Halothane induced hepatitis
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PHARMACOVIGILANCE CASE
Dr Pranesh PawaskarFirst Year Resident
Department Of PharmacologyL.T.M.M.C. Sion, Mumbai
400022Date = 14/10/2016
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HALOTHANE INDUCED HEPATITIS
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CASE• Female• 42 years• Post Operative > Uterine Fibroid ~ 4d• c/o Fever, Pain Abdomen ~ 3d Nausea and Vomiting ~ 2d Yellow Sclera ~ 2d Constipation ~ 1d
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COURSE OF REACTION• Asymptomatic ( prior 4 mo. )• Prior h/o Appendix Operation 15 yrs back.Now C/o :-• Heavy Menses, Dysmenorrhoea…. 4 mo.• Fullness of Abdomen, Increased frequency of
Urination…. 3 mo.• Progressive Enlargement of abdomen…. 2 mo.• 15 days back….. Abdo USG > 17 x 7 x 4 cm
Subserosal Fibroid and Cystic Ovary (Rt/Lt).On 16 SEP 2016 :-• Surgery:- TAH + B/l salpingo oophorectomy by Inhal.
Halothane (1%) General Anaesthesia. (5 pints BT)
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COURSE OF REACTIONOn 17 SEP 2016:-• Pain abdomen and Fever.• Generalised Malaise.On 19 SEP 2016:-• Nausea Vomiting• Yellow scleraOn 20 SEP 2016:-• Constipation• Refered
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COURSE OF REACTION20 SEP 2016 –
• Patient refered to Sion Hospital in view of –
TAH + B/L Salpingo- oophorectomy
With Post Operative Icterus
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EVALUATION• Temp – Normal CVS - Normal• Pulse – 80/min CNS – Conscious ,
Oriented• B.P.- 130/86 mmHg RS - Normal• Icterus – Present GIT - Hepatomegaly• Pallor - Present
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COURSE OF REACTIONON 20 SEP 2016:-At SION Hospital Pt admitted in Wd 20 under Dr. THT• Treatment started was - Inj. Taxim 1 gm TDS (infection) Inj. Metro 100 mg TDS (infection) Inj. Pan 40 mg OD (gastritis) Inj. Ondem 4 mg TDS (vomiting) Vit K 10 mg OD (haemolysis)• Blood sent for analysis.
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DOCTORS IMPRESSIONBLOOD ANALYSIS :- • Raised > SGPT, SGOT, LDH, T. Bili, D. Bili, GGT.• Normal > ALP, T. Prot, Blood Urea, Creatinine, BUN,
UA.• HBsAg = Negative• Hep C Ag = Negative• ELISA = Negative.• Abdo USG = Mild Hepatomegaly.OTHER :-• Addiction (x)• No h/o BT
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DOCTORS IMPRESSIONPREANAESTHETIC MEDICATIONS –• Inj. Atropine 0.5 mg i.m.• T. Chlorpromazine 50 mg p.o.• Inj. Midaz 1mg i.v. • Inj. Pan 40mg i.v.• Inj. Ondem 4mg i.v.SUSPICION –• Drug induced Hepatitis.• Probably HALOTHANE.
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COURSE OF REACTION• ADR REPORTED > 22 Sep 2016
• Patient = Improved
• Discharge = 30 Sep 2016
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INVESTIGATIONS
Date SGPT SGOT LDH Tot. Bili Dir. Bili GGT
15 SEP 2016
34 (0-40IU/L)
23 (0-40IU/L)
312 (225-450
IU/L)
0.9 (0.1-1.0mg/dl
)
0.3 (0.1-0.5mg/dl
)-
19 SEP 2016
169 (0-40IU/L)
188 (0-40IU/L)
1168 (225-450
IU/L)
10.8 (0.1-
1.0mg/dl)
2.8 (0.0-0.5mg/dl
)39 (9-37IU/l)
21 SEP 2016
105 (0-40IU/L)
70 (0-40IU/L) -
10.0 (0.1-
1.0mg/dl)
2.4 (0.0-0.5mg/dl
)-
24 SEP 2016
87 (0-40IU/L)
50 (0-40IU/L)
700 (225-450
IU/L)
7.7 (0.1-1.0mg/dl
)
2.0 (0.1-1.0mg/dl
)-
27 SEP 2016
37 (0-40IU/L)
30 (0-40IU/L) -
2.1 (0.1-1.0mg/dl
)
1.2 (0.1-1.0mg/dl
)28 (9-37IU/l)
30 SEP 2016
25 (0-40IU/L)
31 (0-40IU/L)
360 (225-450
IU/L)
0.9 (0.1-1.0mg/dl
)
0.2 (0.1-1.0mg/dl
)-
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INVESTIGATIONS
Date Hb WBC Plt
15 SEP 2016 10.1 mg/dl 7500 /uL 200000 /uL
19 SEP 2016 8.6 mg/dl 8500 /uL 180000 /uL
21 SEP 2016 9.0 mg/dl 9000 /uL 225000 /uL
24 SEP 2016 10.8 mg/dl 8600 /uL 154000 /uL
27 SEP 2016 11.6 mg/dl 9700 /uL 170000 /uL
30 SEP 2016 12.0 mg/dl 6600/uL 210000 /uL
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INVESTIGATIONS
ALP Albumin Sr. Tot. Prot.
