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Extracorporeal Treatment for Salicylate Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup

      Study objective

      Salicylate poisoning is a challenging clinical entity associated with substantial morbidity and mortality. The indications for extracorporeal treatments such as hemodialysis are poorly defined. We present a systematic review of the literature along with evidence- and consensus-based recommendations on the use of extracorporeal treatment in salicylate poisoning.

      Methods

      The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup is a multidisciplinary group with international representation whose aim is to provide evidence-based recommendations on the use of extracorporeal treatments in poisoning. We conducted a systematic literature review followed by data extraction and summarized findings, following a predetermined format. The entire work group voted by a 2-round modified Delphi method to reach consensus on voting statements, using a RAND/UCLA Appropriateness Method to quantify disagreement. Anonymous votes were compiled, returned, and discussed in person. A second vote determined the final recommendations.

      Results

      Eighty-four articles met inclusion criteria, including 1 controlled clinical trial, 3 animal studies, and 80 case reports or case series, yielding an overall very low quality of evidence for all recommendations. Clinical data on 143 patients (130 sets of which could be analyzed for patient-level entry data), including 14 fatalities, were reviewed. Toxicokinetic data on 87 patients were also included. After the second round of voting, the workgroup concluded that salicylates are dialyzable by hemodialysis and hemoperfusion (level of evidence=B) and recommended extracorporeal treatment in patients with severe salicylate poisoning (1D), including any patient with altered mental status (1D), with acute respiratory distress syndrome requiring supplemental oxygen (1D), and for those in whom standard therapy is deemed to be failing (1D) regardless of the salicylate concentration. High salicylate concentrations warrant extracorporeal treatment regardless of signs and symptoms (>7.2 mmol/L [100 mg/dL] [1D]; and >6.5 mmol/L [90 mg/dL] [2D]), with lower thresholds applied for patients with impaired kidney function (>6.5 mmol/L [90 mg/dL] [1D]; >5.8 mmol/L [80 mg/dL] [2D]). Extracorporeal treatment is also suggested for patients with severe acidemia (pH ≤7.20 in the absence of other indications) (2D). Intermittent hemodialysis is the preferred modality (1D), although hemoperfusion (1D) and continuous renal replacement therapies (3D) are acceptable alternatives if hemodialysis is unavailable, as is exchange transfusion in neonates (1D).

      Conclusion

      Salicylates are readily removed by extracorporeal treatment, with intermittent hemodialysis being the preferred modality. The signs and symptoms of salicylate toxicity listed warrant extracorporeal treatment, as do high concentrations regardless of clinical status.
      SEE EDITORIAL, P. 182.

      Introduction

      Despite improvements in supportive care, salicylate poisoning remains an important cause of poisoning-related mortality in the United States and around the world. Although comprehensive epidemiologic data are lacking, several deaths related to acetylsalicylic acid (aspirin) toxicity are still reported to poison control centers each year in the United States alone.
      • Mowry J.B.
      • Spyker D.A.
      • Cantilena Jr., L.R.
      • et al.
      2013 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st annual report.
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      2012 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th annual report.
      Although extracorporeal treatment is often considered for severe cases, their indications and specific applications are poorly defined. We present the results of a systematic review of the literature and clinical recommendations for the use of extracorporeal treatment in salicylate poisoning.
      What is already known on this topic
      Salicylate poisoning remains an important cause of poisoning-related morbidity. Specific indications for extracorporeal treatment are poorly defined.
      What question this study addressed
      This systematic review of 84 articles, including a single controlled clinical trial, derived consensus-based recommendations for extracorporeal treatment in salicylate poisoning.
      What this study adds to our knowledge
      Extracorporeal treatment is recommended for severe poisoning, including evidence of altered mental status, acute respiratory distress syndrome, or failure to respond to standard therapy. Asymptomatic patients with significantly elevated salicylate concentrations also merit consideration of extracorporeal treatment. Hemodialysis is the preferred extracorporeal treatment method.
      How this is relevant to clinical practice
      Although clinical data were limited, the consensus recommendations provide specific guidance for extracorporeal treatment use in the management of these patients with complex disease.
      The term “salicylates” refers to all forms of salicylate, most commonly acetylsalicylic acid (aspirin) and methyl salicylate. Although other salicylates such as sodium salicylate and bismuth subsalicylate are also available, the most commonly encountered salicylate in clinical practice is acetylsalicylic acid, which is a small organic acid with a mass of 180 Da. It is extensively bound to albumin (90%), but this process is saturable and can decrease to 30% after overdose.
      • Lee S.
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      Protein binding of acetylsalicylic acid and salicylic acid in porcine and human serum.
      After ingestion, acetylsalicylic acid is rapidly absorbed and hydrolyzed to salicylic acid (the negative logarithm of the acid dissociation constant, pKa 2.98), which exists primarily in the dissociated (salicylate) form at physiologic pH. Acetylsalicylic acid has a low volume of distribution (0.2 L/kg), although higher values (≅0.5 L/kg) have been reported after overdose
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      Pharmacokinetics of salicylate elimination in man.
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      Relationship between dose and apparent volume of distribution of salicylate in children.
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      Some aspects of salicylate distribution and metabolism in man.
      (Table 1).
      Table 1Salicylate physicochemical and toxicokinetic properties.
      Physciochemical characteristicResult
      Molecular mass, Da180 (acetylsalicylic acid)
      Volume of distribution, L/kg0.2 (up to 0.5 in overdose)
      Protein binding, %90 (30 in overdose)
      Oral bioavailability, %68 (acetylsalicylic acid)
      Therapeutic range, mmol/L (mg/dL)0.4–1.8 (5–25)
      Toxic exposure, mg/kg>150
      Lethal exposure, mg/kg>500
      Half-life (therapeutic), h2–4
      Conversion factormg/dL×0.072=mmol/L
      The pathophysiology and clinical manifestations of acetylsalicylic acid poisoning are described in detail elsewhere.
      • Temple A.R.
      Acute and chronic effects of aspirin toxicity and their treatment.
      • Temple A.R.
      • George D.J.
      • Done A.K.
      • et al.
      Salicylate poisoning complicated by fluid retention.
      • Chyka P.A.
      • Erdman A.R.
      • Christianson G.
      • et al.
      Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management.
      • Hill J.B.
      Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations.
      • Hill J.B.
      Salicylate intoxication.
      Briefly, salicylates uncouple oxidative phosphorylation, liberating heat while interfering with the generation of adenosine triphosphate.
      • Miyahara J.T.
      • Karler R.
      Effect of salicylate on oxidative phosphorylation and respiration of mitochondrial fragments.
      • Penniall R.
      The effects of salicylic acid on the respiratory activity of mitochondria.
      A metabolic acidosis with accumulation of lactate and ketoacids ensues as glucose is rapidly but inefficiently consumed and mitochondrial adenosine triphosphate synthesis fails.
      • Hill J.B.
      Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations.
      • Miyahara J.T.
      • Karler R.
      Effect of salicylate on oxidative phosphorylation and respiration of mitochondrial fragments.
      • Sproull D.H.
      The glycogenolytic action of sodium salicylate.
      Many organ systems are subject to injury in patients with severe salicylism. However, death is typically associated with cerebral edema resulting from entry of salicylate into the central nervous system, a process heavily influenced by systemic pH.
      • Hill J.B.
      Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations.
      • Hill J.B.
      Salicylate intoxication.
      • Goldberg M.A.
      • Barlow C.F.
      • Roth L.J.
      The effects of carbon dioxide on the entry and accumulation of drugs in the central nervous system.
      The early features of salicylate poisoning are nonspecific and include nausea and vomiting, although unexplained tinnitus or primary respiratory alkalosis are suggestive of the diagnosis. Other features of salicylate poisoning include volume depletion, tachycardia, acute respiratory distress syndrome, hypoglycemia (with or without hypoglycorrhachia), hypoprothrombinemia, hyperthermia, acute kidney injury, and, rarely, rhabdomyolysis. In the absence of another explanation, agitation and altered mental status in the setting of salicylate toxicity are features of severe poisoning.
      Salicylate poisoning is a medical emergency and is easily underestimated. Treatment should proceed with the involvement of a clinical toxicologist or regional poison center. The cornerstones of therapy include good supportive care, gastrointestinal decontamination in selected patients after acute overdose, repletion of intravascular volume, and bicarbonate administration. Bicarbonate produces alkalemia, which minimizes passage of salicylate into the central nervous system, and alkaluria, which reduces renal tubular reabsorption and thus promotes renal excretion of salicylate, particularly when urinary pH values reach 7.5 to 8.
      • Temple A.R.
      Acute and chronic effects of aspirin toxicity and their treatment.
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      Existing recommendations differ in regard to the indications for extracorporeal treatment in patients with salicylate poisoning.
      • Lugassy D.N.
      Salicylates.
      Salicylates.

      Boyer EW, Weibrecht KW. Salicylate (aspirin) poisoning in adults. UpToDate. Wolters Kluwer Health; 2014. Available at: www.uptodate.com. Accessed April 10, 2015.

      Waseem M. Salicylate toxicity. In: WebMD, ed. Medscape. New York, NY: 2014. Available at www.webmd.com. Accessed April 10, 2015.

      Salicylates. WikiTox. Vol 2014; 2013. Available at: http://curriculum.toxicology.wikispaces.net/2.1.1.4+Salicylates. Accessed April 10, 2015.

      Salicylate in Micromedex 2.0. Truven Health Analytics, Greenwood Village, Colorado. 2014.

      Most recommend hemodialysis in patients with altered mental status, evidence of acute respiratory distress syndrome or cerebral edema, fluid overload that precludes administration of sodium bicarbonate, or clinical deterioration despite good supportive care. High salicylate concentrations are often given as a potential indication for extracorporeal treatment; quoted thresholds include 5.8 mmol/L (81 mg/dL),
      Salicylates.
      6.5 mmol/L (90 mg/dL),
      • Lugassy D.N.
      Salicylates.
      7.2 mmol/L (100 mg/dL),

      Boyer EW, Weibrecht KW. Salicylate (aspirin) poisoning in adults. UpToDate. Wolters Kluwer Health; 2014. Available at: www.uptodate.com. Accessed April 10, 2015.

      Waseem M. Salicylate toxicity. In: WebMD, ed. Medscape. New York, NY: 2014. Available at www.webmd.com. Accessed April 10, 2015.

      Salicylate in Micromedex 2.0. Truven Health Analytics, Greenwood Village, Colorado. 2014.

      and 9.4 mmol/L (130 mg/dL), and concentrations greater than 3.6 to 4.2 mmol/L (50 to 60 mg/dL) are suggested to warrant extracorporeal treatment in chronic poisoning. However, most sources acknowledge that clinical status is a more important factor than the salicylate concentration in the decision to initiate extracorporeal treatment.

