Transcript Toxicology - sums.ac.ir
IN THE NAME OF GOD
AN APPROACH TO A POISONED PATIENT
DR. FAZEL GOUDARZI;TRAUMATO PATHOLOGIST AND CLINICAL TOXICOLOGIST SHIRAZ UNIVERCITY OF MEDICAL SCIENCES
Introduction
What is a poison?
In common usage - poisons are chemicals or chemical products that are distinctly harmful to human More precisely - a poison is a foreign chemical (xenobiotic) that is capable of producing a harmful effect on a biologic system
Other terminology
What is a toxin?
It originally referred to a poison of animal or plant origin Toxicant is the currently preferred scientific term for all poisons.
Epidemiology Ingestion of a potentially poisonous substance by a young child is common.
American Association of Poison Control Centers reported 1.2 million ingestions in children < 6 years of age in 2001. Death is uncommon in this age group.
Decline in death rate from 500 mortalities per year in the 1940s to 25 mortalities in 1997
Epidemiology Decline in mortality attributed to: child resistant containers safer medications anticipatory guidance public education legislation establishment of poison control centers sophisticated medical care antidotes
Clinical assessment
Approach to the Poisoned Patient History Time of ingestion Medications in the household Amount ingested Onset of symptoms Intentionality Underlying medical conditions
Approach to the Poisoned Patient Physical Examination Vital Signs Pupillary exam (miosis, mydriasis) Skin (dry, cyanotic) Lungs (crackles, wheezing) Cardiac (tachycardia, bradycardia) Abdomen (decreased bowel sounds, tenderness) Neurologic (altered mental status, seizure)
Approach to the Poisoned Patient Initial Management Airway Breathing Circulation Disability Exposure
Clinical assessment
Airway - ensure clear airway, clear secretions, check for cough/gag
Breathing - check oxygenation, supplemental O2, breathing pattern & adequacy
Circulation - heart rate, rhythm, blood pressure
Clinical assessment
Neurologic - GCS, seizures, agitation, spasms, pupils, autonomic dysfunction
Miscellaneous - odour, temperature, pallor, cyanosis, jaundice
Abdomen - rigidity, bleeding, urine output
Laboratory and imaging(paraclinical) assessment
Approach to the Poisoned Patient Diagnostic Evaluation CBCD Electrolytes ABG LFTs CXR ECG AXR Serum Tox Urine Tox ASA level Tylenol level Serum OSM Cholinstrase
Laboratory assessment
Electrolytes
Hypokalemia
– Oduvanthalai poisoning (Clistanthis collinis) – Diuretics, Methyl xanthine, Toluene
Hyperkalemia
– Digoxin – Beta-blocker
Liver function tests
– Acetaminophen, Ethanol, Carbon tetrachloride
Renal function tests
– Ethylene glycol, NSAIDS
Anion Gap (AG)
Anion Gap = Na
+
- [Cl
-
+ HCO
3 -
] Normal AG: 8-16
Toxins associated with increased AG Methanol Paraldehyde INH Fe Ethylene glycol Salicylates CO Cyanide Hydrogen Sulfide ETOH (ketones) Metformin Phenformin Sulfur Theophylline Toluene
Toxins associated with decreased AG Lithium Bromide
Osmolal Gap (OG)
Serum OSM: 2[Na] + [ Glc]/18 + [BUN]/2.6
OG: Measured OSM-Calculated OSM Normal OG: -3 to 10 mOSM/kg H2O
Toxins associated with increased OG Methanol Ethanol Ethylene glycol Acetone Isopropanol
Useful Toxin Levels Set time point Acetaminophen Carbon Monoxide Ethanol Ethylene glycol Heavy metals Iron Methanol Methemoglobin Serial levels Salicylates Carbamazepine Digoxin lithium Phenobarbital Phenytoin Theophylline Valproate
ECG and Imaging Assessment
ECG
Digoxin toxicity
TCA overdose - sinus tachycardia, QT prolongation, increased QRS
Beta-blockers - conduction abnormalities
Imaging
Chest x-ray
Abdominal x-ray
Cervical x-ray (lateral) C.T scan or MRI in decrease L.O.C.
Radiopaque drugs Bezoars/Bags Calcium carbonate Chloral hydrate Enteric-coated tablets Heavy metals Iodine Fe Phenothiazines Potassium compounds
Other terminology
What is a toxidrome?(TOXICOLOGIC SYNDROME)?
