Oslerian Mycotic Aneurysms: Embolization of Infected Cardiac Vegetations

Osler, in coining the term mycotic aneurysm, both named the condition and described what would be the most prevalent cause of primary arterial infection in the preantibiotic era. As he described it, a mycotic aneurysm is limited to the unique clinical condition characterized by bacterial endocarditis with septic embolization from valvular vegetations. These septic emboli lodge within the arterial wall, where a suppurative infection develops. The arterial wall is destroyed by the infection, and the resultant pseudoaneurysm is recognized as a mycotic aneurysm.

Considerable confusion has arisen because the term mycotic aneurysm has been expanded and applied to various types of infected aneurysms. Crane⁴ attempted to classify mycotic aneurysms as primary and secondary types. He introduced the term primary mycotic aneurysm to refer to infected aortic aneurysms not associated with endocarditis or an infectious focus; secondary types were those that formed as a result of preceding endocarditis. Ponfick⁵ and Eppinger⁶ were among the first to characterize the anatomic features of these aneurysms pathologically. Ponfick⁵ proposed that the initial insult to the arterial wall was a mechanical injury inflicted by the embolization of septic material. Eppinger in 1887 provided further support for the theory of septic emboli by culturing the same strain of bacteria from both vegetative lesions and the wall of an aneurysm in a patient with endocarditis. He applied the term embolomycotic to describe the combination of infectious and embolic components that led to the formation of mycotic aneurysms.⁶

Microbial Arteritis with Aneurysm Formation: Hematogenous Seeding

The second mechanism of arterial infection involves hematogenous microbial seeding of arteries during an episode of bacteremia. Microbial arteritis with aneurysm formation occurs when a normal or atherosclerotic artery becomes infected and the weakened artery becomes aneurysmal.

In 1906, the German pathologist Weisel⁷ described distinctive pathologic changes in arterial walls that occurred during the course of an infectious disease, but were not related to cardiac valve vegetation emboli.⁷ Lewis and Schrager⁸ and Cathcart⁹ presented case reports of infected peripheral aneurysms that developed in normal arteries of patients with osteomyelitis and typhoid fever, respectively. Despite these reports, nearly 30 years passed before consideration was given to the mechanism by which bacteremia led to arterial infection. Crane⁴ described an infected aneurysm in a patient with hypoplasia of the aorta, but no associated bacterial endocarditis or other identifiable source of infection.⁴ He proposed that the combination of the “force of the blood stream” and abnormal development of the aorta allowed bacteria to invade that portion of the aorta. This resulted in an arterial infection, disruption of the aortic wall, and an infected pseudoaneurysm. Revell extended the concept of aortic bacterial seeding one step further and proposed that the route of infection was through the aortic vasa vasorum.¹⁰ Hawkins and Yeager,¹¹ acknowledging the resistance of arterial intima to infection, suggested that an intimal defect such as that produced by arteriosclerosis allowed bacterial localization and infection.

Infected Aneurysms

The term infected aneurysm refers to an infection of a preexisting aneurysm, most often by hematogenous microbiologic seeding of the aneurysm. The original aneurysm is most commonly atherosclerotic; however, it may also be the result of trauma or arteritis. The diseased artery becomes host to bacterial pathogens when these lodge within the intramural thrombus and arteriosclerotic intima.

Arterial Injury with Contamination

Another cause of arterial infections is mechanical arterial injury by contaminated instruments. This type of infection can occur after an inadvertent arterial puncture with a contaminated needle in a drug abuser, as an accidental contamination during radiologic procedures, during placement of hemodynamic monitoring catheters, or as a result of traumatic injury. The combination of mechanical disruption of the intima and seeding of the arterial lesion with pathogenic bacteria leads to the formation of suppurative arteritis and destroys a portion of the arterial wall. This subsequently becomes an infected arterial pseudoaneurysm.

Arteritis from Contiguous Spread

Arterial infections can also develop through the spread of infection from a contiguous focus. Contiguous infections that have been recognized as potential sources of bacteria include lesions such as osteomyelitis, infected lymph nodes, tuberculous lymph nodes, and abscesses from narcotic injection.¹² Bacteria, and less commonly mycobacteria or fungi, invade the artery either by direct extension or via lymphatics. They subsequently produce a necrotizing invasive infection of the arterial wall, with eventual destruction of the wall.

Other Forms of Arterial Infection

There are three other, less common forms of infected aneurysms: syphilitic aortitis, true fungal aneurysms, and primary (spontaneous) aortoenteric fistulas. Because of significant differences in the pathogens and pathogenesis of these lesions, they merit separate discussion.

