Practical Toxicology Cases

1. Practical Toxicology Cases IRON TOXICITY

2. Distribution in body Fe 17.5% 65% erythrocytes • Cytoxidase • Myoglobin formation of Hb → carry O2 (Fe2+) 17.5% • stored as • Ferritin (soluble) • hemosiderin (Insoluble) (Fe3+) (in Macrophages)

3. Types of iron Fe2+ Fe3+ blood Stomach  Intestine  Blood Bind with mucoprotein Become Fe3+ & bind with transferrin Fe2+ Types of Fe2+ salts

4. Elemental iron & degree of intoxication • < 20 mg/kg → mild (asymptomatic). • 20 – 60 mg/kg → moderate. • 60 – 180 mg/kg → severe. • 200 – 250 mg/kg → lethal. E.g:patient (55 kg) ingested 60 tablets of FeSO4 325mg each. 60 tab x 325 mg = 19500 mg. 20% …..i.e 100 mg FeSO4 → 20 mg elemental Fe. 19500 mg → X so X = 3900 mg. 3900 mg → 55 kg. X ← 1kg so X = 70 mg/kg so severe.

5. Clinical manifestations • Patients who remains asymptomatic 6 or more hrs after ingestion are unlikely to develop symptoms later. • Iron poisoning can be divided into 4 stages. Stage I: 1 -6 hrs. Stage II: 6 – 14 hrs. Stage III: 14 – 48 hrs. Stage IV: 4 – 6 weeks.

6. Fe Stage I: 1 -6 hrs GIT Vomiting Diarrhoea Irritation Irritation Corrosion Corrosion Bloody vomitus (Hematemesis) Bloody diarrhoea (Melena)

7. Stage I: 1 -6 hrs GIT Bleedding Nausea & Vomiting Diarrhoea Ferritin Released from damaged GIT tissue Fluid Loss Blood Loss VD of arterioles CVS ↑ capillary permeability Hypovolemia Hypotension Reflex tachycardia

8. Stage I: 1 -6 hrs (cont.) CNS Lethargy, severe coma or seizures. Lactic acidosis • ↓ B.P  hypoperfusion  hypoxemia  anaerobic  lactic à. • Fe →uncoupling oxidation phosphorylation →↓ ATP production. Glucose not consumed  Hyperglycemia (at early stage). Acidosis  H+ + HCO3- H2CO3  H2O + CO2 BBB RS ↑Medullary respiratory center ↑R.R Tachypnea

9. Stage II: 6 – 14 hrs • Stage of recovery(Signs & symptoms of GIT subsides, patient feel normal). • If patients treated early in right way  cure at this stage

10. Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Fe Stage III: 14 – 48 hrs (hepatic stage) FeinGIT (erosion) deposition in soft tissue. blood carrier (part of iron) + Free iron Ferritin Hepatic Necrosis Transferrin ↓ Prothrombin ↓ NH3 detoxification ↓ Glycogenolysis & gluconeogenesis Hepatic encephalopathy (Hepatic coma) ↑Prothrombin time Hypoglycemia

11. Stage III: 14 – 48 hrs (cont.) Uncoupling oxidative phosphorylation Metabolic Acidosis ↓ Hypoperfusion Hypoxia Fe  Lipolysis (due to Hypoglycemia)  FFA   Ketones bodies  Excretion of HCO3-

12. Stage III: 14 – 48 hrs (cont.) Invasion of damaged intestinal mucosa by bacteria Passed into blood Sepsis Fever Shock Leukocytosis Uncoupling oxidative phosphorylation Hypotension

13. Stage IV: 4 – 6 weeks • Hepatic cirrhosis. • Pyloric stricture (pyloric stenosis) → corrosive action.

14. Laboratory Diagnosis • Serum iron concentration: (70 – 170 mg/dl) • If > 170 mg/dl but < 300 mg/dl→ Mild toxicity (rarely). • If = 300–500 mg/dl→ Moderate toxicity (potential). • If > 500 mg/dl →Severe & Lethal. • N.B: we must make X-ray in the same time to be sure that all iron is absorbed into the blood & there is no opaque body in the stomach for 48 hrs.

15. Laboratory Diagnosis (cont.) • Total iron binding capacity (TIBC): measurement of transferrin (200 – 400 μg/dl). • % Transferrin saturation • = Serum Fe conc / TIBC • Normal: 15-50% in♀, 20-50 % in ♂ •  % indicates  amount of free Fe in serum • Blood glucose > 150 mg/dl serious (early stage). • Leucocytes > 15000/cm³ serious. •  PT. • Electrolytes (HCO3, Vomiting). • Blood matching test (exchange transfusion). • X-ray → opaque.

