60%• Ethanol 35%• Salicylate 30%• Carbon monoxide 25%• Tricyclics & phenothiazines 12%• Others 30%

Laboratory support for drug-related emergencies:

• standard laboratory tests

• specific drug concentrations

• drug screens

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

Standard laboratory tests ii

• Glucose– Differential diagnosis of coma– Hypoglycaemic

agents/EtOH/salicylates

• LFTs– Paracetamol– Iron salts– Halogenated hydrocarbons

Standard laboratory tests iii

• Creatine kinase– Rhabdomyolysis

• FBC/INR– Paracetamol

• Urine tests– Colour– Hb, (myoglobin)– Crystals

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

Toxicological testing in overdose

1. Toxicity predictable based on serum levels. Drug-specific therapy can be instituted when levels dictate:

Salicylate Theophylline LithiumDigoxin ParacetamolMethanol Ethylene glycol

2. Toxicity correlates with serum level, but supportive care only required:

Ethanol Barbiturates Phenytoin

Toxicological testing in overdose

3. Toxicity and requirement for specific treatment depend on clinical parameters - testing only confirms:

Tricyclics Narcotics (naloxone)Cyanide OrganophosphatesBenzodiazepines (flumazenil)

4. Toxicity poor correlation with serum level - supportive care only required:

Neuroleptics CocaineHallucinogens PhenylpropanolamineAmphetamine Phencyclidine

(Mahoney, 1990)

Reducing absorption

• ((emesis))• (lavage)• ORAL CHARCOAL

Increasing elimination

• (forced diuresis)• Urine alkalinization• Dialysis• Charcoal/resin haemoperfusion• Multiple-dose oral charcoal

Specific antidotes

• Paracetamol:N-acetylcysteine Methionine

• Methanol/ ethylene glycol: Ethanol, fomepizole

• Opiates : Naloxone• Metals: Chelators

(DFO, EDTA, etc)

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

Concentration measurements required at

any time:(NPIS/ACB, 2002)

• Salicylate• Paracetamol• Iron• Lithium• Theophylline

• Ethanol• CoHb, MetHb• Digoxin• Paraquat (qual)

within 2h

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

Drug screens

• Usually of very limited value

Mahoney et al., 1990 - Boston, USA

Impact of qualitative toxic screening in management of suspected OD

176 cases of drug OD164 screened by:

GC, HPLC x3, acid GCMS, basic GCMS

Mahoney et al., 1990 - Boston, USA

81% screens POSITIVE

19% screens NEGATIVE

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

Mahoney et al., 1990 - Boston, USA

Impact of screens on disposition:

35/176 admitted to hospital:

20 because of clinical findings7 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)

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

Urgent drug screens

• Poisoned patient very ill – ? Nature of poison

• Deteriorating unconscious patient without

“Routine” toxicology

• Diagnosis of brain death• Suitability of organs for Tx• Medico-legal (e.g. “date rape”)• Forensic

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)

Poisonings other than drugs

• “Detection of poisonings by substances other than drugs: a neglected art”

Badcock NR Ann Clin Biochem 2000; 37:

146-57

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

Gaps

• ANION GAP:Raised in:

– lactic acidosis– ketoacidosis– salicylate

poisoning– methanol/ethylene

glycol poisoning– CRF

• OSMOLAR GAPRaised with:

– Unmeasured osmoles:

• ethanol/methanol• (ethylene glycol)• mannitol/glycine

– severe shock– high

lipid/protein

Methanol / ethylene glycol

• Usually latent period before symptoms (12-72h)

• Headache• Pale, restless• Sweating• Convulsions• Nausea/vomiting

• Visual symptoms• Severe metabolic

acidosis• Cardiorespirator

y failure• Crystalluria &

renal tubular necrosis (glycol)

Ethanol(intoxication)

Methanol(intoxication)

Ethylene glycol(intoxication)

Acetaldehyde(hangover, flushing)

Formaldehyde(blindness,

cerebral oedema)

Glycoaldehyde(CNS effects)

Acetic acid Formic acid(metabolic acidosis)

Glycolic acid(metabolic acidosis)

CO2 + H2O Glyoxylate(lactic acidosis)

Oxalate(cerebral and renal

damage, hypocalcaemia)

Alcoholdehydrogenase

Aldehydedehydrogenase

LDH or glycolic acid oxidase

LDH or aldehyde oxidase

Diagnosis of methanol poisoning

• Metabolic acidosis• High anion gap• High osmole gap• Eye signs

presumptive

Estimation of alcohol concentration

• Ethanol (mg/dL) / 4.6 = osmolalityi.e. 80 mg/dL = 17 mmol/kg

• Methanol (mg/dL) / 3.2 = osmolality

• Ethylene glycol (mg/dL) / 6.2 = osmolality

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)

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.

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.