David J. Carr

Push-pull sorbent based pheresis for treatment of acute hepatic failure : the biologic-detoxifier/plasma filter System

The BIOLOGIC-DTR (detoxifier) System is an extracorporeal blood treatment device that uses the membranes of a cellulosic plate dialyzer to propel blood in and out through a single lumen access (on a 12 sec cycle) and circulates a suspension of powdered charcoal and cation exchanger through the dialysate spaces to absorb many soluble toxins in the treatment of hepatic failure. The BioLogic-DTPF (detoxifier/plasma filter) System adds two Gambro plasma filters downstream from the plate dialyzer, which allows most of the blood plasma to pass out of the blood, contact powdered charcoal in a suspension, and then return to the blood during each 12 sec cycle (creating push-pull sorbent based pheresis). A roller pump exchanges charcoal suspension between the plasma filter case and a 700 ml bag of powdered charcoal suspension. At a blood flow rate of 150–200 ml/min, 100 ml/min of plasma moves bidirectionally through the plasma filter membranes. Direct contact of plasma with charcoal outside the plasma filter membranes removes creatinine with a clearance rate equal to plasma flow (100 ml/min); clearance of strongly protein bound toxins, such as unconjugated bilirubin, is lower (10–40 ml/min). In this article, the authors explain the mechanisms of operation of this system and present in vitro tests that define its chemical efficiency. Also described are potential problems, tests that indicate the severity of these problems, and monitors and algorithms to detect or avoid these problems in clinical use of the system. The results of the treatment of two patients with acute hepatic failure and coma using the BioLogic-DTPF System are reviewed. ASAIO Journal 1998; 44:129–139.

Sorbent suspensions vs. sorbent columns for extracorporeal detoxification in hepatic failure.

Abstract:  Hepatic failure is a significant medical problem which has been unsuccessfully treated by hemodialysis. However, similar therapies using recirculated dialysate regenerated by sorbents in place of single‐pass dialysate have been beneficial in treating acute‐on‐chronic liver failure. The advantages of sorbent‐based treatments include some selectivity of toxin removal and improved removal of protein‐bound toxins. Activated carbon has been extensively used in detoxification systems, but has often had insufficient toxin capacity. Powdered activated carbon, because of its large surface area, can provide greater binding capacity for bilirubin and other toxins than granular carbon commonly used in detoxifying columns. Methods of using powdered carbon in extracorporeal blood treatment devices are reviewed in the present paper, including liver dialysis and a new sorbent suspension reactor (SSR); and the abilities and limitations of the SSR and columns to process protein solutions are discussed.

Systemic inflammatory response syndrome treatment by powdered sorbent pheresis: the BioLogic-Detoxification Plasma Filtration System.

Systemic inflammatory response syndrome (SIRS) is one of the most common causes of death in intensive care unit patients. The detoxification plasma filtration (DTPF) system (HemoCleanse, Inc., West Lafayette, IN) combines the DT hemodiabsorption system in series with a push-pull pheresis PF system (a suspension of powdered sorbents surrounding 0.5 microm plasma filter membranes). Bidirectional plasma flow (at 80-100 ml/min) across the PF membranes provides direct contact between plasma proteins and powdered sorbents, as well as clearance of cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6) at a rate of 15-25 ml/min, without evidence of saturation for 90 minutes. In a U.S. Food and Drug Administration approved study we treated eight patients with SIRS and organ failure with a single DTPF treatment, using powdered charcoal as sorbent in four patients and powdered charcoal and silica in four patients. Treatments proceeded for 6 hours with proper heparin anticoagulation (activated clotting time 250-300 sec) and appeared safe. All patients improved during the treatments and each had increased blood pressure and decreased need for pressor agents. Plasma cytokine levels stabilized or decreased during treatment and were significantly lower the morning after treatment. Multiple organ dysfunction (MOD) and Acute Physiology Chronic Health Evaluation II scores and organ function gradually improved in most patients, and two patients survived for more than 28 days and two for more than 14 days. The DTPF System may prove beneficial in treatment of patients with sepsis.

Push-pull sorbent-based pheresis treatment in an experimental canine endotoxemia model: preliminary report.

