Activated Carbon Hemoperfusion and Plasma Adsorption PDF

Advances in Small Animal Care 2 (2021) 131–142 ADVANCES IN SMALL ANIMAL CARE Activated Carbon Hemoperfusion and Plasma Adsorption Rediscovery and Veterinary Applications of These Abandoned Therapies Jeff Barnesa,*, Larry D. Cowgill, DVM, PhD, DACVIM (SAIM)b,c, Jose Diaz Auñon, PhDd a AimaLoji...

Advances in Small Animal Care 2 (2021) 131–142 ADVANCES IN SMALL ANIMAL CARE Activated Carbon Hemoperfusion and Plasma Adsorption Rediscovery and Veterinary Applications of These Abandoned Therapies Jeff Barnesa,*, Larry D. Cowgill, DVM, PhD, DACVIM (SAIM)b,c, Jose Diaz Auñon, PhDd a AimaLojic Animal Health, 3620 Homestead Street, Rapid City, SD 57703, USA; bUniversity of California Veterinary Medical Center-San Diego; cDepartment of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, 2108 Tupper Hall, One Shields Avenue, Davis, CA 95616, USA; dImmutriX Therapeutics, Inc., 3620 Homestead Street, Rapid City, SD 57703, USA KEYWORDS  Hemoperfusion  Hemoadsorption  Plasma adsorption  Blood purification  Intoxication  Poisoning  Cytokines  Extracorporeal KEY POINTS  Hemoperfusion witnessed a rise in adoption in the 1970s and 1980s and then a decline in the 1990s as modern dialytic devices dramatically improved. With new improvements in adsorbent technology, there is promise of a comeback for this extracorporeal therapy.  Modern hemoadsorbents are extremely effective at removing drugs and other toxins from blood and is poised to play a significant role in other disease conditions moving forward.  The availability of equipment to deliver stand-alone hemoperfusion has never been commercially available. New dedicated equipment will open up the therapy to be delivered in any clinical setting. INTRODUCTION BACKGROUND Hemoperfusion (HP), or what may be better described HP was first introduced in the 1940s, refined in the as hemoadsorption, is an extracorporeal blood purifica- 1950s and 1960s, introduced as a therapeutic procedure tion therapy delivered in a method similar to hemodial- in the 1970s, and used frequently throughout the 1970s ysis (HD). Blood is continuously withdrawn from and 1980s. Biomass-derived activated charcoal has been a vein and pumped through a tubing circuit and a the primary adsorbent used because of its large surface filtering device and then returned to the patient via a area and excellent filtering capability. High-quality char- standard dual lumen dialysis catheter. The filtering de- coal can be produced by using a biomass such as coconut vice (HP column) contains adsorbent media which shells or bamboo and heating it to a very high tempera- can remove a large quantity of specific or spectrum of ture in the absence of oxygen. The result is an extremely molecules that are associated with drug overdose, porous carbon that is then activated using superheated poisoning, or other disregulated molecules associated CO2, steam, or chemicals to further increase the surface with disease conditions. This must be done without area and to create microscopic transport channels to con- extracting or affecting normal blood components. nect the individual voids or pores. *Corresponding author, E-mail address: [email protected] https://doi.org/10.1016/j.yasa.2021.07.010 www.advancesinsmallanimalcare.com 2666-450X/21/ © 2021 Elsevier Inc. All rights reserved. 131 132 Barnes, Cowgill, Diaz Auñon The historical challenges with activated charcoal as it Throughout the 1970s, HP was used for removal of pertains to purifying blood were numerous. Charcoal uremic metabolites because the devices were much particles derived from plants are irregularly shaped more effective for the clearance of creatinine, uric acid, with sharp edges that caused activation of platelets and middle molecules than the dialyzers available at and blood complements and may damage or destroy that time. Clinical investigators also studied HP in series cellular components such as red blood cells (Fig. 1). He- with HD for patients with dialysis-resistant uremic molysis and thrombocytopenia were commonly toxins. Results showed improvement in “well-being” observed in legacy HP procedures. Other complica- and decreased treatment times when compared with tions occur due to the soft and crumbly nature of acti- HD alone. Since then, modern HD membranes have vated charcoal forming microparticles that can leach significantly improved clearance for middle molecules; out of the device and cause emboli. Lastly, the pore however, even the most modern dialyzers are not as structure of plant-derived charcoal is designed by nature effective for middle molecule clearance as legacy HP de- to transport water, and the micropores are somewhat vices. The introduction of new and more efficient dia- random and vary in size, shape, and consistency. Char- lytic devices created a steady decline in the use of HP coal is a powerful adsorbent that will remove a wide to the point where it has become essentially forgotten range of molecules, but the specific molecules and ki- in modern medicine (Fig. 2). netics are somewhat uncontrollable. Hemodynamic Extracorporeal therapies (ECTs) in veterinary medi- instability, hypocalcemia, hypokalemia, hypoglycemia, cine, including