Blood Urea Sr. Creat
113 (37-147 IU/L)
4.2 (3.4-5.5gm/dl)
6.7 (6-8 gm/dl)
32.5 (17-50 mg/dl)
0.82 mg/dl (0.5-1.5mg/dl)
BUN Sr. Ca Sr. UA Sr. IP
12.9 (6-21mg/dl) 9.0 (8.5-10.0mg/dl)
3.0 (2.4-5.7 mg/dl)
3.96 (3.5–5.5mEq/L)
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SERIOUSNESS OF REACTION • Reaction was serious as it prolonged hospitalisation
of patient.
OUTCOME • Patient recovered.
DIAGNOSIS• Halothane induced Hepatitis.
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NARANJO SCALE
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CAUSALITY ASSESSMENTAccording to NARANJO CAUSALITY assessment scale –
POSSIBLE(Score = 4)
Because-----1) Reasonable Drug-Event temporal relationship.2) De-challange response POSITVE.
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HEPATITIS
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HEPATITIS• Hepa = Liver, Itis = Inflammation• Inflammatory Cells • Symptoms = Jaundice, Poor Appetite, Fatigue
Hepatitis
Acute Chronic• Scarring = Cirrhosis.• M/c/c = Viral > Alcoholic > non Alcoholic• Others
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HEPATITISSIGNS AND SYMPTOMS - Fatigue, Nausea, Vomiting, Poor Appetite, Headache, Yellowing of skin and sclera, Deranged liver enzyme values.
CAUSES OF HEPATITIS -Viral – A,B,C,D,EParasiticBacterialAlcoholicToxic and Drug induced- PCM, INH,VLP, PHN, CTXAutoimmuneIschemic
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VIRAL HEPATITIS
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ALCOHOLIC HEPATITIS• Very high Mortality.
• M > F ….But….
• Other Factors …
• Obesity And AH
• AH > Cirrhosis
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NON ALCOHOLIC HEPATITIS• NASH > Liver Transplant• Prevalance = 3-5%• NASH and Hepatocellular Carcinoma • Hepatocellular Carcinoma Prevalance = 15 – 30 %
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BACTERIAL AND PARASITIC• PYOGENIC = M/c by E.Coli, K. pneumonia.• ACUTE = N. meningitis, N. gonorrhoea, Bartonella,
Borellia• CHRONIC = Mycobacteria, Treponema Pallidum
• Parasitic = Acute Hepatitis = Increased IgE • M/c = E. histolytica• Worms = Cestodes• Liver Flukes = C. Sinensis
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AUTOIMMUNE HEPATITIS• Abn immune response.• HLA Ab• M/c ANA, SMA, p-ANCA• Drugs = Nitrofurantoin, Hydralazine, Methyldopa • Viruses = Hep A, EBV, measles
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GENETIC • Causes = Alpha 1 anti-trypsin deficiency,
Haemochromatosis , Wilsons disease.• A1AtD = mutation in gene…abn prot accumulation• Haemochromatosis And Wilsons = Autosomal
Recessive…abn storage of minerals.
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ISCHEMIC HEPATITIS• Insufficient blood/ oxygen.• Shock Liver• M/C in Heart failure• AST ALT ….Very High• Permenant Damage = Rare
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DRUG INDUCED HEPATITIS• Chemicals, medicines, industrial toxins, herbal
remedies, dietary suppliments.
• Mechanisms = Direct cell damage, Cell membrane disruption, Structural changes.
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DRUG INDUCED HEPATITISDrugs which can lead to Hepatitis are :- • Paracetamol Methyldopa• Amiodarone Isoniazid• Methotrexate Anabolic steroids• OC Pills Statins• Sulfa drugs Chlorpromazine• Erythromycin Anti HIV drugs• Halothane Amoxicillin-
clavulanate• Sodium Valproate
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MECHANISMSPARACETAMOL –• Centrilobular necrosis.• Fatal = >25 g • Phase 2 > Phase 1• NAPQI ~ Glutathione = Mercapturic acid• Antidote =
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MECHANISMSISONIAZIDE – • 10% T.B.• 1% = Viral Hepatitis(?)• CFR = 10%• Age > 35 … highest = >50yr.• Isoniazid Acetylhydrazine• Rapid Acetylators.
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MECHANISMVALPROATE• Children > Adult• Asymptomatic elevations = 45% patients.• No major hepatotoxicity….continue• Tissue = microvesicular fat and hepatic necrosis.• 4 - pentanoic acid• L - carnitine
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MECHANISMMETHYLDOPA • Minor alteration = 5%• 15% = mod to severe chr. Hepatitis.• Chollestatic Injury / Hepatocellular Injury.
