Critical care toxicology Poisoningrelated bradycardia Dr Chan Yan

Critical care toxicology Poisoning-related bradycardia Dr Chan Yan Fat Alfred ICU 15/8/2007

What is toxicology? • Toxon Latin for “Bow”

What is toxicology • Toxicon pharmacon Latin for “Arrow poison”

Paracelsus (1493 -1541) Alchemist Physician Surgeon Scientist

Paracelsus—father of modern chemical pathology (Toxicology) • As he taught alchemistry: “Stop making gold, instead find medicines. ” He made medicines and used on patients. • When challenged by people about that his drugs were poisons, he replied “All things are poisons, for there is nothing without poisonous qualities…. . . It is only the dose which makes a thing poison”

What to know about toxicology • Chemical pathology 1. Toxicokinetics: absorption, distribution, 2. • 1. 2. elimination Toxicodyamics: mechanism of toxicity Clinical toxicology Assessment: “poisoning history”, examination, toxic syndrome (Toxidrome) Treatment: supportive, enhanced elimination, antidote, specific (Rarely)

Clinical toxicology—history • 1. 2. 3. 4. • 1. 2. 3. Toxic substance related What is the agent What form and what route of exposure When and How much Any other people involved Symptoms related The symptoms and temporal sequence Attempted self-treatment Past medical health

Clinical toxicology—examination 1. BP shock (Inderal) vs. hypertension 2. 3. 4. 5. 6. 7. (Metamphetamine) Pulse brady (Digoxin) vs. tachy (Nuelin) Temp hypo (OHA) vs. fever (ASA) RR hypo (Opioid) vs. hyper (CH 3 OH) H’stix hypo (OHA) vs. hyper (CCB) Sa. O 2 desaturate (Met. Hb) vs. 100 (CO) Neurological pupil, central, motor

Examination form toxidrome 1. 2. 3. 4. 5. Opioid: miosis; ileus, coma; apnea; Symathomimetic: BP and HR; agitation Anticholinergic: mydriasis; delirium; AROU Cholinergic toxidrome: SLUDGE + kill “B” Special syndromes Serotonin syndrome Neuroleptic malignant syndrome

Intervention Antidote Decontamination Supportive care Exposure termination Management pyramid Specific treatment

Intervention—ask yourself first • Is exposure confirmed? • Is substance potentially toxic? • Is toxicity potentially lethal? • Can we stop the absorption? • Can we enhance elimination? • Is there any effective antidote? • Is our intervention potentially kill? All procedures can kill

Multi-dose activated charcoal (MDAC) • Abolish enterohepatic circulation • Enteroenteric removal e. g. aminophylline • Dose: 1 mg/kg BW for 3 doses Q 6 hours • NOT if caustics; in IO; drugs not bound • A aminophylline (aspirin) B C D Q barbiturates carbamazepine digoxin; dapsone qunine

Whole bowel irrigation • • 1. 2. 3. PEG via RT 1 -2 L/ hour Until rectal output as clear as RT input +/- erythromycin and maxolon Indications Toxin not bound by AC e. g. Li, Fe Sustain release preparation Bodypacker

Mechanism of bradycardia • Altered autonomic tone Enhanced cholinergic Sympatholytic • Cardiac conduction blockage • Membrane depressant • Other medical illnesses and metabolic disturbances e. g. hypothermia, electrolyte

Cholinergic agents Digitalis glycosides Organophosphates/ carbamates Physostigmine/ neostigmine Aconitine Ciguatera Tetrahydropalmitine Sympatholytic agents Beta-blocker Alpha 2 -agonist: clonidine Opiates/ sedatives Membrane depressant TCA Chloroquine Quninine Propanalol Flecainide Calcium antagonist Alpha 1 -agonist

PACED common agents • Propranolol and other beta-blockers • Anticholinesterase • Calcium channel blocker, Clonidine • Ethanol and other sedatives • Digoxin

47 -year-old divorced woman • History of suicidal attempt in April 2007 by overdosing 30 tablets of Imovane • Depression FU WPC psychiatry, on PRN benzodiazepines and SSRI • Found collapse in a running MTR train near Cheung Sha Wan station • No detailed history A/V • No seizure/ vomiting/ empty bottle