HP and HD, are performed infrequently; and inflammatory responses were also commonly however, HP has been an accepted extracorporeal mo- observed with early activated charcoal HP devices. dality since the inception of ECTs in animal patients, The bioincompatibility issue of charcoal sorbents and its interest and application is growing among the was first addressed in 1969 (T M S. Chang) by applying Internal Medicine and Emergency and Critical Care spe- a thin coating of cellulose nitrate and albumin to the cialties. Reasons for historical low adoption of these charcoal particles. The coating improved hemocom- therapies are the cost of the treatments and equipment, patibility and biocompatibility to an acceptably safe lack of an established network of dialysis units, lack of level but at the same time reduced the adsorptive per- training programs, and lack of veterinary-specific de- formance and capacity, diminishing the effectiveness vices and delivery systems. of the therapy. Subsequent coating attempts were The growing number of veterinary dialysis programs made by others using acrylic hydrogel, cellulose, collo- relies on devices designed for adult human patients, dion, cross-linked gelatin, and modified hydrogel with and special considerations and procedures need to be varying yet similar results. used to treat smaller companion animals. Access to a Animal studies demonstrated the effectiveness of blood bank may be required for very small animals as charcoal HP in the treatment of acute intoxication of extracorporeal circuit volume can exceed safe extracor- glutethimide, pentobarbital, and salicylate leading to poreal limits or even the total blood volume of the an- the first clinical trials for adult patients with suicidal imal. HP in veterinary medicine makes up only a small or accidental drug poisoning. The success of the first hu- percentage of the totality of ECTs. Existing HP columns man clinical trial , led to routine clinical use in pa- need to be connected to HD or other continuous renal tients around the world. replacement treatment (CRRT) machines to deliver the FIG. 1 (A) Activated charcoal. (B) Scanning electron micrograph (SEM) of naturally derived activated charcoal showing irregular shaped surface and rough edges. (Courtesy of John Dinsley, Crawford, NE.)  Activated Carbon Hemoperfusion 133 precolumn, and postcolumn to allow detection and location of catheter restrictions and circuit clotting. ADSORPTION FUNDAMENTALS The mechanism at work in HP is adsorption, not to be confused with absorption. Absorption is the process of a fluid going within an absorbent like a sponge. Adsorp- tion is the adhesion of atoms, ions, or molecules to the surface of an adsorbent. Confusing the matter is the fact that activated carbon (AC) has adsorptive surface distributed throughout the material, so in reality, sol- utes are going within the carbon structure where they are being attached to the carbon surface via adsorption. FIG. 2 Human cases reported to U.S. poison centers that Adsorption is the result of four forces: van der Waals required extracorporeal toxin removal. The number of force, hydrogen bonds, ionic bonds, and covalent hemodialysis procedures has grown while hemoperfusion is bonds. van der Waals force is a weak bond comprising all but forgotten. (From Holubek WJ, Hoffman RS, Goldfarb London dispersion forces and stronger dipole–dipole DS, Nelson LS. Use of hemodialysis and hemoperfusion in interactions. Hydrogen bonds are 10 times stronger poisoned patients. Kidney Int. 2008 Nov;74(10):1327-34.) than van der Waals force although weaker than ionic bonds. Covalent bonds or chemical adsorption also therapy, which requires the prescriber to have a high de- can occur and are the strongest bond. van der Waals gree of skill as these machines were not designed to force is the primary force participating in adsorption. deliver HP, and no commercially available HP-specific These are weak electrical forces that attract molecules delivery systems have been available until recently. to one another. Another fundamental property of adsorption is size exclusion. Modern sorbents can be designed with very HEMOPERFUSION DEVICES precise pore sizes, with nanometer precision. Large There are several HD and CRRT machines available and structures, like RBCs, can be excluded completely while capable of running either a direct HP treatment or a molecules that fit into the pore structure may be bound combination therapy in line with dialysis. Conven- to the inner pore surface of the adsorbent. Molecules tional systems are designed for human patients and with physical dimensions smaller than the pore size are not intuitively adaptable for routine use in smaller are typically adsorbed if they are susceptible to adsorp- veterinary patients. These systems also were not specif- tion forces (electrical charge and van der Waals force). ically designed for HP, so a user must seek training to Pore size can be precisely controlled and adjusted to learn the nuances of each platform to use them for HP. target a specific range of molecules associated with There are advantages to a combination of the