1. Hemoperfusion Dr. Vinant Bhargava DNB( Nephrology) Consultant
Institute of Renal Science
Sir Gangaram Hospital, New Delhi

2. History
Physical properties of hemoperfusion
Indications
Types of therapies and comparison
Complications
Summary

3. Index case 1 25/M , Farmer, No comorbities Alleged substance intake
On presentation
Comatose
Hypotension
Bradycardia
Oliguria(8 hrs)
Tachypnea
alleged

4. How will we manage this gentleman?
Charcoal hemoperfusion
Resin based hemoperfusion
Hemodialysis only
CVVHD (F) plus hemoperfusion
Hemodialysis plus hemoperfusion

5. 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

6. How will we manage this pleasant lady?
Charcoal hemoperfusion
Resin based hemoperfusion
Hemodialysis only
CVVHD (F) plus hemoperfusion
Hemodialysis plus hemoperfusion

7. 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

8. 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
The most commonly available adsorbent particles are activated charcoal and resin:
Charcoal hemoperfusion has been used to treat a variety of conditions, including poisoning and hepatic failure
Certain resins (polystyrene, XAD series) are most effective for the removal of lipid-soluble drugs, with drug clearance rates from the blood frequently exceeding those achieved by charcoal hemoperfusion. Although available in Europe, they are no longer available in the United States since the market was limited.
Polymyxin B: endotoxin is bound by chemi-sorption.
J Biomed Mater Res. 1975;9(2):143.

9. Mechanism of adsorption

10. Mechanism Contd.... Sorbents: Synthetic resins Ion exchange resins
remove lipid and protein soluble substances
Ion exchange resins
remove ionic and organic substances
Activated carbon
Charcoal
irreversibly binds drug and chemicals; removes water and protein soluble substances

11. 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
The choice of cartridge depends upon body size and drug involved
a small cartridge is utilized for a child, while XAD-4 should be used for a lipid-soluble drug, such as glutethimide.
Heparin requirements are similar to hemodialysis .

12. 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
With "rebound," the drug redistributes from tissues into the plasma following its removal from the plasma
compartment. This is consistent with the pharmacokinetic handling of drugs after their removal from the
central compartment; the rebound in drug concentration in plasma may be clinically significant, including a
return to severe neurologic dysfunction or coma (as with glutethimide poisoning). Intermittent hemoperfusion helps minimize this "rebound" effect (as with paraquat and glutethimide). An additional advantage of intermittent hemoperfusion is a reduction in the hematologic side effects of
prolonged hemoperfusion (see 'Complications' below). Replacement of saturated devices with fresh devices is not usually necessary, but is another positive aspect of short intermittent hemoperfusion
Clin Toxicol (Phila) Jun;50(5):403-13

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
Should only be employed in the setting of intoxication with a drug or poison that can be removed at a rate that exceeds endogenous elimination by the liver or kidney.
Trans Am Soc Artif Intern Organ. 1967; 13:369

14. 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 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.

15. 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):
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 , 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 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 Volume 37 - Issue 12 - pp

16. 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.

17. 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)

18. 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:
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:
Medicine (Baltimore) Mar;96(12):e6160, J Dermatolog Treat Oct 24:1-7

19. Other Indications for Hemoperfusion
SLE
Rheumatoid arthritis
HLA antibodies removal
ABO incompatible transplants
Glycosorb column
Adsopak column
No randomised controlled trials

20. 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

21. 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

22. Available hemoperfusion devices
Manufacturer
Device
Sorbent type
Amount of sorbent
Polymer coating
Cost
Asahi
Hemosorba
Spherical charcoal
170 g
Polyhema
14,000
Gambro
Adsorba
Norit charcoal
100 or 300 g
Cellulose acetate
12,800
Toray Industries
Toraymyxin*
Toraymycin ?
None
1,08,000
Cytosorbents
Cytosorb*
Polystyrene divinylbenzene copolymer
300 g
None 
77,500

23. 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-molecular-weight 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

24. 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)
Hemodialysis (HD) is rarely needed in the care of poisoned patients, although HD is used in greater than 95 percent of patients.
Hemodialysis is better in ethanol poisoning, because charcoal is rapidly saturated by ethanol
Handbook of Dialysis, 4th ed., Daugirdas JT, Blake PG, Ing TS (Eds), Lippincott Williams & Wilkins, Philadelphia p.300.

