Advertisement
American Journal of Kidney Diseases

Extracorporeal Treatment for Barbiturate Poisoning: Recommendations From the EXTRIP Workgroup

      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.

      Index Words

      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,
      • Bronstein A.C.
      • Spyker D.A.
      • Cantilena Jr., L.R.
      • Green J.L.
      • Rumack B.H.
      • Giffin S.L.
      2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report.
      and barbiturate intoxication remains an important cause of morbidity and mortality today.
      • Mowry J.B.
      • Spyker D.A.
      • Cantilena Jr., L.R.
      • Bailey J.E.
      • Ford M.
      2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report.
      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.
      • Mowry J.B.
      • Spyker D.A.
      • Cantilena Jr., L.R.
      • Bailey J.E.
      • Ford M.
      2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report.
      • Botti P.
      • Garcia P.
      • Dannaoui B.
      • Ieri A.
      • Pistelli A.
      Hemodialysis vs forced alkaline diuresis in acute barbiturate poisoning [abstract].
      • Cantrell F.L.
      • Nordt S.
      • McIntyre I.
      • Schneir A.
      Death on the doorstep of a border community—intentional self-poisoning with veterinary pentobarbital.
      • Srinivas S.
      • Karanth S.
      • Nayyar V.
      Does it matter how we treat phenobarbitone overdose of moderate severity?.
      • Morikawa N.
      • Mori K.
      • Fujii I.
      • Takeyama M.
      Pharmacokinetic study in acute antiepileptic intoxication treated with hemodialysis and hemoperfusion [in Japanese].
      • Soylemezoglu O.
      • Bakkaloglu A.
      • Yigit S.
      • Saatci U.
      Haemodialysis treatment in phenobarbital intoxication in infancy.
      • Quan D.J.
      • Winter M.E.
      Extracorporeal removal of phenobarbital by high-flux hemodialysis.
      • Palmer B.F.
      Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.
      • Jacobs F.
      • Brivet F.G.
      Conventional haemodialysis significantly lowers toxic levels of phenobarbital.
      • Lal R.
      • Faiz S.
      • Garg R.K.
      • Baweja K.S.
      • Guntupalli J.
      • Finkel K.W.
      Use of continuous venovenous hemodiafiltration in a case of severe phenobarbital poisoning.
      • Thompson T.M.
      • Aks S.E.
      Case files of the toxikon medical toxicology fellowship in Chicago: the poisoned anesthesiologist.
      • Kamijo Y.
      • Soma K.
      • Kondo R.
      • Ohwada T.
      Transient diffuse cerebral hypoperfusion in Tc-99m HMPAO SPECT of the brain during withdrawal syndrome following acute barbiturate poisoning.
      • Bouma A.W.
      • van Dam B.
      • Meynaar I.A.
      • Peltenburg H.G.
      • Walenbergh-van Veen M.C.
      Accelerated elimination using hemoperfusion in a patient with phenobarbital intoxication [in Dutch].
      • Lin J.L.
      • Lim P.S.
      Continuous arteriovenous hemoperfusion in acute poisoning.
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      • van de Plas A.
      • Stolk L.
      • Verhoeven M.A.
      • Kooman J.P.
      • van Mook W.N.
      Successful treatment of acute phenobarbital intoxication by hemodiafiltration.
      • Bironneau E.
      • Garrec F.
      • Kergueris M.F.
      • Testa A.
      • Nicolas F.
      Hemodiafiltration in pentobarbital poisoning.
      • Roberts D.M.
      • Chau A.M.
      • Nair P.
      • Day R.O.
      Enhanced elimination of phenobarbital using charcoal haemoperfusion in a patient with severe poisoning.
      • Agarwal S.K.
      • Tiwari S.C.
      • Dash S.C.
      Spectrum of poisoning requiring haemodialysis in a tertiary care hospital in India.

      Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose [published online ahead of print November 21, 2013]. BMJ Case Rep. http://dx.doi.org/10.1136/bcr-2013-010011.

      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.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
      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.

      Pharmacokinetics of Barbiturates

      All barbiturates are derivatives of barbituric acid and are classified according to their pharmacokinetic properties into long-acting and short-acting agents (consisting of ultrashort-, short-, and intermediate-acting agents).
      • Mihic S.
      • Harris R.
      Chapter 17. Hypnotics and sedatives.
      Each barbiturate has a unique structure that relates to its effective duration of action. Short-acting barbiturates are more protein bound and lipid soluble than their long-acting counterparts; have a more rapid onset, higher pKa (logarithmic acid dissociation constant), and shorter duration of action; and are metabolized nearly exclusively in the liver.
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      • Mihic S.
      • Harris R.
      Chapter 17. Hypnotics and sedatives.
      • Doenicke A.
      General pharmacology of barbiturates. Duration of action, metabolism, physicochemical factors.
      • Bruni J.
      • Albright P.S.
      The clinical pharmacology of antiepileptic drugs.
      • Breimer D.D.
      Clinical pharmacokinetics of hypnotics.
      Conversely, long-acting barbiturates accumulate less extensively in tissue (ie, their volume of distribution is smaller), are less lipid soluble, and are excreted as active drugs by the kidneys more readily. For example, the long-acting agent phenobarbital is a weak acid and approximately 20%-25% is excreted unchanged in urine, whereas <5% of pentobarbital is excreted unchanged.
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      • Doenicke A.
      General pharmacology of barbiturates. Duration of action, metabolism, physicochemical factors.
      Consequently, long-acting agents are more amenable to enhanced removal using urinary alkalinization; historically, forced alkaline diuresis was used in cases of moderate phenobarbital poisoning. Table 1 summarizes physicochemical and pharmacokinetic data for barbiturates.
      Table 1Physicochemical and Pharmacokinetic Properties of Barbiturates
      Long ActingShort Acting
      Representative barbituratePhenobarbitalPentobarbital
      Molecular weight (Da)232226
      pKa7.27.9
      Volume of distribution (L/kg)0.25-1.20.5-1.0
      Protein binding (%)20-6035-70
      Elimination half-life (h)80-12015-48
      Duration of action (h)6-123-4
      Total endogenous clearance (mL/min)5-1218-39
       Hepatic clearance (mL/min)4-918-37
       Renal clearance (mL/min)1-30.2-2
      MDAC clearance (mL/min)84NA
      HD clearance (mL/min)23-1748-85
      HP clearance (mL/min)26-29049-115
      PD clearance (mL/min)4-84-8
      ET clearance (mL/min)7NA
      Potentially fatal ingested dose (g)>5>3
      Potentially fatal serum concentration (mg/L)8050
      Note: Data from.
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      • Bruni J.
      • Albright P.S.
      The clinical pharmacology of antiepileptic drugs.
      • Breimer D.D.
      Clinical pharmacokinetics of hypnotics.
      • Setter J.G.
      • Maher J.F.
      • Schreiner G.E.
      Barbiturate intoxication. Evaluation of therapy including dialysis in a large series selectively referred because of severity.
      • Sagraves R.
      • Bradberry J.C.
      The effects of exchange transfusion on the pharmacokinetics of phenobarbital.
      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.
      Hepatic metabolism is the main route of endogenous clearance of all barbiturates. They are well-known inducers of the hepatic cytochrome P450 (CYP) enzyme system and thus increase the metabolic clearance of medications that are CYP substrates.
      • Mihic S.
      • Harris R.
      Chapter 17. Hypnotics and sedatives.
      Barbiturates undergo CYP-mediated metabolism and exhibit autoinduction, which leads long-term users to develop tolerance. Although tolerance to the sedative-hypnotic effects of barbiturates develops, tolerance to the serum drug concentration associated with lethal toxicity (ie, respiratory failure) does not appear to develop. Thus, long-term users tolerate a higher dose but not a higher serum concentration before being at risk of lethal toxicity and will be at greater risk of drug withdrawal if concentrations are reduced rapidly using ECTR.
      • Mihic S.
      • Harris R.
      Chapter 17. Hypnotics and sedatives.
      • Barbiturates Sampson I.
      When barbiturates are combined with other central nervous system (CNS) depressants, such as alcohol, opiates, or benzodiazepines, overdose is even more dangerous due to additive depressant effects on the CNS and respiratory system.

      Overview of Barbiturate Poisoning

      In the United States, United Kingdom, and most other developed countries, intermediate-acting barbiturates such as butobarbital, secobarbital, and amobarbital are no longer licensed for use and can be prescribed only to patients who already take these drugs for intractable insomnia. Pentobarbital is used clinically as well as in veterinary practice and thus may be acquired and used for intentional poisoning.
      • Cantrell F.L.
      • Nordt S.
      • McIntyre I.
      • Schneir A.
      Death on the doorstep of a border community—intentional self-poisoning with veterinary pentobarbital.
      Therefore, the current recommendations focus on only barbiturates that are licensed for use at this time and use phenobarbital and pentobarbital as the representative barbiturates for long- and short-acting agents, respectively.
      Comprehensive clinical assessment is necessary when considering whether patients have a severe enough overdose to warrant ECTR. In particular, it is essential to evaluate the severity of barbiturate poisoning objectively, based primarily on its toxic effects observed in the CNS, pulmonary, and cardiovascular systems.
      • Setter J.G.
      • Freeman R.B.
      • Maher J.F.
      • Schreiner G.E.
      Factors influencing the dialysis of barbiturates.
      • CNS effects. Barbiturates mainly act in the CNS, though they may affect other organ systems indirectly. Direct effects include sedation and hypnosis at lower dosages. Symptoms of a moderate overdose typically include sluggishness, lack of coordination, slow speech, faulty judgment, and drowsiness. Shallow respiration and coma occur in severe poisoning.
        • Setter J.G.
        • Freeman R.B.
        • Maher J.F.
        • Schreiner G.E.
        Factors influencing the dialysis of barbiturates.
      • Pulmonary effects. Barbiturates suppress the medullary respiratory center to induce respiratory depression. Patients with underlying chronic obstructive pulmonary disease are more susceptible to respiratory depression even at doses that would be considered therapeutic in healthy individuals. Death from barbiturate overdose often is due to aspiration pneumonia caused by respiratory depression.
        • Ferguson M.J.
        • Grace W.J.
        The conservative management of barbiturate intoxication: experience with 95 unconscious patients.
        • Schreiner G.E.
        • Teehan B.P.
        Dialysis of poisons and drugs—annual review.
      • Cardiovascular effects. Cardiovascular depression is possible after medullary vasomotor centers are depressed. Individuals with congestive heart failure are more vulnerable to cardiovascular effects. Cardiac vascular tone and contractility are compromised at higher doses. This may cause hypotension and can decrease the effectiveness of ECTR by reducing cardiac output.
      Evaluating the severity of barbiturate overdose objectively requires quantifying the serum barbiturate concentration (particularly phenobarbital). A simultaneous urine drug screen and blood ethanol concentration might confirm the presence of co-ingested drugs, which could influence the clinical assessment of the patient. Serum concentrations confirm the diagnosis of poisoning and help determine whether to institute ECTR, but are not reliable in predicting the duration or severity of toxicity.
      • Setter J.G.
      • Freeman R.B.
      • Maher J.F.
      • Schreiner G.E.
      Factors influencing the dialysis of barbiturates.
      The therapeutic range for anticonvulsant activity of phenobarbital is 10-25 mg/L. Serum concentrations > 50 mg/L may induce coma and concentrations > 80 mg/L may be fatal.
      • Mowry J.B.
      • Spyker D.A.
      • Cantilena Jr., L.R.
      • Bailey J.E.
      • Ford M.
      2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report.
      Optimal supportive care is mandatory in all cases of barbiturate poisoning. In general, interventions to enhance elimination should provide substantially greater elimination than endogenous mechanisms alone to be considered effective and must produce clinical benefit to justify the costs and potential risks of the intervention.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
      The use of multiple-dose activated charcoal (MDAC) may enhance the elimination of barbiturates,
      • Boldy D.A.
      • Vale J.A.
      • Prescott L.F.
      Treatment of phenobarbitone poisoning with repeated oral administration of activated charcoal.
      • Mohammed Ebid A.H.
      • Abdel-Rahman H.M.
      Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose.
      • Pond S.M.
      • Olson K.R.
      • Osterloh J.D.
      • Tong T.G.
      Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal.
      but only limited improvement in clinical outcome has been reported.
      • Mohammed Ebid A.H.
      • Abdel-Rahman H.M.
      Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose.
      Gastric emptying appears to decrease in the setting of barbiturate toxicity,
      • Holzer P.
      • Beubler E.
      • Dirnhofer R.
      Barbiturate poisoning and gastrointestinal propulsion.
      so patients may be at increased risk of impaction and gut perforation with the use of MDAC, as well as being at higher risk of aspiration. MDAC (15-20 g taken orally every 6 hours) should be administered only after the airway is protected and hemodynamic stabilization has been addressed. Urinary alkalinization is no longer recommended as first-line treatment in cases of barbiturate poisoning because it does not increase renal clearance significantly and MDAC is considered superior.
      • Mohammed Ebid A.H.
      • Abdel-Rahman H.M.
      Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose.
      • Proudfoot A.T.
      • Krenzelok E.P.
      • Vale J.A.
      Position paper on urine alkalinization.
      • Frenia M.L.
      • Schauben J.L.
      • Wears R.L.
      • Karlix J.L.
      • Tucker C.A.
      • Kunisaki T.A.
      Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination.

