Toxicology for the Anaesthetist

Toxicology for the Anaesthetist

• The concepts of management of drug overdose in general

• Specific drugs(Paracetamol, salicylates, opiates, TCA, digoxin,

beta blockers, Organophosphates, Cyanide/Nitroprusside, Methaemaglobinaemia, Carbon monoxide)

The Principles of management

• 1) Exposure PhaseIrrigation, dilution, Adsorbants

2) Toxokinetic phase

• Accelerated passage: Emesis, Gastric Lavage, Laxatives• Enhanced elimination: Manipulation of urinary pH, forced diuresis,

Dialysis, Haemofiltration

SLIME (Salicylate, lithium, Isopropanol, Mg laxatives, ethylene glycol)

3) Toxodynamic phase – Antidote/supportive care

• Neutralisation/ complexation (Digoxin Fab)• Increased biotransformation (NAC)• Decreased biotransformation to toxic

metabolites (Ethanol vs ethylene glycol)• Elevated threshold of toxicity due to

competitive antagonism (Amyl Nitrate)

Paracetamol• Toxic metabolite: N-acetyl-p-benzoquinoneimine depletes

the liver's natural antioxidant glutathione and directly damages cells in the liver – centrilobular necrosis

• Single ingestion >12g (200mg/kg) vs staggered• Time since ingestion (4hrs) ?Activated Charcoal (<1hr)• High Risk (Etoh, Induced liver enzymes, fasting/anorexia

nervosa, INH) Acute toxicity rare in children• Guidelines to managment readily available• N-Acetylcysteine (Precursor for glutathione production)

Problems with NAC

• Oral NAC + activated charcoal and the taste• The most common adverse effect to acetylcysteine

treatment is an anaphylactoid reaction, usually manifested by rash, wheeze, or mild hypotension

• More common with IV acetylcysteine (4 to 23%)• Severe life-threatening reactions are rare - may occur in

predisposed individuals - eg asthma• If a anaphylactoid reaction occurs acetylcysteine is

temporarily halted or slowed and antihistamines and other supportive care is administered

Salicylates• Acute overdose has a mortality rate of 2%. Chronic overdose

is more commonly lethal - 25%. Children are at greater risk• Mild :nausea and vomiting, abdominal pain, lethargy,

tinnitus, and dizziness• Severe: hyperthermia, tachypnea, respiratory alkalosis,

metabolic acidosis, hypokalemia, hypoglycemia, hallucinations, confusion, seizure, cerebral edema, and coma

• Spectrophotometric plasma salicylate levels generally range from 30-100 mg/L (3-10 mg/dL) after usual therapeutic doses, 50-300 mg/L in patients taking high doses and 700-1400 mg/L following acute overdose

Treatment options• Activated Charcoal: Additional charcoal if serum salicylate levels are

increasing • D5W to keep a urinary output between 2 - 3 ml/kg/hr• Alkalinization of the urine: (salicylate level greater than 35 mg/dl 6

hours after ingestion – aim urine pH 7.5 - 8.0)) Sodium bicarbonate administered regardless of the serum pH as it enhances elimination of aspirin in the urine

• Haemodialysis: Acute ingestions (100 mg/dL), Chronic ingestions(40 mg/dL),or significant neurotoxicity (agitation, coma, convulsions), renal failure, pulmonary edema, or cardiovascular instability.

Advantage of restoring electrolyte and acid-base abnormalities while removing salicylate

TCA’s

• Narrow TI• ANS,CNS,CVS• 4 major pharmacological effects: • Anticholinergic effects• Excessive blockade of norepinephrine reuptake at the

postganglionic synapse• Direct alpha adrenergic blockade• Blockade of sodium membrane channels with slowing of

membrane depolarization -quinidine like effects on the myocardium

Management• Assess and treat ABCs as appropriate• ECG - QRS>0.10 seconds• Gastric lavage only if within one hour and life-threatening• Activated charcoal if within one hour • Give sodium bicarbonate (50 ml of 8.4%) if

– pH <7.1, QRS >0.10 sec, arrhythmias, ↓ BP • Arrhythmias

– Avoid antiarrhythmics (phenytoin, lignocaine)– Correct hypoxia, ↓BP, acidosis, hypokalemia

• Hypotension – IV fluids, inotropes• Cardiac arrest – prolonged resuscitation successful• Monitoring – minimum 6-12 hours without sign of toxicity in ICU• Highly protein bound with a large volume of distribution; therefore

hemodialysis, hemoperfusion or other techniques are unlikely to be of any significant benefit

