Extracorporeal treatment for carbamazepine poisoning: Systematic review and recommendations from the EXTRIP workgroup

Figures & data

Table 1. Represented societies.

American Academy of Clinical Toxicology	European Renal Best Practice
American College of Emergency Physicians	European Society of Emergency Medicine
American College of Medical Toxicology	European Society of Intensive Care Medicine
American Society of Nephrology	French Language Society of Resuscitation
American Society of Pediatric Nephrology	German Society of Nephrology
Asia Pacific Association of Medical Toxicology	International Pediatric Nephrology Association
Australian and New Zealand Intensive Care Society	International Society of Nephrology
Australian and New Zealand Society of Nephrology	Latin American Society of Nephrology and Hypertension
Brazilian Association of Poison Control Centers and Clinical Toxicologists	National Kidney Foundation
Brazilian Society of Nephrology	Pediatric Continuous Renal Replacement Therapy
Brazilian Society of Toxicology	Pediatric Critical Care Medicine
Canadian Association of Poison Control Centres	Quebec Association of Emergency Physicians
Canadian Association of Emergency Physicians	Quebec Association of Specialists in Emergency Medicine
Canadian Society of Nephrology	Quebec Society of Nephrology
Chinese College of Emergency Physicians	Renal Association
Chinese Medical Doctor Association	Society of Critical Care Medicine
European Association of Poison Centres and Clinical Toxicologists	Spanish Clinical Toxicology Foundation

Table 2. Carbamazepine physicochemical and toxicokinetic data.

Molecular weight	236 Daltons
Volume of distribuition	0.8–1.4 L/kg
Protein binding	75%
Oral bioavailability	80–100%
Therapeutic range	4–12 mg/L (17–51 the μ in μmol/L looks weird.)
Toxic exposure	> 20 mg/kg
Toxic blood concentrations	Adults: > 20 mg/L (85 the μ in μmol/L looks weird.)Children: > 12 mg/L (51 the μ in μmol/L looks weird.)

Table 3. Strength of recommendation and level of evidence scaling on clinical outcomes.

Strength of recommendation (consensus-based)

Level of evidence (based on GRADE system)

Level 1 = Strong recommendation = “We recommend…” The course of action is considered appropriate by the majority of experts with no major dissension. The panel is confident that the desirable effects of adherence to the recommendation outweigh the undesirable effectsLevel 2 = Weak recommendation = “We suggest…” The course of action is considered appropriate by the majority of experts, but some degree of dissension exists among the panel members. The desirable effects of adherence to the recommendation probably outweigh the undesirable effectsLevel 3 = Neutral recommendation = “It would be reasonable…” The course of action could be considered appropriate in the right contextNo recommendation No agreement was reached by the group of experts

Grade A=High level of evidence The true effect lies close to our estimate of the effectGrade B=Moderate level of evidence The true effect is likely to be close to our estimate of the effect, but there is a possibility that it is substantially differentGrade C=Low level of evidence The true effect may be substantially different from our estimate of the effectGrade D=Very low level of evidence Our estimate of the effect is just a guess, and it is very likely that the true effect is substantially different from our estimate of the effect

Table 4. Criteria of dialyzability.

	Primary criteria	Alternative criteria 1	Alternative criteria 2	Alternative criteria 3
Dialyzability^A	% Removed^B	CLECTR/CLTOT (%)^C	T1/2 ECTR/T1/2 (%)	ReECTR/ReTOT (%)^C
D, Dialyzable	> 30	> 75	< 25	> 75
M, Moderately dialyzable	> 10–30	> 50–75	> 25–50	> 50–75
S, Slightly dialyzable	≥ 3–10	≥ 25–50	≥ 50–75	≥ 25–50
N, Not dialyzable	< 3	< 25	> 75	< 25

^AApplicable to all modalities of ECTR, including hemodialysis, hemoperfusion, and hemofiltration.

^BCorresponds to % removal of ingested dose or total body burden in a 6-hour ECTR period.

^CMeasured during the same period of time.

ECTR = Extracorporeal treatment, CL_ECTR = Extracorporeal clearance, CL_TOT = Total clearance, RE_ECTR = Extracorporeal removal, RE_TOT = Total removal, T_{1/2 ECTR} = Half-life with ECTR, T_1/2 = Half-life without ECTR.

