Scientific Letter
Renal replacement therapy in severe phenobarbital poisoning: Another brick in the wall
Diálisis extracorpórea en el caso de grave fenobarbital envenenamiento: otro ladrillo en la pared
a Service de Réanimation Médicale, AP-HP, Hôpitaux Universitaires Henri Mondor, DHU A-TVB, Créteil, France
b Groupe de recherche clinique CARMAS, Université Paris Est Créteil, Faculté de Médecine, Créteil, France
c Service d’Accueil des Urgences, AP-HP, Hôpitaux Universitaires Henri Mondor, DHU A-TVB, Créteil, France
d Service de Réanimation Chirurgicale Cardio Vasculaire, AP-HP, Hôpitaux Universitaires Henri Mondor, DHU A-TVB, Créteil, France
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"apellidos" => "de Prost" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Service de Réanimation Médicale, AP-HP, Hôpitaux Universitaires Henri Mondor, DHU A-TVB, Créteil, France" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Groupe de recherche clinique CARMAS, Université Paris Est Créteil, Faculté de Médecine, Créteil, France" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Service d’Accueil des Urgences, AP-HP, Hôpitaux Universitaires Henri Mondor, DHU A-TVB, Créteil, France" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Service de Réanimation Chirurgicale Cardio Vasculaire, AP-HP, Hôpitaux Universitaires Henri Mondor, DHU A-TVB, Créteil, France" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Diálisis extracorpórea en el caso de grave fenobarbital envenenamiento: otro ladrillo en la pared" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1324 "Ancho" => 1670 "Tamanyo" => 136537 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time course of phenobarbital plasma levels (left <span class="elsevierStyleItalic">y</span>-axis) and patient consciousness (Richmond Agitation-Sedation Scale, right <span class="elsevierStyleItalic">y</span>-axis). There was a dramatic decrease in phenobarbital plasma levels after two hemodialysis sessions, concomitant with neurological status improvement.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The prevalence of severe poisoning with sedatives or hypnotics has been increasing dramatically over the last years.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> In this setting, barbiturates remain one of the most common classes of drugs associated with fatal poisoning. The current report aims at illustrating the usefulness of renal replacement therapy with intermittent hemodialysis in the acute care of massive phenobarbital poisoning.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 56-year old woman was addressed to the intensive care unit (ICU) for a massive phenobarbital poisoning (assumed ingested dose: 5.5<span class="elsevierStyleHsp" style=""></span>g). The estimated maximum delay between phenobarbital ingestion and ICU admission was 6<span class="elsevierStyleHsp" style=""></span>hours. The patient presented with hypotension (77/44<span class="elsevierStyleHsp" style=""></span>mmHg), hypothermia (33<span class="elsevierStyleHsp" style=""></span>°<span class="elsevierStyleSmallCaps">C</span>) and altered mental status (Glasgow Coma Scale: 3) requiring endotracheal intubation, fluid loading with 1000<span class="elsevierStyleHsp" style=""></span>mL of saline and noradrenalin infusion up to 0.33<span class="elsevierStyleHsp" style=""></span>μg/kg/min before ICU admission. Her neurological examination revealed bilateral mydriasis with no pupillary response, together with the disappearance of other brainstem reflexes. A trans-thoracic echocardiography showed preserved left ventricle ejection fraction and cardiac output consistent with a vasoplegic shock. In spite of the profound coma and respiratory depression, there was no evidence for aspiration. The diagnosis of massive phenobarbital poisoning was confirmed by high barbiturate plasma levels measured upon admission (273<span class="elsevierStyleHsp" style=""></span>mg/L).</p><p id="par0015" class="elsevierStylePara elsevierViewall">Initial management of barbiturate poisoning included supportive care of organ failures (<span class="elsevierStyleItalic">i.e.