Use of extracorporeal treatments in the management of poisonings
2018; Elsevier BV; Volume: 94; Issue: 4 Linguagem: Inglês
10.1016/j.kint.2018.03.026
ISSN1523-1755
AutoresMarc Ghannoum, Robert S. Hoffman, Sophie Gosselin, Thomas D. Nolin, Valéry Lavergne, Darren M. Roberts,
Tópico(s)Pesticide Exposure and Toxicity
ResumoHistorically, the clinical application of extracorporeal treatments (ECTRs), such as hemodialysis or hemoperfusion, was first intended for poisoned patients. With time, ECTRs were used almost indiscriminately to facilitate the elimination of many poisons, albeit with uncertain clinical benefit. To determine the precise role of ECTRs in poisoning situations, multiple variables need to be considered including a careful risk assessment, the poison's characteristics including toxicokinetics, alternative treatments, the patient's clinical status, and intricacies of available ECTRs, all of which are reviewed in this article. Recently, evidence-based and expert opinion-based recommendations from the EXTRIP workgroup were also published to help minimize the knowledge gap in this area. Historically, the clinical application of extracorporeal treatments (ECTRs), such as hemodialysis or hemoperfusion, was first intended for poisoned patients. With time, ECTRs were used almost indiscriminately to facilitate the elimination of many poisons, albeit with uncertain clinical benefit. To determine the precise role of ECTRs in poisoning situations, multiple variables need to be considered including a careful risk assessment, the poison's characteristics including toxicokinetics, alternative treatments, the patient's clinical status, and intricacies of available ECTRs, all of which are reviewed in this article. Recently, evidence-based and expert opinion-based recommendations from the EXTRIP workgroup were also published to help minimize the knowledge gap in this area. The use of hemodialysis for enhancing the elimination of exogenous poisons predates its use for end-stage kidney disease (ESKD) by many decades (Here, the general term poison refers to any medicine, drug, natural toxin, or other potentially toxic substance that may induce illness following poisoning regardless of the intention.). In fact, the first successful in vivo experiment with hemodialysis was carried out in 1913 and demonstrated removal of salicylates from poisoned animals.1Abel J.J. Rowntree L.G. Turner B.B. On the removal of diffusible substances from the circulating blood by dialysis.Trans Assoc Am Physicians. 1913; 58: 51-54Google Scholar Yet, more than 100 years later, the application of extracorporeal treatment (ECTR) in the management of poisoned patients remains a topic of controversy, uncertainty, and debate. Recently, a multidisciplinary and multinational collaborative known as EXTRIP (EXtracorporeal TReatment In Poisoning) aimed to clarify the role of ECTRs in clinical practice through the development of evidence- and expert opinion–based recommendations.2Lavergne V. Nolin T.D. Hoffman R.S. et al.The EXTRIP (Extracorporeal Treatments In Poisoning) workgroup: guideline methodology.Clin Toxicol. 2012; 50: 403-413Crossref PubMed Scopus (93) Google Scholar This article will review both the theoretical rationale of ECTRs and their practical application in the management of the poisoned patient. Clinical toxicity results from a complex interplay of factors that include a poison's intrinsic properties, dose, formulation, route of administration, and the presence of co-ingestants, as well as the underlying health of the patient. Despite the ubiquity of poisons, the vast majority of poisoned patients who present to a modern health care facility are successfully treated and recover without sequelae, having only received supportive care.3Gummin D.D. Mowry J.B. Spyker D.A. et al.2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report.Clin Toxicol (Phila). 