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Intoxications Amenable to Extracorporeal Removal

2011; Elsevier BV; Volume: 18; Issue: 3 Linguagem: Inglês

10.1053/j.ackd.2010.10.007

1548-5609

James F. Winchester, Nikolas B. Harbord,

Methemoglobinemia and Tumor Lysis Syndrome

Extracorporeal removal of drugs was first attempted in 1913, by John Jacob Abel. Previously known to be a rarity, dialysis and to a lesser extent hemoperfusion have now become obvious tools for nephrologists in treating life-threatening cases of poisoning. Moreover, for dialysis patients, dialysis along with chelation therapy for removal of aluminum, once known to be common in the United States, is resurging in some countries. This article will discuss the principles of drug removal, the indications for dialysis, and give a brief outline of poisons amenable to dialysis. Extracorporeal removal of drugs was first attempted in 1913, by John Jacob Abel. Previously known to be a rarity, dialysis and to a lesser extent hemoperfusion have now become obvious tools for nephrologists in treating life-threatening cases of poisoning. Moreover, for dialysis patients, dialysis along with chelation therapy for removal of aluminum, once known to be common in the United States, is resurging in some countries. This article will discuss the principles of drug removal, the indications for dialysis, and give a brief outline of poisons amenable to dialysis. Clinical Summary•Poisoning is a major cause of mortality and morbidity.•Extracorporeal removal of toxins is an integral component of nephrology practice.•Not all toxins are amenable to extracorporeal removal.Approximately 37,000 deaths as a result of poisoning occur every year in the United States,1Available at: http://www.cdc.gov.Google Scholar and the number of cases related to unintentional poisoning is on the rise; the CDC Fact Sheet reports that among individuals aged 35 to 54 years, unintentional poisoning caused more deaths as compared with those caused by motor vehicle accidents; 96% of deaths related to unintentional poisoning were caused by drugs (CDC 2009). Opioid pain medications were found to be most commonly involved, followed by cocaine and heroin. •Poisoning is a major cause of mortality and morbidity.•Extracorporeal removal of toxins is an integral component of nephrology practice.•Not all toxins are amenable to extracorporeal removal. In 2008, reports to the U.S. poison control centers totaled to 2.5 million, and within that group there were 1750 fatalities and 2235 patients who required extracorporeal treatment (hemodialysis: 2177; hemoperfusion and/or others: 58).2Bronstein A.C. Spyker D.A. Cantilena Jr., L.R. et al.American Association of Poison Control Centers. 2008 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th Annual Report.Clin Toxicol (Phila). 2009; 47: 911-1084Crossref PubMed Scopus (308) Google Scholar Some of the fatalities could have been treated with dialysis and/or hemoperfusion (Table 1). The spectrum of poison ingested by individuals in European nations is similar to that seen in the United States and United Kingdom,3Bateman D.N. Good A.M. Five years of poisons information on the internet: the UK experience of TOXBASE.Emerg Med J. 2006; 23: 614-617Crossref PubMed Scopus (17) Google Scholar whereas in the Far East, paraquat and organophosphates are more commonly ingested.4Marahatta S.B. Singh J. Shrestha R. et al.Poisoning cases attending emergency department in Dhulikel Hospital-Kathmandu University Teaching Hospital.Kathmandu Univ Med J. 2009; 7: 152-156PubMed Google ScholarTable 1Selected Fatalities (Number) Reported to American Association of Poison Control Centers for Which Dialysis and/or Hemoperfusion Could Have Played a Role2Bronstein A.C. Spyker D.A. Cantilena Jr., L.R. et al.American Association of Poison Control Centers. 2008 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th Annual Report.Clin Toxicol (Phila). 