pediatric toxicology

1. PEDIATRIC TOXICOLOGY Nga B. Pham, M.D.

3. Epidemiology Most commonly fatal classes of poisoning Analgesics (375) 62 Tylenol only, 52 Tylenol + 1 other, 100 Tylenol combination products (Lortab, etc.) 23 ASA � more than half did not have ASA levels >100mg/dl � early and more aggressive dialysis recommended Street drugs (124) Antidepressants (112) Amitriptyline

4. Epidemiology Most common Pediatric Exposure Cosmetics and personal care products (13%) Cleaning substances (10%) Analgesics (7.8%) Foreign Bodies (7.4%) Topicals (7.4%) Cold and Cough Preparations (5.5%) Plants (4.6%) Pesticides (4.1%)

5. Epidemiology Unintentional (1-2 years) Exploratory Boys > girls Unable to discriminate safe from unsafe liquid Intentional (adolescent) Purposeful Girls > boys

6. Epidemiology Around meal time Grandparents home Kerosene or gasoline in a soda bottle Older sibling can pharmaceutically treat younger sibling

7. Evaluation of Suspected Poisoning ABC�s and routine ICU management Establishing the diagnosis Must consider poisoning, especially in �at risk� age groups Less than 6 year old with acute decompensation (AMS, arrhythmias, hypotension, metabolic acidosis, etc.)

8. Evaluation History of poisoning Physical Examination Laboratory studies Gastrointestinal decontamination

9. History What? When? How much? Reliability�

10. What? Medication Illicit drug Hazardous chemical

11. What forms? Pill Solid Liquid Gaseous

12. What route? Ingestion Inhalation Topical Intravenous

13. When? Elapsed time

14. How much? Estimate amount Concentration

15. PICU Admission Tricyclic antidepressants (TCA) Anticonvulsants Digoxin Opiates Hydrocarbon-based household products

16. Toxic Exposure - Death Analgesics Sedative-hypnotics Alcohols Gases & fumes Cleaning substances

17. Toxidromes Anticholinergics Atropine, scopolamine, TCA�s, phenothiazines, antihistamines, mushrooms, jimson weed �Hot as a hare, dry as a bone, red as a beet, mad as a hatter� Neuro: agitation, hallucinations, coma, extrapyramidal movements, mydriasis, hyperthermia CV: tachycardia, hypotension, hypertension, arrhythmia GI/GU: decreased bowel sounds, urinary retention

18. Toxidromes Cholinergics Organophosphates and carbamates

19. Muscarinic Effects of Organophosphate Poisoning S alivation *D iaphoresis/diarrhea L acrimation *U rination U rination *M iosis D efecation *B radycardia/bronchospasm G I secrestion/upset *E mesis E mesis *L acrimation excess *S alivation excess

20. Nicotinic Effects of Organophosphate Poisoning Muscle fasciculation Cramping Weakness (extreme is diaphragmatic failure) Autonomic nicotinic effects include hypertension, tachycardia, pupillary dilation, and pallor

21. CNS Effects ofOrganophosphate Poisoning Anxiety Restlessness Confusion Ataxia Seizures Insomnia Dysarthria Tremors Coma

22. Toxidromes Opiates: Morphine, Methadone, Dextromethorphan

23. Toxidromes Opiates Morphine, methadone, dextromethorphan Resp: decreased respiratory rate, pulmonary edema CV: hypotension, bradycardia Neuro: miosis, AMS, coma, hypothermia, seizures

24. Toxidromes Sedatives/hypnotics Benzodiazepines, barbiturates Resp: slow respirations CV: tachycardia, hypotension Neuro: AMS, coma, seizures, hypothermia

25. Toxidromes Tricyclic antidepressants Amitryptiline, nortryptiline, etc. See anticholinergic effects CV: arrhythmias, hypotension Neuro: coma, seizures

