Critical Care Toxicology

1. Critical Care Toxicology Division of Critical Care Medicine University of Alberta

2. Objectives Approach to the poisoned patient General treatment strategies Common Poisonings in the ICU Toxicology literature

3. Epidemiology Approximately 2.4million exposures reported per year in the U.S. (2004) True incidence unknown 91% - single substance exposures 12.8% required ICU admission 7.0% required non-critical care 1183 fatalities (0.05%) 50.6% of fatal cases were multi-substance exposures Poisonings are common Very few are fatal � and fatal poisonings often involve more than one drug WA Watson et al, 2004 AAPCC Annual ReportPoisonings are common Very few are fatal � and fatal poisonings often involve more than one drug WA Watson et al, 2004 AAPCC Annual Report

4. Immediate Stabilization Airway with cervical spine control LOC, emesis, evidence of trauma Breathing Oxygen, ventilation if respiratory suppression Circulation IVs, fluid resuscitation Cardiac monitor Decontamination Enhance elimination Find an antidote Failure to secure the airway is most lethal toxicological complication Failure to secure the airway is most lethal toxicological complication

5. Important historical information Often incomplete, unreliable or unobtainable What was ingested, how much and when What was the patient doing when they became ill Past medical history Information from family, friends, EMS Pill containers � pill count May need to contact pharmacy

6. Toxicological Physical Exam CNS � level of arousal, GCS, pupils, behavior, neurological exam CVS � rate, rhythm Resp � pattern, depth, wheezing GI � bowel sounds, distention Skin � color, temp, signs of trauma Odors Brief, but detailed physical exam, hyperalert � look for anticholinergic toxidrome, nystagmus �PCP, phenytoin GI � may alert to toxidrome or to contraindication to decon methods Brief, but detailed physical exam, hyperalert � look for anticholinergic toxidrome, nystagmus �PCP, phenytoin GI � may alert to toxidrome or to contraindication to decon methods

7. Toxidromes Sympathomimetics Cholinergic Anticholinergic Opiate Sedative hypnotic Withdrawal (EtOH, BDZ, opiates) After PE � may be alerted to one of the more common toxidromes Can quiz residents on these � or notAfter PE � may be alerted to one of the more common toxidromes Can quiz residents on these � or not

8. Laboratory investigations General labs: CBC, lytes, BUN, Cr, glucose, ABG, anion gap Special laboratory investigation indicated in following cases Intentional ingestion Substance unknown Potential for moderate to severe toxicity Numerous studies in both adult and pediatric populations demonstrate that tox screen does not contribute to management of ptNumerous studies in both adult and pediatric populations demonstrate that tox screen does not contribute to management of pt

9. Laboratory investigations Labs considered essential and available within 4 hrs: EtOH, acetaminophen, salicylate, digoxin, carbamazepine, phenobarb, phenytoin, valproate, theophylline Labs available through referral center: Methanol, ethylene glycol, isopropyl alcohol, iron, lithium Tox screen � generally does not contribute to patient management

10. Additional Tests ECG � TCA or other cardiotoxic drugs, arrhythmias, ischemia Radiology CXR � aspiration, noncardiogenic pulmonary edema Abdominal films useful in screening for ingestions of radio-opaque materials What substances are visible on AXR?

11. Antidotes If after stabilization a toxin is identified, there may be a specific antidote There are approximately 18 antidotes commonly stored in tertiary care centers in N. America

12. Antidotes If, after your history, physical and lab investigations � you�ve id�d a toxin � there may be a specific antidote There are approximately 18 antidotes commonly stocked in tertiary care centers in N. AmericaIf, after your history, physical and lab investigations � you�ve id�d a toxin � there may be a specific antidote There are approximately 18 antidotes commonly stocked in tertiary care centers in N. America

13. Gastrointestinal Decontamination AACT/EAPCCT Position statement on gastrointestinal decontamination Clinical Toxicology 2004, 2005 Ipecac Gastric Lavage Whole bowel irrigation Single dose activated charcoal Cathartics

14. Ipecac Emetic � both peripherally and central acting >90% effective Dose: 30cc PO >5yrs, 15cc 1-5yrs, 10cc 6-12 mo Indications None, really consider in the out of hospital toxic ingestion Contraindications Unprotected or anticipated unprotected airway Hydrocarbons, caustics Debilitated patients Complications Diarrhea, lethargy/drowsiness, prolonged vomiting Historical value onlyHistorical value only