2009; 47: 911-1084Crossref PubMed Scopus (308) Google ScholarSedative/hypnotics/antipsychotics (467)Opioids (401)Antidepressants (247)Cardiovascular drugs (238)Acetaminophen combinations (235)Alcohols (210)Stimulants and street drugs (184)Acetaminophen alone (168)Antihistamines (98)Anticonvulsants (85)Muscle relaxants (83)Acetylsalicylic acid alone (73)Cyclic antidepressants (71)Oral hypoglycemics (36)Barbiturates (25) Open table in a new tab The key elements in the treatment of poisoning, that is, initial supportive care and specific treatment, such as decontamination using multiple dose-activated charcoal, antidotes, and enhanced renal elimination (“ion trapping”), will not be discussed in this topic and the reader is referred to a recent review for further information.5Winchester J.F. Harbord N.B. Rosen H. Management of poisonings: core curriculum 2010.Am J Kidney Dis. 2010; 56: 788-800Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Selection of a patient for extracorporeal therapy should follow the algorithm seen in Figure 1. In this article, we will outline the principles and techniques of dialysis and other methods used for the removal of drugs and chemicals from blood. Many drugs are excreted without undergoing any changes in the kidney, many more get metabolized, and drug action eventually ceases by a variety of mechanisms. The elimination rate constant (Kel) of a drug describes its removal rate, and usually follows first-order kinetics, in which a constant fraction of the drug is removed per unit time, and the half-life is given by the following formula: t½ = 0.693/Kel. This elimination is characterized by a straight line on a logarithmic concentration versus linear time graph. Clearance of a drug (Cl, mL/min) is given by the following equation: Kel = Cl/Vdapp, where Vdapp is the apparent volume of distribution of the drug. Salicylate is evenly distributed in whole-body water, whereas drugs, such as digoxin and amitriptyline, have a Vdapp many times higher than that of whole-body water. Zero-order elimination is seen in some cases of intoxication. This is characterized by a constant rate of drug removal per unit time, independent of concentration, and is seen in severe salicylate poisoning. Some drugs fit a multicompartmental model with 2 or more Kels (eg, digoxin). Using the basic tenets of Maher and Schreiner,6Maher J.F. Schreiner G.E. The dialysis of poisons.Trans Am Soc Artif Intern Organs. 1968; 14: 440-453PubMed Google Scholar an extracorporeal device should add to endogenous elimination by 30% to 40% to be considered therapeutic in cases involving poisoning. Few pharmacokinetic studies have been performed in clinical poisoning, and most investigators have extrapolated animal data or human data from pharmacokinetics of therapeutic drugs. Hemoperfusion or hemodialysis can augment drug elimination during the active procedure, similar to that documented in animals for acetaminophen, digoxin, theophylline, ethchlorvynol, adriamycin, and possibly paraquat. Peritoneal dialysis is most efficient when long dialysate exchange times bring mesothelial transport rate to its maximum solute equilibrium (ie, dialysate/plasma solute concentrations reach equilibrium, or D/P = 1). Peritoneal clearance is considered to be too slow for reversal of drug intoxication. Its use is restricted: for dialyzable poisons, when other methods are not available, and to increase core temperature in the hypothermic-poisoned patient with warm solutions. Most of the drug removal data are derived from studies involving the use of dialyzers, conducted between the 1970s and 1980s, when the membranes were largely cellulosic and not as permeable as the larger pore (synthetic) membranes available today. In fact, modern studies have shown that highly porous membranes have a greater capacity to remove drugs to the point that they might obviate the need for hemoperfusion. Many factors affect drug removal during hemodialysis. The drug characteristics include solute size, lipid solubility, protein binding, distribution volume, and concentration gradient between plasma and dialysate. The physical factors include rate of blood flow through the dialyzer, dialysate flow rate, dialyzer surface