WO2004082737A2 - Extracorporeal blood treatment device for removing blood toxins, and methods thereof - Google Patents
Extracorporeal blood treatment device for removing blood toxins, and methods thereof Download PDFInfo
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- WO2004082737A2 WO2004082737A2 PCT/US2004/007590 US2004007590W WO2004082737A2 WO 2004082737 A2 WO2004082737 A2 WO 2004082737A2 US 2004007590 W US2004007590 W US 2004007590W WO 2004082737 A2 WO2004082737 A2 WO 2004082737A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0017—Filtration
Definitions
- a recycle path connected for returning the diluent removed from the blood by the concentrator device to a diluent source is provided, hi one embodiment, the recycle path comprises a filter.
- the recycle path includes one or more membrane modules and/or a recycle pumps.
- a filter device connected to receive blood from the source and to supply a portion of the blood to a system component is provided.
- the filter device supplies at least a portion of the blood to an irradiator or to another filter and returns the remainder of the received blood to the source.
- a reservoir connected to receive material filtered from the blood by the concentrator device is provided.
- a system to treat blood using at least two types of filters is provided.
- more than two types of filters are used.
- 3 to 6 different types of filters are used.
- 7-10, 11-15, 16-20, or more than 20 different filter types are used.
- two filter types are used, h one embodiment, the first filter is a hemoconcentrator filter having a porosity of about 70 to about 90 kilodaltons.
- the second filter is a cytoldne filter having a porosity of about 10 to about 30 kilodaltons.
- the second filter includes two filters connected in parallel, each filter having a porosity of about 10 to about 30 kilodaltons. In one embodiment, the second filter has a porosity of about 10 kilodaltons. In one aspect, at least one of the filters comprises polysulfone fibers. In another embodiment, one or more concentrators are provided. In one embodiment, the concentrator device has a membrane or filter having a transmembrane pressure greater than 76 mmHg. In one embodiment, the concentrator device includes two hemoconcentrators connected in series. Each hemoconcentrator can be connected to a separate hemoconcentrator pump or two or more hemoconcentrators can share pumps.
- the concentrator device filters the blood received based on certain characteristics of the blood, hi one embodiment, the blood is filtered based on the size of the constituents of the blood.
- the concentrator device includes a hollow cylinder and a central core formed of hollow fibers axially disposed within the hollow cylinder.
- the hollow cylinder has a length of about 10 inches and a diameter of about 1.5 inches, and the central core has a surface area in the range of between about 1.2 m 2 to about 2.4 m 2 .
- an inlet monitoring means is provided at or near the concentrator device for monitoring the pressure of the blood.
- a system and method for treating blood using a device having a concentrator or first filter that has a transmembrane pressure (TMP) that is greater than 76 liimHg is provided.
- TMP transmembrane pressure
- the range of TMP includes the following: about 80 mmHg to about 85 mmHg, about 86 n_tnHg to about 95 liimHg, about 96 mmHg to about 105 mmHg, and greater than about 105 mmHg.
- at least one pump is connected to the system for moving blood, diluent or other fluid through the system.
- the combined blood/diluent flow rate is less than about 400 ml/min.
- the range of the combined flow rate includes the following: about 75 ml/min to about 125 ml/min, about 126 ml/min to about 200 ml/min, about 201 ml/min to about 300 ml/min and about 301 ml/min to 400 ml/min.
- the blood flow rate alone is about 50 ml/min to about 300 ml/min, preferably about 100 ml/min.
- an oxygenator is connected between the source and filter device in order to oxygenate the blood received from the source, hi one embodiment, oxygen or ozone therapies are used to stimulate white blood cell production, inactivate pathogens and/or increase the efficiency of antioxidant enzymes.
- the temperature of at least a portion of the blood is altered, hi one embodiment, a heater to warm at least a portion of the blood or a heat exchanger to cool at least a portion of the blood is provided.
- blood is heated or cooled by about 1°C to about 10°C.
- a system to irradiate blood is provided, h one embodiment, the irradiation system comprises a UV irradiation device.
- the UV irradiation device receives and irradiates blood containing biological toxins from a source of blood.
- the irradiator device includes a UV light source and a fluid chamber adjacent to the UV light source, where the fluid chamber confines the fluid to a thin film for exposure to the UV light source, hi one embodiment, the UV light source delivers ultraviolet radiation to the blood in a dose ranging from about 2 mW/cm 2 to about 20 mW/cm 2 . In another embodiment, the effective dose of ultraviolet radiation applied to the blood is about 1 mW/cm 2 to about 19 mW/cm 2 .
- the fluid chamber is a bag for holding the diluted blood, the bag having a length in the range of about 15 inches to about 20 inches, a width in the range of about 8 inches to about 10 inches, and a fluid path having a width of about 0.75 inches to about 1 inch.
- one or more sensors are provided to monitor ultraviolet radiation emitted by the irradiator device.
- a system for a patient having an inflammatory disease is provided.
- Inflammatory diseases include, but are not limited to one or more of the following: sepsis, acute renal failure, ischemic stroke, Sudeck's syndrome, chronic fatigue syndrome, heat stroke, Hodgkin's Disease, lupus, myocardial infarction, AIDS, viremia, HCV, HBV, tuberculosis, muscular dystrophy or multiple sclerosis, Acute Respiratory Distress Syndrome, and heart disease.
