Surgery – Blood drawn and replaced or treated and returned to body – Constituent removed from blood and remainder returned to body
Reexamination Certificate
1998-09-14
2001-02-27
Sykes, Angela D. (Department: 3762)
Surgery
Blood drawn and replaced or treated and returned to body
Constituent removed from blood and remainder returned to body
C604S004010, C604S005010, C422S024000, C205S432000, C205S435000, C205S437000, C607S088000, C607S090000, C607S094000
Reexamination Certificate
active
06193681
ABSTRACT:
BACKGROUND
1. Field of the Invention
The present invention relates, generally, to methods of and apparatus for killing bloodborne microorganisms by ultraviolet irradiation and removing target molecules from the blood by a hemoconcentrator/filter and, subsequently, removing some target molecules from the ultrafiltrate by additional filtration for endotoxins and cell mediators before returning to the blood.
2. Prior Art
Septicemia refers to a microbe-induced condition in which the patient experiences an exaggerated inflammatory response. This response can lead to varying degrees of hypotension (possibly shock), and hypoxemic and edema-related organ failure called multiple organ dysfunction syndrome (MODS). Because trauma and burns, among other causes, can lead to MODS, in the absence of infection, the more current and generic term is systemic inflammatory response syndrome (SIRS).
Between 1980 and 1992 the death rate due to septicemia increased 83% from 4.2 to 7.7 per 100,000 population. The greatest increases were seen in patients at least 65 years old. Bacterial infections accounted for approximately 200,000-300,000 cases of septicemia as of 1992, and was the 13th leading cause of death nationally. The mortality rate averaged 35%, with a range of 20-65%, and accounted for approximately 100,000 deaths.
Septicemia is usually categorized by the particular group of microorganism involved, i.e., bacterial, gram negative or gram positive, and fungal. Gram negative bacteria of concern include
Pseudomonas aeruginosa, Eschericia coli,
and
Enterobacter aerogenes.
Gram positive bacteria of interest include
Staphylococcus aureus, Streptococcus pneumoniae,
and Enterococcus spp. The usual fungus involved is the yeast, Candida spp. Septicemia and related conditions develop when certain microorganisms, the cellular products, and other target molecules stimulate cascade reaction and an exaggerated inflammatory response leading to multiple organ and system failure. Selected microbial products and other target molecules, with molecular weights, are shown in Table 1.
TABLE 1
Selected Target Molecules of Concern in Septicemia
and Potentially Removed by SPATS
Molecular Weight -
Molecule
KiloDaltons (kD)
Endotoxins (gram negative bacteria)
10-40
Tumor Necrosis Factor, alpha(TNF-a)
17-51
Interleukin 1, beta(IL 1-p)
17
Exotoxins (gram positive and gram negative bacteria
gram+ (Diphtheria)
65
gram− (Cholera)
82
RAP, protein (
Staphylococcus aureus
)
50
Complement 3a and 5a
9-11
Bradykinin
1
These target molecules may enhance the microbe's virulence and/or stimulate the patient's defense mechanisms, but, when excessive, they may lead to multiple organ system failure. These microorganisms, their cellular products and the target molecules can stimulate various cascade reactions which may result in a life-threatening inflammatory disease state.
Prevention of these medical conditions is difficult at best because the early signs and symptoms may be quite vague. Treatment has generally been instituted when the condition is recognized which is, unfortunately, often very late in the course of the disease. With prophylaxis difficult and therapy often late, the results may be fatal for the patients in many cases. Treatment of the early viremic stage of H.I.V. on the other hand, is possible. The signs and symptoms are recognizable by a trained physician and reduction of the viral load has been shown to improve the prognosis of the disease. This reduction in viral load may also be effective at later stages of H.I.V. infections. We believe that the ability of SPATS to reduce bacterial load, as well, by 99% or more will also serve a significant role in the prevention of septicemia in patients undergoing coronary bypass, dialysis, and probably other conditions. SPATS can also be used to treat septicemia in patients undergoing such invasive procedures.
Ultraviolet blood irradiation (UBI)—originally the Knott technique—has been used in the United States since 1928 for the successful extracorporeal treatment of microbial infections. Over the years there have been scientific arguments concerning the mechanism by which UBI works and the consensus appears to be that some organisms are killed and a stimulated immune system then protects the patient by clearing the remaining organisms from the body.