*These criteria should only be applied if measured or calculated (not reported) endogenous half-life is > 4h (otherwise, ECTR is not considered clinically relevant). Furthermore, the primary criteria are preferred for poisons having a large Vd (> 5 L/Kg).

Reproduced with permission from Clinical Toxicology

Fig. 1. Strength of recommendation algorithm.

Fig. 2. Flow diagram for the literature search (Last performed Oct 1st 2014).

Table 5. Clinical outcomes of the 71 patients described in case reports or case series.

Patient demographics
Mean age (years)	27.2 (range 1.3–58)
Sex (% male)	40.8%
Poisoning exposure
Mean carbamazepine ingestion (grams)	20.9 (0.7–120)
Mean peak carbamazepine concentration (mg/L)	46.2 (range 20–130)
Mean delay between ingestion and admission (hours)	7.8 (range 1–28)
Clinical symptoms and signs
Respiratory depression	39.4%
Decreased consciousness	100%
Seizure (1 or more)	40.8%
Hypotension	18.3%
Dysrhythmias	12.7%
Other administered
MDAC	33.8%
Mechanical ventilation	56.3%
ECTR
Hemodialysis	16.9%
Hemoperfusion	42.2%
Continuous renal replacement therapy	5.6%
Hemoperfusion-Hemodialysis	5.6%
Therapeutic plasma exchange	7.0%
Others	5.6%
More than 1 ECTR	16.9%
Outcome
Sequelae	1.4%
Fatalities	4.2%

MDAC, Multiple-dose activated charcoal; ECTR, Extracorporeal treatment.

*The other fatalities were described in observational cohorts`.

Table 6. Median clearance for all ECTRs.

Type of ECTRs	N	Median extracorporeal clearance (mL/min)
Albumin dialysis	2	32.9 (range: 18.8–47)
Continuous renal replacement therapy	5	18.5 (range: 16–24)
Hemodialysis	27	59.8 (range: 20–127)
Hemodialysis–hemoperfusion in series	2	97.8 (range: 86.6–109)
Hemoperfusion	28	96.9 (range: 23–173)
Peritoneal dialysis	1	11.7
Exchange transfusion	1	1.5
Therapeutic plasma exchange	1	21.7

*Patients who had more than one ECTR may appear more than once.

N, number of patients

Table 7. Kinetic grading for individual patients.

PK/TK grading	TPE	PD	HP	HD	CRRT	Albumin dialysis	HD–HP (in series)	ET
Dialyzable			14	8			1
Moderately dialyzable			9	20	3	1	2
Slightly dialyzable	1		3	2	1
Not dialyzable		1	1	1				1

*Patients who had more than 1 ECTR may appear at more than 1 place.

PK, Pharmacokinetics; TK, Toxicokinetics; TPE, Therapeutic plasma exchange; PD, Peritoneal dialysis; HD, Hemodialysis; HP, Hemoperfusion; CRRT, Continuous renal replacement therapy; ET, Exchange transfusion; ECTR: Extracorporeal treatment.

Table 8. Executive summary of recommendations.

General statement

ECTR is suggested in severe carbamazepine poisoning (2D)

Indications for ECTR

ECTR is recommended if ANY of the following conditions are present:

○ If multiple seizures refractory to treatment occur (1D)

○ If life-threatening dysrhythmias occur (1D)

ECTR is suggested if ANY of the following conditions are present:

○ If prolonged coma or respiratory depression requiring mechanical ventilation are present or expected (2D)

○ If significant toxicity persists, especially if carbamazepine concentrations rise or remain elevated, despite MDAC and support measures (2D)

Cessation of ECTR

Cessation of ECTR is indicated when:

○ Clinical improvement is apparent (1D)

○ Carbamazepine concentration is below 10 mg/L (42 the μ in μmol looks weird/L) (2D)

Choice of ECTR

○ Intermittent hemodialysis is the preferred ECTR in carbamazepine poisoning (1D)

○ The following are alternatives if hemodialysis is not available:

• Intermittent hemoperfusion (1D)

• Continuous renal replacement therapy (3D)

Miscellaneous

MDAC should be continued during ECTR (1D)

ECTR, Extracorporeal treatment; MDAC, Multiple-dose activated charcoal.