Arrived AED • Deeply comatose, GCS E 1 V 2 M 4 • Pupils bilaterally fixed and dilated • Limb reflexes equal both side • No neck stiffness/ needle mark • Pulse 35, BP 105/40, Sa. O 2 N/A • Temperature 34. 0 • H’stix 3. 1

Impression: Collapse ? DO • Atropine 0. 6 mg IV, pulse raised to 60 • Intubated with #7. 5 tube, no sedation • PEA after intubation, 2 doses of adrenaline 1 mg IV given. BP returned 134/60, Sa. O 2 now 100% • Relative was contacted, pending to come • Consulted ICU

ICU assessment • BP 60/22, pulse 56 per minute • ABG: p. H 7. 45, CO 2 31, O 2 224, HCO 3 22 • RFT: Na 139, K 3. 6, Creat 69 • Hb 10. 3, WCC 14. 9 • Cardiovascular collapse not able to be explained • • by BDZ, imovane, SSRI Too unstable for CT scan To ICU for management

ICU management • ECG showed first degree AV block, intermittent sino-atrial arrest with escape • Bedside echo global LV impaired 30% • Start adrenaline and noradrenaline infusion at the same time via CVC • Insert RT for gastric lavage. Send GA and urine for urgent toxicology assay • Empirical trial of antidote + RT charcoal

ICU medication chart • 1501: Adrenaline 1 mg IV • 1505: D 50 IV 20 ml • 1508: Adrenaline 1 mg IV • 1515: 8. 4% Na. HCO 3 IV 100 ml • 1525: Calcium Chloride IV 5 ml then 5 ml • 1535: Glucagon 1 mg IV • 1540: Dextrose-insulin-K drip, 60 ml/ hour • 1540: Glucagon 5 mg bolus

Temp ml 37 40 36 Temp BP/P SBP 140 Pulse 130 120 30 110 35 20 100 90 34 80 NE infusion 10 70 60 Extubation 50 Glucagon 3 p 2/5 6 p 2/5 9 p 2/5 MN 3/5 3 A 3/5

Mother arrived ICU 1700 • Missing of one bottle of Betaloc 50 mg tablets, ~80 tablets. She was a known case of HT FU at GOPD • Phone result from PMH Toxicology reference laboratory strong signal for Betaloc from gastric aspirate!

ICU progress • Tail off adrenaline infusion 2000 • Off Dextrose-insulin-K drip for poorly controlled glucose • Returned consciousness at Mid-night • Extubated 3/5/07 at 10 am • Off NE infusion 4/5/07 at 10 am • ARF requiring IHD for ~1/52, home D 13

Beta-blocker overdose (1) • Beta-1: cardiac contractility, conduction • Beta-2: hepatic glycogenolysis and • • gluconeogenesis; SM relaxation Overdose: rapid onset ~1 -4 hours lipid soluble CNS effect++ non-lipid soluble renal excretion Propranolol: membrane depressant effect Na channel block arrythmia

Beta-blocker overdose (2) • CNS: delirium, coma, seizure • CVS: shock, bradycardia, QRS widen • Resp: suppression and apnea • Hypoglycemia: especially children • Hypothermia • Rarely hyperkalemia • Bronchospasm at susceptible individual

Management of this patient (1) Gastric lavage • Ingested > 1 hour not very effective • May increase vagal tone further • However, already intubated to protect airway. Uncertain drug nature with definitely fatal manifestation

Management of this patient (2) Antidote trials • Atropine not likely to help hypotension as myocardium is depressed globally Na. HCO 3 • More useful in context of QRS widen, and particularly for Inderal

Management (3)---- Glucagon • Bypass beta-receptor to activate adenyl cyclase more c. AMP improved Ca flux • Effects will be seen in minutes • 2 -5 mg bolus, repeat 5 min PRN til 10 mg • Infusion: rate set at minimum effective dose to reach stable hemodynamics • No direct trial to compare E/NE infusion

83 -year-old woman • HT/DM/CRF with Creat 250, WC bound • Adalat Retard induced facial flush • FU CMC, on Betaloc 125 mg BD, Herbesser SR 90 mg BD, Minipress 4 mg BD • Seen by MO Dr L on 8/6/2007, BP 209/90. Hebesser SR increased to 180 mg BD • Attend AED because of dizziness at home