      Materials and Methods

      The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup is composed of international experts representing diverse specialties and professional societies (Figure 1). Its mission is to provide evidence-based recommendations on the use of extracorporeal treatment for toxin removal in poisoned patients (http://www.extrip-workgroup.org). The rationale, background, objectives, methodology, and other recommendations have been published previously.
      • Ghannoum M.
      • Nolin T.D.
      • Goldfarb D.S.
      • et al.
      Extracorporeal treatment for thallium poisoning: recommendations from the EXTRIP Workgroup.
      • Gosselin S.
      • Juurlink D.N.
      • Kielstein J.T.
      • et al.
      Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP Workgroup.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup: guideline methodology.
      • Lavergne V.
      • Ouellet G.
      • Bouchard J.
      • et al.
      Guidelines for reporting case studies on extracorporeal treatments in poisonings: methodology.
      • Mactier R.
      • Laliberte M.
      • Mardini J.
      • et al.
      Extracorporeal treatment for barbiturate poisoning: recommendations from the EXTRIP Workgroup.
      • Yates C.
      • Galvao T.
      • Sowinski K.M.
      • et al.
      Extracorporeal treatment for tricyclic antidepressant poisoning: recommendations from the EXTRIP Workgroup.
      • Ghannoum M.
      • Nolin T.D.
      • Lavergne V.
      • et al.
      Blood purification in toxicology: nephrology's ugly duckling.
      • Ghannoum M.
      • Yates C.
      • Galvao T.F.
      • et al.
      Extracorporeal treatment for carbamazepine poisoning: systematic review and recommendations from the EXTRIP Workgroup.
      • Roberts D.M.
      • Yates C.
      • Megarbane B.
      • et al.
      Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement.
      • Decker B.S.
      • Goldfarb D.S.
      • Dargan P.I.
      • et al.
      Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP Workgroup.
      Predetermined methodology, incorporating guidelines from the Appraisal of Guidelines for Research and Evaluation

      Appraisal of Guidelines for Research and Evaluation. AGREE instrument. http://www.agreetrust.org/resource-centre/the-original-agree-instrument/. Accessed April 10, 2015.

      and Grades of Recommendation Assessment, Development and Evaluation,
      • Atkins D.
      • Best D.
      • Briss P.A.
      • et al.
      Grading quality of evidence and strength of recommendations.
      is described in detail elsewhere.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup: guideline methodology.
      The primary literature search was conducted on July 10, 2012, in MEDLINE, EMBASE, and the Cochrane Library (Reviews and Central).
      The following search strategy was used: [(salicylate OR aspirin OR salicylic) AND (dialysis OR hemodialysis OR haemodialysis OR hemoperfusion OR haemoperfusion OR plasmapheresis OR plasma exchange OR exchange transfusion OR hemofiltration OR haemofiltration OR hemodiafiltration OR haemodiafiltration OR extracorporeal therapy OR CRRT)].
      A manual search of conference proceedings from the European Association of Poison Control Centres and Clinical Toxicologists and North American Congress of Clinical Toxicology annual meetings (from 2002 to 2012) and Google Scholar was performed, as was a review of the bibliography of each article obtained during the literature search.
      A designated subgroup of EXTRIP completed the literature search, reviewed articles, extracted data, and summarized findings. Dialyzability was determined according to criteria listed in Table 2. The potential benefit of the procedure was weighed against its cost, availability, and alternative treatments, and its related complications. The level of evidence assigned to each clinical recommendation was determined by the subgroup and the appointed epidemiologist (Figure 2). This information was submitted to the entire workgroup for consideration, along with structured voting statements based on a predetermined format. The strength of recommendations was evaluated by a 2-round modified Delphi method for each proposed voting statement (Figure 3), and the RAND/UCLA Appropriateness Method was used to quantify disagreement between voters.
      • Fitch K.
      • Bernstein S.J.
      • Aguilar M.D.
      • et al.
      The RAND/UCLA Appropriateness Method User's Manual.
      Anonymous votes with comments were compiled by the epidemiologist and returned to each participant. The workgroup met in person to exchange ideas and debate statements. A second vote was later submitted in the summer of 2012, and these results were used in developing the core EXTRIP recommendations. The literature search was updated on October 1, 2014, following the same methodology as described above. Any new articles were summarized and the data were then submitted to all participants, who updated their votes.
      Table 2Criteria used to define dialyzability.
      These criteria should be applied only if measured or calculated (not reported) endogenous half-life is greater than 4 hours (otherwise, ECTR is considered not clinically relevant). Furthermore, the primary criterion is preferred for poisons having a large volume of distribution (>5 L/kg). Reproduced with permission from Clinical Toxicology. Lavergne V, Nolin TD, Hoffman RS, et al. The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup: guideline methodology. Clin Toxicol. 2012;50:403-413.25
      Dialyzability
      Applicable to all modalities of extracorporeal treatment, including hemodialysis, hemoperfusion, and hemofiltration.
      Primary Criteria, % Removed
      Corresponds to percentage removal of ingested dose or total body burden in a 6-hour extracorporeal treatment period.
      Alternative Criteria, %
      CLECTR/CLTOT
      Measured during the same period.
      T1/2 ECTR/T1/2REECTR/RETOT
      Measured during the same period.
      D>30>75<25>75
      M>10–30>50–75>25–50>50–75
      S≥3–10≥25–50≥50–5≥25–50
      N<3<25>75<25
      CLECTR, Extracorporeal clearance; CLTOT, total clearance; T1/2 ECTR, half-life during ECTR; T1/2, half-life off ECTR; REECTR, extracorporeal removal; RETOT, total removal; D, dialyzable; M, moderately dialyzable; S, slightly dialyzable; N, not dialyzable.
      These criteria should be applied only if measured or calculated (not reported) endogenous half-life is greater than 4 hours (otherwise, ECTR is considered not clinically relevant). Furthermore, the primary criterion is preferred for poisons having a large volume of distribution (>5 L/kg). Reproduced with permission from Clinical Toxicology. Lavergne V, Nolin TD, Hoffman RS, et al. The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup: guideline methodology. Clin Toxicol. 2012;50:403-413.
      • Lavergne V.
      • Nolin T.D.
      • Hoffman R.S.
      • et al.
      The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup: guideline methodology.
      Applicable to all modalities of extracorporeal treatment, including hemodialysis, hemoperfusion, and hemofiltration.
      Corresponds to percentage removal of ingested dose or total body burden in a 6-hour extracorporeal treatment period.
      § Measured during the same period.
      Figure thumbnail gr2
      Figure 2Strength of recommendation and level-of-evidence scale for clinical outcomes.
      Figure thumbnail gr3
      Figure 3Delphi method (2 rounds) for each recommendation.

