Host Defenses

The peritoneal cavity is a complex space lined with mesothelial cells in visceral and parietal layers. The healthy peritoneal cavity is quiescent immunologically but responds rapidly to bacterial contamination. Normally, about 50 to 100 mL of peritoneal fluid circulates freely among several potential and actual spaces within the peritoneal cavity.¹ Net fluid movement is cephalad toward the diaphragm, facilitated by normal peristalsis, normal diaphragmatic excursions, splanchnic blood flow, and factors that maintain normal membrane permeability of the microcirculation. Conversely, ileus, mechanical ventilation, splanchnic hypoperfusion, and intraperitoneal inflammation can disrupt normal fluid movement and cause intraperitoneal fluid sequestration.

The three major intraperitoneal host defense mechanisms include clearance of bacteria by lymphatics, phagocytosis of bacteria by immune cells, and mechanical sequestration with abscess formation. A few phagocytic cells circulate as peritoneal macrophages, and opsonic proteins that facilitate phagocytosis are present. Experimentally, a small bacterial inoculum placed in the peritoneal cavity is cleared within a few minutes when the peritoneal fluid is absorbed by specialized lacunae on the undersurface of the diaphragm.¹ The bacteria then pass into the central venous system via diaphragmatic and mediastinal lymphatics for disposition by systemic host defenses. When an infectious inoculum is introduced, a brisk inflammatory response attempts to localize the infection, leading to abscess formation rather than generalized peritonitis. Intraabdominal abscess formation is a source-containment process; mortality is lower for patients with abscess(es) than for patients with generalized peritonitis.^2,3

Intraabdominal infection stimulates both local and systemic inflammatory responses. Locally, influx and activation of phagocytic cells (neutrophils, monocytes, and macrophages) promotes bacterial killing but also impairs microvascular integrity and fosters interstitial edema and formation of exudative ascites. The surface area of the peritoneum is approximately the same as the skin, so edema of the submesothelial interstitial space to a thickness of 1 mm sequesters about 1.7 L of fluid in a 70-kg patient. Large volumes of interstitial and free peritoneal fluid can accumulate, requiring very large infusions of intravenous (IV) fluid to correct intravascular hypovolemia, a common occurrence in patients with generalized peritonitis. Intraperitoneal fluid accumulation is detrimental to intraabdominal host defenses, diluting opsonins and impairing neutrophil function, but there is no alternative to fluid administration for the hypovolemic patient.

With inflammatory injury, peritoneal mesothelial cells are denuded, exposing the underlying basement membrane. When platelets and fibrin come into contact with the basement membrane, fibrin polymerization occurs and produces a typical exudative rind on peritoneal surfaces. Fibrin and apoptotic neutrophils contribute to the formation of adhesions and the walls of abscesses. Normally the process is self-limited by up-regulation and/or activation of fibrinolytic factors such as plasminogen within the first week after mesothelial injury. If the insult is self-limited, peritoneal repair occurs within 3 to 5 days. Under local hypoxic conditions, the adhesions are invaded by fibroblasts, angiogenesis is up-regulated, and the adhesions become tenacious.⁴

Microbiology

Most of the bacteria normally resident in the gut are commensal flora that play little if any role in the pathogenesis of intraabdominal infections. Currently it is estimated that more than 500 bacterial species are present within the lumen of the healthy human colon. Most of these species are obligate anaerobes. Under normal conditions, the intestinal microbiota supports enterocyte and colonocyte function and prevents overgrowth of more pathogenic species, including Bacteroides fragilis, Escherichia coli, Klebsiella spp., and Enterobacter spp. Overgrowth of these potentially pathogenic microbes can occur after patients are treated with broad-spectrum antibiotics.

Gastrointestinal perforation releases bacteria into the peritoneal cavity. Bacterial density within the gut lumen increases along the length of the gastrointestinal tract from the stomach to the colon. The bacteria must proliferate to cause infection, while local host defenses seek to prevent or contain the establishment of infection. In addition to the microbes present in peritoneal fluid, microbial colonization of peritoneal surfaces occurs rapidly after perforation or penetrating injury as a result of expression by the microorganisms of specific adherence factors. Enterobacteriaceae predominate within the first 4 hours but are superseded within 8 hours by members of the B. fragilis group. Adherent bacteria are difficult to eradicate by operative peritoneal lavage.⁵

