Profound acidosis caused by isoniazid ingestion

ProfoundAcldorlsCausedby IsonlazldIngestIon DANIEL Q. HANKINS, MD, KUSUM SAXENA, MD, RALPH J. FAVILLE, JR,, MD, BRYAN J. WARREN, MD

Iaoniazid(INH)overdorcand aeizurasbothprediapoeato lacticacidorio.Wereporta caaoof rurvivalwithoutequelae from profoundacidorir rerultingfrom INH ingestion.Tho initial pH level of 6,49 ie tho lowortpH with rurvivalreportedin the literature, RCPORT OFACASE A 1%yoar=old Southout Aeian boy was brought by par= amodical pomonnol to the omorgoncyroom in status opilopticur.Ho had been experiencingeeizumrfor about 15 minutes,The patientWMin the midrt of a one-yearcoucma of INH therapyfor a positive tuberculorir&in te& Tho pationt’ebrotherstatedthat ho had wbn the pationttake a “handful”of INH. It did not becomoclear until muchlater (after etabilizationin the omeqoncy department)that this couldhave been as much8t115 8, Transportof tho patient initiallywasundertakenby hir paranti, but whenho rtarted to havo~~oizuroa, the paramedicaWOEcalled, On pnrrentationin thoemergencydepartment,thopatient wanin rtatueopilopticurwithgeneralizedgrandmalactivity. Initially, his blood prooeureWM80 mm Hg palpable,hie pulse wan 120 bpm, and his respirationswere shallowat 4O/minute.His pupils wore midpolritionand rlu&h; tho fundi showedsharpdisks. Cheat examination rovoalod bilateralrhonchi. Initially his heart had a sinus tachycardia, but immediatelyon omorgoncyroom presentationho oxperionccdbmdycardiaof 40 bpm. This resolvedwith inFromtha DopaMonta of Emwgwy Mdldno, Podlakkr, ~IKI IntwnrlMOUC4O,St.Plul-~~DOntOf,O4OJlok#nStNOt, St. Paul, Mlnnowta, Suppottod In part by the 81, PaubRamwy Foundation. Manu#o~Ipt roodvod June 0,108d; rovbbn awoptod Sopbmbor 9, 198(1, Addrau roprlnt twquwta to Dr. Hankh: Dopartmont of Emoqonoy bktlolno, St. Paul=Ftamwy Madbal Dwtor, 040 JaWon Strwt, St. Paul, MN 1101. Key Mda; Addoh, loonlazld.

tubation,vontilationwith 100%oxy#on,and tho adminirtrationof a&opine,0,s mg intrnvanou#ly (IV).The abdomM examinationwan unnmarkablo,Tho deep tondonrefloxor woregenerallydecnancd, and Babinrkirignr woreequivocal. Initial arterial blood gawe rhowada pH level of 6,49, pCO2of 43 mm Hg, pOaof 440 mm Hg, and bicarbonate of 3,2 mmol/L,All arterial blood 8~~0 wore determined from 1 cm3of attcrial blood uring the Corning170Blood GarrAnalyzer. Aftor initial calibrationand determination, the rerultr worechockedtwice after mcrlibration.The patient wantreatedon arrivalwith intubation,ventilation,30 mgdiazepamIV, 0.5-mgatropinoIV (aumentionedearlier), 2-mgnaloxonoIV, and 2,s ampulor(125mEq)of aodium bicarbonatesolution,Ho WMgiven 25 8 of glucoseby tho paramedice.Ho also receivedan initial 5-8 IV doro pyri= doxino,which ie the urrualempiricalstartingdoae of this vitaminin INHovordoso~ of unknownamount.Hir aoizurer stoppedinitially, but rerumedafter about 15 minuter. Other laboratorydata includeda hemoglobincount of l&3 g/d&homatocrit47.7%, leukocytecount of 22,900 (16%noutrophils,5% bandr, 63% lymphocyter,6% monocytet~,6% eoeinophile,3% motamyolocyter).Hir platelet countwas368,000.HL olectrolytarworesodium149mEq/ L, potassium4,7 mEq/L,chloride109mEq/L,carbondioxidebra than 10mEq/L,blood-ureanitrogen10m#dl, blood auugar 240 mgldl. Urinalyrirrwas unremarkable,A norum ralicylatelevel was6.1 mg/dl.BloodalcoholWM negative. Hir acotominophon lovolwaslorrthan 10mcg/ml.A second mt of arterialbloodgasesdetermined10 minute6after the initialst showeda pH lovolof 6.77, pCO2of 40 mm Hg, pO2of 244 mm Hg, and bicarbonateof 5,8 mmol/l.The initial anion gap was calculatedto bo 37. Otherpertinentlaboratorydata showedan alkalinephoaphatasolevel of 333 IU/L (normalrango,30 to 115IU/L), cmatinepho!iphokinasa gmaterthan12cQIv/L (nomlalrange, 0 to 225 IU/L),and an SOOTof 87 IU/L(normalqo, 0 to 41 IUIL). The patientwas admittedto tho pediatricintensivecare unit(ICU).Ho rocoivod a second5-g IV dorroof pyridoxino andanadditional10mgof diazepamIV becausethe seizurur pcnieted, althoughthey wore lou frequent,Initial blood gaser in the pediatricICU were pH love1of 7.22, PO, of 263 mm Hg, and pCO2of 33 mm Ha, with a bicarbonate of 13.3mmol/l.Thopatientawokewithinminutorafterthe seconddoeeof pyrldoxinoand had no Mhor eeizuns. Ho

