Pediatric Toxicology In-Training Review

1. Pediatric Toxicology In-Training Review Steven J Walsh, MD

2. Case 1 • A 3 year old boy presents to your ED with sonorous respirations, altered mental status, pinpoint pupils, vomiting, and flaccidity. His vitals are: T: 37.2 PR, P: 48, BP: 68/36, RR: 6, SaO2: 78% RA Mom and Dad report that he may have drunk some of a pesticide stored in their garage.

3. Case 1 • The most consistent physical exam finding in patients suffering this intoxication is: a) Paralysis b) Bradycardia c) Miosis d) Bronchorrhea e) Lacrimation

4. Case 1 • The most consistent physical exam finding in patients suffering this intoxication is: a) Paralysis b) Bradycardia c) Miosis d) Bronchorrhea e) Lacrimation

5. Organophosphates • 55,000 exposures reported to poison centers from 1998-2002 • 8 deaths per year • 2 million suicide attempts and 1 million accidental poisonings per year worldwide

6. Organophosphates • Most commonly available as pesticides (malathion, parathion) • Also notorious as “nerve gas” (sarin, tabun, VX) • Carbamates available as pesticides and medications (aldicarb, physostigmine)

7. Organophosphate Pathophysiology • Standard structure includes a leaving group • Binding inactivates acetylcholinesterase resulting in elevated synaptic acetylcholine levels

8. Organophosphate Pathophysiology • Aging • 24-48 hours • Cleaving of an R group results in irreversible binding • Peripheral neuropathy • Delayed by days to weeks • Inhibition of axonal neurotoxic esterase • Peripheral motor neuropathy (Ginger Jake)

9. Organophosphate: Clinical Manifestations

10. Organic Phosphate: Clinical Manifestations • Presenting symptoms may be sympathetic, parasympathetic, or both • Earlier cholinergic symptoms correlate with more severe toxicity • Treatment of muscarinic toxicity does not prevent nicotinic toxicity (e.g. paralysis)

11. Organophosphates: Clinical Manifestations • D: Defecation/Diaphoresis • U: Urination • M: Miosis • B: Bronchorrhea • B: Bronchospasm • E: Emesis • L: Lacrimation • S: Salivation

12. Organophosphates: Diagnostics • Primarily clinical suspicion, history, and physical exam findings • Laboratory analysis includes pseudocholinesterase and erthrocyte cholinesterase activity • EMG is useful in monitoring treatment and recovery

13. Organophosphates: Treatment • Atropine • 1-5 mg IV in adults, 0.05 mg/kg in peds to start • Titrate to effect  dried bronchial secretions • Large doses may be required (1,000 mg in a day; 11,000 total during treatment reported) • Glycopyrrolate • May be considered in patients with central antimuscarinic effects from atropine therapy • 1-2 mg in adults, 0.025 mg/kg in peds

14. Organophosphates: Treatment • Pralidoxime • Binds to remote site on cholinesterase to prevent aging • Adults: 1-2 g IV over 15 minutes, 500 mg/hr • Peds: 20-40 mg/kg over 15 minutes, then 10-20 mg/kg/hr • Titrated to effect • Re-initiation indicated for the treatment of Intermediate Syndrome • Not necessary for the treatment of carbamates

15. Pralidoxime

16. Organophosphates: Disposition • Patients may be discharged once asymptomatic without therapy for greater than 24 hours AND • Serum and RBC cholinesterase activity and/or EMG has remained stable without treatment

17. Case 2 • A 15 year old girl presents to the ED complaining of fatigue, headache, nausea, and vomiting that worsens when she is in her basement and improves while out of the house. She slept in the basement last night and her symptoms have worsened today. This morning she felt unsteady on her feet but did not pass out. Her pregnancy test is negative and her COHb level is 22%.

