Healthy individuals with an intact immune system are able to mount a normal immune response to a microbe exposure, preventing colonization of the host. Patients with cancer are at a significantly increased risk for infection because their immune response is impaired as a result of the malignant process and its treatment. As a complication in patients with cancer, infection frequently leads to sepsis and prolongs hospitalization.
The pathophysiologic progression of infection to sepsis to multiorgan dysfunction syndrome (MODS) is a continuum of an inflammatory response to a microbial invasion that becomes increasingly pathologic as organ dysfunction progresses. In 1992, the American College of Chest Physicians and the Society of Critical Care Medicine Consensus Panel defined the various stages of sepsis.
Infection
Infection is an inflammatory response to the presence of microbes; invasion of normally sterile host tissue by these organisms is characteristic. Infection is the most significant complication of cancer therapy and a major cause of sepsis.
A presumed or known site of infection is indicated by one of the following:
• Purulent sputum or respiratory sample, or a chest x-ray film showing new infiltrates not explained by a noninfectious process.
• Spillage of bowel contents noted during an operation.
• Radiographic or physical exam evidence of an infected collection.
• WBCs in a normally sterile body fluid.
• Positive blood culture.
• Physical exam or x-ray film evidence of infected mechanical hardware.
Bacteremia
Bacteremia is the presence of viable bacteria in the blood. The most prevalent organisms in cancer are coagulase-negative staphylococci, viridans group streptococci, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Predisposing factors for nosocomial bacteremias (within 48 hours), in order of occurrence, are the presence of a central venous access device (VAD), peripheral VAD, or urinary catheter; administration of total parenteral nutrition (TPN); intensive care unit (ICU) stay; ventilator support; presence of an arterial line; and dialysis. No significant seasonal or geographic patterns of bacteremia are apparent in the oncology population (Wisplinghoff et al., 2003).
Systemic Inflammatory Response Syndrome
Systemic inflammatory response syndrome (SIRS) is a nonspecific inflammatory process that may follow a variety of clinical insults, including trauma, infection, burns, pancreatitis, ischemia, hemorrhagic shock, or immune-mediated diseases, The inflammatory reaction exceeds local mechanisms of containment, and inflammatory mediators invade the bloodstream, causing systemic disturbances.
Evidence of a systemic inflammatory response includes at least two or more of the following:
• Fever or hypothermia: Core body temperature of 38° C or higher or 36° C or lower.
• Tachypnea: Respiratory rate of 20 breaths/min or higher, or the need for mechanical ventilation for an acute process.
• Tachycardia: HR of 90 beats/min or higher, unless the patient has a pre-existing tachycardia.
• WBCs: WBC count of 12,000 cells/mm3 or higher, or 4000 cells/mm3 or lower, or greater than 10% bands on differential.
Sepsis
Sepsis is a systemic response to infection or SIRS. It is an autodestructive process of malignant intravascular inflammation that permits extension of the normal pathophysiologic response to infection.
Severe Sepsis (Septic Shock)
Severe sepsis, or septic shock, is sepsis with hypotension (systolic BP less than 90 mm Hg or a reduction of 40 mm Hg from baseline) despite adequate fluid resuscitation. Vasoactive mediators and nitric oxide cause vasodilation and increase vascular permeability, which results in widespread interstitial edema. Changes in both systolic and diastolic function by myocardial depressant substances result in perfusion abnormalities, as evidenced by acidosis, oliguria, and obtundation. Patients with pre-existing cardiac disease are unable to increase cardiac output appropriately, and venous return is diminished. All these events result in profound hypotension.
Multiorgan Dysfunction Syndrome
Multiorgan dysfunction syndrome is the presence of altered organ function in a patient who is acutely ill such that homeostasis cannot be maintained without intervention. Primary MODS is the direct result of a well-defined insult in which dysfunction occurs early and can be directly attributed to the insult itself. Secondary MODS develops as a consequence of a host response and is identified within the context of SIRS.
Sepsis-induced organ failure is indicated by one of the following criteria:
• Cardiovascular dysfunction: Mean arterial pressure (MAP) equal to or less than 60 mm Hg; need for vasopressors to maintain this blood pressure despite adequate intravascular volume (CVP greater than 8 cm H2O or PAOP greater than 12 torr) or after an adequate fluid challenge.
• Respiratory organ failure: PaO2/FiO2 ratio less then 250 in the absence of pneumonia or less than 200 with pneumonia.
• Hematologic dysfunction: Thrombocytopenia, with 80,000 platelets/mm3, a 50% drop in the previous 3 days, or an INR greater than 1.2 that cannot be explained by liver disease or concomitant warfarin use.
• Unexplained metabolic acidosis: pH less than 7.3 and plasma lactate greater than 1.5 times the upper limit of normal for the lab.