It is the association of several clinically recognizable features, signs, symptoms, phenomena or characteristics which often occur together others. , so that the presence of one feature alerts the physician to the presence of the
Common toxidromes
Opiate toxidrome
Opiate toxidrome
Opiate toxidrome
Toxidromes Opiates Miosis Respiratory depression Cns depression Hypotension Sedation Decreased GI motility Urinary retention
Toxidromes Opiates Seizures-Meperidine; occur secondary to the metabolite normeperidine Dysrhythmias-Propoxyphene; occur from the metabolite norpropoxyphene Rigid Chest-Fentanyl
Common toxidromes
The cholinergic toxidrome
The cholinergic toxidrome
The cholinergic toxidrome
Toxidromes Cholinergics-Muscarinic Effects Salivation Lacrimation Urination Defecation Gastrointestinal Distress Emesis
TOXIDROME CHOLINERGIC CNS EFFECT RESTLESSNESS AGITATION CONFUSION CONVULSION COMA DEATH
Toxidromes Cholinergics-Nicotinic Effects Muscle Fasciculations Weakness Paralysis Sympathomimetic effect
What toxidrome?
The anticholinergic toxidrome
Hot as a hare Dry as a bone Red as a beet Mad as a hatter Blind as a bat
The anticholinergic toxidrome
Hot as a hare Dry as a bone Red as a beet Mad as a hatter Blind as a bat
The anticholinergic toxidrome
Hot as a hare Dry as a bone Red as a beet Mad as a hatter Blind as a bat
Toxidromes Anticholinergics “Red as a beet”- Flushed skin “Hot as a hare”-Hyperthermia “Mad as a hatter”-Psychosis “Dry as a bone”-Dry skin, urinary retention Tachycardia Mydriasis
What toxidrome?
Hallucinogenic Toxidrome disorientation hallucinations hyperactive bowel panic seizure Hypertension Tachycardia Tachypnea Amphetamine Cocaine Pseudoephedrine Phencyclidine Ephedrine Benzodiazepenes
Hallucinogenic Sympathomimetic toxidrome
Hallucinogenic and stimulants Toxidrome disorientation hallucinations Amphetamine Cocaine hyperactive bowel panic seizure Hypertension Tachycardia Tachypnea Pseudoephedrine Phencyclidine Ephedrine Benzodiazepenes
Hallucinogenic Sympathomimetic toxidrome
Hallucinogenic Toxidrome disorientation hallucinations hyperactive bowel panic seizure Hypertension Tachycardia Tachypnea Amphetamine Cocaine Pseudoephedrine Phencyclidine Ephedrine Benzodiazepenes
Hallucinogenic Sympathomimetic toxidrome
Hallucinogenic Toxidrome disorientation hallucinations hyperactive bowel panic seizure Hypertension Tachycardia Tachypnea Amphetamine Cocaine Pseudoephedrine Phencyclidine Ephedrine Benzodiazepenes
Hallucinogenic Sympathomimetic toxidrome
Hallucinogenic Toxidrome disorientation hallucinations hyperactive bowel panic seizure Hypertension Tachycardia Tachypnea Amphetamine Cocaine Pseudoephedrine Phencyclidine Ephedrine Benzodiazepenes
Common toxidromes
Sedative/hypnotic toxidrome
Sedative/hypnotic toxidrome
Sedative/hypnotic toxidrome
Common toxidromes
Serotonergic syndrome
Serotonergic syndrome
Serotonergic syndrome
Toxidromes Sympathomimetics Hypertension Tachycardia Psychomotor Agitation Hyperthermia Diaphoresis Mydriasis
Recognition of poisoning
May be difficult because of non-specific symptoms
High index of suspicion - especially occult poisoning
history may be unreliable look for corroborative history - missing pills, empty container
Course that a poison runs (toxidromes) ! - may help
Toxicology screening - helpful only in a few
Clinical manifestations
Very diverse and varied - depends on the poison
Clinical examination should be focused on the possible manifestations of common poisons in the geographical area
Clinical manifestations
Skin and mucosal damage
Neurotoxic manifestations
Cardiovascular manifestations
Metabolic consequences
Eye manifestations
Hepatic dysfunction
When do you consider ICU?
Respiratory
Airway protection
Respiratory failure
Cardiovascular
Hypotension despite fluid challenge
Heart block, arrhythmias, QTc prolongation as in TCA
When do you consider ICU?
