1. Desflurane Toxicity 17 February 2004

2. Case • 27 year-old female, ASA II, presented for Right VATS/thoracotomy for excision of mediastinal extension of medullary thyroid cancer. • PMHx: Medullary thyroid CA, GERD (no meds) • Social: 1.5 pack-year smoking history. • Meds: OCP, thyroid replacement in the past. • CT chest: Right paratracheal mass; no compression or deviation of trachea. • Wt: 79 kg Ht: 5’6” (BMI = 28)

3. Case • PSH: • 8 July 2002: Right partial thyroidectomy • 15 July 2002: Completion thyroidectomy • 1 Oct 2003: Neck dissection

4. Case • Anesthetic History: Elevated LFTs after 10/03 surgery; attributed by surgeons to “anesthesia.” • Comprehensive Metabolic Panel ordered post-op. • Unknown if occurred after other surgeries. • LFTs: • 10/1 at 0722 (pre-op): AST 19, ALT 30, TBil 0.5 • 10/1 at 2108 (post-op): AST 755, ALT 594, TBil 2.1 • 10/2: AST 156, ALT 332, TBil 0.5

5. Differential Diagnosis • Pre-existing hepatic disease • Infection: Hepatitis A, B, C, D, E; CMV; EBV • Drugs: Acetaminophen, OCPs, alcohol, isoniazid, phenytoin, volatile anesthetics (esp. Halothane), mushrooms, etc. • Sepsis • TPN • Biliary obstruction • Intra-operative • Hypoxemia • Hepatic Ischemia: Increased venous pressure, decreased arterial pressure. • Drugs: Volatile anesthetics, hydralazine

6. What did we do? (pre-op clinic) • Hepatitis Panel ordered (was not performed). • Related to OCPs? • Re-check LFT: • 11/2 (pre-op): AST 28, ALT 24, TBil 0.4

7. What did we do? (Day of Surgery) • Review labs – back to normal. • Review record • Records unavailable at the time for previous surgeries. • 10/1/03- propofol, succinylcholine, sufentanyl, cefazolin, dexamethasone, ondansetron. Isoflurane/N2O/O2 for first 1.5 hours then Desflurane/N20/O2 for 6.75 hours. • Proceed with surgery using Desflurane (minimal, if any, hepatic biotransformation). • Discuss plan with patient

8. 10/03 Anesthesia Record (p. 1)

9. 10/03 Anesthesia Record (p. 2)

10. 10/03 Anesthesia Record (p. 3)

11. 11/3-Right VATS/Thoracotomy • Pre-Med: midazolam, vancomycin • Thoracic epidural: 0.2% ropivicaine • Induction: fentanyl, propofol, rocuronium, granisetron • DLT, A-line • Maintenance: desflurane/O2, fentanyl, rocuronium • Other: ondansetron, neostigmine/glycopyrolate

12. 11/3 Anesthesia Record (p. 1) Epidural dosed.

13. 11/3 Anesthesia Record (p. 2)

14. 11/3 Anesthesia Record (p. 3)

15. Post-op Labs • 11/3-AST 444, ALT 304, TBil 1.1 • 11/5-AST 59, ALT 112, TBil 0.5 • The patient denied any further testing at the time (hepatic US), saying “if anything is wrong with my liver, I don’t want to know. I’ve got too much going on with my thyroid already.” • Viral Hepatitis Panel—negative. • Discharged home on POD #3.

16. Differential Diagnosis • Pre-existing hepatic disease • Infection: Hepatitis A, B, C, D, E; CMV; EBV • Drugs: Acetaminophen, OCPs, alcohol, isoniazid, phenytoin, volatile anesthetics (esp. Halothane), mushrooms, etc. • Sepsis • TPN • Biliary obstruction • Intra-operative • Hypoxemia • Hepatic Ischemia: Increased venous pressure, decreased arterial pressure. • Drugs: Volatile anesthetics, hydralazine

17. Duplicated Drugs (10/1 & 11/3) • Propofol • Ondansetron • Desflurane

18. Further Investigation • Previous Surgeries: • 8 July 2002: Right hemithyroidectomy • Midazolam, propofol, isoflurane/N2O/O2, sufentanyl. • 15 July 2002: Completion thyroidectomy • Midazolam, propofol, sevoflurane/N2O/O2, sufentanyl. **No LFTs checked after either surgery.

