In-Depth Review

Extracorporeal Treatment for Lithium Poisoning:

Systematic Review and Recommendations from the
EXTRIP Workgroup
Brian S. Decker, David S. Goldfarb, Paul I. Dargan, Marjorie Friesen, Sophie Gosselin, Robert S. Hoffman,
Valéry Lavergne, Thomas D. Nolin, and Marc Ghannoum on behalf of the EXTRIP Workgroup

Due to the number of

Abstract
contributing authors,
The Extracorporeal Treatments in Poisoning Workgroup was created to provide evidence-based recommenda- the affiliations are
tions on the use of extracorporeal treatments in poisoning. Here, the EXTRIP workgroup presents its provided in the
recommendations for lithium poisoning. After a systematic literature search, clinical and toxicokinetic data were Supplemental
extracted and summarized following a predetermined format. The entire workgroup voted through a two-round Material.
modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method
Correspondence:
was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote
Dr. Marc Ghannoum,
was conducted to determine the final workgroup recommendations. In total, 166 articles met inclusion criteria, Department of
which were mostly case reports, yielding a very low quality of evidence for all recommendations. A total of Nephrology, Verdun
418 patients were reviewed, 228 of which allowed extraction of patient-level data. The workgroup concluded that Hospital, 4000 Lasalle
lithium is dialyzable (Level of evidence=A) and made the following recommendations: Extracorporeal treatment is Boulevard, Verdun, QC
H4G2A3, Canada.
recommended in severe lithium poisoning (1D). Extracorporeal treatment is recommended if kidney function is Email: marcghannoum@
impaired and the [Li+] is >4.0 mEq/L, or in the presence of a decreased level of consciousness, seizures, or life- gmail.com
threatening dysrhythmias irrespective of the [Li+] (1D). Extracorporeal treatment is suggested if the [Li+] is >5.0
mEq/L, significant confusion is present, or the expected time to reduce the [Li+] to <1.0 mEq/L is >36 hours (2D).
Extracorporeal treatment should be continued until clinical improvement is apparent or [Li+] is <1.0 mEq/L (1D).
Extracorporeal treatments should be continued for a minimum of 6 hours if the [Li+] is not readily measurable (1D).
Hemodialysis is the preferred extracorporeal treatment (1D), but continuous RRT is an acceptable alternative (1D).
The workgroup supported the use of extracorporeal treatment in severe lithium poisoning. Clinical decisions on
when to use extracorporeal treatment should take into account the [Li+], kidney function, pattern of lithium toxicity,
patient’s clinical status, and availability of extracorporeal treatments.
Clin J Am Soc Nephrol 10: 875–887, 2015. doi: 10.2215/CJN.10021014

Introduction remains poorly elucidated. Lithium is known to mod-

The Extracorporeal Treatments in Poisoning (EXTRIP) ulate effects of two signal transduction pathways and
Workgroup consists of an international panel of experts three neurotransmitters. Specifically, lithium suppresses
whose primary mission is to develop evidence-based rec- inositol signaling through depletion of intracellular
ommendations for the use of extracorporeal treatments inositol and inhibits glycogen synthase kinase-3 (8,12).
(ECTRs) for poisonings (1–7). Members of the EXTRIP Glycogen synthase kinase-3 is a constitutively active en-
Workgroup provide expertise from a broad range of zyme that is thought to decrease neurotrophic and neu-
medical specialties and represent diverse professional roprotective processes (8). Lithium has also been
societies (Table 1). This document presents recommen- shown to decrease the release of norepinephrine
dations for ECTR in the setting of lithium poisoning and dopamine from nerve terminals and may tran-
based on the evidence from a systematic review. siently increase the release of serotonin (12).
Lithium was the first agent with demonstrable thera- Lithium is a small (molecular mass=7 Da) monova-
peutic use in the manic phase of bipolar disorder (8) and lent cation with properties similar to those of sodium.
remains effective at both protecting against depression Lithium is administered as either lithium citrate (liquid
and mania and reducing the risk of suicide (8–11). The formulation) or lithium carbonate (solid formulation)
positive clinical attributes of lithium, however, need to be (8,13). After therapeutic oral administration, immediate-
considered in light of its significant adverse effect profile release lithium preparations are almost completely ab-
and exceedingly narrow therapeutic index. sorbed, with peak serum lithium concentrations (Li+)
occurring in 30 minutes to 2 hours (8,14,15), whereas
Pharmacology modified-release preparations yield peak [Li+] generally
Despite considerable research, the mechanism of at 4–5 hours (13). In overdose, prolonged gastric absorp-
action of lithium in the treatment of bipolar disorder tion and clumping from insoluble aggregates may occur,

www.cjasn.org Vol 10 May, 2015 Copyright © 2015 by the American Society of Nephrology 875
876 Clinical Journal of the American Society of Nephrology

Table 1. Represented societies and official representative

Acute Dialysis Quality Initiative (Marc Ghannoum)