25. Hemodialysis+ Hemoperfusion
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.

26. Hemoperfusion Hemofiltration
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 .
Hemofiltration
Continuous renal replacement therapy (CRRT) has gained acceptance as an effective alternative treatment.
It includes continuous veno-venous hemofiltration (CVVHF) and continuous veno-venous hemodiafiltration (CVVHDF) .
The evidence for these techniques is scant.
In general, CRRT has lower clearance rates than conventional HD. It might offer some benefit in unstable or hypotensive patients .

27. HD and hemoperfusion may not be feasible in hypotensive patients.
Contraindications  
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.
Complications 
 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).
Complications 
 Potential side effects of HD include hypotension, bleeding due to anticoagulation, hypothermia, air embolus, and complications that may result from obtaining central venous access .
Hemoperfusion has these same complications, but also poses potential risks of charcoal embolization, hypocalcemia, hypoglycemia, leukopenia (10 percent reduction), and thrombocytopenia (30 percent reduction).
Thrombocytopenia
average loss of 30 percent of platelets with coated or uncoated charcoal or resin occurs;
the reduced platelet count usually returns to normal within 24 to 48 hours following a single hemoperfusion.
Greater degrees of thrombocytopenia are observed with resin than with charcoal
hypocalcemia, hypoglycemia, transient leucopenia,Transient hypothermia,Hypotension

28. 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.
The principle of Charcoal Hemoperfusion:
ADsorption vs ABsorption:
Absorption is when atoms molecules or ions diffuse into a bulky volume
Adsorption is when the atoms molecules or ions settle on a surface
Charcoal or resin in the cartridge will compete with plasma proteins for the drug molecules; these molecules will adsorb onto the charcoal surface
Clearance of any given molecule depends not only on its size but also on the affinity of the charcoal or resin for that molecule
Hemoperfusion is effective at clearing protein-bound and lipid-soluble drugs (not just water soluble molecules)
Hemoperfusion has variable effectiveness at removing small water-soluble molecules,
Brochure from the “Adsorba C” range by Gambro, for the Prismaflex machines

29. 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

30. Devices designed to remove endotoxin and cytokines in sepsis.
Mediators of Inflammation Volume 2013, Article ID

31. 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.
[Slide name] Toraymyxin is the blood purifier that is filled with polystyrene derivative fiber immobilized by Polymyxin B.
[PR point]
It is the detailed view of Toraymyxin column. In this case, the figure shown in the attached document is changed and the description is changed in a way that polystyrene derivative fiber is upwards and polymyxin B downwards.
[Explanation]
Inside the column, the sheets are piled up in a case made up of polypropylene. The sheets then turn into a knitted fabric. Individual threads that formed the knitted fabric maintain the strength due to the exterior of the column being made of polystyrene and interior of chemically stable polypropylene. Polystyrene of the exterior side and polymyxin B are covalently bonded through a chemical process. In addition, the surface of the fiber is porous. Therefore, it increases its surface area.
[Explanation of terms/words]
 Polymyxin B
It is an antibiotic that is responsible for the antibacterial action against gram-negative bacteria. It has great affinity with Endotoxin; therefore it neutralizes the Endotoxin binding activity. However, there are chances of strong renal damage/nerve damage by intravenously-administering and the injection becomes contraindicated. Currently, it is internally used for the disinfection in the intestine at the time of leukemia, or locally administered against infection (Pseudomonas aeruginosa etc.).
Polymyxin B Approx. 5mg per 1 gram fiber (approx. 40,000 unit).
In case of PMX-20R the fiber is 56g, therefore, 280mg (approx. 22, unit) of Polymyxin is bonded. Incidentally, usage of polymyxin B as a drug is 30, unit in a day.
Further, polymyxin B manufactured by Dumex Inc., Denmark and Kaken Pharmaceutical Co., Ltd., Japan sells this drug. Polymyxin B that is used to make Toraymyxin is purchased from Kaken Pharmaceutical Co., Ltd.
 Can the destroyed fiber flow into the blood?
No, it cannot. There is a fine mesh-filter of polystyrene in the header; therefore it cannot enter into the blood draining away from the column
NH2
NH2
The endotoxin adsorbing
capacity of Toraymyxin was found to be 64,000 ng contained in bovine serum
Polymyxin B
NH2 NH
NH2
CH2NHCOCH2Cl
CH2NHCOCH2
CH2NHCOCH2Cl
Toraymyxin:(PMX-B DHP)
Endotoxin Binding without Systemic Side Effects
CH2CH
CH2CH
CH2CH
Polystyrene derivative fiber
Sakai Y. et al.
Therapeutic Plasmapheresis (XII): , 1993