The Biologic-DTPF System™ (DTPF), an extracorporeal blood treatment device with potential to treat sepsis, was tested in a preliminary study using a canine endotoxemia model. Six dogs were used and they formed four treatment groups, as control group (n=1) and three groups based on the type of sorbent present in the plasma filter (PF) system: sham treatment with no sorbent (n=1), charcoal as sorbent (n=2), and charcoal/silica as sorbent (“silica” group, n=2). Cardiodynamic data were recorded before treatment and every 30 minutes, and blood samples were collected to determine blood chemistry and to detect the levels of endotoxin and selected plasma cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). The dogs were given Escherichia coli endotoxin (2 mg/kg) as an intravenous drip (extended over a period of 30 minutes). Thirty minutes after the end of infusion all animals except the control were treated with the DTPF system for four hours. To determine the effect of treatment, data collected at one hour from the initiation of treatment until the end of treatment were compared between control and treated dogs. The endotoxin levels in the control dog were higher (P < 0.05) than other groups. The control dog had lower levels of TNF than other groups. The control dog had similar levels of IL-1 (P > 0.05) and higher levels (P < 0.05) at 4 hours into treatment compared to other groups. The control dog had similar levels of IL-6 as other groups (P > 0.05). In the control dog, the mean arterial pressure (MAP) fell and then remained low but stable at 1–4 hours. The charcoal group had lower MAP than the control dog at 1–4 hours (P < 0.05). The silica group had higher MAP levels similar to the control dog. After treatment, the control dog had higher (P < 0.05) values of hematocrit, hemoglobin, calcium, potassium, and albumin compared to the treated groups. As expected for a system removing plasma during sepsis, the DTPF System had some adverse effects on the physiologic status of the dogs, especially when loaded with charcoal sorbent only. The findings of the present study suggest that the filters are capable of eliminating endotoxin and there is some evidence of cytokine removal. Although the charcoal dogs did poorly, addition of silica to the sorbent offset any negative effects. Further work is underway to improve the efficiency of the system, primarily, to enhance the capacity of the sorbents for cytokines. A more realistic canine sepsis model with mortality after several days (the Escherichia coli- infected intraperitoneal clot) will also be considered in future studies.

Effect of sorbent-based dialytic therapy with the biologic-DT on an experimental model of hepatic failure

An experimental model of hepatic failure in the dog has been developed in which the liver is devascularized in two stages. Under general anesthesia, a portacaval shunt is created, ligatures placed around the hepatic and gastroduodenal arteries, and the dog recovered. Two days later under general anesthesia, the ligatures are pulled, converting hepatic insufficiency to hepatic failure. Five control animals developed hypotension, severe lactic acidosis, hypoglycemia, and increasing liver enzyme levels during 6 hrs of follow-up. The BioLogic-DT system includes a cellulosic plate dialyzer with a suspension of powdered charcoal and cation exchangers as dialysate. Five animals were treated with the BioLogic-DT for 6 hrs after creation of hepatic failure. These animals were more stable physiologically, developed less lactic acidosis and less enzyme elevation, and maintained high normal blood glucose levels. The results help explain the clinical improvement demonstrated in patients with hepatic failure treated by the BioLogic-DT, and confirm that many of the toxins of hepatic failure are dialyzable and bound by simple sorbents such as charcoal and cation exchangers.

Predicting dialysate sodium composition in sorbent dialysis using single point and multiple-dilution conductivity measurement.

This research establishes the ability to predict the sodium composition in dialysate from a single conductivity measurement over the wide range of concentrations of chloride, bicarbonate, and acetate that occur during sorbent dialysis. The ranges explored in mEq/L were sodium 100–180, chloride 76–143, bicarbonate 16–31, and acetate 4–11. Through mathematical optimization using a pattern search method, a single point measurement technique was shown to predict the total sodium concentration within approximately ± 4.2 mEq/L in solutions with varying relative concentrations of chloride, bicarbonate, and acetate. The data analysis showed that the total sodium concentration can be predicted within ± 2.1 mEq/L in most cases. Another potential approach to determining sodium concentration, a multiple-dilution measurement method, was tested and is also described. It is based on the varying relationship of activity to concentration for each of the sodium–anion pairs. This technique has practical limitations because of interactions between the various ions in solution at normal concentrations of dialysis along with the complexities involved in creating high dilutions of dialysate for on-line assays during dialysis.

The Sorbent Suspension Reciprocating Dialyzer for Use in Peritoneal Dialysis

The greatest cost of peritoneal dialysis is in the preparation, packaging, and shipping of sterile dialysis fluid. CAPD and CCPD represent attempts to support patients on the minimal volumes of such dialysis fluid. Sorbent chemicals which regenerate dialysate could decrease the shipping weight of disposables, while allowing much higher dialysate flows.