Acute PoisoningAcute Poisoning

Michael Eddleston

NPIS Edinburgh

SpR in Clinical Toxicology, RIE NPIS

Edinburgh

THE IMPORTANCE OF PHARMACOLOGYTHE IMPORTANCE OF PHARMACOLOGY

“You may experience a difficulty in remembering the antidotes for the various poisons. If so, rest assured that your knowledge of pharmacology is defective. All rational treatment of cases of poisoning is founded on a correct appreciation

of the physiological action of drugs.”

What to do in cases of poisoning, William Murrell, 1925

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EPIDEMIOLOGYEPIDEMIOLOGY

• most common cause of medical presentation accounting for 10-20% of acute medical admissions (RIE 3000 of 15000/annum)

• females > males, but male rate rising NPIS

Edinburgh

APPRAISAL OF THE POISONED APPRAISAL OF THE POISONED PATIENTPATIENT

• history from patient

• tablets / circumstances found

• clinical features (“TOXIDROMES”)» Opiate» anticholinergic» stimulant» metabolic acidosis

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Gastric lavageWard 3, Royal Infirmary of Edinburgh, 1973

(courtesy of Alex Proudfoot)

PREVENTION OF ABSORPTIONPREVENTION OF ABSORPTION

• activated charcoal

• binds non-specifically

• binds about 1/10 of charcoal weight

• (charcoal dose 50 g in an adult)

• Slow release products

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Christophersen et al, Br J Clin Pharmacol 2002; 53: 312-7.

ACTIVATED CHARCOALACTIVATED CHARCOAL

• timing - use within 1 hour

• airway - don’t if problems

• agent - eg iron, lithium, hydrocarbons NOT bound

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PARACETAMOLPARACETAMOL

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PROBLEMS

• Indications for treatment

• Staggered overdose

• Late presentations

• Reactions to antidote

• Interpretation of results in poisoning

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Paracetamol Quantity

Activity

Quantity

RISK FACTORS IN PARACETAMOL OD

PARACETAMOL: RISK FACTORSPARACETAMOL: RISK FACTORS

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Nutritional deficiencyEating disordersAlcoholism Malabsorption syndromesAIDS?? Acute starvation

(CLUE: Blood urea)

PARACETAMOL: RISK FACTORSPARACETAMOL: RISK FACTORS

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Enzyme inducers: carbamazepinephenytoin

barbituratesrifampicin

St Johns wortchronic ethanol

PARACETAMOL: RISK FACTORSPARACETAMOL: RISK FACTORS

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Enzyme inducers: carbamazepinephenytoinbarbituratesrifampicinSt Johns wortchronic ethanol

CLUE: Gamma GT

Schmidt et al Hepatol 2002; 35: 876-882.

The cumulative survival rates for every time to acetylcysteine for each alcohol subgroup. There was a significant difference between the chronic and other subgroups (p < 0.0001 by Cox’s F test)

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Paracetamol Quantity

Activity

Quantity

RISK FACTORS IN PARACETAMOL OD

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Outcome – ALT >1000 related to original plasma level and time of ingestion- ORAL NAC

Rumack 2002 Clin Toxicol 40: 3-20.

Current use of Acetylcysteine

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• Before 4 hours - WAIT until 4 hours• 4-8 Hours - Blood sample and wait **• 8- 24 Hours - Treat on history, do bloods• After 24 hours - Do bloods unless toxic

• STAGGERED INGESTION – use first dose time for treatment decisions

**ASSUMES RESULT SOON

What to do if patient presents >20hWhat to do if patient presents >20h post ingesionpost ingesion

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• Do bloods (U&E, LFTs, INR, pcm)

• If transaminase less than 2x elevated, INR < 1.4, creatinine normal, and paracetamol is not detected:

• The patient has not been poisoned and can be safely discharged home

PARACETAMOL: ANTIDOTEPARACETAMOL: ANTIDOTE

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Acetylcysteine IV

Adverse effects Vomiting flushinghypotensionbronchospasm Anaphylactoid reaction - treat with antihistamines

Intravenous acetylcysteineIntravenous acetylcysteine

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• adverse reactions common • Treatment is symptomatic: antihistamine and beta agonists.

NOT ANAPHYLAXIS• fatalities uncommon (usually miscalculation), caution in

asthmatics • Patients with a late presentation seem to have a higher

incidence of anaphylactoid reactions that relates to lower paracetamol levels.

Risk factors for ADRs to acetylcysteine Risk factors for ADRs to acetylcysteine

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• asthmatics 2.9 (95% CI 2.1, 4.7) more likely to develop ADR

• allergy to other medicines not a risk factor

Schmidt and Dalhoff. BJCP 2001:51; 87-91)

What to do after 20 hours antidote??What to do after 20 hours antidote??

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• Transaminase, sensitive. If normal or less than 2x elevated risk of hepatotoxicity is low

• INR more specific, if above 1.3

• ALWAYS also check creatinine

STIMULANTSSTIMULANTS

• amphetamine• ecstasy• cocaine• LSD• psilocybe mushrooms• phencyclidine

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STIMULANTSSTIMULANTS

• Key issue is control of central excitation and hyperthermia

• Use of judicious HIGH DOSES of diazepam and cooling

• Watch for coronary spasm and infarction

• Caution with antipsychotics and flumazenil

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CALCIUM ANTAGONIST CALCIUM ANTAGONIST POISONINGPOISONING

• cardiac effects - diltiazem, verapamil

• peripheral effects - dihydropyridines (eg nifedipine, amlodipine)

Both seen in overdose

Beware bradycardic hypotensive patient NPIS

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MANAGEMENT OF CALCIUM MANAGEMENT OF CALCIUM ANTAGONIST POISONINGANTAGONIST POISONING