American Academy of Clinical Toxicology (Robert S. Hoffman)
American College of Emergency Physicians (Timothy J. Wiegand)
American College of Medical Toxicology (Timothy J. Wiegand)
American Society of Nephrology (Kathleen D. Liu)
American Society of Pediatric Nephrology (Timothy Bunchman/Véronique Phan)
Asia Pacific Association of Medical Toxicology (Darren M. Roberts, Ashish Bhalla)
Association of Physicians of India (Ashish Bhalla)
Australian and New Zealand Intensive Care Society (Darren M. Roberts)
Australian and New Zealand Society of Nephrology (Darren M. Roberts)
Brazilian Association of Poison Control Centers and Clinical Toxicologists (Tais F. Galvao)
Brazilian Society of Nephrology (Emmanuel A. Burdmann)
Brazilian Society of Toxicology (Tais F. Galvao)
Canadian Association of Poison Control Centres (David N. Juurlink)
Canadian Association of Emergency Physicians (Martin Laliberté)
Canadian Society of Nephrology (Marc Ghannoum)
Chinese College of Emergency Physicians (Yi Li)
Chinese Medical Doctor Association (Yi Li)
European Association of Poison Centres and Clinical Toxicologists (Bruno Mégarbane, Paul I. Dargan)
European Renal Best Practice (Jan T. Kielstein, Robert Mactier)
European Society for Emergency Medicine (Kurt Anseeuw)
European Society of Intensive Care Medicine (Bruno Mégarbane)
French Society of Intensive Care (Bruno Mégarbane)
German Society of Nephrology (Jan T. Kielstein)
International Pediatric Nephrology Association (Timothy Bunchman/Véronique Phan)
Indian Society of Critical Care Medicine (Ashish Bhalla)
INDO-US Emergency & Trauma Collaborative (Ashish Bhalla)
International Society of Nephrology (Emmanuel A. Burdmann)
Latin American Society of Nephrology and Hypertension (Emmanuel A. Burdmann)
National Kidney Foundation (David S. Goldfarb)
Pediatric Continuous Renal Replacement Therapy (Timothy Bunchman/Véronique Phan)
Pediatric Critical Care Medicine (Timothy Bunchman/Véronique Phan)
Quebec Association of Emergency Physicians (Sophie Gosselin)
Quebec Association of Specialists in Emergency Medicine (Sophie Gosselin)
Quebec Society of Nephrology (Marc Ghannoum)
Renal Association (Robert Mactier)
Society of Critical Care Medicine (James B. Mowry and Rob Maclaren)
Spanish Clinical Toxicology Foundation (Cristopher Yates)

especially with lithium carbonate, which is the least soluble of age, kidney function, and duration of lithium therapy (13).
the lithium salts, providing a reservoir of lithium for contin- Typically, the half-life of lithium is 12–27 hours, but it can be
ued absorption (16,17). as high as 58 hours in the elderly or patients who take lith-
Lithium distributes widely in total body water and does ium chronically (14).
not bind to serum proteins (14). The initial volume of dis-
tribution of lithium is 0.5 L/kg; however, it subsequently Overview of Lithium Poisoning
increases to 0.7–0.9 L/kg with time (8,13). Tissue distribution Data from the US Poison Control Centers documented
of lithium follows a multiple compartment model with a de- 6815 toxic lithium exposures in 2012, 17% of which had at
layed diffusion from the extracellular to the intracellular com- least a moderately severe effect, including 11 deaths (20). There
partment (18). Lithium is rapidly taken up by the kidney, are three clinically recognized patterns of lithium poisoning:
thyroid, and bone (15,18). However, diffusion into the cere- acute, acute on chronic, and chronic (13,21,22). Acute lithium
brospinal fluid and the brain is delayed by approximately 24 poisoning occurs in patients who are lithium naïve and over-
hours compared with its appearance in plasma (15,19). Lith- dose on lithium. Acute-on-chronic lithium poisoning occurs in
ium undergoes no metabolism, is freely filtered in the glo- patients who have an existing body burden of lithium from
merulus, and is excreted entirely in the urine (8,14). maintenance therapy and are acutely exposed to a large bur-
Approximately 80% of the lithium that is filtered by the glo- den of lithium. Chronic lithium poisoning occurs in patients
merulus is reabsorbed: 60% by the proximal tubule and 20% on maintenance lithium therapy in the clinical context of a
by the thick ascending limb of the loop of Henle and collect- recently increased lithium dose, a decline in kidney function,
ing duct (13). Clinical conditions that decrease GFR or given or a drug-drug interaction that impairs elimination (13,21).
its biochemical similarity to sodium, increase proximal tubule The clinical relationship between [Li+] and toxicity is
reabsorption, such as volume depletion and thiazide diuret- complex (23–25). The therapeutic steady-state [Li + ] is
ics, will increase [Li+] (13,15). The terminal elimination half- 0.6–1.2 mEq/L (8,13,21,26,27) (Table 2). In general, mild
life of lithium is widely variable and depends on a patient’s lithium toxicity is observed at steady-state [Li + ] of
Clin J Am Soc Nephrol 10: 875–887, May, 2015 Blood Purification for Lithium Poisoning, Decker et al. 877