• Indications for RSI: TCA overdose delays gastric emptying and may cause vomiting, increasing• aspiration risk, particularly in patients with reduced level of consciousness. A low threshold for early• intubation should be adopted and the need should be continually reassessed. It is imperative to• ensure the availability of adequate expertise during rapid sequence induction.• Gastric decontamination: Activated charcoal may be considered for use within 1 hour of TCA• ingestion but only in patients with an intact or secured airway. The potential risk of aspiration should• be strongly considered before use. Gastric lavage may be considered for potentially lifethreatening• TCA overdoses only when it can be delivered within 1 hour of ingestion and the airway• is protected.• Hypotension: TCA overdose causes hypotension by reducing preload and afterload as well as• direct effects on the myocardium. Optimising the preload may reverse hypotension. This may be• achieved by head-down tilt and bolus of intravenous fluid. Sodium bicarbonate may reverse• hypotension even in the absence of acidosis and is indicated if hypotension is persistent. If• hypotension still persists, vasopressors/inotropes should be used. There is some evidence that• epinephrine may be preferable to norepinephrine in this situation.• Arrhythmias: Administration of sodium bicarbonate, even in the patient without acidosis, may• reverse TCA-induced arrhythmias. If arrhythmias are persistent, magnesium sulphate may be given,• although there is limited available evidence for its efficacy.• ECG abnormalities: QRS prolongation (>0.10s) and right axis deviation are associated with• increased risk of cardiac arrhythmias. The use of sodium bicarbonate should be strongly considered• in this situation.• Sodium bicarbonate: For life-threatening toxicity use 50-100ml 8.4% sodium bicarbonate. The dose• can be repeated with blood gas monitoring to a target pH of 7.45-7.55. For more stable patients• 500ml 1.26% sodium bicarbonate carries less risk of skin necrosis in the event of extravasation.• Seizures: Prolonged seizures should be treated initially with benzodiazepines. Phenytoin should be• avoided because of a possible interaction with TCA’s. If there is no response to benzodiazepines• RSI should be considered.• ECG monitoring is essential for all patients at moderate/high risk. Serial 12-lead ECG recording is• recommended in all patients to monitor for changes in QRS duration.

Digoxin

• Very narrow therapeutic window• Nonspecific: fatigue, blurred vision, change in color

vision (eg. "yellow" vision"), anorexia, nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, confusion, delirium

• Therapeutic level for digoxin is 0.5-0.8 ng/mL• Low serum potassium increases the risk of digoxin

toxicity and cardiac dysrhythmias• Classic arrhythmia is a paroxysmal atrial tachycardia

with block.

Treatment

• Supportive measures – Hypokalaemia exacerbates digoxin toxicity

• The primary treatment of digoxin toxicity is digoxin immune Fab

• Other treatment: magnesium, phenytoin, and lidocaine

• Atropine can also used in cases of bradyarrhythmias

Other drugs and their antidotes

Opiates• Naloxone

Benzodiazepines• Flumazenil• Not to be used in mixed

overdoses

Beta blockers• If the patient is hypotensive, administer 20 mL/kg of isotonic intravenous

fluids and place the patient in the Trendelenburg position. If the patient does not respond to these measures, the following interventions may be considered:

• Inotropes and chronotropes• Glucagon (Diagnostic and DOC)• Gastric decontamination• Benzodiazepines (in patients with seizures)• Hemodialysis (Atenolol, low protein binding)• Cardiac pacing/cardiopulmonary resuscitation• Insulin (effects on contractility)• Intravenous fat emulsion (Propanolol, verapamil, other lipid soluble drugs)

Local Anaesthetics

• Myonecrosis• Nerve injury/TNS• Neurotoxicity• Cardiotoxicity – Intralipid• Methaemaglobinaemia (Prilocaine/EMLA,

Benzocaine)

Cyanide/SNP

• Potential adverse effects on organ systems• Toxicity – Plasma CN > 8µg/ml• Increased risk (tachyphylaxis, hypothermia,

renal failure, hepatic failure, B12 deficiency)• Uncouples oxidative phosphorylation• Met Acidosis, increased venous sats,

arrhythmias, tachyphylaxis

Electron transfer from

Fe2+(ie SNP + OxyHb)

Red blood Cells

SNP

5CN-

MetHbN=O

• N=O activates guanylate cyclasecGMP effects free intracellular Ca2+Smooth muscle relaxation• Methaemoglobin (Fe3+)• CN- + Cytochrome oxidase = Cyanide Toxicity

