Volume 13 Number 5 May 1991
studies have shown the specific interaction of type V collagen with heparin or heparan sulfate. The binding of these anticoagulant molecules to type V collagen may explain why some grafts have short-term compatibility. Since heparin enhances the action of growth factors for endothelial cells and suppresses smooth muscle proliferation or migration, it is unclear if heparin molecules control or limit thrombus formation directly or through endothelial cells. However, since human vascular grafts never become endothelialized, we have hypothesized that type V collagen modulates the proliferation and/or migration of endothelial cells. Bovine collagen types I, II, III, IV, V; bovine vitronectin and fibronectin were coated on plastic surfaces Dacron and expanded polytetrafluoroethylene (ePTFE) disks in vitro. Bovine aortic endothelial cell (BAEC) attachment and growth was evaluated on these surfaces. Bovine aortic endothelial cells were used as additional serum supplements, and growth factors are not necessary for their maintenance in culture. Type V collagen significantly inhibited endothelial cell attachment and growth, whereas all other proteins showed no effect and/or enhanced cell attachment and growth. Bovine aortic smooth muscle cells and bovine lung fibroblasts were not inhibited when cultured on protein coated surfaces, suggesting specificity of type V collagen to endothelial cells. In 1984 we hypothesized that the foreign body reaction with its attendant macrophages and foreign body giant cells played a major role in controlling the anastomotic and pseudointimal healing responses of human vascular grafts. Studies addressing this hypothesis have involved human monocyte/macrophage adhesion and activation to vascular prostheses and NHLBI-DTB reference materials. Using the release of interleukin 1 as a marker for activation, we have determined that macrophage activation on polymers may be polymer dependent, protein dependent, or a combination of both. Variable release of interleukin-1 from the respective polymers leads to variable fibroblast proliferation and synthesis of collagen. In vitro-in vivo correlations between the release of interleukin-1 and the extent of fibrous capsule formation have been made. Biomer activates macrophages to release interleukin-I, but minimal fibroblast proliferation and collagen synthesis is observed. Interleukin-1 has been found to bind to the Biomer surface. In summary, our studies suggest that components of the extracellular matrix may influence thrombus formation by inhibiting endothelialization or inhibiting platelet interactions. Other proteins such as Hageman factor, factor VIII/vWF, fibrinogen, IgG, and fibronectin may promote the adhesion of platelets or be procoagulant. Expanding our techniques to analyze other extracellular matrix proteins, blood proteins, and growth factors may lead to a new understanding of the events leading to coagulation, thrombosis, fibrinolysis, endothelialization, as well as cellular events occurring in the interaction of materials with blood. James M. Anderson,
MD, PhD Nicholas P. Ziats, PbD Case Western Reserve Unive@ Cleveland, Ohio
Special
commt4nicatbn 75 1
REFERENCES 1. Ziats NP, Pankowsky DA, Tiemey BP, Ramoff OD, Anderson JM. Adsorption of Hageman factor (factor XII) and other human plasma proteins to biomedical polymers. J Lab Clin Med, 1990;116:687-96. 2. Pankowsky DA, Ziats NP, Topham NS, Ramoff OD, Anderson JM. Morphological characteristics of adsorbed human plasma proteins on vascular grafts and biomaterials. J VAX SURG 1990;11:599-606. 3. Ziats NP, Topham NS, Pankowsky DA, Anderson JM. Analysis of protein adsorption on retrieved human vascular grafts using immunogold labelling with silver enhancement. Cell Mater 1991;1:73-82. 4. Hering TM, Suzuki Y, Anderson JM. Collagen type distribution in healing of synthetic arterial prostheses. Corm Tiss Res, 1986;15:141-154. 5. Miller KM, Rose-Caprara V, Anderson JM. Generation of ILI-like activity in response to biomedical polymer implants: a comparison of in vitro and in vivo models. J Biomed Mater Res 1989;23:1007-26. 6. Miller KM, Anderson JM. In vitro stimulation of fibroblast activity by factors generated from human monocytes activated bybiomedicalpolymers. J BiomedMater Res 1989;23:911-30. 7. Bon6eld TL, Colton E, Anderson JM. Plasma protein adsorbed biomedical polymers: activation of human monocytes and induction of interleukin 1. J Biomed Mater Res 1989;23: 535-48.
