Host Factors

The host is defined by genotype, expressed phenotypically as characteristic traits. Innate immunity provides continuous surveillance against tissue invasion by foreign antigens in the interstitial spaces just beneath epithelial barriers. Potential pathogens are ubiquitous in the environment, but although colonization of epithelia occurs even in healthy hosts, invasion generally requires a portal of entry, which for surgical patients might include injured tissue, incision, puncture site for vascular access, or indwelling catheter. Injury also stimulates a repair response (inflammation), which may cause a wide-ranging autodestructive augmentation of the inflammatory response.

The phenotypic stress response augments cardiovascular function through the autonomic nervous system, promotes glycogenolysis, catabolizes peripheral lean tissue and fat for gluconeogenesis, enhances coagulation to stanch hemorrhage, and stimulates a proinflammatory cytokine response to begin the tissue repair process (Box 12-1).¹ Innate and adaptive immunity are depressed in large part by the actions of cortisol (Table 12-1 and Box 12-2).²

Table 12-1 Principal Hormonal Responses to Surgical Stress

Older age (generally, age ≥65 years) is a definite risk factor for adverse outcomes from infection,³ related to immune senescence and an increased incidence of nosocomial infection. Hyperglycemia induces immune cell dysfunction (Box 12-3) and is a recognized risk factor for infection (Box 12-4). Even transitory hyperglycemia is associated with an increased risk of SSIs^4–7 and other nosocomial infections, and translates into increased mortality after trauma^8,9 and critical surgical illness^10,11 for diabetic and nondiabetic patients.

Genetics and Genomics of Trauma and Sepsis

It is controversial as to whether gender makes a difference in outcome following infection and sepsis. Androgens are immunosuppressive in vitro and in animal studies, and male animals have higher mortality after trauma and sepsis,^12,13 but human data are conflicting. Population-based studies have cast doubt on the clinical importance of the laboratory observations of gender-based differences. Gannon and colleagues¹⁴ have found no gender-based difference of mortality among 18,892 trauma patients; of interest, males were more likely to develop pneumonia, but females were more likely to succumb. Angus and associates¹⁵ were unable to detect any adverse outcomes from sepsis among females in a nationwide U.S. population-based study.

Modern high-throughput, multiplexed assays allow the molecular characterization of pathologic conditions. Most genes have hundreds or thousands of nucleotides, but only a relatively short sequence is needed for the precise identification of each. The DNA microarray, minute quantities of vast numbers (i.e., many thousands) of short, gene-specific probe nucleotides affixed to a slide chip can be used to identify messenger RNA that can be isolated from cells or tissues and labeled to produce complimentary nucleotides (cDNA or cRNA). When incubated with the microarray, the cDNA or cRNA will bind by conventional base pairing. With a scanner and the aid of computational biomedicine, the label signal intensity (mRNA abundance) may be calculated and compared, generating an expression profile called the transcriptome for the cell or tissue of interest. Such techniques have furthered the understanding of host predisposition and response to sepsis^16,17; application of related techniques of cell separation, genome-wide expression, and cell-specific pathway analyses may be useful to characterize alterations in human disease or the presence of specific microbes. However, their presence does not distinguish whether the microbe is a colonist or a pathogen.

In infection, genomic variability may correlate with disease susceptibility. Single nucleotide polymorphisms (SNPs), single point mutations in the nucleotide structures of genes related to inflammation (e.g., tumor necrosis factor-α [TNF-α], interleukin [IL]-1, -6, and -8), the anti-inflammatory response (e.g., IL-10, IL-1 receptor antagonist), the innate immune response (e.g., Toll-like receptor 4), and the coagulation system (e.g., factor V, plasminogen activator inhibitor-1) have been associated with a predisposition to sepsis.¹⁸ However, heterogeneity in the immune response and predisposition to infection, as well as the severity of infections and resultant mortality, make conclusions difficult to determine, which makes it unlikely that a single SNP will be identifiable in an individual patient to characterize risk.