18. Case 2 • What is the appropriate management of this patient? a) Reassurance and discharge home b) Intubation and hypothermia c) Immediate transfer to a Toxicology Treatment Center for Hyperbaric Oxygen d) Oxygen by facemask until asymptomatic e) Repeat CO levels every 2 hours until 0

19. Case 2 • What is the appropriate management of this patient? a) Reassurance and discharge home b) Intubation and hypothermia c) Immediate transfer to a Toxicology Treatment Center for Hyperbaric Oxygen d) Oxygen by facemask until asymptomatic e) Head CT and Neurology consult

20. Carbon Monoxide • Most common cause of poisoning morbidity and mortality in the U.S. • >15,000 ED visits for CO toxicity over two years (2001-2003)

21. CO: Sources • Furnaces • Automobiles • Space heaters • Charcoal grills • Gas water heaters • Ovens and ranges • Any gas-powered equipment

22. CO binds hemoglobin with a higher affinity than oxygen Shifts oxyhemoglobin curve to the left (e.g. harder to unload oxygen leading to cellular asphyxia) CO: Pathophysiology

23. CO: Pathophysiology • Inactivates cytochrome oxidase thereby inhibiting oxidative phosphorylation (similar to cyanide) • Direct neuronal toxicity from NMDA activity, lipoperoxidation, free radical formation • Myocardial suppression from myoglobin binding

24. CO: Clinical Manifestations • Non-specific symptoms initially • Headache, fatigue, nausea • Moderate • Ataxia, chest pain, shortness of breath, syncope • Severe • Coma, seizure, arrythmias, MI, pulmonary edema

25. CO: Diagnostics • You must consider it to find it • COHb level measured by co-oximetry on either venous or arterial blood (Do NOT need a gas) • Consider EKG or neuroimaging as indicated

26. Interpreting a CO Level • Less important than presenting symptoms and physical examination findings • Timing of the test as well as preceding treatment may make levels difficult to interpret • 0-5% can be normal readings • 6-10% found in heavy smokers • >25% general indication for HBO

27. CO: Treatment • REMOVAL FROM THE SOURCE • High flow oxygen • Supportive care • Consider HBO: • Loss of consciousness • Persistent neurologic deficits • Myocardial ischemia/arrhythmia • COHb level > 25% (relative) • Unclear in pregnancy, we use COHb > 10%

28. CO: HBO • 3 treatments over 16 hours • COHb half-lives • Room air: 250-320 minutes • 100% oxygen: 50-80 minutes • HBO: ~20 minutes • May prevent delayed neurologic sequelae • Human evidence to support benefits is lacking

29. CO: Disposition • No need to repeat levels, will always be lower • If patients do not qualify for HBO, then treat with supplemental oxygen until symptoms resolve • Ensure safety of home or alternate destination prior to discharge • HBO: transfer to HBO treatment facility for observational admission

30. Case 3 • A 12 year old girl drank a large mouthful of what she thought was Gatorade from a clear plastic squeeze bottle that her father had out while he was cleaning a shotgun. She immediately had throat and chest pain associated with vomiting. She presents to the ED with ongoing symptoms within 30 minutes of the ingestion.

31. Case 3 • How should this patient be managed? a) IV Protonix with GI consultation the following morning b) ED observation with IV fluids until symptoms resolve c) Reassurance and discharge home d) Activated Charcoal administration e) Airway stabilization and immediate endoscopy

32. Case 3 How should this patient be managed? a) IV Protonix with GI consultation the following morning b) ED observation with IV fluids until symptoms resolve c) Reassurance and discharge home d) Activated Charcoal administration e) Airway stabilization and immediate endoscopy

33. Caustics • Acid and alkali ingestions from a number of household products • Toilet bowl cleaners • Antirust agents • Drain cleaners • Battery Acid • Gun bluing solution (selenious acid) • Bleach (Sodium hypochlorite) • Symptom onset may be immediate or delayed

34. Caustics: Pathophysiology • Tissue damage related to: • Acid or alkali • Duration of contact • pH • Volume • Concentration • Titratable Acid/Alkaline Reserve (TAR)

35. Caustics: Diagnostics • Observe if asymptomatic • Duration depends on substance ingested • Pharyngeal examination is notoriously unreliable • Blood tests (e.g. blood gas, lactate, CBC, LFTs, lipase) are of limited utility • Radiographic evaluation (CXR, CT scan, esophagram) may be of benefit in evaluating perforation