      Results

      Results of the literature search and reasons for study exclusion are presented in Figure 4. A total of 306 citations were identified. After full-text screening for eligibility criteria, 84 articles were selected for extraction of clinical or toxicokinetic data, including 1 controlled clinical trial,
      • Summitt R.L.
      • Etteldorf J.N.
      Salicylate intoxication in children—experience with peritoneal dialysis and alkalinization of the urine.
      3 animal studies,
      • Engel H.P.
      • Metcalfe J.O.
      Extracorporeal hemodialysis in the treatment of salicylate intoxication in dogs.
      • Etteldorf J.N.
      • Montalvo J.M.
      • Kaplan S.
      • et al.
      Intermittent peritoneal dialysis in the treatment of experimental salicylate intoxication.
      • James J.A.
      • Kimbell L.
      • Read W.T.
      Experimental salicylate intoxication. I. Comparison of exchange transfusion, intermittent peritoneal lavage, and hemodialysis as means for removing salicylate.
      and 80 case reports or case series,
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      • Adams J.T.
      • Bigler J.A.
      • Green O.C.
      A case of methyl salicylate intoxication treated by exchange transfusion.
      • Aleguas A.
      • Foran M.P.
      Delayed salicylate treatment requiring massive potassium supplementation.
      • Aleguas A.
      • Sheroff A.
      Treatment of a potentially fatal dose of methyl salicylate utilizing high volume volume fluid administration.
      • Birnbaum K.
      • Culp J.
      • Cantrell F.L.
      Survival despite potentially deadly salicylate level.
      • Buselmeier T.J.
      • Lynch R.E.
      • Davin T.D.
      • et al.
      Severe salicylate intoxication in small children.
      • Cannon R.D.
      • O'Connor A.D.
      Survival with an extremely high salicylate level.
      • Caseley R.T.
      Salicylate poisoning: a case in infancy treated by exchange transfusion.
      • Chase P.B.
      • Walter F.G.
      • James S.
      Whole bowel irrigation, hemodialysis, and continuous venovenous hemodiafiltration in the successful treatment of severe salicylate poisoning: case report.
      • Cohen D.L.
      • Post J.
      • Ferroggiaro A.A.
      • et al.
      Chronic salicylism resulting in noncardiogenic pulmonary edema requiring hemodialysis.
      • Diamond E.F.
      • Deyoung V.R.
      Acute poisoning with oil of wintergreen treated by exchange transfusion.
      • Dmitriev S.N.
      • Nabatov M.S.
      • Stashenko V.D.
      • et al.
      A case of successful treatment of severe poisoning with acetylsalicylic acid in a child.
      • Done A.K.
      • Otterness L.J.
      Exchange transfusion in the treatment of oil of wintergreen (methyl salicylate) poisoning.
      • Doolan P.
      Acetylsalicylic acid intoxication—a proposed method of treatment.
      • Drummond R.
      • Kadri N.
      • St-Cyr J.
      Delayed salicylate toxicity following enteric-coated acetylsalicylic acid overdose: a case report and review of the literature.
      • Dulaney A.
      • Kerns II, W.
      Delayed peak salicylate level following intentional overdose.
      • Elliott G.B.
      • Crichton J.U.
      Peritoneal dialysis in salicylate intoxication.
      • Etchart L.W.
      Peritoneal dialysis in salicylate intoxication.
      • Etteldorf J.N.
      • Dobbins W.T.
      • Summitt R.L.
      • et al.
      Intermittent peritoneal dialysis using 5 per cent albumin in the treatment of salicylate intoxication in children.
      • Fantozzi R.
      • Martinelli F.
      • Masini E.
      • et al.
      Use of haemoperfusion with uncoated charcoal in the management of acute intoxications with barbiturate and salicylate.
      • Farmer B.
      • Chen B.
      • Hoffman R.S.
      • et al.
      Ketamine and midazolam for procedural sedation prevents respiratory depression in lifethreatening aspirin toxicity.
      • Fine R.N.
      • Stiles Q.
      • DePalma J.R.
      • et al.
      Hemodialysis in infants under 1 year of age for acute poisoning.
      • French L.K.
      • McKeown N.J.
      • Hendrickson R.G.
      Continuous renal replacement therapy for salicylate overdose in a patient with multi-system trauma.
      • Gelfand M.C.
      • Winchester J.F.
      • Knepshield J.H.
      • et al.
      Treatment of severe drug overdosage with charcoal hemoperfusion.
      • Goulding R.
      Experience with hemoperfusion in drug abuse.
      • Grandey K.
      • Lu J.
      • Bryant S.
      Negligible initial salicylate concentrations: are they inconsequential?.
      • Halle M.A.
      • Collipp P.J.
      Treatment of methyl salicylate poisoning by peritoneal dialysis.
      • Hampel G.
      • Crome P.
      • Widdop B.
      • et al.
      Experience with fixed-bred charcoal haemoperfusion in the treatment of severe drug intoxication.
      • Higgins R.M.
      • Connolly J.O.
      • Hendry B.M.
      Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient.
      • Jacobsen D.
      • Wiik-Larsen E.
      • Bredesen J.E.
      Haemodialysis or haemoperfusion in severe salicylate poisoning?.
      • Jimramovsky F.
      • Dolezel Z.
      • Stejskal J.
      Forced diuresis and exchange transfusion in the treatment of severe salicylate poisoning.
      • Karabocuoglu M.
      • Nayir A.
      • Taner Z.
      • et al.
      Active charcoal hemoperfusion in acute salicylism.
      • Kent K.
      • Ganetsky M.
      • Cohen J.
      • et al.
      Non-fatal ventricular dysrhythmias associated with severe salicylate toxicity.
      • Kleinman K.S.
      • Schweitzer S.
      • Nissenson A.R.
      Accidental salicylate intoxication in a hemodialysis patient.
      • Kloss J.L.
      • Boeckman C.R.
      Methyl salicylate poisoning. Case report and discussion of treatment by peritoneal dialysis.
      • Knutsen K.M.
      • Skuterud B.
      • Halvorsen S.
      Hemoperfusion in poisoning.
      • Koffler A.
      • Bernstein M.
      • LaSette A.
      • et al.
      Fixed-bed charcoal hemoperfusion. Treatment of drug overdose.
      • Kostic M.A.
      • Gummin D.D.
      Persistent cerebral edema and death after hemodialysis for chronic salicylism.
      • Leikin S.L.
      • Emmanouilides G.C.
      The use of exchange transfusion in salicylate intoxication: report of 7 cases.
      • Leikin S.L.
      • Lopresti J.M.
      • Pohl D.R.
      Severe salicylate intoxication treated by exchange transfusion.
      • Lemesh R.A.
      Accidental chronic salicylate intoxication in an elderly patient: major morbidity despite early recognition.
      • Leonards J.
      Use of artificial kidney for purposes other then treatment of uremia.
      • Levine M.
      • Nikkanen H.
      • Nadel E.S.
      • et al.
      Weakness and mental status change.
      • Levy R.I.
      Overwhelming salicylate intoxication in an adult. Acid-base changes during recovery with hemodialysis.
      • Lu J.J.
      Perilous propositions: intubating the salicylate poisoned patient.
      • Lund B.
      • Seifert S.A.
      • Mayersohn M.
      Efficacy of sustained low-efficiency dialysis in the treatment of salicylate toxicity.
      • Magness J.L.
      • Murray J.B.
      Treatment of salicylate intoxication using extracorporeal hemodialysis.
      • Manikian A.
      • Stone S.
      • Hamilton R.
      • et al.
      Exchange transfusion in severe infant salicylism.
      • Marquardt K.A.
      • Anderson K.
      • Offerman S.R.
      Severe salicylate poisoning from Hong Hoa oil.
      • Meehan T.J.
      • Kalimullah E.A.
      • Erickson T.B.
      Two for the price of one: occult salicylate overdose masked by sodium cyanide ingestion.
      • Millar R.J.
      • Bowman J.
      Oil of wintergreen (methyl salicylate) poisoning treated by exchange transfusion.
      • Minns A.B.
      • Cantrell F.L.
      • Clark R.F.
      Death due to acute salicylate intoxication despite dialysis.
      • Montagnac R.
      • Schillinger F.
      • Milcent T.
      • et al.
      Extrarenal purification in severe salicylate poisoning in adults.
      • Muniandy R.K.
      • Sinnathamby V.
      Salicylate toxicity from ingestion of traditional massage oil.
      • Nawata Y.
      • Kagami M.
      • Nakajima H.
      • et al.
      Chronic salicylate intoxication and rhabdomyolysis in a patient with scleroderma and Sjogren's syndrome.
      • O'Shura J.S.
      • Brooks D.E.
      • Pizon A.F.
      Highest reported salicylate level with survival.
      • Palatnick W.
      • Tenenbein M.
      Aspirin poisoning during pregnancy: increased fetal sensitivity.
      • Pec J.
      • Strmenova M.
      • Palencarova E.
      • et al.
      Salicylate intoxication after use of topical salicylic acid ointment by a patient with psoriasis.
      • Pertoldi F.
      • D'Orlando L.
      • Mercante W.P.
      Acute salicylate intoxication after trancutaneous absorption.
      • Quintero Parra N.
      • Wurgaft Kirberg A.
      • Orellana Araya Y.
      • et al.
      Haemodialysis management for salicylate intoxication.
      • Raschke R.
      • Arnold-Capell P.A.
      • Richeson R.
      • et al.
      Refractory hypoglycemia secondary to topical salicylate intoxication.
      • Reblin T.
      • Wolf G.
      • De Weerth A.
      • et al.
      Extracorporeal elimination of salicylate by hemofiltration.
      • Rentsch J.B.
      • Bradley A.
      • Marsh S.B.
      Two cases of salicylate intoxication successfully treated by exchange transfusion.
      • Satar S.
      • Alpay N.R.
      • Sebe A.
      • et al.
      Emergency hemodialysis in the management of intoxication.
      • Schlegel R.J.
      • Altstatt L.B.
      • Canales L.
      • et al.
      Peritoneal dialysis for severe salicylism: an evaluation of indications and results.
      • Schreiner G.E.
      The role of hemodialysis (artificial kidney) in acute poisoning.
      • Schreiner G.E.
      • Berman L.B.
      • Griffin J.
      • et al.
      Specific therapy for salicylism.
      • Sieniawska M.
      • Bialasik D.
      • Korniszewska J.
      • et al.
      Case of asprocol poisoning of a 20-month-old child treated with peritoneal dialysis.
      • Snodgrass W.
      • Rumack B.H.
      • Peterson R.G.
      • et al.
      Salicylate toxicity following therapeutic doses in young children.
      • Spritz N.
      • Fahey Jr., T.J.
      • Thompson D.D.
      • et al.
      The use of extracorporeal hemodialysis in the treatment of salicylate intoxication in a 2-year-old child.
      • Sterne T.L.
      Exchange transfusion for aspirin poisoning.
      • Thomas B.
      • Valcarcel M.R.
      • Aglieco F.
      • et al.
      Salicylate toxicity and early hemodialysis.
      • Thomsen A.C.
      • Dalgard O.Z.
      Haemodialysis in acute acetylsalicylic acid poisoning.
      • Todd P.J.
      • Sills J.A.
      • Harris F.
      • et al.
      Problems with overdoses of sustained-release aspirin.
      • Varela N.
      • Bognar M.
      • Agudelo C.
      • et al.
      Salicylate toxicity in the older patient.
      • Wanscher M.C.
      • Frifelt J.J.
      • Molsted K.
      Double-lumen hemodialysis catheters in the treatment of acetylsalicylic acid and lithium poisoning.
      • Watson J.E.
      • Tagupa E.T.
      Suicide attempt by means of aspirin enema.
      • Wrathall G.
      • Sinclair R.
      • Moore A.
      • et al.
      Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose.
      • Zachau-Christiansen B.
      3 Cases of salicylic acid poisoning in infants.
      • Zimmerman G.A.
      • Clemmer T.P.
      Acute respiratory failure during therapy for salicylate intoxication.
      whereas in vitro studies were excluded.
      Figure thumbnail gr4
      Figure 4Study selection flow diagram (October 1, 2014).
      The only controlled clinical trial of extracorporeal treatment in salicylate poisoning
      • Summitt R.L.
      • Etteldorf J.N.
      Salicylate intoxication in children—experience with peritoneal dialysis and alkalinization of the urine.
