«INFLAMMATORY PROTEINS, GENETIC VARIATION, AND ENVIRONMENTAL INFLUENCES ON HEALTH CARE ASSOCIATED INFECTION DEVELOPMENT IN SEPSIS A Dissertation ...»
Rates of infections vary but the most common hospital infections in descending order are urinary tract infection, surgical wound infection, lower respiratory tract infection, bacteremia, and others.41 Infections are generally classified as primary or secondary and the source may be endogenous or exogenous.41 The National Nosocomial Infections Surveillance (NNIS) System collects surveillance information across medical intensive care units in the United States. An analysis of NNIS data (n = 181,993) determined the most frequent types of HAI in the ICU were urinary tract infections (31%), pneumonia (27%), and primary bloodstream infection (19%) from surveillance data between 1992 and 1997.42 The most common pathogens reported were Coagulatenegative Staphylococcus, Staphylococcus aureus, and Enterococcus spp. The authors provide a comprehensive summary with percentages for each type of infection.
In contrast to the pattern of infections among all US ICU patients, a one day ICU prevalence study conducted in 1992 provides a similar pattern of infection types occurring in European ICU patients. In descending order, Vincent et al. reported the most common ICU infection as pneumonia (46.9%), lower respiratory tract infection (17.8%), UTI (17.6%), and bacteremia (12%) in a large European study of 10,038 subjects in 1,417 intensive care units with a total of 4051 infections.43 These authors reported the most common organism as Enterobacteriaceae (34.4%) followed by Staphylococcus aureus (30.1%), Pseudomonas aeruginosa (28.7%), Coagulate-negative Staphylococci (19.1%), and fungi (17.1%). Organisms were not reported for each type of infection separately.43 In a more recent study of a combined medical and surgical ICU, the most frequent infections (in descending order) were ventilator associated pneumonia, surgical site infection, lower respiratory tract infection, intrabdominal infection, sinusitis, soft tissue or skin infection, bacteremia, and finally, UTI.2 This study examined risk factors for mortality and organisms were not provided. The pattern of infections in the ICU varies.
The rates of NI may vary widely depending on the type of ICU and population served.
Eggiman and Pitet provide a comprehensive list of infection rates by type of ICU.40 The causative organism may not be detected in all infections and the rate of viral infections in the ICU may be underappreciated. There is evidence that despite causative organism type (gram negative, gram positive, polymicrobial, or fungal) the host’s inflammatory and coagulation response is similar in severe sepsis.12
Several factors in the ICU contribute to promoting antimicrobial resistance. These include (1) cross-transmission often caused by the urgency of care that may result in inconsistent aseptic technique or hand washing, (2) compromise of host defenses through the use of invasive devices which may become colonized, (3) the use of antibiotics.44 The emergence of antibiotic resistant organisms such as Methicillin resistant Staphylococcus aureus (MRSA), Vancomycin resistant Enterococcus, and other multidrug resistant organisms are major concerns.44-47 Caution in antibiotic prescribing in both the community and hospital setting has been advised. Only approximately 30% of antimicrobials used in hospitals are being given as definitive therapy for known infection associated pathogens based on microbiologic susceptibility.44 Cycling empiric antimicrobial therapy has been proposed to reduce antimicrobial resistance and has had favorable results in the susceptibility profile of gram positive but not gram negative organisms.48,49 The concept of antibiotic cycling to reduce antimicrobial resistance has been around since at least 1986.50 Since microorganisms are generally adaptive to their environment, limiting the introduction of particular antimicrobial for periods of time may help to decrease resistance patterns. There are few controlled trials published. A number of methods have been proposed to assist with cycling including the use of hospital formularies.51 The use of local antibiograms should be used to guide empiric therapy and antimicrobial therapy should be guided by susceptibility testing as soon possible since a delay in appropriate antimicrobial therapy worsens outcome. Antibiograms are frequently used to adjust antibiotics in the ICU; however, failure to use them in other settings is a contributor to antimicrobial resistance.52
Risk Factors for Developing HAI
Patients admitted to the ICU have an increased risk for developing HAI which may be related to underlying disease conditions, impaired immunity, invasive devices, inappropriate aseptic technique, or secondary infections after broad spectrum antibiotics.2 Eggimann identifies severity of illness, prolonged length of stay, and vascular access as independent risk factors for the development of HAI. He provides a thorough review of infection control practices in the ICU, and attributes most infections to inadequate infection control practice, and also implicates understaffing and overcrowding of the ICU as contributing factors.40 Genetic susceptibilities are known to increase the risk of developing infections;20,21 however, the influence of these genetic susceptibilities on development of subsequent HAI is unknown. Recommendations for standard practices to prevent the development of HAIs in the ICU have been reported by the Infectious Disease Society of America (IDSA), the Center for Disease Control (CDC), and others.53-57