36. Caustics: Endoscopy • If symptomatic, immediate endoscopy • Grade I: Superficial mucosal irritation w/o ulcer • Grade IIa: Non-circumferential submucosal lesions, ulcerations, and exudates • Grade IIb: Grade IIa, but circumferential • Grade III: Deep ulcers and necrosis into periesophageal tissues

37. Caustics: Treatment • Airway management as needed • Volume resuscitation, supportive/symptomatic care • Immediate surgical consultation if significant injury suspected • Endoscopy within 12-24 hours • Antibiotics only if evidence of perforation • Steroids should be avoided

38. Caustics: Treatment • Surgical evaluation and resection as needed • NPO • NG tube only under video guidance or following endoscopy

39. Caustics: Disposition • Observation in ED until asymptomatic and tolerating PO • Pts. with more severe symptoms should be admitted and endoscopy performed • Pts may be discharged once tolerating a regular diet without pain • Pts with severe burns should have interval outpatient GI/surgical follow up to be evaluated for stricture formation

40. Case 4 4 year old girl presents after being found in her pregnant mother’s bathroom with an empty bottle of prenatal vitamins. Mom believes there were between 50 and 60 pills in the bottle. There are currently 6 left. The child has been acting normally for the last 5 hours and drank juice while being observed in the ED. Her vital signs are normal.

41. Case 4 How would you treat this patient? a) Observe for one more hour and discharge b) Send a urine comprehensive drug screen c) Check an iron level and administer deferoxamine d) Administer activated charcoal e) Admit for overnight observation and serial labs

42. Case 4 How would you treat this patient? a) Observe for one more hour and discharge b) Send a urine comprehensive drug screen c) Check an iron level and administer deferoxamine d) Administer activated charcoal e) Admit for overnight observation and serial labs

43. Case 4 This toxicity and treatment of it can place patients at risk for what bacterial infection? a) Clostridium difficile b) Yersinia entercolitica c) Staphylococcus aureus d) Vibrio cholera e) Haemophilus influenza

44. Case 4 This toxicity and treatment of it can place patients at risk for what bacterial infection? a) Clostridium difficile b) Yersinia entercolitica c) Staphylococcus aureus d) Vibrio cholera e) Haemophilus influenza

45. Iron Leading cause of poisoning death of children under 6 in the 1990s Incidence of toxicity has continued to decrease since then Iron supplements and prenatal vitamins are the primary source in pediatrics

46. Iron: Pathophysiology Redox reaction of ferrous to ferric states creates oxidative stress and creates protons Inhibitor of multiple enzymatic reactions Disrupts mitochondrial oxidative phosphorylation

47. Iron: Toxic Dose • Toxicity present at 10-20 mg/kg • Serious toxicity at 40-60 mg/kg • Toxic dose calculated using percent of elemental iron in each formulation • Ferrous chloride 28% elemental iron • Ferrous fumarate 33% • Ferrous gluconate 12% • Ferrous sulfate 20%

48. Iron: Clinical Manifestations Stage I (0-6 hrs): Nausea, vomiting, diarrhea, abdominal pain (absence excludes serious toxicity) Stage II (6-24 hrs): “latent stage”; resolution of GI symptoms though toxicity is ongoing Stage III (<24 hrs): Shock from hypovolemia, metabolic acidosis, coagulopathy, altered mental status

49. Iron: Clinical Manifestations Stage IV (2-3 days): Hepatic failure secondary to direct hepatocyte injury from oxidative stress Stage V (2-8 weeks): Gastric outlet obstruction from scarring

50. Iron: Diagnostics • AXR: does not reliably exclude ingestion • Blood gas, lactate, LFTs, CBC, PT/INR, PTT aid in diagnosis and resuscitation endpoints • TIBC and transferrin less useful • Iron levels (peak 2-6 hrs post-ingestion) • 300-500µg/dL associated with significant GI toxicity • 500-1000µg/dL modest systemic toxicity • >1000µg/dL significant morbidity and mortality