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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time course of phenobarbital plasma levels &#40;left <span class="elsevierStyleItalic">y</span>-axis&#41; and patient consciousness &#40;Richmond Agitation-Sedation Scale&#44; right <span class="elsevierStyleItalic">y</span>-axis&#41;&#46; There was a dramatic decrease in phenobarbital plasma levels after two hemodialysis sessions&#44; concomitant with neurological status improvement&#46;</p>"
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The patient presented with hypotension &#40;77&#47;44<span class="elsevierStyleHsp" style=""></span>mmHg&#41;&#44; hypothermia &#40;33<span class="elsevierStyleHsp" style=""></span>&#176;<span class="elsevierStyleSmallCaps">C</span>&#41; and altered mental status &#40;Glasgow Coma Scale&#58; 3&#41; requiring endotracheal intubation&#44; fluid loading with 1000<span class="elsevierStyleHsp" style=""></span>mL of saline and noradrenalin infusion up to 0&#46;33<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#47;min before ICU admission&#46; Her neurological examination revealed bilateral mydriasis with no pupillary response&#44; together with the disappearance of other brainstem reflexes&#46; A trans-thoracic echocardiography showed preserved left ventricle ejection fraction and cardiac output consistent with a vasoplegic shock&#46; In spite of the profound coma and respiratory depression&#44; there was no evidence for aspiration&#46; The diagnosis of massive phenobarbital poisoning was confirmed by high barbiturate plasma levels measured upon admission &#40;273<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Initial management of barbiturate poisoning included supportive care of organ failures &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; mechanical ventilation and noradrenalin infusion&#41;&#44; the administration of activated charcoal &#40;a single 1<span class="elsevierStyleHsp" style=""></span>g&#47;kg dose&#41; so that to limit the enterohepatic recirculation of barbiturates&#44; together with urinary alkalinization in an attempt to increase their urinary excretion&#46; On day-1&#44; hemodynamic improvement allowed for noradrenalin discontinuation&#46; Yet&#44; the neurological examination was no significantly improved &#40;GCS&#58; 3&#41;&#44; except for a spontaneous breathing activity under mechanical ventilation&#46; Multiple-dose activated charcoal &#40;MDAC&#41; was introduced on day-2&#44; with no significant decrease in plasma phenobarbital levels or neurological improvement &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; On day-4&#44; because the patient was still deeply comatose&#44; renal replacement therapy &#40;RRT&#41; initiation was decided&#46; Intermittent dialysis was performed using an Artis Physio&#8482; dialysis system &#40;Gambro AB&#44; Meyzieu&#44; France&#41; with a Sureflux&#8482;-19E dialyzer &#40;Nipro Europe&#44; Saint Beauzire&#44; France&#41;&#44; achieving an estimated average creatinine clearance of 188<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; A 4-hour session allowed for dramatically reducing plasma phenobarbital levels from 313 to 125<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46; The second dialysis session&#44; performed on day-5&#44; further reduced plasma levels from 129 to 47<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The patient awoke twenty-four hours after RRT initiation&#44; as illustrated by an increase in the Richmond Agitation-Sedation Scale from &#8722;5 &#40;patient unarousable&#41; to 0 &#40;patient alert and calm&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The clinical course was eventually favorable&#44; allowing for the patient to be successfully extubated on day-7 and discharged to a psychiatric unit on day-10&#46;</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&#46; Medical interventions to enhance phenobarbital elimination &#40;activated charcoal and urinary alkalinization&#41; had failed to improve the neurological status of our patient&#46; Also&#44; this strategy did not significantly alter phenobarbital plasma levels&#46; In a previous study&#44; the administration of repeated doses of activated charcoal enhanced the elimination of barbiturates but had no clear effect on clinical outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Furthermore&#44; activated charcoal could hypothetically increase the risk of gastric impaction&#46; This may partially explain the variation in serum concentrations during the initial course &#40;between day-1 and day-4&#41;&#44; as phenobarbital is a long-acting barbiturate&#46; Regarding urinary alkalinization&#44; there is to date no clinical evidence of a clinical benefit in barbiturate poisoning&#44; despite its pharmacokinetic rationale&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the current case&#44; RRT with intermittent hemodialysis dramatically improved the clearance of phenobarbital and&#44; hence&#44; neurological status improved concomitantly&#46; Two 4-hour sessions were sufficient to achieve a dramatic reduction in phenobarbital levels&#46; Hemodialysis was