Extracorporeal Treatment for Barbiturate Poisoning

Recommendations From the EXTRIP Work Group

Robert Mactier, MD; Martin Laliberté, MD, MSc; Joelle Mardini, MD; Marc Ghannoum, MD; Valery Lavergne, MD, MSc; Sophie Gosselin, MD; Robert S. Hoffman, MD; Thomas D. Nolin, PharmD, PhD

Disclosures

Am J Kidney Dis. 2014;64(3):347-358.

Abstract and Introduction

Abstract

The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup conducted a systematic review of barbiturate poisoning using a standardized evidence-based process to provide recommendations on the use of extracorporeal treatment (ECTR) in patients with barbiturate poisoning. The authors reviewed all articles, extracted data, summarized key findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 617 articles met the search inclusion criteria. Data for 538 patients were abstracted and evaluated. Only case reports, case series, and nonrandomized observational studies were identified, yielding a low quality of evidence for all recommendations. Using established criteria, the workgroup deemed that long-acting barbiturates are dialyzable and short-acting barbiturates are moderately dialyzable. Four key recommendations were made. (1) The use of ECTR should be restricted to cases of severe long-acting barbiturate poisoning. (2) The indications for ECTR in this setting are the presence of prolonged coma, respiratory depression necessitating mechanical ventilation, shock, persistent toxicity, or increasing or persistently elevated serum barbiturate concentrations despite treatment with multiple-dose activated charcoal. (3) Intermittent hemodialysis is the preferred mode of ECTR, and multiple-dose activated charcoal treatment should be continued during ECTR. (4) Cessation of ECTR is indicated when clinical improvement is apparent. This report provides detailed descriptions of the rationale for all recommendations. In summary, patients with long-acting barbiturate poisoning should be treated with ECTR provided at least one of the specific criteria in the first recommendation is present.

Introduction

Barbiturates frequently are implicated in poisoning. In 2008, they were the 15th most common class of drugs associated with fatal poisoning in the United States,^[1] and barbiturate intoxication remains an important cause of morbidity and mortality today.^[2] Recognition of the low therapeutic index of barbiturates and the high historical incidence of fatal and nonfatal barbiturate poisoning has led to strict guidelines dictating barbiturate prescription, and these guidelines have contributed to the decreased availability of barbiturates worldwide. The barbiturate most frequently associated with self-poisoning is phenobarbital, although cases of severe poisoning and death from other barbiturates continue to be reported worldwide.^[2–21]

The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup (www.extrip-workgroup.org), comprising international experts representing diverse specialties and professional societies, was assembled to provide recommendations on the use of extracorporeal treatment (ECTR) in poisoning. The rationale, background, objectives, and methods of the Workgroup have been reported previously.^[22] We present recommendations on the use of ECTR in patients with barbiturate poisoning based on a systematic review of relevant literature using a standardized evidence-based process.

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The National Kidney Foundation

Published by Elsevier

Table 1. Physicochemical and Pharmacokinetic Properties of Barbiturates
	Long Acting	Short Acting
Representative barbiturate	Phenobarbital	Pentobarbital
Molecular weight (Da)	232	226
pKa	7.2	7.9
Volume of distribution (L/kg)	0.25–1.2	0.5–1.0
Protein binding (%)	20–60	35–70
Elimination half-life (h)	80–120	15–48
Duration of action (h)	6–12	3–4
Total endogenous clearance (mL/min)	5–12	18–39
Hepatic clearance (mL/min)	4–9	18–37
Renal clearance (mL/min)	1–3	0.2–2
MDAC clearance (mL/min)	84	NA
HD clearance (mL/min)	23–174	8–85
HP clearance (mL/min)	26–290	49–115
PD clearance (mL/min)	4–8	4–8
ET clearance (mL/min)	7	NA
Potentially fatal ingested dose (g)	>5	>3
Potentially fatal serum concentration (mg/L)	80	50

Note: Data from.^{16,25,26,105,135}
Abbreviations: ET, exchange transfusion; HD, intermittent hemodialysis; HP, hemoperfusion; MDAC, multiple dose activated charcoal; NA, not available; PD, peritoneal dialysis; pKa, logarithmic acid dissociation constant.

Table 2. Number of Articles, Patients, and Deaths Related to Barbiturate Poisoning, by ECTR Modality (1951–2013)
	1951–1970	1971–1990	1991–2013	Total
HD articles	33	15	10	58
Patients	165	106	58	329
Deaths	34	16	6	56
HP articles	0	36	4	40
Patients	0	167	4	171
Deaths	0	9	0	9
HD + HP articles	1	3	1	5
Patients	1	4	1	6
Deaths	0	0	0	0
HDF & CVVHDF articles	0	0	4	4
Patients	0	0	4	4
Deaths	0	0	1	1
PD articles^[a]	4	7	0	11
PD patients	4	13	0	17
PD + HP/HD patients	2	6	0	8
Deaths	2	1	0	3
TPE & ET articles	0	1	2	3
Patients	0	1	2	3
Deaths	0	0	0	0
Total number of articles^a	38	62	21	114^a
Total patients	172	297	69	538
Total deaths	36	26	7	69

Abbreviations: CVVHDF, continuous venovenous hemodiafiltration; ECTR, extracorporeal treatment; ET, exchange transfusion; HD, intermittent hemodialysis; HDF, intermittent hemodiafiltration; HP, hemoperfusion; PD, peritoneal dialysis; TPE, therapeutic plasma exchange.
^aSeven of 11 articles about PD reported multiple modalities, so were also included in previous HD, HP, or HD + HP categories, resulting in an overall total of 114 articles.