      Methodology for EXTRIP Evaluation

      The EXTRIP evaluation methodology is described in detail elsewhere
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
      and was evaluated and validated during the preparation of recommendations for the use of ECTR in severe thallium poisoning.
      • Ghannoum M.
      • Nolin T.D.
      • Goldfarb D.S.
      • et al.
      Extracorporeal treatment for thallium poisoning: recommendations from the EXTRIP Workgroup.
      The process is summarized briefly next.
      A literature search of the different forms of ECTR used in barbiturate poisoning during 1951-2013 was performed. Articles were obtained initially by the preliminary search database. Thereafter, a specific search, last accessed on January 18, 2014, retrieved other articles from MEDLINE, EMBASE, the Cochrane Library (Review and Central), conference proceedings, meeting abstracts, and Google Scholar. The bibliographies of all articles were manually reviewed. The search strategy was as follows: (barbiturate OR barbit OR phenobarb* OR pentobarbit* OR secobarbital OR quinalbarbitone OR amobarbital OR amylobarbitone OR butabarbital) AND (toxicity OR poison* OR intoxication OR overdose) AND (hemoperfusion OR haemoperfusion OR hemofiltration OR haemofiltration OR hemodialysis OR haemodialysis OR hemodiafiltration OR haemodiafiltration OR dialysis OR plasmapheresis OR plasma exchange OR exchange transfusion OR CRRT OR renal replacement therapy OR extracorporeal therapy).
      The group members completed the literature search, reviewed articles, extracted data, summarized findings, and proposed structured voting statements using a predetermined format. All non–English language publications were translated into English for extraction of clinical data. The level of evidence for clinical recommendations (Box 1) and dialyzability were determined using established criteria.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
      The strength of these recommendations was evaluated by a 2-round modified Delphi method for each proposed voting statement, and the RAND/UCLA Appropriateness Method was used to quantify disagreement between voters, as reported previously.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
      Blinded votes were compiled, returned, and discussed during a conference. The same representatives from the list of participating societies (Item S1) performed a second vote after the conference. Then, recommendations were graded as previously described.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
      The results of the voting and grading process led to the statements that are reported here as the EXTRIP recommendations.
      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.

      Results of the Literature Search

      Study Selection

      A total of 617 articles were identified. After screening for eligibility criteria, 114 articles that comprised 74 case reports
      • Morikawa N.
      • Mori K.
      • Fujii I.
      • Takeyama M.
      Pharmacokinetic study in acute antiepileptic intoxication treated with hemodialysis and hemoperfusion [in Japanese].
      • Soylemezoglu O.
      • Bakkaloglu A.
      • Yigit S.
      • Saatci U.
      Haemodialysis treatment in phenobarbital intoxication in infancy.
      • Quan D.J.
      • Winter M.E.
      Extracorporeal removal of phenobarbital by high-flux hemodialysis.
      • Palmer B.F.
      Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.
      • Jacobs F.
      • Brivet F.G.
      Conventional haemodialysis significantly lowers toxic levels of phenobarbital.
      • Lal R.
      • Faiz S.
      • Garg R.K.
      • Baweja K.S.
      • Guntupalli J.
      • Finkel K.W.
      Use of continuous venovenous hemodiafiltration in a case of severe phenobarbital poisoning.
      • Thompson T.M.
      • Aks S.E.
      Case files of the toxikon medical toxicology fellowship in Chicago: the poisoned anesthesiologist.
      • Kamijo Y.
      • Soma K.
      • Kondo R.
      • Ohwada T.
      Transient diffuse cerebral hypoperfusion in Tc-99m HMPAO SPECT of the brain during withdrawal syndrome following acute barbiturate poisoning.
      • Bouma A.W.
      • van Dam B.
      • Meynaar I.A.
      • Peltenburg H.G.
      • Walenbergh-van Veen M.C.
      Accelerated elimination using hemoperfusion in a patient with phenobarbital intoxication [in Dutch].
      • van de Plas A.
      • Stolk L.
      • Verhoeven M.A.
      • Kooman J.P.
      • van Mook W.N.
      Successful treatment of acute phenobarbital intoxication by hemodiafiltration.
      • Bironneau E.
      • Garrec F.
      • Kergueris M.F.
      • Testa A.
      • Nicolas F.
      Hemodiafiltration in pentobarbital poisoning.
      • Roberts D.M.
      • Chau A.M.
      • Nair P.
      • Day R.O.
      Enhanced elimination of phenobarbital using charcoal haemoperfusion in a patient with severe poisoning.

      Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose [published online ahead of print November 21, 2013]. BMJ Case Rep. http://dx.doi.org/10.1136/bcr-2013-010011.