Interactions Between the Host and Therapy

The risk of infection may exist as the result of injury itself, impairment of host defenses, resuscitation, or definitive care. Hypothermia may occur as the result of exposure, large-volume infusion of unwarmed fluids or blood products, or evaporative losses during intracavitary surgery, especially if the chest and abdomen are opened. Peripheral and cutaneous vasoconstriction occur to preserve core heat, but vasoconstriction decreases microcirculatory blood flow, which may also be disrupted by hypovolemia, inflammatory response, activation of coagulation, and decreased deformability of transfused red blood cells (see below).¹⁹ Hypothermia is immunosuppressive, affects cardiovascular performance adversely, and increases mortality after trauma and surgery.^20,21

Tissue hypoxia after trauma may result from injury to the face, airways, lungs, or chest wall, inability to secure the airway, massive blood loss, cardiovascular instability, disruption of the microcirculation, or acute respiratory distress syndrome (ARDS). Tissue hypoxia appears to predispose to SSI.²² Administration of supplemental oxygen (FIO₂ = 0.8) reduces the risk of SSI after elective surgery (meta-analysis).²¹

The manner of resuscitation may influence outcome. Fluids are necessary to restore hemodynamics and microcirculatory perfusion, but the quantity and type of fluid that should be administered is still debated. Historically, crystalloid fluids were preferred to colloids, being less expensive and with results that were at least equivalent.²³ Although some trials, such as that of the SAFE investigators,²⁴ have led to a reappraisal, the question remains controversial. Delaney and coworkers²⁵ have conducted a meta-analysis of 17 trials (1977 subjects); eight trials were specifically of colloid versus crystalloid for resuscitation of patients with sepsis. Using a fixed effects model, colloid resuscitation was associated with reduced mortality (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.67 to 1.0; P = 0.047), but not when a more robust random effects model was used for the meta-analysis (OR, 0.84; 95% CI, 0.69 to 1.02; P = 0.08). However, six of the trials included, by a single investigator, have been called into question for scientific misconduct²⁶; omission of those results from the meta-analysis still produced a significant result by fixed effects meta-analysis (OR, 0.76; 95% CI, 0.62 to 0.95; P = 0.015). Functionally, resuscitation of the immune system may be the crucial determinant, as evidenced by observations that a persistent systemic inflammatory response after injury is associated with an increased risk of nosocomial infection and death.²⁷

Catheter Care

Optimal catheter care includes avoidance when unnecessary, appropriate skin preparation and barrier protection during insertion, proper catheter selection (e.g., antimicrobial- or antiseptic-coated), proper dressing of indwelling catheters, and removal as soon as no longer needed, or as is practicable, but no longer than 24 hours, after insertion under less than ideal circumstances (e.g., trauma bay, cardiac resuscitation).

Risks and benefits must be weighed when deciding to place any catheter, including the risk of infection. Almost all indwelling catheters carry such a risk, but nontunneled central venous catheters and pulmonary artery catheters pose the highest risk, including local site infections and CLABSIs. Other catheters that pose increased infection risk include endotracheal tubes, intercostal thoracostomy catheters (inserted as an emergency), ventriculostomy catheters for intracranial pressure monitoring, and urinary bladder catheters. Each day of endotracheal intubation and mechanical ventilation increases the risk of pneumonia by 1% to 3%⁵⁴; it is controversial whether tracheostomy decreases that risk.⁵⁵

Chlorhexidine gluconate, a phenolic biguanidine derivative, is used in concentrations of 0.5% to 4.0% alone or in lower concentrations in combination with an alcohol as a skin antiseptic. The microbicidal action, which is bactericidal, viricidal, and fungicidal, is somewhat slow, but persistent. Chlorhexidine should be used preferentially for skin preparation for vascular catheter insertion; it is superior to povidone-iodine solution⁵⁶ and is also recommended for surgical skin preparation,⁵⁷ topical bathing of critically ill patients,^58,59 and as an antiseptic coating for indwelling central vascular catheters.⁶⁰ If povidone-iodine solution is used for surgical site preparation, it must be allowed to dry for microbicidal effect. Note that its use is discouraged unless a mucous membrane is to be prepped. Full barrier precautions are mandatory for all bedside catheterization procedures, except arterial and urinary bladder catheterization, for which sterile gloves and a sterile field suffice if maintained meticulously. Whenever a central venous catheter is inserted under suboptimal conditions, it must be removed—and replaced at a different site if still needed—as soon as permitted by the patient’s hemodynamic status, but no longer than 24 hours after insertion. A single dose of a first-generation cephalosporin (e.g., cefazolin) may prevent some infections following emergency tube thoracostomy or ventriculostomy, but is not indicated for vascular or bladder catheterizations.