      was a very-low-quality study in which the design and risk of bias could not be reliably assessed. The study involved 13 young children with salicylate poisoning, including 10 who ingested acetylsalicylic acid and 3 who ingested methyl salicylate. All patients were treated with intravenous fluids and bicarbonate, whereas the intervention group underwent peritoneal dialysis with 5% albumin. Treatment was continued until clinical improvement was apparent and salicylate concentrations were approximately 2.2 mmol/L (30 mg/dL). No deaths were reported in either treatment arm. Treatment was shorter in patients allocated to extracorporeal treatment than standard care (7.9 versus 12.4 hours), but the clinical significance of this is uncertain. It is difficult to draw valid conclusions from this study in light of its low quality and small sample size.
      The remaining evidence is composed of case reports and case series: A total of 143 patients were reported from the included studies, including 130 for whom sufficient patient-level data were available. Individual patients are presented in Table 3, whereas aggregate data are presented in Table 4. Because of their inherent limitations (lack of control group and publication bias), reliable conclusions about clinical outcomes cannot be drawn from these reports, resulting in a very low quality of evidence for all recommendations. This is particularly true in light of variability in the amount ingested, differences in the acuity of poisoning, the interval from exposure to treatment, and the variable and uncontrolled nature of treatments used. Nevertheless, case reports occasionally note significant clinical improvement during or shortly after extracorporeal treatment.
      • Magness J.L.
      • Murray J.B.
      Treatment of salicylate intoxication using extracorporeal hemodialysis.
      • Millar R.J.
      • Bowman J.
      Oil of wintergreen (methyl salicylate) poisoning treated by exchange transfusion.
      • Spritz N.
      • Fahey Jr., T.J.
      • Thompson D.D.
      • et al.
      The use of extracorporeal hemodialysis in the treatment of salicylate intoxication in a 2-year-old child.
      • Thomsen A.C.
      • Dalgard O.Z.
      Haemodialysis in acute acetylsalicylic acid poisoning.
      Table 3Individual clinical data reported after ECTR for salicylate poisoning.
      CitationTypeNPeak [SA], mg/dLECTR ModalityTime From Ingestion to ECTRAliveDead
      Summit, 1964
      • Summitt R.L.
      • Etteldorf J.N.
      Salicylate intoxication in children—experience with peritoneal dialysis and alkalinization of the urine.
      RCT6PD4.5–306
      7None7
      Doolan, 1951
      • Doolan P.
      Acetylsalicylic acid intoxication—a proposed method of treatment.
      Case report155ET1
      Leonards, 1955
      • Leonards J.
      Use of artificial kidney for purposes other then treatment of uremia.
      Case report1130HD1
      Schreiner, 1955
      • Schreiner G.E.
      • Berman L.B.
      • Griffin J.
      • et al.
      Specific therapy for salicylism.
      Case report190HD1
      Done, 1956
      • Done A.K.
      • Otterness L.J.
      Exchange transfusion in the treatment of oil of wintergreen (methyl salicylate) poisoning.
      Case report186ET5.51
      Adams, 1957
      • Adams J.T.
      • Bigler J.A.
      • Green O.C.
      A case of methyl salicylate intoxication treated by exchange transfusion.
      Case report173ET281
      Diamond, 1958
      • Diamond E.F.
      • Deyoung V.R.
      Acute poisoning with oil of wintergreen treated by exchange transfusion.
      Case report1960ET1
      115HD16.51
      Schreiner, 1958
      • Schreiner G.E.
      The role of hemodialysis (artificial kidney) in acute poisoning.
      Series3110HD5.31
      101HD71
      Thomsen, 1958
      • Thomsen A.C.
      • Dalgard O.Z.
      Haemodialysis in acute acetylsalicylic acid poisoning.
      Case report152HD481
      100ET231
      Leikin, 1959
      • Leikin S.L.
      • Lopresti J.M.
      • Pohl D.R.
      Severe salicylate intoxication treated by exchange transfusion.
      Series3103ETCHR1
      102ET>81
      Rentsch, 1959
      • Rentsch J.B.
      • Bradley A.
      • Marsh S.B.
      Two cases of salicylate intoxication successfully treated by exchange transfusion.
      Series279ET141
      69ET91
      Spritz, 1959
      • Spritz N.
      • Fahey Jr., T.J.
      • Thompson D.D.
      • et al.
      The use of extracorporeal hemodialysis in the treatment of salicylate intoxication in a 2-year-old child.
      Case report162HD>481
      Sterne, 1959
      • Sterne T.L.
      Exchange transfusion for aspirin poisoning.
      Case report135ETCHR1
      38PDCHR1
      Elliott, 1969
      • Elliott G.B.
      • Crichton J.U.
      Peritoneal dialysis in salicylate intoxication.
      Series3PDCHR1
      74PD>81
      Leikin, 1960
      • Leikin S.L.
      • Emmanouilides G.C.
      The use of exchange transfusion in salicylate intoxication: report of 7 cases.
      Series778–160ET61
      Etteldorf, 1961
      • Etteldorf J.N.
      • Dobbins W.T.
      • Summitt R.L.
      • et al.
      Intermittent peritoneal dialysis using 5 per cent albumin in the treatment of salicylate intoxication in children.
      Series741–62PD7
      Magness, 1961
      • Magness J.L.
      • Murray J.B.
      Treatment of salicylate intoxication using extracorporeal hemodialysis.
      Case report199HD271
      Millar, 1961
      • Millar R.J.
      • Bowman J.
      Oil of wintergreen (methyl salicylate) poisoning treated by exchange transfusion.
      Case report170ET>191
      Caseley, 1962
      • Caseley R.T.
      Salicylate poisoning: a case in infancy treated by exchange transfusion.
      Case report170ETCHR1
      Etchart, 1965
      • Etchart L.W.
      Peritoneal dialysis in salicylate intoxication.
      Case report187PD>191
      Kallen, 1966
      • Temple A.R.
      Acute and chronic effects of aspirin toxicity and their treatment.
      Series1342–100HD112
      Schlegel, 1966
      • Schlegel R.J.
      • Altstatt L.B.
      • Canales L.
      • et al.
      Peritoneal dialysis for severe salicylism: an evaluation of indications and results.
      Series545–100PD12–2241
      Kloss, 1967
      • Kloss J.L.
      • Boeckman C.R.
      Methyl salicylate poisoning. Case report and discussion of treatment by peritoneal dialysis.
      Case report1118PD1
      Levy, 1967
      • Levy R.I.
      Overwhelming salicylate intoxication in an adult. Acid-base changes during recovery with hemodialysis.
      Case report1114HD311
      Fine, 1968
      • Fine R.N.
      • Stiles Q.
      • DePalma J.R.
      • et al.
      Hemodialysis in infants under 1 year of age for acute poisoning.
      Case report189HD11
      Zachau-Christiansen, 1968
      • Zachau-Christiansen B.
      3 Cases of salicylic acid poisoning in infants.
      Series286PD1
      53PD1
      Halle, 1969
      • Halle M.A.
      • Collipp P.J.
      Treatment of methyl salicylate poisoning by peritoneal dialysis.
      Case report1121PD51
      Goulding, 1976
      • Goulding R.
      Experience with hemoperfusion in drug abuse.
      Case report166HP
      Buselmeier, 1977
      • Buselmeier T.J.
      • Lynch R.E.
      • Davin T.D.
      • et al.
      Severe salicylate intoxication in small children.
      Case report196HD1
      Gelfand, 1977
      • Gelfand M.C.
      • Winchester J.F.
      • Knepshield J.H.
      • et al.
      Treatment of severe drug overdosage with charcoal hemoperfusion.
      Series258HP1
      70HP1
      Koffler, 1978
      • Koffler A.
      • Bernstein M.
      • LaSette A.
      • et al.
      Fixed-bed charcoal hemoperfusion. Treatment of drug overdose.
      Case report193HP1
      Sieniawska, 1978
      • Sieniawska M.
      • Bialasik D.
      • Korniszewska J.
      • et al.
      Case of asprocol poisoning of a 20-month-old child treated with peritoneal dialysis.
      Case report1180PD1
      Knutsen, 1979
      • Knutsen K.M.
      • Skuterud B.
      • Halvorsen S.
      Hemoperfusion in poisoning.
      Case report1137HP>2.51
      Hampel, 1980
      • Hampel G.
      • Crome P.
      • Widdop B.
      • et al.
      Experience with fixed-bred charcoal haemoperfusion in the treatment of severe drug intoxication.
      Series2100HP1
      68HP1
      Fantozzi, 1981
      • Fantozzi R.
      • Martinelli F.
      • Masini E.
      • et al.
      Use of haemoperfusion with uncoated charcoal in the management of acute intoxications with barbiturate and salicylate.
      Case report148HP1
      Snodgrass, 1981
      • Snodgrass W.
      • Rumack B.H.
      • Peterson R.G.
      • et al.
      Salicylate toxicity following therapeutic doses in young children.
      Series2168PDCHR1
      77HDCHR1
      Todd, 1981
      • Todd P.J.
      • Sills J.A.
      • Harris F.
      • et al.
      Problems with overdoses of sustained-release aspirin.
      Case report158PD1
      Zimmerman, 1981
      • Zimmerman G.A.
      • Clemmer T.P.
      Acute respiratory failure during therapy for salicylate intoxication.
      Case report197HD1
      Wanscher, 1986
      • Wanscher M.C.
      • Frifelt J.J.
      • Molsted K.
      Double-lumen hemodialysis catheters in the treatment of acetylsalicylic acid and lithium poisoning.
      Case report187HD41
      Montagnac, 1987
      • Montagnac R.
      • Schillinger F.
      • Milcent T.
      • et al.
      Extrarenal purification in severe salicylate poisoning in adults.
      Case report1150HD171
      Jacobsen, 1988
      • Jacobsen D.
      • Wiik-Larsen E.
      • Bredesen J.E.
      Haemodialysis or haemoperfusion in severe salicylate poisoning?.
      Series2123HP61
      95HD131
      Jimramovsky, 1988
      • Jimramovsky F.
      • Dolezel Z.
      • Stejskal J.
      Forced diuresis and exchange transfusion in the treatment of severe salicylate poisoning.
      Case report1144ET1
      Kleinman, 1988
      • Kleinman K.S.
      • Schweitzer S.
      • Nissenson A.R.
      Accidental salicylate intoxication in a hemodialysis patient.
      Case report181HDCHR1
      Dmitriev, 1990
      • Dmitriev S.N.
      • Nabatov M.S.
      • Stashenko V.D.
      • et al.
      A case of successful treatment of severe poisoning with acetylsalicylic acid in a child.
      Case report1HP1
      Raschke, 1991
      • Raschke R.
      • Arnold-Capell P.A.
      • Richeson R.
      • et al.
      Refractory hypoglycemia secondary to topical salicylate intoxication.
      Case report144HDCHR1
      Pec, 1992
      • Pec J.
      • Strmenova M.
      • Palencarova E.
      • et al.
      Salicylate intoxication after use of topical salicylic acid ointment by a patient with psoriasis.
      Case report183HD191
      Lemesh, 1993
      • Lemesh R.A.
      Accidental chronic salicylate intoxication in an elderly patient: major morbidity despite early recognition.
      Case report182HD1
      Nawata, 1994
      • Nawata Y.
      • Kagami M.
      • Nakajima H.
      • et al.
      Chronic salicylate intoxication and rhabdomyolysis in a patient with scleroderma and Sjogren's syndrome.
      Case report191HD, CRRT1
      Watson, 1994
      • Watson J.E.
      • Tagupa E.T.
      Suicide attempt by means of aspirin enema.
      Case report1120HD281
      Karabocuoglu, 1996
      • Karabocuoglu M.
      • Nayir A.
      • Taner Z.
      • et al.
      Active charcoal hemoperfusion in acute salicylism.
      Case report167HD241
      Higgins, 1998
      • Higgins R.M.
      • Connolly J.O.
      • Hendry B.M.
      Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient.
      Case report172HD71
      Palatnik, 1998
      • Palatnick W.
      • Tenenbein M.
      Aspirin poisoning during pregnancy: increased fetal sensitivity.
      Case report162HD1
      Reblin, 1998
      • Reblin T.
      • Wolf G.
      • De Weerth A.
      • et al.
      Extracorporeal elimination of salicylate by hemofiltration.
      Case report1149HP121
      Varela, 1998
      • Varela N.
      • Bognar M.
      • Agudelo C.
      • et al.
      Salicylate toxicity in the older patient.
      Case report173HDCHR1
      Pertoldi, 1999
      • Pertoldi F.
      • D'Orlando L.
      • Mercante W.P.
      Acute salicylate intoxication after trancutaneous absorption.
      Case report170HDCHR1
      Cohen, 2000
      • Cohen D.L.
      • Post J.
      • Ferroggiaro A.A.
      • et al.
      Chronic salicylism resulting in noncardiogenic pulmonary edema requiring hemodialysis.
      Case report154HD1
      Drummond, 2001
      • Drummond R.
      • Kadri N.
      • St-Cyr J.
      Delayed salicylate toxicity following enteric-coated acetylsalicylic acid overdose: a case report and review of the literature.
      Case report171HD≅341
      Wrathall, 2001
      • Wrathall G.
      • Sinclair R.
      • Moore A.
      • et al.
      Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose.
      Series397HD, CRRTCHR1
      117HD, CRRT191
      86CRRT1
      Chase, 2002
      • Chase P.B.
      • Walter F.G.
      • James S.
      Whole bowel irrigation, hemodialysis, and continuous venovenous hemodiafiltration in the successful treatment of severe salicylate poisoning: case report.
      Case report183HD, CRRT191
      Manikian, 2002
      • Manikian A.
      • Stone S.
      • Hamilton R.
      • et al.
      Exchange transfusion in severe infant salicylism.
      Case report185ET1
      Lund, 2005
      • Lund B.
      • Seifert S.A.
      • Mayersohn M.
      Efficacy of sustained low-efficiency dialysis in the treatment of salicylate toxicity.
      Case report1110HD141
      Birnbaum, 2006
      • Birnbaum K.
      • Culp J.
      • Cantrell F.L.
      Survival despite potentially deadly salicylate level.
      Case report1195HD101
      Levine, 2006
      • Levine M.
      • Nikkanen H.
      • Nadel E.S.
      • et al.
      Weakness and mental status change.
      Case report159HD1
      Satar, 2006
      • Satar S.
      • Alpay N.R.
      • Sebe A.
      • et al.
      Emergency hemodialysis in the management of intoxication.
      Series2227HD1
      238HD1
      Aleguas, 2007
      • Aleguas A.
      • Sheroff A.
      Treatment of a potentially fatal dose of methyl salicylate utilizing high volume volume fluid administration.
      Case report187HD11
      Cannon, 2007
      • Cannon R.D.
      • O'Connor A.D.
      Survival with an extremely high salicylate level.
      Case report1152CRRT81
      Marquardt, 2007
      • Marquardt K.A.
      • Anderson K.
      • Offerman S.R.
      Severe salicylate poisoning from Hong Hoa oil.
      Case report193HDCHR1
      Kent, 2008
      • Kent K.
      • Ganetsky M.
      • Cohen J.
      • et al.
      Non-fatal ventricular dysrhythmias associated with severe salicylate toxicity.
      Case report1152HD, CRRT1
      Kostic, 2008
      • Kostic M.A.
      • Gummin D.D.
      Persistent cerebral edema and death after hemodialysis for chronic salicylism.
      Same patient with 2 distinct poisonings.
      Series255HDCHR1
      46HDCHR1
      O’Shura, 2008
      • O'Shura J.S.
      • Brooks D.E.
      • Pizon A.F.
      Highest reported salicylate level with survival.
      Case report1176HD1
      Aleguas 2009
      • Aleguas A.
      • Foran M.P.
      Delayed salicylate treatment requiring massive potassium supplementation.
      Case report178HD, CRRT
      Lu, 2009
      • Lu J.J.
      Perilous propositions: intubating the salicylate poisoned patient.
      Case series675HD1
      89HD1
      101HD1
      45HD1
      90HD1
      94HD1
      Meehan, 2009
      • Meehan T.J.
      • Kalimullah E.A.
      • Erickson T.B.
      Two for the price of one: occult salicylate overdose masked by sodium cyanide ingestion.
      Case report191HD>41
      Quintero, 2009
      • Quintero Parra N.
      • Wurgaft Kirberg A.
      • Orellana Araya Y.
      • et al.
      Haemodialysis management for salicylate intoxication.
      Case report168HD181
      Thomas, 2009
      • Thomas B.
      • Valcarcel M.R.
      • Aglieco F.
      • et al.
      Salicylate toxicity and early hemodialysis.
      Case report192HD121
      Dulaney, 2010
      • Dulaney A.
      • Kerns II, W.
      Delayed peak salicylate level following intentional overdose.
      Case report1102HD281
      Grandey, 2010
      • Grandey K.
      • Lu J.
      • Bryant S.
      Negligible initial salicylate concentrations: are they inconsequential?.
      Series299HD1
      123HD1
      French, 2011
      • French L.K.
      • McKeown N.J.
      • Hendrickson R.G.
      Continuous renal replacement therapy for salicylate overdose in a patient with multi-system trauma.
      Case report145CRRT1
      Minns, 2011
      • Minns A.B.
      • Cantrell F.L.
      • Clark R.F.
      Death due to acute salicylate intoxication despite dialysis.
      Case report192HD9.51
      Muniandi, 2012
      • Muniandy R.K.
      • Sinnathamby V.
      Salicylate toxicity from ingestion of traditional massage oil.
      Case report1112HD>41
      Farmer, 2013
      • Farmer B.
      • Chen B.
      • Hoffman R.S.
      • et al.
      Ketamine and midazolam for procedural sedation prevents respiratory depression in lifethreatening aspirin toxicity.
      Case report1104HD91
      —, information unknown or unavailable.
      ECTR, Extracorporeal treatment; [SA], salicylate concentration; PD, peritoneal dialysis; ET, exchange transfusion; HD, intermittent hemodialysis; HP, hemoperfusion; CHR, chronic salicylate poisoning; CRRT, continuous renal replacement therapy.
      Same patient with 2 distinct poisonings.
      Table 4Aggregate clinical data related to the 130 reported patients who received extracorporeal treatment for salicylate toxicity.
      These include only cases in which patient-level data could be extracted (patients from the controlled trial by Summit and Etteldorf36 were not included).
      Clinical DataResult
      Demographics
      Median age, y14.5 (range 0.1–88)
      Male, %52
      Poisoning exposure
      Acute exposure, %77
      Form
      Oral salicylate, %86
      Oral methyl salicylate, %11
      Rectal salicylate, %1
      Topical salicylate, %2
      Median salicylate exposure, g28 (range 0.8–230)
      Median exposure/body weight, mg/kg798 (range 182–6,614)
      Median peak salicylate concentration, mg/dL86 (range 35–238)
      Median delay between acute exposure and admission, h9.8 (0.4–72)
      Toxic manifestations
      These data were often underreported in case reports, so the real incidence is likely higher.
      Altered consciousness, %62
      Seizure (≥1), %11
      Vomiting, %22
      Hyperthermia, %43
      Hypotension, %15
      Pulmonary edema, %5
      Median lowest arterial bicarbonate, mmol/L12.9 (range 3.5–29)
      Median arterial PCO2, mm Hg21 (9.6–71)
      Median initial serum potassium, mmol/L3.9 (range 2.1–7.2)
      Acute kidney injury, %15
      Other treatments administered
      Gastric lavage, %18
      Activated charcoal, %14
      Intravenous bicarbonate, %49
      Mechanical ventilation, %19
      Vasopressors, %10
      Extracorporeal treatments
      Median time from admission to ECTR initiation, h4.0 (range 0.5–150)
      Hemodialysis, %50
      Hemoperfusion, %9
      Continuous renal replacement therapy, %2
      Peritoneal dialysis, %18
      Intermittent hemofiltration-hemoperfusion, %1
      Exchange transfusion, %15
      More than 1 ECTR, %5
      Outcome
      Death, %11
      Permanent sequelae, %1
      These include only cases in which patient-level data could be extracted (patients from the controlled trial by Summit and Etteldorf
      • Summitt R.L.
      • Etteldorf J.N.
      Salicylate intoxication in children—experience with peritoneal dialysis and alkalinization of the urine.
      were not included).
      These data were often underreported in case reports, so the real incidence is likely higher.
      The review identified 14 fatalities in patients with extracorporeal treatment for salicylate poisoning, including 8 who received intermittent hemodialysis,
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      • Grandey K.
      • Lu J.
      • Bryant S.
      Negligible initial salicylate concentrations: are they inconsequential?.
      • Kostic M.A.
      • Gummin D.D.
      Persistent cerebral edema and death after hemodialysis for chronic salicylism.
      • Lu J.J.
      Perilous propositions: intubating the salicylate poisoned patient.
      • Minns A.B.
      • Cantrell F.L.
      • Clark R.F.
      Death due to acute salicylate intoxication despite dialysis.
      • Schreiner G.E.
      The role of hemodialysis (artificial kidney) in acute poisoning.
      1 treated with hemoperfusion,
      • Knutsen K.M.
      • Skuterud B.
      • Halvorsen S.
      Hemoperfusion in poisoning.
      2 treated with peritoneal dialysis,
      • Schlegel R.J.
      • Altstatt L.B.
      • Canales L.
      • et al.
      Peritoneal dialysis for severe salicylism: an evaluation of indications and results.
      • Snodgrass W.
      • Rumack B.H.
      • Peterson R.G.
      • et al.
      Salicylate toxicity following therapeutic doses in young children.
      2 treated with exchange transfusion,
      • Doolan P.
      Acetylsalicylic acid intoxication—a proposed method of treatment.
      • Leikin S.L.
      • Emmanouilides G.C.
      The use of exchange transfusion in salicylate intoxication: report of 7 cases.
      and 1 with continuous venovenous hemodialfiltration.
      • French L.K.
      • McKeown N.J.
      • Hendrickson R.G.
      Continuous renal replacement therapy for salicylate overdose in a patient with multi-system trauma.
      In some of these reports, death occurred despite significant reductions in salicylate concentrations with extracorporeal treatment.
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      • Schreiner G.E.
      The role of hemodialysis (artificial kidney) in acute poisoning.
      In most cases, death appeared to result from salicylate toxicity; in at least 1 case, however, extracorporeal treatment may have contributed to the outcome. Snodgrass et al
      • Snodgrass W.
      • Rumack B.H.
      • Peterson R.G.
      • et al.
      Salicylate toxicity following therapeutic doses in young children.
      described the case of an 18-month-old with a peak salicylate concentration of 12.2 mmol/L (168.4 mg/dL) who showed clinical improvement after peritoneal dialysis but deteriorated and died of peritonitis on the fourth hospital day. It is not otherwise possible to draw meaningful inferences from these reports, which represent only a small proportion of salicylate-related fatalities and offer little insight into the incidence of complications associated with extracorporeal treatment.
      A systematic review of complications associated with various extracorporeal removal techniques for poisoning has not yet been published, to our knowledge. In the studies reviewed for this article, adverse effects of the procedures used were inconsistently reported, although many are expected complications related to the procedure used, including hypotension during hemodialysis,
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      • Aleguas A.
      • Foran M.P.
      Delayed salicylate treatment requiring massive potassium supplementation.
      • Snodgrass W.
      • Rumack B.H.
      • Peterson R.G.
      • et al.
      Salicylate toxicity following therapeutic doses in young children.
      • Zimmerman G.A.
      • Clemmer T.P.
      Acute respiratory failure during therapy for salicylate intoxication.
      bleeding from the catheter site,
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      • Wanscher M.C.
      • Frifelt J.J.
      • Molsted K.
      Double-lumen hemodialysis catheters in the treatment of acetylsalicylic acid and lithium poisoning.
      peritoneal dialysis–associated peritonitis,
      • Snodgrass W.
      • Rumack B.H.
      • Peterson R.G.
      • et al.
      Salicylate toxicity following therapeutic doses in young children.
      transfusion reaction during exchange transfusion,
      • Leikin S.L.
      • Emmanouilides G.C.
      The use of exchange transfusion in salicylate intoxication: report of 7 cases.
      and moderate thrombocytopenia during hemoperfusion sometimes related to bleeding (hemoperfusion).
      • Gelfand M.C.
      • Winchester J.F.
      • Knepshield J.H.
      • et al.
      Treatment of severe drug overdosage with charcoal hemoperfusion.
      • Hampel G.
      • Crome P.
      • Widdop B.
      • et al.
      Experience with fixed-bred charcoal haemoperfusion in the treatment of severe drug intoxication.
      • Koffler A.
      • Bernstein M.
      • LaSette A.
      • et al.
      Fixed-bed charcoal hemoperfusion. Treatment of drug overdose.
      Multiple studies describe the use of various extracorporeal treatment modalities for the treatment of salicylate poisoning in animals. Hemoperfusion markedly decreases salicylate concentrations in rats.
      • Hill J.B.
      • Palaia F.L.
      • McAdams J.L.
      • et al.
      Efficacy of activated charcoal hemoperfusion in removing lethal doses of barbiturates and salicylate from the blood of rats and dogs.
      In a canine model, peritoneal dialysis removed between 5.4% and 14% of intravenously administered sodium salicylate, whereas exchange transfusion removed approximately 20% and hemodialysis approximately 50%.
