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Hemoperfusion Dr. Vinant Bhargava DNB( Nephrology) Consultant Institute of Renal Science Sir Gangaram Hospital, New Delhi • • • • • • History Physical properties of hemoperfusion Indications Types of therapies and comparison Complications Summary Index case 1 • 25/M , Farmer, No comorbities • Alleged substance intake • On presentation – Comatose – Hypotension – Bradycardia – Oliguria(8 hrs) – Tachypnea How will we manage this gentleman? • • • • • Charcoal hemoperfusion Resin based hemoperfusion Hemodialysis only CVVHD (F) plus hemoperfusion Hemodialysis plus hemoperfusion Index case 2 • 67/F, Diabetes Mellitus(20 yrs), Hypertension(5 years) – – – – Fever (8 days) Stuporous (12 hrs) Oliguria (4 hrs) Jaundice(2 days) • Hospital course – – – – – Ventilated Inotropic support(12 hrs) Consolidation in the right middle lobe Urine infection ( Klebsiella sp) ABG: metabolic acidosis, hyperkalemia How will we manage this pleasant lady? • • • • • Charcoal hemoperfusion Resin based hemoperfusion Hemodialysis only CVVHD (F) plus hemoperfusion Hemodialysis plus hemoperfusion History - 1948: Muirhead and Reid killed several lab animals. - Cation and anion exchange resin filters shown to remove 3.5gm urea - 1958: Schreiner - removed a useful amount of pentobarbital out of an overdose patient with 2 x 15-minute sessions on a lactated anion resin column. - 1964: Yatzidis et al - treated barbiturate overdoses with coconut shell charcoal - 1973: Chang et al - demonstrate that though uremic toxin removal is greater with hemoperfusion than with hemodialysis, urea itself could not be removed in clinically useful quantities - 1990: endotoxin removal Physical principles(Hemoperfusion) • Adsorption of chemicals. – Activated charcoal, drugs are irreversibly bound via van der Waals forces. – Resins, drugs are not irreversibly bound and can be eluted with organic solvents. • Water- and lipid-soluble substances with molecular weights ranging from 100 to 40,000 daltons are well adsorbed with hemoperfusion. • Chemicals at higher molecular weights are adsorbed less efficiently to polymer-coated charcoal J Biomed Mater Res. 1975;9(2):143. Mechanism of adsorption Mechanism Contd.... Methodology(Hemoperfusion) • Hemoperfusion is conducted using – – – – dialysis blood lines, a blood pump, pressure gauges, and a column that contains between 100 and 300 g of activated charcoal or 300 to 650 g of resin. • Heparin requirements are similar to hemodialysis • Performed for three to four hours. – Reuse of devices is not performed • Efficient drug removal occurs with blood flow rates of approximately 300 mL/min Efficacy of Hemoperfusion in poisoning • Animal models – hemoperfusion increases drug elimination rates of acetaminophen, amobarbital, ethchlorvynol, doxorubicin, digoxin, and digitoxin. – rebound of drug concentration occurs following hemoperfusion. • Human experience(international working group (Extracorporeal Treatments in Poisoning [EXTRIP]) – Does not support except in case of severe intoxication Clin Toxicol (Phila). 2012 Jun;50(5):403-13 Criteria for considering hemoperfusion • Poisoning – Progressive deterioration despite intensive supportive therapy – Severe intoxication with depression of midbrain function, thereby leading to hypoventilation, hypothermia, and hypotension – Development of complications of coma, such as pneumonia or septicemia – Impairment of normal drug excretory function due to hepatic, cardiac, or renal insufficiency. – Intoxication with agents with metabolic and/or delayed effects, such as paraquat Trans Am Soc Artif Intern Organ. 