• CNS effects often seen late

• hypotension and rhythm disturbance

• hyperglycaemia and lactic acidosis

• beware slow release preparations

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TREATMENT OF CALCIUM TREATMENT OF CALCIUM ANTAGONIST POISONINGANTAGONIST POISONING

• atropine

• calcium

• glucagon

• catecholamines

• cardiac pacing

• insulin and glucose

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INSULIN-GLUCOSE AS ADJUNCTIVE INSULIN-GLUCOSE AS ADJUNCTIVE THERAPY FOR CALCIUM CHANNEL THERAPY FOR CALCIUM CHANNEL ANTAGONIST POISONINGANTAGONIST POISONING

• insulin 10-30 u/hr with dextrose (mean 0.5 IU/kg/hr) in five patients:

4 verapamil

1 amlodipine and atenolol

Yuan et al. Clin Tox 1999; 37, 463-74

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ANTIDEPRESSANTSANTIDEPRESSANTS

Tricyclics amitriptyline dosulepinSNRI venlafaxineSSRIs paroxetine fluoxetine

sertraline citalopramNRI reboxetine

Presynaptic -2 antgst mirtazepine

MAOI phenelzineSMAOI moclobemide

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TRICYCLICSTRICYCLICS

ACTIONS

Amine reuptake inhibitors

Anticholinergics

Membrane effects (Na channel blockade)

Antihistamine

TOXICITY

Arrythmias and fits

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ANTIDEPRESSANTSANTIDEPRESSANTS

ECG of patient at risk:QRS > 100ms possible arrythmia

(higher risk for fits) > 160ms definite arrythmia

Dosulepin (Dothiepin ) most toxic

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ANTIDEPRESSANTSANTIDEPRESSANTS

Treatment of patient at risk:Monitor using serial 12 lead ECGsConsider Bicarbonate IV if risk factors (QRS >100, and decreased conscious level) are present

Magnesium additionally if torsade NPIS

Edinburgh

Metabolic acidosis

• Definition: process that lowers serum HCO3-

• Occurs when H+ ion production exceeds body’s ability to compensate adequately via buffering or ventilation

Mechanisms of metabolic acidosis in poisoning

• Increased acid production• Impaired acid elimination

Mechanisms of increased acid production

• Poisons are acids (eg HCl vs. sulphuric acid) • Poisons have acid metabolites (eg metabolism

of alcohols to acids)• Poisons affect ATP consumption/production in

mitochondria (eg pcm, valproate, ARVs, metformin, CO, cyanide, formate, +++ adrenergic stimulation)[uncoupling oxidative phosphorylation or inhibiting cytochromes of the electron transport chain]

• Poisons create ketoacids (eg ethanol, isoniazid)

Mechanisms of impaired acid elimination

• Toxic metabolites damage kidneys (ethylene glycol)

• Poison causes distal RTA (eg toluene)

Calculations

• Note the low pH (or high H+)

• Then calculate Anion Gap (AG) AG = [Na+] – ([Cl-] + [HCO3

-])Usual range = 12 +/- 4 m/Eq/L (more recently 7 +/- 4)

• If toxic alcohols suspected, calculate osmolality:2 x [Na+] + [glucose] + [urea] andrequest a measured osmolality on a blood sample

Osmol Gap = measured osmolality – calculated osmolality

AG & metabolic acidosis

• High AGOccurs when an acid is paired with an unmeasured anion (eg lactate, formate)

• Normal AGOccurs with gain of both H+ and Cl- ions, or a loss of HCO3

- and retention of Cl-, preserving electroneutrality

• However, AG can be affected by errors of calculation or assay and by many disease states.So the lack of a high AG does not exclude any particular cause

Use of the osmol gap in patients with a high AG metabolic acidosis

• Osmol gap may provide extra information if a toxic alcohol is suspected.

• However, be aware that other medical conditions such as ketoacidosis and renal failure also cause a raised OG

• Normal osmol gap = less than 10 +/- 6 mOsm/L

• However, normal range has problems due to wide variability between people and assays

Toxins associated with a high osmol gap

• Mannitol• Alcohols: ethanol, etylene glycol, isopropanol,

methanol, propylene glycol• Diatrizoate (amidothizoate)• Glycerol• Acetone• Sorbitol

Metabolism of toxic alcohols

• Ethylene glycol

• Glyceraldehyde

• Glycolate

• Glyoxylate

• Oxalate

• Methanol

• Formaldehyde

• Formate

The mountain

Mycyk & Aks, 2003

METHANOL & ETHYLENE GLYCOLMETHANOL & ETHYLENE GLYCOL

• action - CNS depressantsmetabolic toxicity secondary to

metabolites - formic acid, aldehydes - renal failure, blindness

• Treatment - block metabolic production- ethanol- fomepizoleincrease removal- dialysis

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Metabolism of toxic alcohols

• Ethylene glycol

• Glyceraldehyde

• Glycolate

• Glyoxylate

• Oxalate

• Methanol

• Formaldehyde

• Formate

DELIBERATE RELEASEDELIBERATE RELEASE

• Irritant gases- Chlorine• Toxic chemicals- Cyanide• Nerve agents- sarin, VX

• Infective agents- anthrax NPIS

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NERVE AGENTSNERVE AGENTS

Cholinesterase inhibitors– Bronchorrhoea– Increased gut motility– Small pupils– CNS activity, Fits

Atropine

Oximes

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CARE AFTER RECOVERYCARE AFTER RECOVERY

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1. psycho-social assessment

2. approximately 15% of patients have

psychiatric illness

3. most never re-attend with self harm