26. Toxidromes Salicylates ASA, oil of wintergreen Resp: tachypnea

27. Laboratory Tests Suggestive ofPoisoning Elevated osmolar gap (>10) Serum osm = (Na x 2) + BUN/2.8 + glucose/18 Volatile alcohols, mannitol Elevated anion gap (>12) MUDPILES Low anion gap Lithium, iodine, bromine, fluoride Hyperkalemia Postassium, lithium, digoxin, fluoride Hypokalemia Theophylline, toluene

28. Laboratory Tests Suggestive ofPoisoning Hyperglycemia ASA, theophylline, caffeine, iron Hypocalcemia Ethylene glycol, ASA UA Glowing urine � ethylene glycol Calcium oxalate crystals � ethylene glycol

29. Laboratory Testing What is in a �urine drug screen�? Amphetamines, Barbiturates, Cocaine, Benzodiazepine, Opiates, THC, PCP What is in a �serum drug screen�? Acetaminophen, ETOH, Salicylate, TCA What is in a �comprehensive drug screen�? Barbiturates, Salicylates, Cannabinoids, PCP, TCA, Sedatives, Benzodiazepines, Stimulants, Opium alkaloid, Synthetic Narcotics, Tranquilizers, Cocaine

30. Laboratory Testing Grady unfortunately doesn�t do HPLC anymore Options for more �comprehensive� screen Quest lab � if needed in 24 hours or less ARUP � 2-4 days turn around SERUM: Acetaminophen, alcohols, barbiturates, benzodiazepines, carbamazepine, carisoprodol, disopyramide, meprobamate, phenytoin, primidone, salicylate, theophylline, tricyclic and other antidepressants URINE: acetaminophen, alcohols, barbiturates, benzodiazepines, carbamazepines, carisoprodol, chlorpheniramine, cocaine & metabolites, diphenhydramine,ethchlorvynol, ibuprefen, lidocaine, meprobamate, narcotics & synthetics, phencyclidine, phenothiazines, phenytoin, primidone & metabolites, pyrilamine, salicylate, sympathomimetic amines, theophylline, tricyclic and other antidepressants, trimethoprim

31. Laboratory Testing Additional testing is helpful if you have a specific substance that you suspect Usually less helpful as a �fishing expedition� and won�t affect management Am J Emerg Med. 1999 May:17(3):221-4. Belson MG, Simon HK Evaluate the clinical utility and cost-effectiveness of the limited component vs the HPLC component of comprehensive toxicologic screens in children Retrospective from HSCH ED Jan 1994-July 1995 The comprehensive test included a broad-spectrum HPLC component as well as a limited component that examined serum for ethanol, aspirin, and acetaminophen and urine for benzodiazepines, barbiturates, amphetamines, cocaine, phencyclidien, and opiates Comprehensive toxicology screens were performed in 463 cases during the study period; 234 (51%0 were positive for exogenous toxin

32. Laboratory Testing In 227 of 234 positive screens (97%), toxins were either suspected by history and/or physical, were present on the limited portion of the toxicology screens, or were clinically insignificant The remaining 7 of the 234 positive screens (3%) were clinically significant and detected solely by the broad-spectrum HPLC portion of the comprehensive screen However, in none of these 7 cases was patient management clinically altered as a result of the positive screen The total additional cost of the HPLC component was $16,205 ($35x464), an average distributive charge of $2,315 per patient in whom the HPLC portion provided additional clinical information ($16,205/7) Although adding significant charges to the evaluation of suspected toxic exposures in children, the HPLC component of the comprehensive drug screen was of no additional clinical benefit compared with its limited component alone

33. Urine Drug Screens THC 1-3 weeks* Cocaine 2-4 days Amphetamine 2 days Barbiturates 1-2 days Opiates 1-2 days PCP 5-7 days LSD 1-2 days Steroids 3 days or longer * Longer if prolonged exposure

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48. Elimination of Poisons Surface decontamination Reduce any additional absorption Ipecac Not routinely recommended anymore Possible useful in an observed, in hospital poisoning Gastric Lavage Most effective 1-2 hours after ingestion Can be effective later in drugs that delay gastric emptying