It is crucial to maintain dressings carefully, which can be challenging if the patient is agitated or the body surface is irregular (e.g., the neck [internal jugular vein catheterization] as opposed to the chest wall [subclavian vein catheterization]). Marking the dressing clearly with the date and time of each change is simple and effective. Dressing carts or similar equipment should not be brought from patient to patient; instead, sufficient supplies should be kept in each patient’s room. The potential for transmission of pathogens on inanimate fomites (e.g., scissors) must be borne in mind. Implementation of care bundles and dedicated catheter care teams substantially reduces the risk of CLABSIs and UTIs.^61,62

The choice of catheter may play a role in decreasing the risk of infection related to endotracheal tubes, central venous catheters, and urinary catheters. Continuous aspiration of subglottic secretions (CASS) via an endotracheal tube with an extra lumen that opens to the airway just above the balloon facilitates the removal of secretions that accumulate below the vocal cords but above the endotracheal tube balloon, an area that cannot be reached by routine suctioning. The incidence of VAP is decreased by 50% by CASS.⁶³ Silver-impregnated endotracheal tubes are effective in reducing airway colonization⁶⁴ and may reduce the incidences of VAP and mortality.⁶⁵ Antibiotic-coated (e.g., minocycline/rifampin) or antiseptic-coated central venous catheters (e.g., chlorhexidine, silver sulfadiazine) can reduce the incidence of catheter-related bloodstream infections (CRBSIs),^44,66 especially in high-prevalence units; minocycline- or rifampin-coated catheters may be more effective. Urinary bladder catheters coated with ionic silver reduce the incidence of catheter-related bacterial cystitis by a similar amount.^67,68

Ventilator weaning by protocol, including daily sedation holidays and spontaneous breathing trials, allows endotracheal extubation sooner and decreases the risk of VAP (see later).⁶⁹ An even better strategy may be avoidance of endotracheal intubation entirely. Respiratory failure can sometimes be managed with noninvasive positive-pressure ventilation delivered by mask (e.g., continuous positive airway pressure [CPAP]).⁷⁰ Improved resuscitation and noninvasive monitoring techniques have decreased the utilization of pulmonary artery catheters, which pose a particularly high risk of infection.⁷¹ Most drains do not decrease the risk of infection; in fact, the risk is probably increased⁷² because the catheters hold open a portal for invasion by bacteria.

Surgical Site Infection

The spectrum of bacterial contamination of the surgical site is well described.⁷² Clean surgical procedures affect only skin structures and other soft tissues. Clean-contaminated procedures open a hollow viscus under controlled circumstances (e.g., elective aerodigestive or genitourinary tract surgery). Contaminated procedures introduce a large inoculum of bacteria into a normally sterile body cavity, but too briefly for infection to become established during surgery (e.g., penetrating abdominal trauma, enterotomy during adhesiolysis for mechanical bowel obstruction). Dirty procedures are those performed to control established infection (e.g., colon resection for perforated diverticulitis).

The microbiology of SSI depends on the nature of the procedure, location of the incision, and whether a body cavity or hollow viscus is entered during surgery. Most SSIs are caused by skin flora that are inoculated into the incision during surgery, therefore, the most common SSI pathogens are all gram-positive cocci—Staphylococcus epidermidis, S. aureus, and Enterococcus spp. For infrainguinal incisions and intracavitary surgery, gram-negative bacilli such as Escherichia coli and Klebsiella spp. are potential pathogens. When surgery is performed on the pharynx, lower gastrointestinal tract, or female genital tract, anaerobic bacteria become potential SSI pathogens. Antibiotic prophylaxis should be suitably directed against likely pathogens (see later).

The incidence of SSIs has been estimated to be about 3% in the United States, although the incidence varies greatly from less than 5% for clean surgery to more than 20% for emergency colon surgery, which is often performed in a dirty field. Moreover, the overall estimate is almost certainly an underestimate, considering that SSI following ambulatory surgery, which now represents more than 70% of all operations in the United States, is seldom reported. Numerous factors determine whether a patient will develop an SSI, including those related to the patient, environment, and treatment (Box 12-5).⁷² As incorporated in the National Nosocomial Infections Surveillance System (NNIS) and its successor program, the National Healthcare Safety Network (NHSN),^73–75 the most recognized factors are wound classification, American Society of Anesthesiologists class 3 or higher (class 3 is chronic active medical illness), and prolonged operative time, where time is longer than the 75th percentile for the given procedure. According to the NNIS-NHSN, the risk of SSI increases as the number of risk factors present increases, irrespective of the type of operation.⁷⁶ Laparoscopic surgery is associated with a decreased incidence of SSI under most circumstances. There are several possible reasons why laparoscopic surgery decreases the risk of SSI, including decreased wound size, limited use of cautery in the abdominal wall, and a diminished stress response to tissue injury.