1.5–2.5 mEq/L. Moderate toxicity can be observed when recommended more stringent patient selection for lithium
[Li+] reach 2.5–3.5 mEq/L, and severe toxicity can be ob- therapy, lower therapeutic [Li+] as a prophylactic measure,
served when [Li + ] are .3.5 mEq/L (18,21). However, and aggressive extracorporeal lithium removal, even after
clinical features are both highly variable and greatly de- nontoxic concentrations have been achieved in those with
pendent on the specific pattern of poisoning (21); symp- lithium poisoning (36).
toms may be absent or minor, with markedly elevated Management of patients with severe lithium poisoning
[Li+] in acute lithium poisoning (18,21,28), whereas they begins with supportive care, including discontinuation of
may be prominent in chronic toxicity, with serum lithium lithium and volume resuscitation with intravenous isotonic
concentrations as low as 1.5 mEq/L, reflecting higher saline (14,21). Activated charcoal is not favored for gastro-
brain lithium concentrations (18,21). The delayed diffu- intestinal decontamination after an acute overdose because it
sion of lithium to the brain explains the absence or delay does not bind lithium (38,39). If required, gastric lavage (40)
of symptoms in patients with acute lithium poisoning, and/or whole bowel irrigation with a polyethylene glycol
despite highly elevated [Li +] (18,21,29). For these rea- electrolyte lavage solution may be performed (41,42), al-
sons, these serum lithium concentrations are only a guide though there are no data to show improved outcome with
to potential risk of toxicity and should always be inter- any decontamination procedure (43). Sodium polystyrene
preted in the context of the patient’s history, clinical find- sulfonate has been suggested to enhance elimination of lith-
ings, and kidney function. ium but is yet to have a clearly demonstrable role (44).
The central nervous system (CNS) is the organ system Owing to its favorable pharmacokinetic parameters, the
predominantly affected, particularly in those patients with most efficient reported intervention to remove lithium
chronic lithium poisoning: mild lithium poisoning typically from a poisoned patient is intermittent hemodialysis (HD),
encompasses drowsiness, nausea, vomiting, tremor, hyper- and it is currently advocated for patients with severe toxicity
reflexia, agitation, muscle weakness, and ataxia (18,21). More (21,22). In fact, lithium remains one of the poisons where
prominent symptoms include stupor, rigidity, hypertonia, ECTR is most often reported and recommended (45,46), al-
and hypotension. The most severe cases manifest as coma, though it is still infrequently used in this context (47,48).
convulsions, myoclonus, and cardiopulmonary collapse Currently, there is discordance in published recommenda-
(18,21). Because the distinction between these gradations tions and variability in decision making by clinicians regard-
can often be subtle, they are best thought of as a natural ing indications for ECTR in the setting of lithium poisoning
progression of a potentially severe overdose. Only the gas- (28). This lack of a clinical consensus stems in part from the
trointestinal symptoms tend to distinguish acute poisoning, complex pharmacology of lithium that prevents a direct re-
where they are expected and prominent, from chronic tox- lationship between [Li+] and toxicity, which may lead to
icity, where they are almost invariably absent. Other clini- some patients currently being either undertreated or unnec-
cal findings can include electrocardiographic changes, such essarily exposed to ECTR. Moreover, no large-scale study on
as transient ST segment depression, bradycardia, sinus lithium poisoning has been published to date. Thus, the cur-
node dysfunction, and inverted T waves in the lateral pre- rent [Li+] thresholds that serve as indicators for ECTR are
cordial leads (13,14,30–34). largely derived from the opinion of a few authors without a
The syndrome of irreversible lithium-effectuated neuro- systematic review of the evidence. Some examples of these
toxicity (SILENT) is a neurologic complication of lithium current recommendations are shown in Table 3 (28).
toxicity (35–37). Currently, the prevalence of SILENT is
unknown and limited to a small number of case reports.
Patients with SILENT have chronic, largely cerebellar se- Methodology
quelae, even after lithium has been discontinued and con- Predetermined methodology incorporating guidelines
centrations have fallen to therapeutic or nondetectable from the Appraisal of Guidelines for Research and Evaluation
values. The clinical features of SILENT may include tremor, (49) and Grades of Recommendation Assessment, Develop-
extrapyramidal symptoms, gait difficulties, nystagmus, dys- ment and Evaluation (50) is described in detail elsewhere
arthria, and cognitive deficits (35–37). Currently, there are no (2,3). The latest literature search was conducted on October
definitive treatments for SILENT, although clinicians have 1, 2014, and included searches in Medline, Embase, the Co-
chrane library (Review and Central), conference proceedings
of the European Association of Poisons Centres and Clinical
Toxicologists and North American Congress of Clinical Tox-
Table 2. Lithium physicochemical and toxicokinetic
properties
icology annual meetings, and Google Scholar.
The search strategy was as follows: ([lithium] and [di-
Molecular mass 7 Da alysis or hemodialysis or haemodialysis or hemoperfusion
Volume of distribution 0.7–0.9 L/kg or haemoperfusion or plasmapheresis or plasma exchange or
Protein binding 0% exchange transfusion or hemofiltration or haemofiltration or
Oral bioavailability Immediate release: 95%–100%; hemodiafiltration or haemodiafiltration or extracorporeal
modified release: 60%–90% therapy or continuous RRT (CRRT)]).
Therapeutic serum 0.6–1.2 mEq/L Dialyzability (on the basis of criteria listed in Supplemental
concentration Table 1) and clinical data from every included article were
Half-life (therapeutic) 12–27 h summarized. The potential benefit of the procedure was
Conversion factor 1 mmol/L=1 mEq/L
weighed against its cost, availability, alternative treatments,
Toxic dose (acute .1 g elemental Li
poisoning) and related complications. The level of evidence assigned to
each clinical recommendation was determined by the
878 Clinical Journal of the American Society of Nephrology