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thus reached two of the endpoints for titrating empiric pyridoxine: the seizures stopped, and he awoke. He was discharged on the third hospital day after an uneventful course. On discharge and on subsequent pediatric clinic follow-up examination, he appeared normal with no sequelae from his medical ordeal. He has had no formal testing of intellectual functioning to this point, however. DISCUSSION The patient had a wide-anion-gap type of metabolic acidosis. He did not have one of the more common causes of wide-anion-gap acidosis such as uremia, diabetes, or ingestion of drugs such as salicylates , methanol, ethanol, ethylene glycol, or paraldehyde. He had two good reasons for lactic acidosis: the INH ingestion and the resultant status epilepticus. His acidosis resolved because of several factors, including better ventilation and oxygenation, the administration of antidote for INH, elimination of the INH by catharsis, the cessation of seizures, and the administration of the 100 mE!qof bicarbonate. Thus, only a small part of his estimated 600 mEq total base deficit needed to be corrected with bicarbonate. INH can be considered to be the cause of one of the most severe drug overdoses. INH may cause permanent brain damage and mortality may be as high as 19%. ’ INH is very well absorbed after oral administration, with peak plasma levels at one to three hours postingestion. Toxic effects can occur as early as 30 minutes postingestion. The initial symptoms are nausea, vomiting, dizziness, slurred speech, and blurred vision. Coma and grand ma1 seizures follow. The differential diagnosis must include phenytoin, phenobarbital, aminophylline, strychnine, and propoxyphen toxicity. INH antagonizes the coenzyme effects of pyridoxine in the brain and inhibits monoamine oxidase. This leads to increased sympathetic activity in the brain. In addition, INH decreases the amount of y amino butyric acid (GABA) in the brain.2 These factors lead to the seizure activity. The seizure activity then contributes to the lactic acidosis. INH

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also directly causes lactic acidosis, probably by blocking the conversion of lactate to pyruvate in the Kreb’s cycle.’ Wason et aI recommend single high-dose pyridoxine treatment. Pyridoxine may act synergistically with anticonvulsant medication, because phenytoin, phenobarbital, and diazepam work to increase GABA in the brain. The dose of pyridoxine should at least equal the dose of INH. An initial dose of 5 g of pyridoxine can be repeated at 5- to lo-minute intervals until the INH dose is exceeded, the seizures cease, or consciousness returns. I As much as 52 g of pyridoxine have been administered without toxic effects. Pyridoxine is water soluble and excreted by the kidneys. Pyridoxine toxicity signs can include tachypnea, paralysis, and seizures. This patient received 10 g of pyridoxine to counteract the approximate overdose of 15 g of INH (which was partly eliminated by lavage and charcoal administration) . This patient was remarkable because of the extremely low pH level (6.49) after which he survived without sequelae. The previous low pH levels of which we are aware are 6.554 and 6.57,5 both caused by strychnine poisoning. Our patient apparently had the lowest pH level ever recorded in conjunction with patient survival. We express our appreciation to Ms. Lynn Gilsrud for her editorial assistance in the preparation of this manuscript.

REFERENCES 1. Kingston RL, Saxena K. isoniazid In Skoutakia V (ed): Clinical Toxicology of Drugs: Principles and Practice. Philadelphia, Lea and Febiger, 1982; pp 279-286 2. Nelson MV, Bailiie OR, Krenzeiok EP. Central nervous system stimulation from isoniazid therapy. Vet Hum Toxkoi 1983; 2590-91 3. Wason S, LaCourture P, Lovejoy F. Single high-dose pyridoxine treatment for INH OD. JAMA 1981; 248:1102-l 104 4. Boyd RE, Brennan PT, Deng J, Strychnine poisoning; recovery from profound lactic acldoeia, hyperthermia, and rhabdomyoiysis. Am J Med 1983; 74507-512 5. Qoidstein MR. Recovery from severe metabolic acidosis (correspondence). JAMA 1975; 234(11):1119