Bacteria are the pathogens most commonly associated with sepsis, but fungi, viruses, and parasites may also be the culprits, particularly in patients with prolonged immunosuppression. The outer membrane components of both gram-negative bacteria (endotoxin, lipid A, lipopolysaccharide) and gram-positive bacteria (peptidoglycan) initiate the pathophysiology of sepsis by binding to the CD14 toll-like receptors on the surface of monocytes. This sends a signal to the cell, leading to the production of proinflammatory cytokines (TNF alpha and IL-1). These cytokines have a toxic effect on tissues and also activate phospholipase, which leads to further tissue damage. Cytokines promote nitric oxide production, tissue infiltration by neutrophils, generation of oxygen free radicals, and increased concentrations of platelet-activating factor. IL-1 and TNF also have direct effects on the endothelial surface of cells; as a result of these inflammatory cytokines, tissue factor, which is the first step in the extrinsic pathway of coagulation, is activated. Tissue factor leads to the production of thrombin, which also is a proinflammatory substance. Thrombin results in fibrin clots in the microvasculature, leading to decreased tissue perfusion. IL-1 and TNF alpha also lead to the production of plasminogen activator inhibitor-1, a potent inhibitor of fibrinolysis.
Proinflammatory cytokines also disrupt the body’s modulators of coagulation and inflammation, activated protein C and antithrombin. Activated protein C has direct antiinflammatory properties, such as inhibiting production of proinflammatory cytokines and inhibiting leukocyte adhesion and neutrophil accumulation. Although neutrophils are essential for the eradication of pathogens, excessive release of oxidants and proteases by neutrophils is also believed to be responsible for injury to organs, particularly the lungs.
Antithrombin inhibits thrombin production at multiple steps in the coagulation cascade. Binding of antithrombin to the surface of endothelial cells leads to the production of the antiinflammatory molecule prostacyclin. This accounts for the fact that sepsis initially is characterized by increases in inflammatory mediators but, as the sepsis persists, a shift occurs toward an antiinflammatory immunosuppressive state.
Apoptotic cell death may trigger sepsis-induced anergy, a state of nonresponsiveness to an antigen, and cytokine release. A potential mechanism of lymphocyte apoptosis may be stress-induced endogenous release of glucocorticoids. Large numbers of lymphocytes and gastrointestinal epithelial cells die by apoptosis during sepsis. A second wave of bacterial multiplication (known as the second hit) occurs in late sepsis, 4 to 5 days after the initial insult, that is related to this immune dysfunction and intestinal translocation of bacteria. Autopsy studies in people who died of sepsis have shown a profound apoptosis-induced loss of cells of the adaptive immune system (i.e., B cells, CD4 T cells, and follicular dendritic cells), cells that should have proliferated during life-threatening infection. These cells are responsible for antibody production, macrophage activation, and antigen presentation.
This vicious cycle of inflammation and coagulation, if unchecked, leads to cardiovascular insufficiency. TNF exerts a myocardial-depressant effect, as well as promoting vasodilation and capillary leakage (LaRosa, 2002). Additional organ systems fail as a result of poor perfusion. Autopsy studies reveal a discordance between histologic findings and the degree of organ dysfunction. It is speculated that organ dysfunction in sepsis is due to “cell stunning,” or hibernation, rather than cellular necrosis. This explains why patients who survive sepsis with associated organ dysfunction can return to baseline function. (Hotchkiss & Karl, 2003).
EPIDEMIOLOGY AND ETIOLOGY
Nosocomial bacteremias are the thirteenth leading cause of death in the United States, with approximately 250,000 cases reported annually; this represents a 78% increase in the past two decades. Of these patients with bacteremias, 10% have an underlying malignancy. Gram-positive organisms account for 60% to 75% of bacteremias in patients with cancer, and gram-negative organisms for 14% to 22%; 30% to 35% of bacteremic patients are neutropenic.
In 2004, critical care and infectious disease experts representing 11 international organizations developed management guidelines for severe sepsis and septic shock for practical use by the bedside clinician. This was an international effort to increase awareness and improve the outcome in severe sepsis. A set of core changes extracted from these guidelines have been incorporated into a package of key elements or goals that, when introduced into clinical practice, have a high likelihood of reducing mortality from severe sepsis. The package is referred to as the sepsis bundle (Levy et al., 2004). Areas addressed in the sepsis bundle include initial resuscitation, diagnosis, antibiotic therapy, source control, fluid therapy, vasopressors, inotropic therapy, steroids, recombinant human activated protein C (Xigris), blood product administration, mechanical ventilation of sepsis-induced acute lung injury with sedation, analgesia, and neuromuscular blockade guidelines, glucose control, renal replacement therapy, DVT prophylaxis, stress ulcer prophylaxis, consideration for limitation of support, and pediatric considerations (Dellinger et al., 2004).