subgroup and epidemiologist (Supplemental Table 2). All of

Neurotoxicity
2nd Ed. (210)
this information was submitted to the entire workgroup for

Toxicology
Handbook,
Murray’s
consideration along with structured voting statements on the

.2.5
basis of a predetermined format. The workgroup met in per-
son to exchange ideas and debate statements. The strength of
recommendations was evaluated by a two-round anonymous
modified Delphi method for each proposed voting statement
(Supplemental Figure 1), and the RAND/UCLA Appropri-

toxicity, kidney
(uptodate.com)

ateness Method was used to quantify disagreement between

UpToDate

impairment
voters (51).
(211)

.2.5

Significant
.4

Results
The results of the literature search are shown in Figure 1.
In total, 507 articles were identified after duplicates were
removed, of which 341 full-text articles were retrieved and
and Drug Overdose,

impaired mental

166 studies were finally included for analysis. In total, 156

Olson’s Poisoning

status, kidney
6th Ed. (212)

case reports/case series (235 patients) (16,18,23,25,26,30–

impairment

34,37,44,52–193), five descriptive cohorts (101 patients)

Seizures or

(24,47,48,194,195), three observational studies (80 pa-

tients) (196–198), and two pharmacokinetic studies (two
patients) (199,200) were included. Reliable information on
patient-level data was possible in 228 patients (Table 4).
Neurotoxicity

Clinical Outcomes
(toxinz.com)

One prospective cohort study included patients in whom

Toxinz

(213)

.4

HD was recommended by a poison control center and

compared those who actually received HD (n=8) with
those who did not (n=9) (196). Groups were deemed com-
parable for all baseline characteristics, although the small
number of patients included does not allow reliable com-
Neurotoxicity
(toxbase.org)

parison (for example, initial [Li+] was 4.30 in the HD group

Toxbase

and 2.71 in the control group with a P value=0.18). Addition-

(214)

$7.5
Table 3. Indications for extracorporeal treatment in the treatment of lithium poisoning

.4

ally, patient selection was potentially subject to confounding

by indication. Clinical outcome (death and sequalae) in both
groups were not found to be statistically different, but this
ECTR, extracorporeal treatment. Modified from reference 28, with permission.

interpretation is limited by the study being underpowered

and by potential confounders (age, type of poisoning, [Li+],
Neurotoxicity
(emedicine.
EMedicine

medscape.
com) (215)

coingestants, etc).
$2.5

Another observational retrospective study of 14 patients

$4

identified clinical and biochemical makers on admission

that were associated with a greater number of HD sessions
(197); no significant association between the number of HD
sessions and outcomes, including length of intensive care
unit stay, can be derived from the study, because the analysis
Neurotoxicity,
9th Ed. (216)

impairment
Emergencies,
Goldfrank’s
Toxicologic

was also underpowered. A third comparative study showed

$2.5

significant worsening neurologic status in a group of patients

kidney
$4

who were dialyzed, but the study was only presented in

abstract form (198). Because these studies had serious limita-
tions and because the rest of the clinical literature review was
solely comprised of case reports and uncontrolled descriptive
cohorts, the quality of the evidence was considered to be very
Absolute [Li+] regardless of

low for all recommendations.

