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Home , Lithium toxicity

Fatal self- with carbonate

M.R. Achong, b sc, mb; P.G. Fernandez, mrcp, frcp[c]; P.J. McLeod, md, frcp[c]

Summary: In a fatal case of self- is used in the con¬ psychiatric care for a manic-depressive poisoning with lithium carbonate there trol of acute and in the preven¬ illness. For the 6 months preceding the was a progressive increase in serum tion of recurrent attacks of overdose her treatment consisted of 1500 lithium concentration for 48 hours and mania. The mg of lithium carbonate and 200 mg of optimum therapeutic each after ingestion of the overdose. It is serum concentration of lithium 8 to 12 chlorpromazine day. that the continuous increase hours after the last dose is between 0.7 She was alert, oriented and in no physi¬ suggested cal distress. The oral temperature was in serum lithium concentration reflects and 1.3 meq/l.1 However, the margin 36.7 °C, the heart rate 80 beats/min, the prolonged absorption of lithium from of safety is small, for adverse effects blood pressure 100/78 mm Hg and the relatively insoluble aggregates of usually occur with serum concentrations respiratory rate 20/min. There were no lithium carbonate in the gastrointestinal of more than 2 meq/l. The most com¬ abnormal physical findings. Blood urea tract. ln this case there was an mon clinical manifestations of lithium (BUN) and serum electrolyte interval of 45 hours between ingestion intoxication are gastrointestinal (nau¬ values (Table I), chest radiograph and of the overdose and the onset of sea, and and neuro¬ electrocardiogram (ECG) were normal. ) Gastric and were central nervous aspiration lavage per¬ system depression. logic (hand , sedation, , formed a wide-bore tube. A Simultaneous and convulsions and through mod¬ peritoneal dialysis weakness, coma).1'2 erate amount of particulate matter was were effective in Cardiac arrhythmias3 and renal dysfunc¬ recovered. After lavage a slurry of 100 g rapidly reducing the serum lithium tion45 are less common. of activated charcoal (Norit A) was in- concentration but there was little Lithium intoxication can result from stilled into the stomach. One month be¬ concomitant change in the patient's (a) accidental or deliberate ingestion of fore admission the lithium value had been level of consciousness. The terminal a large amount of or (b) 0.75 meq/l; on admission it was 3.7 meq/l. drug gradual Because of the of of event was a respiratory accumulation of lithium in patients re¬ history ingestion of the comatose state. doses of lithium large amounts of three drugs the patient ceiving therapeutic was admitted to the medical intensive care carbonate. The accumulation of lithium unit (MICU) for observation. may result from an increase in dose her first 2 in the MICU Resume: Un cas fatal d'autointoxication During days or a decrease in renal excretion of she remained alert and oriented. Oral le carbone de lithium par lithium due to renal dysfunction, re¬ temperature increased to 37.8 °C and a few Dans un cas fatal d'autointoxication duced sodium intake or diuretic ther¬ scattered rhonchi were heard. There were no abnormal par le carbonate de lithium nous apy. The majority of reported cases of neurologic findings. lithium intoxication fail into the second BUN and serum electrolyte values (Table avons observe une augmentation I), chest radiograph and ECG remained progressive de la concentration serique category,2,5"11 and in this situation pro- dromal and normal. Increasing serum lithium values de lithium pendant 48 heures apres gastrointestinal neurologic were noted (Fig. 1) but the adverse effects are a only ingestion de la dose toxique. Nous prominent feature. There effects observed were nausea, vomiting estknons que cette augmentation are few case reports6'12 describing the continue reflete une absorption clinical course after the ingestion of a prolongee de lithium a partir d'agregats large overdose of lithium carbonate. 15.0 de carbonate de lithium, relativement The case we report demonstrates cer¬ insolubles, situes dans le tube digestif. tain unusual features and raises many 10 Dans le cas present nous avons note questions regarding the management of un intervalle de 45 heures entre acute lithium intoxication. 1 de la dose et E I'ingestion toxique le 2 Case 3 debut de la depression du systeme report I nerveux central. Grace a I'application A 29-year-old woman presented to The simultanee d'une dialyse peritoneale Montreal General Apr. 2, 1974, et d'une hemodialyse, nous avons pu claiming to have ingested, 1 to 2 hours rapidement reduire la concentration before, about 200 tablets (60 g) of lithium de lithium, mais cette 150 tablets of CNS serique carbonate, (15 g) chlorpro¬ admission depression V death maneuvre n'a pas ete suivie d'une mazine and 30 tablets (0.9 g) of fluraze- ^ ¦¦¦?¦¦¦¦? amelioration notable du niveau de pam hydrochloride. She denied drinking 1 2 3 conscience du malade. Le stade ultime ethanol and before arrival at hospital had DAYS vomited twice. a ete une She had been hospitalized complication respiratoire 4 before with an de I'etat comateux. years intentional drug FIG. 1.Log serum lithium concentration overdose and since then had been under and time course.

