Practice Teaching Case Report results of urine and serum toxicology and a lithium level of 14.5 mmol/L. The screens were positive for lithium; no patient had a history of suicidal Negative anion gap other toxins were present. The lithium ideation, bipolar affective disorder and level was above 6 mmol/L, and the pa- hypertension. His medications in- and elevated osmolar gap tient was subsequently transferred to cluded hydrochlorothiazide and long- our hospital for acute hemodialysis. term lithium therapy. due to lithium overdose On arrival, the patient’s blood pres- Aggressive rehydration was begun sure was 91/64 mm Hg, heart rate with 3 L of normal saline, as was con- The case: A 65-year-old man was found 111 beats/min, respiratory rate 22 and ventional hemodialysis using a 1.8-m2 in a state of clouded consciousness of temperature 35.6°C; the jugular venous high-flux dialyzer at a blood pump unknown duration. At hospital his Glas- pressure was not visible. His urine out- speed of 300 mL/min and a dialysate gow Coma Scale score was 9. Naloxone put over 6 hours was 2.4 L and dilute in flow rate of 750 mL/min. A bicarbonate and thiamine were administered. A CT appearance. Repeat blood work re- bath dialysate was used. The lithium head scan showed no acute injury. The vealed an anion gap of –2 mmol/L, an level rapidly fell to 4.7 mmol/L over serum anion gap was 1 mmol/L, and the osmolar gap of 36 mOsmol/kg, a osmolar gap 12.8 mOsmol/kg (Table 1). serum creatinine level of 89 μmol/L, a The patient was normoglycemic, and serum calcium level of 2.64 mmol/L Box 1: Adverse effects of lithium Central nervous system • Altered level of consciousness Table 1: Results of laboratory tests • Dysarthria • Psychomotor retardation Results • Vertigo available from Results at • Nystagmus Test (normal range) transferring hospital presentation • Tremor Sodium, mmol/L (135–145) 143 142 • Parkinsonian movements • Seizures Potassium, mmol/L (3.2–5.0) 3.6 3.8 • Pseudotumour cerebri Chloride, mmol/L (100–110) 109 115 Dermatologic Bicarbonate, mmol/L (23–29) 36 26 • Folliculitis μ Creatinine, mol/L (< 99) 95 89 • Alopecia Calcium, mmol/L (2.20–2.62) 2.68 2.64 Cardiovascular Albumin, g/L (35–45) 40 40 • Cardiac arrhythmia Anion gap, mmol/L (7–13) –2 1 • Hypotension Lithium, mmol/L (0.6–1.2) > 6* 14.5 • Bradycardia • Syncope Urea, mmol/L (2–8) 5.2 6.6 Endocrine Plasma glucose, mmol/L (3.8–7) 4.0 4.9 • Hypo- or hyperthyroidism Plasma osmolality, mOsm/kg (275–295) 308 324 • Goiter Calculated osmolality, mOsm/kg (275–295) 295.2 295.5 • Hyperglycemia Osmolar gap, mOsm/kg (< 20) 12.8 28.5 • Hypercalcemia Phosphate, mmol/L (0.8–1.4) — < 0.5 • Hyperparathyroidism Hemoglobin, g/L (110–145) — 138 Gastrointestinal pH (7.35–7.45) — 7.38 • Anorexia Partial pressure of carbon dioxide, • Nausea or vomiting mm Hg (35–45) — 47 • Diarrhea • Metallic taste Partial pressure of oxygen, mm Hg (80–100) — 80 • Excessive salivation Serum and urine toxicology screen Positive for Positive for lithium only lithium only Renal • Nephrogenic diabetes insipidus Note: The electrolytes were measured using the Badebehring Dimension (colorimetric).The osmolality was • Glucosuria measured using the freezing point, and the plasma sample for lithium levels was collected using a nonheparized tube. About 12 hours elapsed between values obtained at the referring hospital and those • Chronic renal failure obtained at our institution. Toxicology tests performed included screening for toxic alcohols, • Proteinuria acetylsalicylic acid, acetaminophen, theophylline, digoxin, opiates, benzodiazepines and cocaine. *Exact value unavailable. DOI:10.1503/cmaj.061057