19. Hepatic Effects of Volatile Anesthetics • Decreased portal hepatic blood flow (halothane most, isoflurane least). • Decreased hepatic arterial flow (except isoflurane increases). • Decreased hepatic metabolism.

20. Halothane Hepatitis

21. Halothane Hepatitis • Varies from asymptomatic LFT elevation to fulminant hepatic necrosis. • As high as 20% incidence in adults on 2nd exposure. Children seem to be more resistant. • Fatal hepatic necrosis estimated 1:35,000. • Risk factors: middle age, obesity, female sex, repeat exposure (esp. if within 28 days). • Diagnosis of exclusion. • Appears to be immune-modulated. • May have eosinophilia.

22. Biotransformation of Volatile Agents Degree of volatile degradation is directly related to the potential for hepatic injury.

23. *Isoflurane-one “isolated” chlorine atom; Desflurane-”devoid” of chlorine. * * *Substitution of fluorine for chlorine yields less biodegradation.

24. Cases of Hepatotoxicity Reported as of 1995 • Desflurane: 1 • Isoflurane: 5 • Enflurane: 15 • Sevoflurane: few • Halothane: many

25. Case Report of Desflurane Hepatic Injury—Only 1 in literature • Anesthesiology, Nov 1995 • 65 year-old female • Left hemithyroidectomy for adenoma • PSH: T&A 1935; BTL 1952; TAH 1969; Ex lap 1976; Cholecystectomy 1982. Halothane in 1976 & 1982, 45 minutes each. • PMHx: HTN, rare EtOH, no liver disease. • Allergy: iodine

26. Case Report • SBP in mid-80’s just before incision, otherwise normal BP. Treated with ephedrine. • Maintenance with desflurane/N2O in 37-39% O2. • Minimal EBL. • Total anesthetic time of 90 minutes. • Discharged home.

27. Case Report • POD #12: pruritis, malaise, nausea, polyarthralgias, rash on buttocks and thighs, dark urine noticed by patient. • POD #16: Jaundice, epigastric abdominal pain. Admitted to hospital. • LFTs elevated. • Viral hepatitis panel negative. • POD #22: Transferred to hepatology unit for potential liver transplantation. Repeat viral hepatis panel was negative; HSV and EBV tests revealed past infection. • POD #97: Symptom free with nearly normal liver function. No transplant was performed.

28. Case Report • POD #48: ELISA for antibodies that react to liver-microsomes from halothane-treated rats versus untreated rats. • Antibody reactivity was higher against liver microsomes of halothane-treated rats than control rats, suggesting presence of antibodies in the patients serum formed by exposure to halothane.

29. Trifluoroacetylated Antibodies (TFA) • Only patients with halothane hepatitis have antibodies that react with liver microsomal proteins that have been trifluoroacetylated (TFA) by the reactive trifluoroacetyl chloride halothane metabolite. • Similar immune process thought to occur with other volatile anesthetics but at lower incidence due to significantly less hepatic biodegradation.

30. The Rest of the Story…. • Our patient will have specimen drawn on Feb 20th to be sent to John-Hopkins to have the ELISA for TFA performed (will be roughly POD #110).

31. Conclusions • Of interest, our patient and the one patient reported were both having thyroid-related procedures. Could there be some immune mechanism induced by the thyroid cancer/adenoma? • Asymptomatic desflurane hepatitis may be more common than reported, we just don’t routinely check for it. • Desflurane still appears to be the most hepatic-friendly volatile agent from an immunology standpoint. Isoflurane may be best for the patient with known hepatic disease due to less net decrease in hepatic blood flow.

32. Conclusions • Avoid hypoxia, hypotension. • DVT prophylaxis of choice (of course).