Syphilitic aneurysms are a rarely encountered complication of advanced syphilis. These lesions occur in approximately 10% of patients with the tertiary form of the disease.¹³ These aneurysms commonly arise in the ascending aorta, frequently involve the aortic valve, and are secondary to treponemal invasion of the vasa vasorum. The reasons why Treponema species prefers this portion of the aorta remain unclear. After spirochete penetration, an infiltrate develops within the vessel wall consisting of plasma cells, epidermal cells, and giant cells. This infiltrate results in destruction of the elastic and muscular components of the tunica media, replacement of the normal wall with fibrous tissue, and dilatation and subsequent formation of saccular aneurysms.

Fungal arterial infections are also extremely rare and occur most often in patients who are immunosuppressed. Common risk factors include diabetes, immunosuppressive medications, and chronic hematologic disorders such as leukemia or lymphoma. The species most often implicated are Histoplasma capsulatum, Aspergillus fumigatus, Candida albicans, and Penicillium species. These lesions most commonly result from either colonization of a preexisting aneurysm or infection of a damaged artery.

HIV-related vasculitis can result in aneurysmal degeneration of the arterial wall. Radiologic appearance may be identical to that which results from a bacterial arterial infection. The distinction is noted in the pathologic evaluation of the affected arterial wall, which demonstrates acute and chronic adventitial inflammatory changes. Secondary bacterial infections may be present, and cultures may be positive in a minority of these patients. There appears to be a predilection toward carotid and femoral arteries; however, the aorta may also be involved.^14–16

Spontaneous or “primary” aortoenteric fistulas (AEFs) arise as a consequence of progressive aneurysmal enlargement, with gradual erosion into an adjacent segment of the gastrointestinal tract. The erosion is thought to be facilitated by the indurated, atherosclerotic artery pressing against a tethered portion of bowel. The most common location for this erosion is the third portion of the duodenum. In their 1951 review of a series of 16,633 autopsies, Hirst and Affeldt¹⁷ reported the incidence of this type of fistula to be 0.05%. Because the majority of patients with aortic aneurysms now undergo elective operation before they can progress to develop a primary aortoenteric fistula, the incidence of these lesions is thought to be considerably lower today. Patients with spontaneous AEFs may have an initial or “herald” bleed, which represents the initial hemorrhage of blood into the duodenum. In this presentation, the initial hemorrhage may abate then later resume in a more prolonged and dramatic manner. Presumably, clot within the AEF is responsible for the intermittent nature of the bleeding episodes. This condition is considerably different from that associated with aortic graft infection, or secondary AEF. Secondary AEF is more common, more dangerous, and more difficult to manage.

Graft excision and remote reconstruction are the standard management of secondary AEF. In contrast, significant evidence exists that primary AEF can be managed by closure of the duodenal rent, debridement of the aorta, and in situ reconstruction with an arterial prosthesis. The prerequisites of this approach are the absence of purulence at the fistula site, a small defect in the duodenum, and a relatively healthy patient. It should be noted that the management of primary aortic infections (mycotic aneurysms) is similar to that of primary AEF, in that the absence of gross infection along with adequate debridement may allow in situ graft reconstruction of the aorta.¹⁸

Blood Cultures

The demonstration of bacterial organisms in association with an arterial lesion is central to the diagnosis of an arterial infection. The bacteria may be detected by either blood cultures or cultures of the arterial wall itself. Blood cultures, by virtue of their availability, are frequently one of the first tests done in patients suspected of having a significant infection. If the patient is floridly bacteremic, the blood culture may detect the circulating bacteria. However, several problems limit the usefulness of blood cultures. The incidence of negative blood cultures testifies to the fact that they are helpful in only a fraction of symptomatic patients; many patients with arterial infections never have positive blood cultures. In the review by Brown and associates,¹⁹ only 60% of patients had positive preoperative blood cultures. In addition, blood cultures might not detect the infectious organism until several days or weeks have elapsed, limiting the test’s effect on clinical management.

The presence of bacteria in the blood may be an important early clue to an arterial infection, but the information from such tests must be evaluated in the proper clinical context. Most bacteremic patients have an evident source of bacteremia that should be identified and treated. Patients with positive blood cultures and no clinical evidence of a concurrent infection should be examined for possible arterial lesions. The significance of a positive blood culture in an otherwise asymptomatic patient is difficult to determine without considering the patient’s underlying problems and risk factors. It should also be noted that patients who are relatively asymptomatic (no systemic manifestations of sepsis) tend to have fewer positive blood cultures. As a result, in a study of patients undergoing clean arterial procedures, only 2% of blood cultures were positive, whereas 12% of arteries and 14% of periarterial adipose tissues harbored bacteria.²⁸ Obvious clues, such as a recently noted aneurysm or a history of drug abuse, may promote further investigation.