Table I.Fluid intake, urine output and BUN and serum electrolyte values during hospital stay Hospital day Variable 1 Fluid intake (ml) 610 2970 4850 5000 From the division of clinical pharmacology Urine output (ml) 500* 1950* 210 650 of The Montreal General Hospital BUN (mg/dl) 6 7 10 5 Reprint requests to: Dr. M.R. Achong, Serum Na (meq/l) 137 135 136 139 Division of clinical pharmacology, The Montreal Serum K (meq/l) 4.2 5.9 4.1 General Hospital, 1650 Cedar Ave., Montreal. 3.9 Que. H3G 1A4 *Underestimates: several specimens were lost in the watery feces. 868 CMA JOURNAL/APRIL 5, 1975/VOL. 112 (two episodes/day) and diarrhea (three the onset of central de¬ formed in the . A episodes/day). Intravenous fluids were pression within 6 to 12 hours after an comparable situation may be salicylate given to supplement the oral intake. overdose of the Matthew et aP* have The first in consciousness was phenothiazines (e.g. self-poisoning; change or recovered of seen on the of about 45 chlorpromazine) benzodiazepines large quantities salicylate morning day 3, as hours after admission. At 8 am she was (e.g. flurazepam).13 in fluid long as 9 drowsy but rousable. By noon she was The most unusual feature of this case hours after ingestion of the overdose. comatose, with minimal response to max- was the progressive increase in serum The slow release of lithium into solu¬ imally painful stimuli and without lateral- lithium concentration for 48 hours tion from insoluble aggregates of lithi¬ izing neurologic signs. There was no after admission. There are three pos¬ um carbonate could account for con¬ clinical change in cardiac or pulmonary sible explanations for this phenomenon: tinued lithium absorption long after function. The diarrhea had decreased but (a) impaired excretion, (b) altered dis¬ the ingestion of the overdose. The only because pills had been seen in the feces for this the sulfate tribution or (c) continued absorption of support hypothesis is that pills previous evening, magnesium of an unknown nature were seen in the was administered through a nasogastric lithium. Lithium is excreted almost en¬ tube to hasten elimination of any drug tirely by the kidneys,14 and the patient's feces about 36 hours after admission. that was still in the gastrointestinal tract. renal function, as judged by the BUN Activated charcoal binds mainly to Because her clinical condition rapidly de¬ values, was always normal (Table I). the un-ionized moiety of lipid-soluble teriorated, peritoneal dialysis was started Her urine output was adequate during drugs,27 so one would not expect ac¬ at 2 pm and hemodialysis at 8 pm that the of tivated charcoal to bind lithium ions Because of the phase progressively increasing day. magnesium-sulfate- serum lithium concentration (Table I) and thereby reduce the amount of induced diarrhea and the fluid loss due but she became after lithium available for In this to intravenous fluids were in¬ oliguric dialysis absorption. dialysis, was case, activated charcoal was adminis¬ creased to 5 1 per 24 hours to maintain started. The oliguria probably re¬ fluid balance. Urine output decreased dur¬ sulted from a negative fluid balance tered for its possible benefit in binding ing dialysis but BUN and serum electro¬ during dialysis but it is possible that it any chlorpromazine or flurazepam in lyte values remained normal (Table I). reflects lithium-induced renal dysfunc¬ the gastrointestinal tract. During dialysis the serum lithium value tion. The claim by Almy and Taylor15 Another unusual feature of this case but was rapidly decreased (Fig. 1) there that manic patients retain more orally was the very high serum lithium con¬ no concomitant in the change patient's administered lithium during the active centration; a peak of 14 meq/l was level of consciousness. not 4 comatose but manic phase than normals is sup¬ recorded (Fig. 1). The highest serum On day she remained the work of other lithium value was more responsive to painful stimuli. ported by investiga¬ recorded in previously Her serum lithium value had decreased tors.16 Inhibition of renal excretion of reported cases of lithium intoxication to less than 2 meq/l (Fig. 1) and hemo¬ lithium by chlorpromazine seems un¬ was about 7 meq/l.9 The lack of corre¬ dialysis was discontinued at noon. Peri¬ likely because chlorpromazine induces lation between both the increasing and toneal dialysis was