Lithium is considered the drug of choice in the treatment and prophylaxis of manic-depressive illness,1,2 but it has narrow therapeutic serum concentration range, high toxicity potential, and a relatively long serum halflife.5,4 Dosages necessary for therapy and prophylaxis are not much lower than those that produce intoxication, and steady state serum concentrations vary widely among patients given standard doses because of large interpatient variability in body clearance.5'7 Any factor that reduces the body clearance can potentially induce lithium toxicity, which is a serious condition possibly leading to permanent organ dysfunction or damage or even death. It is therefore very important for the clinician to understand the etiology and treatment methods of lithium toxicity so that timely therapeutic intervention can avoid these sequelae.
TYPES OF LITHIUM INTOXICATION
Lithium intoxication can be divided into three types on the basis of the rapidity with which it develops.
Chronic intoxication usually develops after prolonged therapy. The patient develops increased diuresis, probably due to a lithiumproduced impaired renal response to antidiuretic hormone and an impaired renal concentrating ability caused by the chronic nephrotoxic effect of lithium.
Subacute intoxication develops when a patient is started on a dose higher than that indicated by body clearance. More lithium is ingested than is excreted and it accumulates in the body. It can also occur in a previously stabilized patient when additional extraneous factors cause a reduction in the body clearance of lithium. In a period of weeks the patient may show signs of severe intoxication.
Acute intoxication always develops after the ingestion of a large amount of lithium and as a result the patient shows signs of severe toxicity. It is usually the result of a suicide attempt.
SYMPTOMS OF INTOXICATIONS
Intoxication is classified as mild, moderate, or severe and includes the following symptoms.8"17
* Mild Intoxication
Mild intoxication is de6ned as a serum concentration of 1.0 to 1.5 mEq/L and includes:
* dull, sluggish, and listless behavior with uneasiness and restlessness;
* difficulty in focusing attention;
* muscle weakness, heaviness of limbs;
* unsteady gait;
* increased muscle tone, rigidity with impaired motor coordination;
* coarse and irregular hand tremor;
* facial muscle twitchings, especially when patient is about to fall asleep;
* diarrhea, nausea, vomiting;
* indistinct and sometimes slurred speech;
* leucocytosis; and
The first three of these clinical features can easily be misinterpreted as the development of an agitated depressive state and the differential diagnosis is therefore critical.
* Moderate Intoxication
A serum concentration of 1.5 to 2.5 mEq/L is characteristic of moderate intoxication symptoms include:
* muscle fasciculation;
* incoordination of muscle movements, pronounced ataxia;
* coarse tremor;
* extrapyramidal syndrome;
* visual disturbances; and
* confusion, delirium.
* Severe Intoxication
If the early signs of lithium intoxication are overlooked, they may progress and become severe. Severe intoxication (a serum concentration greater than 2.5 mEq/L) may develop within a few hours to a few days after the intake of an overdose of the drug. Symptoms include:
* drawn, cold, gray, worn-out look;
* changes in EKG (depression of the ST segment and inversion of T waves);
* stupor with restlessness;
* latent epilepsy, convulsive movements;
* EEG changes (decrease of alpha activity, increase in delta activity, and unstable rhythms);
* impaired kidney function, fluid and electrolyte imbalance; and
* coma and death,
CAUSES OF LITHHlM INTOXICATIOH
Some principal factors that reduce lithium body clearance and thus produce intoxication in previously stabilized patients are kidney disease, salt deficiency (sodium deficiency), water deficiency (dehydration), and drug interactions. Factors leading to body salt deficiency include physical disease (fever, gastroenteritis, respiratory disease), heavy sweating, manic or depressive relapse with lowered intake of food and fluid, concomitant treatment with diuretics, low-salt diet, and slimming diets with no extra intake of salt.
TREATMEHT OF LITHIUM INTOXICATION
There is no specific antidote for lithium intoxication. Treatment8.i2.]4.ib,i8-26 is directed at rapidly removing lithium from the body and correcting electrolyte abnormalities and any associated disease. The patient should be questioned about the lithium dosage, frequency of lithium intake, the time of the last dose, and the intake of other drugs and circumstances. Serum lithium concentration should be immediately determined.
