CJASN ePress. Published on August 22, 2019 as doi: 10.2215/CJN.02560319 Extracorporeal Removal of Poisons and Toxins Joshua David King,1,2 Moritz H. Kern,3,4 and Bernard G. Jaar 5,6,7,8 Abstract Extracorporeal therapies have been used to remove toxins from the body for over 50 years and have a greater role than ever before in the treatment of poisonings. Improvements in technology have resulted in increased efficacy of removing drugs and other toxins with hemodialysis, and newer extracorporeal therapy modalities have expanded the role of extracorporeal supportive care of poisoned patients. However, despite these changes, for at least the 1Division of past three decades the most frequently dialyzed poisons remain salicylates, toxic alcohols, and lithium; in addition, Nephrology, the extracorporeal treatment of choice for therapeutic removal of nearly all poisonings remains intermittent University of hemodialysis. For the clinician, consideration of extracorporeal therapy in the treatment of a poisoning depends Maryland, Baltimore, Maryland; 2Maryland upon the characteristics of toxins amenable to extracorporeal removal (e.g., molecular mass, volume of Poison Center, distribution, protein binding), choice of extracorporeal treatment modality for a given poisoning, and when the Baltimore, Maryland; benefit of the procedure justifies additive risk. Given the relative rarity of poisonings treated with extracorporeal 3Department of therapies, the level of evidence for extracorporeal treatment of poisoning is not robust; however, extracorporeal Medicine, University Hospital Heidelberg, treatment of a number of individual toxins have been systematically reviewed within the current decade by the University of Extracorporeal Treatment in Poisoning workgroup, which has published treatment recommendations with an Heidelberg, improved evidence base. Some of these recommendations are discussed, as well as management of a small Heidelberg, Germany; number of relevant poisonings where extracorporeal therapy use may be considered. 4DZHK (German ccc–ccc Centre for CJASN 14: , 2019. doi: https://doi.org/10.2215/CJN.02560319 Cardiovascular Research), Partner Site Heidelberg/ Introduction is determined primarily by the lipophilicity of a sub- Mannheim, Since 1914, when the first in vivo hemodialysis (HD) stance; nonpolar, lipophilic toxins have high volumes Mannheim, Germany; 5Department of was performed, extracorporeal therapies have been of distribution and are not generally dialyzable, Medicine, Johns used for the removal of drugs and other toxins (1). whereas hydrophilic toxins have lower volumes of Hopkins School of Over the past 50 years, there has been increasing use of distribution and are more easily dialyzable. Solutes Medicine, Baltimore, 6 extracorporeal therapies for the treatment of poisoning, with volumes of distribution .1–1.5 L/kg are poorly Maryland; Welch both for removal of toxins and supportive therapy; this Center for Prevention, amenable to extracorporeal removal (see Table 2) (5,6). Epidemiology and review focuses primarily upon the former (2). Although In plasma, almost all solutes are protein-bound to Clinical Research, the increasing importance of extracorporeal therapies some degree (5). The plasma proteins that bind drugs Johns Hopkins in managing poisons is likely due in part to the greater are too large to be removed via extracorporeal ther- University, Baltimore, Maryland; number of available modalities, intermittent HD has apies other than apheresis, and the fraction of toxins 7 fi Department of become more ef cacious at removing toxins over time that are protein-bound are not removed via HD (6,7). Epidemiology, Johns as technology has progressed, and it is likely that Substances with ,80% protein binding are typically Hopkins Bloomberg the role of extracorporeal therapies for poisoning amenable to extracorporeal removal via HD (6,8). The School of Public will continue to grow and evolve over time (3,4). logarithmic nature of extracorporeal solute removal Health, Baltimore, Maryland; and (Figure 1) results in little difference between the 8Nephrology Center of removal of a substance that is, for example, 20% Maryland, Baltimore, Principles of Toxin Removal by Extracorporeal protein-bound and one that is 70% protein-bound, but Maryland Therapies at .80% protein binding clearance drops sharply (8). A number of parameters influence the ability of Protein binding is saturable: certain drugs (salicylates, Correspondence: extracorporeal therapies to remove poisons; the ideal valproic acid, carbamazepine, and phenytoin, among Dr. Joshua David King, Division of dialyzable substance is a small molecule, has a low others) have high protein binding at therapeutic Nephrology and volume of distribution, low protein