Role of the ICU Environment and HAI
As noted in the prior sections, being a patient in the ICU presents several inherent risks factors for the development of HAI including: presence of invasive devices, use of broad spectrum antibiotics, use of blood products, and generally more physical contact with the health care team administering care. A standard patient to nurse ratio for most critical care units is 2:1 depending upon patient acuity. The implementation of open visitation in the ICU has the potential to introduce additional risk of cross-contamination to this vulnerable population. Appropriate hand hygiene is essential to prevent crosscontamination, in addition the CDC reports the potential role of HAI transmission by health care provides wearing rings and long or artificial nails.58 Routine isolation practices are used when any multi-drug resistant organism is detected.59 The floors are mopped and cleaned daily as well as between patients according to CDC guidelines.60 The areas closest to the patient including the bed side rails, bed controls, bedside tray, and call light are typically only cleaned between patients unless soiled and may represent items that needs to be targeted for more frequent cleaning.
Severity of Illness
Severity of illness can be quantified by using the Acute Physiology and Chronic Health Evaluation (APACHE) II, a composite score that ranks a patient’s worst physiologic functioning within the first 24 hours of ICU admission.38 The APACHE II is in the public domain and was used for this study. Severity of illness has been investigated as a risk factor for developing HAI. Girou et al, conducted a retrospective case-control study (n = 82) with 1:1 matching based on initial severity of illness using APACHE II and also obtained serial APACHE II scores to determine the influence of severity of illness on development of infections. Among several variables assessed, they identified day three APACHE II score as significantly higher in the cases (p = 0.04).61 All patients had similar APACHE II scores at baseline, and worsening of APACHE II score provides evidence of worsening severity of illness among those who developed HAI. In contrast, Vincent et al, in a one day prevalence study across 17 European ICUs (n = 10,038), identified a high APACHE II score of greater than 31 to be independently associated with risk of mortality; however, they reported the highest HAI rates in patients with APACHE II scores ranging from 11-20.43
Invasive devices bypass the body’s first line of defense, the integument, and may lead to infection if penetrating organisms are not promptly sequestered by the innate immune system.25 Common invasive devices in the ICU include endotracheal tubes, central venous catheters, peripheral venous catheters, arterial catheters, chest tubes, nasal feeding tubes, and Foley catheters. Several studies have been published describing the relationship between invasive devices and infections.8,40,42,53,62-64 In many cases HAIs are used as a benchmark for quality of care, and Maki suggests that peripheral intravenous catheters (previously considered low risk) should begin to be targeted by infection control practices to reduce invasive device related infections.64 The use of antibiotic impregnated devices and targeted strategies have helped to reduce the rates of invasive devise related infections.65,66 Invasive devices may be colonized with bacteria or fungi through biofilm formation. Biofilms generally forms when microorganisms adhere to invasive devices which provide them with an environment capable of evading antibiotics. They initially adhere to the foreign surface and then begin to secrete extracellular polymeric substance (EPS) to protect formation of the biofilm and attract other organisms. The microorganisms within a biofilm exhibit different physiologic and growth characteristics than do free floating (or planktonic) organisms.67 They use quorum sensing to communicate and control the gene expression of other organisms within the biofilm, and to control each phase of biofilm formation: attachment, cell-to-cell aggregation, proliferation, EPS production, grown, and detachment or degradation.68 Acute infections are generally caused by the planktonic (free floating micro-organisms) but the role of biofilm formation on chronic and acute infection is an area of research.67,69,70
Systemic Inflammatory Response Syndrome
The body is subject to a variety of insults daily and the immune system is usually able to isolate and clear potential pathogens without systemic effects. When the body is not able to maintain inflammation at the local level, inflammation becomes systemic. The systemic inflammatory response syndrome (SIRS) is the clinical manifestation of the body’s host defense response to a variety of insults and initially manifests in at least two of four major organ systems (cardiovascular, hematopoietic, neurologic, and respiratory system). These insults can be infectious or noninfectious in nature. Noninfectious insults include pancreatitis, burns, trauma, tissue ischemia or necrosis, massive transfusion, chemical aspiration, foreign bodies, and immune hypersensitivity reactions.29,71,72 The goal of the inflammatory response is to control the initial insult or injury.