continued because she a very small increase in lithium excre¬ decreasing serum lithium concentration was still oliguric (Table I). Later that day tion.17 There is nothing to suggest that and the patient's level of consciousness she became more responsive to painful flurazepam may influence lithium ex¬ is not surprising because presumably it stimuli, and involuntary, jerking move¬ cretion the is the brain content of lithium that is ments of her head were observed for the by . first time. Respiratory distress developed. Redistribution of lithium from stor- important in producing the neurologic Rectal temperature was then 38.9 °C. Oro- age sites to the vascular space is an¬ effects. Slow equilibration between pharyngeal suction yielded viscid, creamy- other consideration. Recent work sug¬ lithium in blood and that in the brain white secretions. Chest radiograph re¬ gests that bone may be an important is well documented in animal experi¬ vealed mild, subsegmental atelectasis. Ar¬ storage site18 and intermittent urinary ments.18 terial blood values were as follows: Po2, excretion of lithium has been observed A controversial aspect of this pa¬ 70.8 mm Hg; Pco2, 36.5 mm Hg; pH, for tient's was the of total 24.5 To facilitate several months after discontinuation management timing 7.42; C02, meq/l. of the In case serum lithi¬ and to an drug.19 several reports of dialysis. Despite increasing suctioning improve oxygenation, um values in the toxic we chose endotracheal tube was inserted after the lithium intoxication20"22 the serum li¬ range, patient had been sedated with intravenous thium value continued to increase for to initiate dialysis only when there was diazepam. Ventilation with 30% O* by a 2 to 3 days after discontinuation of the a change in consciousness. Our ra- volume-cycled respirator was started. Her drug. This feature remains unexplained, tionale was that the main aim of dial¬ condition remained stable until respiratory for the reports all concerned the inges¬ ysis is to accelerate removal of lithium distress suddenly developed at 1 am on tion of the usual formulations of li¬ from the body in an attempt to shorten day 5. It was believed that the endo¬ thium and not sustained-release prep¬ the duration of coma and its attendant tracheal tube was blocked by secretions arations. complications. In our patient there was and, as the tube was being replaced, no evidence of renal and ventricular fibrillation supervened. Cardiac The most plausible explanation for the impairment followed. Direct-current counter- progressive increase in serum lithium no neurologic effects of lithium intoxi¬ asystole cation were shock and resuscitative measures were un¬ concentration in this patient is con¬ observed in her initial 45 successful. Autopsy was not performed. tinued absorption from the gastroin¬ hours in hospital. Dialysis was very testinal tract. Surreptitious intake of effective in rapidly decreasing the Discussion the drug was not possible because the serum lithium concentration (Fig. 1) patient was closely observed in an in¬ but the patient's mental state improved In self-poisoning by means of a tensive care unit and no drug was only slightly. Furthermore, death8 and single overdose the actual amount of available at her bedside. With thera¬ persistent neurologic sequelae28 despite any drug ingested is open to question. peutic doses of lithium carbonate, peak rapid reduction of serum lithium con¬ In this case, particularly because she serum lithium concentrations are at¬ centration by dialysis have been re¬ had been apparently well for 45 hours, tained in 1 to 2 hours23 and absorption ported. The terminal event was a res¬ we doubted whether the patient had is complete in 4 hours.24 However, piratory complication of the comatose ingested the large amounts of the vari¬ lithium carbonate is the least soluble state. Similar complications have been ous drugs claimed. Any ingested chlor¬ of the lithium salts25 and, with the in¬ prominent in other cases of lithium promazine and flurazepam probably gestion of a large amount of the drug, intoxication. did not have a major influence on her it is possible that relatively insoluble ag- Based on other case reports and our clinical course, for one would expect gregates of lithium carbonate could be present experience, we make the fol- CMA JOURNAL/APRIL 5, 1975/VOL. 112 869 lowing suggestions concerning the