      • James J.A.
      • Kimbell L.
      • Read W.T.
      Experimental salicylate intoxication. I. Comparison of exchange transfusion, intermittent peritoneal lavage, and hemodialysis as means for removing salicylate.
      In another report, hemoperfusion removed 41% of orally administered acetylsalicylic acid (500 mg/kg).
      • Widdop B.
      • Medd R.K.
      • Braithwaite R.A.
      • et al.
      Experimental drug intoxication: treatment with charcoal haemoperfusion.
      In salicylate-poisoned dogs, approximately half of the administered dose was removed by dialysis during a 4-hour period compared with 17% recovered in the urine of control animals.
      • Engel H.P.
      • Metcalfe J.O.
      Extracorporeal hemodialysis in the treatment of salicylate intoxication in dogs.
      Several human case reports and case series also demonstrate efficient removal of salicylate by both hemodialysis
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      • Doolan P.
      Acetylsalicylic acid intoxication—a proposed method of treatment.
      • Jacobsen D.
      • Wiik-Larsen E.
      • Bredesen J.E.
      Haemodialysis or haemoperfusion in severe salicylate poisoning?.
      • Magness J.L.
      • Murray J.B.
      Treatment of salicylate intoxication using extracorporeal hemodialysis.
      and hemoperfusion (Table 5).
      • Fantozzi R.
      • Martinelli F.
      • Masini E.
      • et al.
      Use of haemoperfusion with uncoated charcoal in the management of acute intoxications with barbiturate and salicylate.
      • Hampel G.
      • Crome P.
      • Widdop B.
      • et al.
      Experience with fixed-bred charcoal haemoperfusion in the treatment of severe drug intoxication.
      • Jacobsen D.
      • Wiik-Larsen E.
      • Bredesen J.E.
      Haemodialysis or haemoperfusion in severe salicylate poisoning?.
      Where documented, the extent of removal is typically on the order of 50% to 60% of the ingested dose, although it is considerably lower with peritoneal dialysis compared with hemoperfusion or hemodialysis.
      • Buselmeier T.J.
      • Lynch R.E.
      • Davin T.D.
      • et al.
      Severe salicylate intoxication in small children.
      • Etchart L.W.
      Peritoneal dialysis in salicylate intoxication.
      • Kloss J.L.
      • Boeckman C.R.
      Methyl salicylate poisoning. Case report and discussion of treatment by peritoneal dialysis.
      • Zachau-Christiansen B.
      3 Cases of salicylic acid poisoning in infants.
      For example, in one report, only approximately 5% of the reported amount of acetylsalicylic acid ingested was recovered in dialysate after 16 hours of peritoneal dialysis.
      • Etchart L.W.
      Peritoneal dialysis in salicylate intoxication.
      Although a few case reports describe continuous extracorporeal treatment in patients with salicylate toxicity,
      • Chase P.B.
      • Walter F.G.
      • James S.
      Whole bowel irrigation, hemodialysis, and continuous venovenous hemodiafiltration in the successful treatment of severe salicylate poisoning: case report.
      • French L.K.
      • McKeown N.J.
      • Hendrickson R.G.
      Continuous renal replacement therapy for salicylate overdose in a patient with multi-system trauma.
      • Wrathall G.
      • Sinclair R.
      • Moore A.
      • et al.
      Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose.
      the clearance of salicylate by these methods (7.5 mL/min) is several-fold inferior to hemodialysis or hemoperfusion.
      • French L.K.
      • McKeown N.J.
      • Hendrickson R.G.
      Continuous renal replacement therapy for salicylate overdose in a patient with multi-system trauma.
      Several reports describe the use of exchange transfusion in very young children with salicylate poisoning.
      • Adams J.T.
      • Bigler J.A.
      • Green O.C.
      A case of methyl salicylate intoxication treated by exchange transfusion.
      • Caseley R.T.
      Salicylate poisoning: a case in infancy treated by exchange transfusion.
      • Done A.K.
      • Otterness L.J.
      Exchange transfusion in the treatment of oil of wintergreen (methyl salicylate) poisoning.
      • Leikin S.L.
      • Emmanouilides G.C.
      The use of exchange transfusion in salicylate intoxication: report of 7 cases.
      • Leikin S.L.
      • Lopresti J.M.
      • Pohl D.R.
      Severe salicylate intoxication treated by exchange transfusion.
      • Manikian A.
      • Stone S.
      • Hamilton R.
      • et al.
      Exchange transfusion in severe infant salicylism.
      • Millar R.J.
      • Bowman J.
      Oil of wintergreen (methyl salicylate) poisoning treated by exchange transfusion.
      In these, the amount of salicylate removed typically represented 20% to 25% of the estimated dose that was reportedly ingested, and salicylate concentrations decreased by approximately 50% of values obtained before exchange. The rationale for exchange transfusion rests in the very low volume of distribution of salicylate.
      Table 5Toxicokinetic results and grading in humans.
      ArticleECTRExposure, GramsPeak [SA], mg/dLAmount Removed by ECTR (Approximate %, Where Applicable)Apparent Half-life, HoursECTR Clearance, mL/minKidney Clearance, mL/minDialyzability Grading
      Doolan, 1951
      • Doolan P.
      Acetylsalicylic acid intoxication—a proposed method of treatment.
      HD42551,300 mg in 60 min (3.1)39MD
      HD (volunteer, ESRD)3.1111,000 mg in 180 min (32.6)64D
      HD (volunteer, ESRD)3.1131,326 mg in 180 min (43.2)76D
      Leonard, 1955
      • Leonards J.
      Use of artificial kidney for purposes other then treatment of uremia.
      HD1309,500 mg in 360 min321.9D
      Schreiner, 1955
      • Schreiner G.E.
      • Berman L.B.
      • Griffin J.
      • et al.
      Specific therapy for salicylism.
      HD210909,400 mg in 450 min (3.9)4.1 h during HD43MD
      Done, 1956
      • Done A.K.
      • Otterness L.J.
      Exchange transfusion in the treatment of oil of wintergreen (methyl salicylate) poisoning.
      ET (1.4 L total)2886542 mg in 214 min (1.9)3.81.8SD
      Adams, 1957
      • Adams J.T.
      • Bigler J.A.
      • Green O.C.
      A case of methyl salicylate intoxication treated by exchange transfusion.
      ET (1 volume)7737.2 h during HD vs 24 h post-HDDD
      Schreiner, 1958
      • Schreiner G.E.
      The role of hemodialysis (artificial kidney) in acute poisoning.
      HD421103,500 mg in 180 min (8.3)1.6 h during HD25.9MD
      Leikin, 1959
      • Leikin S.L.
      • Lopresti J.M.
      • Pohl D.R.
      Severe salicylate intoxication treated by exchange transfusion.
      ET5.8 (during 3 days)103752 mg (13.0)5.1MD
      7.31501,940 mg (26.6)9.8D
      Spritz, 1959
      • Spritz N.
      • Fahey Jr., T.J.
      • Thompson D.D.
      • et al.
      The use of extracorporeal hemodialysis in the treatment of salicylate intoxication in a 2-year-old child.
      HD622,000 mg in 300 min3.4 h during HD23.8D
      Leikin, 1960
      • Leikin S.L.
      • Emmanouilides G.C.
      The use of exchange transfusion in salicylate intoxication: report of 7 cases.
      (3 of 7 patients are duplicates from Leikin, 1959
      • Leikin S.L.
      • Lopresti J.M.
      • Pohl D.R.
      Severe salicylate intoxication treated by exchange transfusion.
      ; the other 4 are shown here)
      ET double volume12.8104
      ET double volume>51401,676 mg9.4D
      ET double volume>81601,826 mg8.9D
      Etteldorf, 1961
      • Etteldorf J.N.
      • Dobbins W.T.
      • Summitt R.L.
      • et al.
      Intermittent peritoneal dialysis using 5 per cent albumin in the treatment of salicylate intoxication in children.
      Albumin PD41310 mg in 360 min9.1 h during PD5.00.6D
      Albumin PD62771 mg in 420 min11.5 h during PD
      Based on 2 points only (all data available).
      7.30.8D
      Albumin PD51602 mg in 660 min9.5 h during PD
      Based on 2 points only (all data available).
      3.60.7MD
      Albumin PD45441 mg in 570 min11 h during PD
      Based on 2 points only (all data available).
      3.00.6MD
      Albumin PD40393 mg in 360 min8.9 h during PD
      Based on 2 points only (all data available).
      7.70.9D
      Albumin PD521,085 mg in 600 min10.9 h during PD
      Based on 2 points only (all data available).
      7.71.6D
      Albumin PD42419 mg in 360 min7.6 h during PD
      Based on 2 points only (all data available).
      4.81.0MD
      Magness, 1961
      • Magness J.L.
      • Murray J.B.
      Treatment of salicylate intoxication using extracorporeal hemodialysis.
      HD32.5993,200 mg in 120 min (9.8)3.8 h on HD
      Based on 2 points only (all data available).
      37.6D
      Millar, 1961
      • Millar R.J.
      • Bowman J.
      Oil of wintergreen (methyl salicylate) poisoning treated by exchange transfusion.
      ET double volume2170852 mg in 180 min (4.1)3.3 h during ET
      Based on 2 points only (all data available).
      8.9SD
      Caseley, 1962
      • Caseley R.T.
      Salicylate poisoning: a case in infancy treated by exchange transfusion.
      ET9 during 4 days705.8 h during ET vs 22 h post-ETM
      Etchart, 1965
      • Etchart L.W.
      Peritoneal dialysis in salicylate intoxication.
      PD65873,000 mg in 960 min (4.6)5.64.7ND
      Fine, 1968
      • Fine R.N.
      • Stiles Q.
      • DePalma J.R.
      • et al.
      Hemodialysis in infants under 1 year of age for acute poisoning.
      HD5.6897.3 h during HD vs 14.9 h post-HDS
      Fantozzi, 1981
      • Fantozzi R.
      • Martinelli F.
      • Masini E.
      • et al.
      Use of haemoperfusion with uncoated charcoal in the management of acute intoxications with barbiturate and salicylate.
      HP484,677 mg in 180 min4.4 h during HP100D
      Jacobsen, 1988
      • Jacobsen D.
      • Wiik-Larsen E.
      • Bredesen J.E.
      Haemodialysis or haemoperfusion in severe salicylate poisoning?.
      HD1239,000 mg in 190 min5.9 h during HD vs 1.9 h during HD862D
      HP60–709516,900 mg in 300 min (24.4 to 28.2)6.2 h during HP8125D
      Pec, 1992
      • Pec J.
      • Strmenova M.
      • Palencarova E.
      • et al.
      Salicylate intoxication after use of topical salicylic acid ointment by a patient with psoriasis.
      HD837.5 h during HD vs 13.6 post-HDD
      Watson, 1994
      • Watson J.E.
      • Tagupa E.T.
      Suicide attempt by means of aspirin enema.
      HD227.512026.6 h pre-HD vs 1.3 h during HD
      Based on 2 points only (all data available).
      D
      Reblin 1998
      • Reblin T.
      • Wolf G.
      • De Weerth A.
      • et al.
      Extracorporeal elimination of salicylate by hemofiltration.
      CRRT501497,312.5 mg in 600 min (14.6)8 h during CRRT5.5SD
      Manikian, 2002
      • Manikian A.
      • Stone S.
      • Hamilton R.
      • et al.
      Exchange transfusion in severe infant salicylism.
      ET double volume8535 h pre-ET vs 8.2 h during ET vs 12.5 h post-ETSD
      Lund, 2005
      • Lund B.
      • Seifert S.A.
      • Mayersohn M.
      Efficacy of sustained low-efficiency dialysis in the treatment of salicylate toxicity.
      HD, SLED32.51106.2 h during HD vs 7.4 h during SLED vs 12.3 h post-ECTR1.7M for HD, SD for SLED
      Kent, 2008
      • Kent K.
      • Ganetsky M.
      • Cohen J.
      • et al.
      Non-fatal ventricular dysrhythmias associated with severe salicylate toxicity.
      HD-CRRT1522 h during HD-CRRT vs 16 h post-HD-CRRTD
      —, unknown.
      SLED, sustained low-efficiency dialysis; HD-CRRT, hemodialysis with continuous renal replacement therapy; PD, peritoneal dialysis.
      Based on 2 points only (all data available).
      In accordance with the individual pharmacokinetic and toxicokinetic grading (Table 6), the group agreed that salicylates are dialyzable by the most efficient extracorporeal treatment techniques (level of evidence B). Many of these reports describe older extracorporeal treatment technologies, and removal is likely to be considerably greater with present-day techniques that use more efficient filters (ie, with higher surface area) and higher blood flow rates.
      Table 6Summary of kinetic outcomes for salicylate poisoning (n=35).
      Some patients received more than 1 ECTR and so their data can appear at more than 1 place.
      TK/PK GradingPD, nHP, nHD, nCRRT, nET, nSLED, nHD-CRRT, n
      D: Dialyzable4280401
      M: moderately dialyzable3040200
