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

Figures & data

Table 1. Represented societies.

Acute Dialysis Quality Initiative	European Renal Best Practice
American Academy of Clinical Toxicology	European Society For Emergency Medicine
American College of Emergency Physicians	European Society of Intensive Care Medicine
American College of Medical Toxicology	French Society of Intensive Care
American Society of Nephrology	German Society of Nephrology
American Society of Pediatric Nephrology	Indian Society of Critical Care Medicine
Asia Pacific Association of Medical Toxicology	INDO-US Emergency & Trauma Collaborative
Association of Physicians of India	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 Information Centres and Toxicologic Assistance	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 Toxicologist	Spanish Clinical Toxicology Foundation

Table 2. VPA: Physical and TK properties.

Molecular mass	144 D
Volume of distribution	0.1–0.5 L/kg
Protein binding	Variable 94% at therapeutic concentration 15% when [VPA] > 1000 mg/L
Oral bioavailability	68–100%
Elimination half-life (therapeutic)	12 h
Endogenous clearance	5–10 mL/min
Conversion factor	1 mg/L = 6.94 μmol/L
Therapeutic range	50–100 mg/L (347–694 μmol/L)
Toxic exposure	> 200 mg/kg
Lethal exposure	> 1000 mg/kg

Table 3. Strength of recommendation and level of evidence scale for 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 large majority of experts with no major dissension. The panel is confident that the desirable effects of adherence to the recommendation outweigh the undesirable effects. Level 2 = Weak recommendation = “We suggest…” The course of action is considered appropriate by the majority of experts but some degree of dissension exists amongst the panel. The desirable effects of adherence to the recommendation probably outweigh the undesirable effects. Level 3 = Neutral recommendation = “It would be reasonable…” The course of action could be considered appropriate in the right context No 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 effect Grade 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 different Grade C = Low level of evidence The true effect may be substantially different from our estimate of the effect Grade 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 for dialyzability.*

Dialyzability^A	Primary criteria % Removed^B	Alternative criteria 1 CLECTR/CLTOT (%)	Alternative criteria 2 T1/2 ECTR/T1/2 (%)	Alternative criteria 3 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 on ECTR; T_1/2, Half-life off ECTR.

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

Reproduced with permission from Lavergne V, Nolin TD, Hoffman RS, et al. The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology. Clin Toxicol 2012; 50:403–413.

Fig. 1. Delphi method (2 rounds) for each recommendation.

Fig. 2. Flow diagram for literature search (November 15, 2014).

Table 5. Clinical data related to the 82 reported patients that received ECTR for VPA toxicity.*

Demographics	Average age (years)	27.9 (range: 0.2–62)
	% Male	36.5%
Poisoning exposure	Form
	Modified-release VPA	25.6%
	Regular-release VPA	74.4%
	Mean number of co-ingestants	0.6 (range: 0–6)
	Mean acute VPA ingestion (grams)	39.8 (range: 4–160)
	Mean VPA peak concentration (mg/L)	974.5 (range: 132–2493)
	Delay between acute exposure and admission (hours)	5.0 (1–24)
Symptoms and signs**	Decreased consciousness	96.3%
	Seizure(s)	11.0%
	Metabolic acidosis	28.0%
	Elevated lactate	23.2%
	Respiratory depression	65.9%
	Peak ammonia concentration (μmol/L)	319.4 (range: 30–1052)
	Cerebral edema	7.3%
	Thrombocytopenia	14.6%
	Hypotension	39.0%
	Hypernatremia	4.9%
Other treatments administered	AC	58.5%
	MDAC	11.0%
	Mechanical ventilation	62.2%
	L-carnitine	25.6%
	Vasopressors	23.2%
Extracorporeal treatments	Mean time from admission to ECTR initiation (hours)	13.3 (range: 2–48)
	Hemodialysis	45.1%
	Hemoperfusion	12.2%
	CRRT	14.6%
	Hemoperfusion–hemodialysis in series	7.3%
	Therapeutic plasma exchange	1.2%
	Liver support therapy	2.4%
	Other	3.7%
	More than 1 ECTR	10.9%
Outcome	Death	0%***

VPA, valproic acid; ECTR, extracorporeal treatments; AC, activated charcoal; MDAC, multiple-dose activated charcoal.

*These only include cases in which patient data could be extracted.

**Symptoms and other treatments were often underreported in case reports, so the real incidence is likely higher.

***2 deaths were reported in the cohort from Spiller et al, but there were none from reported cases.

Table 6. Kinetic aggregates of clearance and half-life for ECTR.