Hemoconcentrator/filtration units are used to remove water from patients who are in acute renal failure and become overly hydrated. The devices are designed to retain all plasma proteins, including the smallest albumin, (molecular weight of 67-69 kD), while ridding the blood of excess water. Current membranes and/or hollow fiber systems have effective pore sizes which will pass molecules up to 30-50 kD.
The Lee et al patent describes the removal of the “toxic mediators” of SIRS by the continuous arteriovenous hemofiltration of whole blood by processing with a filter having a pore size adequate to remove substances up to 100-150 kD (although the probable size of the molecules removed is 10-40% less due to occlusion of the pores by plasma proteins).
PRIOR ART STATEMENT
U.S. Patents
5,571,418
11/1996
Lee et al.
5,211,850
5/1993
Shettigar et al
5,211,849
5/1993
Kitaevich et al
5,151,192
9/1992
Matkovich et al
5,150,705
9/1992
Stinson
Other Publications
Barger, G. and E. K. Knott. 1950. “Blood: Ultraviolet Irradiation (Knott Technique)”, Medical Physics 11: 132-6.
Miley, G. P., R. C. Olney, and H. T. Lewis. 1997. “Ultraviolet Blood Irradiation: A History and Guide to Clinical Application (1933-1997)”, Silver Spring, Md.: Foundation for Blood Irradiation.
Schleicher, C. 1995. “Application of Ultraviolet Blood Irradiation for Treatment of HIV and Other Bloodborne Viruses.” Townsend Letter for Doctors and Patients, 147:66-72.
Lee, P. A., G. W. Weger, R. W. Pryor, and J. R. Matson. 1998. “Effects of Filter Pore Size on Efficacy of Continuous Arteriovenous Hemofiltration Therapy for Staphylococcus Aureus-induced Septicemia in Immature Swine”. Crit. Care Med. 26(4):730-37.
Sibbald, W. J. and J.-L. Vincent (Eds.) 1995. “Clinical Trials for the Treatment of Sepsis”, Springer-Verlag, Berlin, Heidelberg.
SUMMARY OF THE INVENTION
A method and apparatus for preventing and treating septicemia is described. The extracorporeal system includes an anti-microbial device to kill at least 99% of bloodborne microorganisms, a hemoconcentrator/filtration unit to remove approximately 90% of the bloodborne target molecules from patient's blood and a filter unit to remove the same target molecules from the ultra-filtrate. Target molecules are produced by microorganisms, as well as the patient's cells, and include endotoxins from gram negative bacteria, exotoxins from gram positive and gram negative bacterial and mediators such as RAP protein from
Staphylococcus aureus,
and cell mediators such as tumor necrosis factor-alpha, and interleukin 1-beta, complement proteins C3a and C5a and bradykinin.
The present invention is a method and apparatus for the continuous processing of diluted blood by a venovenous route using a double lumen cannula and a filter having a pore size of 60-95 kD. The system will remove substances, including target molecules, comparable to Lee et al.
The present invention also can filter the plasma filtrate for subsequent return of important smaller molecules to the patient.
Since hemodilution has already occurred during cardiopulmonary bypass, the filter will function in an extracorporeal circuit to remove inflammatory mediators caused by the cardiopulmonary bypass. Currently, special bonded circuits as well as pharmaceutical products are used to reduce the effects described during extracorpreal circulation.
REFERENCES:
patent: 4559034 (1985-12-01), Kirita et al.
patent: 4683889 (1987-08-01), Edelson
patent: 4708715 (1987-11-01), Troutner et al.
patent: 4737140 (1988-04-01), Lee et al.
patent: 5288605 (1994-02-01), Lin et al.
patent: 5433738 (1995-07-01), Stinson
patent: 5459030 (1995-10-01), Lin et al.
patent: 5496637 (1996-03-01), Parham et al.
patent: 5730713 (1998-03-01), O
Chan Richard G. L.
Davidner Alan
Roohk H. Vernon
American Immuno Tech, LLC.
Bianco Patricia
Sykes Angela D.
Weber, Jr. G. Donald
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