VASCULAR GMT INFECTIONS: EXPERIENCE OF 170 CASES
A 25-YEAR
Infection of a vascular graft is a dreaded complication after vascular surgery. The incidence of this postoperative infection is approximately 1.3% to 6%. Mortality rates from vascular graft infection in published reviews range from 25% to as high as 75%, with percent morbidity of limb loss about the same. From 1963 to 1988, 170 vascular graft infections (grade III) were evaluated and treated at the University of California at San Francisco. We retrospectively reviewed the clinical presentation, diagnosis, microbiology, and medical aspects of management in these infections. The graft infections were divided into perigraft infection (PGI) comprising 115 patients or aortoenteric fistula (AEF) comprising 55 patients. Hospital records, oflice records, and phone surveys were used to obtain the data. Most of the 170 patients were men. The average age was 64 years (range 38 to 86 years). The most common indications for the original vascular graft operation were symptomatic peripheral vascular disease or aneurysm repair. In the PGI group, most grafts were aortofemoral or femoropopliteal grafts. In the AEF group all were in the aortofemoral area. Predisposing factors in our patient population to vascular graft infection included multiple vascular procedures (30% PGI, 50% AEF), early wound problems (23%), emergency operation (7% PGI, 15% AEF), and diabetes ( 10%). The clinical presentation of PGI occurred “early’ (within 60 days from original operation) in 27 patients and “late” in 87 patients. The average time elapsed from the
752
Special
Journal of VASCULAR SURGERY
wmmunicatin
initial operation to infection presentation was 31 months (3 days to 12 years). In the AEF group, four patients presented “early” and 48 “late” with the average time to onset of clinical symptoms at 54 months. Most patients in both groups had clinical symptoms lasting for 2.5 months before the diagnosis of a vascular graft infection was established. The symptoms and signs of PGI included sinus tract drainage (58%), local mass or swelling (58%), and local pain (40%). Pain was generally localized to the visibly infected area, but 20% of patients with pain complained of diffuse abdominal or flank pain. Fever (27%), erythema (24%), and bleeding (7%) were less common. In 15% of patients infection was occult and was discovered at operation for other reasons. The clinical manifestations of AEF included 31 of 55 with bleeding (7 patients presented in shock), local pain (50%), fever (39%), and sinus tract drainage (18%). Diagnostic procedures and their usefulness in helping to establish the diagnosis were reviewed. In patients with AEF, 9 of 16 endoscopies were considered “helpful,” but the fistula itself was observed in only four. In patients with PGI, 13 of 18 performed sinograms were useful in detailing the anatomy and extent of infection. Angiography was necessary in 104 patients for anatomy and surgical considerations but was helpful in making the diagnosis in less than 25% of cases. Two of five gallium scans were positive; five of seven Iridium” ’ white blood cell scans were positive, and in two of these the positive indium scan prompted the first suggestion of a vascular graft infection. Helpful diagnostic perigraft fluid or air collections were noted in 12 of 13 patients with AEF who had a CT scan, and in 14 of 22 PGI cases. Recent use of magnetic resonance imaging showed five of six magnetic resonance imaging scans with changes consistent with vascular graft infection. Culture data from the sinus tract drainage of patients with PGI, and from the infected intraoperative graft material were analyzed. Only 29% of sinus tract drainage cultures grew the same organism as that recovered from the infected graft at operation, Overtly infected PGI graft material was negative in culture in 42%. Review of prior or concomitant antibiotic therapy in these culture-negative cases did not suffice to explain this result. In patients with PGI 54% of the positive cultures were single organism. Stapbybcoccus aureus and epidemzidis predominated but enterococci, diphtheroids, and aerobic gram-negative rods were present. In the AEF group, 32 of 44 (72%) of intraoperative cultures were positive (22 of 32 were polymicrobial) . The predominant organisms were KZebsiella, Eschericbia co&, bacteroides, and enterococci. Antibiotic therapy was usually directed at the organisms cultured from the operative specimens. However, the culture-negative cases were also treated with broad spectrum antibiotics that included antistaphylococcal and anti-gram-negative rod regimens. Vancomycin, cephalosporins, and aminoglycosides were commonly used in PGI cases; clindanycin or metromidazole were often added in AEF cases. An average of 3.6 different antibiotics were administered, for an average of 10 days. Patients who were