- a system for reducing free radicals in blood is provided.
- one or more free radical quenchers are added to the blood prior to, during and/or after treatment with the concentrator/filter embodiments described herein.
- a strain gauge beam type load cell is provided to measure the weight of the diluent bag.
- a 70-90 kD polysulfone hollow fiber filter used for hemoconcentrating dilute blood and two 10 kD polysulfone hollow fiber filters for cytokine removal are also provided.
- An ultraviolet irradiator lamp assembly is also provded.
- the UV irradiator assembly is used to irradiate dilute extracorporeal blood with 254 nm UV-C energy.
- the assembly comprises a 200 W UVC grid lamp and lamp support structure, two quartz glass plates and compression plates to constrain the diluted blood in the irradiator bag to approximately 0.025" thickness. UV-C and temperature sensors are used to optimize ultraviolet output of the bulb.
- a safety interlock switch is provided to prevent unwanted user exposure to UV-C when loading/unloading the disposable set of materials.
- five pressure sensors are used; one each on the patient inlet and return lines, one before the irradiator bag assembly inlet, one at the hemoconcentrator inlet, and one located between the hemoconcentrator ultrafiltrate outlet and the concentrator pump.
- the inlet pressure sensor can be used to determine maximum allowable blood flow rate based on vascular access and catheter placement parameters; the patient return line sensor can likewise indicate catheter placement issues on the return side, as well as provide a measure of safety against excessive return pressures.
- the sensor located before the irradiator bag assembly provides an indication of bag pressure and is used to prevent over pressurization of the irradiator bags.
- monitoring and regulation of hematocrit is automated using an electronic weight scale, or load cell, which measures the volume or mass of diluent.
- Computer hardware and software is also used in some embodiments.
- a blood treatment apparatus for removing one or more cell mediators from blood is provided.
- the apparatus comprises a dilution source for supplying a diluent to the blood, thereby diluting the blood to produce diluted blood and reducing the hematocrit of the blood, a concentrator for extracting one or more cell mediators and diluent from said diluted blood thereby producing filtered blood, and a return path for returning the filtered blood from the concentrator to the patient after one or more cell mediators and diluent have been extracted therefrom, h one embodiment, the concentrator has a transmembrane pressure greater than 76 mmHg. hi another embodiment, at least a portion of blood has a hematocrit greater than about 36%. In a further embodiment, the blood is received at a combined flow rate of less than 400 ml/min.
- this method comprises providing a source of blood, diluting at least a portion of the blood with a diluent to provide diluted blood, thereby reducing the hematocrit of said at least a portion of the blood, transporting the diluted blood to a concentrator with a flow rate of less than 400 ml/min, concentrating the diluted blood using the concentrator thereby removing at least a portion of the diluent therefrom, and filtering said diluted blood to remove one or more cell mediators from said diluted blood, thereby producing filtered blood.
- yet another method of removing one or more cell mediators from blood comprises providing a source of blood, diluting at least a portion of the blood with a diluent to provide diluted blood, thereby reducing the hematocrit of said blood, concentrating the diluted blood using a membrane having a transmembrane pressure greater than 76 mmHg, thereby removing the diluent therefrom, and filtering said diluted blood to remove one or more cell mediators from said diluted blood, thereby producing filtered blood.
- the methods of removing one or more cell mediators from blood comprises irradiating at least a portion of the blood.
- the methods of removing one or more cell mediators from blood comprises inactivating one or more blood toxins.
- Figure 1 is a schematic representation of one embodiment of the system of the instant invention.
- Figure 2 shows a schematic of one embodiment of the UV irradiator and bag.
- Figures 3A-3E show various views of one embodiment of the UV system.
- Figure 4 shows an irradiator bag in open position.
- Figure 5 shows an irradiator bag in closed position.
- Figure 6 shows an irradiator in open position.
- Figure 7 shows UV-C penetration as a function of blood thickness.
- FIG. 1 shows a schematic representation of one embodiment of the present invention.
- blood is pumped from the patient 100 at a flow rate of about 100-300 ml/min, using a blood pump 102.
- blood can also be pumped at a flow rate less than about 50 ml/min and at a rate greater than about 300 ml/min.
- a blood flow rate of less than about 50 ml/min may lead to clotting in certain cases.
- a blood flow rate of greater than 300 ml/min may not be supported by certain hypovolemic and/or hypotensive patients and may lead to venous stenosis or collapse.
- Blood is diluted using diluent pump 114 to adjust the hematocrit to about 10%, and then circulated into a bag within the UV irradiator 104.
- the irradiated blood then flows towards the 70-90 kD filter 106, which removes an ultrafiltrate containing molecules less than about 90 kD in weight. Through removal of the ultrafiltrate, the cellular blood elements are restored to their original concentration before returning the blood to the patient.
- the ultrafiltrate is pumped through a 10 kD filter 112 using a hemoconcentrator pump 110, where molecules greater than about 10 kD are retained, and those less than about 10 kD are allowed to pass through and into the diluent source or reservoir 113 where they become available for mixing with blood that is being removed from the patient.