2017; 55: 1072-1252Crossref PubMed Scopus (284) Google Scholar ECTR is typically reserved for the small subset of patients who either are likely to suffer life-threatening toxicity (e.g., salicylate overdose), prolonged admission in the intensive care unit with coma and mechanical ventilation (e.g., barbiturate overdose), a high likelihood of permanent disability (e.g., methanol overdose) or develop toxicity despite standard supportive measures. The following discussion provides an approach to assess the potential usefulness of ECTR in a poisoned patient. This approach (Figure 1) should be used when evidence-based decision support (such as those developed by EXTRIP4The Extracorporeal Treatments in Poisoning Workgroup.http://www.extrip-workgroup.orgGoogle Scholar) are lacking. The risk assessment attempts to estimate the likelihood of significant sequelae after a specific exposure. If the identified poison has limited intrinsic toxicity and if the estimated threshold dose (in mg/kg) or plasma concentration is not associated with toxicity, ECTR is usually not indicated. When the actual poison concentration cannot be readily measured, the maximum possible concentration can be approximated from the following equation:Concentration=bioavailabledose/(volumeofdistribution×bodyweightinkg) The applicability of this estimation is limited by many toxicokinetic factors such as unpredictable bioavailability in overdose and a changing volume of distribution at high concentration (e.g., salicylates). The next step is to evaluate whether alternative modalities to prevent, limit, or reverse toxicity are available, such as antidotes. For example, sulfonylureas can cause lethal hypoglycemia, but the use of ECTR is unnecessary given the relative efficacy, ease, safety, and cost-effectiveness of dextrose and octreotide administration. A similar argument can be constructed regarding the use of naloxone in opioid overdoses. Likewise, for most patients with acetaminophen (paracetamol) poisonings, acetylcysteine is highly cost-effective at preventing or mitigating toxicity, making ECTR unnecessary, except in rare cases of massive ingestions with acidemia due to mitochondrial toxicity when the efficacy of acetylcysteine is reduced.5Gosselin S. Juurlink D.N. Kielstein J.T. et al.Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup.Clin Toxicol (Phila). 2014; 52: 856-867Crossref PubMed Scopus (67) Google Scholar In addition to antidotes, several therapies may either prevent absorption (gastric emptying, activated charcoal, or whole bowel irrigation) or enhance elimination (multiple dose activated charcoal or urinary alkalinization). When used appropriately, these techniques slow the progression of toxicity thereby negating requirements for ECTR. Further discussion regarding techniques for decontamination and enhanced elimination are beyond the scope of this work, so the reader is referred to standard reviews.6Hoegberg L.C. Techniques used to prevent gastrointestinal absorption.in: Hoffman R.S. Howland M.A. Lewin N.A. Goldfranks Toxicologic Emergencies. 10th ed. McGraw Hill, New York2015: 83-96Google Scholar, 7Goldfarb D.G. Ghannoum M. Principles and techniques applied to enhance elimination.in: Hoffman R.S. Howland M.A. Lewin N.A. Goldfranks Toxicologic Emergencies. 10th ed. McGraw Hill, New York2015: 124-134Google Scholar When the patient has either developed life-threatening manifestations of poisoning or appears likely to do so, and alternative treatments are either not available or unlikely to be sufficient, timely consideration for ECTR is indicated if the poison is considered dialyzable (Figure 1). The physicochemical and toxicokinetic properties of a poison predict whether it is "dialyzable", or able to be cleared from the plasma by an extracorporeal device. Perhaps more importantly, these properties predict the extent to which ECTR enhances total body clearance, thereby lowering the total body load faster than without the treatment. The primary determinants of poison removal by ECTR are the molecular weight (MW), volume of distribution (VD), hydro- and lipophilicity, protein and tissue binding, and endogenous clearance. The lower the MW the more likely that a poison is dialyzable. Contemporary high-efficiency high-flux dialyzers with diffusive modalities are capable of clearing poisons in the middle MW range (< ≅ 15,000 Da). Convective modalities such as hemofiltration and hemodiafiltration can permit clearance of solutes approaching 25,000 Da. New high-cutoff and middle-cutoff membranes may remove poisons up to 50,000 Da, although data are limited and the membranes' availability restricted.8Wolley M. Jardine M. Hutchison C.A. Exploring the clinical relevance of providing increased removal of large middle molecules.Clin J Am Soc Nephrol. 