Chapter 25

Intra-abdominal sepsis (IAS) is a common condition in critically ill patients that frequently originates from localized or diffuse intra-abdominal infections (IAIs). In its most severe form, IAS can lead to severe sepsis and ultimately to multiple organ failure. Those conditions are the leading causes of death in patients admitted in non-cardiac intensive care units (ICUs).1–4 The key elements in the management of patients with IAS are: early recognition of the problem, aggressive resuscitation, hemodynamic support, prompt administration of broad-spectrum antibiotics, and definitive source-control by means of surgical and/or non-surgical procedures.^5–8 Even though certain recommendations from published guidelines have led to improved survival in sepsis, the mortality rate of this condition remains extremely high.^2,9 A recent meta-analysis, compared 28-day mortality of severe sepsis in patients enrolled in multicenter randomized trials (1991–2009) to that of administrative data (1993–2009). Results showed a mortality rate of approximately 30%; Despite an annual mortality decline of 3.0–3.5%, respectively.¹⁰

The aim of this chapter is to review the clinical manifestations, microbiology, host defenses, and general principles of the management of IAS.

Epidemiology

Every year there are approximately 20 to 30 million cases of sepsis worldwide. A recent study in the United States showed an increase of approximately 71% in the number of cases of severe sepsis from 415,280 cases in 2003 to 711 and 736 in 2007.2 The infection site was located in the abdomen for roughly 19% of the patients with a statistically significant increase throughout the years (p < 0.001).² Approximately 1.3–2.5% of all ICU admissions for severe sepsis or septic shock result from IAIs.⁴

Severe sepsis is a frequent cause of mortality in surgical patients. A study with 200,000 septic patients from hospitals in seven different states of the United States showed that a surgical condition was present in approximately 30% of the cases.¹¹ Surgical patients admitted to ICUs also have several risk factors for sepsis. A recent study assessed prospective data from more than 1,300 surgical patients admitted to ICUs to determine preoperative, intraoperative and postoperative risk factors for sepsis. Patients with previous infections and those on antibiotics were excluded generating a final sample size 625 patients; 54% underwent neurosurgical or gastro-intestinal (GI) procedures.¹² Approximately 30% of the patients had an infectious complication, 13% had sepsis/severe sepsis and 11.5% presented septic shock; the mortality rate was 18%. An intra-abdominal source was found in 15% of the patients and approximately 50% had an infectious source in the lung. Multivariate analysis of the significant risk factors showed that urgent surgeries, mechanical ventilation, need for vasopressors/fluid resuscitation, and higher sepsis related organ failure assessment (SOFA). Scores at ICU admission were independent predictors for sepsis and septic complications.¹² Similar findings were reported in a study using data from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) on approximately 6,500 patients with sepsis or septic shock.¹ The authors report that in general surgery patients aged older than 60, emergency surgery, and presence of comorbid conditions were significant risk factors for death from sepsis and septic shock; Co-morbidities increased the risk of sepsis or septic shock by fivefold.¹ For the most part, these studies underscore the fact that an urgent abdominal operation to treat IAS in a patient with pre-existing clinical conditions sets the stage for poor prognosis. That is a timely concern, because the growing elderly population with pre-existing clinical conditions is prone to IAIs that frequently require urgent surgical interventions.

Definitions

To better understand IAIs and IAS, it is important to review the definitions of: Systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock.¹³ SIRS can be triggered by infectious and non-infectious sources. In general terms, a patient with more than one of the following clinical findings is deemed to have SIRS: temperature > 38°C or < 36°C, heart rate > 90/min, respiratory rate > 20/min or PaCO₂ < 32 mmHg, white blood cell count > 12,000/μL or < 4,000/μL. In contrast to SIRS, sepsis is defined by the presence of both SIRS and infection. Septic shock is defined as the state of acute circulatory failure as a result of sepsis; it is characterized by persistent hypotension (systolic pressure < 90 mmHg, MAP <60 mmHg or a reduction in systolic blood pressure of > 40 mmHg from baseline) despite adequate volume resuscitation, in the absence of other causes of hypotension. Severe sepsis refers to sepsis complicated by organ dysfunction.13 Pneumonia is the most common cause of severe sepsis, followed by IAIs and urinary tract infections.

