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Lithium
SPECIFIC SUBSTANCES
nephropathy.4 STeT changes on an electrocardiogram and, more rarely, conduction disturbances may also occur.5 Documented laboratory abnormalities include leucocytosis, a reduced anion gap, hypercalcaemia and hyperamylasaemia. Chronic lithium therapy may cause hypothyroidism, but lithium-induced thyrotoxicosis also is seen very occasionally.6 Features of thyroid dysfunction may therefore complicate presentations of chronic or acute-on-therapeutic poisoning.
Lithium Sally Bradberry
Abstract Lithium has a narrow therapeutic index and most poisonings are chronic, secondary to impaired renal elimination. Neurological features predominate. Serum lithium concentrations must be interpreted according to the type of poisoning (acute, acute-on-therapeutic or chronic). Apart from symptomatic measures, the major therapeutic objective is to enhance lithium elimination either by administration of normal saline, if renal function is normal and poisoning is mild, or by extracorporeal removal by haemodialysis or haemodiafiltration. Haemodialysis or diafiltration is especially indicated in patients presenting with neurological symptoms, an increased serum lithium half-life and/or impaired renal lithium elimination.
Toxicokinetics Although the gastrointestinal absorption of lithium is rapid and efficient, distribution is complex and slow. Peak brain lithium concentrations lag behind plasma concentrations by at least several hours, with gradual equilibration between intracellular and extracellular compartments. The resulting multicompartment model of lithium pharmacokinetics explains why the serum lithium half-life in acute poisoning is considerably shorter, at 12e25 hours, than in those with acute-on-therapeutic or chronic poisoning, when the serum elimination half-life is more typically 30e50 hours.7,8 Lithium is almost exclusively eliminated renally; total clearance is therefore reduced markedly in the presence of renal failure.
Keywords Haemodiafiltration; haemodialysis; lithium; poisoning
Introduction Lithium is used widely in the treatment of manic-depressive psychosis as a mood stabilizer. Chronic poisoning is relatively common because the therapeutic index of lithium is low. Patients on chronic therapy may develop lithium toxicity as a result of too high a dose, deterioration in renal clearance or concomitant administration of an interacting drug (usually a drug associated with sodium loss such as a thiazide diuretic). Important causes of reduced renal clearance include an agerelated decline in glomerular filtration rate and intercurrent illness associated with dehydration and/or impaired renal function.
Lithium concentrations Therapeutic serum lithium concentrations are in the range 0.8e1.2 mmol/litre. In poisoned patients, however, the relationship between serum lithium concentration and symptoms depends very much on the type of poisoning. After an acute overdose in those not prescribed lithium, symptoms may be absent or minor despite serum concentrations >4 mmol/litre. In those who take an acute overdose and are prescribed lithium (acute on therapeutic), severe symptoms may be present with lithium concentrations >4 mmol/litre. In chronic poisoning, symptoms become progressively more severe at lithium concentrations of more than 1.5 mmol/litre. At concentrations >2.5 mmol/litre, neurological features may be severe and permanent. These differences result from the slow distribution of lithium between the extracellular and intracellular compartments. For this reason, acutely poisoned patients may develop symptoms only after a delay. Clinical improvement may lag behind the fall in the serum lithium concentration in chronic poisoning.
Clinical features Neurological symptoms predominate but gastrointestinal, cardiovascular and renal disturbances may occur.1,2 Early neurological features include a fine tremor, ataxia, slurred speech, hyperreflexia, generalized weakness and either agitation or psychomotor slowing. Hypertonia, muscle rigidity and stupor are signs of worsening lithium-induced neurotoxicity, which in the most severe cases progresses to coma and convulsions or myoclonus. Non-convulsive status epilepticus is recognized.3 Neurological damage may become irreversible. Dehydration often leads to hypovolaemia, hypotension and possibly renal failure. Acute renal failure and nephrogenic diabetes insipidus may be seen, but these features (which are adverse effects of chronic lithium therapy) are usually a cause of lithium intoxication rather than a consequence. Chronic lithium treatment is also associated with a cystic tubulointerstitial
Management The management of lithium poisoning has been reviewed.2 Gut decontamination In addition to symptomatic treatment, gastric lavage may be considered in patients who have ingested >40 milligrams of lithium carbonate per kilogram body weight less than 1 hour previously. A joint position paper on the role of whole-bowel irrigation (WBI) for gastrointestinal decontamination, published by the European Association of Poison Centres and Clinical Toxicologists and the American Academy of Clinical Toxicology, recommends that WBI can be considered for patients who have ingested substantial amounts of lithium.9
Sally Bradberry BSc MD FRCP FAACT FEAPCCT is Director of the West Midlands Poisons Unit and Deputy Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, and Honorary Senior Lecturer, University of Birmingham, UK. Competing interests: none declared.