bacteremic (10 of 20 febrile cases in the PGI group; 5 of 8 febrile patients in the AEF group) tended to have longer duration of antibiotic therapy. Follow-up for most of these patients ranged from 2 months to 12.5 years, with a mean of 40 months in AEF cases and 30 months in PGI cases. There were 7 (6%) deaths in PGI group and 10 (18%) in the AEF group during or within 72 hours of operation. Cause of death was acute myocardial infarction in three, aortic stump disruption in four, hemorrhage in five (two in the PGI, three in AEF), sepsis in three and multiorgan system failure in two. In the 60 days after operation, there were three deaths in the PGI group, two caused by persistent infection. There were eight deaths in the AEF group (5 after aortic stump disruption, two clearly from persistent sepsis). The total death rate in the 60 days after operation was 8.7 in the patients with PGI and 32.7% in the patients with AFF. This large retrospective clinical review of vascular graft infections revealed several observations. The clinical presentation was surprisingly insidious especially in the PGI group, but also in the patients with AEF. The bacteriology of vascular graft infections is quite broad provoking the appropriate use of broad-spectrum coverage for staphylococci, streptococci, enterococci, and enteric gram-negative organisms (plus anerobes in the AEF group). The large percentage of culture negative yet grossly infected grafts cannot be adequately explained by the prior use of antibiotics. Other explanations, such as the role of biofilm, bacterial glycocalyx, fibronectin binding of certain bacteria in preventing bacteria to be expressed or culturable, are areas of ongoing clinical research. The exact nature of the adherence of bacteria to prosthetic vascular graft material is perhaps the key to inventing methods to prevent this interaction and ultimately further reduce the incidence of vascular graft infection. Lastly, the recently improved clinical outcome as compared to previously published reports likely reflects a multitude of advances including improved surgical techniques (2-stage procedure), radiologic technology for establishing the diagnosis and defining the extent of infection, and the improved antibiotic armamentarium. Vincent Rebecca Divisim Univedy
G. Pans, MD Wurtz, MLl of Infectious Disease of Ca&n-nia, San Francisco
This work was the result of the following coauthors: Margaret Houston, MD, Howard Altman, MD, Richard Jacobs, MD, Joseph Guglielmo, PharmD, Linda Reilly, MD, William Ehrenfeld, MD, and Ronald Stoney, MD. REFERENCES
1. Beridge DC, Earnshaw JJ, Frier M, et al. lllIn-labelled leucocyte imaging in vascular graft infection. Br J Surg 1989;76:41-4. 2. Bunt TJ. Synthetic 93:733-46. 3. Golan JF. Vascular 1989;3:247-58.
vascular graft
graft
infection.
infections. Infect
Surgery
Dis Clin North
1983; Am
Vohme 13 Number 5 Mav 1991
4.
Special communication
Lorentzen JE, Nielsen OM, Are&up H, et al. Vascular graft infection: an analysis of sixty-two graft infections in 2411 consecutively implanted synthetic vascular grafts. Surgery 1985;98:81-6.
Mark AS, McCarthy SM, Moss AA, Price D. Detection of abdominal aortic graft infection: comparison of CT and in-labeled white blood cell scans. AJR 1985;144:315-8. 6. O’Hara PJ, Hertzer NR, Beven EG, Krajewski LP. Surgical management of infected abdominal aortic grafts: review of a 25-year experience. J VASC SURG 1986;3:725-31. 7. Olofsson PA, Auffermann W, Higgins CB, Rabahie GN, Tavares N, Stoney RJ. Diagnosis of prosthetic aortic graft infection by magnetic resonance imaging J VASC SURG 5.
1988;8:99-105. 8.
Riley LM, Altrnan H, Lusby RJ, et al. Late results following surgical management of vascular graft infection. J VASC SURG 1984;1:36-44.