HD– intoxication or other disease conditions. Pore size is HP extracorporeal circuit including the control of characterized as microporous, mesoporous, and macro- body temperature, balancing electrolytes, and adding porous based on pore diameter (Table 1). convective and diffusive clearance capability; however, Typically, molecules targeted for drug overdose and in routine use, a combination circuit may not be neces- poisoning are between 150 Da and 1,500 Da, which sary and adds cost and complexity to the procedure. For also includes drug metabolites. These molecules can some acute toxicities, adsorptive clearance of the toxin be effectively cleared by microporous adsorbents if may be all that is needed. pharmacokinetic parameters are met (see “Use of Hemo- A new dedicated delivery system for direct HP is now perfusion In Drug Overdose and Poisoning”). Pathologic available for use in veterinary patients. It consists of an molecules associated with other disease conditions extracorporeal tubing circuit, blood pump, disposable can exceed 50 kDa or even 100 kDa, and mesoporous adsorption column, and integrated monitoring system or macroporous structured adsorbent is needed. Legacy to ensure the safety of the procedure (Fig. 3). The system activated charcoal is almost purely microporous in perfuses blood through the extracorporeal circuit and structure. Modern ACs in contrast can be manufactured provides anticoagulation delivery and pressure moni- in virtually any pore size, either broadly or narrowly toring. Pressures are measured on the inlet line, distributed, depending on the needs of the application. 134 Barnes, Cowgill, Diaz Auñon FIG. 3 (A) AimaLogic direct hemoperfusion system. (B) Hemoperfusion column. (C) Diagram of extracorporeal circuit. Surface area is one of the principal determinants of The final step is activation, a thermal–chemical reac- how much and how fast a solute will be adsorbed. Sur- tion, where fractures and channels are created within face area is created in modern synthetic sorbents by the porous carbon to open the internal structure of forming a series of voids in a cured polymer resin the carbon and thus create a massive internal surface with alcohols or other agents that can be removed area of interconnecting pores. These fractures and chan- easily via solvent dissolution or burning it off at high nels are known as transport pores and are responsible temperature. The precursor polymer resin subse- for making the internal surface area available for quently is transformed into a porous pure carbon adsorption. Transport pores are critical for a rapid rate adsorbent through the process of pyrolysis (heating of adsorption. After activation, modern carbon sorbents the resin to high temperatures in the absence of oxy- can have a surface area greater than 2,000 m2/g, and a gen), and in this process, anything that is not carbon single modern therapeutic HP column can have a sur- is burned off. Porous carbon at this stage can have sur- face area greater than 30 football fields. face area in excess of 600 m2/g; however, the created Thermal activation is measured in “burn-off” or the voids (pores) in the original polymer are not yet mass reduction percentage attained during the process. interconnected. Surface area increases as burn-off increases to a critical point, and then, surface area declines (with decreasing carbon mass) as burn-off surpasses this point. One hun- TABLE 1 dred percent (100%) burn-off would mean there is no Characteristic of Pore Size solid product left, and everything has been converted to gas, primarily CO2. Adsorbents with larger surface Microporous 50 nm A final characteristic controlling which adsorbates will bond to an adsorbent is determined by the surface  Activated Carbon Hemoperfusion 135 chemistry of the adsorbent. Point of zero charge (PZC) broad-spectrum pathogenic toxins, and Polymixin B is the pH value required for the net surface charge of AC functionalization of LPS Adsorber (Alteco Medical AB, to be zero. A low PZC-AC has a positively charged sur- Lund, Sweden) to promote adsorption of endotoxin. face, and a high PZC will have a negative surface charge. Activation of carbon (as discussed earlier) is the step Normally, it is easier to adsorb a cation onto a nega- that opens the internal structure and connects the pores tively charged surface and an anion onto a positively of a carbon-based adsorbent. In contrast, polymer- charged surface. Other interactions may be stronger based beads are not activated, limiting the inner pore than electrostatic forces which can make the surface accessibility of these sorbent materials which conse- charge less important. PZC of AC can be made to be quently limits their functional surface area. Nitrogen very high, very low, or neutral. One can think of PZC porosimetry and mercury porosimetry are analytical as the characteristic that gives the adsorbent a greater af- techniques used to quantify surface area, pore size, finity for one molecule over another. pore structure, and density of porous materials (Ta- ble 2). Examining polymer beads by these methods demonstrates the relatively low functional surface area LEGACY AND MODERN SORBENTS of