See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/289243855 Near Fatal Poisoning by Isoniazid and Rifampicin a Case Report and Review of Literature Article in Indian Journal of Forensic Medicine & Toxicology · January 2016 DOI: 10.5958/0973-9130.2016.00034.7 CITATIONS READS 0 316 5 authors, including: Arun Agarwal Samiksha Sharma Fortis Escorts Hospital,Jaipur Birla Institute of Technology and Science Pilani 28 PUBLICATIONS 36 CITATIONS 12 PUBLICATIONS 26 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: a case report View project HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS(HLH) View project All content following this page was uploaded by Arun Agarwal on 22 September 2017. The user has requested enhancement of the downloaded file. SEE PROFILE 88 Journal of The Association of Physicians of India ■ Vol. 64 ■ December 2016 Near Fatal Poisoning by Isoniazid and Rifampicin Arun Agarwal1, Samiksha Sharma2, Ritu Bansal 3, Meghraj Meena 4, Mala Airun5 Abstract Since six decades, Isoniazid and Rifampicin are used as first line drugs for treatment of tuberculosis. The minimum acute lethal or toxic dose of Rifampicin is not well established. However, non-fatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm and fatal acute overdoses with doses ranging from 14 to 60 gm. Isoniazid, if acutely ingested, even 1.5 to 2 gram may cause toxicity in adults. We report a case of Pott’s spine on ATT, who took massive overdose of Rifampicin (>18 gm) and Isoniazid (>12 gm) and reported late (almost 36 hours) after ingestion. He was treated successfully with pyridoxine, hemodialysis and supportive care. Introduction I soniazid and Rifampicin are one of the most effective and widely used anti tubercular drugs. Long treatment duration and easy access to these drugs increases the potential for deliberate self poisoning. Acute INH toxicity frequently presents as altered mental status, seizures, metabolic acidosis or coma; and chronic INH toxicity frequently manifests as peripheral neuropathy or hepatotoxicity. An acute ingestion of even 2 grams may cause toxicity. 1 Higher doses (≥20 mg/kg) are associated with increased likelihood of seizures. In toxic doses, rifampicin produces hepatic, renal, hematological disorders, convulsions and sometimes red man syndrome. The prognosis and outcome depends on rapid diagnosis and timely management of complications. Case Presentation A 25 year male, 62 kg body weight, had been taking Antitiubercular treatment for Potts Spine without follow-up consults. He was brought to triage on May 13, 2015 with alleged history of ingesting around 15 to 20 tablets of Rifampicin 450 mg + Isoniazid 300 mg on the night of May 11, 2015. He was initially taken to a local hospital where he developed generalized tonic clonic seizure and became comatose. H e wa s t h e n r e f e r r e d t o a h i g h e r centre where he was managed with antiepilectics, vasopressors, N-acetyl cysteine and supportive treatment. No gastric lavage was done. He was then shifted to our facility, almost 36 hours after ingestion. On admission, there was history of nausea, vomiting, shortness of breath after ingesting alleged tablets followed by generalized tonic clonic seizures and altered sensorium. All this happened within 2 hours of ingestion of tablets. He was admitted to our medical intensive care unit for further management. On examination he was restless, irritable, had tachycardia (heart rate 115/m), BP 150/90 mm Hg, afebrile, acidotic breathing, mild jaundice, GCS E2V2M4,bilateral plantars extensors, and basal coarse crackles. Rest of the clinical examination was normal. His serology, serum electrolytes, thyroid function tests, electrocardiogram and abdominal ultrasound were normal. His other investigations are mentioned in Table 1. Further evaluation revealed orange to red color urine (no other features of red-man syndrome), high anion gap metabolic acidosis, r h a b d o m y o l y s i s ( ve r y h i g h C P K ) a n d h e p a t i c d y s f u n c t i o n . H e wa s managed conservatively with high dose oral pyridoxine, single session of hemodialysis, torsemide, anti epileptic drugs (levitiracetam and lorazepam), fluids and other supportive treatment. He improved over next 48 hours and was discharged on 19.05.2015. On follow up, patient revealed that he had taken more than 40 tablets (more than 12 gm of Isoniazid and 18 gm of Rifampicin). A pre-discharge MRI Lumbo-sacral spine showed chronic changes of spondylodiscitis. His anti tubercular treatment was stopped. We did not measure blood levels of isoniazid and rifampicin because of non-availability and the diagnosis of intoxication was based on history and photographs of the used labeled drug strips. Discussion Most of us monitor liver function tests to detect hepatotoxicity in patients with tuberculosis who are being treated with isoniazid or rifampicin. However,many of us may not be aware that the acute ingestion of as little as 1.5 to 2.0 g of INH can be toxic. 1 Ingestion of more than 10-15 g or 80 mg/ kg is usually fatal without aggressive treatment. Clinical manifestations may appear as early as 30 minutes after ingestion. Early manifestations include nausea, vomiting, slurred speech, dizziness and tachycardia. Recurrent seizures, profound metabolic acidosis, coma and even death can occur. 