Continuing Education Activity

Septic embolism is an obstruction of a blood vessel, typically by an infected thrombus that has traveled through the bloodstream from a distant infectious source and blocked a blood vessel. Septic emboli result in two insults—the early embolic/ischemic insult due to vascular occlusion that may lead to infarction and the infectious insult that leads to inflammation and possible abscess formation. This activity outlines the evaluation and management of septic emboli and highlights the role of the interprofessional team in evaluating and managing patients with this condition.

Objectives:

• Identify the etiology of septic emboli medical conditions.
• Review the history, physical, and evaluation of septic emboli.
• Summarize the treatment and management options available for septic emboli.
• Describe interprofessional team strategies for improving care coordination and communication to advance the management of septic emboli and improve outcomes.

Introduction

Septic embolism is an obstruction of a blood vessel, typically by an infected thrombus that travels through the bloodstream from a distant infectious source and blocks a blood vessel. Septic emboli result in two insults—the early embolic/ischemic insult due to vascular occlusion that may lead to infarction and the infectious insult that leads to inflammation and possible abscess formation.[1]

Septic embolism frequently results from infective endocarditis. In fact, Osler nodes (the tender purplish-colored papules), which are pathognomonic of infective endocarditis, are indeed evidence of embolism, a biopsy of which results in the isolation of respective causative microorganisms.[2]

Etiology

Infective endocarditis is an established common cause of septic emboli from case studies as early as 1883.[3] Parts of the vegetations on the valves infected dislodge and travel through the bloodstream and block blood vessels based on the size and the location. Previously, septic embolism was almost exclusively a complication of septic pelvic thrombophlebitis secondary to both septic abortion and post-puerperal uterine infection. Currently, risk factors for septic emboli include intravenous drug use, indwelling vascular catheters, and patients with prosthetic cardiovascular devices.

The clinician should suspect endovascular infection and septic embolism in patients with endovascular devices/cannulations who present with recurrent or persistent bacteremia.

Septic emboli originate depending on the anatomical location of the infection and the vasculature surrounding that area. For example, orbital cellulitis with Streptococcus constellatus was complicated with cavernous sinus thrombosis and pulmonary embolism.[4]

Paradoxical septic emboli to the brain could occur secondary to right-sided pacemaker endocarditis, and the septic emboli cross via potent foramen ovale, creating a right to left shunt.[5]

Also, there are reports of septic pulmonary emboli from the right atrial thrombus related to tunneled hemodialysis catheters.[6]

Septic superior vena cava thrombus has been reported from an infection at the peripherally inserted central catheter (PICC) line in a neutropenic patient with MRSA bloodstream infection.[7]

Cardiac implantable electronic devices (CIED) infections occur in about 0.5% of de novo CIED implants and approximately 2% of CIED replacements.[8]T The CIED diagnosis derives from lead vegetation detected by echocardiogram, possibly complicated by septic embolism. One case study described septic thrombophlebitis involving the internal jugular vein due to staphylococcus aureus after insertion of implantable cardiovertor defibrillator.[9]

Microbiological organisms usually involved include Staphylococcus aureus, coagulase-negative Staphylococcus, streptococcal group, enterococcus group, polymicrobial infections, and less frequently, gram-negative organisms may be involved in the causation of septic emboli. In addition, fungi, mostly Candida and Aspergillus, may be found in septic emboli (E. Rubinstein et al., 1995).

A recent multinational study on infective endocarditis showed that (91.7%) endocarditis patients had any identified pathogen. Leading pathogens (Staphylococcus aureus ( 33.6%), Streptococcus viridans 18.7%), enterococci (16.1%), coagulase-negative staphylococci ( 11.6%)) displayed substantial resistance profiles. A total of (44.4%) patients had major embolic events, most frequently to the brain ( 26.3%).[10]

Epidemiology

The rate of septic emboli among patients with infective endocarditis varies widely among studies. In a study including 437 patients with surgical endocarditis, septic emboli were present in 10.52% of patients with infective endocarditis.[11] Also, systemic embolization complicates about 20% to 50% of cases of infective endocarditis of left-sided heart valves.[12] Another study, including 493 with Infective endocarditis, septic embolism was diagnosed in 57% of cases of infective endocarditis.[13] In a systematic review and metanalysis, the pooled prevalence of septic embolism in patients with infective endocarditis accounted for 25 %.[14] Septic embolization occurs in at least 30% of patients with infective endocarditis referred for cardiac valve replacement. [15]