this category of sorbents. While polymer sorbents In 1973, research began in Ukraine (V. Nikolaev and col- can have unique capabilities, the sorbent columns leagues) (Vladimir Nikolaev, personal communication, need to be larger and necessitate longer treatments to 2018) at the then Soviet Union National Institute of Sci- compensate for the relatively low surface area compared ence to develop an AC specifically intended for HP from with AC counterparts. They often can suffer earlier satu- synthetic resins (Note the distinction of activated char- ration that carbon-based devices undergo. coal vs AC. The author will use “carbon” to distinguish Saturation of HP sorbents can be difficult to predict synthetically derived “carbon” vs “charcoal” which is car- in a living model and is an ongoing challenge during bon derived from natural materials.). These new syn- therapy. Sorbents can be measured for saturation thetic hemoadsorbents were the first of their kind points for different solutes ex vivo in a solution such possessing a uniform spherical shape, larger surface as water, polyelectrolyte solution, or blood. As the car- area (1,200 m2/g – 1,600 m2/g), and a smooth external rier solution becomes more complex with a large num- surface that were hemocompatible without additional ber of constituents as is the case with plasma or blood, polymeric coatings. Somewhat later this team developed the predictability of saturation becomes more compli- specialized ACs for targeting highly protein-bound mol- cated. Interactions between molecules in the carrier so- ecules, which were named “deliganding” or HemoSorb- lution and adsorption affinities and competition ent Granulated Deliganding AC with an even larger between solutes become more involved with more surface area of 2,000 m2/g to 3,000 m2/g. These sorbents constituents. Add in a multicompartment living sub- form the basis for the highly specialized ACs for HP that ject where solute distribution and generation rates are manufactured today (Fig. 4). might be occurring in real time, and the system and Considerable research and clinical experience was predictability becomes more complex still. Testing gained in the Soviet Union over two decades on the ap- blood in vitro can provide some prediction for satura- plications of AC in HP in a wide variety of disease condi- tion at various toxicity concentrations but only in the tions including acute radiation sickness, chronic most simplistic cases does it equate directly to in vivo glomerulonephritis, biliary and portal cirrhosis, severe treatment conditions. forms of leptospirosis, skin psoriasis, psoriatic arthritis, Until there are better patient-side diagnostics and idiopathic dilated cardiomyopathy, chronic kidney fail- available clinical experience, the rule of thumb for HP ure, and gonadotoxic side effects of intense cancer is to use the largest, highest capacity device that is safe chemotherapy. for the size of the patient. HP should be provided until Other modern sorbents have been formulated for clinical signs improve (for acute toxicity) with the antic- therapeutic HP from polymer beads (Cytosorbents, ipated possible need to replace the HP column based on Inc, Exthera Medical, Alteco Medical). These manufac- any available manufacturer recommendations if pro- tured sorbents also are highly porous and work in a vided. Saturation is concentration dependent, and it is similar fashion as AC. Synthetic sorbents also can be rarely known what the actual toxin or solute concentra- functionalized with a drug or other substance to pro- tion is before treatment. Mild to moderate toxicities vide selective adsorption capabilities. An example is based on estimated exposure or clinical signs may be the heparin functionalization of Seraph 100 (ExThera treatable with a single device, while more severe toxic- Medical Corporation, Martinez, CA), for adsorption of ities may require exchange of a second or third column. 136 Barnes, Cowgill, Diaz Auñon FIG. 4 (A) Photograph of synthetically derived activated carbon beads. (B) SEM illustrates the smooth surface and uniformity of beads. (C) SEM of crushed activated carbon illustrates the inner structure of 20 nm pore size. The craters are air bubbles that were trapped inside the resin as it cured. (D) Activated carbon bead with surface stripped off revealing 3,000 nm pore size inner structure. (Courtesy of ImmutriX Therapeutics, Inc.) The requirement to exchange HP devices becomes more TABLE 2 likely for devices with lower adsorptive surface areas. Characteristics of Contemporary Adsorbents Pore Surface Name Size (nm) Area (m2/g) PZC USE OF HEMOPERFUSION IN DRUG AimaLojic #1 24 1956 10.4 OVERDOSE AND POISONING AimaLojic #2 78.7 2162 10.72 Volume of Distribution and Water Solubility Toxins that are most susceptible to rapid clearance via AimaLojic #3 82 1902 10.4 HP have a low volume of distribution (Vd), may be pro- Activated 4 1390 7.1 tein bound or nonprotein bound, and have a molecular charcoal weight between 150 Da and 50,000 Da. Toxins with a Pitch- 3.85 1776 10.9 larger Vd or high water solubility may not be suscepti- based AC ble to clearance with HP. Polymer 45 473.29 3.04 Toxins with low Vd (