Three primary responses (vascular, neutrophil, and plasma protein) function to increase blood flow to the affected area, increase vascular permeability to allow leukocytes and plasma proteins into the site of injury or infection.71 SIRS is a dysregulated inflammatory response caused by activation of inflammatory cells. It is a generalized response regardless of the type of insult. This dysregulated inflammatory response leads to generalized systemic inflammation, damaged vascular endothelium, altered immune function, fluid shifts, and organ hypoperfusion.71 If this process is not controlled, it can progress to multiple organ dysfunction syndrome.71 SIRS occurs in approximately one third of all hospitalized patients and one half of ICU patients.71
Cytokines are produced by a variety of cells (lymphocytes, macrophages, epithelium, endothelium, connective tissue, adopocytes, and myocytes) which modulate the function of other cell types.72 Cytokines are pleotropic which means that one cytokine can act on a number of cell types and have many effects.73 They have autocrine, paracrine, and endocrine effects. Cytokines play a role in both acute and chronic infections.72 Activated lymphocytes and macrophages are their primary secretor.
Cytokines are not stored in their active states in the cell. Their production requires new mRNA and protein synthesis. Most are encoded as pro-peptides, transported to the Golgi body for glycosylation, and secretion as smaller mature cytokine proteins.74 A growing number of cytokines are still being discovered. Interleukins mediate communication between leukocytes. IL-1β and TNF-α promote the acute inflammatory response, thus they are typically referred to as pro-inflammatory cytokines. IL-6 is another potent inducer of the acute inflammatory response. It stimulates the liver to release acute phase proteins. Although IL-6 is often referred to in the literature as a proinflammatory cytokine, evidence is accumulating regarding its’ anti-inflammatory properties. IL-6 inhibiting effects of IL-1β and TNF-α.75 IL1-ra and IL-10 are both know as anti-inflammatory cytokines. Table 2-1 summarizes the function of well known pro- and anti-inflammatory cytokines.
HAI Risk Posed by the Inflammatory Response
There is some evidence that cytokines may enhance extracellar and intracellular growth of bacteria76-79 and that anti-inflammatory cytokines may promote the development of infections.11,80 Kanangat et al. found, in an in vitro model, that monocytes that were primed with higher levels of proinflammatory cytokines experienced higher levels of intracellular bacterial growth; whereas monocytes primed with lower levels of proinflammatory cytokines experienced lower levels of intracellular bacterial growth.77 In another in-vitro study, Kanangat also found that cytokines enhanced the extracellular growth of Staphylococcus aureus.76 Because of the complexity of the inflammatory response which includes redundancy of the inflammatory networks, competing feedback loops, and simultaneous amplification pathways35, it is uncertain that a relationship that exists in-vitro will exist in-vivo.
It is possible that high levels of cytokines function as bacterial growth factors76-79 or that anti-inflammatory cytokines may promote the development of infections.11,80 It is also possible that an exaggerated inflammatory response may promote HIAs by inhibition Table 2-1. Summary of Cytokine Function.