      • Alwall N.
      • Lunderquist A.
      On the artificial kidney XXV. Dialytic treatment of severe barbiturate poisoning in two patients.
      • Kyle L.H.
      • Jeghers H.
      • Walsh W.P.
      • Doolan P.D.
      • Wishinsky H.
      • Pallotta A.
      The application of hemodialysis to the treatment of barbiturate poisoning.
      • Brown I.A.
      • Ansell J.S.
      • Schiele B.C.
      The use of hemodialysis in the treatment of barbiturate intoxication.
      • Gal G.
      • Nemeth A.
      • Pinter I.
      Hemodialysis in the therapy of severe barbiturate poisoning [in Hungarian].
      • Pender J.C.
      • Beebe R.T.
      • Garrett J.J.
      • Kiley J.E.
      Emergency treatment of barbiturate intoxication with hemodialysis.
      • Balme R.H.
      • Lloyd-Thomas H.G.
      • Shead G.V.
      Severe barbitone poisoning treated by haemodialysis.
      • Maher J.F.
      Hemodialysis and peritoneal dialysis; a review of their use in renal insufficiency and acute poisoning.
      • Duerr F.
      • Glogner P.
      Osmotic diuresis, alkalotherapy and extracorporeal hemodialysis in the treatment of severe intoxication with hypnotics [in German].
      • Fritzer W.
      • Puxkandl H.
      • Ratzenboeck W.
      Hemodialysis in the treatment of severe acute poisoning with sedatives [in German].
      • Mullan D.
      • Platts M.
      • Ridgway B.
      Barbiturate intoxication [letter].
      • Pogglitsch H.
      • Zeichen R.
      On the use of extracorporeal hemodialysis in acute hypnotic poisoning [in German].
      • Whiting Jr., E.G.
      • Barrett Jr., O.
      • Inmon T.W.
      Treatment of barbiturate poisoning. The use of peritoneal dialysis.
      • Herms W.
      Therapeutic possibilities of exogenous poisoning with extracorporeal hemodialysis [in German].
      • Terplan M.
      • Unger A.M.
      Survival following massive barbiturate ingestion.
      • Wieth J.O.
      Hemodialysis in barbiturate poisoning.
      • Cruz I.A.
      • Cramer N.C.
      • Parrish A.E.
      Hemodialysis in chlordiazepoxide toxicity.
      • Rosland G.A.
      Hemodialysis in acute barbiturate poisoning [in Norwegian].
      • Bird T.D.
      • Plum F.
      Recovery from barbiturate overdose coma with a prolonged isoelectric electroencephalogram.
      • Susa S.
      • Popovic E.P.
      • Dumovic B.
      Successful treatment of babiturate coma by hemodialysis [in Serbian].
      • Hudson J.B.
      • Dennis Jr., A.J.
      • Hobbs D.R.
      • Sussman H.C.
      Extended hemodialysis in short acting barbiturate poisoning: case report.
      • Logi G.
      • Baldari G.
      • Rossi M.
      • Fontana E.
      Extracorporeal dialysis in resuscitation in acute optalidon poisoning [in Italian].
      • Rosenbaum J.L.
      • Winsten S.
      • Kramuer M.S.
      • Moros J.
      • Raja R.
      Resin hemoperfusion in the treatment of drug intoxication.
      • Whang R.
      • Orndorff M.
      • Papper S.
      Lipid-electrolyte (“lipo-lyte”) dialysis—experimental and preliminary clinical observations.
      • Falda Z.
      • Polec R.
      • Madalinska M.
      Tardyl poisoning treated with extracorporeal hemodialysis using rape-oil seed [in Polish].
      • Mantz J.M.
      • Tempe J.D.
      • Jaeger A.
      • Kurtz D.
      • Lobstein A.
      • Mack G.
      24-Hour cerebral electric silence during a massive poisoning with 10g of pentobarbital. Hemodialysis cure [in French].
      • Hurwich B.J.
      • Goldstein M.
      • Levi Y.
      • Herishanu Y.
      Successful 44-hour hemodialysis for multiple drug intoxication.
      • Sorensen E.
      • Baerentsen H.
      Dialysis treatment of barbiturate poisoning [in Danish].
      • Bosl R.
      • Shideman J.R.
      • Meyer R.M.
      • Buselmeier T.J.
      • von Hartitzsch B.
      • Kjellstrand C.M.
      Effects and complications of high efficiency dialysis.
      • Puka J.
      • Szajewski J.M.
      Case of exceptionally severe luminal poisoning (over 25 g) successfully treated with hemodialysis and forced diuresis [in Polish].
      • Larcan A.
      • Lambert H.
      • Ginsbourger F.
      Acute intoxication by phenformine hyperlactatemia reversible with extra-renal purification.
      • Zawada Jr., E.T.
      • Nappi J.
      • Done G.
      • Rollins D.
      Advances in the hemodialysis management of phenobarbital overdose.
      • Durakovic Z.
      • Plavsic F.
      Use of hemodialysis in the treatment of phenobarbitone and phenytoin poisoning [in Croatian].
      • Bismuth C.
      • Gaultier M.
      • Conso F.
      • Assan R.
      • Heuclin C.
      Lactic acidosis induced by excessive ingestion of metformin [in French].
      • Musson V.J.
      Nursing care study: haemoperfusion in the treatment of severe barbiturate poisoning.
      • Rosenbaum J.L.
      • Kramer M.S.
      • Raja R.
      • Winsten S.
      • Dalal F.
      Hemoperfusion for acute drug intoxication.
      • Voigtmann R.
      • von Baeyer H.
      • Sieberth H.G.
      Charcoal-activated hemoperfusion—an important adjunct therapeutic method in severe poisoning [in German].
      • Arriagada Tapia S.
      • Martinez del Rio G.
      • Llorente Herbach J.
      Barbiturate coma treated with peritoneal dialysis [in Spanish].
      • Jorgensen K.A.
      • Christensen K.N.
      • Pedersen R.S.
      • Klitgaard N.A.
      Hemoperfusion in deliberate drug poisoning. Review and 2 case reports [in Danish].
      • Knutsen K.M.
      • Skuterud B.
      • Halvorsen S.
      Hemoperfusion in poisoning [in Norwegian].
      • van Dijk B.
      • Vonk C.R.
      • Dijkhuis I.C.
      Detoxification of toxic agents from the blood. Clinical results with a new hemoperfusion system: the Hemopur 260 [in Dutch].
      • Garcia Perez J.J.
      • Mendez Perez M.L.
      • Redondo Rodriguez M.
      • et al.
      Treatment of acute drug poisoning with hemoperfusion through active coal and dialysis [in Spanish].
      • Helliwell M.
      Severe barbiturate and paracetamol overdose: the simultaneous removal of both poisons by haemoperfusion.
      • Trafford A.
      • Horn C.
      • Sharpstone P.
      • O'Neal H.
      • Evans R.
      Hemoperfusion in acute drug toxicity.
      • Ciliberto G.
      • Corticelli A.S.
      • Di Nino G.F.
      • Rossi R.
      • Petrini F.
      Clinical use of hemoperfusion over activated charcoal in cases of drug poisoning [in Italian].
      • Bambauer R.
      • Jutzler G.A.
      • Stolz D.
      • Doenecke P.
      Detoxication using a technically simplified plasma filtration system [in German].
      • Cohan S.L.
      • Winchester J.F.
      • Gelfand M.C.
      Treatment of intoxication with charcoal hemadsorption.
      • Pond S.
      • Jacob III, P.
      • Humphreys M.
      • Weiss R.
      • Tong T.
      Impaired metabolism of methylphenobarbital after a combined drug overdose: treatment by resin hemoperfusion.
      • Raper S.
      • Crome P.
      • Vale A.
      • Helliwell M.
      • Widdop B.
      Experience with activated carbon-bead haemoperfusion columns in the treatment of severe drug intoxication. A preliminary report.
      • Bjaeldager P.A.
      • Friberg L.
      • Kampmann J.P.
      • Christensen M.S.
      • Jensen K.
      Hemoperfusion in severe barbiturate poisoning [in Danish].
      • van Heijst A.N.
      • de Jong W.
      • Seldenrijk R.
      • van Dijk A.
      Coma and crystalluria: a massive primidone intoxication treated with haemoperfusion.
      • Barber K.
      • Chen S.M.
      • Ferguson R.
      • Kramer M.S.
      • Raja R.M.
      Lidocaine removal during resin hemoperfusion for phenobarbital intoxication.
      • Pach J.
      • Groszek B.
      • Brandys J.
      • Negrusz A.
      Use of hemoperfusion in the treatment of acute poisoning with the preparation Reladorm [in Polish].
      • Smolle K.H.
      • Kullnig P.
      • Logar C.
      • Udermann H.
      Clinical assessment and therapy of barbiturate poisoning (based on 2 case reports) [in German].
      • Bentley C.
      • Kjellstrand C.M.
      The treatment of severe drug intoxication with charcoal hemoperfusion in series with hemodialysis.
      • Kirchmair W.
      Hemoperfusion and hemodialysis in severe poisoning with hypnotic drugs [in German].
      • Wehner J.
      • Arand J.
      • Todt H.
      • Richter K.
      Phenobarbital poisoning in a eutrophic term newborn infant. A case report [in German].
      • Lin J.L.
      • Jeng L.B.
      Critical, acutely poisoned patients treated with continuous arteriovenous hemoperfusion in the emergency department.
      • Sancak R.
      • Kucukoduk S.
      • Tasdemir H.A.
      • Belet N.
      Exchange transfusion treatment in a newborn with phenobarbital intoxication.
      (describing ≤2 patients) and 40 case series
      • Botti P.
      • Garcia P.
      • Dannaoui B.
      • Ieri A.
      • Pistelli A.
      Hemodialysis vs forced alkaline diuresis in acute barbiturate poisoning [abstract].
      • Srinivas S.
      • Karanth S.
      • Nayyar V.
      Does it matter how we treat phenobarbitone overdose of moderate severity?.
      • Agarwal S.K.
      • Tiwari S.C.
      • Dash S.C.
      Spectrum of poisoning requiring haemodialysis in a tertiary care hospital in India.
      • Berman L.B.
      • Jeghers H.J.
      • Schreiner G.E.
      • Pallotta A.J.
      Hemodialysis, an effective therapy for acute barbiturate poisoning.
      • Schreiner G.E.
      The role of hemodialysis (artificial kidney) in acute poisoning.
      • Landmann J.
      • Ribeiro R.M.
      • Bedran Y.
      • Vianna T.
      • Gentile A.
      Treatment of acute barbiturate poisoning: dialysis by artificial kidney [in Portuguese].
      • Del Greco F.
      • Arieff A.J.
      • Simon N.M.
      Acute barbiturate and glutethimide intoxication. Management by hemodialysis and peritoneal dialysis.
      • Kessel M.
      • Ibe K.
      • Neuhaus G.
      • Remmer H.
      • Weller H.
      Extracorporeal dialysis of luminal [in German].
      • Lubash G.D.
      • Ferrari M.J.
      • Scherr L.
      • Rubin A.L.
      Sedative overdosage and the role of hemodialysis.
      • Klinkmann H.
      • Huebel A.
      • Roehring A.
      • Scharz F.
      • Tredt H.J.
      • Precht K.
      Hemodialysis in severe poisoning [in German].
      • Linton A.L.
      • Luke R.G.
      • Speirs I.
      • Kennedy A.C.
      Forced diuresis and haemodialysis in severe barbiturate intoxication.
      • Gal G.
      • Fazakas A.
      • Nemeth A.
      Dialysis in the treatment of barbiturate poisoning [in German].
      • Setter J.G.
      • Maher J.F.
      • Schreiner G.E.
      Barbiturate intoxication. Evaluation of therapy including dialysis in a large series selectively referred because of severity.
      • Kennedy A.C.
      • Briggs J.D.
      • Young N.
      • Lindsay R.M.
      • Luke R.G.
      • Campbell D.
      Successful treatment of three cases of very severe barbiturate poisoning.
      • Stein G.
      • Gerhardt W.
      Application of hemodialysis in exogenous poisoning [in German].
      • Premel-Cabic A.
      • Alquier P.
      • Bonhomme R.
      • Allain P.
      Study of barbiturate elimination during acute poisoning in man [in French].
      • von Baeyer H.
      • Kunst H.
      • Freiberg J.
      • Grosser K.D.
      • Sieberth H.G.
      Haemodialysis in intoxication with hypnotics [in German].
      • Sanz Guajardo A.
      • Montero Garcia A.
      • Aguado Matorras A.
      • Torre Carballada M.A.
      • Sanchez Sicilia L.
      Value of hemodialysis in the treatment of acute poisoning by barbiturates [in Spanish].
      • Pedersen R.S.
      Barbiturate poisoning treated with hemodialysis [in Danish].
      • Codina S.
      • Del Castillo R.
      • Bartolome J.
      • et al.
      Acute barbiturate poisoning and its treatment with hemodialysis [in Spanish].
      • Darnell A.
      • Garcia M.
      • Bergada E.
      • Revert L.
      Long-term hemodialysis in acute barbiturate intoxication [in Spanish].
      • Rosenbaum J.L.
      • Kramer M.S.
      • Raja R.
      • Boreyko C.
      Resin hemoperfusion: a new treatment for acute drug intoxication.
      • Vale J.A.
      • Rees A.J.
      • Widdop B.
      • Goulding R.
      Use of charcoal haemoperfusion in the management of severely poisoned patients.
      • Barbour B.H.
      • LaSette A.M.
      • Koffler A.
      Fixed-bed charcoal hemoperfusion for the treatment of drug overdose.
      • Grabensee B.
      • Konigshausen T.
      • Schnurr E.
      Treatment of severe hypnotic poisoning with extracorporeal haemoperfusion [in German].
      • Hennemann H.
      • Naujoks R.
      • Gattenlohner W.
      • et al.
      Charcoal haemoperfusion in the treatment of sleeping-drug intoxication [in German].
      • de Groot G.
      • Maes R.A.
      • van Heyst A.N.
      The use of haemoperfusion in the elimination of absorbed drug mixtures in acute intoxications.
      • Gelfand M.C.
      • Winchester J.F.
      • Knepshield J.H.
      • et al.
      Treatment of severe drug overdosage with charcoal hemoperfusion.
      • Janos L.
      • Peter O.
      • Lajos H.
      • Imre L.
      “Haemocol” hemoperfusion in the treatment of barbiturate poisoning [in Hungarian].
      • Koffler A.
      • Bernstein M.
      • LaSette A.
      • Massry S.G.
      Fixed-bed charcoal hemoperfusion. Treatment of drug overdose.
      • Trafford J.A.
      • Jones R.H.
      • Evans R.
      • Sharp P.
      • Sharpstone P.
      • Cook J.
      Haemoperfusion with R-004 Amberlite resin for treating acute poisoning.
      • de Groot G.
      • Maes R.A.
      • van Heijst A.N.
      An evaluation of the use of hemoperfusion in acute poisoning.
      • de Torrente A.
      • Rumack B.H.
      • Blair D.T.
      • Anderson R.J.
      Fixed-bed uncoated charcoal hemoperfusion in the treatment of intoxications: animal and patient studies.
      • Iversen B.M.
      • Willassen Y.
      • Bakke O.M.
      • Wallem G.
      Assessment of barbiturate removal by charcoal hemoperfusion in overdose cases.
      • Bismuth C.
      • Fournier P.E.
      Biological evaluation of hemoperfusion in acute poisoning.
      • Crome P.
      • Hampel G.
      • Widdop B.
      • Goulding R.
      Experience with cellulose acetate-coated activated charcoal haemoperfusion in the treatment of severe hypnotic drug intoxication.
      • Keusch-Beck M.
      • Keusch G.
      • Bammatter F.
      • Schiffl H.
      • Baumann P.C.
      • Binswanger U.
      Hemoperfusion with activated charcoal in the treatment of drug overdose. Clinical experiences with 20 patients [in German].
      • Bismuth C.
      • Fournier P.E.
      • Galliot M.
      Biological evaluation of hemoperfusion in acute poisoning.
      • Fantozzi R.
      • Martinelli F.
      • Masini E.
      • Sodi A.
      • Amaducci L.
      • Mannaioni P.
      Use of haemoperfusion with uncoated charcoal in the management of acute intoxications with barbiturate and salicylate.
      • Stein G.
      • Demme U.
      • Sperschneider H.
      • et al.
      Detoxication by hemoperfusion [in German].
      (describing ≥3 patients) were suitable for extraction of clinical data and thus included in the final analysis. We included only clinical studies of ECTR that reported patient survival or mortality outcomes; review articles, in vitro studies, and animal studies were excluded (Table 1).
      • Berman L.B.
      • Vogelsang P.
      Removal rates for barbiturates using two types of peritoneal dialysis.
      Results of the literature search, including the reason studies were excluded, are presented in Fig 1.
      Figure thumbnail gr1
      Figure 1Summary of literature search on use of extracorporeal treatment in barbiturate poisoning (1951-2013).