In a 25 year review of infective endocarditis, intracardiac device-associated infective endocarditis was more frequent in the last decade than native valve endocarditis: pacemaker (5.4 vs. 23% p < 0.0001) and prosthetic valve infective endocarditis (8.5% vs. 19.2% vs. 47.5% p < 0.0001).[16]

In a recent study of Infective endocarditis by Erdem et al., 44.4% of patients had major embolic events. The distribution of embolism was as follows: cerebral (26.3%), splenic (6.8%), pulmonary (6.1%), renal ( 2.9%), peripheral (2.2%), coronary (n = 4), mesenteric (n = 3).[10]

Pathophysiology

Septic emboli originate from a source of infection that becomes complicated with bloodstream infection. A large bacterial inoculum forms on the vulnerable vascular territory, e.g., vegetations on a heart valve or a pacemaker lead or a thrombus in an indwelling vascular catheter or graft. The vegetation dislodges into smaller particles that travel through the bloodstream and blocks an individual blood vessel based on the invaded new area causing double hit injury: ischemic insult and inflammatory/infectious insult. 

Right-sided endocarditis vegetations usually embolize to the lungs and cause septic pulmonary emboli. Patent foramen ovale (PFO) is a congenital cardiac anomaly that correlates with cryptogenic strokes and may provide a conduit for paradoxical emboli. Left-sided endocarditis vegetations usually embolize to the brain, causing strokes (occlusion of cerebral arteries by emboli derived from endocardial vegetation). Septic embolic stroke caused brain abscesses, increased mortality, and upregulated Orm1 and Cxcl2 gene expressions compared to non-infected embolic stroke.[17]

In an experimental study on canine brains by Molinari, M.D concluded that both ischemic injury and infection might be caused simultaneously by a single event, septic embolism. Septic cerebral embolism may cause either a mycotic aneurysm or brain abscess. The virulence of the organism determines the pathology and clinical course of the cerebral lesions. The more virulent pathogens, S. aureus and E. coli, cause immediate and dramatic infections of the arterial wall, with aneurysm and hemorrhage. In contrast, streptococci usually cause progressive lesions, beginning in areas of infarction or ischemia.[18]

Histopathology

There is fibrinoid necrosis of the vessel walls, as well as, a neutrophilic infiltrate, both in the vessel walls and in the vicinity surrounding the vessels. The presence of dense paucicellular fibrinoid material mixed/interspersed with clusters of bacterial cocci. This clot morphology specific to septic embolus was present in histopathology in clots retrieved after endovascular thrombectomy in four patients with Infective endocarditis who had an acute ischemic stroke.[19]

History and Physical

Septic emboli have an extensive range of presentation from asymptomatic to severe with high mortality.

Right-sided endocarditis vegetations embolize to the lungs causing septic pulmonary emboli present with fever, dyspnea, pleuritic chest pain, cough, and occasionally hemoptysis. Left-sided endocarditis may result in systemic emboli in different organs with different clinical presentations:

Septic cerebral emboli: symptoms and signs of neurological deficits depending on the stroke location and the extent of infarcted/inflamed area, and the number of the affected areas. Embolism to the brain in a patient with infective endocarditis can be clinically silent. In one prospective study of 56 patients with left-sided endocarditis, embolization to the brain was detected on MRI scan in 80% of cases and was subclinical in 48%.[20] 

Septic splenic emboli resulting in splenic infarctions/hemorrhages/abscesses: The spleen is the most common abdominal site for systemic septic emboli that often complicate infective endocarditis.[21]

Septic coronary artery embolization has been described after aortic valve endocarditis and successfully treated with aspiration thrombectomy.[22]

Septic mesenteric emboli: Septic embolic occlusion of the superior mesenteric artery induced by mitral valve endocarditis has been described and successfully treated with resection of the affected bowel and mitral valve replacement.[23]

Also, there is a case outlining infective endocarditis caused by Streptococcus bovis with complications including systemic septic emboli and superior mesenteric artery mycotic aneurysm in a patient with colon diverticulitis who received successful treatment with surgical resection of the mycotic aneurysm, removal of the mycotic thrombi, and mitral valve replacement.[24]

Pylephlebitis: portal vein thrombosis due to intrabdominal infection such as ascending cholangitis or diverticulitis usually presents with non-specific symptomatology of fever and abdominal pain and diagnosed with CT abdomen with contrast and abdominal ultrasound, and the etiology is often polymicrobial.