- a hemoconcentrator pump 110 where molecules greater than about 10 kD are retained, and those less than about 10 kD are allowed to pass through and into the diluent source or reservoir 113 where they become available for mixing with blood that is being removed from the patient.
- Much of the whole blood extracorporeal volume is returned to the patient 100 in an attempt to preserve total red cell volume.
- pro-inflammatory/anti-inflammatory mediators have a molecular weight of 10 to 90 kD, it is expected that about 50-75% of immune system mediators will be removed from blood after about 3 hours of treatment. In several embodiments, reduction of target molecules is accompanied by substantial irradiation-induced bacterial reduction. In one embodiment, the TNF- ⁇ trimer, the principal form in blood with a molecular weight of about 45-55 kD, will be removed by this method. One skilled in the art will understand that several embodiments of this invention can also be used to remove mediators or agents that have molecular weights less than about 10 kD and greater than about 90 kD.
- a system to reduce bacterial load in septic patients is provided. Diagnosis and prevention of septicemia and related conditions is difficult because the early signs and symptoms are usually vague. Because these conditions are typically recognized late in the course of the disease, morbidity and mortality rates are unduly increased. In one embodiment, bacterial load is reduced by about 99%. In several aspects of this invention, septicemia is prevented or treated in patients undergoing coronary bypass, dialysis and other conditions.
- the system disclosed herein can be used to prevent or treat septicemia in patients undergoing any invasive procedure, hi several embodiments, the device described herein can prevent and/or treat systemic inflammatory response syndrome by any etiology, including, but not limited to septicemia or microbial sepsis, hi one embodiment, patients with acute renal failure can be treated. In another embodiment, patients with ischemic stroke can be treated. In one embodiment of the invention, a prevention and treatment system for
- Sudeck's Syndrome is provided.
- Sudeck's Syndrome also known as Reflex Sympathetic Dystrophy, is characterized by acute atrophy of bones, commonly of the carpal or tarsal bones. Biochemical mediators and an excessive inflammatory reaction are involved in the etiology and progression of this disease. (Cook and Ward, 1990; Goris, 1998, both herein incorporated by reference), hi one embodiment, a hemoconcentrator/filter system is used to remove target molecules from the blood of a patient afflicted with Sudeck's Syndrome. Molecules targeted for removal include, but are not limited to, prostaglandins, endothelium- derived relaxing factor and histamine. One skilled in the art will understand that other cell mediators involved in this syndrome can also be removed in accordance with several embodiments of the present invention.
- a hemoconcentrator/filter system is used to remove target molecules from the blood of a patient afflicted with Chronic Fatigue Syndrome.
- Molecules targeted for removal include, but are not limited to, TNF- ⁇ , IL-6 and other cytokines.
- TNF- ⁇ tumor necrosis factor
- IL-6 IL-6
- other cell mediators involved in Chronic Fatigue Syndrome can also be removed in accordance with several embodiments of the present invention.
- other embodiments of the present invention provide a system for reducing TNF- ⁇ levels, and/or other immune system mediators, in any illness in which these mediators are involved in the etiology or progression of the disease.
- a prevention and treatment system for other inflammatory related diseases includes, but are not limited to, heat stroke, Hodgkin's Disease, lupus, myocardial infarction, AIDS, viremia, HCV, HBV, tuberculosis, muscular dystrophy or multiple sclerosis, Acute Respiratory Distress Syndrome (ARDS), and heart disease.
- ARDS Acute Respiratory Distress Syndrome
- the system is used to cleanse, purify, and/or filter blood obtained entirely from a commercial source, such as a blood bank, a research institution, or a clinical facility. Blood obtained from an external source may be from humans, or other mammals or organisms. The blood may be comprised of one or more synthetic fluids and may be obtained from one or more donors.
- Transmembrane Pressure TMP
- TMP Hemoconcentrator transmembrane Pressure
- the TMP is between about 1-200 imriHg, preferably between about 9-105 mmHg.
- a decrease in hematocrit results in a lesser pressure drop and lower inlet pressure
- an increase in hematocrit results in a greater pressure drop and higher inlet pressure.
- changes in inlet pressure signal changes in hematocrit.
- on-line pressure monitors or optical devices can aid a technician in regulating hematocrit.
- monitoring and regulation of hematocrit is automated using a load cell, described below.
- the pressure across the hemoconcentrator was designed to decrease 70-100 mmHg from inlet port to outlet port.
- the TMP of the original system was about 50-75 mmHg.
- a design in which the pressure across the hemoconcentrator decreases 1-69 mmHg and in which the TMP is greater than about 76 mmHg provided surprising and unexpected advantages. For example, hemoconcentration was achieved more efficiently allowing a higher flux rate which translates into greater target molecule sieving. More importantly, using a TMP greater than about 76 mmHg and a blood flow rate of about 100 ml/min allows processing of blood with a hematocrit of greater than about 36%.
- the system disclosed in United States Patent Number 6,193,681 was able to process blood having a hematocrit less than about 35%.
- Embodiments of the current invention are particularly advantageous because it is estimated that over 20% of septic patients have a hematocrit that exceeds 35%.
- a system which uses a TMP greater than 76 lTimHg also provides a novel and unique method of treating several other disorders in which hematocrit exceeds 35%.