16. Therapeutic Measures A) Gut decontamination: • Emetics:as Ipeca syrup(if no hypotension or vomiting (hematemesis)). • b. Gastric lavage: by NaHCO3 2-3% • NaHCO3 + Fe2+ → ferrous carbonate (insoluble salt, thus prevent absorption to blood)

17. Therapeutic Measures (cont.) A) Gut decontamination (cont.): • c. Activated charcoal:Not used (has no affinity). • d. Cathartics: used if no diarrhea & some iron reach intestine.

18. Therapeutic Measures (cont.) B) Antidote (Deferoxamine, Desferal) • Used when? • Serum iron > 500 mg/dl, ↑ blood glucose, ↑ WBCs, ↓ B.P, seizures. • Bind what? • Deferoxamine + free iron (Fe3+ )→ Ferrioxamine(sol coloured). • Also bind with  transferrin, ferritin, hemosiderin • Not bind with  iron in Hb or in cyt P 450.

19. Therapeutic Measures (cont.) B) Antidote (cont.) • Dose: • Provocative dose: 25 – 50 mg/kg I.M if vin rose colour of urine excessive iron in blood. • Dose: 50 mg/kg I.M every 4-6hrs. • In Severe case: 15 mg/kg/hr I.V infusion. • If ↑ rate: hypotension, erythema & urticaria. • Antidote must be tapered on 24hrs to prevent pulmonary edema. • Endpoint of ttt is the disappearance of vin rose colour.

20. Therapeutic Measures (cont.) B) Antidote (cont.) • N.B: • Deferoxamine is not contraindicated in pregnancy. • Deferoxamine may be transported across the placenta, chelating iron in utero so making iron therapy necessary at birth.

21. Therapeutic Measures (cont.) C) Adjunctive treatment: • Hypotension: • Patients should be placed in Trendlenburg position. • Normal saline (I.V, 1-2 liter)- not ↑ to avoid cerebral & pulmonary oedema) • Dopamine (2-5 mg/kg/min). • NE (0.1 – 0.2 mg/kg/min, if ↑ dose tissue ischemia). • Seizures:diazepam. • Exchange transfusion:may be attempted in patients who remain oliguric.

22. CASE-1 A 5 year old girl, weighing 25 kg, was brought 5 hours to hospital after ingesting 25 tablets of her mother’s ferrous chloride medicament. The girl was lethargic, with abdominal pain, diarrhea and hemotemesis. Her vital signs were B.P 70/50mmHg, R.R 30/min. Blood analysis revealed elevated level of lactic acidosis, and a serum iron level of 400µg/dl.

23. Answer the following: • Was this a toxic dose, CALCULATE in details. • If this was a toxic dose, what is the degree of toxicity, WHY? • In which stage is this girl?, rationalize your answer. • What is the cause of her low blood pressure?

24. CASE-2 A 16 year old boy, weighing 60 kg, committed suicide by ingesting 70 tablets of ferrous sulfate. He was brought to the E.D 6 hours after ingestion. The boy was lethargic and complained of homotemesis and abdominal pain. Upon examination he was found hypotensive, with increased level of lactic acid; testing his serum iron level it was 400µg/dl. In the department they started giving him an antidote, and shortly after his urine turned vin-rose.

25. Answer the following: • Was this a toxic dose, CALCULATE in details • If this was a toxic dose, what is the degree of toxicity, WHY? • Explain WHY was the urine color turned vin-rose? What does this color indicate? • What is the cause of his elevated lactic acid level?

26. CASE-3 C. B. is a 35-year-old 55 kg female who ingested sixty 325 mg tablets of ferrous sulfate six hours before coming to the hospital. On admission, she was diaphoretic, lethargic, and complained of abdominal pain, nausea, and vomiting. Emesis in the emergency department was guaiac positive. Vital signs were BP 85/60 mm Hg, pulse 135/minute, respirations 34/minute, and temperature 98.6° F.

27. Answer the following: • Assess the potential severity of this ingestion. • What additional laboratory information would be useful? • A flat plate x-ray of the abdomen revealed a clump of undissolved tablets in C. B.’s stomach. What measures can be taken to decrease iron absorption?

28. C. B.’s serum iron concentration (on admission was 680 mcg/dL (70 to 170); her TIBC was 400 mcg of iron/dL (300 to 400). Is chelation therapy with deferoxamine indicated? • How should deferoxamine be administered? What side effects are associated with its use? What are the endpoints of treatment? • What general treatment measures are necessary in C. B.’s case?