Type of ECTR	ECTR clearance (mL/min)			T1/2 (hours)
	Median	Range	N	Median	Range	N
Endogenous (therapeutic)	5–10			12
CRRT*	11.0	1.8–23.9	3	9.6	3.2–16.1	14
HD (therapeutic)	22.4	17.7–29.6	4	9.1	5–19.9	5
HD (overdose)	87.5	51.4–140	7	2.5	1.3–8.2	32
PD (therapeutic)	0.7		1	17.8	8.4–27.2	2
PD (overdose)				21.9		1
SLEDD-f				6.2		1
TPE (therapeutic)	18.3	17.1–19.4	2	3.2	2.1–4.2	2
LST	88.3		1	4.9		1
HD–HP	60.5	28.5–80.1	5	3.7	1.7–24.5	8
HDF	93.0		1	2.2	2.2–4.6	3
HP	29.2		1	3.4	0.7–9.2	9
HP–CRRT				3.9		1

PK, Pharmacokinetics; TK, Toxicokinetics; HD, Hemodialysis; CRRT, Continuous renal replacement therapy; HP, Hemoperfusion; TPE, Therapeutic plasma exchange; HP–HD, Hemoperfusion and hemodialysis in series; PD, Peritoneal dialysis; HDF, Intermittent hemodiafiltration; LST, Liver support therapy; SLEDD-f, Sustained low-efficiency daily dialysis and filtration; CAVH, continuous arterio-venous hemofiltration; CAVHD, continuous arterio-venous hemodialysis; CAVHDF, continuous arterio-venous hemodiafiltration; CVVH, continuous veno-venous hemofiltration; CVVHD, continuous veno-venous hemofiltration with dialysis; CVVHDF, continuous veno-venous hemodiafiltration.

*CRRT includes CAVH, CAVHD, CAVHDF, CVVH, CVVHD, and CVVHDF.

Table 7. Summary of the kinetic grading for individual patients.

GRADING	HD	CRRT*	HP	TPE	HP–HD	PD	HDF	LST	SLEDD-f
TK articles
D = Dialyzable	14	2	3		4		2	1
MD = Moderately dialyzable	9	4	2						1
SD = Slightly dialyzable	1	2	2		1
ND = Not dialyzable		3				1
PK articles
D = Dialyzable	2
MD = Moderately dialyzable	2			1		1
SD = Slightly dialyzable				1
ND = Not dialyzable					1	1

PK, Pharmacokinetics; TK, Toxicokinetics; HD, Hemodialysis; CRRT, Continuous renal replacement therapy; HP, Hemoperfusion; TPE, Therapeutic plasma exchange; HP–HD, Hemoperfusion and hemodialysis in series; PD, Peritoneal dialysis; HDF, Intermittent hemodiafiltration; LST, Liver support therapy; SLEDD-f, Sustained low-efficiency daily dialysis and filtration; CAVH, continuous arterio-venous hemofiltration; CAVHD, continuous arterio-venous hemodialysis; CAVHDF, continuous arterio-venous hemodiafiltration; CVVH, continuous veno-venous hemofiltration; CVVHD, continuous veno-venous hemofiltration with dialysis; CVVHDF, continuous veno-venous hemodiafiltration.

*CRRT includes CAVH, CAVHD, CAVHDF, CVVH, CVVHD, and CVVHDF.

Table 8. Executive summary of recommendations.

General Recommendation

ECTR is recommended in severe VPA poisoning (1D)

Indications

ECTR is recommended if any of the following is present:

If the [VPA] is > 1300 mg/L (9000 μmol/L) (1D)

If shock is present (1D)

If cerebral edema is present (1D)

ECTR is suggested if any of the following is present:

If the [VPA] is > 900 mg/L (6250 μmol/L) (2D)

If coma or respiratory depression requiring mechanical ventilation is present (2D)

If acute hyperammonemia is present (2D)

If pH is ≤ 7.10 (2D)

Cessation of ECTR is indicated if any of the following is present:

Clinical improvement is apparent (1D)

[VPA] is between 50 and 100 mg/L (350–700 μmol/L) (2D)

Choice of ECTR

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

If hemodialysis is not available, both intermittent hemoperfusion (1D) and CRRT (2D) are acceptable alternatives

VPA, valproic acid; ECTRs, extracorporeal treatments; CRRTs, continuous renal replacements therapies.