The type of organism identified in blood cultures may suggest a source of the infection. If a blood culture reveals Salmonella species in a patient with an aneurysm, an arterial infection should be seriously considered. Although Staphylococcus organisms are a common pathogen in arterial infections, their ubiquitous presence on skin often confuses the diagnosis and calls into question the results of the blood culture.

The importance of the preoperative blood culture is difficult to understate. It represents the earliest reliable clue to the presence of an arterial infection. Even in the event of a delayed result, such as when several days are required before the blood culture can identify the bacteria, the information provided may be invaluable in managing the patient.

Arterial Cultures

Arterial wall cultures may also help secure the diagnosis of an arterial infection. In any circumstance in which the diagnosis of an infectious aneurysm is entertained, arterial cultures should be attempted. The principal drawback to arterial wall cultures is the time required before any information about the infection is available. Patient management must therefore depend on other factors, such as the clinical setting, the index of suspicion, the presence of prior blood culture data, and the results of angiographic studies.

Because clinical decisions cannot always be based on arterial culture results, other techniques such as intraoperative Gram staining and frozen section of the arterial tissue are often considered. Unfortunately, these methods might not provide significant improvement in the detection of bacteria. In the study by Brown and associates,¹⁹ although 60% of patients had positive preoperative blood cultures, only 20% of intraoperative Gram stains were positive. Arterial wall frozen sections have not seen widespread use, but they may prove helpful. Histologic findings of inflammation and bacterial invasion are strong evidence supporting the diagnosis of arterial infection.

When obtaining blood or arterial wall cultures, it should be noted that the type of organism can affect the yield of the tests. Brown and associates¹⁹ noted that 60% of arterial wall cultures were negative. Approximately 25% of their cultures failed to detect any organism at all. Presumably, these were difficult organisms to collect and culture. S. epidermidis may be difficult to culture without sonicating the specimen. Treponema pallidum may require darkfield examination for identification. Mycobacterium tuberculosis is a fastidious organism that is difficult to grow. These considerations should prompt the special attention of the pathology laboratory and the collection of adequate specimens.

Molecular Diagnosis of Arterial Infection

Molecular biology technique allows the evaluation of biological specimens for the detection of bacterial nucleic acids. This has been applied to the detection of bacteria within arterial samples. The application of techniques such as polymerase chain reaction (PCR) may allow the detection and amplification of genetic material from the bacteria within the arterial wall. These techniques diagnose the presence of microbiological organisms, identify the organism, and may identify the presence of resistant strains allowing for direction of antimicrobial therapy.

Da Silva and colleagues reported use of PCR for detection of bacterial ribosomal nucleic acid (RNA) in specimens of normal aortic tissue removed at the time of surgical repair.²⁹ Using universal eubacteria primers to amply 16SrRMA, they were able to identify the RNA from a wide variety of bacteria in the arterial specimen, thus demonstrating the potential of the technique. Their report is striking in its ability to detect bacteria that are ordinarily difficult to culture. Dickinson and colleagues³⁰ reported the application of this technique in the case of a 72-year-old man with a suspected mycotic femoral artery aneurysm and blood cultures that showed S. pneumoniae. Arterial wall samples subjected to routine culture technique yielded no microorganisms. The same samples analyzed with pneumococcal primers for PCR were able to identify the presence of S. pneumoniae.

Dickinson used PCR to confirm the presence of a suspected pathogen, whereas da Silva used PCR to identify a wide spectrum of bacteria which were present in arterial tissue. Although widely available, these molecular techniques are not commonly used; they are costly, and interpretation of the test results might not be intuitive because they can detect both pathogenic and symbiotic bacteria. Still, these techniques could prove beneficial in the diagnosis of organisms that are notoriously difficult to culture, such as slow-growing organisms (e.g., mycobacteria) or those that produce biofilms (e.g., S. epidermidis). These techniques would likely allow improved diagnosis of bacteria present in the approximately 20% to 60% of suspected mycotic aneurysms that fail to yield bacterial growth on culture examination.