49. Elimination of Poisons Activated charcoal Adsorbs many drugs, thus decreasing systemic absorption Doesn�t work well for lithium, iron, hydorcarbons, alcohols, solvents, acid/alkali ingestions Role of charcoal in gastrointestinaldialysis Cathartics Not generally used Some charcoal has sorbitol in it Whole bowel irrigation Golytely infusions Initially done with success in iron ingestions Used mostly for drugs that charcoal doesn�t work well with

50. Elimination of Poisons Diuresis +/- alteration of urine pH Obviously, only useful for renally excreted drugs Altering pH example ASA � pkA3 At a pH of 3, there is a 1:1 ratio of ionized/unionized At a pH of 7.4, the ratio is 25,000:1 Ionized form can�t cross cell membranes � so when you dump ASA into the tubule, if the pH is 4.5 you would have about 5,00:1 ratio, if you increase urine pH to 8.0, then essentially all of it is in the ionized form, and can�t get reabsorbed

51. Elimination of Poisons Altering pH Alkalinize the urine � ASA, isoniazid, phenobarb Use bicarb in the fluids Don�t use acetazolamide (Diamox) in ASA poisoning Metabolic acidosis increases unionized form which can cross into CNS, worsening poisoning Acidify the urine (usually not needed) � quinidine, PCP, fenfluramine, amphetamine

52. Elimination of Poisons Dialysis What makes things �dialyzable� Low molecular weight Low volume of distribution Low protein binding Charge Methods Intermittent Hemodialysis CVVH/CVVHD/CVVHDF Albumin dialysis

53. Elimination of Poisons Charcoal hemoperfusion Clear chemicals by direct adsorbtion with charcoal in an extracorporeal circuit Doesn�t depend of molecular size, protein binding Can be used for a variety of otherwise difficult to manage poisonings Digoxin, ASA, barbiturates, TCA�s, theophylline Not used that much anymore

54. Elimination of Poisons Plasmapheresis Works very well with highly protein (albumin) bound drugs Not a routine methodology, but has been used to remove theophylline and digoxin/digibind complexes Exchange transfusion Use in smaller infants where vascular access for extracorporeal techniques can�t be done

55. Tylenol Ingestion Clinical manifestations Stage 1 First 12-24 hours Nausea, vomiting, anorexia No CNS involvement � of you see it, think of polysubstance ingestion Stage 2 Resolution of GI symptoms 36 hours after ingestion see biochemical evidence of liver dysfunction � AST/ALT, bilirubin, PT

56. Tylenol Ingestion Clinical manifestation Stage 3 Liver dysfunction reaches a peak on day 3-4 Start GI symptoms again High transaminases (>10,000) do not necessarily predict liver failure Fulminant liver failure can occur Stage 4 Recovery stage � lasts 7-8 days Chronic hepatitis does not occur � LFT�s/biopsy return to normal

57. Tylenol Ingestion Prediction of toxicity Rumack nomogram for single ingestion Rough guide for potential toxicity Children � 150 mg/kg Adults � 7.5 gm Uncommon 150mg/kg 50% with 250 mg/kg 100% with 350mg/kg

58. Tylenol Ingestion Therapy N-acetylcysteine (Mucomyst) Oral � 140 mg/kg load, followed by 70mg/kg q4 hours for 17 doses Repeat dose if vomits within 1 hour Can mix with carbonated drinks or grapefruit juice Intravenous � 150 mg/kg load over 15 minutes, then 50mg/kg over 4 hours, then 100mg/kg over 16 hours

59. Volatile Alcohols Diagnosis High index of suspision Elevated osmolar gap Volatile alcohol screen + separate test for ethylen glycol Methanol and ethylene glycol � no ketones Isopropyl alcohol � marked acetone Ethanol � acetoacetate and B-hydroxybutyrate

60. Volatile Alcohols Isopropyl Alcohol Toxic dose is 1 ml/kg of 70% solution More than one swallow in children should be presumed toxic About 20% is broken down by liver ADH to acetone Symptoms are like ethanol ingestion Nystagmus is common More CNS depressant than ETOH, because acetone is a CNS depressant as well Management Supportive (without hypotension essentially 0% mortality) Levels don�t mean much prognostically Dialysis will remove it Coma + hypotension � 30% mortality Level over 400 (implied severe ingestion)