Besides adherence factors, bacteria possess several other features that can enhance their virulence. Peptidoglycans and lipoteichoic acid in the cell walls of gram-positive bacteria, especially streptococci and staphylococci, stimulate a proinflammatory response. These organisms can elaborate exotoxins and proteases that cause tissue injury and promote the dissemination of the bacteria. Lipopolysaccharide (LPS) in the outer cell wall of gram-negative bacteria can interact with many cell types to stimulate an inflammatory response. As bacteria proliferate and the size of the inoculum increases, acidic bacterial metabolites can impair neutrophil function.⁶ Larger inocula can render antibiotics, particularly β-lactams, ineffective via a process called the inoculum effect.⁷ Additionally, bacteria demonstrate a quorum-sensing effect that maximizes survival and reproduction by altering their behavior based upon signaling pathways.⁸

Synergistic interactions, usually among members of the B. fragilis group and either facultative gram-negative bacilli or enterococci, can suppress local host defenses and promote bacterial survival and growth.¹ B. fragilis produces a capsular polysaccharide antigen that suppresses complement activation and inhibits leukocyte recruitment and function.⁹ Anaerobic bacteria produce short-chain fatty acids that can impair the function of neutrophils. Facultative bacteria consume residual oxygen in the microenvironment, permitting the survival and proliferation of obligate anaerobes. Anaerobic bacteria lower the redox potential in the microenvironment, also favoring their growth. Aerobic and anaerobic bacteria can enhance the growth of other species by providing crucial nutrients or the producing enzymes that inactivate antibiotics.

In some respects, bacteria have evolved to take advantage of host defenses. As an example, bacterial adherence to colonocytes and bacterial growth is enhanced by physiologic concentrations of norepinephrine, which is secreted as part of the counter-regulatory response to stress, as well as being administered as an exogenous drug to promote arteriolar constriction and increase myocardial contractility.¹⁰

Peritonitis

Peritonitis can be classified as primary, secondary, or tertiary. Most critically ill patients with intraabdominal infection have secondary or tertiary peritonitis. The bacteriology characteristic of these classes of peritonitis is shown in Table 105-1.

TABLE 105-1 Microbiology of Intraabdominal Infection

Primary, or spontaneous bacterial, peritonitis develops in the absence of gastrointestinal perforation and rarely causes critical illness. This type of peritonitis, which afflicts adults with hepatic cirrhosis or collagen vascular disease or children with certain glomerulopathies, is almost always monomicrobial. The typical pathogen is usually an enteric gram-negative bacillus such as E. coli or Klebsiella spp., although infection with streptococci is also known to occur. Definitive diagnosis is made by paracentesis and culture, and operative treatment is not indicated. Polymicrobial or anaerobic flora confirm the presence of an occult perforation that must be found and treated.

Device-associated peritonitis is a variant of primary peritonitis that also almost always is monomicrobial. The great majority of cases occur with chronic ambulatory peritoneal dialysis (CAPD) catheters, which become infected as often as once per year of dialysis.¹¹ The most common pathogens are Staphylococcus aureus and species of Pseudomonas and Candida. Catheter removal is usually necessary to eradicate these infections, especially when caused by P. aeruginosa or Candida spp. Although rare, recurrent CAPD-related peritonitis due to methicillin-resistant S. aureus (MRSA) has been associated with the emergence of vancomycin-resistant strains after treatment with multiple courses of vancomycin.¹²

Secondary peritonitis follows perforation of a hollow gastrointestinal viscus. The vast majority of cases are community acquired. Appendicitis is the most common cause, and the polymicrobial bacterial flora typically are highly susceptible to antibiotics. Thorough microbiologic analysis of a carefully collected specimen of purulent peritoneal fluid from a patient with secondary peritonitis yields an average of five organisms. B. fragilis the most commonly isolated obligate anaerobe, and E. coli is the most commonly isolated facultative organism. Less common isolates include Enterococcus spp., Candida spp., Clostridium spp., and P. aeruginosa. These uncommon isolates do not need to be covered by the antibiotic regimen if the patient was previously healthy and does not have comorbid conditions that increase the risk for an adverse outcome. Early operative source control, combined with a short course of broad-spectrum antibiotics, are curative in more than 85% of all cases and more than 90% of appendicitis cases.¹³ Most cases of community-acquired peritonitis do not result in severe illness, and these cases seldom require care in an intensive care unit (ICU).

Tertiary peritonitis describes recurrent or persistent intraabdominal infection after failure of more than one source control procedure to control the infection.^14–16 The flora usually include one or more strains of staphylococci (often methicillin-resistant S. epidermidis or MRSA) and Enterococcus spp., Candida spp., or Pseudomonas spp.^17–19 It is debated whether tertiary peritonitis represents invasive infection or permissive colonization of the peritoneal cavity in the face of devastated host defenses. The notion that host defenses are compromised is supported by the observation that fluid collections are often poorly localized and serosanguineous rather than purulent. Cases of tertiary peritonitis are fortunately uncommon, but class I data regarding management are lacking.