      Clinical Outcomes

      The clinical data were subdivided into 3 time periods that largely reflect the major eras of barbiturate poisoning and ECTR techniques during the 60-year search period (Table 2). An improvement in level of consciousness and reduction in duration of coma during ECTR was reported in the majority of cases published in 1951-2013 that involved hemodialysis (HD), hemodiafiltration (HDF), hemoperfusion, peritoneal dialysis (PD), exchange transfusion, therapeutic plasma exchange (TPE; plasmapheresis), and combinations of hemoperfusion and HD, although the improvement usually was delayed (>1 day) or absent in most cases of patients receiving PD, exchange transfusion, or TPE. There were 69 deaths in the 538 patients treated with ECTR (Table 2), indicating significant patient mortality in severe barbiturate poisoning even if patients received ECTR. These data also may indicate that ECTR was being reserved for use in patients at significant risk of death due to barbiturate poisoning. During the last 20 years, HD remained the most common mode of ECTR for barbiturate poisoning, and there were still 7 deaths in 67 patients despite the use of more modern ECTR techniques (Table 2).
      Table 2Number of Articles, Patients, and Deaths Related to Barbiturate Poisoning, by ECTR Modality (1951-2013)
      1951-19701971-19901991-2013Total
      HD articles33151058
       Patients16510658329
       Deaths3416656
      HP articles036440
       Patients01674171
       Deaths0909
      HD + HP articles1315
       Patients1416
       Deaths0000
      HDF & CVVHDF articles0044
       Patients0044
       Deaths0011
      PD articles
      Seven 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.
      47011
       PD patients413017
       PD + HP/HD patients2608
       Deaths2103
      TPE & ET articles0123
       Patients0123
       Deaths0000
      Total number of articles
      Seven 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.
      386221114
      Seven 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.
      Total patients17229769538
      Total deaths3626769
      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.
      a Seven 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.
      To date, there are no randomized controlled trials of ECTR in humans with barbiturate poisoning. Two randomized controlled trials and a single case series using MDAC in patients with serum phenobarbital concentrations > 100 mg/L documented enhanced elimination of phenobarbital with MDAC use, but did not demonstrate clinical benefit in patient outcomes.
      • Boldy D.A.
      • Vale J.A.
      • Prescott L.F.
      Treatment of phenobarbitone poisoning with repeated oral administration of activated charcoal.
      • Mohammed Ebid A.H.
      • Abdel-Rahman H.M.
      Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose.
      • Pond S.M.
      • Olson K.R.
      • Osterloh J.D.
      • Tong T.G.
      Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal.
      However, in a study in rats and dogs exposed to a lethal dose of sodium pentobarbital and then randomized to either charcoal hemoperfusion or an empty control circuit, the treated groups showed significantly decreased mortality rates: 58% to 14% in rats and 100% to 15% in dogs.
      • Hill J.B.
      • Palaia F.L.
      • McAdams J.L.
      • Palmer P.J.
      • Maret S.M.
      Efficacy of activated charcoal hemoperfusion in removing lethal doses of barbiturates and salicylate from the blood of rats and dogs.
      These data suggest that ECTR may be more beneficial than MDAC alone in barbiturate poisoning. Observational data also provide limited evidence of the benefit of ECTR over urinary alkalinization. Botti et al
      • Botti P.
      • Garcia P.
      • Dannaoui B.
      • Ieri A.
      • Pistelli A.
      Hemodialysis vs forced alkaline diuresis in acute barbiturate poisoning [abstract].
      assessed outcomes in an observational study of patients with a mean phenobarbital concentration of 116 mg/L. The mean duration of coma in 16 patients treated with HD was 12.2 hours with no deaths, whereas the mean duration of coma in 9 patients treated with urine alkalinization was 61.3 hours with one death. In the only other observational study of ECTR in barbiturate poisoning, Srinivas et al
      • Srinivas S.
      • Karanth S.
      • Nayyar V.
      Does it matter how we treat phenobarbitone overdose of moderate severity?.
      reported a median phenobarbital concentration of 83.4 mg/L in 9 patients treated with both urine alkalinization and HD with 2 deaths, compared to a median concentration of 75.5 mg/L and no death in 9 patients treated with urine alkalinization alone. This study is difficult to interpret because all participants had ingested “moderate” overdoses (ie, the phenobarbital ingested dose was <3 g) and it was limited by confounding by indication. Nevertheless, this study suggests that there is no benefit from treatment with HD in moderate phenobarbital overdoses.

      Dialyzability

      On the basis of the literature reviewed, the EXTRIP Workgroup concluded that it considered long-acting barbiturates dialyzable (level of evidence: B) and short-acting barbiturates moderately dialyzable (level of evidence: C).

      Rationale

      Predefined criteria were used to assess dialyzability.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
      The determination of barbituate dialyzability is supported by a large number of case reports over a period of 60 years during which the modalities and efficacy of ECTR changed considerably. Variability in reported clearance with HD and hemoperfusion most likely reflects variation in achieved blood and dialysate flow rates, choice of dialyzer or hemoperfusion device, and duration of ECTR. Most of the case reports used reasonable pharmacokinetic methods (ie, serial measurements, appropriate calculations in dialysate, and correct interpretation) but used older ECTR technology. Because there is a trend for reported clearance rates to improve over time, we restricted our assessment of dialyzability to data from the last 20 years to reflect the use of ECTR in the modern era. A summary of this evidence is provided in Table 3.
      • Morikawa N.
      • Mori K.
      • Fujii I.
      • Takeyama M.
      Pharmacokinetic study in acute antiepileptic intoxication treated with hemodialysis and hemoperfusion [in Japanese].
      • Soylemezoglu O.
      • Bakkaloglu A.
      • Yigit S.
      • Saatci U.
      Haemodialysis treatment in phenobarbital intoxication in infancy.
      • Quan D.J.
      • Winter M.E.
      Extracorporeal removal of phenobarbital by high-flux hemodialysis.
      • Palmer B.F.
      Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.
      • Jacobs F.
      • Brivet F.G.
      Conventional haemodialysis significantly lowers toxic levels of phenobarbital.
      • Lal R.
      • Faiz S.
      • Garg R.K.
      • Baweja K.S.
      • Guntupalli J.
      • Finkel K.W.
      Use of continuous venovenous hemodiafiltration in a case of severe phenobarbital poisoning.
      • Thompson T.M.
      • Aks S.E.
      Case files of the toxikon medical toxicology fellowship in Chicago: the poisoned anesthesiologist.
      • Kamijo Y.
      • Soma K.
      • Kondo R.
      • Ohwada T.
      Transient diffuse cerebral hypoperfusion in Tc-99m HMPAO SPECT of the brain during withdrawal syndrome following acute barbiturate poisoning.
      • Bouma A.W.
      • van Dam B.
      • Meynaar I.A.
      • Peltenburg H.G.
      • Walenbergh-van Veen M.C.
      Accelerated elimination using hemoperfusion in a patient with phenobarbital intoxication [in Dutch].
      • Lin J.L.
      • Lim P.S.
      Continuous arteriovenous hemoperfusion in acute poisoning.
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      • van de Plas A.
      • Stolk L.
      • Verhoeven M.A.
      • Kooman J.P.
      • van Mook W.N.
      Successful treatment of acute phenobarbital intoxication by hemodiafiltration.
      • Bironneau E.
      • Garrec F.
      • Kergueris M.F.
      • Testa A.
      • Nicolas F.
      Hemodiafiltration in pentobarbital poisoning.
      • Roberts D.M.
      • Chau A.M.
      • Nair P.
      • Day R.O.
      Enhanced elimination of phenobarbital using charcoal haemoperfusion in a patient with severe poisoning.
      Table 3Barbiturate Ingestion, Clinical Presentation, Serum Barbiturate Concentrations, and Outcomes in Individual Case Reports of Barbiturate Poisoning in the Modern ECTR Era (1991-2013)
      ECTR ModalityStudyBarbiturate Ingested(dose, if reported)Main Clinical FeaturesCp(mg/L)Post-ECTR Cp(mg/L)Died(Y/N)
      HDMorikawa et al
      • Morikawa N.
      • Mori K.
      • Fujii I.
      • Takeyama M.
      Pharmacokinetic study in acute antiepileptic intoxication treated with hemodialysis and hemoperfusion [in Japanese].
      (1992)
      PhenoComa8839N
      HDSoylemezoglu et al
      • Soylemezoglu O.
      • Bakkaloglu A.
      • Yigit S.
      • Saatci U.
      Haemodialysis treatment in phenobarbital intoxication in infancy.
      (1993)
      PhenoComa12064N
      HDQuan & Winter
      • Quan D.J.
      • Winter M.E.
      Extracorporeal removal of phenobarbital by high-flux hemodialysis.
      (1998)
      PhenoComa223130, 87
      Values correspond to concentrations after first and second ECTR sessions, respectively.
      N
      HDPalmer
      • Palmer B.F.
      Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.
      (2000)
      PhenoComa14753N
      HDJacobs & Brivet
      • Jacobs F.
      • Brivet F.G.
      Conventional haemodialysis significantly lowers toxic levels of phenobarbital.
      (2004)
      PhenoComa18080, 46
      Values correspond to concentrations after first and second ECTR sessions, respectively.
      N
      HDThompson & Aks
      • Thompson T.M.
      • Aks S.E.
      Case files of the toxikon medical toxicology fellowship in Chicago: the poisoned anesthesiologist.
      (2007)
      PhenoComa15290N
      HDHoyland et al

      Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose [published online ahead of print November 21, 2013]. BMJ Case Rep. http://dx.doi.org/10.1136/bcr-2013-010011.

      (2013)
      PhenoComa11584, 55
      Values correspond to concentrations after first and second ECTR sessions, respectively.
      N
      HPKamijo et al
      • Kamijo Y.
      • Soma K.
      • Kondo R.
      • Ohwada T.
      Transient diffuse cerebral hypoperfusion in Tc-99m HMPAO SPECT of the brain during withdrawal syndrome following acute barbiturate poisoning.
      (2002)
      Amobarb (15 g)Hyperthermia8738N
      HPBouma et al
      • Bouma A.W.
      • van Dam B.
      • Meynaar I.A.
      • Peltenburg H.G.
      • Walenbergh-van Veen M.C.
      Accelerated elimination using hemoperfusion in a patient with phenobarbital intoxication [in Dutch].
      (2004)
      PhenoComa11255, 30
      Values correspond to concentrations after first and second ECTR sessions, respectively.
      N
      HPLin & Jeng
      • Lin J.L.
      • Jeng L.B.
      Critical, acutely poisoned patients treated with continuous arteriovenous hemoperfusion in the emergency department.
      (1994)
      PhenoComa803.4N
      HP + MDACRoberts et al
      • Roberts D.M.
      • Chau A.M.
      • Nair P.
      • Day R.O.
      Enhanced elimination of phenobarbital using charcoal haemoperfusion in a patient with severe poisoning.
      (2011)
      Pheno (6 g)Coma9550N
      HD + HPMorikawa et al
      • Morikawa N.
      • Mori K.
      • Fujii I.
      • Takeyama M.
      Pharmacokinetic study in acute antiepileptic intoxication treated with hemodialysis and hemoperfusion [in Japanese].
      (1992)
      PhenoRespiratory arrest7613N
      HDFvan de Plas et al
      • van de Plas A.
      • Stolk L.
      • Verhoeven M.A.
      • Kooman J.P.
      • van Mook W.N.
      Successful treatment of acute phenobarbital intoxication by hemodiafiltration.
      (2006)
      PhenoComa12030N
      CVVHDFLal et al
      • Lal R.
      • Faiz S.
      • Garg R.K.
      • Baweja K.S.
      • Guntupalli J.
      • Finkel K.W.
      Use of continuous venovenous hemodiafiltration in a case of severe phenobarbital poisoning.
      (2006)
      Pheno (4.8 g)Coma + AKI10641N
      CVVHDFBironneau et al
      • Bironneau E.
      • Garrec F.
      • Kergueris M.F.
      • Testa A.
      • Nicolas F.
      Hemodiafiltration in pentobarbital poisoning.
      (1996)
      Pento (20 g)Coma + AKI19865Y
      CVVHDFRoberts & Buckley
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      (2011)
      Pento (6.5 g)Coma60NAN
      ETWehner et al
      • Wehner J.
      • Arand J.
      • Todt H.
      • Richter K.
      Phenobarbital poisoning in a eutrophic term newborn infant. A case report [in German].
      (1991)
      Pheno (0.3 g)Coma11768N
      ETSancak et al
      • Sancak R.
      • Kucukoduk S.
      • Tasdemir H.A.
      • Belet N.
      Exchange transfusion treatment in a newborn with phenobarbital intoxication.
      (1999)
      Pheno (0.2 g)Coma11251N
      Abbreviations: AKI, acute kidney injury; amobarb, amobarbital; Cp, 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.
      a Values correspond to concentrations after first and second ECTR sessions, respectively.
      The 3 case series of barbiturate poisonings treated with ECTR in the past 20 years provide no detailed pharmacokinetic or toxicokinetic data.
      • Botti P.
      • Garcia P.
      • Dannaoui B.
      • Ieri A.
      • Pistelli A.
      Hemodialysis vs forced alkaline diuresis in acute barbiturate poisoning [abstract].
      • Srinivas S.
      • Karanth S.
      • Nayyar V.
      Does it matter how we treat phenobarbitone overdose of moderate severity?.
      • Agarwal S.K.
      • Tiwari S.C.
      • Dash S.C.
      Spectrum of poisoning requiring haemodialysis in a tertiary care hospital in India.
      However, the largest series reported that 24 of the 30 patients were in a grade 4 coma before HD treatment was initiated; in these patients, 40% of the barbiturate was removed during a 4- to 6-hour HD session and 4 patients died despite 1 (n = 25) or 2 (n = 5) sessions of intermittent HD.
      • Agarwal S.K.
      • Tiwari S.C.
      • Dash S.C.
      Spectrum of poisoning requiring haemodialysis in a tertiary care hospital in India.
      Although PD was used in several patients, its measured barbiturate removal was always inferior to HD in a comparable time frame; in patients receiving multiple modalities, calculated clearance values in patients undergoing PD were several-fold lower than in those receiving hemoperfusion or HD, and rarely surpassed 10 mL/min.
      • Setter J.G.
      • Maher J.F.
      • Schreiner G.E.
      Barbiturate intoxication. Evaluation of therapy including dialysis in a large series selectively referred because of severity.
      • Trafford J.A.
      • Jones R.H.
      • Evans R.
      • Sharp P.
      • Sharpstone P.
      • Cook J.
      Haemoperfusion with R-004 Amberlite resin for treating acute poisoning.
      Exchange transfusion appeared to accelerate barbiturate elimination only marginally in 2 poisoned infants,
      • Wehner J.
      • Arand J.
      • Todt H.
      • Richter K.
      Phenobarbital poisoning in a eutrophic term newborn infant. A case report [in German].
      • Sancak R.
      • Kucukoduk S.
      • Tasdemir H.A.
      • Belet N.
      Exchange transfusion treatment in a newborn with phenobarbital intoxication.
      which is consistent with a pharmacokinetic study showing phenobarbital clearance to be 7 mL/min.
      • Sagraves R.
      • Bradberry J.C.
      The effects of exchange transfusion on the pharmacokinetics of phenobarbital.
      TPE has a mild effect on barbiturate clearance.
      • Sketris I.S.
      • Parker W.A.
      Verrier Jones J. Plasmapheresis: its effect on toxic agents and drugs.
      • Lai C.W.
      • Leppik I.E.
      • Jenkins D.C.
      • Sood P.
      Epilepsy, myasthenia gravis, and effect of plasmapheresis on antiepileptic drug concentrations.