man- References agement of severe lithium intoxication: 1. SCHOU M, BAASTRLIP PC, GROF P, et al: Pharmacological and clinical problems of Apresoline lithium prophylaxis. Br I Psychiatry 116: Investigations 615, 1970 2. SARAN BM, GAIND R: Lithium. Clin Toxacol 6: 257, 1973 the unique 1. Assessment of renal function by 3. TANGEDAHL TN, GAU GT: Myocardial irri- tability associated with lithium carbonate measurement of BUN, serum creatinine therapy. N Engi I Med 287: 867, 1972 and creatinine clearance (since the kid- 4. LEE RV, JAMPOL LM, BROWN WV: Nephro- "ADD ON" gemc diabetes insipidus and lithium intoxi- ney is the major site of elimination of cation: complications of lithium carbonate antihypertensive therapy. N Engi I Med 284: 93, 1971 lithium). 5. LAVENDER 5, BROWN JN, BARSILL WT: Acute 2. Continuous ECG monitoring for renal failure and lithium intoxication. Post- INDICATIONS: Various forms of hypertension: grad Med 1 49: 277, 1973 fixed essential hypertension, whether of benign cardiac arrhythmias. 6. ScHou M, AMDISEN A, TRAP-JENSEN J: Li- thium poisoning. Am I Psychiatry 125: 520, or malignant character; hypertension associated 3. Serial determinations of serum 1968 with acute and chronic glomerulonephritis; lithium concentration during the first 7. AMDI5EN A, SLJOLDIIORG H: Haemodialysis nephrosclerosis; hypertensive toxemias of for lithium poisoning (C). Lancet 2: 213, few days after ingestion of the overdose 1969 pregnancy, pre-eclampsia, and eclampsia. 8. HAWKINS JB, DOREEN PR: Lithium (C). to exclude the possibility of progressive Lancet 1: 839, 1969 DOSAGE: Hypertension: Orally: In general after increase in concentration. 9. WiLsoN JEP, DONKER MM, VAN DEE HEM initiating therapy gradually increase dosage, GK, et al: Peritoneal dialysis for lithium adjusting according to individual response. As a poisoning. Br I Med 2: 749, 1971 10. HERRERO FA: Lithium carbonate . single agent, initially 10mg, four times daily Treatment JAMA 226: 1109, 1973 increasing slowly to a maximum practical dosage 11. HURTIG HI, DYSON WL: Lithium toxicity of 200mg daily. In combination with other hypo- 1. Institution of supportive measures enhanced by diuresis (C). N Engi / Med 290: 748. 1974 tensive agents, lower dosages of APRESOLINE to prevent , to maintain 12. GAIND R, SARAN EM: Acute lithium - will be appropriate. ing. Posigrad Med 1 46: 629, 1970 blood pressure and urine output with 13. DAVIS JM, BARTLETr E, TERMINI BA: OVer- Parenterally: When there is urgent need, therapy intravenous fluids, to ensure adequate dosage of psychotropic drugs: a review. I. in the hospitalized patient may be initiated intra- Major and minor tranquilizers. Das Nerv Syst venously or intramuscularly. Usual dose is 20 oxygenation, and to correct electrolyte 29: 157, 1968 to 14. THOMSEN K, ScHOu M: Renal lithium ex- 40 mg, repeated as necessary. Certain patiehts, and acid-base imbalance. cretion in man. Am I Physsol 215: 823, 1968 especially those with marked renal damage, may 2. Prevention of further drug ab- 15. ALMY GL, TAYLOR MA: Lithium retention require a lower dose. in mania. Arch Gen Psychiatry 29: 232, Pressure may begin to fall sorption by means of gastric aspiration 1973 within a few minutes after injection, with an and lavage through a wide-bore naso- 16. FYRO B, PETrERSON V, SEDVALL G: Pharma- average maximal decrease occurring in 10 to 80 cokinetics of lithium in manic-depressive pa- minutes. gastric tube in all cases provided the tients. Acta Psychiatr Scand 49: 237, 1973 Most patients can be transferred to oral char- 17. SLETrEN I, PICHARDO J, KOROL B, et al: APRESOLINE within 24 to 48 hours. gag reflex is present. Activated The effect of chiorpromazine on lithium Toxemia of Pregnancy: a) Early toxemia so its use excretion in psychiatric subjects. Curr Ther and coal does not bind lithium, Res 8: 441, 1966 hypertension of pregnancy: One 10-mg tablet as a gastrointestinal adsorbent is not 18. BIRcH NJ: Lithium accumulation in bone orally 4 times daily, slowly increasing the dosage after oral administration in rat and man. indicated unless one suspects a multiple Clin Sci Molec Med 46: 409, 1974 up to 400 mg per day, or until a therapeutic result drug intoxication. 