[Li+] in chronic exposure
Indication for ECTR

The clinical features of reported patients with lithium

symptoms (mEq/L)

toxicity are presented in Table 4. There were slightly more

Symptoms/signs

patients with chronic than acute toxicity (123 versus 93 pa-

tients, respectively); it was often impossible to ascertain
whether patients had been taking lithium previously, and
(mEq/L)

therefore, it was not feasible to differentiate between acute

and acute-on-chronic poisoning. Average [Li+] were higher in
those patients after an acute ingestion (5.7 versus 3.4 mEq/L
for patients with chronic toxicity). Prominent neurologic
Clin J Am Soc Nephrol 10: 875–887, May, 2015 Blood Purification for Lithium Poisoning, Decker et al. 879

Figure 1. | Flow diagram for lithium records search (October 1, 2014).

symptoms were present in both types of poisoning, although can achieve a lithium clearance of 180 mL/min (21,89,148,202)
they appeared less frequently and less severely in patients with when operator characteristics are maximized (Table 5)
acute cases, especially if ECTR was performed within 24 hours (185,203). Comparatively, kidney (and total body) clear-
of ingestion. Seizures were reported almost as frequently in ance of lithium can reach, at best, approximately 25% of
chronic and acute poisonings (63,66,88,115,128,137,161,165,187). GFR or 30–40 mL/min. Because impairment of kidney
Many types of abnormal cardiac rhythms were identified function often accompanies lithium toxicity and because
from our literature search in both types of toxicity patterns. lithium itself has long-term effects on kidney function,
AKI was a common feature on presentation (more so in pa- lower lithium clearances are usually reported, reaching
tients with chronic toxicity). an average of 10.6 mL/min for our cohort (14,204). The
For all groups, HD was, by far, the predominant ECTR reported lithium half-life during HD was always shorter
modality used. Most (83%) of the reported patients experi- than that before and/or after dialysis, when it was calculated
enced some degree of clinical improvement either during or on (18,70,71,97,110,111,149,193,202). Exact lithium removal by
cessation of ECTR. There were 14 deaths reported from 228 ECTR was quantified in several reports (usually using older
patients included (23,25,52,70,74,75,93,96,104,119,139,159,162) dialysis technology) (56,62,71,107,126,172,183,192,202)
(slightly more in those who were acutely poisoned). In these and shown to be significant, sometimes even in excess of
patients, the cause of death was cardiopulmonary failure, 25 mEq/h (71).
sepsis, brain death, or unrelated to lithium. Although its in- There are limited data with intermittent hemodiafiltration
terpretation should be cautioned by the presence of con- and sustained low-efficiency HD, but both seem to provide
founders and publication bias, the mean peak [Li+] after excellent clearance (60). As expected by their lower effluent
acute exposures was higher in fatalities compared with that and blood flow rates, CRRTs are approximately three times
of survivors (8.7 versus 5.5 mEq/L, respectively). The major- less efficient than HD (205). This difference is best confirmed
ity of reported adverse events observed during ECTR in- in patients undergoing both CRRT and HD (60,82,138,140).
cluded hypotension (112,159,161,185), an acute drop in Likewise, PD only provides clearance of 9–14 mL/min
hemoglobin (179), upper extremity vein thrombosis (125), (14,89,128,190).
peritonitis attributed to a peritoneal dialysis (PD) catheter The effect of ECTR on lithium elimination from other body
(137,186), and HD catheter-related sepsis (144). Although clin- compartments is less often reported, but the decrease of lithium
ical improvement was usually observed during ECTR, dete- concentration in red blood cells (71,167,172) and cerebrospinal
rioration during the procedure was reported in some patients fluid (111,149,193) seems to parallel that from the serum. In
(198,201). One review suggested that several patients with one report, ECTR did not seem to reduce endogenous renal
cognitive deterioration were reported during ECTR, but the elimination (18). Like other small solutes (e.g., urea), there is
search strategy for the review of patient worsening is unclear, evidence that maximizing blood flow (128,185,193), increasing
and individual patients were not referenced (201). effluent flow (105,128), and using a high-efficiency dialyzer
(149) improve lithium clearance during ECTR.
Averaged clearance parameters (Table 5) and kinetic
Dialyzability grading of individual patients (Table 6) confirm the high
The favorable chemical and pharmacologic properties of dialyzability for lithium. This is substantiated by a large
lithium (low molecular weight, low protein binding, rel- number of reports where systematic measurements and
atively low VD, and low endogenous clearance) (Table 2) correct calculations were performed, including several
suggest that lithium should be readily dialyzable, and this where lithium removal was quantified in effluent/dialysate,
is confirmed by the literature review. High-efficiency HD the preferred method for assessing dialyzability (2,206).
880 Clinical Journal of the American Society of Nephrology

Table 4. Clinical data related to the accepted cases of patients who received extracorporeal treatment for lithium toxicity

Acute/Acute on
Clinical data Chronic (n=123) Unknown (n=12)
Chronic (n=93)