MEDICINE 44:3
180
Ó 2016 Published by Elsevier Ltd.
SPECIFIC SUBSTANCES
Haemodiafiltration is less effective than haemodialysis (clearance 20e50 ml/minute), and 12e24 hours is required to remove by haemodiafiltration the amount of lithium eliminated by 6 hours of haemodialysis.13 It has been shown that sustained low-efficiency dialysis also increases lithium clearance.14 A
Sodium chloride 0.9% Because the renal handling of lithium is similar to that of sodium, administration of an isotonic solution of sodium chloride (0.9%) 2e3 litre/day, is indicated in the absence of renal failure or congestive cardiac failure. Low-dose dopamine A single but well-documented case report has demonstrated that dopamine 2 micrograms/minute caused a threefold increase in sodium excretion and the lithium clearance more than doubled.10 Forced diuresis is not indicated.
REFERENCES 1 Hansen HE, Amdisen A. Lithium intoxication (report of 23 cases and review of 100 cases from the literature). QJM 1978; 47: 123e44. 2 Waring WS. Management of lithium toxicity. Toxicol Rev 2006; 25: 221e30. 3 Madhusudhan BK. Nonconvulsive status epilepticus and CreutzfeldteJakob-like EEG changes in a case of lithium toxicity. Epilspsy Behav Case Rep 2014; 2: 203e5. 4 McCartney Y, Browne C, Little DM, Gulmann C. Lithium-induced nephrotoxicity: a case report of renal cystic disease presenting as a mass lesion. Urol Case Rep 2014; 2: 186e8. 5 Anantha Narayanan M, Mahfood Haddad T, Bansal O, et al. Acute cardiomyopathy precipitated by lithium: is there a direct toxic effect on cardiac myocytes? A case report and review of literature. Am J Emerg Med 2015; http://dx.doi.org/10.1016/j.ajem.2015.03. 023. online early. 6 Chalasani S, Benson KA. Lithium-induced thyrotoxicosis in a patient with treatment-resistant bipolar type I affective disorder. Med J Aust 2014; 201: 541e2. 7 Jaeger A, Sauder P, Kopferschmitt J, et al. When should dialysis be performed in lithium poisoning? A kinetic study in 14 cases of lithium poisoning. J Toxicol Clin Toxicol 1993; 31: 429e47. 8 Dyson EH, Simpson D, Prescott LF, Proudfoot AT. Self-poisoning and therapeutic intoxication with lithium. Hum Toxicol 1987; 6: 325e9. 9 Thanacoody R, Caravati EM, Troutman WG, et al. Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. Clin Toxicol 2015; 53: 5e12. 10 Macdonald TM, Cotton M, Prescott LF. Low dose dopamine in lithium poisoning. Br J Clin Pharmacol 1988; 26: 195e7. 11 Ghannoum M, Lavergne V, Yue CS, et al. Successful treatment of lithium toxicity with sodium polystyrene sulfonate: a retrospective cohort study. Clin Toxicol 2010; 48: 34e41. 12 Decker BS, Goldfarb DS, Dargan PI, et al. Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin J Am Soc Nephrol 2015; 10: 875e87. 13 Leblanc M, Raymond M, Bonnardeaux A, et al. Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996; 27: 365e72. 14 Fiaccadori E, Maggiore U, Parenti E, et al. Sustained lowefficiency dialysis (SLED) for acute lithium intoxication. NDT Plus 2008; 1: 329e32.
