Suits and Cases: Potential Pitfalls in the management of Poisoned Patients

1. Suits and Cases: Potential Pitfalls in the management of Poisoned Patients John Kashani DO St. Josephs Regional Medical Center New Jersey Poison Center

3. Case 1 • An 18 year old female, with a past medical history significant for asthma and depression, presents to the ED for shortness of breath • She has a respiratory rate of 34, is diaphoretic, is actively vomiting and appears confused

4. Case 1 • Her blood pressure is 90/54, Heart rate is 150 and a rectal temperature is 102. farenheit and pulse oximetry is 99% on supplemental oxygen • Her mother states that this is the worst asthma attack she has ever had • She is emergently intubated

5. Case 1 • Shortly after being intubated she seizes and develops ventricular fibrilation • Despite your best efforts she dies • An autopsy is requested by the family • A post mortem salicylate level was 150mg/dL

6. Introduction • Salicylates are the most widely used analgesic, anti-pyretic and anti-inflamatory and is the standard for the comparison and evaluation of others • Because salicylates are so widely available the potential for misuse is often underappreciated

7. Introduction • The physician taking care of the salicylate intoxicated patient must be familiar with the pathophysiology, pharmakokinetics, potential pitfalls, and treatment options

8. Sources of Salicylates • Found in Willow bark (Salix alba vulgaris) • Available in a multitude of formulas/preparations • Over-the-counter (pepto-bismol) • Topical preparation (wart removal) • Combinations (excedrin, fiorinal, percodan) • Other (oil of wintergreen)

9. Pharmakokinetics • Peak levels • Regular preparations • Enteric coated • Liquids preparations • Overdose • Distribution • Metabolism • Excretion

10. Distribution • Volume of distribution (Vd) • Apparent volume the drug is dissolved in • Measured in Liters or Liters/Kg • not a real volume

12. Salicylates: Toxic Dose • Therapeutic Range: 10–20 mg/kg • Mild Toxicity: 150 mg/kg • Moderate Toxicity: 150-300 mg/kg • Severe Toxicity: > 300 mg/kg

13. Inflamatory Mediators • Inhibits cyclooxygenase • Decrease in prostaglandins • Increase leukotrienes • Increases microvascular permeability

14. matrix pyruvate acetyl-CoA CO2 NADH NAD+ citrate oxaloacetate NADH NAD+ malate isocitrate NAD+ CO2 NADH a-ketoglutarate fumarate FADH2 NAD+ CO2 NADH succinyl-CoA succinate FAD

15. Glucose Glucose 2 ATP Urea Pyruvate Lactate 6 ATP Pyruvate 4 ATP X ALT NH2 Alanine Alanine Liver Muscle

16. Respiration • Uncouples oxidative phosphorylation • Disrupts hydrogen ion gradient • Unable to generate ATP using electron transport • Increased oxygen consumption, increased heat production, increased metabolic rate, decreased ATP production, increased CO2 production

17. H+ H+ H+ H+ H+ H+ H+ H+ intermembrane space R-COO- R-COOH R-COO- R-COOH matrix H+ H+ H+

18. intermembrane space 3H+ H+ 4H+ 4H+ R-0- 2H+ R-0H CytC I III Q R-0H II IV R-0- + H+ 2H+ ADP + Pi + H+ 4H+ 4H+ H+ O2 H2O succinate ATP + H2O heat 3H+ NADH + H+ matrix

19. Metabolic • Increased lipolysis • Increased production of ketones • Ketonuria present in almost all overdose patients

20. Ketone bodies Fatty Acids Acetyl CoA

21. Metabolic • Hyperglycemia in acute setting • Glycogenolysis • May cause glucosuria • Hypoglycemia may subsequently develop

22. Metabolic • Causes a respiratory alkalosis • Due to respiratory center stimulation • Increase in respiratory rate and depth

23. Hematologic • Platelet dysfunction • Inhibition of Vitamin K dependent clotting factors • II, VII, IX, X, Protein C, Protein S • Hypoprothrombinemia