area, and characteristics of the dialyzer membrane. An ideal dialyzable drug is one that has a low molecular weight, low protein binding, low distribution volume, and is water soluble. Drug removal is limited by the product of surface area of the membrane and its permeability. The clearance of solute from the blood is determined by the product of blood flow rate (Qb) and the drug extraction ratio, or A−V/A, where A is arterial (inlet) concentration and V is the venous (outlet) concentration of drug passing through the dialyzer. Modern dialyzers are constructed from synthetic porous membranes that allow drugs to pass through more readily as compared with cellulosic dialyzers. They are constructed from polymers such as polysulfone and polyacrylonitrile. In general, higher the rate of blood flow, higher would be the clearance rate of most drugs; however, dialysate blood flow rate, if more than 1.5 times the blood flow rate, does not achieve any higher clearance. Most drugs are approximately 300 Da in size, and using porous membranes, it would be theoretically possible for molecules with sizes to a maximum of approximately 11.8 kDa (beta-2-microglobulin) to undergo dialysis. The various modifications of hemodialysis with large-pore membrane dialyzers (continuous arteriovenous hemofiltration, continuous arteriovenous hemodialysis, continuous venovenous hemofiltration, and continuous venovenous hemodialysis) that rely on convection for solute and fluid removal are highly efficient at removing drugs. Although the continuous dialysis methods may achieve total greater drug removal as compared with standard hemodialysis, if rapid reversal of a poison effect is necessary (reversal of coma, or hypotension as a result of sedative poisoning), it would probably be better treated by a standard dialysis followed by a slower session for enhanced cumulative drug removal. Hemoperfusion is the passage of anticoagulated blood through a column containing sorbent particles (activated charcoal particles or resin beads containing column). Uncoated charcoal hemoperfusion has been previously associated with platelet depletion, but this has been improved by coating the particle surface with a thin biocompatible membrane. Charcoal is efficient at removing lipid- and water-soluble drugs. Certain resins are most effective for removal of lipid-soluble drugs. Antibody- or antigen-coated particle hemoperfusion devices have been constructed for the removal of specific toxins. The available hemoperfusion devices include Asahi Hemosorba (available in the United States, Asahi Medical, Tokyo, Japan), B Braun Hemoresin (available in Europe, B Braun, Melsungen, Germany), Gambro Adsorba (available in the United States and Europe, Gambro, Ab, Lund, Sweden), Smith and Nephew Haemocol (available in Europe, Smith and Nephew, London, UK). Adsorption relies on the physical process of drug adsorption, and in many instances drug removal is superior to hemodialysis, peritoneal dialysis, or diuresis. Water- and lipid-soluble substances with molecular weights ranging from 113 to 40,000 Da may be adsorbed. Short lists of drugs amenable to dialysis and hemoperfusion are given in Table 2, Table 3, respectively (specific references are given to support the use of dialysis or hemoperfusion in certain drug and/or chemical poisoning cases).Table 2A Short List of Drugs and Chemicals Amenable to DialysisAlcohols Ethanol Ethylene glycol∗Fomepizole can be used alone or in conjunction with dialysis for toxic alcohol poisoning.7Brent J. McMartin K. Phillips S. et al.Methylpyrazole for Toxic Alcohols Study Group. Fomepizole for the treatment of ethylene glycol poisoning.N Engl J Med. 1999; 340: 832-838Crossref PubMed Scopus (310) Google Scholar Isopropanol Methanol8Hovda K.E. Andersson K.S. Urdal P. et al.Methanol and formate kinetics during treatment with fomepizole.Clin Toxicol (Phila). 