- about 50% of patients with renal failure, 99% of stroke patients and 99% of patients with autoimmune disorders have blood hematocrit levels that are greater than 35%.
- Embodiments of the current system which use a TMP of greater than about 76 mmHg, offers this treatment opportunity to these patients. Indeed, using a TMP that is greater than 76 liimHg with a blood flow rate that is greater than 100 ml/min allows treatment of septic patients that have a hematocrit less than 36%.
- the TMP of the present invention is greater than 76 mmHg, preferably from about 76-150 mmHg, and more preferably from about 76-105 mmHg. TMP ranges from about 76-85 mmHg, 86-95 mmHg and 96-105 mmHg are also provided in accordance with several embodiments of the current invention.
- Blood is received from the patient through a canula placed in the femoral subclavian or internal jugular vein.
- a filter device is connected to receive blood from the source and to supply a portion of the received blood to a UV irradiation device and to return the remainder of the received blood to the source
- a canula is connected to a patient and a tubing is connected to the canula through a pump and into a hollow fiber filter device to receive blood from the source.
- a blood pump When receiving blood from the patient, a blood pump controls the flow rate of the blood in several embodiments.
- a preferred embodiment of the present invention has three pumps. As shown in FIG. 1, one embodiment has a blood pump 102, a diluent pump 114, and a concentrator pump 110.
- blood from pump 102 passes through a polycarbonate "Y" connector where the blood mixes with a suitable isotonic diluent, such as PlasmalyteTM solution.
- a suitable isotonic diluent such as PlasmalyteTM solution.
- plasmalyteTM solution a suitable isotonic diluent
- a variety of such solutions, referred to as "crystalloids” are available.
- the diluent is supplied from diluent source 113 which, typically, comprises a large capacity reservoir for storing an admixture of reclaimed (or converted) ultrafiltrate.
- the diluent is delivered by pump 114, which can be a roller pump or the like, at a flow rate which results in a hematocrit of about 5-20%.
- pump 114 which can be a roller pump or the like
- a flow rate which results in a hematocrit of about 5-20%.
- hi United States Patent Number 6,193,681 we described a method and apparatus in which the combined blood/diluent pump flow rate was 400-500 ml/min.
- a design in which the combined pump flow rate is less than 400 ml/min provides unexpected advantages over a flow of greater than 400 ml/min. Surprisingly, the slower combined flow rate is safer and easier to manage on a patient and there is a lower probability of developing cavitation from -the blood source catheter (e.g., the arterial catheter).
- filtration fraction ultrafiltation rate/ combined flow rate
- UF ultrafiltration
- Less protein in the blood solution results in less protein deposition on the surface of the hemoconcentrator. This, in turn, helps retain the integrity of the hemoconcentrator' s pore size allowing for more consistent removal of target molecules for longer periods of time.
- the greater blood dilution allows for increased UF rates, which in turn increase target molecule sieving.
- the combined blood/diluent pump flow rate is less than about 400 ml/min, preferably from about 10 ml/min to about 390 ml/min, more preferably from about 200 ml/min to about 380 ml/min. In one embodiment, when using a blood flow rate of about 100 ml/min, the combined blood/diluent flow rate is about 280-380 ml/min.
- the ultrafiltrate side of the system is a continuous length of tubing that runs through a pump into a secondary filter.
- the concentrator pump 114 propels the admixture of crystalloid and filtrate from the secondary circuit back to the primary circuit via Y-connector.
- pump flow is initially based on the hematocrit of the patient 100 and can be subsequently regulated with knowledge of hemoconcentrator inlet pressure as determined by an inlet port. That is, a port may include a stopcock for monitoring the inlet pressure and/or for sampling of the fluid.
- connection of the components in the secondary circuit is by tubing.
- blood pump flow is fixed at about 100 ml/min.
- the blood pump flow is lowered below 100 ml/min to accommodate hemodynamically unstable patients
- pump flow is regulated using TMP measurements. Blood flow can be monitored manually or via an automated feedback system, based upon TMP values.
- only two pumps are used, a combined blood/diluent pump and a concentrator pump. A separate blood pump is not used.
- a single pump positioned substantially as pump 102 shown in FIG. 1, regulates both patient blood and diluent flows.
- the interior of the cylinder is filled with filter material comprising polysulfone hollow fibers, has a surface area of between about 1.2 m 2 to about 2.4 m 2 with a pore size of about 70-90 l D and is capable of removing blood proteins and cell mediators whose molecular weight is less than about 85 kD.
- filter material comprising polysulfone hollow fibers
- the gel layer formed by the blood is not thick enough to substantially reduce the effective pore size of the hollow fibers, as it is in conventional hemofiltration techniques.
- it estimated that the pore size is reduced by about 5% to 20% by the gel layer formed, whereas in traditional hemofiltration techniques, the pore size is reduced significantly more.
- two hemoconcentrators connected in series are used.
- the irradiator includes a bag 204 and UV channel (grid lamp) 211 shaped in a serpentine path. Two quartz plates 212 used to compress the blood within the bag are also provided.
- a cross-sectional view 204a of the UV bag 204 and an enlarged view thereof 204b is shown in FIG. 2.