Szilagyi DE, Smith RF, Elliot JP, Vrandecic Ml’. Infection in arterial reconstruction with synthetic grafts. Ann Surg 1972; 176:321-33. 10. Vogelzang RL, Limpert JD, Yao JS. Detection of prosthetic vascular complications: comparison of CT and angiography. AJR 1987;148:819-23.
753
different type of infection, often by bacteria that are not usually pathogenic, ensues. The biology of the host implant interface is just beginning to be unraveled. Recently our laboratory has shown that vascular prostheses induce the selective expression of the intercellular adhesion molecule (ICAM-I).’ The latter is the ligand for the LFA-I receptor on neutrophils. Activated neutrophils respond with a burst of oxidative metabolism, which produces highly reactive superoxide anion. Interleukins are also produced by activated effector cells. Rather than destruction of the implant, a milieu is established in which small numbers of bacteria survive, perhaps in fibrin, macrophages, or in the interstices of the implant, to become clinically obvious weeks or months after a seemingly successful vascular reconstruction.
9.
UTILIZING VASCULAR DRUG DELIVERY
PROSTHESES FOR
Infection is the most catastrophic complication associated with the use of prosthetic vascular conduits. The magnitude of this problem must be inferential, based on current estimates of the frequency of their use and retrospective reports of incidence. Eight years ago it was estimated that 350,000 prosthetic grafts were used. Assuming an increase of 5% per year, this number now approaches one-half million. The incidence of prosthetic graft infection varies according to the material and the location of the graft. Nevertheless, even at a rate of 2%, the conclusion is that as many as 10,000 such infections occur each year. Since morbidity and mortality rates are generally accepted to be at least one third each, including limb loss, the human toll is great. AU of this occurs in the face of the universal use of prophylactic systemic antibiotics. A prospective randomized trial clearly supports their use. Established vascular prosthetic infection is a notably intransigent clinical syndrome. Although there are advocates for less aggressive management, most surgeons agree that treatment of an established infection requires massive doses of parenteral antibiotics, removal of the infected graft and extraanatomic bypass.
Background Vascular prostheses are foreign bodies that provoke an inflammatory response that is undoubtedly a factor in their propensity to become infected. The classic paper of Elek and Cohen’ published 30 years ago set the stage for this concept by demonstrating the enhancement of infection by silk sutures. Tissue injury can usually be coped with by lost defenses even when challenged by large inocula of bacteria. The foreign body subverts these defenses and a new and
Surface modification During the 1960s the novel concept of noncovalently bonding heparin to implantable devices was described.3 In 1978 our group hypothesized that implant infections occurred because of contamination of the prosthesis by a small number of bacteria that were protected in the interstices of the implant or on its surface. Here they eventually multiplied, thrived, and became clinically obvious. It was our view that the implant itselfwas particularly susceptible because the matrix of the graft, lacking a blood supply, was unlikely to contain significant concentrations of the large doses of antibiotics given these patients parenterally. We, therefore, developed a system in which antibiotics were noncovalently bound to the vascular graft through electrostatic attraction to surfactants of opposite charge. We focused on quaternary ammonium compounds with long chain alkyl groups to generate positively-charged coatings. The surfactant must be water-insoluble so that the coating is not leached on exposure of the prosthesis to aqueous environments. Water insoluble quaternary compounds have the further advantage that they show low biologic toxicity. This contrasts with the well documented toxicity of water-soluble and moderately insoluble quaternary ammonium compounds widely used as emulsifiers and dispersing agents. The interaction of negatively charged drug with positively charged surfactant coating shows a simple hyperbolic binding isotherm. Surface-bound drugs are bound rather loosely with dissociation constants of about lo-?o 10m4 mol/l. Some high molecular weight ligands, such as tissue plasminogen activator, show a much higher binding affinity, but the stoichiometry of maximal binding is much less than one drug per surfactant. This suggests that only some surfactant molecules are involved in drug binding. The rate of dissociation of drug is relatively slow with half-times from hours to several days. The rate of release can be significantly decreased if the drug-surfactant complex is applied to the prosthesis in chloroform, or another solvent that causes the device to swell. The prosthesis is first allowed to swell in the presence of