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MECHANISMAMIODARONE• ultrastructural phospholipidosis• <5% • Desethyl-amiodarone• Injury = Pseudo alcoholic Injury• idiosyncracy > Metabolite generated
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MECHANISMERYTHROMYCIN • Children > adults• Cholestatic reaction • Bx = Cholestasis, portal inflammation, PMNs
Eosinophils
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MECHANISMOC PILLS• Intrahepatic cholestasis • Susceptible = recurrent idiopathic jaundice of
pregnancy, severe pruritis of pregnancy, Family history.• Bx = cholestasis with bile plugs.• Estrogen > progesterone (synergistic).
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MECHANISMSULFA DRUGS• Unpredictable• Uniform latency period.• Hepatocellular necrosis > cholestatic injury• Attribute = Sulpha group• Risk more = HIV
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MECHANISMCHLORPROMAZINE • Well known = ALI • Cholestatic• 1 : 1500• Onset = within 1 week• Vanishing Bile Duct Syndrome.• Hypersensitivity
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OTHER DRUGS• STATINS = Idiosyncratic Mixed Hepatocellular and
Cholestatic Reaction.• ANABOLIC STEROIDS = Cholestatic Reaction• TOTAL PARENTERAL NUTRITION = Steatosis,
Cholestasis• ALTERNATIVE AND COMPLEMENTARY
MEDICINES = Idiosyncratic Hepatitis, Steatosis• HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
(HAART) FOR HIV INFECTION = Mitochondrial Toxic, Idiosyncratic, Steatosis; Hepatocellular, Cholestatic, and Mixed
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HALOTHANE
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HALOTHANE
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HALOTHANE• High blood: gas partition coefficient• High fat: blood partition coefficient• MAC = 0.75• Slow induction• Soluble = fat & tissues = the speed of recovery is
more
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HALOTHANE• 60-70% = eliminated unchanged.
• Rest = Hepatic CYP
• Tri-Fluoroacetic Acid.
• Excreted in Urine
• Protein (tri-fluoro)Acetylation.
• Immune reaction = Hepatic necrosis
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CLINICAL USE• Since 1958• Maintainance Anaesthesia.• Child > Adult.• Low cost
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SIDE EFFECTS1) Cardiovascular – mean arterial blood pressure,
cardiac output, brady cardia normal heart rate.
2) Respiratory - alveolar ventilation, no compensatory ventilation.
3) CNS – intra cranial pressure, cerebral metabolism
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SIDE EFFECTS4) Muscular System – Relaxation of Sk. Muscle,
potentiation of non depolarisers, Malignant hyperthermia
5) Smooth Muscle – Uterus relaxed
6) Kidney – Less vol. more conc. Urine, GFR reduced.
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SIDE EFFECTS ON LIVER• Fulminant Necrosis = Minority
• Fever, Anorexia , Nausea, Vomiting > 3-14 d
• If Rapid Progression = 50% fatality
• 1~10000 Halothane Hepatitis.
• Trifluoroacetylated proteins.
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MANAGEMENT AND CONCLUSION
• Most important aspect of management is Avoid Repeat Exposure within next 3 months.
• History of Unexplained Jaundice following Halothane use is an Absolute Contraindication for its further usage.
• Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults and it is replaced by Enflurane, Isoflurane, Sevoflurane etc.
• But caution is must for all Halothane hepatitis patients for future exposure to Fluorinated Hydrocarbons.
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REFERENCES• Chalasani et al: Causes, clinical features, and
outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924, 2008[PMID: 18955056] [Full Text]• Chang CY, Schiano TD: Review article: drug
hepatotoxicity. Aliment Pharmacol Ther 25:1135, 2007[PMID: 17451560] [Full Text]• Navarro VJ, Senior JR: Drug-related hepatotoxicity. N
Engl J Med 354:731, 2006[PMID: 16481640] [Full Text]• Lee WM: Drug-induced hepatotoxicity. N Engl J Med
349:474, 2003[PMID: 12890847] [Full Text]• Kaplowitz N, Deleve LD (eds): Drug-Induced Liver
Disease. 2nd ed, New York, Informa Healthcare, 2007
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REFERNCES• Bahlman SH, Eger EI, Holsey MJ, et al. The
cardiovascular effects of halolthane in man during spontaneous ventitation. Anesthesiology, 1972, 36:494–502. [PMID: 5021951]• Hirshman CA, McCullough RE, Cohen PJ, Weil JV.
Depression of hypoxic ventilatory response by halothane, enflurane and isoflurane in dogs. Br J Anaesth, 1977, 49:957–963. [PMID: 921874]• Study SotNH. Summary of the National Halothane
Study. Possible association between halothane anesthesia andpostoperative hepatic necrosis. JAMA, 1966, 197:775–788.• Urbinati G, Figliuzzi M. [Jaundice caused by
chlorpromazine.] Clin Ter 1960; 18: 611-39. Italian.
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