      Long-Acting Barbiturates

      Evidence from the 1991-2013 literature indicates that long-acting barbiturates are dialyzable (level of evidence: B). In one report, high-flux HD resulted in phenobarbital clearance rates up to 188 mL/min (average, 174 mL/min) during a 4-hour dialysis session.
      • Palmer B.F.
      Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.
      The phenobarbital half-life during HD was 3.2 hours, compared with half-lives of 29 hours prior to dialysis (ratio, 0.11) and 57 hours after dialysis (0.06).
      • Palmer B.F.
      Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.
      A single hemoperfusion session (5 hours; Gambro Adsorba 30C cartridge; blood flow rate, 300 mL/min) successfully removed >30% of an ingested phenobarbital dose, with extracorporeal clearance as high as 163 mL/min.
      • Roberts D.M.
      • Chau A.M.
      • Nair P.
      • Day R.O.
      Enhanced elimination of phenobarbital using charcoal haemoperfusion in a patient with severe poisoning.
      Treatment with continuous arteriovenous hemoperfusion for 8 hours resulted in a phenobarbital clearance of 290 mL/min.
      • Lin J.L.
      • Lim P.S.
      Continuous arteriovenous hemoperfusion in acute poisoning.

      Short-Acting Barbiturates

      ECTR appears to be less effective in removing short-acting barbiturates than their long-acting counterparts. Urinary alkalinization does not enhance the clearance of short-acting agents, whereas extracorporeal techniques enhance their clearance only minimally because they have a larger volume of distribution and greater lipid solubility. Endogenous clearance in adults is 20-60 mL/min for most of this group of barbiturates and overlaps with ECTR clearance with HD, HDF, or hemoperfusion.
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      Continuous venovenous HDF (CVVHDF) treatment (AN69 filter; blood flow rate, 100-150 mL/min; dialysate flow rate, 16.6 mL/min; average ultrafiltration rate, 750 mL/h) for 48 hours leads to a median pentobarbital clearance of 7.6 mL/min during ECTR and ∼15% removal of the ingested dose.
      • Bironneau E.
      • Garrec F.
      • Kergueris M.F.
      • Testa A.
      • Nicolas F.
      Hemodiafiltration in pentobarbital poisoning.
      Similarly, extracorporeal pentobarbital clearance of 9.2 mL/min with CVVHDF (blood flow rate, 160 mL/min; dialysate flow rate, 25 mL/min) was reported recently.
      • Roberts D.M.
      • Buckley N.A.
      Enhanced elimination in acute barbiturate poisoning—a systematic review.
      On the basis of 15% removal, short-acting barbiturates appear to be moderately dialyzable (level of evidence: C).

      Recommendations

      An executive summary of the EXTRIP recommendations is provided in 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.

      General Statement Regarding Suitability of ECTR

      1: ECTR is recommended in severe long-acting barbiturate poisoning. (1D)

      Rationale

      Both HD and hemoperfusion enhance elimination of barbiturates significantly, but the clinical benefits relative to the potential procedure-related complications and cost are not established. This literature review identified no randomized controlled trials of any form of ECTR in patients with barbiturate poisoning; publications of ECTR with patient outcome data consisted mainly of 74 case reports (n = 87 patients) and 40 case series (n = 431 patients). The lack of control groups, presence of multiple confounders, heterogeneity of ECTR modality over more than 60 years, and publication bias complicate interpretation of the available data and its extrapolation into recommendations for ECTR.
      In evaluating the risks and benefits of ECTR in barbiturate poisoning, the EXTRIP Workgroup took the following issues into account: (1) without ECTR, death after severe barbiturate poisoning is commonly reported despite full supportive care
      • Mowry J.B.
      • Spyker D.A.
      • Cantilena Jr., L.R.
      • Bailey J.E.
      • Ford M.
      2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report.
      ; (2) there is no highly effective antidote or alternative therapeutic intervention to ECTR for barbiturate poisoning; (3) ECTR significantly enhances barbiturate removal compared to endogenous (renal and stool) elimination; (4) complications associated with ECTR in acute poisoning are infrequent, but occur; and (5) the cost of ECTR may be balanced by a reduction in duration of coma and treatment time in a critical care setting.
      Based on these arguments, the EXTRIP Workgroup reached a consensus that the balance of the risk-benefit ratio in severe barbiturate poisoning supports the use of ECTR in patients who are clinically assessed as being at high risk (as defined in Recommendation 2 below). Therefore, we recommend using ECTR in patients with clinical signs and symptoms of a severe barbiturate overdose to reduce the duration of coma and incidence of complications such as pneumonia, cardiorespiratory compromise, and kidney failure.
      The workgroup acknowledges that other interventions for enhancing the removal of barbiturates (eg, MDAC) should be used before and during ECTR. There have been 2 small randomized controlled trials of MDAC in phenobarbital poisoning,
      • Mohammed Ebid A.H.
      • Abdel-Rahman H.M.
      Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose.
      • Pond S.M.
      • Olson K.R.
      • Osterloh J.D.
      • Tong T.G.
      Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal.
      and the American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists (AACT/EAPCCT) position paper on MDAC recommends that it is a useful adjunctive therapy and should be used in all significant cases of phenobarbital poisoning.
      • Vale J.G.
      • Krenzelok E.P.
      • Barceloux V.D.
      Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.
      The combination of MDAC and ECTR should provide greater removal of the barbiturate body burden than either alone and may improve patient outcomes.

      Indications for ECTR

      2: ECTR is indicated to treat long-acting barbiturate poisoning when any of the following conditions are met:
      • Prolonged coma is present or expected (1D)
      • Shock is present after fluid resuscitation (1D)
      • Despite MDAC treatment, toxicity persists (1D)
      • Despite MDAC treatment, serum barbiturate concentration rises or remains elevated (2D)
      • Respiratory depression necessitating mechanical ventilation is present (2D)

      Rationale

      The indications for ECTR represent the workgroup’s consensus on the criteria that define a patient with severe life-threatening barbiturate overdose. Death from barbiturate poisoning is confined mainly to patients with prolonged coma with depression of autonomic control of respiratory and/or circulatory function and is more likely in patients with preexisting chronic lung disease. Therefore, the main indications to initiate ECTR are clinical signs and symptoms of severe poisoning that carry a poor prognosis and indicate either clinical deterioration or failure to improve with optimal medical therapy of poisoning. In such circumstances, ECTR can be justified despite a lack of evidence of benefit in randomized controlled studies because the prognosis without additional intervention likely is poor. The main reason for using ECTR in long-acting barbiturate poisoning is to reduce the duration and severity of complications.
      ECTR will have the most benefit if it is initiated as soon as technically possible once at least one of the indications above is present, ideally within 24 hours of barbiturate exposure. Avoiding prolonged coma in barbiturate poisoning should reduce the risks associated with immobilization and mechanical ventilation, as well as the secondary issue of reducing health care costs associated with prolonged hospitalizations, particularly in the critical care setting.
      While the EXTRIP Workgroup accepted the clinical indications of severe barbiturate poisoning outlined as criteria for initiating ECTR, we did not consider ingested dose and serum barbiturate concentrations to be reliable indicators of the need for ECTR. This stems from the fact that estimates of the ingested dose are often inaccurate, and there is uncertainty regarding what constitutes a potentially fatal dose or fatal serum drug concentration. This uncertainty is due at least in part to interpatient variability in the dose-effect relationship in barbiturates, which results from metabolism autoinduction and the acquired tolerance associated with long-term use.
      • Mihic S.
      • Harris R.
      Chapter 17. Hypnotics and sedatives.
      Nevertheless, establishing drug concentrations and estimations of ingested dose is useful in confirming the diagnosis and potential severity of poisoning and in supporting the use of ECTR if other indications are present. Furthermore, if a massive ingested dose or high serum concentrations are recorded, early referral to a unit capable of performing ECTR should be considered. Consequently, the EXTRIP Workgroup recommends that a decision to perform ECTR should not be based on ingested dose only (1D) and suggests that a decision to perform ECTR should not be based solely on the serum concentrations of a long-acting barbiturate (2D). That being said, it is unlikely that patients would exhibit one of the indications for ECTR unless concentrations were >100 mg/L.
      • Setter J.G.
      • Freeman R.B.
      • Maher J.F.
      • Schreiner G.E.
      Factors influencing the dialysis of barbiturates.
      No consensus was reached regarding ECTR use in short-acting barbiturate poisoning, likely because of the shorter duration of action and reduced dialyzability of this class of barbiturates.

      Choice of ECTR

      3.1: Intermittent HD is the preferred mode of ECTR of severe barbiturate poisoning. (1D)
      3.2: HP (1D) or CRRT (3D) are acceptable alternative modalities in adults if HD is not available.