At AED “R” room 0100 • BP 51/22, pulse 35/ min • Temp 36. 6, Sa. O 2 90% on room air • H’stix HHH (Later glucose 30 mmol/L) • Alert, deny chest pain • Deny suicidal attempt by DO • JVP elevated, chest with basal fine creps+

AED management • Junctional bradycardia on ECG • Impression: ACS with hypotension • NS 500 ml IV over one hour • IV atropine 0. 6 mg nil effect seen • Humulin-R SC 4 units • TCP: rate 60, output 60 m. V • Discuss with ICU senior (MO SL) to CCU

ICU management • Suspected CCB overdose • Ca Gluconate 10% IV 10 ml at 0207 • BP 63/37, still pacing dependent • Dopamine 200 mg in 100 ml NS, start at 20 ml per hour at 0215 • In view of CHF with obliguria for TVP • Transvenous pacing performed smoothly: rate 80, output 2, sensitivity 1

CCU progress • MAP soon maintained at 60 -80 mm. Hg • Insulin sliding scale for glycemic control • Dopamine: 20 ml/ hour 0220 16 ml/ hour 0310 8 ml/ hour 0700 4 ml/ hour 0900 • Off Dopamine and pacing at 1600

Further progress • Echo showed mild AR and LVH, no segmental movement abnormality • Serial troponin within normal limit • Creat: 250 327 239 198 12/6 13/6 14/6 15/6 • Home on 16/6/2007, with hydralazine 25 mg tds; Minipress 1 mg BD

Management of this patient (1) GI decontamination • Gastric lavage is not useful and potentially dangerous for this old woman in CHF • Considered multi-dose activated charcoal • If more concrete drug overdose history consider whole bowel irrigation (WBI) by instillation of PEG via RT

Management of this patient (2) Use of IV calcium preparations • Of first priority • 10 ml Ca. Cl 2 or 3 ampoules Ca gluconate IV slowly over 3 minutes • Up to 5 g of Ca. Cl 2 may be given, but subsequent dosing need serum Ca/PO 4 monitoring. • Transient effect re-dosing + backup

Management of this patient (3) Dextrose-insulin drip • Restore cellular uptake and utilization of glucose of myocardium and vascular SM • Cautious about glucose and K • 50 ml D 50 + 10 units insulin IV over 30 minutes, then 0. 2 -1. 0 u/kg BW/ hour infusion along with Dextrose solution • Onset most rapid at higher dose

A nurse of X hospital medical • 22 year-old girl • Relationship problem with BF • Admitted at 18: 51 pm because found • • • drowsy at hostel with empty bottle Last seen at Noon Nausea & vomited some tablets Complained blurred vision BP 80/45, pulse 35 per minute Sa. O 2 100% on NRM, H’stix 7. 0

Transferred to ICU • Patient refused to talk • Fluid challenge of 1 L NS BP 95/45 • Dopamine 200 mg in 100 ml NS, 20 ml/hour • Blood test: K 5. 6, creatinine 133 • D-I infusion and atropine nil effect

A-line

During transvenous pacing • Runs of wide-complex tachycardia during procedure, and pacing was abandoned finally. • Put on TCP, rate 60, output 50 m. V • One very important test was done after case reviewed by on-site physician

Digoxin level 12. 4 ng/ml On direct questioning • Took 45 tablets of digoxin (0. 25 mg) at noon! • took 40 more tablets of digoxin (0. 25 mg) at 2 pm!!

ICU progress • 21 vials of Digitalis antidote were given • Entered into diuresis phase the next day • Vigorous K and Mg replacement in the following days • Direct in-patient transfer to KCH after stabilization in ICU then CCU • ? Still working as nurse

Digoxin toxicity manifestation • Extracardiac: Nausea/ vomiting always + Headache and blurred vision Delirium for elderly Hyperkalemia • ECG: typically reverse tick change of ST • VT/ VF (increased automaticity) AV nodal blockage

K level determine prognosis

Management of this patient (1) Supportive measure • Lavage is not without risk, and not better than the other measures • Effectively adsorbed by activated charcoal. In renal failure, multi-dose will enhance elimination

Management of this patient (2) Treatment of arrhymias • Always maintain K > 4 as hypokalemia enhance digoxin toxicity • Avoid Mg if already in extreme bradycardia • NEVER use Ca because more toxicity • Amiodarone as treatment of choice for VT • TVP easily induced tachy-arrhymias!