Sodium polystyrene sulfonate Limited data suggest that sodium polystyrene sulfonate, a cationexchange resin, reduces the half-life of lithium and promotes its elimination.11 Haemodialysis and haemodiafiltration Haemodialysis is the treatment of choice for rapid removal of lithium from the body.12 Lithium fulfils almost all the physicochemical and kinetic criteria for effective removal: low molecular weight (6.94 Da) high water solubility no protein binding low volume of distribution (0.8e1.2 litre/kg) a total endogenous clearance (15e20 ml/minute) that is low compared with haemodialysis clearance (80e120 ml/ minute). During haemodialysis, lithium clearance increases to 180 ml/ min12 (total body clearance is at best normally 30e40 ml/min and 10 ml/min in those on lithium12), with >25 Eq lithium being excreted per hour, thereby shortening the duration of symptoms. The serum half-life of lithium is reduced to 3e6 hours, although a rebound increase in the serum lithium concentration may be observed after haemodialysis because of the slow diffusion of lithium from the intracellular to the extracellular compartment. Haemodialysis is the treatment of choice for severe lithium poisoning.12 It may prevent irreversible neurotoxicity in these cases. Haemodialysis is strongly recommended in all patients with lithium-induced neurological features such as decreased consciousness, cerebellar signs or convulsions. This is irrespective of the serum lithium concentration providing it is above the therapeutic range. Haemodialysis should also be considered in all patients with symptomatic lithium toxicity and: serum lithium concentration >5.0 mmol/litre after acute overdose in those not prescribed lithium serum lithium concentration >4.0 mmol/litre after acute overdose in those prescribed lithium (acute-on-therapeutic poisoning) serum lithium concentration >2.5 mmol/litre in those with chronic poisoning increased serum half-life of lithium secondary to renal impairment.
MEDICINE 44:3
181
Ó 2016 Published by Elsevier Ltd.
nephropathy.4 STeT changes on an electrocardiogram and, more rarely, conduction disturbances may also occur.5 Documented laboratory abnormalities include leucocytosis, a reduced anion gap, hypercalcaemia and hyperamylasaemia. Chronic lithium therapy may cause hypothyroidism, but lithium-induced thyrotoxicosis also is seen very occasionally.6 Features of thyroid dysfunction may therefore complicate presentations of chronic or acute-on-therapeutic poisoning.
Lithium Sally Bradberry
Abstract Lithium has a narrow therapeutic index and most poisonings are chronic, secondary to impaired renal elimination. Neurological features predominate. Serum lithium concentrations must be interpreted according to the type of poisoning (acute, acute-on-therapeutic or chronic). Apart from symptomatic measures, the major therapeutic objective is to enhance lithium elimination either by administration of normal saline, if renal function is normal and poisoning is mild, or by extracorporeal removal by haemodialysis or haemodiafiltration. Haemodialysis or diafiltration is especially indicated in patients presenting with neurological symptoms, an increased serum lithium half-life and/or impaired renal lithium elimination.
Toxicokinetics Although the gastrointestinal absorption of lithium is rapid and efficient, distribution is complex and slow. Peak brain lithium concentrations lag behind plasma concentrations by at least several hours, with gradual equilibration between intracellular and extracellular compartments. The resulting multicompartment model of lithium pharmacokinetics explains why the serum lithium half-life in acute poisoning is considerably shorter, at 12e25 hours, than in those with acute-on-therapeutic or chronic poisoning, when the serum elimination half-life is more typically 30e50 hours.7,8 Lithium is almost exclusively eliminated renally; total clearance is therefore reduced markedly in the presence of renal failure.