33. 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
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.
oXiris

34. 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

35. Hemoperfusion: FDA Summary and Recommendations

36. 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.

37. FDA Recommendations
The FDA recommends a split classification and the following revision to Section § :
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.

38. Clinical studies

39. J Bras Nefrol 2010;32(4):

40. 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

41. Clearance of Drugs: comparison of conventional hemodialysis with charcoal hemoperfusion
at least a modest benefit
Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6

42. Blood purification & Mortality

43. 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:

44. 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.

45. 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:

46. ABDOMIX trial Toraymyxin

47. 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

48. oXiris – studies Status August 2015
Source:

49. septeX – studies Status August 2015
Source:

50. Different Extra Corporeal Therapies
Cytosorb

51. 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

52. 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

53. 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

54. 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.
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
Hemoperfusion may be considered when
there is impairment of normal drug excretory function due to hepatic, cardiac, or renal insufficiency;
when there is intoxication with agents with metabolic and/or delayed effects, such as mushrooms and paraquat; and
in patients with end-stage renal disease with aluminum intoxication.

55. Thank you

57. 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

58. 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

59. 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

60. FDA Assessment of Risks With Hemoperfusion
Risks Identified by Original Panel
Newly Identified Risks

61. 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
Hemofiltration using charcoal hemoperfusion doubles the rate of removal of the deferoxamine-aluminum chelate, compared with
standard hemodialysis membranes [24,25]. However, given the necessity for roughly one year of
therapy, the most economical alternative is the use and reuse of a high-flux hemodialyzer rather than
the very expensive charcoal hemoperfusion cartridge. In acute aluminum poisoning, high-flux dialysis
(using deferoxamine as the chelating agent) was superior to that of charcoal hemoperfusion in
removing aluminum
Eur J Gastroenterol Hepatol. 1997;9(4):407
Lancet. 1983;2(8358):1051

62. septeX - Procedure

65. 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 Mar;59(2):99-106
Status August 2015

66. oXiris – studies Status August 2015
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 Mar;59(2):99-106
Status August 2015

67. 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.

68. 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.

69. Creatinine clearance in hemoperfusion-hemodialysis combined patient
Urate clearence in hemoperfusion-hemodialysis combined patient

70. Change in platelet count in hemoperfusion-hemodialysis combined patient
Conclusion: Combined hemoperfusion and hemodialysis can increase the efficacy of dialysis and is not associated with unacceptable platelet depletion

71. Cuprophane hemodialysis Coated OR uncoated charcoal hemoperfusion
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 -
Digoxin
0.2
0.3 to 0.6
0.4
Glutethimide
0.16
0.65
0.8
Paraquat
0.6
0.9¶
PhenobarbitalΔ
0.27
0.85
Theophylline
0.7
0.75
Tricyclic antidepressants◊
0.35
Fibers upon which immobilized polymyxin B are attached have also been placed in hemoperfusion cartridges for direct contact with blood for the removal of endotoxin and cytokines
Hemoperfusion devices have been approved in Europe and Japan for removing cytokines (eg, interleukin (IL)-6, tumor necrosis factor, and others) in conditions such as septic shock and acute lung injury.
They are not yet available in the US. Studies of these devices are ongoing, and their characteristics are shown in the table
XAD (resins) - highly absorbent resins used in continuous sampling of organic materials, especially for monitoring of pollutants in gas streams
* 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 drug.
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73. Concurrent Hemoperfusion and Hemodialysis in Patients with Acute Pesticide Intoxication
Blood Purif. 2016;42(4): 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).

74. 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.

75. 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)