Pyogenic liver abscesses could experience complications with metastatic infections, including septic embolism.[25]

Septic emboli of the extremities: The presentation of peripheral vascular emboli is that of acute extremity ischemia complicating Infective endocarditis with varying severity, from transient ischemia treated with antibiotics and anticoagulants to severe ischemia necessitating limb amputation. Acute lower limb ischemia has also occurred after MRSA pneumonia.[26]

Septic emboli of the skin: Septic microemboli were present in a Janeway lesion of bacterial endocarditis.[27]

Lemierre syndrome is an acute oropharyngeal infection caused by Fusobacterium necrophorum with secondary septic thrombophlebitis of the internal jugular vein (IVJ), first reported in the literature in 1936. It involves the progression of the disease from a focal suppurative peritonsillar infection to local septic thrombophlebitis with hematogenous progression to and distant septic emboli. (Jafri FN et al. 2018) Lemierre syndrome has correlations with septic emboli to the liver and lungs, often causing multiple abscesses.[28] The report indicated it also caused extensive epidural abscess formation, and neurological weakness was successfully managed with the combination of IV antibiotics and extensive hemilaminectomies for decompression. The patient exhibited no long-term sequela as a result of either the epidural abscess or of its treatment.[29]

Septic emboli have also been described from infected radial artery catheters causing Janeway lesions and splinter hemorrhages.[30]

Recurrent septic retinal emboli have occurred following dental surgery.[31]

Renal septic emboli: Renal infarction/hemorrhages may lead to renal failure if a significant portion of the renal parenchyma is involved. In the case of methicillin-resistant Staphylococcus aureus, bloodstream infection in an HIV-infected patient was complicated with septic pulmonary embolism, right renal abscess, and ipsilateral renal vein thrombosis.[32]

Evaluation

Laboratory: blood cultures are usually positive in patients with septic emboli. Obtain at least three blood cultures.

Arterial and venous duplex studies are necessary to pursue arterial emboli and venous thrombophlebitis.

Echocardiography: transesophageal echocardiography has a better yield for the detection of vegetations than transthoracic echocardiography.

Chest X-ray imaging usually shows nonspecific findings for septic pulmonary emboli. A chest CT scan with IV contrast is needed to diagnose septic pulmonary emboli and demonstrates findings of multiple, nodular lung infiltrates peripherally, with or without cavitation. Ultrasound may detect hypoechoic lesions in the spleen and or kidneys.

A splenic septic embolus is common in endocarditis. Abdominal computed tomography is necessary for all patients.[33]

Bellomy et al. presented a case where femoral occlusive septic emboli were identified by point-of-care ultrasound after mitral valve replacement.[34] 

A ventilation/perfusion scan of the lung is in order if contrast could not be administered to diagnose septic pulmonary emboli.

Septic emboli to the brain usually diagnosed with MRI with and without gadolinium. F-FDG-PET/CT has proven its high diagnostic value for detecting peripheral emboli in patients with infective endocarditis and cardiac device infections, substantially affecting patients’ outcomes and treatment. F-FDG-PET/CT is limited for detecting brain foci, where CTA and/or MRI are mandatory.[35] The use of white blood cell SPECT/CT and [18F] FDG PET/CT allows for the early detection of septic emboli.[36]

Treatment / Management

Source control and prolonged antibiotic therapy are the cornerstones of the management of septic emboli.

The choice of antimicrobial therapy in the management of septic emboli targets the causative organisms, the organ involved, and the pharmacokinetics and pharmacodynamics of the available drugs. 

The management would vary based on the location of the septic embolus and the size of the surrounding infarct or inflammatory area.

Anticoagulation has been a controversial topic in the management of infective endocarditis and septic emboli. Continuation of anticoagulation in patients with a definitive pre-existing indication should merit consideration in patients with left-sided infective endocarditis in the absence of other contraindications.[37]

Patients with endocarditis and acute onset of symptoms are at increased risk of septic in-hospital complications and mortality. Therefore, early surgery, performed within the first two days after diagnosis, plays a pivotal role in treating these patients.