1967; 13:369 WELL ESTABLISHED INDICATIONS for hemoperfusion PARAQUAT - Near-continuous charcoal hemoperfusion prevents progression to pulmonary fibrosis and improves mortality ORGANOPHOSPHATES - Indicated in SEVERE massive overdose - less beneficial in mild overdose CARBAMAZEPINE - Indicated in SEVERE massive overdose THEOPHYLLINE - Charcoal hemoperfusion decreases progression to seizures and improves mortality Holubek et al, Use of hemodialysis and hemoperfusion in poisoned patients idney International (2008) 74, 1327–1334; Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis By John Francis Maher, the 20th chapter by james F. Winchester (pp 439) Pilapil M, Petersen J. Efficacy of hemodialysis and charcoal hemoperfusion in carbamazepine overdose. Clin Toxicol (Phila) 2008;46:342-3. LESS WELL ETABLISHED APPLICATIONS of hemoperfusion - Methotrexate - Better with uncoated charcoal - Diltiazem - Especially sustained release - Phenytoin - Half life reduced from 100 to 7 hrs - Valproate - Chloramphenicol in children - Muscarine (from Amanita Muscaria) Parish RC, Treatment of Amanita mushroom poisoning: a review. Vet Hum Toxicol. 1986 Aug;28(4):318-22. Grafft et al, High-dose continuous venovenous hemofiltration combined with charcoal hemoperfusion for methotrexate removal NDT Plus (2011) 4 (2): 87-89 Greenberg et al, Severe theophylline toxicity: Role of conservative measures, antiarrhythmic agents, and charcoal hemoperfusion The American Journal of Medicine Volume 76, Issue 5 , Pages 854-860, May 1984 Molina, Fabian, et al; Use of charcoal hemoperfusion to reduce serum methotrexate levels in a patient with acute renal insufficiency Am J Med 82: 350, 1987 Roberts et al, Lessons learnt in the pharmacokinetic analysis of the effect of haemoperfusion for acute overdose with sustained-release diltiazem Anaesthesia Volume 63, Issue 7, pages 714–718, July 2008 Eyer F, Felgenhauer N, Pfab R, Thürmel K, Zilker T. Treatment of severe intravenous phenytoin overdose with hemodialysis and hemoperfusion. Med Sci Monit. 2008 Dec;14(12):CS145-8. Licari, Elisa MD; Calzavacca, Paolo MD; Warrillow, Stephen J. MD; Bellomo, Rinaldo MD Life-threatening sodium valproate overdose: A comparison of two approaches to treatment. Critical Care Medicine: December 2009 - Volume 37 - Issue 12 - pp 3161-3164 Charcoal Hemoperfusion in Hepatic Encephalopathy in 1972, Chang et al first reported the use of charcoal hemoperfusion in an encephalopathic woman. (She survived) - In theory, the mercaptans and ammonia are adsorbed more easily than they are dialysed - The idea is to intervene BEFORE Stage IV coma by West Haven Criteria (i.e. before unresponsiveness, when cerebral oedema is irreversibly established) Exactly when to intervene? Nobody agrees. Some useful things may also be removed. Studies of Hemoperfusion in hepatic encephalopathy • From 1972 to 1985: • as methodology improved, treatment effect deteriorated Treatment effect may be owed more to cessation of the agent or condition which is responsible for the induction of the coma. Opinion of experts: - Nobody knows at what stage to start HP - Everyone seems to agree that resin rather than charcoal should be used (as not all molecules responsible for encephalopathy are removed) Non standard indications for hemoperfusion 1976, McEwoy et al Psoriasis improved during dialysis. Effect was not sustained in RCT. 1977, Wagemaker and Cade: “dramatic” improvement in delusions and paranoid ideation in 5 out of the 6 chronic schizophrenics , attributed to the hemoperfusion removal of leucine-endorphin. Not supported by subsequent series. 2009, EUPHAS trial: Significant reduction in mortality following hemoperfusion with Polymyxin-B containing column, in 64 surgical patients with severe septic shock. Trial terminated: unethical to withhold lifesaving polymyxin. Aluminium toxicity: In conjunction with chelating agents (deferoxamine) Uremic pruritis: RCT confirms utility Toxic epidermolysis necrolysis Wagemaker, Cade ; the use of hemodialysis in chronic schizophrenia. Am J Psychiatr 134: 684 1977. McEwoy et al, psoriatic clearance during hemodialysis Ulster Med J 76: 1976 Cruz DN, Antonelli M, Fumagalli R, et al. Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock: The EUPHAS Randomized Controlled Trial JAMA. 2009;301:2445-2452 Medicine (Baltimore). 2017 Mar;96(12):e6160, J Dermatolog Treat. 