Neurologic
GCS < 8 (grade 3 and4) Seizures
Metabolic
Hypoglycaemia
Significant electrolyte abnormalities metabolic acidosis Hepatic failure Coagulopathy with bleeding
Goals of treatment
Goals of treatment
Reduce absorption of the toxin (xenobiotic)
Enhance elimination
Neutralise toxin
Reduce absorption of the toxin
Reduce absorption
Removal from surface skin & eye Emesis induction Gastric lavage Activated charcoal administration & cathartics Dilution - milk/other drinks for corrosives Whole bowel irrigation Endoscopic or surgical removal of ingested chemical
Reduce absorption
Skin decontamination
– Important aspect – not to be neglected – Remove contaminated clothing – Wash with soap and water (soaps
containing 30% ethanol advocated)
– However, no evidence for benefit even in
OP poisoning
Decontamination
Gastric decontamination
– Forced emesis if patient is awake by gag
stimulation or by ipecac(?)
– Gastric lavage – Activated charcoal 1g/kg and MDAC in
some cases
– Sorbitol as cathartic – Whole bowel irrigation
Ipecac NO!!!!
Had been previously been recommended for administration at home immediately following ingestion ( No longer recommended in the AAP policy statement - Poison Treatment in the Home Pediatrics Vol. 112 No. 5, November 2003)
Why Not Ipecac?
Variable percentage of removal of toxic medication In adult volunteers: 51-83% removal (5 minutes after ingestion) 2-59% removal (30 minutes after ingestion) May cause persistent vomiting, lethargy, and diarrhea Vomiting may preclude later administration of oral antidotes
Why Not Ipecac?
Lethargy and vomiting together increase risk of aspiration Inappropriate use-following ingestion of acid or lye Misuse-children with eating disorders Misuse-Munchausen by proxy
Gastric Lavage Early following ingestion Airway must be protected Use the largest available tube (40 French) Contraindicated in caustic ingestions, hydrocarbons, previous vomiting
Reduce absorption
Gastric lavage
Gastric lavage decreases absorption by 42% if done 20 min and by 16% if performed at 60 min
Performed by first aspirating the stomach and then repetitively instilling & aspirating fluid Left lateral position better - delays spont. absorption No evidence that larger tube better Simplest, quickest & least expensive way - funnel Choice of fluid is tap water - 5-10 ml/kg Choice of fluid is NL SALIN for children
Reduce absorption
Gastric lavage
Preferrably done on awake patients Presence of an ET tube does not preclude aspiration, though preferred if GCS is low
Activated Charcoal Single Dose Toxic ingestions that adhere to charcoal Dose is 1 g/kg PO or NGT Administered with Sorbitol Airway must be protected Contraindicated in caustics, hydrocarbon, foreign body, ileus or gastric perforation
Activated Charcoal Multiple Doses Large ingestions Drugs that undergo enterohepatic circulation Drugs with low V d Drugs with low protein binding Drugs with long t 1/2
Activated Charcoal Multiple Doses Only the FIRST dose should be administered with Sorbitol Dose 1 g/kg PO or NGT Q6 x 24 hours or until charcoal is passed in the stool
Which drugs do not adsorb to charcoal?
Lithium Iron Alcohols Acids Alkalis Cyanide Hydrocarbons
Whole Bowel Irrigation Life threatening ingestion Sustained-release toxin Prolonged absorption time of the toxin Must protect the airway Contraindicated in caustic, hydrocarbon, foreign body, ileus, gastric perforation
Whole Bowel Irrigation Polyethylene Glycol Dose: up to 500 ml/h Continue until stool is clear Patient may get bloated and vomit Antiemetics (metoclopramide or ondansetron) may be helpful Monitor electrolytes closely
Toxins and their Antidotes Acetaminophen N-acetylcysteine Anticholinergics Anticholinesterases/ Cholinergics Physostigmine Atropine (muscarinic effects) Pralidoxime (nicotinic effects) -controversial in carbamate ingestions
Toxins and their Antidotes Benzodiazepines Botulism Beta-blockers Calcium channel blockers Carbon monoxide Cyanide, Nitrites Flumazenil Botulinum antitoxin Glucagon Calcium Hyperbaric O 2 , O 2 Amil nitrit;Na nitrit(300mg/10ml); ;Sodium Na thiosulfate(12.5g/50ml)