</span>, mechanical ventilation and noradrenalin infusion), the administration of activated charcoal (a single 1<span class="elsevierStyleHsp" style=""></span>g/kg dose) so that to limit the enterohepatic recirculation of barbiturates, together with urinary alkalinization in an attempt to increase their urinary excretion. On day-1, hemodynamic improvement allowed for noradrenalin discontinuation. Yet, the neurological examination was no significantly improved (GCS: 3), except for a spontaneous breathing activity under mechanical ventilation. Multiple-dose activated charcoal (MDAC) was introduced on day-2, with no significant decrease in plasma phenobarbital levels or neurological improvement (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). On day-4, because the patient was still deeply comatose, renal replacement therapy (RRT) initiation was decided. Intermittent dialysis was performed using an Artis Physio™ dialysis system (Gambro AB, Meyzieu, France) with a Sureflux™-19E dialyzer (Nipro Europe, Saint Beauzire, France), achieving an estimated average creatinine clearance of 188<span class="elsevierStyleHsp" style=""></span>mL/min. A 4-hour session allowed for dramatically reducing plasma phenobarbital levels from 313 to 125<span class="elsevierStyleHsp" style=""></span>mg/L. The second dialysis session, performed on day-5, further reduced plasma levels from 129 to 47<span class="elsevierStyleHsp" style=""></span>mg/L (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patient awoke twenty-four hours after RRT initiation, as illustrated by an increase in the Richmond Agitation-Sedation Scale from −5 (patient unarousable) to 0 (patient alert and calm) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The clinical course was eventually favorable, allowing for the patient to be successfully extubated on day-7 and discharged to a psychiatric unit on day-10.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">We herein report a case of massive phenobarbital poisoning with a favorable course under intermittent hemodialysis. Medical interventions to enhance phenobarbital elimination (activated charcoal and urinary alkalinization) had failed to improve the neurological status of our patient. Also, this strategy did not significantly alter phenobarbital plasma levels. In a previous study, the administration of repeated doses of activated charcoal enhanced the elimination of barbiturates but had no clear effect on clinical outcome.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Furthermore, activated charcoal could hypothetically increase the risk of gastric impaction. This may partially explain the variation in serum concentrations during the initial course (between day-1 and day-4), as phenobarbital is a long-acting barbiturate. Regarding urinary alkalinization, there is to date no clinical evidence of a clinical benefit in barbiturate poisoning, despite its pharmacokinetic rationale.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the current case, RRT with intermittent hemodialysis dramatically improved the clearance of phenobarbital and, hence, neurological status improved concomitantly. Two 4-hour sessions were sufficient to achieve a dramatic reduction in phenobarbital levels. Hemodialysis was discontinued after neurological status improved, rather than targeting a specific concentration. All barbiturates are inducers of the hepatic cytochrome P450 and hepatic metabolism is the main component of their endogenous clearance. Barbiturates are thus classified according to their pharmacokinetic properties. Long-acting barbiturates (such as phenobarbital) have a smaller volume of distribution, which tends to limit post-dialysis rebound, and are less protein-bound and lipid soluble than short-acting barbiturates. Importantly, up to 20–25% of phenobarbital can be excreted as an active drug in urine. During dialysis, phenobarbital clearance has been shown to vary from 150 to 200<span class="elsevierStyleHsp" style=""></span>mL/min.