- a blood flow channel 205 is shown in the cross-sectional view 204a.
- the UV bag contains one or more of the following: plasma 206, red blood cells 207, white blood cells 208, platelets 209 and bacteria 210.
- the bag 204 is disposable and made of a biocompatible ethylene vinyl acetate ("EVA") material, hi another embodiment, the bag is made of a fluoropolymer.
- EVA ethylene vinyl acetate
- the bag is typically open at each end and with a small inlet therethrough.
- the bag 204, or fluid chamber is approximately 15 to 20 inches long and about 8 to 10 inches wide with a fluid path having a width of about 0.75-1 inches.
- the inlet has an inside diameter of about 3/16 inch and is about 1/2 inch long. Any suitable length for secure connection to the tubing can be used. This design optimizes the appropriate amount of turbulence to ensure bacterial reduction while preventing cellular debris from building up on the surface of the UV bag.
- FIGS. 3A-E show various views of one embodiment of the UV system.
- the assembly consists of a UV grid lamp 303 and lamp support structure 301, comprising a lamp support 302.
- the UV grid lamp 303 is supported in the UV lamp holder by buss wire 317.
- Quartz glass plates 305 are affixed to each side of the UV lamp holder with frames 306.
- a thermister 310 is held against the UV grid lamp 303 by a mounting block 309 to sense lamp temperature during use. Screws 311, 312, and 313 are provided as attachment means.
- the assembly consists of a 200 W UV-C grid lamp 411 and lamp support structure 413, and two quartz glass plates (compression plates) to constrain the diluted blood in the irradiator bag to approximately 0.025" thickness.
- At least one UV-C sensor 414 is also provided. UV sensors and temperature sensors are used to optimize ultraviolet output of the bulb.
- an optical sensor 414 for monitoring ultraviolet light during irradiation is used. According to data received from the sensor, the dose or intensity of UV light is adjusted. The UV light can be adjusted manually or adjustment can be automated, hi one arrangement, electrical feedback control is provided from the sensor to the UV irradiator, thereby eliminating the need for manual control of light intensity.
- a safety interlock switch is provided to prevent unwanted user exposure to UV-C when loading/unloading the disposable set of materials
- the irradiator includes a conventional ultraviolet light source with a radiation wavelength of about 254 nm.
- an electronic weight scale, or load cell 160 shown in FIG. 1, is provided.
- the load cell is used to measure or quantify the volume or mass of diluent
- a strain gauge beam-type load cell is used to measure the weight of the diluent bag.
- the load cell is used to weigh the diluent bag continuously and control pump speeds.
- the load cell maintains a constant diluent weight, thereby maintaining return patient hematocrit at the same value as input patient hematocrit.
- the diluent volume is kept constant at 750 ml in the diluent bag.
- any given setpoint volume can be used.
- the HemaCharge system is a computer- controlled device running off-the-shelf (OTS) DasyLab® software under Windows® 98.
- OTS off-the-shelf
- FIG. 12 shows an overview of one embodiment of the present invention.
- a heater warms the contents of the diluent bag to normal body temperature. Once the circuit is primed, debubbled, and up to temperature, the clinician then pauses the system, and connects inlet and outlet lines to the patient catheter.
- a heater or heat exchanger is used to warm or cool at least some portion of the blood or diluent to between about 34°C to about 42°C. hi some instances, a heat exchanger is used to warm or cool the blood temperature to body temperature prior to reintroduction into the patient.
- a heater is used to increase the temperature of at least a portion of the blood by about 1°C to about 10°C.
- a system is provided to reduce bacterial load in patient blood, hi many embodiments, cytokines and other immune system mediators are removed.
- the term "removed", and any tense thereof, shall be given its ordinary meaning, and shall also mean reduced in concentration, quantity and/or efficacy.
- FIG. 7 shows UV-C penetration as a function of hematocrit and blood thickness.
- FIG. 8 shows dilutional effect on bacterial reduction in vitro.
- FIG. 9 shows bacterial reduction data at various patient hematocrits in the HemaCharge system at 6 L blood volumes.
- FIG. 10 shows bacterial reduction data at 30% patient hematocrit at 3 L blood volumes.
- FIG. 11 shows cytokine sieving/reduction data in vitro at 6 L blood volumes, hi one embodiment of the present invention, diluted blood passes through tubing to the bactericidal ultraviolet (UN) irradiation device, shown schematically in FIGS. 2A-D.
- UV irradiation penetrates the blood more effectively when whole blood (26-55% hematocrit) is diluted to a hematocrit of about 5-20% (see FIG. 7) thus translating into a more efficient microbicidal activity (see FIG. 8).
- the concentration of at least one inflammatory mediator is reduced by about 75% in less than about 4 hours using embodiments of the current invention, fri another embodiment, the concentration of T ⁇ F- ⁇ is reduced by about 50% in less than about 4 hours.
- Vitamin Therapy Vitamin therapy is used in several embodiments of the current invention as an adjunctive therapy. In several embodiments, a system and method of reducing toxins in a patient's blood using vitamin therapy is provided.