Nuclear Imaging: Tagged White Blood Cell Scans

Nuclear imaging has become an important tool in the identification of arterial graft infections, but it has not played as important a role in identifying primary arterial infections. The technique is based on the ability of various radioisotope markers to be linked to white blood cells, which then become involved in an inflammatory process. The advantages of these tests are their relatively low risk to the patient and the facility of their application. The principal drawback is that the tests may detect many inflammatory lesions, not just those that are the result of an arterial infection. The interpretation of the results of a nuclear scan must account for many clinical issues. Although the usefulness of these tests has been debated, in the absence of recent trauma or infection, the use of radiolabeled indium or gallium as markers may allow localization of an arterial infection.

Computed Tomography and Magnetic Resonance Imaging

The success of techniques such as computed tomography (CT) and MRI in identifying primary arterial infections depends largely on their ability to resolve the characteristic anatomic features of the lesions. Because of the detailed anatomic data these scans present, they have become popular in the evaluation of intraabdominal vascular lesions. There are some significant limitations, however, in regard to their ability to secure the diagnosis of an arterial infection.

The essential diagnostic characteristics of arterial infections include the presence of a focal defect in the wall of the aorta, the saccular shape of the aneurysm, and the tissue edema that accompanies the inflammatory reaction. Routine two-dimensional reconstruction of CT images does not readily allow recognition of the diagnostic features of mycotic aneurysms. A three-dimensional reconstruction does allow their recognition, but such reconstruction is not routinely performed and must be specifically requested.

MRI represents an improvement over CT scanning because current computer analysis allows a more flexible assemblage of the data and facilitates the recognition of essential diagnostic characteristics. MRI may not require intravascular contrast agents, which are frequently needed with CT. Finally, MRI is able to detect tissue differences with regard to certain molecular constituents. Another advantage of MRI is its ability to detect the accumulation of water in tissues; this tissue edema is frequently the hallmark of an inflammatory process and may identify an arterial infection.

Angiography

Angiography is the most widely used technique for the investigation and definition of arterial infections (Figure 10-4). Historically, it was the first method by which the characteristics of primary arterial infections were identified. Angiography served to define the characteristics of these lesions. Angiography is clearly superior in areas such as the intestinal mesentery and the visceral vessels, where the size of the arterial lesion may be less than the resolution of computed techniques. In the case of aortic mycotic aneurysms, the angiogram usually provides excellent definition of the defect in the aortic wall, the saccular pseudoaneurysm, and the contiguous arterial anatomy. Finally, the arteriogram offers the best definition of the relationship between the visceral vessels and the arterial defect—an essential step in planning patient management.

FIGURE 10-4 Angiogram of mycotic aortic aneurysm.

The role of arteriography in the management of a peripheral arterial infection has been questioned. Because some peripheral arterial infections can be managed with ligation and debridement without reconstruction, an angiogram might not be necessary. However, there is a benefit to assessing the native circulation before attempting arterial ligation. Should the limb require urgent revascularization after arterial ligation, an angiogram obtained before the ligation would be helpful in planning the revascularization. For this reason, an arteriogram of the involved vessels is strongly advised in all but emergent cases.

Hybrid Positron Emission Tomography and Computed Tomographic Scan

Positron emission tomography (PET) is a technique in which positron emissions from a biomarker are detected and displayed in an image. The PET scan relies on the ability of fludeoxyglucose, a glucose analog which has a positron-emitting radioactive isotope, to be taken up by high–glucose-using cells. In the setting of infections, these cells are macrophages, leucocytes, granulocytes, and inflammatory cells. The positron emission may then be detected by the PET scanner.

New “fusion technology” allows the images acquired from both a CT scanner and a PET scanner to be taken sequentially in the same session and combined into a single superposed or co-registered image. This allows combining the metabolic information of the PET scan with the spatial information of the CT scan. The technique may provide greater sensitivity and specificity in the detection and localization of an infection. Fukuchi and colleagues³¹ described their initial experience with this technique when applied to suspected vascular graft infections in 2005.³¹ They observed that this technique may be of particular benefit in patients who might have an infection; however, the presentation is not clinically evident or severe. Their experience indicated that the PET/CT had a high sensitivity and that in several instances this resulted in false-positive scans. In addition, the PET techniques suffer the general limitation of requiring the production of radiopharmaceuticals for the scan—a process that is highly specialized, requires significant infrastructure, and is expensive. This technique is still far from general clinical application.

Control of Sepsis

Antibiotic therapy and surgical débridement represent the primary treatment modalities for the control of sepsis in arterial infections. All infected arterial tissue must be debrided. It is important that the arterial resection encompass all inflamed tissues and continue to the point where the arterial tissue is normal and healthy. This helps to prevent recurrence of the infection and disruption of the arterial suture line.