Patient demographics
Mean age (yr) 40.3 (range=16–69) 52.5 (range=0–80) 41.2 (range=23–69)
Sex (% men) 44 34 20
Mean length of lithium therapy (yr) N/A 7.8 (range=0–42) 5.5 (range=1–10)
Poisoning exposure
Mean elemental lithium ingestion (mEq)a 798 (range=67–2630) N/A N/A
Mean peak lithium concentration (mEq/L) 5.7 (range=1.1–14.6) 3.4 (range=0.6–6.3) 3.7 (range=2.1–6.7)
Mean delay between ingestion and admission (h) 17.6 (range=0.5–288) N/A N/A
Clinical symptoms and signs
Decreased consciousness (%) 52 87 83
Seizure (%) 10 12 0
Ataxia (%) 6 22 17
Hyperthermia (%) 8 4 8
Gastrointestinal (%) 29 19b 25
Dysrhythmias (%) 25 33 8
AKI (%) 30 72 17
Mean creatinine on admission (mg/dL) 2.1 (range=0.6–6.4) 2.9 (range=0.8–16) 2.0 (range=1.1–2.9)
ECTR
Mean delay between admission and 17.6 (range=1–120) 32.3 (range=1–168) 13.5 (range=3–24)
ECTR initiation (h)
Hemodialysis (%) 69.9 82.9 58.3
Continuous RRT (%) 12.9 6.5 0
Sustained low-efficiency dialysis (%) 1.1 0 0
Hemoperfusion (%) 1.1 0 0
Exchange transfusion (%) 0 0.8 0
Peritoneal dialysis (%) 4.3 4.9 41.7
Intermittent hemodiafiltration (%) 0 0.8 0
.1 ECTR (%) 10.8 4.1 0
Outcome
Sequelae n (%) 14 (15.1) 25 (20.3) 1 (8.3)
Fatalities n (%) 7 (7.5) 6 (4.9) 1 (8.3)

These only include cases in which patient-level data could be extracted. Given the nature of the data, it was felt that a statistical
comparison of the groups was inappropriate. N/A, not applicable.
a
Lithium carbonate (300 mg) contains 8 mEq or 56.4 mg elemental lithium.
b
Gastrointestinal symptoms were usually coexisting conditions in chronic lithium poisoning.

caused by either a redistribution of lithium from deeper

Table 5. Aggregate clearances obtained in the reported compartments/red blood cells to the plasma or by on-
patients going absorption from the gastrointestinal tract. Postre-
distribution lithium rebound characteristically occurs
Clearance (mL/min)
Method of Removal after high-efficiency techniques; the rise in [Li+ ] is max-
Mean Range imal after 6–12 hours (reaching 0.5–1.0 mEq/L)
(18,47,64,70,79,89,110,111,207) and not associated with
Endogenous 10.6 1.5–39.6 (n=53) recurrent symptoms as lithium moves away from the
Peritoneal dialysis 10.9 9–14 (n=5) toxic compartment (56). By contrast, rebound from
Hemodialysis 106.9 40–180 (n=39) ongoing absorption can occur in poisonings from
Continuous RRT 43.1 19–64 (n=19)
extended-release formulations or patients with decreased
gastrointestinal motility; they can be noticeably much
According to the dialyzability criteria in Supplemental Ta- greater in extent (16,68,71,72,87,91,152,178) and may
ble 2, the workgroup agreed that lithium was dialyzable be associated with recurrence of symptoms or clinical
(level of evidence=A). deterioration, because the absorbed drug will ultimately
distribute into the CNS and other tissues. In every re-
ported patient with lithium rebound associated with
Lithium Rebound clinical deterioration, the rise was attributed to ongoing
Lithium rebound is defined as an increase in [Li+] ob- absorption of extended-release formulations (16,
served after ECTR cessation. This phenomenon may be 68,72).
Clin J Am Soc Nephrol 10: 875–887, May, 2015 Blood Purification for Lithium Poisoning, Decker et al. 881

(2) Indications for ECTR

Table 6. Kinetic grading for individual patients ECTR is recommended if any of the following conditions
are present (1D):
Number of Patients with PK/TK Grading
TK/PK (1) If kidney function is impaired and the [Li+] is .4.0 mEq/L.
Grading Peritoneal Continuous
Dialysis
Hemodialysis
RRT (2) In the presence of a decreased level of consciousness,
seizures, or life-threatening dysrhythmias, irrespective of
Dialyzable 2 30 9 the [Li+].
Moderately 2 4 3
dialyzable ECTR is suggested if any of the following conditions are
Slightly 3 1 0 present (2D):
dialyzable
Not dialyzable 1 0 0 (3) If [Li+] is .5.0 mEq/L.
(4) If significant confusion is present.
Patients who had more than one extracorporeal treatment may (5) If the expected time to reduce [Li+] to ,1.0 mEq/L with
appear at more than one place. PK, pharmacokinetics; TK, optimal management is .36 hours.
toxicokinetics.
Rationale. Even if the correlation between the [Li+] and
clinical features of toxicity is controversial (23–25), the work-
Recommendations group suggested that ECTR is indicated above a [Li+] of 5.0
(1) General Statement mEq/L; this is because of the possibility that toxicity will
We recommend ECTR in patients with severe lithium occur above this threshold, even if clinical features of toxicity
poisoning (1D). are initially absent. Also, better removal by ECTR is pos-
Rationale. Poisoning to lithium can be life threatening, sible when the [Li+] in the intravascular space is high. The
and treatment options to prevent or reverse toxic symp- workgroup suggests that this clinical approach be consid-
toms are limited (Table 7). Lithium is highly dialyzable, ered, regardless of the pattern of lithium poisoning: the
and data from the majority of reports showed clinical im- literature review revealed that the outcomes of patients
provement when ECTR was used. ECTR, such as HD, can with acute ingestions were less benign than originally
reduce the lithium concentration from the blood at a rate thought and that a threshold of 5.0 mEq/L, which is higher
exceeding normal kidney clearance by severalfold (even than most other quoted sources, would justify ECTR. A
with the addition of aggressive volume expansion), and al- patient who presents with acute lithium poisoning war-
though unproven, it is also likely to remove it more rapidly rants close monitoring and consideration for ECTR, even
from the CNS where toxicity occurs. Despite the absence of if asymptomatic.
randomized clinical trials and the low likelihood that these Because the kidneys are the exclusive organs for lithium
will ever be conducted, all 27 panel members strongly voted elimination, impaired kidney function should lower the
for ECTR in patients with severe lithium poisoning (median threshold for ECTR initiation (4.0 mEq/L, regardless of
vote=9). The benefit of ECTR when lithium poisoning is se- clinical features; 1D). For the purpose of this assessment,
vere, as defined by any of the conditions below, was deemed the EXTRIP Workgroup defined impaired kidney function
to significantly outweigh potential risks, complications, and from the perspective of poison elimination as (1) stage 3B,
costs of the procedure. 4, or 5 CKD (i.e., eGFR,45 mL/min per 1.73 m2); (2)