Indication for digoxin antidotes • Rhythm criteria: brady or VT/VF • Empirical for unexplained bradycardia • Potassium: always give if K > 5 for acute overdose patients • Digoxin ingestion > 10 mg • Digoxin level 10 -15 ng/ml (13 -19. 5 nmol/l)

In HK, digoxin antidote dose = ½ of digibind

In HK, digoxin antidote dose = ½ of digibind

Herbs also contain digitalis • Neutralization of Free Digoxin-like Immunoreactive Components of Oriental Dan Shen and Lu-Shen-Wan by Digiband • Am J Clin Pathol 2005; 121(2): 277 -281

Comparison of 3 major classes BP Herbesser Mentation Other Low Preserved Hyper. G Ca Beta-blocker Low Confused Hypo. G Digoxin Antidote N Confused Glucagon Visual Digoxin antibody VT

54 -year-old man • Chronic polyarticular joint pain for years • Defaulted FU YCH ortho • Took herbal formula 2 weeks ago without side effects. Subjective improvement • Purchase one herb and self-prepare, take the stuff at noon • Palpitation and syncope at home 1600 • Generalized numbness and diarrhea

While waiting at AED • Witnessed convulsion and arrest • First cardiac strip asystole • CPR for 3 minutes, adrenaline 1 mg bolus • Developed polymorphic ventricular tachycardia requiring defibrillation • Amiodarone 300 mg then 300 mg bolus • Amiodarone infusion 1. 5 g over 24 hours

Management at ICU • Pulse 40 per minute with BP 95/45 • Atropine 0. 6 mg IV stat • Overdrive pacing performed, rate set at 80 per minute. Amiodarone infusion continue • Echo showed normal LVEF with no ischemic component. RFT normal • Urine/ herb extracts +ve for Aconitine

Aconitine (烏頭鹼) inside

What cause the problem • The self-purchased item is 草烏 • The previous formula contained 制草烏, which is a pre-processed form of 草烏 • Inappropriate/ inadequate processing will retain large quantity of aconitine derivatives

Aconiti roots • Aconitum: Chuen-WU, Cao-Wu, Fu-Zi • Therapeutic indication: rheumatism and common cold remedies • Narrow therapeutic index easy overdose • Processing too short retain aconitine • May mix-up with other herbs • Hidden aconitine ? Due to contamination

Acontine effect • • 1. 2. 3. Sodium channel effectors Clinical effects GI: nausea/ vomit/ diarrhoea Neurological: numbness, weakness CVS: hypotension, sinus bradycardia, VT

2006 Annual report of TRL

Case from TRL

Management of this patient • If presented early < 1 hour Activated • • charcoal may help Inotrope for hypotension Amiodarone infusion as treatment of choice. Magnesium can also be useful Charcoal haemoperfusion for refractory case of ventricular arrhythmia Send urine to TRL for suspected cases

A couple was admitted PY 1998 • The couple enjoyed anniversary by selfcooking a fish brought in market • Dinner at 6 pm • Abdominal pain and diarrhea at MN • Postural dizziness on wakening 6 am • Feel distressful finger tingling • ECG showed sinus bradycardia 45/ min

紅鮋 (Mangrove Snapper)

Ciguatera • Syndrome caused by ingestion of Ciguatoxin-containing coral fish • Symptoms started 6 -12 hours after ingestion, and may last for months • GI symptoms: first to start and last 1 -2 d • Neurology: Paresthesia and dysesthesia • CVS: bradycardia. Shock may persist • Resp failure in severe cases

Gambierdiscus toxicus

Management of Ciguatara • Prevention is the best. Note that the toxin is heat and acid stable, and bioaccumulated along the food chains • Consider charcoal if early presentation • IV mannitol 1 g/kg BW over one hour • Gabapentine was reported useful to relieve sustained symptoms