Keywords Haemodiafiltration; haemodialysis; lithium; poisoning
Introduction Lithium is used widely in the treatment of manic-depressive psychosis as a mood stabilizer. Chronic poisoning is relatively common because the therapeutic index of lithium is low. Patients on chronic therapy may develop lithium toxicity as a result of too high a dose, deterioration in renal clearance or concomitant administration of an interacting drug (usually a drug associated with sodium loss such as a thiazide diuretic). Important causes of reduced renal clearance include an agerelated decline in glomerular filtration rate and intercurrent illness associated with dehydration and/or impaired renal function.
Lithium concentrations Therapeutic serum lithium concentrations are in the range 0.8e1.2 mmol/litre. In poisoned patients, however, the relationship between serum lithium concentration and symptoms depends very much on the type of poisoning. After an acute overdose in those not prescribed lithium, symptoms may be absent or minor despite serum concentrations >4 mmol/litre. In those who take an acute overdose and are prescribed lithium (acute on therapeutic), severe symptoms may be present with lithium concentrations >4 mmol/litre. In chronic poisoning, symptoms become progressively more severe at lithium concentrations of more than 1.5 mmol/litre. At concentrations >2.5 mmol/litre, neurological features may be severe and permanent. These differences result from the slow distribution of lithium between the extracellular and intracellular compartments. For this reason, acutely poisoned patients may develop symptoms only after a delay. Clinical improvement may lag behind the fall in the serum lithium concentration in chronic poisoning.
Clinical features Neurological symptoms predominate but gastrointestinal, cardiovascular and renal disturbances may occur.1,2 Early neurological features include a fine tremor, ataxia, slurred speech, hyperreflexia, generalized weakness and either agitation or psychomotor slowing. Hypertonia, muscle rigidity and stupor are signs of worsening lithium-induced neurotoxicity, which in the most severe cases progresses to coma and convulsions or myoclonus. Non-convulsive status epilepticus is recognized.3 Neurological damage may become irreversible. Dehydration often leads to hypovolaemia, hypotension and possibly renal failure. Acute renal failure and nephrogenic diabetes insipidus may be seen, but these features (which are adverse effects of chronic lithium therapy) are usually a cause of lithium intoxication rather than a consequence. Chronic lithium treatment is also associated with a cystic tubulointerstitial
Management The management of lithium poisoning has been reviewed.2 Gut decontamination In addition to symptomatic treatment, gastric lavage may be considered in patients who have ingested >40 milligrams of lithium carbonate per kilogram body weight less than 1 hour previously. A joint position paper on the role of whole-bowel irrigation (WBI) for gastrointestinal decontamination, published by the European Association of Poison Centres and Clinical Toxicologists and the American Academy of Clinical Toxicology, recommends that WBI can be considered for patients who have ingested substantial amounts of lithium.9
Sally Bradberry BSc MD FRCP FAACT FEAPCCT is Director of the West Midlands Poisons Unit and Deputy Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, and Honorary Senior Lecturer, University of Birmingham, UK. Competing interests: none declared.
MEDICINE 44:3
180
Ó 2016 Published by Elsevier Ltd.
SPECIFIC SUBSTANCES
Haemodiafiltration is less effective than haemodialysis (clearance 20e50 ml/minute), and 12e24 hours is required to remove by haemodiafiltration the amount of lithium eliminated by 6 hours of haemodialysis.13 It has been shown that sustained low-efficiency dialysis also increases lithium clearance.14 A
Sodium chloride 0.9% Because the renal handling of lithium is similar to that of sodium, administration of an isotonic solution of sodium chloride (0.9%) 2e3 litre/day, is indicated in the absence of renal failure or congestive cardiac failure. Low-dose dopamine A single but well-documented case report has demonstrated that dopamine 2 micrograms/minute caused a threefold increase in sodium excretion and the lithium clearance more than doubled.10 Forced diuresis is not indicated.