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> For all these reasons, long-acting barbiturates are theoretically dialyzable. A few case studies have reported the effectiveness of both hemoperfusion<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,6</span></a> and hemodialysis<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">7,8</span></a> to enhance the clearance of barbiturates. Yet, these two techniques have not been evaluated and compared in randomized control trials. Hemoperfusion is not widely available and requires a specific training. As compared to hemoperfusion, hemodialysis has been shown to be associated with a lower risk of thrombocytopenia or hypocalcemia and seems less costly.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> The 2015 recommendations of the EXTRIP Workgroup suggest using intermittent hemodialysis to treat long-acting barbiturate poisoning in case of prolonged coma, shock (after initial fluid resuscitation), or persistence of toxicity despite MDAC.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">This case provides further support for the early initiation of renal replacement therapy in patients admitted for severe long-acting barbiturates poisoning, especially in those with prolonged coma and/or persistence of toxicity despite multiple-dose activated charcoal.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0035" class="elsevierStylePara elsevierViewall">This research received no specific grant from any funding agency, commercial or not-for-profit sectors.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interests</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interests" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1324 "Ancho" => 1670 "Tamanyo" => 136537 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time course of phenobarbital plasma levels (left <span class="elsevierStyleItalic">y</span>-axis) and patient consciousness (Richmond Agitation-Sedation Scale, right <span class="elsevierStyleItalic">y</span>-axis). There was a dramatic decrease in phenobarbital plasma levels after two hemodialysis sessions, concomitant with neurological status improvement.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33rd Annual Report" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J.B. Mowry" 1 => "D.A. Spyker" 2 => "D.E. Brooks" 3 => "A. Zimmerman" 4 => "J.L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 6 | 14 |
| 2024 October | 90 | 48 | 138 |
| 2024 September | 104 | 40 | 144 |
| 2024 August | 81 | 50 | 131 |
| 2024 July | 56 | 40 | 96 |
| 2024 June | 73 | 54 | 127 |
| 2024 May | 96 | 31 | 127 |
| 2024 April | 66 | 41 | 107 |
| 2024 March | 96 | 28 | 124 |
| 2024 February | 72 | 41 | 113 |
| 2024 January | 53 | 30 | 83 |
| 2023 December | 66 | 47 | 113 |
| 2023 November | 65 | 45 | 110 |
| 2023 October | 57 | 33 | 90 |
| 2023 September | 43 | 40 | 83 |
| 2023 August | 34 | 20 | 54 |
| 2023 July | 30 | 34 | 64 |
| 2023 June | 38 | 26 | 64 |
| 2023 May | 42 | 51 | 93 |
| 2023 April | 26 | 32 | 58 |
| 2023 March | 76 | 42 | 118 |
| 2023 February | 66 | 22 | 88 |
| 2023 January | 39 | 11 | 50 |
| 2022 December | 60 | 26 | 86 |
| 2022 November | 71 | 32 | 103 |
| 2022 October | 49 | 26 | 75 |
| 2022 September | 33 | 27 | 60 |
| 2022 August | 46 | 39 | 85 |
| 2022 July | 34 | 33 | 67 |
| 2022 June | 38 | 20 | 58 |
| 2022 May | 40 | 33 | 73 |
| 2022 April | 81 | 36 | 117 |
| 2022 March | 83 | 45 | 128 |
| 2022 February | 83 | 26 | 109 |
| 2022 January | 77 | 32 | 109 |
| 2021 December | 50 | 40 | 90 |
| 2021 November | 51 | 39 | 90 |
| 2021 October | 58 | 62 | 120 |
| 2021 September | 31 | 34 | 65 |
| 2021 August | 50 | 38 | 88 |
| 2021 July | 25 | 26 | 51 |
| 2021 June | 39 | 13 | 52 |
| 2021 May | 82 | 44 | 126 |
| 2021 April | 88 | 52 | 140 |
| 2021 March | 52 | 21 | 73 |
| 2021 February | 63 | 21 | 84 |
| 2021 January | 52 | 10 | 62 |
| 2020 December | 41 | 13 | 54 |
| 2020 November | 20 | 11 | 31 |
| 2020 October | 26 | 21 | 47 |
| 2020 July | 17 | 8 | 25 |
| 2020 June | 21 | 7 | 28 |
| 2020 May | 26 | 9 | 35 |
| 2020 April | 43 | 10 | 53 |
| 2020 March | 25 | 9 | 34 |
| 2020 February | 67 | 41 | 108 |
| 2020 January | 18 | 6 | 24 |
| 2019 November | 1 | 0 | 1 |
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