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4 hours. Hemodialysis was continued of dialysis, the patient rapidly recovered. sium. Large quantities of positive cations for a total of 24 hours, and the patient’s He was discharged from hospital 2 in the plasma are balanced by the anions level of consciousness improved. Forty- weeks later with no detected neurologic bicarbonate and chloride and can cause a eight hours after discontinuing dialysis, deficits. negative anion gap because sodium, but the lithium levels rebounded to more not lithium, is included in the calculation. than 4 mmol/L, and the patient’s speech Our patient had only a mildly elevated cal- became slurred. Continuous veno- Lithium is highly effective in the treat- cium level with a normal albumin level. venous hemodiafiltration was performed ment of bipolar disease, with success Of note, the severe lithium intoxication in at a blood flow rate of 100 mL/min, a rates approaching 70%. However, be- this case resulted in a negative anion gap dialysate flow rate of 1500 mL/min and a cause of the drug’s narrow therapeutic that was corrected with dialysis (Fig. 1). replacement fluid (75 mmol/L saline) window, toxic effects are common (Box The osmolar gap is another useful flow rate of 1000 mL/min. Dialysis was 1). The most common manifestation of diagnostic clue in cases of overdose. continued for 40 hours. During this pe- toxicity is altered mental status. Our pa- Common causes of an elevated osmo- riod, the patient’s urine output was tient also had a high urine output of 2.4 L lar gap and the formula are outlined in more than 4 L/d, and his speech re- in 6 hours, which suggests polyuria due Box 4. In our patient, the osmolar gap turned to normal. After discontinuation to a concentrating defect. Depending on was elevated at 36 mOsmol/kg. Other the length of lithium use, toxic effects can causes of elevation were excluded since occur with levels as low as 2.5 mmol/L. the results of the toxicology screen Box 2: Principles of management Severe toxic effects have been reported were negative for alcohols, serum ke- of lithium intoxication in acute overdoses with levels of 5– tones and lactate and the patient had a • Recognize clinical and 9 mmol/L. Risk factors for lithium toxic- normal lipid profile. We postulate that biochemical features of ity include the use of thiazide diuretics, the high level of lithium with its anion, intoxication renal insufficiency, congestive heart fail- bicarbonate (from lithium carbonate), • Decrease gastric absorption by ure and volume depletion. The principles contributed to an increase in plasma means of whole-bowel irrigation of management of lithium intoxication osmolality. This is further supported • Stop all further use of lithium, are outlined in Box 2. The mortality is as by the patients’ elevated bicarbonate diuretics and nonsteroidal anti- inflammatories high as 25%, and 10% of survivors will level of 36 on presentation. The ex- have permanent neurologic deficits.1 pected increase in osmolar gap would • Begin aggressive rehydration The anion gap is a key diagnostic be 2 times the lithium level, or about • Begin hemodialysis clue when approaching the differential 28 mOsmol/kg, which is similar to the • Maintain water balance diagnosis of toxidromes and metabolic level in our patient. Lithium has never acidosis. The formula is given in Box 3. been previously reported to lead to an Lithium is a positive charged ion with elevation in the osmolar gap and valence of 1 and electrochemical proper- should be included in the list of cur- Box 3: Anion gap ties similar to those of sodium and potas- rently known causes. The combination Calculation 15 Anion gap = Na — (chloride + 11 bicarbonate) Anion gap The anion gap is the difference 9 12 between measured cations and anions, Lithium level with normal values falling between 7 and 13 mmol/L. This difference is 7 due to charges on plasma proteins, 9 particularly albumin, and must be 5 adjusted downward in patients with hypoalbuminemia. For every decrease in albumin of 10 g/L, the anion gap 3 6 decreases by about 2.5 mmol/L.

Anion gap, mmol/L gap, Anion 1

Differential diagnosis Lithium level, mmol/L of a low anion gap 3 • Hypercalcemia -1 • Hypermagnesemia • Hyperkalemia -3 0 • Cationic immunoglobulins (as in 024487296 plasma cell dyscrasias) • Bromide intoxication Time, h • Nitrates • Lithium Fig. 1: Inverse correlation between lithium level and anion gap over time. Of note, the initial anion gap of –2 mmol/L corresponded to a lithium level of 14.5 mmol/L.