Toxins and their Antidotes Digoxin Digibind aka Digoxin Fab antibodies Ethylene Glycol Ethanol Heparin Iron Isoniazid Protamine Deferoxamine Pyridoxine
Toxins and their Antidotes Lead Methanol Methemoglobin Opioids EDTA, BAL, DMSA Ethanol Methylene blue Naloxone Tricyclic antidepressants Warfarin (Superwarfarins) NaHCO3 Vitamin K
Enhance elimination
Enhance elimination
Increased elimination is possible only if
the drug is distributed predominantly in the ECF has a low protein binding the induced rate of elimination is faster than the normal rate hazards of having a longer time of exposure to the drug are potentially fatal
Enhance elimination
Methods
Keep a good urine output 150-200 ml/hr Alkalinisation of urine - clinical efficacy accepted for salicylate & phenobarbital poisoning Extracorporeal removal
– Hemodialysis - Barbiturates, Salicylates,
Acetaminophen, Valproate, Alcohols, Glycols
– Hemoperfusion - theophylline, digitalis, lipid
soluble drugs
Enhance Elimination Methods Alkalinization and Urinary ion trapping Hemodialysis Charcoal hemoperfusion
Alkalinization/Urinary Ion Trapping Effective for drugs that are excreted renally The drugs must be either weak acids or weak bases e.g. ASA and Phenobarbital HA pKa H + +A At a Urine pH < pKa Non-ionized form *Not excreted in urine At a Urine pH > pKa Ionized form *Excreted in urine
Hemodialysis Low volume of distribution less than 1L/Kg Low protein binding Low molecular weight less than 500 DAL. Also helpful in managing acidosis, electrolyte abnormalities Low fat solubility High Water Solubility
Which drugs are high dialyzable?
Salicylates Methanol and ethanol Lithium Ethylene glycol Amphetamines Theophylline Vancomycin
(p. brophy) CVVHD following HD for Lithium i L
5
Li Therapeutic range 0.5-1.5 mEq/L
Pt #1 Pt #2
CVVHD started m E q / L
4 3 2 1 0 0 5
Hours
6 12
CT-190 (HD) Multiflo-60 both patients BFR-pt #1 200 ml/min HD & CVVHD -pt # 2 325 ml/min HD & 200 ml/min CVVHD
24
PO 4 Based dialysate at 2L/1.73m
2 /hr
Hemoperfusion Blood is passed through a cartridge containing charcoal or carbon Drugs with low Vd Toxins can be larger than those removed by hemodialysis Can be more protein bound than those cleared by hemodialysis Toxin must bind well to charcoal
Which drugs can be removed by hemoperfusion?
Theophylline Phenobarbital Carbamazepine Phenytoin Salicylates Paraquate
Complications of Hemoperfusion Thrombocytopenia Hypocalcemia Leukopenia Rigors
(p. brophy) HEMOFILTRATION optimal drug characteristics for removal: relative molecular mass less than the cut-off of the filter fibres (usually < 40,000) small Vd (< 1 L/Kg) single compartment kinetics low endogenous clearance (< 4ml/Kg/min) (Pond, SM - Med J Australia 1991; 154: 617-622)
(p. brophy) Continuous Detoxification methods CAVHF, CAVHD, CAVHP, CVVHF, CVVHD, CVVHP Indicated in cases where removal of plasma toxin is then replaced by redistributed toxin from tissue Can be combined with acute high flux HD
(p. brophy) Intoxicants amenable to Hemofiltration vancomycin methanol procainamide hirudin thallium lithium methotrexate
(p. brophy) Plasmapheresis / Exchange Blood Transfusions Plasmapheresis (Seyffart G. Trans Am Soc Artif Intern Organs 1982; 28:673) role in intoxication not clearly established most useful for highly protein bound agents Exchange Blood Transfusions Pediatric experience > than adult Methemoglobinemia overall very limited role in poisoning
Summary
Poisoning a common problem in our country
A high index of suspicion required to diagnose
Know common toxidrome
Don’t panic and follow a plan of action
Decreasing absorption Enhancing elimination
Neutralising toxins
Avoid potentially harmful Rxs - risk vs benefit
Thank you
Case Presentation 1
A 15 year old girl presents to the ED four hours after taking 20 extra-strength (500 mg/tablet) Tylenol tablets. The ingestion was prompted by a fight with her boyfriend earlier that day. She has a history of an attempted suicide in the past. She is awake and alert with stable vital signs. She complains of nausea and has had one episode of vomiting. Physical exam is normal. Baseline labs show normal electrolytes, with normal LFTs, normal coags and a Tylenol level of 120 microgram/ml.
What would you do?