2016 Oct 24:1-7 Other Indications for Hemoperfusion • • • • SLE Rheumatoid arthritis HLA antibodies removal ABO incompatible transplants – Glycosorb column – Adsopak column No randomised controlled trials Hemoperfusion for Metabolic Disturbance Disorders characterized by loss of metabolic balance, featuring liver and kidney failure Examples: – Inborn errors of metabolism (e.g., PKU) – Type I diabetes – Gaucher disease – Thyroid disease Symptoms: Respiratory difficulty, altered mental status, seizures, organ failure. Shi and Chang, Int J Artif Organs, 1984 Showed that HP significantly reduced various amino acids in rats • Horky et al, Czech Med, 1981: Showed that HP effectively removed various substances (phenols, urate) in 7/9 patients with metabolic disorders with minimal adverse events Metabolic disturbance • No studies were identified with the criteria for this literature review • Therefore, for this indication, there is insufficient evidence that sorbent hemoperfusion systems are safe and effective Available hemoperfusion devices Manufactur er Device Sorbent type Asahi Hemosorba Spherical charcoal Gambro Adsorba Toray Industries Cytosorbents Amount of sorbent 170 g Polymer coating Cost Polyhema 14,000 Norit charcoal 100 or 300 g Cellulose acetate 12,800 Toraymyxin* Toraymycin None 1,08,000 Cytosorb* Polystyrene 300 g divinylbenzen e copolymer None 77,500 ? Hemodialysis versus hemoperfusion • Hemoperfusion is preferred to hemodialysis for the removal of chemicals that are lipid soluble or are highly protein bound. • Hemodialysis is preferred for water soluble low-molecularweight compounds since these compounds readily cross hemodialysis membranes. • With the advent of high-flux dialysis membranes for routine hemodialysis – high-flux membrane drug removal may be equal to that of hemoperfusion Med J Malaysia. 2006;61(1):109 Nephron. 2002;90(2):213 Hemodialysis versus hemoperfusion • Advantages : – removes the toxic metabolites of methanol and ethylene glycol – Corrects Electrolyte disturbances and metabolic acidosis (drugs) – High clearance relative to total body clearance • Disadvantages : – Low molecular weight (<500 daltons) – Low degree of protein-binding – Small volume of distribution (<1 L/kg) – Low endogenous clearance (<4 mL/min per kg) Handbook of Dialysis, 4th ed., Daugirdas JT, Blake PG, Ing TS (Eds), Lippincott Williams & Wilkins, Philadelphia 2007. p.300. Hemodialysis+ Hemoperfusion • Hemodialysis – can remove only substances that are highly diffusable, non protein bound and with small and middle-molecular weight. • Charcoal hemoperfusion – Removes uric acid, creatinine, middle molecules and other putative uremic toxins. In this it is comparable to hemodialysis. – Unlike hemodialysis it does not remove urea • The combination of Hemodialysis-Hemoperfusion (HD-HF) takes advantage of both techniques. Hemoperfusion • In contrast to HD circuits, hemoperfusion devices – contain thin, highly porous membranes and adsorbents that provide a large surface area to directly bind toxins . – Clearance rates are higher with hemoperfusion than HD – the extraction ratio for hemoperfusion approximates 1.0 for some poisons. – Hemoperfusion may be considered for use in severe poisoning from the toxins Hemofiltration • CVVHF,CVVHDF •The evidence for these techniques is scant. • CRRT has lower clearance rates than conventional HD. •benefit for intoxications with drugs that have a large volume of distribution, tight tissue binding, or slow intercompartmental transfer • It might offer some benefit in unstable or hypotensive patients . Contraindications Complications – HD and hemoperfusion normally require systemic anticoagulation with heparin, and patients with active hemorrhage, severe thrombocytopenia, or coagulopathy may not be candidates for these procedures. – HD and hemoperfusion may not be feasible in hypotensive patients. • Hemodialysis •Hypotension, bleeding due to anticoagulation, hypothermia, air embolus •complications that may result from obtaining central venous access . •Hemoperfusion •charcoal embolization, hypocalcemia, hypoglycemia, •Leukopenia ( 10 percent reduction) •Thrombocytopenia (30 percent reduction). The Charcoal Hemoperfusion Filter - Canister with 300g of activated charcoal - Blood flow though the canister is driven by a normal dialysis machine - There is no ultrafiltration, no fluid removal, no