studies have shown the specific interaction of type V collagen with heparin or heparan sulfate. The binding of these anticoagulant molecules to type V collagen may explain why some grafts have short-term compatibility. Since heparin enhances the action of growth factors for endothelial cells and suppresses smooth muscle proliferation or migration, it is unclear if heparin molecules control or limit thrombus formation directly or through endothelial cells. However, since human vascular grafts never become endothelialized, we have hypothesized that type V collagen modulates the proliferation and/or migration of endothelial cells. Bovine collagen types I, II, III, IV, V; bovine vitronectin and fibronectin were coated on plastic surfaces Dacron and expanded polytetrafluoroethylene (ePTFE) disks in vitro. Bovine aortic endothelial cell (BAEC) attachment and growth was evaluated on these surfaces. Bovine aortic endothelial cells were used as additional serum supplements, and growth factors are not necessary for their maintenance in culture. Type V collagen significantly inhibited endothelial cell attachment and growth, whereas all other proteins showed no effect and/or enhanced cell attachment and growth. Bovine aortic smooth muscle cells and bovine lung fibroblasts were not inhibited when cultured on protein coated surfaces, suggesting specificity of type V collagen to endothelial cells. In 1984 we hypothesized that the foreign body reaction with its attendant macrophages and foreign body giant cells played a major role in controlling the anastomotic and pseudointimal healing responses of human vascular grafts. Studies addressing this hypothesis have involved human monocyte/macrophage adhesion and activation to vascular prostheses and NHLBI-DTB reference materials. Using the release of interleukin 1 as a marker for activation, we have determined that macrophage activation on polymers may be polymer dependent, protein dependent, or a combination of both. Variable release of interleukin-1 from the respective polymers leads to variable fibroblast proliferation and synthesis of collagen. In vitro-in vivo correlations between the release of interleukin-1 and the extent of fibrous capsule formation have been made. Biomer activates macrophages to release interleukin-I, but minimal fibroblast proliferation and collagen synthesis is observed. Interleukin-1 has been found to bind to the Biomer surface. In summary, our studies suggest that components of the extracellular matrix may influence thrombus formation by inhibiting endothelialization or inhibiting platelet interactions. Other proteins such as Hageman factor, factor VIII/vWF, fibrinogen, IgG, and fibronectin may promote the adhesion of platelets or be procoagulant. Expanding our techniques to analyze other extracellular matrix proteins, blood proteins, and growth factors may lead to a new understanding of the events leading to coagulation, thrombosis, fibrinolysis, endothelialization, as well as cellular events occurring in the interaction of materials with blood. James M. Anderson,
MD, PhD Nicholas P. Ziats, PbD Case Western Reserve Unive@ Cleveland, Ohio
Special
commt4nicatbn 75 1
REFERENCES 1. Ziats NP, Pankowsky DA, Tiemey BP, Ramoff OD, Anderson JM. Adsorption of Hageman factor (factor XII) and other human plasma proteins to biomedical polymers. J Lab Clin Med, 1990;116:687-96. 2. Pankowsky DA, Ziats NP, Topham NS, Ramoff OD, Anderson JM. Morphological characteristics of adsorbed human plasma proteins on vascular grafts and biomaterials. J VAX SURG 1990;11:599-606. 3. Ziats NP, Topham NS, Pankowsky DA, Anderson JM. Analysis of protein adsorption on retrieved human vascular grafts using immunogold labelling with silver enhancement. Cell Mater 1991;1:73-82. 4. Hering TM, Suzuki Y, Anderson JM. Collagen type distribution in healing of synthetic arterial prostheses. Corm Tiss Res, 1986;15:141-154. 5. Miller KM, Rose-Caprara V, Anderson JM. Generation of ILI-like activity in response to biomedical polymer implants: a comparison of in vitro and in vivo models. J Biomed Mater Res 1989;23:1007-26. 6. Miller KM, Anderson JM. In vitro stimulation of fibroblast activity by factors generated from human monocytes activated bybiomedicalpolymers. J BiomedMater Res 1989;23:911-30. 7. Bon6eld TL, Colton E, Anderson JM. Plasma protein adsorbed biomedical polymers: activation of human monocytes and induction of interleukin 1. J Biomed Mater Res 1989;23: 535-48.