Adjuvants

Adjuvant substances act to decrease the bacterial inoculum necessary for infection. Adjuvants can increase virulence or interfere with host defenses and invariably are present to some degree in every patient with gastrointestinal perforation. Common adjuvants include ascites, blood, fibrin, bile, urine, chyle, pancreatic juice, and platelets.²⁰ The most important adjuvant is blood. Hemoglobin, fibrin, and platelets all impair host defenses, and iron, which is essential for bacterial growth, also depresses phagocyte function. Fibrin promotes bacterial trapping and abscess formation and can sequester bacteria from neutrophils. Bile salts impair host defenses and are toxic to neutrophils.²¹ Pancreatic enzymes can be activated by bacterial infection, producing necrotic tissue that is an excellent culture medium.

Foreign materials also can act as adjuvants, serving as prime loci for bacterial adherence and sequestration from phagocytes. The foreign material also can elicit an inflammatory reaction, thereby reducing the size of the inoculum needed for infection. Adjuvant foreign materials include surgically placed drains, nonabsorbable suture material, fibers from gauze sponges, prostheses such as vascular grafts and mesh, topical hemostatic agents, talc, barium sulfate, necrotic tissue, and feces. Barium produces a marked chemical peritonitis and activates coagulation via the intrinsic pathway; the combination of barium and feces can be lethal.

Abscess Of Solid Organs

Abscesses of solid organs are rare but must be recognized, as they can be lethal if untreated. Most cases arise as a complication of a community-acquired infection, but on occasion they can be a complication of medical care. The liver is affected most commonly, followed by the spleen and kidney.

Liver abscess is most often the result of ascending biliary infection (cholangitis) or portal bacteremia that complicates an enteric infection (typically colonic diverticulitis). The most common causative organisms, including E. coli, Klebsiella spp., and Enterococcus spp., reflect these pathogenic mechanisms. Systemic sources for bacteremia also can cause liver abscesses and include dental abscess (viridans streptococci) or vascular catheters (S. aureus, Candida albicans, and others). Devitalized liver, as can be present after trauma, angioembolization, or ablation of neoplasms, is at particular risk for infection. The lesions can be solitary or multiple. In rare instances, miliary liver abscesses develop.

Treatment of liver abscesses should be individualized. A source of origin should be sought and treated. Antibiotics are mandatory, and a prolonged course for more than 14 days may be necessary. If feasible, based upon the size and location of the abscess, percutaneous drainage always should be attempted.^26,27 Operative drainage may be required for abscesses that cannot be drained percutaneously. Overall mortality rate is approximately 25% but is higher for patients with multiple abscesses that are too small to drain.²⁸

Splenic abscesses are uncommon and are the result of hematogenous or local contamination. Hematologic sources include endocarditis, urinary tract infections, pneumonia, osteomyelitis, otitis, mastoiditis, and pelvic infections. Splenic abscesses have been reported with other systemic infections including typhoid, paratyphoid, malaria, and candidiasis. Direct extension from adjacent infections of the pancreas, retroperitoneum, subdiaphragmatic spaces, and diverticulitis can involve the spleen. Systemic disorders such as hemoglobinopathies or sickle cell disease, can cause splenic infarction. Devitalized splenic tissue resulting from trauma, infarction, or embolization can become infected and evolve into splenic abscesses.²⁹

S. aureus is the most common pathogen in splenic abscesses, while gram-negative organisms are relatively unusual. Anaerobic infections (e.g., due to Clostridium perfringens) have been described. Empirical antibiotic therapy should address all likely pathogens. Percutaneous drainage can be attempted if conditions are favorable, but splenectomy and drainage are usually definitive as therapy. Overall mortality rate is approximately 20%.

Despite the frequency of urosepsis, true abscesses of the kidney are uncommon compared to either hepatic or splenic abscesses. Ascending infection from the lower urinary tract is the usual source; therefore, any common urinary tract pathogen (E. coli, Klebsiella spp., Enterococcus spp., S. aureus) can be causative, and broad-spectrum antibiotic therapy is necessary until microbiologic data become available. Surgical drainage may be required for nonresponders or patients with recurrent sepsis.