61. Volatile Alcohols Methanol No safe dose. 5ml is lethal in toddler age and can cause blindness in adults. 1ml/kg is lethal in adults Metabolism 30% excreted by lungs 5% kidneys Rest to liver to make toxic metabolites

62. Volatile Alcohols Methanol Clinical symptoms � Biphasic Initial � CNS depression secondary to direct action of methanol on CNS Delayed Visual disturbances Photophobia, �snowflakes�, blurred vision CAN HAVE FIXED DILATED PUPILS Metabolic acidosis Laboratory Elevated anion gap is due to formic acid and lactate Retinal damage is due to locally produced formic acid

63. Volatile Alcohols Methanol Treatment Supportive Ethanol/dialysis Fomepizole +/- dialysis now

64. Volatile Alcohols Ethylene Glycol Minimum lethal dose is 1.4-1.6 ml/kg Clinical symptoms Severe neurotoxicity, metabolic acidosis, renal failure, cardiovascular collapse 1st phase � 30 min �12 hours � CNS symptoms, N/V If LP � pleocytosis and elevated protein 2nd phase � cardiorespiratory failure with pulmonary edema 3rd phase � renal failure Metabolism 25% excreted unchanged by kidneys Remainder rapidly metabolized by liver and kidneys to toxic metabolites

65. Volatile Alcohols Ethylene Glycol Lactic acidosis develops secondary to altered NADH/NAD ratio Oxalic acid chelates calcium Tetany and myocardial dysfunction Renal failure is likely due to glycoaldehyde, glycolic acid, glyoxylic acid Most recover � can be prolonged up to 2 months Can see calcium oxalate crystals in urine

66. Volatile Alcohols Ethylene Glycol Treatment Fomepixole +/- dialysis

67. Cyanide Poisoning Exposures Mostly from fires in children Acetonitrile in some cosmetics reported lethal �Vitamin B17� � cyanogenic glycosides � sold in health food stores � from pits of apricots and bitter almonds Laetrile � only when given orally or rectally Nipride � use sodium thiosulfate to reduce incidence � 1 gram per 100mg of Nipride

68. Cyanide Poisoning Pathophysiology Reversible binding to a-a3 cytochrome Halts aerobic metabolism and ATP formation Pushes to anaerobic metabolism and resultant lactic acidosis Inability to use oxygen at the cellular level Normal oxygen content and oxygen delivery

69. Cyanide Poisoning Treatment 100% oxygen always Eli Lilly Cyanide Antidote Kit No M-76 Amyl nitrate pearls � inhale for 15-30 secs Produces about 5% methemoglobinemia IV sodium nitrite IV sodium thiosulfate Aiming for methemoglobin of 30%

70. Hydrocarbon Ingestion Unintentional vs intentional Clinical presentation Respiratory distress Hydrocarbons dissolve the lipid layer in the lung Surfactant inactivation, distal airway closure, hypoxemia, V/Q mismatch Can progress to ARDS CNS abnormalities Mostly due to hypoxia GI abnormalities

71. Hydrocarbons Ingestion Clinical presentation Fever and leukocytosis common in first 24-48 hours Treatment Supportive Treat the hypoxia No induction of vomiting

72. Iron Intoxication Relatively common ingestion About 5-10% require hospitalization Can be lethal <20 mg/kg elemental Fe � insignificant 20-60 mg/kg mild toxicity >60 mg/kg moderate to severe toxicity >200 mg/kg rapidly lethal if not treated

73. Iron Intoxication Pathophysiology Huge uptake of iron from small bowel Overwhelm transferrin�s ability to bind and thus get free iron circulating in blood Disruption of CMS, GI, CV systems Major oxidant stress � possibly shunts electrons away from cytochromes in the mitochondria Interferes with activation of thrombin and clot formation, leading to coagulopathy Direct gut toxicity with hemorrhagic gastritis and bowel perforation