discontinued after neurological status improved&#44; rather than targeting a specific concentration&#46; All barbiturates are inducers of the hepatic cytochrome P450 and hepatic metabolism is the main component of their endogenous clearance&#46; Barbiturates are thus classified according to their pharmacokinetic properties&#46; Long-acting barbiturates &#40;such as phenobarbital&#41; have a smaller volume of distribution&#44; which tends to limit post-dialysis rebound&#44; and are less protein-bound and lipid soluble than short-acting barbiturates&#46; Importantly&#44; up to 20&#8211;25&#37; of phenobarbital can be excreted as an active drug in urine&#46; During dialysis&#44; phenobarbital clearance has been shown to vary from 150 to 200<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> For all these reasons&#44; long-acting barbiturates are theoretically dialyzable&#46; A few case studies have reported the effectiveness of both hemoperfusion<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> and hemodialysis<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">7&#44;8</span></a> to enhance the clearance of barbiturates&#46; Yet&#44; these two techniques have not been evaluated and compared in randomized control trials&#46; Hemoperfusion is not widely available and requires a specific training&#46; As compared to hemoperfusion&#44; hemodialysis has been shown to be associated with a lower risk of thrombocytopenia or hypocalcemia and seems less costly&#46;<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&#44; shock &#40;after initial fluid resuscitation&#41;&#44; or persistence of toxicity despite MDAC&#46;<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&#44; especially in those with prolonged coma and&#47;or persistence of toxicity despite multiple-dose activated charcoal&#46;</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&#44; commercial or not-for-profit sectors&#46;</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&#46;</p></span></span>"
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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. Bedeta,b,
Autor para correspondencia
alexandre.bedet@aphp.fr

Corresponding author.
, A. Alestrac, D. Vodovard, A. Mekontso Dessapa,b, N. de Prosta,b
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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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time course of phenobarbital plasma levels &#40;left <span class="elsevierStyleItalic">y</span>-axis&#41; and patient consciousness &#40;Richmond Agitation-Sedation Scale&#44; right <span class="elsevierStyleItalic">y</span>-axis&#41;&#46; There was a dramatic decrease in phenobarbital plasma levels after two hemodialysis sessions&#44; concomitant with neurological status improvement&#46;</p>"
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    "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&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> In this setting&#44; barbiturates remain one of the most common classes of drugs associated with fatal poisoning&#46; The current report aims at illustrating the usefulness of renal replacement therapy with intermittent hemodialysis in the acute care of massive phenobarbital poisoning&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 56-year old woman was addressed to the intensive care unit &#40;ICU&#41; for a massive phenobarbital poisoning &#40;assumed ingested dose&#58; 5&#46;5<span class="elsevierStyleHsp" style=""></span>g&#41;&#46; The estimated maximum delay between phenobarbital ingestion and ICU admission was 6<span class="elsevierStyleHsp" style=""></span>hours&#46; The patient presented with hypotension &#40;77&#47;44<span class="elsevierStyleHsp" style=""></span>mmHg&#41;&#44; hypothermia &#40;33<span class="elsevierStyleHsp" style=""></span>&#176;<span class="elsevierStyleSmallCaps">C</span>&#41; and altered mental status &#40;Glasgow Coma Scale&#58; 3&#41; requiring endotracheal intubation&#44; fluid loading with 1000<span class="elsevierStyleHsp" style=""></span>mL of saline and noradrenalin infusion up to 0&#46;33<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#47;min before ICU admission&#46; Her neurological examination revealed bilateral mydriasis with no pupillary response&#44; together with the disappearance of other brainstem reflexes&#46; A trans-thoracic echocardiography showed preserved left ventricle ejection fraction and cardiac output consistent with a vasoplegic shock&#46; In spite of the profound coma and respiratory depression&#44; there was no evidence for aspiration&#46; The diagnosis of massive phenobarbital poisoning was confirmed by high barbiturate plasma levels measured upon admission &#40;273<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Initial management of barbiturate poisoning included supportive care of organ failures &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; mechanical ventilation and noradrenalin infusion&#41;&#44; the administration of activated charcoal &#40;a single 1<span class="elsevierStyleHsp" style=""></span>g&#47;kg dose&#41; so that to limit the enterohepatic recirculation