2005; 43: 221-227Crossref PubMed Scopus (53) Google ScholarAntimicrobials/anticancer Amikacin Chloramphenicol Doxorubicin Gentamicin Tobramycin Clavulanic acid Methicillin†Implies poor removal. Doxycycline†Implies poor removal. Isoniazid Vancomycin†Implies poor removal. Rifampin†Implies poor removal. Zidovudine Ketoconazole†Implies poor removal. Miconazole†Implies poor removal. Cyclophosphamide9Murashima M. Adamski J. Milone M.C. et al.Methotrexate clearance by high-flux hemodialysis and peritoneal dialysis: a case report.Am J Kidney Dis. 2009; 53: 871-874Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Methotrexate†Implies poor removal.Barbiturates Pentobarbital Phenobarbital10Palmer B.F. Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.Am J Kidney Dis. 2000; 36: 640-643Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Secobarbital†Implies poor removal.Nonbarbiturate hypnotics, sedatives, tranquilizers, anticonvulsants Carbamazepine Carbromal Chloral hydrate Diazepam†Implies poor removal. Diphenylhydramine Meprobamate Methaqualone Valproic acid11Thanacoody R.H. Extracorporeal elimination in acute valproic acid poisoning.Clin Toxicol. 2009; 47: 609-616Crossref PubMed Scopus (33) Google ScholarCardiovascular agents Acebutolol Atenolol Clonidine Digoxin†Implies poor removal. Metoprolol Procainamide12Low C.L. Phelps K.R. Bailie G.R. Relative efficacy of haemoperfusion, haemodialysis and CAPD in the removal of procainamide and NAPA in a patient with severe procainamide toxicity.Nephrol Dial Transplant. 1996; 11: 881-884Crossref PubMed Scopus (10) Google Scholar QuinidineAnalgesics, antirheumatics Acetaminophen Acetylsalicylic acid Methylsalicylate D-propoxyphene†Implies poor removal. Salicylic acid TramadolAntidepressants Amitriptyline†Implies poor removal. Clozapine Tranylcypromine Tricyclics†Implies poor removal.Solvents, gases Acetone CamphorPlants, animals, herbicides, insecticides Amanitin DiquatMiscellaneous Aminophylline TheophyllineMetals, inorganics Aluminum‡Removed with chelating agent. Iron‡Removed with chelating agent. Cisplatin∗ Fomepizole can be used alone or in conjunction with dialysis for toxic alcohol poisoning.† Implies poor removal.‡ Removed with chelating agent. Open table in a new tab Table 3A Short List of Drugs and Chemicals Amenable to HemoperfusionAnalgesics/antirheumatics Acetaminophen13Winchester J.F. Tilstone W.J. Edwards R.O. et al.Hemoperfusion for enhanced drug elimination—a kinetic analysis in paracetamol poisoning.Trans Am Soc Artif Intern Organs. 1974; 20A: 358-363PubMed Google Scholar Acetylsalicylic acid Colchicine Methylsalicylate Phenylbutazone D-propoxyphene Salicylic acid TramadolAntidepressants Amitriptyline∗Implies poor removal. Clozapine Imipramine∗Implies poor removal. Tricyclics∗Implies poor removal.Antimicrobials/anticancer Adriamycin14Winchester J.F. Rahman A. Tilstone W.J. et al.Will hemoperfusion be useful for cancer chemotherapeutic drug removal?.Clin Toxicol. 1980; 17: 557-569Crossref PubMed Scopus (15) Google Scholar Chloramphenicol Doxorubicin Chloroquine DapsoneBarbiturates Amobarbital Pentobarbital Phenobarbital SecobarbitalNonbarbiturate, hypnotics, sedatives, tranquilizers, anticonvulsants Carbamazepine Carbromal Chloral hydrate Diazepam∗Implies poor removal. Diphenylhydramine Ethchlorvynol Glutethimide Meprobamate Methaqualone Phenytoin Valproic acidCardiovascular agents Atenolol Digoxin15Hoy W.E. Gibson T.P. Rivero A.J. et al.XAD-4 resin hemoperfusion for digitoxic patients with renal failure.Kidney Int. 1983; 23: 79-82Crossref PubMed Scopus (14) Google Scholar, 16Kaneko T. Kudo M. Okumura T. et al.Successful treatment of digoxin intoxication by haemoperfusion with specific columns for beta2-microgloblin-adsorption (Lixelle) in a maintenance haemodialysis patient.Nephrol Dial Transplant. 2001; 16: 195-196Crossref PubMed Scopus (14) Google Scholar Diltiazem∗Implies poor removal. FlecainideSolvents, gases Acetone CamphorMetals, inorganics Aluminum†Removed with chelating agent. Iron†Removed with chelating agent. Cisplatin†Removed with chelating agent.Plant and animal toxins, herbicides, insecticides Amanitin17Kantola T. Kantola T. Koivusalo A.M. et al.Early molecular adsorbents recirculating system treatment for amanita mushroom poisoning.Ther Apher Dial. 2009; 13: 399-403Crossref PubMed Scopus (24) Google Scholar Chlordane Diquat Methyl parathion Organophosphates†Removed with chelating agent. Paraquat18Kang M.S. Gil H.W. Yang J.O. et al.Comparison between kidney and hemoperfusion for paraquat elimination.J Korean Med Sci. 2009; 24: S156-S160Crossref PubMed Scopus (44) Google Scholar, 19Kalabalikis P. Hatzis T. Papadatos J. et al.Paraquat poisoning in a family.Vet Hum Toxicol. 