Table 7. Executive summary of recommendations

General
ECTR is recommended in patients with severe Li poisoning (1D)
Indications
ECTR is recommended (1D)
If kidney function is impaired and the [Li+].4.0 mEq/L
In the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of [Li+]
ECTR is suggested (2D)
If the [Li+].5.0 mEq/L
If confusion is present
If the expected time to obtain a [Li+],1.0 mEq/L with optimal management is .36 h
Cessation of ECTR is recommended (1D)
When the [Li+],1.0 mEq/L or clinical improvement is apparent
After a minimum of 6 h of ECTR if the [Li+] is not readily available
After interruption of ECTR, serial [Li+] measurements should be obtained over 12 h to determine use of subsequent
ECTR sessions (1D)
Choice of ECTR
Intermittent hemodialysis is the preferred ECTR (1D)
Continuous RRT is an acceptable alternative if intermittent hemodialysis is not available (1D)
After initial treatment, both continuous RRT and intermittent hemodialysis are equally acceptable (1D)
882 Clinical Journal of the American Society of Nephrology

Kidney Disease Improving Global Outcomes stage 2 or 3 of lithium rebound; although this rebound may not be clin-
AKI; (3) in the absence of a baseline, a serum creatinine of ically significant (see above), additional ECTR sessions may
2 mg/dl (176 mmol/L) in adults and 1.5 mg/dL (132 provide for additional opportunity to remove more lith-
mmol/L) in elderly/low-muscle mass patients; and (4) in ium. If ongoing absorption is suspected, a longer obser-
children with no baseline creatinine, a serum creatinine vation period may be warranted (72). The dialysis catheter
greater than two times the upper limit of normal for age should remain in place until no additional ECTRs sessions
and sex. The presence of oligo/anuria should raise aware- are anticipated.
ness of impaired kidney function, regardless of serum cre-
atinine concentration. (4) Choice of ECTR
Regardless of the [Li+], ECTR is recommended (1D) in
any patient manifesting clinical features of decreased con- (1) Intermittent HD is the preferred ECTR modality in lithium
sciousness, seizures, or dysrhythmias to rapidly reduce the poisoning (1D).
lithium burden. Seizures are usually a manifestation of (2) CRRT is an acceptable alternative if intermittent HD is not
severe lithium neurotoxicity (25). Various abnormal car- available (1D).
diac rhythms can occur in lithium poisoning (47), although (3) After an initial treatment with intermittent HD, both CRRT
life-threatening dysrhythmias are rare; when present, they and intermittent HD are equally acceptable modalities for
seemed to improve with active treatment, including ECTR additional lithium removal (1D)
(33,69,75,135,139,141,157).
Rationale. Intermittent HD is the most efficient ECTR at
Any delays in reducing the [Li+] in these symptomatic
reducing the body burden of lithium. The rapid and sustained
patients may increase the risk for chronic neurotoxicity. A
clearance of lithium from poisoned patients provided by HD
similar rationale is used to justify ECTR if the expected
may help ameliorate ongoing signs of toxicity and prevent
time to achieve a safe [Li+] (,1 mEq/L) is .36 hours.
chronic sequelae. Among the various ECTRs, HD is the most
Given the risks inherent in protracted periods of lithium
widely available, the least expensive, and the best adapted
toxicity, it is prudent to proceed with ECTR if this clinical
to quickly eliminate small molecules, like lithium. Although
scenario is anticipated. Finally, the reported amount of in-
CRRT is less efficient at lithium removal, it is an acceptable
gestion is very unreliable and should not be used as the
alternative if intermittent HD is not available. The better
sole clinical justification for ECTR. However, there are re-
hemodynamic tolerance attributed to CRRT over intermittent
ports of patients with massive lithium overdoses who
HD is questionable in lithium poisoning, when net fluid re-
were asymptomatic on admission but eventually devel-
moval is not required. Preliminary data with both sustained
oped life-threatening clinical features (52,60,122). Such pa-
low-efficiency HD and intermittent hemodiafiltration seem
tients should be closely monitored for [Li + ], kidney
to justify their role as potential alternatives to HD. Charcoal
function, and clinical status. Early communication
hemoperfusion is useless (181), because charcoal does not
with a dialysis team should be initiated, and preemptive
adsorb lithium (38,39). The data for other ECTRs, such as