REFERENCES 1 Hansen HE, Amdisen A. Lithium intoxication (report of 23 cases and review of 100 cases from the literature). QJM 1978; 47: 123e44. 2 Waring WS. Management of lithium toxicity. Toxicol Rev 2006; 25: 221e30. 3 Madhusudhan BK. Nonconvulsive status epilepticus and CreutzfeldteJakob-like EEG changes in a case of lithium toxicity. Epilspsy Behav Case Rep 2014; 2: 203e5. 4 McCartney Y, Browne C, Little DM, Gulmann C. Lithium-induced nephrotoxicity: a case report of renal cystic disease presenting as a mass lesion. Urol Case Rep 2014; 2: 186e8. 5 Anantha Narayanan M, Mahfood Haddad T, Bansal O, et al. Acute cardiomyopathy precipitated by lithium: is there a direct toxic effect on cardiac myocytes? A case report and review of literature. Am J Emerg Med 2015; http://dx.doi.org/10.1016/j.ajem.2015.03. 023. online early. 6 Chalasani S, Benson KA. Lithium-induced thyrotoxicosis in a patient with treatment-resistant bipolar type I affective disorder. Med J Aust 2014; 201: 541e2. 7 Jaeger A, Sauder P, Kopferschmitt J, et al. When should dialysis be performed in lithium poisoning? A kinetic study in 14 cases of lithium poisoning. J Toxicol Clin Toxicol 1993; 31: 429e47. 8 Dyson EH, Simpson D, Prescott LF, Proudfoot AT. Self-poisoning and therapeutic intoxication with lithium. Hum Toxicol 1987; 6: 325e9. 9 Thanacoody R, Caravati EM, Troutman WG, et al. Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. Clin Toxicol 2015; 53: 5e12. 10 Macdonald TM, Cotton M, Prescott LF. Low dose dopamine in lithium poisoning. Br J Clin Pharmacol 1988; 26: 195e7. 11 Ghannoum M, Lavergne V, Yue CS, et al. Successful treatment of lithium toxicity with sodium polystyrene sulfonate: a retrospective cohort study. Clin Toxicol 2010; 48: 34e41. 12 Decker BS, Goldfarb DS, Dargan PI, et al. Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin J Am Soc Nephrol 2015; 10: 875e87. 13 Leblanc M, Raymond M, Bonnardeaux A, et al. Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996; 27: 365e72. 14 Fiaccadori E, Maggiore U, Parenti E, et al. Sustained lowefficiency dialysis (SLED) for acute lithium intoxication. NDT Plus 2008; 1: 329e32.
Sodium polystyrene sulfonate Limited data suggest that sodium polystyrene sulfonate, a cationexchange resin, reduces the half-life of lithium and promotes its elimination.11 Haemodialysis and haemodiafiltration Haemodialysis is the treatment of choice for rapid removal of lithium from the body.12 Lithium fulfils almost all the physicochemical and kinetic criteria for effective removal: low molecular weight (6.94 Da) high water solubility no protein binding low volume of distribution (0.8e1.2 litre/kg) a total endogenous clearance (15e20 ml/minute) that is low compared with haemodialysis clearance (80e120 ml/ minute). During haemodialysis, lithium clearance increases to 180 ml/ min12 (total body clearance is at best normally 30e40 ml/min and 10 ml/min in those on lithium12), with >25 Eq lithium being excreted per hour, thereby shortening the duration of symptoms. The serum half-life of lithium is reduced to 3e6 hours, although a rebound increase in the serum lithium concentration may be observed after haemodialysis because of the slow diffusion of lithium from the intracellular to the extracellular compartment. Haemodialysis is the treatment of choice for severe lithium poisoning.12 It may prevent irreversible neurotoxicity in these cases. Haemodialysis is strongly recommended in all patients with lithium-induced neurological features such as decreased consciousness, cerebellar signs or convulsions. This is irrespective of the serum lithium concentration providing it is above the therapeutic range. Haemodialysis should also be considered in all patients with symptomatic lithium toxicity and: serum lithium concentration >5.0 mmol/litre after acute overdose in those not prescribed lithium serum lithium concentration >4.0 mmol/litre after acute overdose in those prescribed lithium (acute-on-therapeutic poisoning) serum lithium concentration >2.5 mmol/litre in those with chronic poisoning increased serum half-life of lithium secondary to renal impairment.
MEDICINE 44:3
181
Ó 2016 Published by Elsevier Ltd.