VASCULAR GMT INFECTIONS: EXPERIENCE OF 170 CASES
A 25-YEAR
Infection of a vascular graft is a dreaded complication after vascular surgery. The incidence of this postoperative infection is approximately 1.3% to 6%. Mortality rates from vascular graft infection in published reviews range from 25% to as high as 75%, with percent morbidity of limb loss about the same. From 1963 to 1988, 170 vascular graft infections (grade III) were evaluated and treated at the University of California at San Francisco. We retrospectively reviewed the clinical presentation, diagnosis, microbiology, and medical aspects of management in these infections. The graft infections were divided into perigraft infection (PGI) comprising 115 patients or aortoenteric fistula (AEF) comprising 55 patients. Hospital records, oflice records, and phone surveys were used to obtain the data. Most of the 170 patients were men. The average age was 64 years (range 38 to 86 years). The most common indications for the original vascular graft operation were symptomatic peripheral vascular disease or aneurysm repair. In the PGI group, most grafts were aortofemoral or femoropopliteal grafts. In the AEF group all were in the aortofemoral area. Predisposing factors in our patient population to vascular graft infection included multiple vascular procedures (30% PGI, 50% AEF), early wound problems (23%), emergency operation (7% PGI, 15% AEF), and diabetes ( 10%). The clinical presentation of PGI occurred “early’ (within 60 days from original operation) in 27 patients and “late” in 87 patients. The average time elapsed from the
752
Special
Journal of VASCULAR SURGERY
wmmunicatin
initial operation to infection presentation was 31 months (3 days to 12 years). In the AEF group, four patients presented “early” and 48 “late” with the average time to onset of clinical symptoms at 54 months. Most patients in both groups had clinical symptoms lasting for 2.5 months before the diagnosis of a vascular graft infection was established. The symptoms and signs of PGI included sinus tract drainage (58%), local mass or swelling (58%), and local pain (40%). Pain was generally localized to the visibly infected area, but 20% of patients with pain complained of diffuse abdominal or flank pain. Fever (27%), erythema (24%), and bleeding (7%) were less common. In 15% of patients infection was occult and was discovered at operation for other reasons. The clinical manifestations of AEF included 31 of 55 with bleeding (7 patients presented in shock), local pain (50%), fever (39%), and sinus tract drainage (18%). Diagnostic procedures and their usefulness in helping to establish the diagnosis were reviewed. In patients with AEF, 9 of 16 endoscopies were considered “helpful,” but the fistula itself was observed in only four. In patients with PGI, 13 of 18 performed sinograms were useful in detailing the anatomy and extent of infection. Angiography was necessary in 104 patients for anatomy and surgical considerations but was helpful in making the diagnosis in less than 25% of cases. Two of five gallium scans were positive; five of seven Iridium” ’ white blood cell scans were positive, and in two of these the positive indium scan prompted the first suggestion of a vascular graft infection. Helpful diagnostic perigraft fluid or air collections were noted in 12 of 13 patients with AEF who had a CT scan, and in 14 of 22 PGI cases. Recent use of magnetic resonance imaging showed five of six magnetic resonance imaging scans with changes consistent with vascular graft infection. Culture data from the sinus tract drainage of patients with PGI, and from the infected intraoperative graft material were analyzed. Only 29% of sinus tract drainage cultures grew the same organism as that recovered from the infected graft at operation, Overtly infected PGI graft material was negative in culture in 42%. Review of prior or concomitant antibiotic therapy in these culture-negative cases did not suffice to explain this result. In patients with PGI 54% of the positive cultures were single organism. Stapbybcoccus aureus and epidemzidis predominated but enterococci, diphtheroids, and aerobic gram-negative rods were present. In the AEF group, 32 of 44 (72%) of intraoperative cultures were positive (22 of 32 were polymicrobial) . The predominant organisms were KZebsiella, Eschericbia co&, bacteroides, and enterococci. Antibiotic therapy was usually directed at the organisms cultured from the operative specimens. However, the culture-negative cases were also treated with broad spectrum antibiotics that included antistaphylococcal and anti-gram-negative rod regimens. Vancomycin, cephalosporins, and aminoglycosides were commonly used in PGI cases; clindanycin or metromidazole were often added in AEF cases. An average of 3.6 different antibiotics were administered, for an average of 10 days. Patients who were
bacteremic (10 of 20 febrile cases in the PGI group; 5 of 8 febrile patients in the AEF group) tended to have longer duration of antibiotic therapy. Follow-up for most of these patients ranged from 2 months to 12.5 years, with a mean of 40 months in AEF cases and 30 months in PGI cases. There were 7 (6%) deaths in PGI group and 10 (18%) in the AEF group during or within 72 hours of operation. Cause of death was acute myocardial infarction in three, aortic stump disruption in four, hemorrhage in five (two in the PGI, three in AEF), sepsis in three and multiorgan system failure in two. In the 60 days after operation, there were three deaths in the PGI group, two caused by persistent infection. There were eight deaths in the AEF group (5 after aortic stump disruption, two clearly from persistent sepsis). The total death rate in the 60 days after operation was 8.7 in the patients with PGI and 32.7% in the patients with AFF. This large retrospective clinical review of vascular graft infections revealed several observations. The clinical presentation was surprisingly insidious especially in the PGI group, but also in the patients with AEF. The bacteriology of vascular graft infections is quite broad provoking the appropriate use of broad-spectrum coverage for staphylococci, streptococci, enterococci, and enteric gram-negative organisms (plus anerobes in the AEF group). The large percentage of culture negative yet grossly infected grafts cannot be adequately explained by the prior use of antibiotics. Other explanations, such as the role of biofilm, bacterial glycocalyx, fibronectin binding of certain bacteria in preventing bacteria to be expressed or culturable, are areas of ongoing clinical research. The exact nature of the adherence of bacteria to prosthetic vascular graft material is perhaps the key to inventing methods to prevent this interaction and ultimately further reduce the incidence of vascular graft infection. Lastly, the recently improved clinical outcome as compared to previously published reports likely reflects a multitude of advances including improved surgical techniques (2-stage procedure), radiologic technology for establishing the diagnosis and defining the extent of infection, and the improved antibiotic armamentarium. Vincent Rebecca Divisim Univedy
G. Pans, MD Wurtz, MLl of Infectious Disease of Ca&n-nia, San Francisco
This work was the result of the following coauthors: Margaret Houston, MD, Howard Altman, MD, Richard Jacobs, MD, Joseph Guglielmo, PharmD, Linda Reilly, MD, William Ehrenfeld, MD, and Ronald Stoney, MD. REFERENCES
1. Beridge DC, Earnshaw JJ, Frier M, et al. lllIn-labelled leucocyte imaging in vascular graft infection. Br J Surg 1989;76:41-4. 2. Bunt TJ. Synthetic 93:733-46. 3. Golan JF. Vascular 1989;3:247-58.
vascular graft
graft
infection.
infections. Infect
Surgery
Dis Clin North
1983; Am
Vohme 13 Number 5 Mav 1991
4.
Special communication
Lorentzen JE, Nielsen OM, Are&up H, et al. Vascular graft infection: an analysis of sixty-two graft infections in 2411 consecutively implanted synthetic vascular grafts. Surgery 1985;98:81-6.
Mark AS, McCarthy SM, Moss AA, Price D. Detection of abdominal aortic graft infection: comparison of CT and in-labeled white blood cell scans. AJR 1985;144:315-8. 6. O’Hara PJ, Hertzer NR, Beven EG, Krajewski LP. Surgical management of infected abdominal aortic grafts: review of a 25-year experience. J VASC SURG 1986;3:725-31. 7. Olofsson PA, Auffermann W, Higgins CB, Rabahie GN, Tavares N, Stoney RJ. Diagnosis of prosthetic aortic graft infection by magnetic resonance imaging J VASC SURG 5.
1988;8:99-105. 8.
Riley LM, Altrnan H, Lusby RJ, et al. Late results following surgical management of vascular graft infection. J VASC SURG 1984;1:36-44.