If the toxicity was brought on by a large lithium dose, emesis or gastric lavage is indicated to prevent further absorption of the drug. Emesis may be induced in moderately toxic patients if they are alert and ipecac syrup may be given in its usual dose of 30 mL for adults and 15 mL for children. Gastric lavage with isotonic saline is preferred in comatose patients.
Other supportive measures include monitoring of blood pressure, kidney function, lung physiotherapy (postural drainage and cupping), and prophylaxis for infection.
Infusion of saline, forced diuresis, peritoneal dialysis, and hemodialysis are specific measures to increase the body clearance of lithium, but they also have been advocated with varying amounts of success.
Infusion of saline solution13,14 has been tried on the premise that a high load of sodium will result in increased excretion of it. Because the kidneys eliminate sodium and lithium by the same mechanism, clearance of lithium will also be increased. Most of the reports of the use of this technique are uncontrolled case reports; there is only one well documented report about the efficacy of this technique in six patients with mild to moderate toxicity.14 An increase in creatinine and sodium clearance was seen during sodium chloride infusion, and in five of these patients lithium clearance was also increased. However, the fractional clearance of lithium decreased in most of the patients. The total amount of lithium excreted during sodium chloride treatment was 26,5 mmol/day as opposed to 29.2 mmol/day before the infusion. This method is therefore not recommended.
Forced diuresis14,2,20 has been tried on the premise that an increased amount of urine will result in an increased amountof lithium being excreted by the kidney, Furosemide in isotonic sodium chloride or isotonic glucose has been used with no increase in lithium clearance, whereas furosemide in isotonic glucose and sodium bicarbonate was found to maintain renal lithium clearance at 23 mL/min during treatment (average clearance 10 to 12 mL/min). Because of the possibility of inducing dehydration, and thus increasing serum lithium levels, this method is of limited usefulness.
Peritoneal dialysis11,14,20 was used by Wilson et al20 on a 45-yearold patient three hours after admission. Lithium serum level on admission was 4.6 mEq/L and dropped to 0. 3 mEq/L at 120 hours. Elimination half-life of lithium in this patient was 14 hours as compared with 30 to 100 hours in patients treated conservatively.
This kind of outcome with peritoneal dialysis has also been reported by other investigators.11,14 The advantage of this method is that it avoids rebound effect and the potential hazards associated with it. Peritoneal dialysis is a slow process and therefore allows sufficient time for the intracellular and the extracellular lithium to reach equilibrium.
The main disadvantage of this process is that its slow action prolongs the period of high serum lithium levels with increased risk of permanent sequelae.
Because lithium is a highly dialyzable drug, hemodialysis4,18,19,21,24 has been tried by different investigators and found to be very effective.4,18,21,22 Currently this is the method of choice in the treatment of moderate to severe toxicity.
When treating patients wiih lithium toxicity using hemodialysis, special attention should be given to the following features:
* Hemodialysis removes lithium from the body at a fast pace and does not give sufficient time for the extracellular and intracellular lithium to reach equilibrium. As a result, there is a rebound effect of increased lithium concentration after the hemodialysis is stopped.
* The lithium plasma:lithium red blood cell ratio might change after dialysis and this parameter cannot be used to correlate with other parameters.
* The extraction of lithium from serum is greater than thai from whole blood or red cells, so hemodialysis clearance should be estimated by using extraction ratio of lithium from whole blood and whole blood flow.
After a review of 100 cases of lithium toxicity, Hansen et al14 reported that prognosis is affected by the height of the serum lithium concentration, duration of lithium intoxication, and individual tolerance to lithium intoxication. The higher the serum concentration and the longer lhe duration of intoxication, the more serious is the prognosis. Decreasing the body load of lithium in the shortest time is therefore always essential in treatment of lithium toxicity.
Prevention is always the most effective measure and can be achieved by properly counseling the patient. The patient should be made aware of the potential toxicity and importance of the directions for taking lithium.
The medication must be taken according to the prescription; the patient must not take more tablets to make up for missed doses. Occasionally, treatment of patients on chronic lithium therapy is changed from one brand to another. This must be regarded as a new treatment and serum lithium levels taken accordingly. Slow/fast release tablets must be reported to the physician. Serum lithium levels should be monitored regularly, and any significant deviations must be investigated thoroughly.