- Agents such as antioxidants and/or free radical quenchers, are administered in several embodiments of the current invention, and include, but are not limited to, one or more of the following: Zn, Cu, manganese, selenium, vitamin A, C, E, B complex, K, P, lycopene, superoxide dismutase, co-enzyme Q10, catechins, polyphenols, flavanols, depsides (chlorogenic acid, coumaroylquinic acid and theogallin), quinic acids, carotenoids, thearubigens, theaflavin and theaflavic acids are used to reduce bacterial load in blood processed by several embodiments of the current invention, hi one embodiment, a combination of Vitamin A, C, E and zinc is used.
- doses to achieve Cmax values of about 10 ng/ml to about 1000 ng/ml are provided, hi one embodiment, the following plasma concentrations are used: Vitamin B12 at 0.2-0.5 mg/ml, Vitamin E at 0.13 IU/ml, Vitamin C at 0.16 mg/ml, Vitamin P at 0.65 mg/ml, Vitamin A at 0.02 IU/ml and Vitamin K 0.003 mg/ml.
- one or more vitamins are added to the blood while the blood is being processed through the system of the current invention, hi other embodiments, patients are treated with a vitamin cocktail prior to treatment using the present invention.
- patients are given the vitamin cocktail after their blood has been treated with one or more embodiments of present invention in order to maintain a reduced cytokine and/or bacterial load.
- vitamin therapy is administered in- between treatments.
- Extracorporeal blood may also be treated at any time before, during or after treatment with the system of the current invention, hi some embodiments in which vitamin therapy is provided simultaneously with treatment by embodiments of the current invention, one or more vitamins can be pre-mixed with the diluent.
- a vitamin cocktail is added to the pump, so that the vitamins and blood and/or diluent mix with the vitamins during processing.
- vitamins can be added at any stage and in any component of the blood treatment system.
- pharmacological therapy is administered in substantially the same way as described above for vitamin therapy
- insulin therapy is provided to facilitate cellular glucose entry for improved mitochondria performance.
- other drugs which facilitate cellular glucose entry and/or for improving mitochondria performance can also be used in accordance with several embodiments of the current invention.
- nitroglycerin is provided to improve microcirculation in order to improve organ oxygenation.
- vitamin therapy is used in conjunction with a UV irradiator.
- antioxidants and other free radical quenchers are used to reduce free radicals which may be produced by the UV light and as a result of typical sepsis-induced cell damage, hi some embodiments, the vitamins used to treat the blood to prevent activation of cells which initiate build-up on the surface of the UV bag and occlude the transmission of the ultraviolet light.
- the UV-C facilitates the penetration of pharmaceutical agents into cells more effectively by activating cell membranes to increase permeability. Examples
- EXAMPLE 1 The HemaChargeTM Device
- the commercialized HemaChargeTM device may or may not include the components, and equivalents, identified in this example, hi this embodiment, the system comprises three pumps (blood pump 1302, diluent pump 1304, and hemoconcentrator pump 1306), an ultraviolet irradiator lamp assembly 1308 and a load cell 1310 to maintain proper hemodilution and hemoconcentration of patient blood.
- the user interface is a backlit LCD touch screen display 1312.
- the device also incorporates clamps, a bubble detector, pressure sensors, temperature sensors, a UN sensor, as well as visual and audible alarms for patient safety.
- a power supply module is provided containing an isolation transformer, a solid-state electronic ballast, and associated electronics to produce about 5-24 NDC to power the pumps, clamps, and sensors.
- a strain gauge beam type load cell is provided to measure the
- a 70-90 kD polysulfone hollow fiber filter 1314 used for hemoconcentrating dilute blood and two 10 kD polysulfone hollow fiber filters 1316 for cytokine removal are also provided.
- the UN irradiator assembly 1308 is used to irradiate dilute extracorporeal blood with 254 nm UV-C energy.
- the assembly consists of a 200 W UVC grid lamp and lamp support structure, two quartz glass plates and compression plates to constrain the diluted blood in the irradiator bag to approximately 0.025" thickness, and UV-C and temperature sensors to optimize ultraviolet output of the bulb.
- a safety interlock switch is provided to prevent unwanted user exposure to UV-C when loading/unloading the disposable set of materials.
- the three pumps consist of a blood pump 1302 for pumping whole blood from the patient to the irradiator, a diluent pump 1304 for introducing diluent into the whole blood before the irradiator, resulting in hemodilution to about 10% HCT, and a concentrator pump 1306 used to provide a transmembrane pressure across the 70-90 kD filter 1314 for hemoconcentration before returning blood to the patient.
- Pump control is accomplished by using proportional-integral-differential (PED) feedback loops from encoders located on each pump motor, along with pump ratio parameters calculated from user input of HCT and blood flow rate.
- PED proportional-integral-differential
- the inlet pressure sensor can be used to determine maximum allowable blood flow rate based on vascular access and catheter placement parameters; the patient return line sensor can likewise indicate catheter placement issues on the return side, as well as provide a measure of safety against excessive return pressures.
- the sensor located before the irradiator bag assembly provides an indication of bag pressure and is used to prevent over pressurization of the irradiator bags.
- Temperature is sensed at one or more of the following locations in the circuit: patient inlet and outlet, irradiator bag assembly outlet 1308, and on the diluent bag. Additionally, the UV lamp temperature is also monitored for optimization of UVC output. Sensors in the extracorporeal circuit are used to assure a safe blood temperature throughout the circuit. Visual and audible alarms are provided for out-of-range temperatures.