Szilagyi DE, Smith RF, Elliot JP, Vrandecic Ml’. Infection in arterial reconstruction with synthetic grafts. Ann Surg 1972; 176:321-33. 10. Vogelzang RL, Limpert JD, Yao JS. Detection of prosthetic vascular complications: comparison of CT and angiography. AJR 1987;148:819-23.
753
different type of infection, often by bacteria that are not usually pathogenic, ensues. The biology of the host implant interface is just beginning to be unraveled. Recently our laboratory has shown that vascular prostheses induce the selective expression of the intercellular adhesion molecule (ICAM-I).’ The latter is the ligand for the LFA-I receptor on neutrophils. Activated neutrophils respond with a burst of oxidative metabolism, which produces highly reactive superoxide anion. Interleukins are also produced by activated effector cells. Rather than destruction of the implant, a milieu is established in which small numbers of bacteria survive, perhaps in fibrin, macrophages, or in the interstices of the implant, to become clinically obvious weeks or months after a seemingly successful vascular reconstruction.
9.
UTILIZING VASCULAR DRUG DELIVERY
PROSTHESES FOR
Infection is the most catastrophic complication associated with the use of prosthetic vascular conduits. The magnitude of this problem must be inferential, based on current estimates of the frequency of their use and retrospective reports of incidence. Eight years ago it was estimated that 350,000 prosthetic grafts were used. Assuming an increase of 5% per year, this number now approaches one-half million. The incidence of prosthetic graft infection varies according to the material and the location of the graft. Nevertheless, even at a rate of 2%, the conclusion is that as many as 10,000 such infections occur each year. Since morbidity and mortality rates are generally accepted to be at least one third each, including limb loss, the human toll is great. AU of this occurs in the face of the universal use of prophylactic systemic antibiotics. A prospective randomized trial clearly supports their use. Established vascular prosthetic infection is a notably intransigent clinical syndrome. Although there are advocates for less aggressive management, most surgeons agree that treatment of an established infection requires massive doses of parenteral antibiotics, removal of the infected graft and extraanatomic bypass.
Background Vascular prostheses are foreign bodies that provoke an inflammatory response that is undoubtedly a factor in their propensity to become infected. The classic paper of Elek and Cohen’ published 30 years ago set the stage for this concept by demonstrating the enhancement of infection by silk sutures. Tissue injury can usually be coped with by lost defenses even when challenged by large inocula of bacteria. The foreign body subverts these defenses and a new and
Surface modification During the 1960s the novel concept of noncovalently bonding heparin to implantable devices was described.3 In 1978 our group hypothesized that implant infections occurred because of contamination of the prosthesis by a small number of bacteria that were protected in the interstices of the implant or on its surface. Here they eventually multiplied, thrived, and became clinically obvious. It was our view that the implant itselfwas particularly susceptible because the matrix of the graft, lacking a blood supply, was unlikely to contain significant concentrations of the large doses of antibiotics given these patients parenterally. We, therefore, developed a system in which antibiotics were noncovalently bound to the vascular graft through electrostatic attraction to surfactants of opposite charge. We focused on quaternary ammonium compounds with long chain alkyl groups to generate positively-charged coatings. The surfactant must be water-insoluble so that the coating is not leached on exposure of the prosthesis to aqueous environments. Water insoluble quaternary compounds have the further advantage that they show low biologic toxicity. This contrasts with the well documented toxicity of water-soluble and moderately insoluble quaternary ammonium compounds widely used as emulsifiers and dispersing agents. The interaction of negatively charged drug with positively charged surfactant coating shows a simple hyperbolic binding isotherm. Surface-bound drugs are bound rather loosely with dissociation constants of about lo-?o 10m4 mol/l. Some high molecular weight ligands, such as tissue plasminogen activator, show a much higher binding affinity, but the stoichiometry of maximal binding is much less than one drug per surfactant. This suggests that only some surfactant molecules are involved in drug binding. The rate of dissociation of drug is relatively slow with half-times from hours to several days. The rate of release can be significantly decreased if the drug-surfactant complex is applied to the prosthesis in chloroform, or another solvent that causes the device to swell. The prosthesis is first allowed to swell in the presence of