Signs and symptoms of impending intoxication and circumstances that may precipitate intoxication should be explained to the patient so that they can be reported immediately to the physician.
The patient's medication history should be kept up to date. We routinely use a two-point method to predict maintenance dosage in patients started on lithium therapy for the first time or without any history of serum lithium levels.27 This has enabled us to avoid many potential complications.
The first step in assessing lithium intoxication is to evaluate the severity of intoxication on the basis of clinical signs and symptoms, collect information about drug intake, and determine serum lithium concentration.
If signs and symptoms indicate severe intoxication or the serum lithium concentration is more than 2.5 mEq/L, the patient should be hemodiaiyzed immediately. Additional supportive measures to correct water and electrolyte imbalance should be implemented as indicated. The patient should be closely monitored for rebound effect and hemodiaiyzed until the serum lithium concentration stays below 1.0 mEq/L even after the rebound effect.
If the medication intake history indicates that the patient had ingested a large amount of lithium, emesis and gastric lavage should be tried. If the signs and symptoms indicate moderate intoxication and the serum level is less than 2.5 mEq/L, another serum level should be determined 3 to 6 hours apart and the 12hour serum level determined by plotting the serum level versus time (hours). If the 12-hour serum level is more ihan 2.5 mEq/L, the patient should be hemodialyzed and the same procedure followed as for severe intoxication. Some investigators recommend different criteria to decide on the indication for hemodialysis in moderate intoxication: two serum levels are taken six hours apart, and if the rate of fall of lithium level is less than 20%, the patient is hemodialyzed. Both methods are equally effective.
Two cases of lithium intoxication are described that prompted our review of literature on lithium intoxication.
RL is a 64-year-old white male admitted to a general medical care unit on Oct 1 5 for complaints of persistent diarrhea. He was started on Lomotil* two tablets every four hours prn. On Oct 16, the white blood cell count was 19.4, segmented neutrophils 71%, band neutrophils 2, lymphocytes 13. On Oct 22, the white blood cell count was 26.3, segmented neutrophils 83%, band neutrophils 1, temperature 103, and heart rate 100-110/min. A presumptive diagnosis of aspiration pneumonia was made and infectious disease consult was requested as the patient became comatose and meningitis was suspected.
On Oct 24 he showed cogwheel rigidity and motor incoordination. He was started on ampiciUin 1 gm intravenous soluset (IVSS) every 6 hours, gentamicin 80 mg IVSS every 12 hours, clindamycin 600 mg IVSS every 6 hours, and aminophylline infusion at 40 mg per hour. Chest xray was clear and cerebrospinal fluid, sputum, urine, blood cultures, and stool examination for organisms were all negative. The patient was intubated on Oct 25 and the white blood celi count was 24.2 on Oct 26. The patient was taking lithium carbonate 600 mg orally b.i.d. on admission and continued until Oct 22. Serum lithium levels are shown in the Table.
On Oct 31 skull computed tomography (CT) scan showed a frontal lobe infarct. On Nov 1 the white blood cell count decreased to 10.4 (segregated neutrophils 88%) and patient was afebrile. The patient was extubated the same day but showed signs of neurological deficit.
Serum Lithium Levels
In retrospect, the patient was intoxicated as a result of dehydration. However, it was never recognized as such and he was treated with aminophylline infusions only. As a result, the half-life of lithium in this patient was 139 hours initially and aminophylline infusion only decreased it to 108 hours.
Another patient, TB. a 52-year-old white male, was admitted that same week with a diagnosis of carcinoma of the lung and was found to have serum lithium concentration of 5.9 on Oct 28.
The patient was hemodialyzed on Oct 29 when the pre and post dialysis serum lithium levels were 4.2 and 2.3 mEq/L. On Oct 31, the pre and post dialysis levels were 3.1 and 0.1. The patient was hemodialyzed twice more and was discharged on Nov 4.
These cases show the dramatic difference in reducing serum lithium levels between hemodialysis and aminophylline/normal saline infusions.
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Serum Lithium Levels