According to Cross and Opal (2003), “Given the likelihood that many processes in the complex pathophysiology of sepsis are simultaneously activated, it is unlikely that therapy directed at one of them will dramatically improve survival; rather, a combination of therapies directed at many arms of the septic process, much like the strategy used for cancer and HIV, is required.”
RISK PROFILE
The exact process that occurs after an infectious insult is still the subject of many studies.
• Cancers: Patients with hematologic malignancies, acute and chronic leukemias (especially in pediatric patients), lymphomas, Hodgkin’s disease, and multiple myeloma have an increased risk of infection. The solid tumor malignancies most frequently associated with infection include lung and bronchus cancers (most common) and colon, esophageal, gastric, head and neck, lung, melanoma, and ovarian cancers.
• Conditions: An absolute neutrophil count of 500/mm3, prolonged neutropenia, marrow-suppressive chemotherapy regimens, radiation therapy, gastrointestinal surgery, loss of mucosal or skin integrity, foreign bodies (e.g., VADs, stents, or catheters), poor nutritional status, poor performance status, the very young or elderly, and the existence of co-morbidities (e.g., collagen vascular diseases; diabetes; and respiratory, cardiac, or renal diseases), particularly if treatment includes glucocorticosteroids (Lyman, et al., 2005; Khan & Wingard, 2001).
• Environment: Neutropenic patients are more susceptible to pathogens in the air, water, food, and animals.
• Chemotherapy medications: Antineoplastics associated with moderate (grade III) neutropenic toxicity include 5-fluorouracil (greater than 500 mg/m2), arsenic trioxide, BCNU, bleomycin, cisplatin (greater than 100 mg/m2), dacarbazine, doxorubicin (greater than 50 mg/m2), gemcitabine, ifosfamide (greater than 1 g/m2), Gleevec (greater than 400 mg/day), lomustine, mechlorethamine, melphalan, procarbazine, vinblastine, and vincristine. Antineoplastics associated with severe (grade IV) neutropenic toxicity include 6-mercaptopurine, 6-thioguanine, Campath, busulfan, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, epirubicin, etoposide (greater than 200 mg/m2), fludarabine, Mylotarg, hydroxyurea, idarubicin, irinotecan, mitoxantrone, paclitaxel, topotecan, ATRA, and vinorelbine.
• Other medications: Other medications that may cause mild neutropenia include acetaminophen, allopurinol, amiodarone, aminophylline, amoxicillin, ace inhibitors, cephalosporins, cimetidine, clindamycin, Dilantin, Bactrim, Flagyl, ganciclovir, gentamicin, haloperidol, HCTZ, ibuprofen, Keppra, NNRTIs, nifedipine, nitrofurantoin, norfloxacin, omeprazole, Phenergan, ranitidine, rifampin, Ritalin, Sinemet, spironolactone, sulfonylurea derivatives, Tegretol, valproate. Combinations of any of these medications may have a synergistic effect on the bone marrow.
• Elderly patients: Many patients have multiple risk factors that exponentially increase their risk for the development of sepsis. The elderly, in particular, have poorer outcomes because of an increased incidence of hematologic malignancies, a higher degree of co-morbidity, and excessive toxicity and complications related to treatment (Norgaard et al., 2005).
PROGNOSIS
The mortality rate for patients with bacteremia who are neutropenic is 30% to 36%. According to Donowitz and colleagues (2001), “Infection in the neutropenic patient has remained a major challenge for over three decades.”
Sepsis is the major cause of mortality worldwide. In the United States, the incidence of severe sepsis is approximately 800,000 cases per year, with a mortality rate ranging from 30% to 50%, depending on the population studied. Sepsis among all patient populations is increasing by an average of 16% per year in the United States, accounting for more than $15 billion in health care costs annually. Severe sepsis is a costly complication of cancer treatment, resulting in approximately 5% of cancer hospitalizations and 8% to 10% of cancer deaths per year at a cost exceeding $3.5 billion annually. Patients with cancer are nearly four times as likely to be hospitalized with severe sepsis than patients without cancer, and patients with hematologic malignancies are 15 times more likely to develop severe sepsis than the general population.
PROFESSIONAL ASSESSMENT CRITERIA (PAC)
1. According to Cohen and colleagues (2004), obtaining a precise bacteriologic diagnosis is paramount for the success of therapeutic strategy during sepsis (see the following table).
2. The admission test for a neutropenic fever should include a comprehensive chemistry panel, CBC with diff, coags, source control by appropriate cultures (peripheral blood and VAD samples, urine, sputum, and wound drainage), and CXR and other radiographic procedures as indicated for source identification.
3. If sepsis is suspected, d-dimer and fibrinogen, lactate, troponin, and ABG tests should be added.
A cortisol stimulation test is indicated for any patient with refractory hypotension (Manglik et al., 2003).