dialysis. Brochure from the “Adsorba C” range by Gambro, for the Prismaflex machines Complications of Charcoal Hemoperfusion EARLY PROBLEMS - Particle embolization in filters with uncontrolled granule diameter Profound platelet depletion with uncoated filters Anaphylactic reactions to dirty coconut charcoal Deposition of hydrocarbons into the patient by treated charcoal PROBLEMS REMAINING - Some platelet depletion with coated filters - Fibrinogen depletion - Leucopenia: complement is activated even by coated filters, and this results in leucocyte margination - Hypotension: due to platelet activation in the filter, and resulting massive release of vasoactive amines - Removal of calcium - Removal of glucose - Removal of hormones, coagulation factors and trace elements Devices designed to remove endotoxin and cytokines in sepsis. Mediators of Inflammation Volume 2013, Article ID 507539 Toraymyxin consists of Polystyrene - based fiber to which Polymyxin B is bound covalently (immobilized) The surface of the fiber is porous. Therefore, it increases its surface area. NH2 NH2 Polymyxin B NH NH2 NH2 CH2NHCOCH2Cl Toraymyxin:(PMX-B DHP) Endotoxin Binding without Systemic Side Effects CH2CH CH2NHCOCH2Cl CH2NHCOCH2 CH2CH The endotoxin adsorbing capacity of Toraymyxin was found to be 64,000 ng contained in bovine serum CH2CH Polystyrene derivative fiber Sakai Y. et al. Therapeutic Plasmapheresis (XII): 837-842, 1993 oXiris • AN69 polyacrylonitrile hemofilter • Additional surface treatment with polyethyleneimine (PEI) and lipid A phosphate groups helps bind endotoxin. • It is further grafted with heparin to reduce membrane thrombogenicity • Surface adsorption is purely selective on endotoxin because of the specific configuration of the membrane. • The bulk adsorption is nonselective and can absorb numerous mediators unselectively oXiris 33 SepteX Therapy principle = Removal of cytokines by dialysis Indications: Adjunctive sepsis therapy for cytokine removal Machines to run: PrismafleX Run mode: CVVHD Treatment: for 48-72h, change of the membrane when diffusion performance drops Anticoagulation: Heparin, Citrate Available studies: Despite two RCT showing broad cytokine removal there is very limited human data with the septeX membrane 34 Hemoperfusion: FDA Summary and Recommendations Hemoperfusion for Drug Overdose/Poisoning • There are often no alternative therapies to hemoperfusion for the removal of certain substances (e.g., paraquat). • Studies show well-understood risks for hemoperfusion for these indications. • FDA believes that medical evidence strongly displays benefit over risk, and that there is sufficient evidence to establish special controls for drug overdose and poisoning. FDA Recommendations • The FDA recommends a split classification and the following revision to Section §876.5870: – For drug overdose/poisoning: Class II – For hepatic coma and metabolic disturbances: Class III (premarket approval) • FDA believes that special controls can be established to permit reclassification of hemoperfusion for the treatment of drug overdose/poisoning to Class II. • FDA believes that adequate special controls cannot be established to permit reclassification of hemoperfusion for the treatment of hepatic coma and metabolic disturbances, and that these devices meet the criteria for Class III devices for these indications. Clinical studies J Bras Nefrol 2010;32(4):340-348 Comparison of conventional hemodialysis with charcoal hemoperfusion Clearance of Drugs Specialised adsorption resins Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Clearance of Drugs: comparison of conventional hemodialysis with charcoal hemoperfusion With charcoal, at least a modest benefit Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Blood purification & Mortality Effects of hemodialysis and hemoperfusion on inflammatory factors and nuclear transcription factors in peripheral blood cell of multiple organ dysfunction syndrome OBJECTIVE: To investigate the effects of hemodialysis (HD) and hemoperfusion (HP) on inflammatory factors and nuclear transcription factors in peripheral blood cell of multiple organ dysfunction syndrome (MODS) patients. PATIENTS AND METHODS: • 92 cases of MODS • Control group was treated with conventional hemodialysis(HD) • Observation group was treated with hemoperfusion combined therapy (HD+HP) Parameters measured: •serum creatinine (SCR), serum total cholesterol (TC), blood urea nitrogen (BUN) and serum albumin (Alb) • TNF-α and IL-6 in peripheral blood were detected between two group European Review for Medical and Pharmacological Sciences 2016; 20: 745-750 Comparison of Scr, BUN, TC, Scr and Alb in two groups before and after treatment. A, Comparison of Scr level; B, Comparison of TC level; C, Comparison of BUN level; D, Comparison of Alb level. Effects of hemodialysis and hemoperfusion on inflammatory factors and nuclear transcription factors CONCLUSIONS: Hemodialysis combined with hemoperfusion in treating MODS patients could significantly improve the biochemical indicators, effectively remove the inflammatory mediums, and significantly inhibit the activation of NK-κB. European Review for Medical and Pharmacological Sciences 2016; 20: 745-750 ABDOMIX trial Toraymyxin 46 Ongoing studies EUPHAS2 EUPHAS2 is a prospective web-based registry of patients treated with PMX-DHP designed to validate the reproducibility of randomized clinical trial results and to observe the 'real world' efficacy and utility of PMX-DHP therapy across a wider variety of patient populations EUPHRATES The EUPHRATES trial is a multi-centered, blinded, randomized controlled trial of PMX-DHP in patients with septic shock and confirmed endotoxemia using EAA greater than 0.60. The trial is being conducted in 50 ICUs in the United States and Canada oXiris – studies Status August 2015 Source: https://www.clinicaltrials.gov/ct2/results?term=oxiris&Search=Search 48 septeX – studies 49 Status August 2015 Source: https://www.clinicaltrials.gov/ct2/results?term=septex&Search=Search Different Extra Corporeal Therapies Cytosorb Indian data (Hemoperfusion) • • • • Single centre, observational studies Case reports Randomized controlled trials: Nil Outcome – Poisoning • Industrial agents( pesticides, herbicides) • Dugs(digoxin,metformin, phenytoin) – Sepsis • Inconclusive SGRH experience(2000-2016) • Number of patients: 164 (poisoning) – Hemoperfusion alone: 104 – Hemoperfusion plus Hemodialysis: 48 – Hemodialysis ( high flux): 12 • Outcomes – Patient mortality: • Hemoperfusion alone: 42/104(40%) • Hemoperfusion plus hemodialysis: 23/48( 48%) • Hemodialysis alone: 7/12( 58%) • Complications: – Thrombocytopenia – Hypoglycemia – Hypocalcemia Summary • Hemoperfusion is preferred to hemodialysis for the removal of chemicals that are lipid soluble or are highly protein bound(paraquat, mushroom). • Hemodialysis is preferred for water-soluble, low-molecular weight compounds. • In humans, in view of the difficulties in conducting controlled prospective clinical trials – a reduction in coma time or overall mortality has not been conclusively demonstrated with hemoperfusion Summary • Hemoperfusion combined with hemodialysis is a promising option in patients with MODS and sepsis. • Concurrent hemodialysis and hemoperfusion is a safe option in poisoning patients. • Hemofiltration has a role only in patients with severe hypotension and in poisoning agents with large volume of distribution. Thank you Prolonged direct hemoperfusion using a polymyxin B immobilized fiber cartridge provides sustained circulatory stabilization in patients with septic shock: a retrospective observational before-after study Methods: • Retrospective study • Compared the effects of prolonged and conventional PMX-DHP durations (2 and12 h) for septic shock. • 18 patients underwent conventional PMX-DHP, and • 18 patients underwent prolonged PMX-DHP. Primary outcome: vasopressor dependency index Miyamoto et al. Journal of Intensive Care (2017) 5:19 Vasopressor dependency index • The conventional PMX-DHP group had vasopressor dependency index values of 0.52 ± 0.29 and 0.39 ± 0.25 at 0 and 12 h after starting PMX-DHP. • The prolonged PMX-DHP group had vasopressor dependency index values of 0.50 ± 0.26 and 0.28 ± 0.18 at 0 and12 