      Rationale

      ECTRs such as HD and hemoperfusion may be performed in selected patients who are assessed as having life-threatening barbiturate poisoning. It is difficult to rank ECTR modalities in terms of efficacy in barbiturate poisoning, but based on changes in barbiturate elimination half-life during ECTR, HD is equivalent to hemoperfusion, both of which are superior to CVVH, which is in turn superior to PD. The recommendation for prioritizing HD over hemoperfusion is based on the considerations reported by Shannon.
      • Shannon M.W.
      Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication.
      HD removes electrolytes and water and replaces bicarbonate if the patient has co-existing kidney failure. Also, HD clearance rates remain relatively stable over time with no need to replace the dialyzer, whereas hemoperfusion columns need to be exchanged regularly to maintain clearance. HD is associated with less risk of thrombocytopenia or hypocalcemia and has lower heparin requirements than hemoperfusion. High-flux HD or HDF are predicted to provide better barbiturate clearances than historical reports. Hemoperfusion may not be available locally or there may be no prior experience with its use. HD is less costly than hemoperfusion, and hemoperfusion cartridges are not available in some countries.
      The case for the use of HD instead of continuous renal replacement therapy (CRRT) depends mainly on the fact that continuous techniques provide lower clearance rates due to lower dialysate and/or blood flow rates. The use of CRRT instead of HD or hemoperfusion will depend on whether either of the latter forms is available because many critical care units provide only continuous modalities. HD may not be a feasible option in neonates, and case reports have described both recovery and no recovery after the use of exchange transfusion to treat severe barbiturate poisoning in neonates.
      • Wehner J.
      • Arand J.
      • Todt H.
      • Richter K.
      Phenobarbital poisoning in a eutrophic term newborn infant. A case report [in German].
      • Sancak R.
      • Kucukoduk S.
      • Tasdemir H.A.
      • Belet N.
      Exchange transfusion treatment in a newborn with phenobarbital intoxication.
      When HD is used, it is important to check serum biochemistries after therapy to ensure that potential complications such as hypokalemia, hypophosphatemia, or alkalemia have not developed. PD and TPE should not be used to treat barbiturate poisoning because achievable clearances are low (Table 1).
      • Berman L.B.
      • Vogelsang P.
      Removal rates for barbiturates using two types of peritoneal dialysis.

      Cessation of ECTR

      4: Cessation of ECTR is indicated when clinical improvement is apparent. (1D)

      Rationale

      Cessation of ECTR should be based on clinical efficacy and response to barbiturate removal (ie, resolution of coma), rather than completing a specific duration of ECTR or reaching a specific drug concentration. This approach should ensure that ECTR is not discontinued before clinical benefit is observed and also reduce the risk of lowering drug concentrations too rapidly, which would increase the risk of withdrawal effects in long-term barbiturate users. Drug concentrations should be monitored in order to document the efficacy of drug removal rather than to determine the timing of ECTR cessation. This approach may not be applicable if the patient has taken a mixed overdose of other sedative drugs, especially drugs that are not removed effectively by ECTR, such as tricyclic antidepressants.

      Conclusions

      Optimal and full supportive care remains the mainstay of treatment in all cases of barbiturate poisoning. There is limited evidence to support the additional use of ECTR despite its use in severe cases of barbiturate poisoning for more than 60 years. Based on a risk-benefit assessment, modern ECTR techniques should be reserved for use in patients in whom one or more criteria of a life-threatening toxicity are present following an overdose of a long-acting barbiturate. ECTR should be initiated as soon as technically feasible after an indication is present. Intermittent HD is the preferred mode of ECTR of severe barbiturate poisoning, but intermittent hemoperfusion or continuous renal replacement modalities are valid alternatives if intermittent HD is not available.

      Acknowledgements

      The other members of the Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup are Kurt Anseeuw, Ashish Bhalla, Emmanuel A Burdmann, Diane Calello, Paul I. Dargan, Brian S. Decker, Tais Galvao, David S. Goldfarb, Lotte C. Hoegberg, David Juurlink, Jan T. Kielstein, Yi Li, Kathleen D. Liu, Robert MacLaren, Bruno Megarbane, James B. Mowry, Veronique Phan, Darren M. Roberts, Kevin M. Sowinski, Timothy J. Wiegand, James F. Winchester, and Christopher Yates.
      We acknowledge the tremendous work of our dedicated translators: Marcela Covica, Alexandra Angulo, Ania Gresziak, Samantha Challinor, Martine Blanchet, Gunel Alpman, Joshua Pepper, Lee Anderson, Andreas Betz, Tetsuya Yamada, Nathalie Eeckhout, Matthew Fisher, Ruth Morton, Denise Gemmellaro, Nadia Bracq, Olga Bogatova, Sana Ahmed, Christiane Frasca, Katalin Fenyvesi, Timothy Durgin, Helen Johnson, Martha Oswald, Ewa Brodziuk, David Young, Akiko Burns, Anna Lautzenheiser, Banumathy Sridharan, Charlotte Robert, Liliana Ionescu, Lucile Mckay, Vilma Etchart, Valentina Bartoli, Nathan Weatherdon, Marcia Neff, Margit Tischler, Sarah Michel, Simona Vairo, Mairi Arbuckle, Luc Ranger, Nerissa Lowe, AngelinaWhite, Salih Topal, John Hartmann, Karine Mardini, Mahala Bartle Mathiassen, Anant Vipat, Gregory Shapiro, Hannele Marttila, Kapka Lazorova; the important contribution from our librarians and secretarial aids: Marc Lamarre, David Soteros, Salih Topal, Henry Gaston; and the assistance of Osama Alshogran in data extraction. Brenda Gallant is gratefully acknowledged for meeting transcription and organizational assistance.
      Support: Funding for EXTRIP was obtained from industry in the form of unrestricted educational grants. These funds were used solely for expenses related to literature retrieval, translation of publications, and for reimbursement of conference calls and travel expenses for attendance at EXTRIP meetings. Current EXTRIP sponsors are Leo Pharma ($40,000), Janssen-Ortho ($15,000), Fresenius Canada ($15,000), Amgen Canada ($10,000), and Servier ($3,000). There was no industry input into scientific content, development, or publication of the recommendations. Furthermore, industry presence at meetings was not allowed, nor was industry awareness or comment on the recommendations accepted.
      Financial Disclosure: The authors declare that they have no other relevant financial interests.

      Supplementary Material

      References

        • Bronstein A.C.
        • Spyker D.A.
        • Cantilena Jr., L.R.
        • Green J.L.
        • Rumack B.H.
        • Giffin S.L.
        2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report.
        Clin Toxicol (Phila). 2009; 47: 911-1084
        • Mowry J.B.
        • Spyker D.A.
        • Cantilena Jr., L.R.
        • Bailey J.E.
        • Ford M.
        2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report.
        Clin Toxicol (Phila). 2013; 51: 949-1229
        • Botti P.
        • Garcia P.
        • Dannaoui B.
        • Ieri A.
        • Pistelli A.
        Hemodialysis vs forced alkaline diuresis in acute barbiturate poisoning [abstract].
        Clin Toxicol (Phila). 2004; 42: 518
        • Cantrell F.L.
        • Nordt S.
        • McIntyre I.
        • Schneir A.
        Death on the doorstep of a border community—intentional self-poisoning with veterinary pentobarbital.
        Clin Toxicol (Phila). 2010; 48: 849-850
        • Srinivas S.
        • Karanth S.
        • Nayyar V.
        Does it matter how we treat phenobarbitone overdose of moderate severity?.
        Indian J Crit Care Med. 2004; 8: 153-156
        • Morikawa N.
        • Mori K.
        • Fujii I.
        • Takeyama M.
        Pharmacokinetic study in acute antiepileptic intoxication treated with hemodialysis and hemoperfusion [in Japanese].
        Jpn J Clin Pharmacol Ther. 1992; 23: 469-474
        • Soylemezoglu O.
        • Bakkaloglu A.
        • Yigit S.
        • Saatci U.
        Haemodialysis treatment in phenobarbital intoxication in infancy.
        Int Urol Nephrol. 1993; 25: 111-113
        • Quan D.J.
        • Winter M.E.
        Extracorporeal removal of phenobarbital by high-flux hemodialysis.
        J Appl Ther Res. 1998; 2: 75-79
        • Palmer B.F.
        Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.
        Am J Kidney Dis. 2000; 36: 640-643
        • Jacobs F.
        • Brivet F.G.
        Conventional haemodialysis significantly lowers toxic levels of phenobarbital.
        Nephrol Dial Transplant. 2004; 19: 1663-1664
        • Lal R.
        • Faiz S.
        • Garg R.K.
        • Baweja K.S.
        • Guntupalli J.
        • Finkel K.W.
        Use of continuous venovenous hemodiafiltration in a case of severe phenobarbital poisoning.
        Am J Kidney Dis. 2006; 48: e13-e15
        • Thompson T.M.
        • Aks S.E.
        Case files of the toxikon medical toxicology fellowship in Chicago: the poisoned anesthesiologist.
        J Med Toxicol. 2007; 3: 31-36
        • Kamijo Y.
        • Soma K.
        • Kondo R.
        • Ohwada T.
        Transient diffuse cerebral hypoperfusion in Tc-99m HMPAO SPECT of the brain during withdrawal syndrome following acute barbiturate poisoning.
        Vet Human Toxicol. 2002; 44: 348-350
        • Bouma A.W.
        • van Dam B.
        • Meynaar I.A.
        • Peltenburg H.G.
        • Walenbergh-van Veen M.C.
        Accelerated elimination using hemoperfusion in a patient with phenobarbital intoxication [in Dutch].
        Ned Tijdschr Geneeskd. 2004; 148: 1642-1645
        • Lin J.L.
        • Lim P.S.
        Continuous arteriovenous hemoperfusion in acute poisoning.
        Blood Purif. 1994; 12: 121-127
        • Roberts D.M.
        • Buckley N.A.
        Enhanced elimination in acute barbiturate poisoning—a systematic review.
        Clin Toxicol (Phila). 2011; 49: 2-12
        • van de Plas A.
        • Stolk L.
        • Verhoeven M.A.
        • Kooman J.P.
        • van Mook W.N.
        Successful treatment of acute phenobarbital intoxication by hemodiafiltration.
        Clin Toxicol (Phila). 2006; 44: 93-94
        • Bironneau E.
        • Garrec F.
        • Kergueris M.F.
        • Testa A.
        • Nicolas F.
        Hemodiafiltration in pentobarbital poisoning.
        Ren Fail. 1996; 18: 299-303
        • Roberts D.M.
        • Chau A.M.
        • Nair P.
        • Day R.O.
        Enhanced elimination of phenobarbital using charcoal haemoperfusion in a patient with severe poisoning.
        Br J Anaesth. 2011; 107: 820-821
        • Agarwal S.K.
        • Tiwari S.C.
        • Dash S.C.
        Spectrum of poisoning requiring haemodialysis in a tertiary care hospital in India.
        Int J Artif Organs. 1993; 16: 20-22
      1. Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose [published online ahead of print November 21, 2013]. BMJ Case Rep. http://dx.doi.org/10.1136/bcr-2013-010011.