19. HULLIN RP, SwINscoE JC, MCDONALD R. is obtained. et al: Metabolic balance studies on the b) Late toxemia and pre-eclampsia: Give 20 to 3. Augmentation of drug elimina- effect of lithium salts on manic-depressive . Br I Psychiatry 114: 1561, 1968 40 mg intramuscularly, or slowly by direct tion, providing renal function is nor- 20. VACAFLOR L, LEHMANN HE, BAN TA: Side intravenous injection or infusion. Repeat as mal, by administration of mannitol to effects and teratogenicity of lithium car- necessary. bonate treatment. I Clin Pharmacol 10: 387, produce an osmotic diuresis. This is 1970 SIDE EFFECTS: Tachycardia, headache, palpi- 21. Wu.sKNKS GD, BsaSSLml B, Pam CH, Ct al: worth a trial in cases of lithium in- Toxic effects of lithium carbonate in a tation, dizziness, weakness, nausea, vomiting, toxication because mannitol hastens the mother and newborn infant. JAMA 213: 865, postural hypotension, numbness and tingling of 1970 the extremities, flushing, nasal congestion, lach- renal elimination of lithium;14'30 on the 22. AoKI FY, RUEDY J: Severe lithium intoxica- tion: management without dialysis and report rymation, conjunctival injection, dyspnea, anginal other hand, administration of furose- of a possible teratogenic effect of lithium. symptoms, rash, drug fever, reduction in hemo- mide, or ethacrynic acid Can Med Assoc J 105: 847, 1971 globin and red cell count, giant urticaria, and 23. SUGITA ET, STOKES JW, FRAZER A, Ct al: a does not promote lithium excretion.14 lithium carbonate absorption in humans. lupus-like syndrome (arthralgia) in some cases I Clin Pharmacol 13: 264, 1973 following administration for long periods. The most efficient way of expediting 24. Orro W, PAAizzow L, SuREN G: Lithium the removal of lithium from the body absorption from ordinary and from sus- CAUTIONS: Use cautiously in the presence of tained-release tablets. Acta Pharm Suec 9: is hemodialysis.7 We do not believe it 595, 1972 advanced renal damage and recent coronary or for 25. AMDISEN A, SCHOU M: Biochemistry of de- cerebral ischemia. APRESOLINE may potentiate is useful to set any arbitrary value pression (C). Lancet 1: 507, 1967 the narcotic effects of barbiturates and . serum lithium above which hemodialy- 26. MAI-rHEW H, MACKINTOSH TF, ToMPSErr SL, et al: Gastric aspiration and lavage in Peripheral neuritis evidenced by paresthesias, sis is to be initiated, but dialysis should acute poisoning. Br Med 1 1: 1333, 1966 numbness and tingling has been observed. con- 27. EDWARDS KDG, MCCREDIE M: Studies on the Published evidence suggests an anti-pyridoxine be started promptly if the clinical binding properties of acidic,, basic and dition deteriorates despite adequate sup- neutral drugs to anion and cation exchange effect and addition of pyridoxine to the regimen if resins and charcoal in vitro. Med I Aust symptoms develop. portive therapy or if there is major 1: 534, 1967 impairment of renal function. Perma- 28. Scssou M: Lithium studies. Distribution he- OVERDOSAGE: Symptoms: Hypotension and tween serum and tissues. Acta Pharmacol tachycardia. nent neurologic sequelae have been Toxicol (Kbh) 15: 115, 1958 29. VON HARTITZSCH B, HOENICH NA, LEIGH RI, Treatment: Gastric lavage or, in the absence of observed in patients exposed to toxic et al: Permanent neurological sequelse de- coma, emetics. In the presence of hypotension, serum lithium concentrations for sev- spite haemodialysis for lithium intoxication. Br Med I 4: 757, 1972 cautiously give norepinephrine (intravenously) or eral days,29 so hemodialysis should also 30. OBEK A: Mannitol infusions and lithium ex- ephedrine to raise the blood pressure without be started if there is a progressive in- cretion. Thid, p 550 increasing tachycardia. Avoid epinephrine. crease in serum lithium concentration, General supportive measures include intravenous even though the patient may be asymp- fluids, external heat and elevation of foot of bed. tomatic at this stage. Dialysis may have SUPPLIED: All forms contain hydralazine hydrochlorideTablets of 10mg (yellow, scored); to be continued for several hours after bottles of 100. Tablets of 25mg (blue, coated); the serum lithium value has returned bottles of 100 and 500. Tablets of 50mg (pink, to the therapeutic range because there coated); bottles of 100 and 500. Ampoules of 1 ml is often a rebound increase in serum aqueous solution containing 20 mg; boxes of 10. lithium concentration on discontinua- tion of the dialysis.7'8 Presumably this rebound effect is due to redistribution CIBA of lithium from the tissues. DORVAL, QUEBEC 0-5003 870 CMA JOURNAL/APRIL 5, 1975/VOL. 112