2018; 13: 805-814Crossref PubMed Scopus (52) Google Scholar, 9Kirsch A.H. Lyko R. Nilsson L.G. et al.Performance of hemodialysis with novel medium cut-off dialyzers.Nephrol Dial Transplant. 2017; 32: 165-172PubMed Google Scholar Perhaps the most important determinant of effective removal by ECTR is the poison's VD. The VD relates the amount of poison in the body to the concentration in plasma or blood. Because ECTR only clears poisons from the intravascular compartment, poisons exhibiting a smaller VD ( 2 L/kg), then overall removal by ECTR will be low. These considerations particularly apply to cases in which the poison has already been absorbed and distributed. However, it is conceivable that early pre-emptive initiation of ECTR during the absorption and distribution phase may promote the removal of a significant amount of poisons with a large VD, although the extent to which this occurs is poorly defined. Hydrophilic poisons distribute primarily in total body water, exhibit a smaller VD, and are more readily removed by ECTR, whereas lipophilic poisons distribute throughout extravascular tissues, especially adipose tissue, leading to a large VD. The degree of plasma protein and tissue binding of a poison inversely relates to its extracorporeal clearance because only unbound poison (free fraction) is removed by most ECTRs. A poison-protein complex may exceed 65,000 Da and is too large to be filtered. In general, poisons that are >80% protein bound are poorly removed by hemodialysis. It is important to note that for some drugs (notably salicylates and valproic acid) protein binding is "high" at therapeutic concentrations, but saturates at high plasma concentrations, increasing the free concentration and rendering them more amenable to removal by ECTR.12van den Broek M.P. Sikma M.A. Ververs T.F. et al.Severe valproic acid intoxication: case study on the unbound fraction and the applicability of extracorporeal elimination.Eur J Emerg Med. 2009; 16: 330-332Crossref PubMed Scopus (13) Google Scholar, 13Lee S. Johnson D. Klein J. et al.Protein binding of acetylsalicylic acid and salicylic acid in porcine and human serum.Vet Hum Toxicol. 1995; 37: 224-225PubMed Google Scholar A final important consideration is the patient's underlying endogenous (systemic) poison clearance, which is the sum of renal and non-renal clearance. If endogenous clearance is high, then an ECTR is unlikely to significantly increase total clearance enough to justify its use.2Lavergne V. Nolin T.D. Hoffman R.S. et al.The EXTRIP (Extracorporeal Treatments In Poisoning) workgroup: guideline methodology.Clin Toxicol. 2012; 50: 403-413Crossref PubMed Scopus (93) Google Scholar, 11Roberts D.M. Buckley N.A. Pharmacokinetic considerations in clinical toxicology: clinical applications.Clin Pharmacokinet. 2007; 46: 897-939Crossref PubMed Scopus (65) Google Scholar For example, endogenous metformin clearance, in the setting of normal kidney function, is 600 ml/min, which far exceeds the clearance achieved by HD (240 ml/min). As such, ECTR is usually not recommended for enhanced elimination in metformin overdose unless there is impaired kidney function;14Calello D.P. Liu K.D. Wiegand T.J. et al.Extracorporeal treatment for metformin poisoning: systematic review and recommendations from the Extracorporeal Treatments in Poisoning Workgroup.Crit Care Med. 2015; 43: 1716-1730Crossref PubMed Scopus (112) Google Scholar however, in cases of acute kidney injury, then even modest metformin removal by ECTR is potentially beneficial. With these considerations, only a small number of poisons are considered amenable to ECTR removal. Table 1 presents some of these, as reported by US poison control centers (2010–2014), although the reason for ECTR may have been for indications other than poison removal (e.g., acute kidney injury or acidemia).15Ghannoum M. Lavergne V. Gosselin S. et al.Practice trends in the use of extracorporeal treatments for poisoning in four countries.Semin Dial. 2016; 29: 71-80Crossref PubMed Scopus (23) Google Scholar, 16Lavergne V. Hoffman R.S. Mowry J.B. et al.Why are we still dialyzing overdoses to tricyclic antidepressants? A subanalysis of the NPDS database.Semin Dial. 2016; 29: 403-409Crossref PubMed Scopus (4) Google ScholarTable 1Number of ECTRs performed in the US, 2010–2014PoisonNumber of ECTRs performedEthylene