24. Gastrointestinal Effects • Nausea • Vomiting • Gastritis • Pylorospasm

25. Neurologic • Occurs from metabolic derangements and salicylate CNS levels • Agitation, irritability • Tinnitus • Occurs at levels of 20-45 mg/dL • Lethargy

26. Laboratories • Salicylate Level • An Level of 100 mg/dL is extremely worrisome (impending doom) • Chronic Levels of > 30 mg/dL are concerning • Difficulty in interpretation due to variable Vd

27. Laboratories • Levels should be obtained every 1 to 2 hours until downward trend is observed • Do not rely on a single level • Levels < 20mg/dl and a downward trend can be medically cleared

28. Case 2 • A 35 year old male presents to the emergency department for profound weakness, bradycardia and emesis • An I stat potassium is 8.5mg/dL and an EKG show a sine wave pattern • IV Calcium chloride is administered and he develops ventricular fibrilitation shortly thereafter

29. Case 2 • Despite your best efforts he dies • The wife said he has no medical problems, but was recently doing a “cleansing diet” that included herbal teas

30. Introduction • Digitalis and digitalis like cardiac glycosides (DG’s) are found in a variety plants, toads and pharmaceutical agents • Dried powders and extracts have been used for centuries for medicinal agents and as arrow poisons

38. Pharmacokinetics • Peak serum concentrations occur in minutes with IV dosing and 1-2 hours after an oral dose • The VD is initially small and increases following a two phase compartment model • Higher in infants and neonates and lower in the elderly

39. Pharmacokinetics • Tissue distribution takes 6-12 hours • Digoxin crosses the placenta with fetal levels approaching that of the mother • Elimination • Hepatic metabolism • Urinary excretion of unchanged drug

40. Pathophysiology • Cardiac glycosides inhibit the sodium potassium atp-ase • Responsible for pumping two sodium ions out of the cell for every two potassium ions in to the cell

41. myocardium 3 Na+ Na+ Na+ Na-KATPase Na+ Na+ 2 K+ K+ Na+ Ca++ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ -90 mv

42. myocardium 3 Na+ Na+ Na+ Na-KATPase Na+ Na+ 2 K+ Na+ Na+ Na+ Na+ Na+ K+ Na+ Na+ Na+ Ca++ Na+ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ -90 mv

43. myocardium 3 Na+ Na+ Na+ Na-KATPase Na+ Na+ 2 K+ Na+ Na+ Na+ Na+ K+ Na+ Na+ Na+ Na+ Na+ Ca++ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ Ca++ -90 mv

44. myocardium 3 Na+ Na+ Na+ Na-KATPase Na+ Na+ 2 K+ Na+ Na+ Na+ Na+ Na+ Na+ K+ Na+ Na+ Na+ [Ca++] Ca++ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ Ca++ -90 mv

45. Inhibition of Na-K-ATPase heart [Nai+] [Cai++] contractility

46. muscle 3 Na+ Na+ Na+ Na-KATPase Na+ [K+] Na+ 2 K+ Na+ Na+ Na+ Na+ Na+ Na+ K+ Na+ Na+ Na+ [Ca++] Ca++ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ Ca++ -90 mv

47. Inhibition of Na-K-ATPase heart skeletal muscle [Nai+] [Ko+] [Cai++] hyperkalemia contractility

48. myocardium 3 Na+ Na+ Na+ Na-KATPase Na+ Na+ 2 K+ K+ Na+ Ca++ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ -90 mv

49. myocardium 3 Na+ Na+ Na+ Na-KATPase Na+ Na+ 2 K+ Na+ Na+ Na+ Na+ K+ Na+ Na+ Na+ Na+ Na+ Ca++ Ca++ Ca++ Ca++ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ Ca++ -90 mv

50. myocardium 3 Na+ Na+ Na+ Na-KATPase Na+ Na+ 2 K+ Na+ Na+ Na+ Na+ K+ Na+ Na+ Na+ Na+ Na+ Ca++ Ca++ Ca++ Ca++ SR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ ATPase Ca++ Ca++ Ca++ -90 mv