        • Lavergne V.
        • Nolin T.D.
        • Hoffman R.S.
        • et al.
        The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
        Clin Toxicol (Phila). 2012; 50: 403-413
        • Mihic S.
        • Harris R.
        Chapter 17. Hypnotics and sedatives.
        in: Brunton L.L. Chabner B.A. Knollmann B.C. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, New York, NY2011: 457-480
        • Doenicke A.
        General pharmacology of barbiturates. Duration of action, metabolism, physicochemical factors.
        Acta Anaesthesiol Scand Suppl. 1965; 17: 11-16
        • Bruni J.
        • Albright P.S.
        The clinical pharmacology of antiepileptic drugs.
        Clin Neuropharmacol. 1984; 7: 1-34
        • Breimer D.D.
        Clinical pharmacokinetics of hypnotics.
        Clin Pharmacokinet. 1977; 2: 93-109
        • Barbiturates Sampson I.
        Mt Sinai J Med. 1983; 50: 283-288
        • Setter J.G.
        • Freeman R.B.
        • Maher J.F.
        • Schreiner G.E.
        Factors influencing the dialysis of barbiturates.
        Trans Am Soc Artif Intern Organs. 1964; 10: 340-344
        • Ferguson M.J.
        • Grace W.J.
        The conservative management of barbiturate intoxication: experience with 95 unconscious patients.
        Ann Intern Med. 1961; 54: 726-733
        • Schreiner G.E.
        • Teehan B.P.
        Dialysis of poisons and drugs—annual review.
        Trans Am Soc Artif Intern Organs. 1971; 17: 513-544
        • Boldy D.A.
        • Vale J.A.
        • Prescott L.F.
        Treatment of phenobarbitone poisoning with repeated oral administration of activated charcoal.
        Q J Med. 1986; 61: 997-1002
        • Mohammed Ebid A.H.
        • Abdel-Rahman H.M.
        Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose.
        Ther Drug Monit. 2001; 23: 209-216
        • Pond S.M.
        • Olson K.R.
        • Osterloh J.D.
        • Tong T.G.
        Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal.
        JAMA. 1984; 251: 3104-3108
        • Holzer P.
        • Beubler E.
        • Dirnhofer R.
        Barbiturate poisoning and gastrointestinal propulsion.
        Arch Toxicol. 1987; 60: 394-396
        • Proudfoot A.T.
        • Krenzelok E.P.
        • Vale J.A.
        Position paper on urine alkalinization.
        J Toxicol Clin Toxicol. 2004; 42: 1-26
        • Frenia M.L.
        • Schauben J.L.
        • Wears R.L.
        • Karlix J.L.
        • Tucker C.A.
        • Kunisaki T.A.
        Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination.
        J Toxicol Clin Toxicol. 1996; 34: 169-175
        • Ghannoum M.
        • Nolin T.D.
        • Goldfarb D.S.
        • et al.
        Extracorporeal treatment for thallium poisoning: recommendations from the EXTRIP Workgroup.
        Clin J Am Soc Nephrol. 2012; 7: 1682-1690
        • Alwall N.
        • Lunderquist A.
        On the artificial kidney XXV. Dialytic treatment of severe barbiturate poisoning in two patients.
        Acta Med Scand. 1953; 147: 119-120
        • Kyle L.H.
        • Jeghers H.
        • Walsh W.P.
        • Doolan P.D.
        • Wishinsky H.
        • Pallotta A.
        The application of hemodialysis to the treatment of barbiturate poisoning.
        J Clin Invest. 1953; 32: 364-371
        • Brown I.A.
        • Ansell J.S.
        • Schiele B.C.
        The use of hemodialysis in the treatment of barbiturate intoxication.
        Minn Med. 1954; 37: 650-652
        • Gal G.
        • Nemeth A.
        • Pinter I.
        Hemodialysis in the therapy of severe barbiturate poisoning [in Hungarian].
        Orv Hetil. 1956; 97: 582
        • Pender J.C.
        • Beebe R.T.
        • Garrett J.J.
        • Kiley J.E.
        Emergency treatment of barbiturate intoxication with hemodialysis.
        Ann Intern Med. 1957; 46: 997-1000
        • Balme R.H.
        • Lloyd-Thomas H.G.
        • Shead G.V.
        Severe barbitone poisoning treated by haemodialysis.
        Br Med J. 1962; 1: 231-232
        • Maher J.F.
        Hemodialysis and peritoneal dialysis; a review of their use in renal insufficiency and acute poisoning.
        Ohio State Med J. 1964; 60: 235-243
        • Duerr F.
        • Glogner P.
        Osmotic diuresis, alkalotherapy and extracorporeal hemodialysis in the treatment of severe intoxication with hypnotics [in German].
        Med Welt. 1965; 15: 755-756
        • Fritzer W.
        • Puxkandl H.
        • Ratzenboeck W.
        Hemodialysis in the treatment of severe acute poisoning with sedatives [in German].
        Wien Z Inn Med. 1965; 46: 72-79
        • Mullan D.
        • Platts M.
        • Ridgway B.
        Barbiturate intoxication [letter].
        Lancet. 1965; 1: 705
        • Pogglitsch H.
        • Zeichen R.
        On the use of extracorporeal hemodialysis in acute hypnotic poisoning [in German].
        Wien Med Wochenschr. 1965; 115: 308-310
        • Whiting Jr., E.G.
        • Barrett Jr., O.
        • Inmon T.W.
        Treatment of barbiturate poisoning. The use of peritoneal dialysis.
        Calif Med. 1965; 102: 367-369
        • Herms W.
        Therapeutic possibilities of exogenous poisoning with extracorporeal hemodialysis [in German].
        Dtsch Med Wochenschr. 1966; 91: 2007-2013
        • Terplan M.
        • Unger A.M.
        Survival following massive barbiturate ingestion.
        JAMA. 1966; 198: 322-323
        • Wieth J.O.
        Hemodialysis in barbiturate poisoning.
        Int Anesthesiol Clin. 1966; 4: 359-371
        • Cruz I.A.
        • Cramer N.C.
        • Parrish A.E.
        Hemodialysis in chlordiazepoxide toxicity.
        JAMA. 1967; 202: 438-440
        • Rosland G.A.
        Hemodialysis in acute barbiturate poisoning [in Norwegian].
        Tidsskr Nor Laegeforen. 1967; 87: 20-21
        • Bird T.D.
        • Plum F.
        Recovery from barbiturate overdose coma with a prolonged isoelectric electroencephalogram.
        Neurology. 1968; 18: 456-460
        • Susa S.
        • Popovic E.P.
        • Dumovic B.
        Successful treatment of babiturate coma by hemodialysis [in Serbian].
        Vojnosanit Pregl. 1968; 25: 252-257
        • Hudson J.B.
        • Dennis Jr., A.J.
        • Hobbs D.R.
        • Sussman H.C.
        Extended hemodialysis in short acting barbiturate poisoning: case report.
        South Med J. 1969; 62: 457-460
        • Logi G.
        • Baldari G.
        • Rossi M.
        • Fontana E.
        Extracorporeal dialysis in resuscitation in acute optalidon poisoning [in Italian].
        Acta Anaesthesiol. 1969; 20: 39-48
        • Rosenbaum J.L.
        • Winsten S.
        • Kramuer M.S.
        • Moros J.
        • Raja R.
        Resin hemoperfusion in the treatment of drug intoxication.
        Trans Am Soc Artif Intern Organs. 1970; 16: 134-140
        • Whang R.
        • Orndorff M.
        • Papper S.
        Lipid-electrolyte (“lipo-lyte”) dialysis—experimental and preliminary clinical observations.
        Clin Toxicol. 1970; 3: 551-560
        • Falda Z.
        • Polec R.
        • Madalinska M.
        Tardyl poisoning treated with extracorporeal hemodialysis using rape-oil seed [in Polish].
        Pol Arch Med Wewn. 1971; 47: 167-171
        • Mantz J.M.
        • Tempe J.D.
        • Jaeger A.
        • Kurtz D.
        • Lobstein A.
        • Mack G.
        24-Hour cerebral electric silence during a massive poisoning with 10g of pentobarbital. Hemodialysis cure [in French].
        Presse Med. 1971; 79: 1243-1246
        • Hurwich B.J.
        • Goldstein M.
        • Levi Y.
        • Herishanu Y.
        Successful 44-hour hemodialysis for multiple drug intoxication.
        Isr J Med Sci. 1974; 10: 495-497
        • Sorensen E.
        • Baerentsen H.
        Dialysis treatment of barbiturate poisoning [in Danish].
        Ugeskr Laeger. 1974; 136: 1687
        • Bosl R.
        • Shideman J.R.
        • Meyer R.M.
        • Buselmeier T.J.
        • von Hartitzsch B.
        • Kjellstrand C.M.
        Effects and complications of high efficiency dialysis.
        Nephron. 1975; 15: 151-160
        • Puka J.
        • Szajewski J.M.
        Case of exceptionally severe luminal poisoning (over 25 g) successfully treated with hemodialysis and forced diuresis [in Polish].
        Pol Tyg Lek. 1975; 30: 1583-1585
        • Larcan A.
        • Lambert H.
        • Ginsbourger F.
        Acute intoxication by phenformine hyperlactatemia reversible with extra-renal purification.
        Vet Hum Toxicol. 1979; 21: 19-22
        • Zawada Jr., E.T.
        • Nappi J.
        • Done G.
        • Rollins D.
        Advances in the hemodialysis management of phenobarbital overdose.
        South Med J. 1983; 76: 6-8
        • Durakovic Z.
        • Plavsic F.
        Use of hemodialysis in the treatment of phenobarbitone and phenytoin poisoning [in Croatian].
        Arh Hig Rada Toksikol. 1986; 37: 59-66
        • Bismuth C.
        • Gaultier M.
        • Conso F.
        • Assan R.
        • Heuclin C.
        Lactic acidosis induced by excessive ingestion of metformin [in French].
        Eur J Toxicol Environ Hyg. 1976; 9: 55-57
        • Musson V.J.
        Nursing care study: haemoperfusion in the treatment of severe barbiturate poisoning.
        Nurs Times. 1976; 72: 1956-1958
        • Rosenbaum J.L.
        • Kramer M.S.
        • Raja R.
        • Winsten S.
        • Dalal F.
        Hemoperfusion for acute drug intoxication.
        Kidney Int Suppl. 1976; 10: S341-S342
        • Voigtmann R.
        • von Baeyer H.
        • Sieberth H.G.
        Charcoal-activated hemoperfusion—an important adjunct therapeutic method in severe poisoning [in German].
        Med Welt. 1976; 27: 752-757
        • Arriagada Tapia S.
        • Martinez del Rio G.
        • Llorente Herbach J.
        Barbiturate coma treated with peritoneal dialysis [in Spanish].
        Rev Chil Pediatr. 1978; 49: 175-177
        • Jorgensen K.A.
        • Christensen K.N.
        • Pedersen R.S.
        • Klitgaard N.A.
        Hemoperfusion in deliberate drug poisoning. Review and 2 case reports [in Danish].
        Ugeskr Laeger. 1978; 140: 960-963
        • Knutsen K.M.
        • Skuterud B.
        • Halvorsen S.
        Hemoperfusion in poisoning [in Norwegian].
        Tidsskr Nor Legeforen. 1979; 99: 172-174
        • van Dijk B.
        • Vonk C.R.
        • Dijkhuis I.C.
        Detoxification of toxic agents from the blood. Clinical results with a new hemoperfusion system: the Hemopur 260 [in Dutch].
        Tijdschr Ziekenverpl. 1979; 32: 728-736
        • Garcia Perez J.J.
        • Mendez Perez M.L.
        • Redondo Rodriguez M.
        • et al.
        Treatment of acute drug poisoning with hemoperfusion through active coal and dialysis [in Spanish].
        Rev Clin Esp. 1980; 156: 413-418
        • Helliwell M.
        Severe barbiturate and paracetamol overdose: the simultaneous removal of both poisons by haemoperfusion.
        Postgrad Med J. 1980; 56: 363-365
        • Trafford A.
        • Horn C.
        • Sharpstone P.
        • O'Neal H.
        • Evans R.
        Hemoperfusion in acute drug toxicity.
        Clin Toxicol. 1980; 17: 547-556
        • Ciliberto G.
        • Corticelli A.S.
        • Di Nino G.F.
        • Rossi R.
        • Petrini F.
        Clinical use of hemoperfusion over activated charcoal in cases of drug poisoning [in Italian].
        Riv Tossicol Sper Clin. 1982; 12: 161-173
        • Bambauer R.
        • Jutzler G.A.
        • Stolz D.
        • Doenecke P.
        Detoxication using a technically simplified plasma filtration system [in German].
        Intensivmed. 1982; 19: 79-82
        • Cohan S.L.
        • Winchester J.F.
        • Gelfand M.C.
        Treatment of intoxication with charcoal hemadsorption.
        Drug Metab Rev. 1982; 13: 681-693