h after starting PMX-DHP Conclusions: Findings suggest that prolonged PMX-DHP provides more sustained circulatory stabilization compared to conventional PMX-DHP. Miyamoto et al. Journal of Intensive Care (2017) 5:19 FDA Assessment of Risks With Hemoperfusion Risks Identified by Original Panel Newly Identified Risks Criteria for considering hemoperfusion • Hepatic failure – in which extraction of hepatic toxins may prevent or delay hepatic coma – serves as a bridge to hepatic transplantation • End-stage renal disease with aluminum intoxication – In conjunction with chelating agents (deferoxamine) to remove aluminum Eur J Gastroenterol Hepatol. 1997;9(4):407 Lancet. 1983;2(8358):1051 septeX - Procedure 62 septeX –Ongoing & planned studies Honore PM et al. Newly Designed CRRT Membranes for Sepsis and SIRS-A Pragmatic Approach for Bedside Intensivists Summarizing the More Recent Advances: A Systematic Structured Review. ASAIO J. 2013 Mar;59(2):99-106 65 Status August 2015 oXiris – studies Honore PM et al. Newly Designed CRRT Membranes for Sepsis and SIRS-A Pragmatic Approach for Bedside Intensivists Summarizing the More Recent Advances: A Systematic Structured Review. ASAIO J. 2013 Mar;59(2):99-106 Status August 2015 66 oXiris Therapy principle = Adsorption; Removal of endotoxin Indications: Adjunctive sepsis therapy for gram-negative sepsis Machines to run: PrismafleX Run mode: The oXiris set can be used in any CRRT modality Treatment: for 48-72h, change of the membrane when diffusion performance drops Anticoagulation: Heparin, Citrate Available studies: Very limited amount of studies. There is only one animal study in septic pigs published. Human trials are totally missing so far. 67 •An activated Charcoal hemoperfusion device containing 300g acrylic hydrogel coated activated charcoal was combined with hemodialysis. • Plasma clearance of both creatine and urate were increased during combined hemodialysis-hemoperfusion period. Creatinine clearance in hemoperfusionhemodialysis combined patient Urate clearence in hemoperfusionhemodialysis combined patient Change in platelet count in hemoperfusionhemodialysis combined patient Conclusion: Combined hemoperfusion and hemodialysis can increase the efficacy of dialysis and is not associated with unacceptable platelet depletion Extraction ratios for some drugs and chemicals with hemodialysis, charcoal hemoperfusion and resin hemoperfusion* Cuprophane hemodialysis Coated OR uncoated charcoal hemoperfusion XAD-2 or XAD-4 resin hemoperfusion Acetylsalicyclic acid 0.5 0.5 - Digoxin 0.2 0.3 to 0.6 0.4 Glutethimide 0.16 0.65 0.8 Paraquat 0.5 0.6 0.9 0.27 0.5 0.85 Theophylline 0.5 0.7 0.75 Tricyclic ◊ antidepressants 0.35 0.35 0.8 Phenobarbital Δ ¶ * Calculated for blood flow rate of 200 mL/min. ¶ Specially prepared ion-exchange resin. Δ 0.36 to 0.47 with high-flux membranes. ◊ Large volume of distribution mitigates against removal of appreciable quantities of ©2017 UpToDate drug. Concurrent Hemoperfusion and Hemodialysis in Patients with Acute Pesticide Intoxication Blood Purif. 2016;42(4):329-336. Epub 2016 Oct 22 Water soluble and insoluble chemicals in the pesticide formulation may be eliminated more effectively in time if hemodialysis (HD) and hemoperfusion (HP) are performed concurrently. AIM: Evaluating the efficacy of concurrent HP and HD in patients with acute pesticide intoxication. METHODS: • Between Jan 2011 and Dec 2012, HP and HD were used consecutively (HP-HD group, 347 cases), • Next 2 years (Jan 2013 to Dec 2014),concurrent HP and HD were used (HPD group, 383 cases). RESULTS: The mortality was higher in the HP-HD group than in the HPD group: (48.1 vs. 20.9%) for the overall mortality CONCLUSION: • Concurrent HP and HD would be an effective and safe treatment for patients with acute pesticide intoxication, in particular, paraquat intoxication. Hemoperfusion in Overdose Notable drugs: -Theophylline -Barbiturates -Tricyclics (incl. Carbamazepine) -Digoxin -Salicylates -Paraquat -Organophosphates Replacement of renal function by dialysis: a textbook of dialysis By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)