      S: Slightly dialyzable0011310
      N: not dialyzable1000000
      TK, Toxicokinetic; PK, pharmacokinetic.
      Some patients received more than 1 ECTR and so their data can appear at more than 1 place.
      One study suggested that urinary alkalinization and hemodialysis were equally effective at removing salicylate.
      • Higgins R.M.
      • Connolly J.O.
      • Hendry B.M.
      Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient.
      However, because the investigators quantified neither removal nor clearance, the 2 interventions could not be directly compared. In a pediatric series in which salicylate removal was quantified, peritoneal dialysis (a low-efficiency technique) was comparable to urinary alkalinization.
      • Summitt R.L.
      • Etteldorf J.N.
      Salicylate intoxication in children—experience with peritoneal dialysis and alkalinization of the urine.
      In another report, high-efficiency extracorporeal treatment provided at least 3 times the clearance generated by intravenous alkalinization when studied in the same patient.
      • Jacobsen D.
      • Wiik-Larsen E.
      • Bredesen J.E.
      Haemodialysis or haemoperfusion in severe salicylate poisoning?.
      Figure 5 summaries our recommendations.
      Extracorporeal treatment is recommended in severe salicylate poisoning (1D). The rationale is that, with the exception of urinary alkalinization, extracorporeal treatment is the only intervention that convincingly and rapidly reduces the burden of circulating salicylate. It does so efficiently (extracorporeal treatment clearance can surpass 100 mL/min
      • Jacobsen D.
      • Wiik-Larsen E.
      • Bredesen J.E.
      Haemodialysis or haemoperfusion in severe salicylate poisoning?.
      ) and also allows correction of acidemia, which will lessen the delivery of salicylate to the brain. In some instances, the availability of alternative means of enhanced elimination (such as multiple-dose activated charcoal and urinary alkalization) may erroneously lead clinicians to delay implementation of extracorporeal treatment.
      • Fertel B.S.
      • Nelson L.S.
      • Goldfarb D.S.
      The underutilization of hemodialysis in patients with salicylate poisoning.
      Considering the relatively low cost and infrequent complications of extracorporeal treatment, the significant morbidity and mortality associated with severe salicylate poisoning, and the lack of an antidote or other definitive therapies, the group concluded that there was sufficient justification to use extracorporeal treatment in patients with severe salicylate poisoning. Despite the paucity of convincing data about the effect of extracorporeal treatment on clinical outcomes and the impracticability of a controlled clinical trial, this conclusion was unanimously supported by all 28 participants. However, the group also acknowledged that salicylate removal is a surrogate measure; the challenge rests in identifying patients with salicylate toxicity for whom extracorporeal treatment is likely to favorably influence the more meaningful outcomes of morbidity and mortality. The available literature does not confidently identify these patients. Extracorporeal treatment affords several advantages over urinary alkalinization, including more rapid clearance of salicylate and more predictable correction of acidemia.
      Salicylate poisoning is a medical emergency and patients may die with or without receiving extracorporeal treatment.
      • Fertel B.S.
      • Nelson L.S.
      • Goldfarb D.S.
      The underutilization of hemodialysis in patients with salicylate poisoning.
      • McGuigan M.A.
      A two-year review of salicylate deaths in Ontario.
      However, when a decision is made to proceed with extracorporeal treatment, it should be implemented promptly because this will give the best chances of survival. This is particularly important for patients with acute salicylate poisoning, who often appear relatively well in the hours shortly after overdose despite substantially elevated salicylate concentrations. Prompt implementation of extracorporeal treatment in these patients may limit the entry of salicylate into the central nervous system, from where it is less rapidly cleared.
      Extracorporeal treatment is recommended if the salicylate concentration is greater than 7.2 mmol/L (100 mg/dL) after acute salicylate poisoning (1D).
      Extracorporeal treatment is suggested if the acetylsalicylic acid concentration is greater than 6.5 mmol/L (90 mg/dL) (2D).
      The rationale is as follows: Unlike patients with chronic salicylate poisoning, those with acute poisoning may have elevated salicylate concentrations despite few other signs or symptoms, particularly in the early period after ingestion. Existing data do not identify a salicylate concentration threshold predictive of a poor outcome. Although its interpretations were contested,
      • Dugandzic R.M.
      • Tierney M.G.
      • Dickinson G.E.
      • et al.
      Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication.
      the study by Done
      • Done A.K.
      Salicylate intoxication. Significance of measurements of salicylate in blood in cases of acute ingestion.
      reported a significantly higher median salicylate concentration in patients who died than in those who did not (7.3 mmol/L [100 mg/dL] versus 4.3 mmol/L [60 mg/dL]). Other studies observed no statistical difference in peak salicylate concentrations between fatal (6.5 mmol/L [90 mg/dL]) and nonfatal cases (6 mmol/L [83 mg/dL]).
      • Chapman B.J.
      • Proudfoot A.T.
      Adult salicylate poisoning: deaths and outcome in patients with high plasma salicylate concentrations.
      A review of all salicylate-related fatalities in the United States during a 17-year period found that the mean salicylate concentration was 6.9 mmol/L (96 mg/dL) but was lower in patients older than 50 years.
      • Smolinske S.
      • Temple K.
      • Lada P.
      • et al.
      Take too (many) ASA and call me from the morgue.
      Other investigators observed that in approximately one quarter of deaths the patients had a salicylate concentration below 5.8 mmol/L (80 mg/dL), but the timing of this concentration is unclear.
      • Martin T.
      Fatal salicylate levels can be lower than expected.
      Finally, yet another abstract suggested that salicylate concentration was predictive of hemodialysis requirement.
      • Mckeever R.G.
      • Sexton K.J.
      • Vearrier D.
      • et al.
      Characteristics of salicylate ingestions reported to the toxic registry.
      The workgroup noted that the interpretation of salicylate concentrations without an understanding of the delay postingestion and concomitant acid-base status of the patient may bias these conclusions because pH modulates salicylate partitioning into the brain. Despite the controversy, the workgroup suggested that extracorporeal treatment be administered regardless of clinical status in any patient with a salicylate concentration greater than 6.5 mmol/L (90 mg/dL). This was unanimously recommended when the concentration was greater than 7.2 mmol/L (100 mg/dL). Over this threshold, the likelihood of a fatal outcome was considered significant.
      • McGuigan M.A.
      A two-year review of salicylate deaths in Ontario.
      In patients with very elevated salicylate concentrations, the workgroup advocates extracorporeal treatment even in the absence of clinical signs and symptoms because subsequent deterioration is common, because salicylate concentrations may increase unpredictably as the result of ongoing gastrointestinal absorption, and because removal from the vascular compartment before distribution into the central nervous system is likely to be an important determinant of a patient’s subsequent course.
      Extracorporeal treatment is recommended if: acetylsalicylic acid concentration is greater than 6.5 mmol/L (90 mg/dL) in patients with impaired kidney function (1D).
      Extracorporeal treatment is suggested if acetylsalicylic acid concentration is greater than 5.8 mmol/L (80 mg/dL) in patients with impaired kidney function (2D).
      The rationale is the following: The EXTRIP nephrology subcommittee proposed a general definition of impaired kidney function relevant to toxin clearance, including any of the following:
      • 1)
        Advanced stage 3b, 4, or 5 chronic kidney disease (ie, estimated glomerular filtration rate, (eGFR) <45 mL/min per 1.73 m2)
      • 2)
        Stage 2 or 3 acute kidney injury from the Kidney Disease Improving Global Outcomes classification
      • 3)
        In the absence of a baseline serum creatinine concentration, 176 μmol/L (2 mg/dL) in adults or 132 μmol/L (1.5 mg/dL) in the elderly or patients with low muscle mass
      • 4)
        In children with no baseline creatinine concentration, a serum creatinine greater than twice the upper limit of normal for age and sex
      • 5)
        The presence of oligo/anuria for more than 6 hours, regardless of serum creatinine concentration
      The workgroup advocates a lower threshold for the implementation of extracorporeal treatment in patients with impaired kidney function because the kidney is the primary route of elimination for salicylate and its metabolites. A recommendation was set at 6.5 mmol/L (90 mg/dL) and a suggestion is made for 5.8 mmol/L (80 mg/dL). All other factors being equal, decreased salicylate clearance is likely to be associated with worse clinical outcomes. In formulating this recommendation, the workgroup acknowledged that these factors would influence clinical decisions on a case-by-case basis.
      Extracorporeal treatment is suggested if the blood pH is less than or equal to 7.20 (2D). The rationale is as follows: The work group acknowledged that even mild acidemia is of concern in patients with salicylate poisoning, regardless of whether the primary disorder is metabolic (reflecting the metabolic effects of salicylate) or respiratory (the converse of the expected respiratory response to salicylate poisoning, reflecting respiratory fatigue, coingestion of a respiratory depressant, or the development of acute respiratory distress syndrome). In the setting of salicylate poisoning, acidemia not only reflects serious organ dysfunction but also favors the formation of nonionized salicylic acid, which crosses readily into the central nervous system. In its discussions, the group recognized that dialysis based on pH alone would apply primarily to patients with acute salicylate poisoning and high anion gap metabolic acidosis because patients with chronic salicylate poisoning who are acidemic would invariably meet other criteria. The target pH chosen by the workgroup (pH ≤7.2) is one associated with poor outcomes in salicylate poisoning.
      • Chapman B.J.
      • Proudfoot A.T.
      Adult salicylate poisoning: deaths and outcome in patients with high plasma salicylate concentrations.
      The group also acknowledged that most patients with this degree of acidemia would most likely have other indications for extracorporeal treatment.
      Extracorporeal treatment is recommended in the presence of altered mental status (1D).
      The rationale is as follows: In patients with salicylate poisoning, altered mental status reflects end-organ toxicity and is a sign of serious toxicity. Even subtle cognitive abnormalities or agitation can reflect accumulation of salicylate into the central nervous system and may be a harbinger of profound toxicity and death. Removal of salicylate by extracorporeal treatment is expected to reduce the burden of salicylate in the central nervous system and may prevent the development of cerebral edema, a common finding at autopsy. Coingestants and other comorbidities can influence mental status and obfuscate the contribution of salicylate, and it is important to consider all factors when implementing extracorporeal treatment solely on the basis of altered mental status.
      Extracorporeal treatment is recommended in the presence of new hypoxemia requiring supplemental oxygen (1D).
      The rationale is as follows: The acute respiratory distress syndrome (ARDS) (formerly known as acute lung injury) is a well-described manifestation of end-organ toxicity of salicylates and as such is indicative of severe poisoning. Although ARDS can develop after acute overdose, it occurs most commonly in patients with chronic salicylate poisoning.