A. Call psychiatry to evaluate the patient. No medical intervention is required.
B. Administer 1g/kg of activated charcoal with sorbitol every 6 hours and 17 doses of oral N-acetylcysteine.
C. Administer one dose of activated charcoal with sorbitol followed by intravenous N-acetylcysteine for 21 hours.
D. Gastric lavage in an attempt to recover pill fragments.
Acetaminophen Poisoning Toxic dose: 150 mg/kg or a total dose of 7.5 g Toxic level: 150 microgram/ml at 4 hours Antidote: N-acetylcysteine
Acetaminophen Metabolism 90% undergoes glucuronidation and sulfate conjugation in the liver to harmless metabolites excreted in the kidney < 5%, together with some insignificant metabolites are excreted in the kidney unchanged Remainder undergoes oxidation by the cyt-p450 system to N-acetyl-p benzoquinoneimine (NAPQI)
NAPQI Electrophile Covalently binds to hepatocytes Results in cell death Half life is about
POTENTIAL TOXICITY
Acute: 7g (10g)
Chronic: 4g per day (7g)
Susceptible patients (alcoholics, ACs, INH)
Similar risk for acute ingestion Potential higher risk in chronic ingestions (4g)
Phases of Toxicity I: (½-24 h):nausea, vomiting, diaphoresis May be normal II: (24-72 h): less nausea, vomiting; RUQ pain; LFTs and coags begin to rise III: (72-96 h): Coagulation abnormalities, renal failure, encephalopathy, death related to hepatic failure IV: (4 d-2 wk):If stage III damage is reversible, resolution of hepatic dysfunction
N-ACETYLCYSTEINE
Very effective – 100% within 8 hours
Oral in U.S. – IV in Europe
Dose: 140mg/kg load, 70mg/kg Q 4hrs
Traditional – 72 hours
Short course – reassess at 20 hours
INTRAVENOUS NAC
Oral preparation vs Acetadote ®
Concern is anaphylactoid reactions
Indications:
Can’t tolerate oral NAC
Contraindication to oral therapy Ongoing GI decon (coingestant) Fulminant hepatic failure?
Pregnant patient?
N-acetylcysteine (NAC) mechanism Prevents binding of NAPQI to hepatocytes Reduces NAPQI Conjugates NAPQI Increases sulfation metabolism***
NAC Must be administered within 8 hours IV dose: 150 mg/kg infused over 60 minutes; followed by a 4-hour infusion of 50 mg/kg; followed by a 16-hour infusion of 100 mg/kg; equivalent to a total dose of 300 mg/kg infused over 21 hours Oral dose: 140 mg/kg x 1 followed by 70 mg/kg x 17 doses
NAC Smells like rotten eggs Oral formulation may need to be given via NGT Dilute with juice Use metoclopramide or ondansetron if not tolerated due to vomiting Use hydrocortisoe and antihistamin in sensitvity cases
Review of case
A 15 year old girl presents to the ED four hours after taking 20 extra-strength (500 mg/tablet) Tylenol tablets. The ingestion was prompted by a fight with her boyfriend earlier that day. She has a history of an attempted suicide in the past. She is awake and alert with stable vital signs. She complains of nausea and has had one episode of vomiting. Physical exam is normal. Baseline labs show normal electrolytes, with normal LFTs, normal coags and a Tylenol level of 120 microgram/ml.
What would you do for our patient?
A. Call psychiatry to evaluate the patient. No medical intervention is required.
B. Administer 1g/kg of activated charcoal with sorbitol every 6 hours and 17 doses of oral N-acetylcysteine.
C. Administer one dose of activated charcoal with sorbitol followed by intravenous N-acetylcysteine for 21 hours.
D. Gastric lavage in an attempt to recover pill fragments.
The correct answer is: C. Administer one dose of activated charcoal with sorbitol followed by intravenous N-acetylcysteine for 21 hours.
Key Points Despite the fact that our patient’s Tylenol level was only 120 microgram/ml at four hours and falls below the toxic level on the nomogram, she must be treated with NAC. She ingested a total of 10 g (20 tablets x 500 mg) which is > 7.5 g and toxic.
NAC may be given orally or IV. IV NAC has only recently been approved for use in the US.
Key Points The administration of activated charcoal in Tylenol ingestion has been controversial as it may interfere with oral NAC.
Some studies have shown decreased absorption of Tylenol when activated charcoal is given in a timely fashion.
Activated charcoal will not interfere with administration of IV NAC and therefore may be given.
Key Points If activated charcoal is administered, only one dose should be given.
For ingestions requiring administration of multiple doses of charcoal, only the first should be given with sorbitol. Gastric lavage is not likely to be efficacious four hours following ingestion.