Endovascular management of acute ischemic stroke secondary to septic emboli from bacterial endocarditis is case-specific and outside established guidelines. Scharf et al. report the management of 3 cases of an acute ischemic stroke secondary to a septic embolus from two different centers.[38] Endovascular treatment can be effective for acute septic emboli and mycotic aneurysms, but the evidence is still limited.[39] 

Management of an embolic splenic abscess usually involves surgical splenectomy or image-guided drainage, but the natural history of splenic abscess without drainage is unknown. Alnasser et al. describe the successful conservative treatment of a large complex splenic abscess with antibiotics alone in a patient with aortic valve infective endocarditis.[21]

Cardiac implantable electronic device infection is treated with transvenous lead explant, but the overall stroke risk is 1.9%.[40]

Mycotic aneurysm of the superior mesenteric artery is successfully treated with surgical resection of the mycotic aneurysm, removal of the mycotic thrombi, and infected valve replacement.[24]

The antimicrobial therapy of Infective endocarditis and subsequent septic emboli guidelines recommend 4-6 weeks of intravenous antimicrobial therapy.

For guidance on the choice of the appropriate antimicrobial therapy, please refer to the Scientific Statement for Healthcare Professionals From the American Heart Association about Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of complications.[41] 

For more details on the treatment of infective endocarditis, one can also refer to the JCS 2017 Guidelines on Prevention and Treatment of infective endocarditis.[42]

Differential Diagnosis

• Marantic endocarditis, Libman-Sacks endocarditis, noninfectious, typically associated with cancer and collagen vascular diseases: should be considered in patients with culture-negative endocarditis and elevated inflammatory markers. 
• Metastatic disease and tumor embolism: requires a high index of suspicion and history of underlying malignancy.
• Disseminated fungal or mycobacterial infections: could have multi-organ manifestations such as disseminated histoplasmosis and disseminated blastomycosis usually depend on the geographic location are common in endemic areas and require microbiologic diagnostic modalities such as tissue biopsy, cultures, antigen detection, and PCR testing may be necessary, and disseminated nontuberculous mycobacteria and miliary tuberculosis should be a diagnostic consideration in immunosuppressed patients such as patients with HIV infections or patients on Immunosuppressive therapy or Immunomodulators. 
• Noninfectious thromboembolic phenomena in patients with atrial fibrillation not on anticoagulation or other arrhythmias.
• Fat embolism also merits consideration following surgical procedures.

Prognosis

The prognosis varies significantly from asymptomatic presentation to high mortality depending on the affected organs and the combined toll of both ischemic and infectious insults. Habib et al. for Infective endocarditis outcomes in a large prospective observational study occurred: In-hospital deaths occurred in 532 (17.1%) patients and occurred more frequently in prosthetic valve infectious endocarditis. Independent predictors of mortality include the Charlson comorbidity index, creatinine greater than 2 mg/dl, congestive heart failure, vegetation length over 10 mm, cerebral complications, abscess, and failure to undertake surgery when indicated.[43]

Complications

Septic emboli could affect multiple organs, and complications depend on the organ affected and the size of the embolus.

Septic cerebral emboli could result in ischemic strokes due to infarction of the ischemic area, brain abscesses causing variable neurological deficits based on the location affected, and the extent of the damage. Septic cerebral emboli are also a risk factor for thrombolysis-related hemorrhagic transformation.[44] Intracranial mycotic aneurysms are relatively rare, accounting for less than 10% of neurologic complications of infective endocarditis.

Mycotic aneurysms (infected arterial aneurysms): mycotic is a misnomer as they rarely result from fungus and are mostly of bacterial etiology. A mycotic aneurysm is a focal dilation of an infected arterial wall.[45] They frequently develop due to septic embolism invading the vasa vasorum. The fact that the veins do not develop MAs despite their denser vasa vasorum supports septic emboli as a major source of MA. Potentially infected emboli often get filtered by the capillary beds of large organs such as the lungs, liver, and spleen.[46] Infected (mycotic) aneurysms result from hematogenous dissemination of septic emboli and occur more frequently in patients with cardiac valvular abnormalities or prosthetic valves and intravenous drug abuse. Mycotic aneurysms may undergo spontaneous thrombosis, size reduction, rapid enlargement, or rupture.[47]

Complications of septic splenic emboli include splenic abscess/splenic infarction resulting in severe abdominal pain or hemorrhage that may warrant urgent surgical intervention.

Septic renal emboli can cause renal infarction.