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15 Box 4: Osmolar gap Intermittent Continuous venovenous Calculation hemodialysis hemodiafiltration Osmolar gap = measured osmolality 12 — calculated osmolality = plasma osmolality — [(2 × Na) + plasma glucose + urea] 9

Differential diagnosis of an elevated osmolar gap 6 • Isopropanolol • N-propanolol

• Propylene glycol mmol/L level, Lithium 3 • Ethylene glycol* • Methanol* • Formaldehyde* 0 • Paraldehyde* 024487296120 • Mannitol Time, h • Diethyl ether ingestion • Lithium overdose Fig. 2: Effects of intermittent hemodialysis and continuous venovenous hemodiafiltra- *Denotes causes associated with an elevated tion on lithium levels. Time zero was arrival at our centre. Arrow indicates rebound in anion gap metabolic acidosis. lithium levels that required initiation of continous venovenous hemodiafiltration. of an elevated osmolar gap and de- of 300 mL/min, which achieved a meas- ovenous hemodiafiltration, with its creased anion gap without metabolic ured lithium clearance of 262 mL/min slower blood flow rates, resulted in acidosis should be considered highly (lithium clearance = blood pump speed much slower lithium clearance. Unfortu- suggestive of severe lithium intoxica- [Qb] × [(lithium level arterial side – nately, our patient’s hemodynamic status tion after exclusion of severe hyperpro- lithium level venous side)/ lithium level did not allow us to safely use intermittent teinemia, hyperlipidemia and mannitol arterial side]). This high rate of clearance hemodialysis, but it is much more effec- ingestion. resulted in a dramatic decrease in the tive at removing lithium from the blood Lithium is absorbed through the gas- plasma lithium levels, from 14.5 to in cases of intoxication. trointestinal tract, with peak plasma lev- 4.7 mmol/L, in 4 hours (Fig. 2). Previous els occurring within 1–4 hours and reports of intermittent hemodialysis for Manish M. Sood steady state levels in 6 days. Lithium has lithium removal achieved clearances of Robert Richardson a large volume of distribution of 0.6– 94–170 mL/min with lower blood and Department of Medicine 0.9 L/kg, and its primary route of excre- dialysate flow rates.3,4 We stopped inter- Division of Nephrology tion is through the kidneys. Because of mittent hemodialysis after 24 hours be- Toronto General Hospital its large volume of distribution, lithium cause our patient’s cognitive status im- University Health Network shifts into the intracellular compartment proved and his plasma lithium level fell Toronto, Ont. of cells. With long-term use, the intracel- to 1.8 mmol/L. Discontinuation of This article has been peer reviewed. lular concentration of lithium increases, hemodialysis often results in a rebound which thereby results in an increased to- of plasma lithium levels as intracellular Competing interests: None declared. tal body lithium load. The intracellular lithium shifts to the extracellular space. concentration is not reflected by the Three days after the ingestion of lithium plasma level, which measures only the and 48 hours after hemodialysis was REFERENCES 1. Adityanjee, Munshi RK, Thanmpy A. The syn- extracellular fluid concentration. In our stopped, our patient’s lithium level re- drome of irreversible lithium-effectuated neurotox- case, assuming a volume of distribution bounded to more than 4 mmol/L. Con- icty. Clin Neuropharmacol 2005;28:38-49. 2. Henry GC. Lithium. In: Goldfrank LR, Flomen- close to 1 L/kg and complete gastric ab- tinuous venovenous hemodiafiltration baum NE, Lewin NA, et al, editors. Goldfrank’s sorption, each 300-mg tablet will in- was then started, because of hemody- toxicologic emergencies. 6th ed. Stamford (CT): crease the plasma lithium level by namic instability, and continued for 40 Appleton & Lange; 1998. p. 894. 3. Fenves AZ, Emmett M, White MG. Lithium intoxi- 0.1 mmol/L. Therefore, a plasma lithium hours. Hazouard and associates previ- cation associated with acute renal failure. South level of 14.5 mmol/L correlates with the ously demonstrated that lithium elimina- Med J 1984;77:1472-4. 2 4. Clendeninn NJ, Pond SM, Kaysen G, et al. Potential ingestion of about 145 tablets. tion with continuous renal replacement pitfalls in the evaluation of the usefulness of he- Intermittent hemodialysis is the treat- therapy linearly correlated with the vol- modialysis for the removal of lithium. J Toxicol Clin Toxicol 1982;19:341-52. ment of choice for lithium intoxication ume of hemofiltration plus dialysate flow 5. Hazouard E, Ferrandiere M, Rateau H, et al. Conti- 5 in patients who are hemodynamically rate. Of note, lithium levels fell rapidly nous veno-venous haemofiltration versus continous veno-venous haemodialysis in severe lithium self- stable. In our case, hemodialysis was with the use of intermittent hemodialy- poisoning: a toxicokinetics study in an intensive initiated at a high blood pump speed sis, whereas the use of continuous ven- care unit. Nephrol Dial Transplant 1999;14:1605-6.

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