15. Gastric Lavage 36-40 Fr NG, sequential instillation and removal of small volumes of isotonic fluid Indications Recent ingestion (<1-2 hr) Substance exceeds adsorptive capacity of initial AC dosing Agents not adsorbed by AC Substances likely to form concretions after overdose Substantial risk of toxicity, or ? LOC requiring intubation (ASA, chloroquine, colchicine, TCA, CCBs)

16. Gastric Lavage Contraindications Unprotected airway Corrosives Hydrocarbons Risk of GI bleed or perforation Complications Aspn pneumonia, laryngospasm, hypoxia, mechanical injury, fluid/electrolyte imbalances

17. Whole bowel irrigation PEG via NG at 1-2 L/h (500cc/h in peds) until effluent clear Indications Potentially toxic ingestion of SR or EC prep Ingested packets of illicit drug (stuffers, packers) Substances not adsorbed by AC Iron ingestions

18. Whole bowel Irrigation Contraindications Bowel perforation or obstruction GI bleed Ileus Unprotected airway Hemodynamic instability Intractable vomiting Complications Nausea, vomiting, aspiration, cramps

19. Activated Charcoal 1g/kg PO or NG Indications Within 1 hour of ingestion Nearly all suspected toxic ingestions except May be considered more than 1 hour after ingestion but insufficient data to support or exclude use Contraindications Unprotected airway When AC therapy may increase risk and severity of aspiration Intestinal obstruction GI tract not anatomically intact (Boerhaave�s�) Complications Aspiration, emesis Produced by pyrolysis of carbonaceous materials to incr surface area, first demonstrated in 1930 by touery who took several times lethal dose of strychnine in front of the Academie Francaise , chased it with charcoal and survived. A number of questions remain to be answered � charcoal vs. nothing, symptomatic patients presenting in first hour after ingestion of agents that slow gastric emptying, sustained release preps, massive or life threatening ingestions, what to do for caustic ingestions, Single-dose activated charcoal should not be administered routinely in the management of poisoned patients. Based on volunteer studies, the administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a poison (which is known to be adsorbed to charcoal) up to one hour previously. Although volunteer studies demonstrate that the reduction of drug absorption decreases to values of questionable clinical importance when charcoal is administered at times greater than one hour, the potential for benefit after one hour cannot be excluded. There is no evidence that the administration of activated charcoal improves clinical outcome. Unless a patient has an intact or protected airway, the administration of charcoal is contraindicated. Produced by pyrolysis of carbonaceous materials to incr surface area, first demonstrated in 1930 by touery who took several times lethal dose of strychnine in front of the Academie Francaise , chased it with charcoal and survived. A number of questions remain to be answered � charcoal vs. nothing, symptomatic patients presenting in first hour after ingestion of agents that slow gastric emptying, sustained release preps, massive or life threatening ingestions, what to do for caustic ingestions, Single-dose activated charcoal should not be administered routinely in the management of poisoned patients. Based on volunteer studies, the administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a poison (which is known to be adsorbed to charcoal) up to one hour previously. Although volunteer studies demonstrate that the reduction of drug absorption decreases to values of questionable clinical importance when charcoal is administered at times greater than one hour, the potential for benefit after one hour cannot be excluded. There is no evidence that the administration of activated charcoal improves clinical outcome. Unless a patient has an intact or protected airway, the administration of charcoal is contraindicated.

20. Enhancing elimination Multiple dose activated charcoal Alkalinization Hemodialysis Hemoperfusion Hemodialysis has been discussed, hemoperfusion is accomplished by running the venous blood through a charcoal hemoperfusion cartridge The advantage of hemodialysis over hemoperfusion is that HD can also correct met acidosis/alkalosis, hyperkalemia, and fluid overloadHemodialysis has been discussed, hemoperfusion is accomplished by running the venous blood through a charcoal hemoperfusion cartridge The advantage of hemodialysis over hemoperfusion is that HD can also correct met acidosis/alkalosis, hyperkalemia, and fluid overload

21. Multiple Dose Activated Charcoal Improves elimination of drugs with enterohepatic circulation Initial dose of 1g/kg, then 1/4 - 1/2 g/kg q1h Consider only if life-threatening amount of: Carbamazepine Phenobarbital Dapsone Quinine Theophylline May also increase elimination of : amitriptyline, propoxyphene, digitoxin, digoxin, disopyramide, nadolol, phenylbutazone, phenytoin, piroxicam, sotalol Contraindications same as for single dose AC