Acute Acalculous Cholecystitis

In contrast to cholecystitis due to gallstones, the etiology of acute acalculous cholecystitis is gallbladder ischemia; infection of the organ occurs secondarily.³⁰ Although acute acalculous cholecystitis can complicate many illnesses, splanchnic hypoperfusion is the common feature. Risk factors in medical patients include congestive heart failure, diabetes mellitus, abdominal vasculitis, and malignancy (including after bone marrow transplantation). Acalculous cholecystitis is more common in surgical patients and can occur following burns, trauma, cardiopulmonary bypass, biliary instrumentation, and emergency aortic surgery.³⁰

The diagnosis of acute acalculous cholecystitis can be challenging, and a high index of suspicion is required. Prompt diagnosis and therapy are necessary, as the disease can be fulminant. Necrosis of the gallbladder occurs in 50% of patients, and perforation of the gallbladder occurs in 20%. Fever and hyperbilirubinemia are common associated findings.²⁹ Serum transaminase and alkaline phosphatase levels also may be elevated. When signs and symptoms can be localized to the right upper quadrant, the differential diagnosis includes gastroduodenal perforation, acute pancreatitis, right colonic ischemia, and acute hepatitis.

Bedside ultrasonography is favored for the diagnosis of acute acalculous cholecystitis; the most accurate diagnostic features are gallbladder wall thickness greater than 3.5 mm and presence of pericholecystic fluid. Computed tomography (CT) is equally accurate and can be utilized when there are no localizing findings and the patient is a candidate for intrahospital transport. Hepatobiliary scintigraphy is not useful to identify or exclude acute acalculous cholecystitis, owing to a high incidence of false-positive findings that result in part from a lack of dietary stimulus for gallbladder contraction. Coadministration of morphine sulfate, which increases biliary hydrostatic pressure, can promote filling of the gallbladder and increase diagnostic accuracy of hepatobiliary scintigraphy.³¹

Percutaneous cholecystostomy is the treatment of choice for acute acalculous cholecystitis in the critically ill patient. Success rates exceed 90% for control of acute acalculous cholecystitis, although the overall mortality rate remains about 30%. When percutaneous cholecystostomy fails to provide adequate control of acute acalculous cholecystitis, the diagnostic possibilities include malposition of the drainage catheter, uncontrolled gallbladder perforation, or another diagnosis. If a cholecystostomy tube study confirms the absence of gallstones once the patient has recovered, the drain can be removed. Interval cholecystectomy is unnecessary if the drain is removable.

Ischemic Colitis And Enteritis

Intestinal ischemia is a dangerous and relatively common complication of critical illness that can progress within hours to gangrene, perforation, and generalized peritonitis.³² The splanchnic circulation is especially vulnerable to low cardiac output, particularly when the cardiac index is less than 2 L/min/m². Most cases are caused by nonocclusive ischemia; the origin is often multifactorial, including hypovolemia, shock, and administration of vasopressors. A number of other causes have been identified. Acquired protein C/protein S deficiency induces a hypercoagulable state that has been associated with mesenteric arterial and venous thrombosis. Chronic atrial fibrillation or dilated cardiomyopathy can lead to mesenteric arterial thromboembolism. Arteriography can cause cholesterol embolization from dislodgement of an atherosclerotic plaque. Intestinal obstruction also must be considered, and this diagnosis may not be obvious with partial or proximal obstructions.

The pattern of injury with intestinal ischemia is variable depending on the mechanism, the presence of heart disease, and the status of the collateral circulation via the celiac and inferior mesenteric arteries. Large thrombi usually occlude the superior mesenteric artery where it narrows just distal to origin of the middle colic artery. The first 30 to 45 cm of small bowel and the left colon may be spared. Smaller emboli are more likely to infarct the small bowel and possibly the ascending colon (Figure 105-1); the distribution can be patchy. Nonocclusive ischemia classically occurs in watershed areas of the mesenteric circulation where collateral vessels bridge the two arterial distributions. A typical site is the splenic flexure of the colon at the watershed junction of the superior and the inferior mesenteric arteries. Although any segment of intestine can be affected by nonocclusive ischemia, the cecum (the point farthest from inferior mesenteric artery collaterals) and the left colon are most likely to be affected (Figure 105-2). The left colon is particularly vulnerable after abdominal aortic operations, especially when the inferior mesenteric artery has been ligated during the procedure.

Figure 105-1 CT after administration of oral and intravenous contrast in a patient with embolic occlusion of superior mesenteric artery and patchy ischemia of small bowel and right colon. Bowel ischemia is evident by marked thickening of intestinal wall.

Figure 105-2 CT with oral and intravenous contrast in a patient with nonocclusive mesenteric ischemia of colon at splenic flexure. Ischemia of colon is evident by marked thickening of wall of colon.

Patients with intestinal ischemia are profoundly ill and will die without prompt intervention. As the blood supply to the mucosa is more vulnerable than to seromuscular layers, transmural necrosis represents late-stage disease. Patients can develop severe sepsis or septic shock before transmural gangrene or perforation. The protean manifestations of the syndrome, including the potential for ischemia anywhere from the ligament of Treitz to the midrectum, make the diagnosis challenging.