Host-derived factors contribute importantly to the risk of SSI, including increased age,⁷⁷ obesity, malnutrition, diabetes mellitus,⁷ hypocholesterolemia,⁷⁸ and several other factors not accounted for specifically by the NNIS-NHSN (see Box 12-5). In a study of 5031 noncardiac surgical patients, the incidence of SSI was 3.2%.⁷⁹ Independent risk factors for the development of SSI included ascites, diabetes mellitus, postoperative anemia, and recent weight loss, but not chronic obstructive pulmonary disease, tobacco use, or corticosteroid use. In another prospective study of 9016 patients, 12.5% of patients developed an infection of some type within 28 days after surgery.⁸⁰ Multivariable analysis revealed that decreased serum albumin concentration, increased age, tracheostomy, and amputations were associated with an early infection, whereas a dialysis shunt, vascular repair, and early infection were associated with hospital readmission. Factors associated with 28-day mortality included increased age, low serum albumin concentration, increased serum creatinine concentration, and an early infection.

Hypothermia during surgery is common if patients are not warmed actively because of evaporative water loss, administration of room temperature fluids, and other factors.⁸¹ Maintenance of normal core body temperature is unequivocally important for decreasing the incidence of SSIs. Mild intraoperative hypothermia is associated with an increased incidence of SSIs following elective colon surgery⁸² and diverse operations⁸³

It is controversial whether perioperative oxygen administration is beneficial for the prevention of infection.⁸⁴ The ischemic milieu of the fresh surgical incision is vulnerable to bacterial invasion. Moreover, oxygen has been postulated to have a direct antibacterial effect.^85,86 Although clinical trials have had conflicting results,^87,88 one recent meta-analysis has suggested a benefit of supplemental oxygen administration specifically to reduce the incidence of SSIs,²¹ but further studies may be needed before the practice becomes routine.

Skin closure of a contaminated or dirty incision is believed to increase the risk of SSIs, but few good studies exist to evaluate the multiplicity of wound closure techniques available to surgeons. Open abdomen techniques of temporary abdominal closure for management of trauma or severe peritonitis are increasingly being used. Retrospective data have indicated that antibiotics are not indicated for prophylaxis of the open abdomen,⁸⁹ although an inability to achieve primary abdominal closure is associated with several infectious complications (e.g., pneumonia, bloodstream infection, SSIs). Infectious complications, in turn, significantly increase costs from prolonged length of stay, but not mortality.⁹⁰

Drains placed in incisions probably cause more infections than they prevent. Epithelialization of the wound is prevented and the drain becomes a conduit, holding open a portal for invasion by pathogens colonizing the skin. Several studies of drains placed into clean or clean-contaminated incisions have shown that the rate of SSI is not reduced^91,92; in fact, the rate is increased.^93–96 Considering that drains pose this risk, they should be used as little as possible and removed as soon as possible.⁹⁷ Under no circumstances should prolonged antibiotic prophylaxis be administered to cover indwelling drains (see later).

Wound irrigation is a controversial means to reduce the risk of SSIs. Routine low-pressure saline irrigation is ineffective,⁹⁸ but high-pressure (i.e., pulsed) irrigation may be beneficial.⁹⁹ Intraoperative topical antibiotics can minimize the risk of SSIs,^100–102 but the use of antiseptics rather than antibiotics might minimize the development of resistance.

Surgical site infection remains a clinical diagnosis. Presenting signs and symptoms depend on the depth of infection, typically as early as postoperative day 4 or 5, although rare necrotizing SSIs caused by Streptococcus pyogenes or Clostridium perfringens may develop within 24 hours after surgery. Clinical signs range from local induration only to the hallmarks of infection (e.g., erythema, edema, tenderness, warmth, pain-related immobility), which may manifest before wound drainage. In cases of deep incisional SSIs, tenderness may extend beyond the margin of erythema, and crepitus, cutaneous vesicles, or bullae may be present. With ongoing infection, signs of systemic inflammatory response syndrome (SIRS; two or more of fever, leukocytosis, tachycardia, or tachypnea) herald the development of sepsis. In intracavitary (organ, space) SSIs, symptoms specific to the involved organ system will usually predominate, such as ileus, respiratory distress or failure, or altered sensorium.