transfer to a unit dispensing ECTR should be considered
exchange transfusion, liver support therapies, and therapeu-
for those patients presenting with a massive lithium in-
tic plasma exchange, are almost nonexistent and would not
gestion if the risk assessment justifies it (208). Efforts
be expected to provide similar clearance to the more com-
should be targeted to limit the time in initiating ECTR
mon and efficient diffusive techniques (209). The clearances
after the patient develops one of the aforementioned
obtained with PD are even inferior to CRRT, and it is, there-
criteria.
fore, not recommended. After an initial treatment, if ECTR is
(3) Cessation of ECTR required to remove more lithium, either a repeat intermittent
Cessation of ECTR is recommended (1D): dialysis session or a switch to CRRT was considered an
equivalent alternative; prolonged treatment with either HD
(1) If either the [Li+] is ,1.0 mEq/L or clinical improvement is (179) or CRRT (128) may help remove lithium from the
apparent. CNS, a compartment that diffuses more slowly into the
(2) After a minimum of 6 hours of ECTR if the [Li+] is not blood. There is limited evidence from simulation models
readily measurable. that HD followed by CRRT will result in lower intracellular
lithium concentration compared with either individually, al-
After interruption of ECTR, serial [Li+] measurements
though repeated HD was not studied in the model (138). To
should be performed over 12 hours to determine the
optimize clearance, it is proposed to maximize operational
need for subsequent ECTR sessions (1D).
parameters (203), including blood flow (128,185,193), efflu-
Rationale. An initial session of ECTR should provide
ent flow (105,128), and performant filters (149). If CRRT is
sufficient time for removal of a toxic lithium burden. At a
chosen, the delivered dose should be also maximized (i.e.,
[Li+] ,1 mEq/L, it is unlikely that the patient will manifest
above the standard 20–25 ml/kg per hour usually prescribed
any life-threatening toxicity, and this is, therefore, an end-
for AKI).
point for ECTR cessation. If [Li+] are not available in a clin-
ically meaningful timeframe, a minimum length of 6 hours
of ECTR will provide for acceptable lithium removal as well Conclusions
as a margin of safety on the assumption of a lithium half-life Lithium’s narrow therapeutic index continues to make it a
of 2 hours on modern high-efficiency HD (72,83,89,149,193). challenging drug to manage, with toxicity always a concern.
It is also reasonable to stop ECTR if significant clinical im- The workgroup recommended that ECTR be used in pa-
provement is apparent. After ECTR cessation, serial [Li+] tients with severe toxicity to minimize the length of time
should be obtained over 12 hours to determine the extent that the brain is exposed to toxic lithium concentrations. ECTR
Clin J Am Soc Nephrol 10: 875–887, May, 2015 Blood Purification for Lithium Poisoning, Decker et al. 883

should be particularly considered when there is concomi- DP, Burdmann EA, Yates C, Laliberté M, Decker BS, Mello-Da-
tant kidney impairment, there is evidence of neurotoxicity, Silva CA, Lavonas E, Ghannoum M: The EXTRIP (EXtracorporeal
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lators: Marcela Covica, Alexandra Angulo, Ania Gresziak, Monique poisoning: Recommendations from the EXTRIP Workgroup.
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sant poisoning: Recommendations from the EXTRIP Work-
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Mckay, Vilma Etchart, Valentina Bartoli, Nathan Weatherdon, Marcia corporeal treatment for barbiturate poisoning: Recom-
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Shapiro,Hannele Marttila, and Kapka Lazorova. We also acknowledge treatment for acetaminophen poisoning: Recommendations from
the important contributions from our librarians and secretarial aids: the EXTRIP workgroup. Clin Toxicol (Phila) 52: 856–867, 2014
7. Ghannoum M, Yates C, Galvao TF, Sowinski KM, Vo TH,
Marc Lamarre, David Soteros, Salih Topal, Henry Gaston, and Brenda
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Funding for Extracorporeal Treatments in Poisoning (EXTRIP) pine poisoning: Systematic review and recommendations from
was obtained from industry in the form of unrestricted educational the EXTRIP workgroup. Clin Toxicol (Phila) 30: 1–12, 2014
grants. These funds were used solely for expenses related to liter- 8. Meltzer H: Antipsychotic agents and lithium. In: Basic and
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