Complications of septic pulmonary emboli vary based on the severity and the size of the damaged pulmonary parenchyma from asymptomatic lung nodules like lesions on pulmonary imaging to severe dyspnea and hypoxemic respiratory failure. They could result in long term pulmonary cavitary lesions. Pneumothorax is also described as a complication of a septic pulmonary embolism due to Methicillin-resistant Staphylococcus aureus bloodstream infection occurring 10 days after treatment.[48]

Postoperative and Rehabilitation Care

Septic emboli could severely impact the patient based on the location and the extent of the damage. In addition, cerebral septic emboli often result in stroke syndromes that require acute rehabilitation.

Septic pulmonary emboli may result in acute hypoxemic respiratory failure requiring mechanical ventilation and prolonged ICU stay and pulmonary rehabilitation.

Acute limb ischemia from septic emboli: if severe enough may result in limb amputation due to critical limb ischemia, and physical rehabilitation is required after that.

Postoperative care after valvular surgery with septic cerebral emboli is challenging due to the risk of hemorrhagic transformation using anticoagulation perioperatively.

Consultations

Consultations usually decided based on the site and the extent of damage from septic emboli, for example:

• Cardiology evaluation for establishing the diagnosis and management of infective endocarditis as a common etiology of septic emboli
• Infectious disease evaluation for the choice of the appropriate antimicrobial regimen
• Cardiothoracic surgery to assess for surgical management of infective endocarditis in selected cases depending on the size of the vegetation, the extent of the valvular damage, and prosthetic cardiac device extraction
• Interventional neurologists for septic emboli the brain requiring endoscopic embolectomy
• Interventional radiologist and general surgery for evaluation of septic emboli to the abdomen commonly involving the spleen
• Ophthalmology evaluation in septic emboli to the eyes and endophthalmitis secondary to Infective endocarditis
• Dermatology evaluation in septic emboli to the skin, e.g., Janeway lesions and other skin manifestations of infective endocarditis

Deterrence and Patient Education

Septic emboli are infected blood clots that arise from a site of infection and travel through the bloodstream to a distant site in the body and cause blockage of the blood supply to the affected area and also inflammation from the infection seeding into that new area causing a double hit on tissues due to insult from lack of blood supply as well as due to the infection itself.

It usually results from a severe infection called infective endocarditis, which is an infection of the inner lining of the heart and the heart valves. It could also arise from intravenous drug abuse, central lines inserted into large veins. The presentation of septic emboli is very variable depending on the site affected and the size of the embolus, and the severity of the underlying infection.

Diagnosis is usually via imaging of multiple body sites, and the organisms are usually identified by cultures of the blood or other tissues involved.

Treatment of septic emboli depends mainly on source control of the originating infection and prolonged antibiotic therapy.

Pearls and Other Issues

• Septic emboli are a common complication of infective endocarditis.
• Septic emboli could affect multiple organs and cause variable insults.
• Blood cultures are usually positive in patients with septic emboli.
• Septic emboli cause tissue injury by two different mechanisms: ischemia and infection.
• The prognosis of septic emboli usually depends on source control of the underlying infection.

Enhancing Healthcare Team Outcomes

Septic emboli frequently pose a diagnostic dilemma due to variable organs affected with variable presentations. Management of septic emboli requires an interprofessional approach and varies based on the organ affected. The treating internist collaborates with a team of consultants that include: Cardiology for the diagnosis and management of the often underlying Infectious endocarditis. Infectious diseases consultants orchestrate the appropriate antimicrobial therapy along with source control of the underlying infection; cardiothoracic surgery is usually required based on the severity of infective endocarditis, the size of the vegetations for valvular resection and replacement and to manage other complications such as a valvular abscess or cardiac device extraction or aspiration thrombectomy.

Pulmonology has involvement in the management of septic pulmonary emboli, which potentially results in hypoxic respiratory failure requiring mechanical ventilation and critical care. Vascular surgery is necessary for endovascular infection control by removal of the infected indwelling catheters or grafts and extraction of the infected thrombi. Interventional neurology plays a role in septic cerebral emboli with endovascular extraction of the septic emboli.

Clinical pharmacists provide valuable insight into the choice of the antimicrobial based on its pharmacokinetics and pharmacodynamics due to the variety of organs and tissues involved in septic emboli, working with the clinicians from the latest antibiogram data available. Cardiology specialty-trained nursing staff can assist throughout the diagnostic and management process, administering medications, counseling patients, monitoring for treatment effectiveness as well as adverse reactions, and notifying the clinicians of any concerns they encounter. Open communication between all members and disciplines of the interprofessional team members is vital if one wants to improve outcomes.