Table 3. Barbiturate Ingestion, Clinical Presentation, Serum Barbiturate Concentrations, and Outcomes in Individual Case Reports of Barbiturate Poisoning in the Modern ECTR Era (1991–2013)
ECTR Modality	Study	Barbiturate Ingested(dose, if reported)	Main Clinical Features	C_p(mg/L)	Post-ECTR C_p(mg/L)	Died(Y/N)
HD	Morikawa et al⁶ (1992)	Pheno	Coma	88	39	N
HD	Soylemezoglu et al⁷ (1993)	Pheno	Coma	120	64	N
HD	Quan & Winter⁸ (1998)	Pheno	Coma	223	130, 87^a	N
HD	Palmer⁹ (2000)	Pheno	Coma	147	53	N
HD	Jacobs & Brivet¹⁰ (2004)	Pheno	Coma	180	80, 46^a	N
HD	Thompson & Aks¹² (2007)	Pheno	Coma	152	90	N
HD	Hoyland et al²¹ (2013)	Pheno	Coma	115	84, 55^a	N
HP	Kamijo et al¹³ (2002)	Amobarb (15 g)	Hyperthermia	87	38	N
HP	Bouma et al¹⁴ (2004)	Pheno	Coma	112	55, 30^a	N
HP	Lin & Jeng⁹⁴ (1994)	Pheno	Coma	80	3.4	N
HP + MDAC	Roberts et al¹⁹ (2011)	Pheno (6 g)	Coma	95	50	N
HD + HP	Morikawa et al⁶ (1992)	Pheno	Respiratory arrest	76	13	N
HDF	van de Plas et al¹⁷ (2006)	Pheno	Coma	120	30	N
CVVHDF	Lal et al¹¹ (2006)	Pheno (4.8 g)	Coma + AKI	106	41	N
CVVHDF	Bironneau et al¹⁸ (1996)	Pento (20 g)	Coma + AKI	198	65	Y
CVVHDF	Roberts & Buckley¹⁶ (2011)	Pento (6.5 g)	Coma	60	NA	N
ET	Wehner et al⁹³ (1991)	Pheno (0.3 g)	Coma	117	68	N
ET	Sancak et al⁹⁵ (1999)	Pheno (0.2 g)	Coma	112	51	N

Abbreviations: AKI, acute kidney injury; amobarb, amobarbital; C_p, peak serum concentration; CVVHDF, continuous venovenous hemodiafiltration; ECTR, extracorporeal treatment; ET, exchange transfusion; HD, intermittent hemodialysis; HDF, intermittent hemodiafiltration; HP, hemoperfusion; MDAC, multiple-dose activated charcoal; NA, not available; pento, pentobarbital; pheno, phenobarbital.
^aValues correspond to concentrations after first and second ECTR sessions, respectively.

Box 1. Strength of Recommendation and Level of Evidence Scaling on Clinical Outcomes
Strength of recommendation (consensus based)
Level 1 = Strong recommendation. (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. (The course of action is considered appropriate by the majority of experts but some degree of dissension exists among the panel. The desirable effects of adherence to the recommendation probably outweigh the undesirable effects.)
Level 3 = Neutral position. (The course of action could be considered appropriate in the right context.)
No recommendation = No agreement was reached by the group of experts.
Level of evidence (based on the GRADE system)
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)

Abbreviation: GRADE, Grading of Recommendations Assessment, Development, and Evaluation.

Box 2. Executive Summary of Recommendations
General Statement Regarding Suitability of ECTR
ECTR is recommended in severe long-acting barbiturate poisoning. (1D)
Indications for ECTR
If prolonged coma is present or expected (1D) If shock is present after fluid resuscitation (1D) If, despite MDAC treatment, toxicity persists (1D) If, despite MDAC treatment, serum barbiturate concentration rises or remains elevated (2D) If respiratory depression necessitating mechanical ventilation is present (2D)
Choice of ECTR
Intermittent HD is the preferred mode of ECTR of severe barbiturate poisoning (1D) HP (1D) or CRRT (3D) are acceptable alternative modalities in adults if HD is not available
Cessation of ECTR
Cessation of ECTR is indicated when clinical improvement is apparent (1D)

Note: Level 1 recommendations are considered strong and level 2 recommendations as weak; level 3 is considered a neutral position. Grades of evidence are based on quality of evidence, with A, B, C, and D corresponding to high, moderate, low, and very low quality of evidence, respectively. MDAC should be continued during ECTR (1D). Abbreviations: CRRT, continuous renal replacement therapy; ECTR, extracorporeal treatment; HD, hemodialysis; HP, hemoperfusion; MDAC, multiple-dose activated charcoal.