Cultures are not mandatory for the management of superficial incisional SSIs, particularly if drainage and wound care alone will suffice without antibiotics and if superficial swab cultures are collected, which are susceptible to contamination by nearby skin colonists. In cases of deeper infection or hospital-acquired infection, exudates or drainage specimens should be sent for analysis from the surgically opened wound—as opposed to the already opened wound, which becomes colonized.

More severe SSIs, especially the dangerous forms of necrotizing soft tissue infection (NSTI), are true emergencies that need immediate surgical attention. Even modest delays can increase mortality substantially. Freischlag and coworkers¹⁰³ have shown that mortality increases from 32% to 70% when therapy is delayed longer than 24 hours. Immediate widespread débridement is indicated for established NSTIs without waiting for identification of the causative pathogen or development of a specific symptom. Sequential surgical débridements may be needed to control the infection.

The first steps in the treatment of SSIs are to open and examine the suspicious portion of the incision and decide about further surgical treatment.¹⁰⁴ If the infection is confined to the skin and superficial underlying subcutaneous tissue, opening the incision and providing local wound care may be all the treatment that is necessary. Antibiotic therapy of superficial incisional SSIs is indicated only for erythema extending beyond the wound margin or for systemic signs of infection. Deeper SSIs may require formal surgical exploration and débridement to obtain local control of the infection. Surgical site infection must also be considered as a cause of delayed or failed wound healing and prompt the same decisions as described earlier.

Organ or space SSIs occur within a body cavity (e.g., intra-abdominal, intrapleural, intracranial) and are directly related to a surgical procedure. These deep infections may remain occult or present with few symptoms, mimicking incisional SSIs and leading to inadequate initial treatment; they become apparent only when a major complication ensues. The diagnosis of organ or space SSIs usually requires some form of imaging to confirm the site and extent of infection. Adequate source control requires a drainage procedure, whether open or percutaneous.

Experimentally, vacuum-assisted wound closure (VAC) was first appraised by Morykwas and colleagues¹⁰⁵ in a porcine model in 1997. Therapy by VAC optimizes blood flow, decreases edema, and aspirates accumulated fluid, thereby facilitating bacterial clearance. Negative pressure promotes wound contraction to cover the defect and may trigger intracellular signaling that increases cellular proliferation.¹⁰⁶ The clinical usefulness of VAC has been described only anecdotally, mostly for sternal infections following cardiac surgery, abdominal wall dehiscence, management of complex perineal wounds, or securing skin grafts.^107,108

Many general and specific tactics for the prevention of SSIs have been brought together in a bundle known as the Surgical Care Improvement Project (SCIP), the effectiveness of which has been called into question.^109,110 A predecessor program, the National Surgical Infection Prevention Project (SIP), focused primarily on the quality of antibiotic prophylaxis, including choice of agent, timing of administration, and duration of prophylaxis. A national audit found that the agents being prescribed for prophylaxis were often inappropriate, the effectiveness of prophylaxis was decreased because the timing of administration was suboptimal, and only 40% of patients administered surgical antibiotic prophylaxis had the antibiotic discontinued within 24 hours, risking adverse events (e.g., superinfection, development of bacterial resistance).¹¹¹ It was advised that antibiotic administration should occur within 60 minutes before incision and that prophylaxis should continue for no longer than 24 hours.¹¹² Implementation demonstrated improved adherence to process measures.¹¹³

The SIP was incorporated into SCIP, with additional process measures added (Box 12-6), including recommendations for agents to be used for prophylaxis in specific circumstances (Table 12-2). As a U.S. federal program, SCIP includes reporting mandates, with financial incentives for compliance that will eventually become penalties for noncompliance.¹¹⁴ Perhaps not unexpectedly, several studies have reported that the incidence of SSIs has not decreased under SCIP,^109,110 possibly for several reasons.¹¹⁵ Baseline infection rates may have increased as a result of improved reporting, masking any decrease from process improvement. The inherent assumption, that a focus on process improvement will result in an improved outcome, may be flawed. Causes and prevention of SSIs are complex and multifactorial and compartmentalization by SCIP may be an oversimplification. Moreover, SCIP is not a smorgasbord of tactics from which the clinician may pick and choose; prevention of SSIs requires the flawless execution of an ensemble of prevention tactics,¹¹⁶ not all of which are included in SCIP. For example, correction of patient factors is notably missing. Nonetheless, all the SCIP measures are supported by ample, good-quality evidence, and the search for processes that lead to meaningful improvements in outcome must continue.

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