- the disposable set comprises a 70-90 kD polysulfone hollow fiber filter 1314 used for hemoconcentrating dilute blood, one or two 10 kD polysulfone hollow fiber filters 1316 for cytokine removal, an EVA irradiator bag assembly, and two PVC bags; one for priming and one for containing diluent.
- Factors investigated included appropriate UV transparent material, hematocrit of blood for optimal UV absorption, ideal blood flow path for adequate UV exposure, ideal UV dosage, ideal pore size of hemofilters, ideal surface area of hemofilters, ideal blood model, development of porcine cytokine assays, various circuit coatings and optimal flow rates.
- FIGS. 8-10 show data from bacterial reduction studies, hi one embodiment, a logarithmic base ten reduction (90%) of Staphylococcus aureus (ATCC 6538p) was provided witliin three hours and in some instances a two logarithmic base ten (99%) reduction within six hours of UV-C exposure.
- Staph. aureus was selected as the bacterial model because it is one of the most common organisms associated with sepsis and because it is considered one of the most difficult to kill.
- FIG. 9 demonstrates a series of 36 bacterial reduction experiments conducted at a blood volume of 6 liters. The maximum UV dosage was 16.14 kJ.
- Patient blood flow rate was 100 ml/min. 31 UV experiments and 5 controls were performed.
- Figure 10 demonstrates a series of 8 bacterial reduction experiments conducted at a blood volume of 3 liters. The maximum UV dosage was 12.90 kJ.
- Patient blood flow rate was 100 ml/min. 5 UN experiments and 3 controls were performed.
- FIG. 11 shows data from cytokine sieving, or reduction, studies.
- cytokine reduction studies have been conducted on TNF- ⁇ , IL-l ⁇ and IL-6 because these cytokines have been well-established as markers for sepsis. Additionally, down-regulating the immune system, as opposed to suppressing it completely, may be important in treatment. A 50-75% reduction in key inflammatory mediators can reverse the exaggerated immune response and allow the immune system to become effective again.
- FIG. 11 shows several embodiments of the current invention provide at least a 50-75% clearance of all tliree target molecules within three hours. Cytokine studies were conducted as described above for the bacterial reduction experiments Additional studies have been conducted at various blood volumes, flow rate and patient hematocrits.
- the current system will be able to remove several cytokines and cell mediators, including, but not limited to, TNF- ⁇ , IL-l ⁇ , IL-6, IL-10, IL-12, LPB, IFN ⁇ , LIF, MIF, MCP-1, C3-a, C5-a, exotoxins and endotoxins.
- cytokines and cell mediators including, but not limited to, TNF- ⁇ , IL-l ⁇ , IL-6, IL-10, IL-12, LPB, IFN ⁇ , LIF, MIF, MCP-1, C3-a, C5-a, exotoxins and endotoxins.
- sham model a 12 french double lumen catheter was placed in the femoral vein and the subject was monitored for six hours.
- the technique was similar to the sham model, with the addition of a simple extracorporeal circuit composed of dialysis tubing with an equivalent extracorporeal volume of the system and one blood pump set to 100 ml/min.
- the breadboard system was run for six hours at a patient blood flow rate of 100 ml/min without exposing the blood to UV-C.
- the complete breadboard system was run for six hours at a patient blood flow rate of 100 ml/min while exposing the blood to UV-C.
- the data for all models demonstrated that the white blood cell counts decreased during the first 60 minutes of the procedure, and tended to increase thereafter.
- the control model had the lowest six-hour white blood cell count; however, this sample was only slightly lower than the experimental model.
- the current system is the major factor affecting the white blood cell count, which is a typical response to extracorporeal circulation.
- the UV-C was not a significant factor in the decrease.
- the increase in post- treatment white blood cell counts is a typical response to anesthesia and extracorporeal devices.
- the one- week (168 hr) sample for all models demonstrated essentially the same white blood cell counts, indicating that the effect of the circuit was temporary.
- the red blood cell counts remained relatively stable throughout the treatment and recovery periods of all models. Overall, the circuit and the UV-C did not have an effect on the red blood cell counts.
- the one-week (168 hr) sample for all models demonstrates platelet counts within the normal range. This appears to indicates that the effect of the circuit and UV-C are temporary. Other cell damage data collected are described and discussed below.
- a methemoglobin assay was used to deteraiine the level of damage to the hemoglobin molecule. A value less than 2% of the total concentration of hemoglobin in the blood is considered normal. All the samples were well within the normal range and did not significantly increase throughout the treatment. This indicates that the UV-C, at the given dosage, is not causing any significant damage to the hemoglobin molecule.
- a white blood cell viability dye exclusion assay was used to determine whether a white blood cell is viable due to damages to the DNA and cell membrane. If a cell takes in the dye, that cell is considered non- viable. Less than or equal to 10% overall reduction from the baseline value is considered normal. All of the samples for each model were within the normal range. This indicates that the circuit and UV-C were not causing any undesired damage to the cells.
- a red blood cell osmotic fragility assay was used to determine any cell membrane damage that could cause future lyses when returned to the subject. Permeability of erythrocyte cell membranes is a factor to consider after UV irradiation.