        • Pond S.
        • Jacob III, P.
        • Humphreys M.
        • Weiss R.
        • Tong T.
        Impaired metabolism of methylphenobarbital after a combined drug overdose: treatment by resin hemoperfusion.
        J Toxicol Clin Toxicol. 1982; 19: 187-196
        • Raper S.
        • Crome P.
        • Vale A.
        • Helliwell M.
        • Widdop B.
        Experience with activated carbon-bead haemoperfusion columns in the treatment of severe drug intoxication. A preliminary report.
        Arch Toxicol. 1982; 49: 303-310
        • Bjaeldager P.A.
        • Friberg L.
        • Kampmann J.P.
        • Christensen M.S.
        • Jensen K.
        Hemoperfusion in severe barbiturate poisoning [in Danish].
        Ugeskr Laeger. 1983; 145: 3653-3655
        • van Heijst A.N.
        • de Jong W.
        • Seldenrijk R.
        • van Dijk A.
        Coma and crystalluria: a massive primidone intoxication treated with haemoperfusion.
        J Toxicol Clin Toxicol. 1983; 20: 307-318
        • Barber K.
        • Chen S.M.
        • Ferguson R.
        • Kramer M.S.
        • Raja R.M.
        Lidocaine removal during resin hemoperfusion for phenobarbital intoxication.
        Artif Organs. 1984; 8: 229-231
        • Pach J.
        • Groszek B.
        • Brandys J.
        • Negrusz A.
        Use of hemoperfusion in the treatment of acute poisoning with the preparation Reladorm [in Polish].
        Pol Tyg Lek. 1987; 42: 333-334
        • Smolle K.H.
        • Kullnig P.
        • Logar C.
        • Udermann H.
        Clinical assessment and therapy of barbiturate poisoning (based on 2 case reports) [in German].
        Wien Klin Wochenschr. 1987; 99: 793-798
        • Bentley C.
        • Kjellstrand C.M.
        The treatment of severe drug intoxication with charcoal hemoperfusion in series with hemodialysis.
        J Dial. 1979; 3: 337-348
        • Kirchmair W.
        Hemoperfusion and hemodialysis in severe poisoning with hypnotic drugs [in German].
        Munch Med Wschr. 1981; 123: 231-232
        • Wehner J.
        • Arand J.
        • Todt H.
        • Richter K.
        Phenobarbital poisoning in a eutrophic term newborn infant. A case report [in German].
        Kinderarztl Prax. 1991; 59: 31-34
        • Lin J.L.
        • Jeng L.B.
        Critical, acutely poisoned patients treated with continuous arteriovenous hemoperfusion in the emergency department.
        Ann Emerg Med. 1995; 25: 75-80
        • Sancak R.
        • Kucukoduk S.
        • Tasdemir H.A.
        • Belet N.
        Exchange transfusion treatment in a newborn with phenobarbital intoxication.
        Pediatr Emerg Care. 1999; 15: 268-270
        • Berman L.B.
        • Jeghers H.J.
        • Schreiner G.E.
        • Pallotta A.J.
        Hemodialysis, an effective therapy for acute barbiturate poisoning.
        JAMA. 1956; 161: 820-827
        • Schreiner G.E.
        The role of hemodialysis (artificial kidney) in acute poisoning.
        AMA Arch Intern Med. 1958; 102: 896-913
        • Landmann J.
        • Ribeiro R.M.
        • Bedran Y.
        • Vianna T.
        • Gentile A.
        Treatment of acute barbiturate poisoning: dialysis by artificial kidney [in Portuguese].
        Med Cir Farm. 1959; 21: 121-132
        • Del Greco F.
        • Arieff A.J.
        • Simon N.M.
        Acute barbiturate and glutethimide intoxication. Management by hemodialysis and peritoneal dialysis.
        Q Bull Northwest Univ Med Sch. 1962; 36: 306-315
        • Kessel M.
        • Ibe K.
        • Neuhaus G.
        • Remmer H.
        • Weller H.
        Extracorporeal dialysis of luminal [in German].
        Klin Wochenschr. 1962; 40: 580-585
        • Lubash G.D.
        • Ferrari M.J.
        • Scherr L.
        • Rubin A.L.
        Sedative overdosage and the role of hemodialysis.
        Arch Intern Med. 1962; 110: 884-887
        • Klinkmann H.
        • Huebel A.
        • Roehring A.
        • Scharz F.
        • Tredt H.J.
        • Precht K.
        Hemodialysis in severe poisoning [in German].
        Dtsch Gesundheitsw. 1964; 19: 60-66
        • Linton A.L.
        • Luke R.G.
        • Speirs I.
        • Kennedy A.C.
        Forced diuresis and haemodialysis in severe barbiturate intoxication.
        Lancet. 1964; 1: 1008-1010
        • Gal G.
        • Fazakas A.
        • Nemeth A.
        Dialysis in the treatment of barbiturate poisoning [in German].
        Z Gesamte Inn Med. 1965; 20: 304-307
        • Setter J.G.
        • Maher J.F.
        • Schreiner G.E.
        Barbiturate intoxication. Evaluation of therapy including dialysis in a large series selectively referred because of severity.
        Arch Intern Med. 1966; 117: 224-236
        • Kennedy A.C.
        • Briggs J.D.
        • Young N.
        • Lindsay R.M.
        • Luke R.G.
        • Campbell D.
        Successful treatment of three cases of very severe barbiturate poisoning.
        Lancet. 1969; 1: 995-998
        • Stein G.
        • Gerhardt W.
        Application of hemodialysis in exogenous poisoning [in German].
        Z Arztl Fortbild (Jena). 1971; 65: 296-301
        • Premel-Cabic A.
        • Alquier P.
        • Bonhomme R.
        • Allain P.
        Study of barbiturate elimination during acute poisoning in man [in French].
        Therapie. 1973; 28: 977-991
        • von Baeyer H.
        • Kunst H.
        • Freiberg J.
        • Grosser K.D.
        • Sieberth H.G.
        Haemodialysis in intoxication with hypnotics [in German].
        Dtsch Med Wochenschr. 1974; 99: 189-190
        • Sanz Guajardo A.
        • Montero Garcia A.
        • Aguado Matorras A.
        • Torre Carballada M.A.
        • Sanchez Sicilia L.
        Value of hemodialysis in the treatment of acute poisoning by barbiturates [in Spanish].
        Rev Clin Esp. 1975; 136: 147-152
        • Pedersen R.S.
        Barbiturate poisoning treated with hemodialysis [in Danish].
        Ugeskr Laeger. 1978; 140: 2430-2432
        • Codina S.
        • Del Castillo R.
        • Bartolome J.
        • et al.
        Acute barbiturate poisoning and its treatment with hemodialysis [in Spanish].
        Rev Clin Esp. 1979; 152: 25-26
        • Darnell A.
        • Garcia M.
        • Bergada E.
        • Revert L.
        Long-term hemodialysis in acute barbiturate intoxication [in Spanish].
        Med Clin (Barc). 1980; 75: 49-53
        • Rosenbaum J.L.
        • Kramer M.S.
        • Raja R.
        • Boreyko C.
        Resin hemoperfusion: a new treatment for acute drug intoxication.
        N Engl J Med. 1971; 284: 874-877
        • Vale J.A.
        • Rees A.J.
        • Widdop B.
        • Goulding R.
        Use of charcoal haemoperfusion in the management of severely poisoned patients.
        Br Med J. 1975; 1: 5-9
        • Barbour B.H.
        • LaSette A.M.
        • Koffler A.
        Fixed-bed charcoal hemoperfusion for the treatment of drug overdose.
        Kidney Int Suppl. 1976; 10: S333-S337
        • Grabensee B.
        • Konigshausen T.
        • Schnurr E.
        Treatment of severe hypnotic poisoning with extracorporeal haemoperfusion [in German].
        Dtsch Med Wochenschr. 1976; 101: 158-162
        • Hennemann H.
        • Naujoks R.
        • Gattenlohner W.
        • et al.
        Charcoal haemoperfusion in the treatment of sleeping-drug intoxication [in German].
        Dtsch Med Wochenschr. 1976; 101: 155-158
        • de Groot G.
        • Maes R.A.
        • van Heyst A.N.
        The use of haemoperfusion in the elimination of absorbed drug mixtures in acute intoxications.
        Neth J Med. 1977; 20: 142-148
        • Gelfand M.C.
        • Winchester J.F.
        • Knepshield J.H.
        • et al.
        Treatment of severe drug overdosage with charcoal hemoperfusion.
        Trans Am Soc Artif Intern Organs. 1977; 23: 599-605
        • Janos L.
        • Peter O.
        • Lajos H.
        • Imre L.
        “Haemocol” hemoperfusion in the treatment of barbiturate poisoning [in Hungarian].
        Orv Hetil. 1977; 118: 277-279
        • Koffler A.
        • Bernstein M.
        • LaSette A.
        • Massry S.G.
        Fixed-bed charcoal hemoperfusion. Treatment of drug overdose.
        Arch Intern Med. 1978; 138: 1691-1694
        • Trafford J.A.
        • Jones R.H.
        • Evans R.
        • Sharp P.
        • Sharpstone P.
        • Cook J.
        Haemoperfusion with R-004 Amberlite resin for treating acute poisoning.
        Br Med J. 1977; 2: 1453-1456
        • de Groot G.
        • Maes R.A.
        • van Heijst A.N.
        An evaluation of the use of hemoperfusion in acute poisoning.
        Vet Hum Toxicol. 1979; 21: 8-11
        • de Torrente A.
        • Rumack B.H.
        • Blair D.T.
        • Anderson R.J.
        Fixed-bed uncoated charcoal hemoperfusion in the treatment of intoxications: animal and patient studies.
        Nephron. 1979; 24: 71-77
        • Iversen B.M.
        • Willassen Y.
        • Bakke O.M.
        • Wallem G.
        Assessment of barbiturate removal by charcoal hemoperfusion in overdose cases.
        Clin Toxicol. 1979; 15: 139-149
        • Bismuth C.
        • Fournier P.E.
        Biological evaluation of hemoperfusion in acute poisoning.
        Dev Toxicol Environ Sci. 1980; 8: 377-385
        • Crome P.
        • Hampel G.
        • Widdop B.
        • Goulding R.
        Experience with cellulose acetate-coated activated charcoal haemoperfusion in the treatment of severe hypnotic drug intoxication.
        Postgrad Med J. 1980; 56: 763-766
        • Keusch-Beck M.
        • Keusch G.
        • Bammatter F.
        • Schiffl H.
        • Baumann P.C.
        • Binswanger U.
        Hemoperfusion with activated charcoal in the treatment of drug overdose. Clinical experiences with 20 patients [in German].
        Schweiz Med Wochenschr. 1980; 110: 1566-1575
        • Bismuth C.
        • Fournier P.E.
        • Galliot M.
        Biological evaluation of hemoperfusion in acute poisoning.
        Clin Toxicol. 1981; 18: 1213-1223
        • Fantozzi R.
        • Martinelli F.
        • Masini E.
        • Sodi A.
        • Amaducci L.
        • Mannaioni P.
        Use of haemoperfusion with uncoated charcoal in the management of acute intoxications with barbiturate and salicylate.
        Subst Alcohol Actions Misuse. 1981; 2: 55-62
        • Stein G.
        • Demme U.
        • Sperschneider H.
        • et al.
        Detoxication by hemoperfusion [in German].
        Z Gesamte Inn Med. 1981; 36: 963-969
        • Berman L.B.
        • Vogelsang P.
        Removal rates for barbiturates using two types of peritoneal dialysis.
        N Engl J Med. 1964; 270: 77-80
        • Hill J.B.
        • Palaia F.L.
        • McAdams J.L.
        • Palmer P.J.
        • Maret S.M.
        Efficacy of activated charcoal hemoperfusion in removing lethal doses of barbiturates and salicylate from the blood of rats and dogs.
        Clin Chem. 1976; 22: 754-760
        • Sagraves R.
        • Bradberry J.C.
        The effects of exchange transfusion on the pharmacokinetics of phenobarbital.
        Drug Intell Clin Pharm. 1983; 17: 901-903
        • Sketris I.S.
        • Parker W.A.
        Verrier Jones J. Plasmapheresis: its effect on toxic agents and drugs.
        Plasma Ther Transfus Technol. 1984; 5: 305-317
        • Lai C.W.
        • Leppik I.E.
        • Jenkins D.C.
        • Sood P.
        Epilepsy, myasthenia gravis, and effect of plasmapheresis on antiepileptic drug concentrations.
        Arch Neurol. 1990; 47: 66-68
        • Vale J.G.
        • Krenzelok E.P.
        • Barceloux V.D.
        Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.
        J Toxicol Clin Toxicol. 1999; 37: 731-751
        • Shannon M.W.
        Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication.
        Acad Emerg Med. 1997; 4: 674-678