22. Alkalinization Enhances elimination of weak bases by ion trapping Useful for: Salicylate, phenobarbital, chlorpropamide, methotrexate, myoglobin NaHCO3 1-2 mEq/kg IV Q3-4H Aim for Urine pH 7-8 Must replace K in order to achieve alkaline urine Not to be confused with forced alkaline diuresis Acidification of urine for weak bases was performed in the past, but not shown any benefit and causes met acidosisNot to be confused with forced alkaline diuresis Acidification of urine for weak bases was performed in the past, but not shown any benefit and causes met acidosis

23. Hemodialysis Blood passed across membrane with countercurrent dialysate flow Toxins removed primarily by diffusion Properties required: Molecular weight < 500 daltons High water solubility Low or saturable plasma protein binding Low Vd (<1L/kg) Low endogenous clearance(<4ml/min/kg)

24. Hemoperfusion Blood passed through extracorporeal circuit containing AC Toxins removed by adsorption Properties required: Low Vd <1L/kg Low endogenous clearance <4cc/min/kg Absorbable to AC Can also perform hemoperfusion/hemodialysis in seriesCan also perform hemoperfusion/hemodialysis in series

25. Substances amenable to hemodialysis LET ME SAV P Lithium Ethylene glycol Theophylline MEthanol Salicylates Atenolol Valproic acid Potassium Atenolol is only b-blocker with low VdAtenolol is only b-blocker with low Vd

27. Acetaminophen Common overdose Normally 90% metabolized by glucuronidation and sulfation, 5-10% metabolized by cytP450 to NAPQI In overdose glutathione stores are depleted ?NAPQI accumulates and directly damages liver, kidneys� ? susceptibility in alcoholics, malnourished b/c upregulated cytP450 and ? glutathione stores

28. Acetaminophen � clinical presentation Stage 1: Pre-injury period� 0-24h Asymptomatic or minor N+V Stage 2: Acute liver injury� 24-48h RUQ pain, ?AST/ALT, PTT, INR, bili +/- ?Cr Stage 3: Maximal liver injury � 48-96h marked hepatic dysfn?fulminant hepatic failure, encephalopathy, coagulopathy, hypoglycemia, acidosis, renal failure Stage 4: Recovery period - 4-14 days Resolution of hepatic dysfunction and recovery

29. Acetaminophen � treatment N-acetylcysteine (NAC) � 20 hr IV protocol Mechanism of action: Glutathione precursor Glutathione substitute Substrate for sulfation Non-specific free radical binder

30. Rumack-Matthew Nomogram

31. Acetaminophen Obtain serum level at 4hrs post ingestion and use Rumack-Matthew nomogram If 8 -24 hrs, or unknown time of ingestion draw level and start IV NAC Efficacy of NAC decreases with time if administered > 8 hrs post ingestion No documented fatalities if given within 8 hrs If over 24 hrs and acetaminophen level undetectable, AST and INR normal � no treatment required If INR > 2 after completion of 20hr protocol, continue infusion until INR < 2

32. Acetaminophen � transplant criteria King�s College Hospital Criteria Metabolic acidosis persisting after resuscitation � pH <7.3 or lactate > 3.0 All 3 of below within 24hrs Progressive coagulopathy � INR >6.5 Hepatic encephalopathy � Grade 3 -4 Renal failure � Cr >300

33. ASA Toxic dose � 200 mg/kg in single ingestion (40-45 x 325mg tab) Pts with chronic ingestion may have serious toxicity with remarkably low serum salicylate concentrations Mortality rate: acute salicylate intoxication 1% chronic salicylate intoxication 25%

34. ASA � preparations Aspirin 325 mg/ tab; 500 mg/ tab Enteric coated aspirin; 325 mg/ tab Children's aspirin 80 mg Oil of Wintergreen (100 % Methyl salicylate)7000 mg/ 5 ml Ben Gay� (20 % methyl salicylate)6000 mg/ 30 ml Pepto Bismol (Bismuth subsalicylate)650 mg/ 60 ml Herbal products contain various amounts

35. ASA � clinical features Initial Sx Hearing loss, tinnitus Significant toxicity Hyperventilation, N & V, dehydration, hyperthermia, altered LOC Serious toxicity Pulmonary edema, cerebral edema, renal failure, rhabdomyolysis, seizures, coma, death

