Toxicology for the Anaesthetist

1. Toxicology for the Anaesthetist

2. The concepts of management of drug overdose in general • Specific drugs (Paracetamol, salicylates, opiates, TCA, digoxin, beta blockers, Organophosphates, Cyanide/Nitroprusside, Methaemaglobinaemia, Carbon monoxide)

3. The Principles of management • 1) Exposure Phase Irrigation, dilution, Adsorbants

4. 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)

5. 3) Toxodynamic phase – Antidote/supportive care • Neutralisation/ complexation (DigoxinFab) • Increased biotransformation (NAC) • Decreased biotransformation to toxic metabolites (Ethanol vs ethylene glycol) • Elevated threshold of toxicity due to competitive antagonism (Amyl Nitrate)

6. 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)

8. 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

9. 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

11. 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

12. 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

14. 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

15. 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.

16. 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.

18. 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

19. Other drugs and their antidotes Opiates Benzodiazepines Flumazenil Not to be used in mixed overdoses • Naloxone

20. 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)

21. Local Anaesthetics • Myonecrosis • Nerve injury/TNS • Neurotoxicity • Cardiotoxicity – Intralipid • Methaemaglobinaemia (Prilocaine/EMLA, Benzocaine)

22. 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

25. N=O activates guanylatecyclase cGMP effects free intracellular Ca2+ Smooth muscle relaxation • Methaemoglobin (Fe3+) • CN- + Cytochromeoxidase = Cyanide Toxicity

26. Handling the CN- 1.Dicobalt edetate Chelation 2.Nitrites (Sodium/Amyl) Converts OxyHb to MetHb – higher affinity for CN- than cytochromeoxidase Produces CyanmetHb 3.Sodium Thiosulphate Relies on Rhodanase and VitB12 to produce Thiocyanate (100x less toxic than CN-) 4.Vitamin B12 No value in the acute setting

27. Assessment and treatment • Signs of cyanide toxicity Central nervous system dysfunction: mental status change, seizure, coma Cardiovascular 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

28. Methaemoglobinaemia

29. 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

30. Congenital: (Enzyme deficiency) Diaphorase I (NADH methaemoglobinreductase) PyruvateKinase G-6-PD • Acquired

31. Gives blood a bluish or chocolate-brown color. • Spontaneous formation of methemoglobin is normally reduced (via electron donation) by protective enzyme systems • NADH methemoglobinreductase/ Cytochrome-b5 reductase (major pathway) • NADPH methemoglobinreductase (minor pathway) The NADPH is generated via the hexosemonophosphateshunt 3) To a lesser extent the ascorbic acid and glutathione enzyme systems

32. Methylene blue provides an artificial electron acceptor for NADPH methemoglobinreductase • 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

34. Organophosphate Poisoning SLUDGEM • Salivation • Lacrimation • Urination • Defecation • Gastrointestinal motility • Emesis • Miosis

35. Nicotinic expression at the neuromuscular junction Muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis • Autonomic ganglia - overstimulation of nicotinic expression in the sympathetic system Hypertension, increased heartbeat and blood pressure, hypertension, and hypoglycemia • CNS - accumulation of Ach Anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma • Muscarinic overstimulation Visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination

36. Treatment • Supportive • Atropine – Glycopyrolate • Irreversible vs reversible Obidoxime, pralidoxime

37. Carbon Monoxide • Naturally produced by the action of haemoxygenase 1 and 2 on the haem from haemoglobin breakdown • Reduces O2 carrying capacity (230x affinity of O2 for Hb) • Adverse effect on mitochondrial cytochromeoxidase, binds to myoglobin and causes brain lipid peroxidation

39. A few points • Patients don’t arrive with labels Consider 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