Soft tissues adjacent to the infected artery that appear to be involved are also debrided. Major structures such as the vena cava and ureters are left intact. Retroperitoneal tissues that appear to be involved are resected as well. Once all infected tissues have been removed, the wound is thoroughly irrigated with an antibiotic solution—ideally, one that contains antibiotic directed toward the suspected pathogens (as detected by preoperative blood cultures). Surgical drains are useful when there is clear evidence of purulence or abscess. When collateral circulation allows, the excision may be accompanied by proximal and distal ligation and no effort to reconstruct the artery.

The use of antibiotics is mandatory in these situations. Broad-spectrum antibiotics must be initiated as soon as a strong clinical suspicion of arterial infection has been established. Blood cultures should be obtained before the initiation of antibiotics. When positive, these cultures are then used to select an antibiotic regimen with the highest therapeutic value and the fewest side effects. Negative cultures should not preclude the institution of broad-spectrum antibiotics when arterial infection is suspected. The use of high-dose preoperative antibiotics is directed toward sterilizing the aneurysm and adjacent tissues in order to minimize bacteremia and local contamination during surgical manipulation of infected tissues. Antibiotics must be continued until the source of the bacteremia has been corrected either surgically or medically. Similarly, the primary source of bacteremia or local bacterial invasion must be controlled as a mainstay of therapy in all types of primary arterial infections. In patients with SBE-related mycotic aneurysms, specific consideration must be given to sterilization of cardiac valvular vegetations. When possible, a period of preoperative antibiotic administration is associated with improved outcome.

The duration of antibiotic treatment is somewhat controversial, and several competing regimens have been proposed. Several authors suggest that IV antibiotics be initiated before surgery and extended for no less than 6 weeks postoperatively.^32–34 In addition, these authors recommend that patients with prosthetic reconstructions, especially in situ prosthetic reconstructions, be prescribed lifelong oral regimens of suppressive antibiotics. Typically, oral trimethoprim-sulfamethoxazole (Bactrim), a sulfa drug, or a first-generation cephalosporin or penicillin is the agent of choice.

Important technical points include the use of monofilament suture material in ligation and oversewing of the arteries. This recommendation is based on the superiority of monofilaments over braided suture in resisting recurrent infection. Whenever possible, the resected arterial stump should be covered with a pedicle of healthy, viable tissue to further reduce the possibility of a recurrent infection and to accelerate healing of the arterial segment. In the abdomen, this tissue pedicle is frequently the omentum. A flap of fascia from the prevertebral fascia and ligaments can be used to reinforce the aortic suture line. In the periphery, muscle transposition is the preferred means of obtaining tissue coverage. In the femoral region, this is most readily accomplished by rotating the head of the sartorius.

Nonoperative Therapy

Nonoperative therapy for arterial infections has been proposed by Kaufman and coworkers³⁵ for high-risk or debilitated patients. This treatment modality, although effective anecdotally, remains controversial, and further investigation is necessary. Hsu and colleagues³⁶ reported a series of 22 cases of infected aortic aneurysms treated with antibiotics only and without surgery.⁶ The in-hospital mortality was 50%. The event-free survival at 1 year was 32%. The authors noted that these results compared poorly to standard surgical approaches.

Arterial Reconstruction

Restoration of arterial continuity is necessary both to control hemorrhage and to provide for perfusion of the distal arterial beds. This can be accomplished with open surgical approaches or by endovascular approaches. Currently, open surgical technique with extraanatomic reconstruction is considered the most conservative approach; however, new reports suggest that this may be changing as familiarity with endovascular technique progresses.

The open surgical management of mycotic aneurysms includes debridement of infected tissues (including the infected artery), along with extraanatomic reconstruction or in situ arterial reconstruction. Reconstruction of the infected arterial tree presents the problem of material interaction with the infectious organisms. Several materials are available for reconstruction: synthetic graft (Dacron), autologous veins, and human cryopreserved arterial allografts.

The material used for reconstruction of the arterial tree in the face of infection represents a significant choice that could influence the outcome of surgery. This is particularly true when the consideration is in situ reconstruction of an infected artery. Reconstruction alternatives include prosthetic grafts, autogenous veins, and cadaveric allografts. Prosthetic grafts are readily available and inexpensive, but present an increased risk of reinfection. Biological grafts are thought to have a better ability to resist infection than do prosthetic grafts. Autologous femoral vein grafts require a time-consuming dissection for graft procurement and may be accompanied by complications related to this dissection. Arterial allograft reconstructions are expensive, are not commonly available, and may be subject to aneurysmal degeneration.

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