binding, and rapidly concentrations, which limits dialyzability, but become Maryland Poison distributes from tissue to plasma (3,5–7). Table 1 explores amenable to removal at various toxic concentrations Center, University of these alongside different extracorporeal modalities. after binding sites are occupied and free drug levels Maryland School of To clear any substance from the body extracorpo- rise (9–12). Medicine, 220 Arch Street, Baltimore, MD really, it must be present in appreciable quantity in Improvements in HD, which have been made to 21201. Email: the intravascular space; thus, volume of distribution clear greater amounts of uremic toxins, particularly JDKing@som. is typically the greatest determinant of extracorporeal middle molecules, have increased the molecular mass umaryland.edu removal of poisons. The volume of distribution, a of substances amenable to extracorporeal removal; for theoretical volume which represents how much of a HD, conventional dialyzers may clear substances up substance is present in plasma versus other spaces, to 15,000 Da, whereas high-cutoff hemofilters may www.cjasn.org Vol 14 September, 2019 Copyright © 2019 by the American Society of Nephrology 1 2 CJASN Table 1. Utility of extracorporeal modalities in poisoning Toxin Toxin Volume Protein Examples of Primary Limitations Modality Molecular of Distribution Binding Toxins Amenable of Therapy Mass (Da) (L/kg) of Toxin to Therapy Hemodialysis Up to 10,000– #1.5–2 #80% Salicylates, toxic Hemodynamic stability 15,000 alcohols, lithium HCO filter HD Up to 50,000 #1.5–2 #80% Small peptide therapeutics; Limited availability any therapy amenable Limited role in to HD poisoning CRRT Up to 15,000– #1.5–2 #80% Lithium Slow toxin clearance 25,000 (excepting toxins with slow redistribution) Hemoperfusion Unclear, but #1 L/kg Any Valproic acid, Limited availability high carbamazepine Clotting Hypocalcemia Plasma exchange No limit #1 L/kg Any Monoclonal antibodies, Limited availability arsine Very slow clearance HCO, high-molecular-mass cutoff; HD, hemodialysis; CRRT, continuous renal replacement therapy. clear substances closer to 50,000 Da in size (5,6,13,14). of toxin. Utilizing a large overdose of methanol (serum level Plasmapheresis may clear substances of any size (15). 400 mg/dl) as an example, in an 80 kg man, intermittent HD As toxins are removed from plasma via HD, they diffuse (2.5 m2 dialyzer, blood flow 400 ml/min, dialysate flow 800 from tissue along their concentration gradient. Although ml/min) would take nearly 8 hours to lower serum concen- most dialyzable substances move relatively quickly from trations to 20 mg/dl, whereas high-dose continuous veno- tissue to plasma, certain toxins exhibit slower transit, leading venous HD (dialysate flow 6000 ml/min) would require to the phenomenon of “rebound,” where plasma levels of a almost 48 hours to achieve this (20). given substance will increase hours after dialysis. Lithium is A complicated issue not fully addressed in this review is the best-known example, although others (metformin, meth- when to consider the use of extracorporeal therapies for otrexate, vancomycin, dabigatran, etc.) may exhibit rebound poisoning. There are relatively few drugs and other toxins after extracorporeal removal (16,17). amenable to extracorporeal removal, and some dialyzable Optimization of extracorporeal removal of poisons poisonings rarely require this (e.g., acetaminophen). In depends primarily on increasing the volume of plasma addition, some toxins have greater endogenous clear- filtered. Consider HD, where increasing blood flow rate, ance (kidney, hepatic, or otherwise) than extracorporeal dialysate flow rate, dialyzer surface area, and time maximize elimination can provide, reducing the added value of the toxin removal (18,19). This process is not linear: doubling procedure; Table 3 displays suitability of extracorporeal therapy time does not result in removal of twice the amount removal for a variety of drug classes. The risks of the Table 2. Sample pharmacokinetic characteristics of toxins Optimal Volume of Speed of Molecular Protein Extracorporeal Toxin Distribution Distribution from Dialyzability Mass (Da) Binding Modality for (L/kg) Plasma to Tissue Removal Amitriptyline 277 19 95% Fast Not dialyzable None Colchicine 399 5–8 40% Fast Not dialyzable None Ethylene glycol 62 0.6–0.8 Little to none Fast Dialyzable HD Lithium 7 0.6–0.9 Approximately Slower, may have Dialyzable HD; CRRT 10% rebound after (nonemergent HD cases) Metformin 129 1–5 None Slower, may have Moderately HD rebound after dialyzable HD Methotrexate 454 0.8–235%–50% Slower, may have Moderately HD rebound after dialyzable HD Rituximab 144,000 ,0.2 None Not applicable Not dialyzable Plasma exchange Vancomycin 1449 ,0.4–1 ,60% (varies)