36. ASA � clinical features Acid Base disturbance Resp. alkalosis - direct stimulation of medulla Compensatory metabolic acidosis � renal HCO3 loss Inhibition Krebs cycle enzymes -? lactate, ?pyruvate ?anion gap metabolic acidosis Uncoupling of oxidative phosphorylation - ? tissue glycolysis and BMR ? hypo/hyperglycemia, hyperpyrexia

37. ASA - treatment 1. Prevent further salicylate absorption Gastric decontamination Activated charcoal Whole bowel irrigation 2. Correct fluid deficits and acid-base abnormalities Volume resuscitation Careful not to over resuscitate to prevent precipitation of pulmonary/cerebral edema Must replace K+ Absorption is rapid with therapeutic doses, but may be significantly delayed in overdose (concretion formation)Absorption is rapid with therapeutic doses, but may be significantly delayed in overdose (concretion formation)

38. ASA -treatment 3. Enhance elimination Ion trapping Alkalinize urine: 3 amps NaHCO3 in 1L D5W Run @ 250cc/h to urine pH 7.5 -8.0 Urine salicylate clearance is directly proportional to urine flow rate, but more importantly, it is logarithmically proportional to urine pH

39. ASA - treatment Hemodialysis Toxic level (>3 mmol/L) and: CNS toxicity � sz, coma, delirium ARDS Renal failure Severe acid-base or electrolyte abnormality Coagulopathy Unstable or deteriorating vital signs CHF Acute level > 7mmol/L Chronic level > 4 mmol/L

40. Cardiac drugs � clinical presentation Calcium channel blockers Bradycardia and hypotension Awake and alert Hyperglycemia Narrow QRS May get reflex tachycardia with dihydropyridines CCBs interfere with activity of insulinCCBs interfere with activity of insulin

41. Cardiac drugs � clinical presentation Beta Blockers Bradycardia and hypotension Depressed LOC Hypoglycemia B-blockers block B-blockers block

42. Cardiac drugs Digoxin Variable HR +/- hypotension GI and visual symptoms Hyperkalemia Characteristic ECG findings Enhanced automaticity and slowed AV conduction Multiple PVCs � ventricular dysrhythmias GI � N and V, visual � yellow-green halos around lights Dig effect does not correlate with toxicityGI � N and V, visual � yellow-green halos around lights Dig effect does not correlate with toxicity

43. Cardiac drugs - treatment Calcium channel blockers IV CaCl or Ca gluconate, Fluids, pressors, pacing, IABP Insulin/glucose - 10-20 units IV, then 0.2-1 U/kg/h, with D5W or D10W infusion Beta blockers IV glucagon - 5-10 mg over 1 min, then 1-10 mg/h milrinone/pressors, pacing, IABP Insulin/glucose - J.A. Kline et al. Cardiovascular Research 34(1997)289�298 Insulin thought to improve myocardial carbohydrate utilization in CCB overdose (acts as an inotrope), insulin release is also a Ca channel dependent processInsulin/glucose - J.A. Kline et al. Cardiovascular Research 34(1997)289�298 Insulin thought to improve myocardial carbohydrate utilization in CCB overdose (acts as an inotrope), insulin release is also a Ca channel dependent process

44. Cardiac drugs - treatment Digoxin � Digoxin immune Fab (Digibind) Indications for Digibind Ventricular dysrhythmia Progressive/refractory hemodynamic instability K > 5 with acute toxicity Acute ingestion > 10 mg Dosing of Digibind Empiric tx acute toxicity� 10 vials Empiric tx chronic toxicity � 4-6 vials Known dose: (dose in mg x 0.8)/0.5 = # vials Steady state Vd at 6hrs: (serum dig level x wt)/100 = # vials

45. Tricyclic antidepressants Rapidly absorbed, large Vd, variable protein binding, lipophilic Mechanism of action Voltage dependent Na channel blockade �prolonged QRS Inward rectifier K channel blockade �prolonged QTc H1 and H2 receptor blockade � mixed effects Muscarinic receptor blockade - anticholinergic a-adrenergic receptor blockade - hypotension Blocks reuptake DA, NE � altered mental status GABA receptor blockade - seizures

46. Tricyclic antidepressants Drug levels do not correlate with toxicity ECG can be diagnostic of Na channel blockade: QRS > 100 msec - 30% risk seizures QRS > 160 msec � 50% risk arrhythmias Right axis deviation of terminal 40 msec of QRS � look in aVR Prolonged QT Sinus tachycardia