      Boyer EW, Weibrecht KW. Salicylate (aspirin) poisoning in adults. UpToDate. Wolters Kluwer Health; 2014. Available at: www.uptodate.com. Accessed April 10, 2015.

      In addition, the development of ARDS complicates other elements of supportive care (such as the administration of crystalloid and bicarbonate), and the associated respiratory fatigue can interfere with the protective hyperventilation of salicylate poisoning. As noted earlier, salicylate poisoning is generally accompanied by tachypnea, hyperpnea, and hyperventilation, and these findings in isolation are not necessarily reflective of acute respiratory distress syndrome. Consequently, the workgroup agreed that in this context the development of new hypoxemia requiring supplemental oxygen (with or without parenchymal infiltrates) be considered presumptive evidence of salicylate-induced ARDS and an independent indication for extracorporeal treatment. Our recommendation is supported by the observation that hypoxemia predicts a poor outcome; in one study, the mean PaO2 was 99 mm Hg in survivors and 80 mm Hg in fatalities.
      • Chapman B.J.
      • Proudfoot A.T.
      Adult salicylate poisoning: deaths and outcome in patients with high plasma salicylate concentrations.
      Extracorporeal treatment is recommended if standard therapy (supportive measures, bicarbonate, etc) fails (1D). The rationale is as follows: Although many patients with salicylate poisoning can be managed with supportive care and urinary alkalinization, in more severe cases these interventions alone often fail. The consensus opinion of the workgroup was that extracorporeal treatment should be implemented in the event that supportive care is deemed to be failing. Given the complexity of salicylate poisoning, the determination that supportive care is failing can be a difficult one to establish but might include a rapidly increasing salicylate concentration despite gastrointestinal decontamination and urinary alkalinization. Timely involvement of a clinical toxicologist is advisable in all cases.
      It is suggested not to perform extracorporeal treatment on the basis of acetylsalicylic acid ingestion history alone (2D).
      The rationale is as follows: The workgroup recognized that in patients with acute salicylate poisoning, the manifestations of toxicity (and, by extension, the appropriateness of extracorporeal treatment) would increase with the reported amount ingested. However, the workgroup agreed that in light of uncertainty surrounding the ingested dose,
      • Monte A.A.
      • Heard K.J.
      • Hoppe J.A.
      • et al.
      The accuracy of self-reported drug ingestion histories in emergency department patients.
      the availability of salicylate assays in most institutions, and the many other factors that influence severity and prognosis of individual poisoning cases, a dose threshold alone is insufficient justification for extracorporeal treatment. Moreover, patients with very large ingestions are likely to meet at least 1 other criterion for the initiation of extracorporeal treatment, and prompt communication and possible transfer to a center that provides extracorporeal treatment is advisable for such patients, even in the absence of an existing indication for extracorporeal treatment.
      Extracorporeal treatment cessation is indicated when clinical improvement is apparent (1D) and a salicylate concentration is less than 1.4 mmol/L (19 mg/dL) (1D) or extracorporeal treatment has been performed for a period of at least 4 to 6 hours when salicylate concentrations are not readily available (2D).
      The rationale is as follows: The workgroup recognized the challenges associated with defining meaningful clinical improvement and with the interpretation of salicylate concentrations in isolation. Clinical improvement is typically characterized by normalization of mental status, resolution of hyperventilation and reduced oxygen requirements, and correction of acid-base abnormalities; these changes are generally (but not always) accompanied by a decline in salicylate concentrations. The possibility of a rebound in salicylate concentrations, either from ongoing absorption or redistribution from the intracellular compartment, was noted in several reports. For this reason, although the workgroup acknowledged that toxicity would be reduced when the salicylate concentration decreased to 2.2 mmol/L (30 mg/dL), a lower threshold was preferred (<1.4 mmol/L [19 mg/dL]). This would offer some security in light of the potential for rebound. Alternatively, if salicylate concentrations were not readily available, the workgroup concluded that at least 4 to 6 hours of high-efficiency extracorporeal treatment would be empirically reasonable. This is based on the assumption that with high-efficiency extracorporeal treatments and optimal operational parameters,
      • Bouchard J.
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      Principles and operational parameters to optimize poison removal with extracorporeal treatments.
      a salicylate half-life of 2 hours will be achieved during extracorporeal treatment.
      • Kent K.
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      • Watson J.E.
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      Suicide attempt by means of aspirin enema.
      As mentioned, the possibility of rebound warrants close monitoring of the patient’s clinical status and salicylate concentration. Therefore, it is generally advisable to leave the dialysis catheter in place until it is clear that the patient will not require a subsequent treatment.
      For choice of extracorporeal treatment, intermittent hemodialysis is the preferred modality of extracorporeal treatment (1D); hemoperfusion (1D) and continuous renal replacement techniques (3D) are acceptable alternatives if hemodialysis is not available.
      Exchange transfusion is an acceptable alternative to hemodialysis in neonates (1D).
      The rationale is as follows: Hemodialysis rapidly enhances salicylate clearance, corrects acidemia, and is widely available, easily implemented in most settings, and associated with a favorable risk profile. In contrast, hemoperfusion is encumbered by the low availability of charcoal cartridges,
      • Shalkham A.S.
      • Kirrane B.M.
      • Hoffman R.S.
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      The availability and use of charcoal hemoperfusion in the treatment of poisoned patients.
      • Ghannoum M.
      • Bouchard J.
      • Nolin T.D.
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      Hemoperfusion for the treatment of poisoning: technology, determinants of poison clearance, and application in clinical practice.
      the need to replace them during treatment, and the potential for thrombocytopenia, which is typically mild but may be of greater significance in patients who have received anticoagulation or whose platelet function is impaired by acetylsalicylic acid. Continuous renal replacement techniques provide lower salicylate dialysance than hemodialysis and should be implemented only if intermittent modalities are not available. The workgroup favored hemodialysis over continuous renal replacement techniques, even in the context of hypotension. The theoretical advantage of continuous renal replacement techniques with hypotension is unproven in situations in which net ultrafiltration (eg, fluid removal) is not required, such as in most cases of poisoning. The workgroup prefers the more efficient intermittent techniques even in the presence of hypotension. The available evidence about exchange transfusions is limited, but this remains a practical consideration in neonates because the technique is used in neonatal and pediatric critical care units and is technically easier to perform. There are no justifications for therapeutic plasma exchange, peritoneal dialysis, or liver support therapies in acetylsalicylic acid poisoning.
      The composition of the dialysis bath should account for the metabolic abnormalities typical of salicylate-poisoned patients, which differ from those of patients with end-stage kidney disease. In particular, the bicarbonate and potassium dialysate concentration need to be tailored to the patient’s requirement. Phosphate can also be added to the bath,
      • Dorval M.
      • Pichette V.
      • Cardinal J.
      • et al.
      The use of an ethanol- and phosphate-enriched dialysate to maintain stable serum ethanol levels during haemodialysis for methanol intoxication.
      if required, and the need for heparinization and ultrafiltration should be carefully considered according to clinical parameters.
      It is recommended to continue intravenous bicarbonate therapy between extracorporeal treatment sessions (1D). The rationale is as follows: Administration of intravenous bicarbonate is relatively safe and promotes alkalemia (if not already present) and alkaluria. The former minimizes entry of salicylate into the central nervous system,
      • Hill J.B.
      Salicylate intoxication.
      whereas the latter reduces renal tubular reabsorption and significantly increases renal excretion of salicylate when urine pH exceeds 7.5 or 8.
      • Kallen R.J.
      • Zaltzman S.
      • Coe F.L.
      • et al.
      Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders.
      For these reasons, intravenous bicarbonate is recommended between extracorporeal treatment sessions. Although, extracorporeal treatment enhances salicylate clearance and achieves alkalemia far more efficiently than bicarbonate, no agreement was reached about the ongoing administration of bicarbonate during extracorporeal treatment.
      Salicylates are capable of causing serious toxicity. The workgroup agreed that salicylates are dialyzable by high-efficiency extracorporeal treatments and unanimously recommended extracorporeal treatments in severe poisoning despite the absence of high-quality evidence. Indications for extracorporeal treatment include changes in mental status, new-onset hypoxemia, failure of supportive therapy, and very elevated salicylate concentrations regardless of clinical status. Emergency physicians should recognize these indications promptly and rapidly contact a dialysis unit for patients with significant salicylate poisoning.
      The authors acknowledge the tremendous work of our dedicated translators: Marcela Covica, Alexandra Angulo, Ania Gresziak, Samantha Challinor, Monique Cormier, 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, Angelina White, Salih Topal, John Hartmann, Karine Mardini, Mahala Bartle Mathiassen, Anant Vipat, Gregory Shapiro, Hannele Marttila, and Kapka Lazorova; and the important contribution from our librarians and secretarial aides: Marc Lamarre, David Soteros, Salih Topal, Henry Gaston, and Brenda Gallant.

      Appendix

       The EXTRIP Workgroup

      Kurt Anseeuw, Ashish Bhalla, Emmanuel A. Burdmann, Diane P. Calello, Paul I. Dargan, Brian S. Decker, David S. Goldfarb, Tais Galvo, Lotte C. Hoegberg, Martin Laliberté, Yi Li, Kathleen D. Liu, Robert MacLaren, Robert Mactier, Bruno Mégarbane, James B. Mowry, Véronique Phan, Darren M. Roberts, Timothy J. Wiegand, James F. Winchester, Christopher Yates

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