2001; 43: 31-33PubMed Google Scholar Parathion TetramineMiscellaneous Aminophylline Phenols Theophylline20Shannon M.W. Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication.Acad Emerg Med. 1997; 4: 674-678Crossref PubMed Scopus (67) Google Scholar∗ Implies poor removal.† Removed with chelating agent. Open table in a new tab For a complete listing of drugs and chemicals removed by dialysis and hemoperfusion the reader is referred to a recent review5Winchester J.F. Harbord N.B. Rosen H. Management of poisonings: core curriculum 2010.Am J Kidney Dis. 2010; 56: 788-800Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar (Supplementary boxes 1 and 2 [available as online supplementary material associated with this article at www.ajkd.org]). A rapid guide to selecting between hemodialysis (in any form) and hemoperfusion is given in Table 4. For some drugs, the best example being lithium (Li), prolonged dialysis may be necessary because of the real possibility of relapse into coma.21Hansen H.E. Amdisen A. Lithium intoxication (Report of 23 cases and review of 100 cases from the literature).Q J Med. 1978; 47: 123-144PubMed Google Scholar Although Li is a very small molecule (atomic weight: 7), its tissue burden is high, and if a standard 4-hour dialysis is performed, there may be a situation of relapse into coma. It is recommended that a dialysis session for Li be of more than 4 hours. The classes of drugs removed by extracorporeal approaches are listed in Table 4.Table 4Suggestions for Choice of Extracorporeal RemovalHemodialysisHemoperfusionWater-soluble drugs and chemicalsLipid-soluble drugs and chemicalsDrugs with metabolic complications (acid–base, electrolyte disturbance); aspirin, alcoholsBarbiturates and nonbarbiturate hypnotics, sedatives and tranquillizersLithiumDigitalis glycosides in renal failure subjects∗Digoxin antibodies are appropriate for most patients, but recrudescence of digoxin poisoning has been observed 24 to 48 hours after digoxin antibodies in subjects with renal failure.22∗ Digoxin antibodies are appropriate for most patients, but recrudescence of digoxin poisoning has been observed 24 to 48 hours after digoxin antibodies in subjects with renal failure.22Ujhelyi M.R. Robert S. Cummings D.M. et al.Disposition of digoxin immune Fab in patients with kidney failure.Clin Pharmacol Ther. 1993; 54: 388-394Crossref PubMed Scopus (21) Google Scholar Open table in a new tab Of equal importance to selection of devices for treatment the clinician should be clear on the indications for dialysis. These indications are provided in Table 5. Although all the criteria involved in choosing an appropriate treatment are important, perhaps the most important is the removability of a drug or chemical at a rate that exceeds whole-body clearance of a drug.Table 5Clinical Criteria for Dialysis or Hemoperfusion5Winchester J.F. Harbord N.B. Rosen H. Management of poisonings: core curriculum 2010.Am J Kidney Dis. 2010; 56: 788-800Abstract Full Text Full Text PDF PubMed Scopus (8) Google ScholarProgressive deterioration despite intensive careSevere intoxication with hypoventilation, hypothermia, and hypotensionPredisposition to complications of coma (eg, chronic obstructive pulmonary disease)Impaired normal drug excretory function because of hepatic, cardiac, or renal insufficiencyPoisoning with agents with metabolic and/or delayed effects (eg, methanol, ethylene glycol, paraquat)Intoxication with an drug or poison that can be extracted at a rate exceeding endogenous elimination Open table in a new tab Extracorporeal removal of drugs and chemicals may be life-saving for the patient and gratifying for the physician.