47. Tricyclic antidepressants � ECG

48. Tricyclic antidepressants - treatment Gastric lavage and AC if indicated Beware rapid decrease in LOC Avoid acidosis (Sz, ?BP) Serum alkalinization (hyperventilation, bicarb) Uncouples TCA from Na channel Increases Na gradient (mass effect) Increased pH decreases tissue penetration of TCA Indications for alkalinization QRS > 100 msec VT/Cardiac arrest Seizures or hypotension

49. Toxic Alcohols Methanol Present in windshield washer fluid, solvents, formaldehyde � bitter tasting Metabolized by alcohol DH, then aldehyde DH to formaldehyde, then formic acid Formic acid � inhibits oxidative phosphorylation and toxic to eyes and CNS Clinical Presentation Early (0-6h)� inebriation, gastritis, altered LOC Late (6-72h)� visual changes �snowstorm blindness�, metabolic acidosis, seizures, ?LOC

50. Toxic alcohols Ethylene glycol Found in antifreeze, coolants � sweet tasting Metabolized by alcohol dehydrogenase to glycoaldehyde, glycolic acid and oxalic acid Inhibit oxidative phosphorylation, and are toxic to CNS, lung and kidney Clinical Presentation Acute neurologic stage (30min-12hrs) Cardiopulmonary stage (12-24hrs) Renal stage (24-72hrs) Delayed neurologic stage (6-12d) Stages Acute neurol � inebriation, N/V, seizures, coma, osmolar gap Cardiopulmonary � HTN, tachycardia, met acidosis +/- pulmonary edema, shock Renal � crystalluria, hematuria, proteinuria, ATN and flank pain Delayed Neurologic � cranial n. palsies, deafness, cognitive and motor abnormalities, personality changesStages Acute neurol � inebriation, N/V, seizures, coma, osmolar gap Cardiopulmonary � HTN, tachycardia, met acidosis +/- pulmonary edema, shock Renal � crystalluria, hematuria, proteinuria, ATN and flank pain Delayed Neurologic � cranial n. palsies, deafness, cognitive and motor abnormalities, personality changes

51. Toxic alcohols - treatment Correct acidemia bicarbonate, allow hyperventilation Prevents diffusion of toxic metabolites into tissues Inhibit alcohol dehydrogenase EtOH � aim for level 22-33mmol/L Fomepizole � easier administration, safer, longer t1/2, but significantly more expensive Treat if EG>3mmol/L, MeOH >6mmol/L Documented or suspected ingestion and OG>10

52. Toxic alcohols - treatment Enhance elimination by hemodialysis Serum EG > 8 or MeOH > 15 Metabolic acidosis (pH < 7.25) End organ symptoms (i.e. visual changes) Renal impairment, electrolyte abnormalities Deteriorating vital signs Continue dialysis until EG < 3 or MeOH <6 Adjunctive treatments Thiamine 100mg IV/IM q6H, pyridoxine 50mg IV/IM q6h (glyoxalate?glycine, other non-toxic) Folate 50 mg IV/IM q6h (Formate?C02 +H20) when alcohol DH blocked, t1/2 MeOH = 45hrs, Ethylene glycol =19hrs With EG watch calcium as oxalate will bindwhen alcohol DH blocked, t1/2 MeOH = 45hrs, Ethylene glycol =19hrs With EG watch calcium as oxalate will bind

53. Summary ABC�s Supportive therapy sufficient for most overdoses Decontamination/enhancing elimination Antidotes/specific treatment indicated for certain overdoses

54. Questions

55. Pupils Miosis Cholinergics/clonidine Opiates/organophosphates Phenothiazines, pilocarpine, pontine bleed Sedative hypnotics Mydriasis Antihistamines Antidepressants Anticholinergics Sympathomimetics

56. Odors Bitter almonds � cyanide Fruity � DKA, isopropanol Minty � methyl salicylates Rotten eggs � sulfur dioxide, hydrogen sulfide Pears � chloral hydrate Garlic � organophosphates, arsenic Mothballs - camphor

57. Drugs that don�t adsorb to AC PHAILS Pesticides Hydrocarbons Acids/alkalis Iron Lithium Solvents

58. Radiodense substances that may be visible on AXR CHIPES Chloral hydrate Heavy metals Iron Phenothiazines Enteric coated preps Sustained release preps Drug Packets