of barbiturates&#44; together with urinary alkalinization in an attempt to increase their urinary excretion&#46; On day-1&#44; hemodynamic improvement allowed for noradrenalin discontinuation&#46; Yet&#44; the neurological examination was no significantly improved &#40;GCS&#58; 3&#41;&#44; except for a spontaneous breathing activity under mechanical ventilation&#46; Multiple-dose activated charcoal &#40;MDAC&#41; was introduced on day-2&#44; with no significant decrease in plasma phenobarbital levels or neurological improvement &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; On day-4&#44; because the patient was still deeply comatose&#44; renal replacement therapy &#40;RRT&#41; initiation was decided&#46; Intermittent dialysis was performed using an Artis Physio&#8482; dialysis system &#40;Gambro AB&#44; Meyzieu&#44; France&#41; with a Sureflux&#8482;-19E dialyzer &#40;Nipro Europe&#44; Saint Beauzire&#44; France&#41;&#44; achieving an estimated average creatinine clearance of 188<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; A 4-hour session allowed for dramatically reducing plasma phenobarbital levels from 313 to 125<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46; The second dialysis session&#44; performed on day-5&#44; further reduced plasma levels from 129 to 47<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The patient awoke twenty-four hours after RRT initiation&#44; as illustrated by an increase in the Richmond Agitation-Sedation Scale from &#8722;5 &#40;patient unarousable&#41; to 0 &#40;patient alert and calm&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The clinical course was eventually favorable&#44; allowing for the patient to be successfully extubated on day-7 and discharged to a psychiatric unit on day-10&#46;</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&#46; Medical interventions to enhance phenobarbital elimination &#40;activated charcoal and urinary alkalinization&#41; had failed to improve the neurological status of our patient&#46; Also&#44; this strategy did not significantly alter phenobarbital plasma levels&#46; In a previous study&#44; the administration of repeated doses of activated charcoal enhanced the elimination of barbiturates but had no clear effect on clinical outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Furthermore&#44; activated charcoal could hypothetically increase the risk of gastric impaction&#46; This may partially explain the variation in serum concentrations during the initial course &#40;between day-1 and day-4&#41;&#44; as phenobarbital is a long-acting barbiturate&#46; Regarding urinary alkalinization&#44; there is to date no clinical evidence of a clinical benefit in barbiturate poisoning&#44; despite its pharmacokinetic rationale&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the current case&#44; RRT with intermittent hemodialysis dramatically improved the clearance of phenobarbital and&#44; hence&#44; neurological status improved concomitantly&#46; Two 4-hour sessions were sufficient to achieve a dramatic reduction in phenobarbital levels&#46; Hemodialysis was discontinued after neurological status improved&#44; rather than targeting a specific concentration&#46; All barbiturates are inducers of the hepatic cytochrome P450 and hepatic metabolism is the main component of their endogenous clearance&#46; Barbiturates are thus classified according to their pharmacokinetic properties&#46; Long-acting barbiturates &#40;such as phenobarbital&#41; have a smaller volume of distribution&#44; which tends to limit post-dialysis rebound&#44; and are less protein-bound and lipid soluble than short-acting barbiturates&#46; Importantly&#44; up to 20&#8211;25&#37; of phenobarbital can be excreted as an active drug in urine&#46; During dialysis&#44; phenobarbital clearance has been shown to vary from 150 to 200<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> For all these reasons&#44; long-acting barbiturates are theoretically dialyzable&#46; A few case studies have reported the effectiveness of both hemoperfusion<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> and hemodialysis<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">7&#44;8</span></a> to enhance the clearance of barbiturates&#46; Yet&#44; these two techniques have not been evaluated and compared in randomized control trials&#46; Hemoperfusion is not widely available and requires a specific training&#46; As compared to hemoperfusion&#44; hemodialysis has been shown to be associated with a lower risk of thrombocytopenia or hypocalcemia and seems less costly&#46;<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&#44; shock &#40;after initial fluid resuscitation&#41;&#44; or persistence of toxicity despite MDAC&#46;<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&#44; especially in those with prolonged coma and&#47;or persistence of toxicity despite multiple-dose activated charcoal&#46;</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&#44; commercial or not-for-profit sectors&#46;</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&#46;</p></span></span>"
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