74. Iron Intoxication Clinical manifestation 1st phase � GI symptoms (N/V/D, hemorrhagic gastritis, GI bleed) � direct effect 2nd phase � temporary recovery � 6-12 hours from ingestion � can last several days 3rd phase � return of GIU symptoms and MSOF Metabolic acidosis, shock, CNS depression, liver dysfunction, renal failure, coagulopathy, etc. Die or get better 4th phase � 4-6 weeks out � pyloric, gastric, or intestinal obstruction � due to healing of initial damage

75. Iron Intoxication Prognosis Ingestion size Serum iron levels Peak 2-6 hours after ingestion <100 � unlikely toxicity 100-300 minimal 300-500 moderate 500-1,000 severe >1,000 potentially lethal After 6 hours even in large ingestion, level may be normal

76. Iron Intoxication Therapy Role of gastric lavage Desferoxamine � iron chelator Binds iron to form ferrioxamine which can be safely excreted renally Red (�vin rose�) color to urine Also has a protective effect of increasing intracellular binding of iron, reducing toxicity Not dialysable

77. Beta Blockers Widely prescribed and available Phamacology Lipophilicity Membrane stabilizing effect Selective vs non-selective agents Propranolol is most common and most dangerous

78. Beta Blockers Toxic dose 2-3 times therapeutic dose Signs and symptoms Bradyarrhythmia Hypotension Decrease LOC Respiratory depression Seizure Ventricular arrhythmia

79. Beta Blockers Prehospital management Aggressive airway management PALS protocol Atropine 1mg prn (max 3 mg) Peds 0.02 mg/kg Transcutaneous pacemaker Do not delay in symptomatic bradycardia

80. Beta Blockers Prehospital management Glucagon 5mg IV bolus Peds 0.2 mg/kg IV bolus Fluid resuscitation � peds 20 ml/kg Pressors Dopamine 5-10 mcg/kg/min Epinephrine drips Titrate to response. May need bigger than normal dose

81. Beta Blockers Other management issues Treat dysrhytmia Pediatric patient Hypoglycemia more common Seizures more likely than adult Consider heroic measures - ECMO

82. Calcium Channel Blocker Pharmacology Negative inotrope Blocks flow of calcium ions through slow channels Decreased amount of calcium from sarcoplasmic reticulum Negative chronotrope Decrease automaticity in SA node and AV junction Reduction in PVR

83. Calcium Channel Blocker Agents Verapamil Significant cardiac depressant Vasodilation AV slowing Diltiazem Nifedipine Felodipine Amlodipine

84. Calcium Channel Blocker Toxicity Hypotension Bradycardia Arrhythmias Respiratory depression Neurologic disorders Seizures etc.

85. Calcium Channel Blocker Prehospital management Aggressive airway management PALS protocol Atropine 1 mg prn (max 3mg) Peds 0.02 mg/kg Atropine most often not effective Transcutaneous pacemaker Do not delay in symptomatic bradycardia

86. Calcium Channel Blocker Prehospital management Calcium chloride 250-500 mg IV Peds 20mg/kg Glucagon 5mg IV bolus Peds 0.1 mg/kg IV bolus Fluid resuscitation � peds 20 ml/kg

87. Calcium Channel Blocker Other management issues Pressors prn Dopamine 5 mcg/kg/min Epinephrine drip 2 mcg/kg/min Titrate to response, may need bigger dose than normal Treat dysrhythmias Pediatric patient Small dose can be lethal Seizures are more likely than adult Consider heroic measures - ECMO

88. Digoxin Toxicity Dysrhythmias PVC�s Slow A-fib Bradycardia, V-fib. V-tach Hypotension Hyperkalemia ( Renal insufficiency is a risk factor) CNS Delirium, hallucinations, lethargy, agitation Ocular disturbances

89. Digoxin Treatment Basic management (ABC�s etc.) Electrolyte disturbances Hyperkalemia Atropine/Pacemaker Manage dysrhythmias Digoxin specific antibody

90. Digoxin Treatment � Digibind Indication Life threatening CV toxicity K > 6.5 mEq/L (except in chronic renal failure) Steady state level >10 ng/ml Ingested dose >10mg (adult)