glycol2072Lithium1924Salicylate1520Acetaminophen959Ethanol423Methanol345Metformin319Benzodiazepines308Cardiac glycosides260Calcium channel blockers205Valproic acid183Beta adrenergic antagonists134Atypical antipsychotics130Methadone97Oxycodone86NSAIDs81Tricyclic antidepressants69Cocaine68Heroin67Isopropanol62ECTR, extracorporeal treatment. Open table in a new tab ECTR, extracorporeal treatment. ECTRs are classified according to their mechanism: diffusion (hemodialysis and peritoneal dialysis), convection (hemofiltration), adsorption (hemoperfusion), and centrifugation (therapeutic plasma exchange).17Ouellet G. Bouchard J. Ghannoum M. et al.Available extracorporeal treatments for poisoning: overview and limitations.Semin Dial. 2014; 27: 342-349Crossref PubMed Scopus (35) Google Scholar, 18Bouchard J. Roberts D.M. Roy L. et al.Principles and operational parameters to optimize poison removal with extracorporeal treatments.Semin Dial. 2014; 27: 371-380Crossref PubMed Scopus (39) Google Scholar Each modality has potentially differing impacts on enhancing the elimination of a poison from the body. During intermittent hemodialysis (HD), the poison diffuses down the concentration gradient from the plasma through a semipermeable membrane to a countercurrent dialysate. HD has several distinct advantages over other ECTRs: it removes poisons rapidly due to the high blood and dialysate flows, and it simultaneously corrects other derangements such as uremia and acid-base and electrolyte abnormalities.19Ghannoum M. Roberts D.M. Hoffman R.S. et al.A stepwise approach for the management of poisoning with extracorporeal treatments.Semin Dial. 2014; 27: 362-370Crossref PubMed Scopus (37) Google Scholar HD is the most available ECTR, the least expensive, and the quickest to implement.20Bouchard J. Lavergne V. Roberts D.M. et al.Availability and cost of extracorporeal treatments for poisonings and other emergency indications: a worldwide survey.Nephrol Dial Transplant. 2017; 32: 699-706Crossref PubMed Scopus (20) Google Scholar For these reasons, HD remains the preferred modality for the majority of poisonings. This is reflected by current practice trends15Ghannoum M. Lavergne V. Gosselin S. et al.Practice trends in the use of extracorporeal treatments for poisoning in four countries.Semin Dial. 2016; 29: 71-80Crossref PubMed Scopus (23) Google Scholar, 21Holubek W.J. Hoffman R.S. 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Roy L. et al.Principles and operational parameters to optimize poison removal with extracorporeal treatments.Semin Dial. 2014; 27: 371-380Crossref PubMed Scopus (39) Google Scholar Because the large majority of known poisons have a low MW ( 95%) or poisons with MW over 50,000 Da such as monoclonal antibodies,42Hastings D. Patel B. Torloni A.S. et al.Plasmapheresis therapy for rare but potentially fatal reaction to rituximab.J Clin Apher. 2009; 24: 28-31Crossref PubMed Scopus (15) Google Scholar but even then the benefit is debatable considering complications of these techniques including bleeding, hypocalcemia, and hypersensitivity reactions.43Couriel D. Weinstein R. Complications of therapeutic plasma exchange: a recent assessment.J Clin Apher. 1994; 9: 1-5Crossref PubMed Scopus (111) Google Scholar, 44Perino G.C. Grivet V. 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Figure 3 shows a graphical illustration of the effect of various ECTRs on time to achieve a safe concentration in a methanol-poisoned patient; the superiority of intermittent HD over other ECTRs is apparent. The following operational parameters maximize extracorporeal elimination: higher blood flow, higher dialysate flow, higher ultrafiltration rate, post-filter replacement with hemofiltration, larger filter or kidney (surface area and flux), and longer duration.18Bouchard J. Roberts D.M. Roy L. et al.Principles and operational parameters to optimize poison removal with extracorporeal treatments.Semin Dial. 2014; 27: 371-380Crossref PubMed Scopus (39) Google Scholar The clearance cannot exceed the lowest flow rate, which for hemodialysis is plasma flow and for CRRT is effluent flow. These relationships are well-described in the nephrology literature, and there are increasing data confirming this in toxicology, including methanol52Zakharov S. Pelclova D. 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