- a sample of blood is mixed with a 0.9% isotonic solution of saline and distilled water is added to the blood mixture until lyses is observed.
- the results are represented as the saline concentration at which the first cells begin to lyses (Initial Osmotic Fragility) and the saline concentration at which all of the cells are lysed (Complete Osmotic Fragility).
- the normal range for Initial Osmotic Fragility is 0.50-0.59% saline.
- the normal range for Complete Osmotic Fragility is ⁇ 0.50% saline. All of the samples for each model were within the normal range. This indicates that the circuit and UV-C were not causing any damage to the cells.
- Platelet activation assays were used to determine the level of platelet activation.
- the assays are listed in order of platelet activation level: Platelet CD62P, Platelet Bound Fibrinogen, Monocyte-Platelet Aggregates and Neutrophil-Platelet Aggregates.
- Samples for each assay were taken across the circuit at the following locations: From Subject, Pre- UV, Post-UN and Post-Hemoconcentrators.
- the level of activation increased as the cells moved through the circuit. In other words, diluting, irradiating and hemoconcentrating the blood had a contributing and cumulative effect on platelet activation.
- the Leukocyte-Platelet Aggregates at the six-hour sample were up to levels seen in cardio-pulmonary bypass systems.
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Applications Claiming Priority (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/390,558 US7207964B2 (en) | 2003-03-17 | 2003-03-17 | Apparatus and method for down-regulating immune system mediators in blood |
US10/391,444 | 2003-03-17 | ||
US10/390,565 US20040185426A1 (en) | 2003-03-17 | 2003-03-17 | Ultraviolet light and filter apparatus for treatment of blood |
US10/391,455 US20040182784A1 (en) | 2003-03-17 | 2003-03-17 | Concentrator and filter based blood treatment system |
US10/391,454 | 2003-03-17 | ||
US10/391,444 US20040185041A1 (en) | 2003-03-17 | 2003-03-17 | Method for extracorporeal treatment of blood |
US10/390,558 | 2003-03-17 | ||
US10/391,443 | 2003-03-17 | ||
US10/391,443 US7201730B2 (en) | 2003-03-17 | 2003-03-17 | Device and method for reducing inflammatory mediators in blood |
US10/390,572 | 2003-03-17 | ||
US10/391,453 US20040186412A1 (en) | 2003-03-17 | 2003-03-17 | Extracorporeal blood treatment system using ultraviolet light and filters |
US10/391,445 US20040182783A1 (en) | 2003-03-17 | 2003-03-17 | Filter and concentrator device for treatment of blood |
US10/391,445 | 2003-03-17 | ||
US10/391,455 | 2003-03-17 | ||
US10/391,454 US20040186407A1 (en) | 2003-03-17 | 2003-03-17 | Concentrator and filter apparatus for treatment of blood |
US10/390,565 | 2003-03-17 | ||
US10/390,572 US7229427B2 (en) | 2003-03-17 | 2003-03-17 | Irradiation and filter device for treatment of blood |
US10/391,453 | 2003-03-17 |
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WO2004082737A2 true WO2004082737A2 (en) | 2004-09-30 |
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PCT/US2004/007590 WO2004082737A2 (en) | 2003-03-17 | 2004-03-12 | Extracorporeal blood treatment device for removing blood toxins, and methods thereof |
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WO2008050148A2 (en) * | 2006-10-27 | 2008-05-02 | Ucl Business Plc | Therapy for liver disease |
WO2012135746A2 (en) * | 2011-04-01 | 2012-10-04 | Aethlon Medical, Inc. | Methods and devices comprising extracorporeal blood flow |
US9095661B2 (en) | 2009-12-22 | 2015-08-04 | Gambro Lundia Ab | Method and apparatus for controlling a fluid flow rate in a fluid transport line of a medical device |
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US4464166A (en) * | 1981-06-12 | 1984-08-07 | Frederic A. Bourke, Jr. | Method for externally treating the blood |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2008050148A2 (en) * | 2006-10-27 | 2008-05-02 | Ucl Business Plc | Therapy for liver disease |
WO2008050148A3 (en) * | 2006-10-27 | 2008-07-17 | Ucl Business Plc | Therapy for liver disease |
CN101541357B (en) * | 2006-10-27 | 2012-07-04 | Ucl商业有限公司 | Therapy for liver disease |
US8480607B2 (en) | 2006-10-27 | 2013-07-09 | Ucl Business Plc | Therapy for liver disease |
US9095661B2 (en) | 2009-12-22 | 2015-08-04 | Gambro Lundia Ab | Method and apparatus for controlling a fluid flow rate in a fluid transport line of a medical device |
EP2343092B2 (en) † | 2009-12-22 | 2016-07-13 | Gambro Lundia AB | Method and apparatus for controlling a fluid flow rate in a fluid transport line of a medical device |
WO2012135746A2 (en) * | 2011-04-01 | 2012-10-04 | Aethlon Medical, Inc. | Methods and devices comprising extracorporeal blood flow |
WO2012135746A3 (en) * | 2011-04-01 | 2012-12-27 | Aethlon Medical, Inc. | Methods and devices comprising extracorporeal blood flow |
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