2 Clinically, seizures commonly start within 30 minutes of ingestion, but may begin up to two hours and last for many hours. The patient may also have mental obtundation in the absence of seizure activity. However, coingestants may affect the time of onset or duration of toxicity. INH is a hydrazid derivative of isonicotinic acid and is rapidly absorbed from the gastrointestinal tract. Its metabolite isoniazid hydrazone inhibits formation of pyridoxal-5 phosphate from pyridoxine by inhibiting pyridoxine p h o s p h o k i n a s e c o m p e t i t i ve l y . T h e functional pyridoxine deficiency induced by INH and inhibition of Glutamate dehydrogenase leads to Gamma Amino Butyric Acid (GABA) deficiency. GABA deficiency may manifest as seizures, particularly in acute overdose. The first signs and symptoms of INH toxicity may appear within 30 minutes to two hours after ingestion and may include nausea, 1 Senior Consultant and Head, Department of Internal Medicine, 2Consultant, Department of Pathology, 3Associate Consultant, Critical Care, 4Resident, Critical Care, 5Clinical Director, Narayana Multispeciality Hospital, Jaipur, Rajasthan Received: 23.10.2015; Revised: 08.01.2016; Accepted: 21.07.2016 Journal of The Association of Physicians of India ■ Vol. 64 ■ December 2016 Table 1: Hematology and biochemistry Normal values 13.05.2015 15.05.2015 17.05.2015 18.05.2015 27.05.2015 Hemoglobin (gm/dl) 13-0-17.0 13.8 15.5 TLC (x 1000 cells/cmm) 4.0-10.0 23.24 12.78 Total platelet count (x 1000 cells/cmm) 150-400 151 129 ESR (mm 1st hour) 0-10 CRP (mg/dl) < 0.6 4.29 60 4.76 S. bilirubin total (mg/dl) 0.0-1.3 3.5 2.5 0.7 S. bilirubin direct (mg/dl) 0.0-0.3 1.8 1.5 0.5 AST (IU/L) 15.0-37.0 1171 1398 526 46 ALT (IU/L) 30.0-65.0 206 528 406 89 ALP (U/L) 38-126 83 128 103 74 S. total proteins (mg/dl) 6.4-8.2 6.77 6.69 6.40 S. albumin (gm/dl) 3.4-5.0 3.82 3.5 3.32 Creatine kinase(U/L) <171.0 >20,000.00 TLC: Total Leucocyte Counts; ESR: Erythrocyte Sedimentation rate; CRP: C Reactive Protein; AST: Aspartate aminotransferase; ALT: Alanine Aminotransferase; ALP: Alkaline Phosphatase vomiting, rash, fever, ataxia, slurring of speech, peripheral neuritis, dizziness and stupor. These symptoms are usually followed by grand mal seizures and coma. Respiratory failure and death can follow. Metabolic abnormalities such as metabolic acidosis, an elevated creatine kinase and later renal insufficiency from rhabdomyolysis are directly related to seizure activity. 3 Despite the reported efficacy of hemodialysis and peritoneal dialysis in isoniazid poisoning, closer scrutiny has revealed that only 9.2 % of dose is dialyzable and the rest is handled through hepatic metabolism. However, metabolites of isoniazid are rapidly cleared through normal kidney, and hence forced diuresis is used to accelerate isoniazid clearance. 4,5 In the present case, forced diuresis was done along with a single session of hemodialysis. Rifampicin in toxic doses produces gastrointestinal, renal, hepatic, hematological and central nervous system manifestations. It often presents with nausea, vomiting, metabolic acidosis, convulsions, thrombocytopenia, cholestatic jaundice, oliguric renal failure, and red-man syndrome. The typical features of red man syndrome are g l o wing red dis co lo r at io n o f skin and facial and periorbital edema. The toxicology findings are attributed to high concentration of rifampicin and two major metabolites 25-desacetyl View publication stats rifampicin and 3-formylrifamycin. The toxic effects have been described with ingestion of 9-12 g and 14-15 g of rifampicin in various situations. 4 With rifampicin intoxication fatal outcomes are exceptional in an otherwise normal person. Rifampicin is not significantly removed by hemodialysis in view of its large molecular weight, wider distribution in tissue, highly lipophilic nature and high (80%) protein binding. However, it has rapid hepatic clearance.6 B l o o d l e ve l s a r e n o t c l i n i c a l l y helpful in managing an acute overdose and results may take days or weeks to perform. Our patient had taken massive overdose of INH and RIF and presented within a few hours with CNS, hepatic and metabolic abnormalities. He reported late at our centre (after 36 hours of ingestion) and had all features of severe INH/RIF toxicity such as convulsions, altered sensorium, coma, metabolic acidosis, rhabdomyolysis, hepatotoxicity with very high creatinine kinase values and some red man syndrome features like persistent orange discoloration of urine and stool for 3-5 days. In terms of management, apart from general measures such as providing a secure airway, gastric lavage with activated charcoal and correction of metabolic acidosis by soda bicarbonate if pH is < 7.1, measures to correct hypotension and hyperkalemia should be done. Correction of GABA deficiency by pyridoxine replacement 89 is the mainstay of treatment.Pyridoxine s h ou l d b e a dm i n i s ter e d i n a d o se equivalent to the suspected maximum amount of isoniazid ingested (i.e. gramper-gram replacement). 4,7 If the amount of ingested isoniazid is unknown, 5 g of pyridoxine is given intravenously over five to 10 minutes. If the intravenous form of pyridoxine is not available, the drug can be given as slurry, using crushed tablets. 8 Repeat dosing may be needed for persistent seizure activity and may also be used to reverse altered sensorium and deep coma. In our case we initially gave around 6 gm of pyridoxine as slurry. Further dosage were also given in view of persistent mental obtundation. Conclusion We have reported a case of nearfatal poisoning from Isoniazid and rifampicin combination. In addition to hepato-toxicity, clinicians should remember acute toxicity with INH as one of the causes for seizures and mental obtundation. 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