4. Other possible procedures include a right upper quadrant (RUQ) ultrasound to rule out cholecystitis, transduced bladder pressure for detection of abdominal compartment syndrome, pan-CT scanning as indicated, and LP if neurologic symptoms persist (Cohen et al., 2004).
6. Neopterin is useful in the diagnosis of viral infection.
7. An endotoxin assay in combination with CRP, PCT, or neopterin may aid the diagnosis of gram-negative bacterial infection (Mitaka, 2005).
8. The most common sources of neutropenic fever should be evaluated; this includes inspection of any catheter, VAD, or drainage site; evaluation for mucositis, a common risk factor for bacterial and fungal infections, including oral and perineal inspection (Khan & Wingard, 2001); and targeted H & P for pharyngitis, gastroenteritis, cellulitis, DVT, and respiratory infection (Perrone et al., 2004).
| Localized Infection | Sepsis (Generalized Infection) | Septic Shock | MODS |
| Vital Signs/Labs | |||
| Fever, chills, malaise, BP may be slightly ↑ + Cultures, ↑ ESR, procalcitonin < 1.5 ng/mL, ↑ thyroid hormones | Fever, BP ↓ ↑ Lactate, ↑ C-reactive protein, ↓ phos phate, procalcitonin 30-150 ng/mL, ↓ thyroid hormones, ↓ Mg | Fever or hypother mia, BP ↓↓ ↑↑ Lactate, ↑ anion gap, ↓ cortisol, ↓albumin, ↑ serum and urine myoglobin, procalcitonin > 150 ng/mL, ↑ troponin, ↑ alk phos | Loss of thermal regulation ↓ Calcium |
| Neurologic Findings | |||
| Headache, meningismus, photophobia (meningitis, encephalitis) | Intellectual impairment, anxiety, agitation | Confusion, obtunda tion, tremors | Coma, seizures |
| Respiratory Findings | |||
| Cough, rales, infiltrates, pleuritic chest pain, DOE (pneumonia) Adenopathy, headache, nasal discharge, sore throat (sinusitis, pharyngitis) | ↓ PaO2, requiring supplemental oxygen, ↓ PaCO2, tachypnea, shortness of breath | Hypoxia, hypercarbia, effusions, atelecta sis, respiratory acidosis, pulmonary capillary leakage; ventilatory support usually required | Apnea, vent- dependent, refractory hypoxia, PEEP, ↑ FiO2 requirement (ARDS) |
| Cardiovascular Findings | |||
| Tachycardia, regurgitant murmur (endocarditis) | Tachycardia, periph eral edema secondary to capillary leakage, hyperdy namic state: ↑ CO and EF, ↓ SVR | Dysrhythmias, fluid refractory hypoten sion, vasopressors necessary to support BP, sluggish CRTs | Vasopressor refractory hypo tension, need for multiple agents to support BP, ↓ EF, anasarca |
| Gastrointestinal/Hepatic Findings | |||
| Abdominal pain, diarrhea, nausea, vomiting, ↑ amylase and lipase (mucositis, enteritis, pancreatitis, cholecystitis) | Gastroparesis, ↓ bowel sounds, intolerance of enteral intake, abdominal distention, ↑bilirubin | Ileus, stress ulcer, translocation of gut bacteria, mesenteric ischemia (second hit) ↑ LFTs (shock liver) | GI bleeding, ascites, stasis cholecystitis, bowel perforation, LFTs may return to normal, ↑↑ bilirubin, ↑ coags (liver failure) |
| Renal Findings | |||
| Dysuria, cloudy urine, CVA tenderness (UTI) | Oliguria or high- output ATN, ↓HCO3–, ↑ BUN and creatinine, proteinuria, ↑ K | Anuria, ↓↓ HCO3– (ARF, Metabolic acidosis) | Dialysis dependent ARF, refractory acidosis |
| Dermatologic/Musculoskeletal Findings | |||
Erythema, induration, edema, local tenderness, pus (unless neutropenic) (cellulitis) Diaphoretic | Flushed, hot Myalgias | Petechiae, purpura; skin may be cold, clammy, mottled, jaundiced (rhabdomyolysis) | Diminished skin integrity; tissue necrosis; cool, clammy; pallor; cyanotic Muscle weakness |
| Hematologic Findings | |||
| ↑ WBC with left shift (unless neutropenic) | ↑ Platelets, ↑ fibrinogen Xigris may be beneficial | + D-dimer, ↓ fibrinogen ↑ DVT risk (DIC) | Bleeding from puncture sights, Relative pancytopenia |
| Endocrine Findings | |||
| ↓ or ↑ in blood sugar | Labile blood sugar, may require exog enous insulin | Stress-induced adre nal insufficiency may require exogenous steroids; hyperglycemia may require insulin drip (shock pancreas) | Refractory glucose control despite insulin drip (necrotizing pancreatitis) |
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