Handling the CN-1.Dicobalt edetateChelation2.Nitrites (Sodium/Amyl)Converts OxyHb to MetHb – higher affinity for CN- than

cytochrome oxidaseProduces CyanmetHb3.Sodium ThiosulphateRelies on Rhodanase and VitB12 to produce Thiocyanate (100x less

toxic than CN-)4.Vitamin B12No value in the acute setting

Assessment and treatment• Signs of cyanide toxicityCentral nervous system dysfunction: mental status change, seizure, comaCardiovascular instability: tachyphylaxis (hypertension); electrocardiogram

changes (arrhythmias, ST segmentchanges)Increasing metabolic acidosis: increasing base deficit; plasma lactate > 10• Treatment of suspected cyanide toxicity• Stop infusion of SNP• 100% oxygen (despite normal 0, saturation)• Mechanical ventilation as indicated• Correction of metabolic acidosis with NaHCO3,• 3% sodium nitrite 4-6 mg/kg slow intravenously (IV)• Sodium thiosulfate 150-200 mg/kg IV over 15 min• Consider hydroxycobalamin (vitamin B12) 25 mg/h

Methaemoglobinaemia

• Methemoglobin is an oxidized form of hemoglobin

ie Result of OXIDATIVE STRESS• Increased affinity for oxygen, resulting in a

reduced ability to release oxygen to tissues.• The oxygen–hemoglobin dissociation curve is

shifted to the left• Tissue hypoxia

• Congenital: (Enzyme deficiency)Diaphorase I (NADH methaemoglobin reductase)Pyruvate KinaseG-6-PD• Acquired

• Gives blood a bluish or chocolate-brown color.• Spontaneous formation of methemoglobin is

normally reduced (via electron donation) by protective enzyme systems

1) NADH methemoglobin reductase/ Cytochrome-b5 reductase (major pathway)

2) NADPH methemoglobin reductase (minor pathway) The NADPH is generated via the hexose monophosphate shunt

3) To a lesser extent the ascorbic acid and glutathione enzyme systems

• Methylene blue provides an artificial electron acceptor for NADPH methemoglobin reductase

• Diaphorase II normally contributes only a small percentage of the red blood cells reducing capacity but is pharmacologically activated by exogenous cofactors. Methylene blue allows the enzyme to function at 5x normal levels

Organophosphate Poisoning

SLUDGEM • Salivation• Lacrimation• Urination• Defecation• Gastrointestinal motility• Emesis• Miosis

• Nicotinic expression at the neuromuscular junctionMuscle weakness, fatigue, muscle cramps, fasciculation, and

paralysis• Autonomic ganglia - overstimulation of nicotinic expression in

the sympathetic systemHypertension, increased heartbeat and blood pressure,

hypertension, and hypoglycemia• CNS - accumulation of AchAnxiety, headache, convulsions, ataxia, depression of respiration

and circulation, tremor, general weakness, and potentially coma

• Muscarinic overstimulationVisual disturbances, tightness in chest, wheezing due to

bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination

Treatment

• Supportive• Atropine – Glycopyrolate• Irreversible vs reversibleObidoxime, pralidoxime

Carbon Monoxide

• Naturally produced by the action of haemoxygenase 1 and 2 on the haem from haemoglobin breakdown

1. Reduces O2 carrying capacity (230x affinity of O2 for Hb)

2. Adverse effect on mitochondrial cytochrome oxidase, binds to myoglobin and causes brain lipid peroxidation

Concentration Symptoms

35 ppm (0.0035%) Headache and dizziness within six to eight hours of constant exposure

100 ppm (0.01%) Slight headache in two to three hours

200 ppm (0.02%) Slight headache within two to three hours; loss of judgment

400 ppm (0.04%) Frontal headache within one to two hours

800 ppm (0.08%) Dizziness, nausea, and convulsions within 45 min; insensible within 2 hours

1,600 ppm (0.16%) Headache, tachycardia, dizziness, and nausea within 20 min; death in less than 2 hours

3,200 ppm (0.32%) Headache, dizziness and nausea in five to ten minutes. Death within 30 minutes.

6,400 ppm (0.64%)Headache and dizziness in one to two minutes. Convulsions, respiratory arrest, and death in less than 20 minutes.

12,800 ppm (1.28%) Unconsciousness after 2-3 breaths. Death in less than three minutes.

A few points

• Patients don’t arrive with labelsConsider the toxidromes• Illicit drug use is more common than we

realise• Don’t forget nutriceuticals and their effects• There are helpful resources on the internet

and poison centres open 24 hrs a day• SAMF is a reasonable reference if you’re still

lost