IAIs arise from a wide variety of sources. If the infection extends beyond the wall of a hollow viscus into the abdominal or retro peritoneal cavity, it is considered a complicated intra-abdominal or retro peritoneal infectious process. Peritonitis and abscess are the most frequent forms of IAIs treated by surgeons.

Peritonitis is usually classified as primary, secondary and tertiary based on its presentation. Primary peritonitis presents without a breach the GI tract. The most common example is the spontaneous bacterial peritonitis (SBP) that occurs in patients with chronic ascites. In dwelling peritoneal catheters can result in a form of peritonitis that is sometimes considered in conjunction with primary peritonitis. Both diseases are microbiologically defined as mono-microbial infections treated with antibiotics, and only infrequently require major surgical intervention. Secondary peritonitis is the most common type of infectious processes in the abdominal cavity and the retro peritoneal space to require surgical treatment. It usually results from GI perforations and frequently presents as intra-abdominal or retro peritoneal abscess.⁶ Abscess formation, is for the most part, an effective immune response that restricts the extension of intraperitoneal/retro peritoneal infections. Experimental data show that abscess formation is hampered in defective immune response where the productions of Tumor Necrosis Factor alpha (TNFα), Interleukin (IL-1), and Intercellular Adhesion Molecule-1 (ICAM-1) are blocked.⁴ Similar findings are also observed in the absence of IL-6.⁴ Aforementioned cytokines are required for adequate polymorphonuclear neutrophil (PMN) function and ultimately abscess formation. Tertiary peritonitis is sometimes considered a “chronic” form of primary or secondary peritonitis that fail to resolve completely.¹⁶ Patients with tertiary peritonitis are severely sick, have pre-existing medical problems, and are incapable of mounting an adequate immune response. Those patients are frequently immuno-suppressed and develop persistent inflammatory response that ultimately leads multiple organ dysfunction17,18

Specific management strategies for common causes of IAIs will be discussed in separate chapters of this book.

Pathophysiology

The peritoneal cavity has roughly 50–100cc of peritoneal fluid that contains macrophages, mast cells, and lymphocytes. Inflammatory and infectious processes in the peritoneal cavity trigger the release of cytokines from the leukocytes of the peritoneal fluid, activate the coagulation cascade, and enhance the recruitment of circulating neutrophils and monocytes.⁶ Localized peritonitis occurs when the activation of the coagulation cascade and the deposition of fibrin isolate the infection to form an abscess. Thus, shielding the rest of the peritoneal cavity from the infectious process.

The greater omentum also plays an important role in restricting the expansion of IAIs.⁴ Leukocyte aggregates within the rich vascular supply of the omentum form what is referred to as “milky spots”. Intra-peritoneal Inflammatory processes are directly exposed to post capillary venules through the “milky spots” facilitating PMN recruitment to the peritoneal cavity.¹⁹ Moreover, the greater omentum is also capable of promoting rapid neovascularization and formation of fibrin and collagen, all important in the process of restricting IAIs.²⁰ Similarly, adhesions between bowel loops, mesentery, and the undersurface of the abdominal wall, also confine and temporarily seal GI perforations and contaminated fluids.

In contrast, generalized peritonitis occurs when local mechanisms are overwhelmed by rapid, or prolonged contamination and the peritoneal cavity becomes acutely inflamed. Bacteria and some particulate matter are carried by peritoneal fluid to the diaphragmatic stomata and removed from the peritoneum. Generalized peritonitis provokes significant fluid shifts (third spacing) that ultimately results in hypovolemic shock. The sympathetic nervous system is activated resulting in catecholamine release. This response leads to significant reduction in urinary output and hinders peristalsis.^6,15 The latter results in stasis of bowel content, promotes microbial overgrowth, and translocation across the bowel wall. Vasodilatation in response to systemic inflammation causes bowel wall edema and further compromise of the natural barrier formed by the gut lining. These processes interfere with intestinal perfusion and contribute to additional ischemic damage to the intestinal barrier.⁶

Microbiology

The microorganisms involved in IAIs generally originate from the resident GI flora. Therefore, when deciding on the antimicrobial usage it is important to consider the origin of the potential source of infection in the GI tract.17,21,22 The upper jejunum and the stomach are usually populated by gram-positive cocci, mainly streptococci and lactobacilli. Given the low PH and rapid peristalsis in those areas the number of microorganisms is low, approximately 103–104 bacteria/mL of fluid content.²³ With decreased peristalsis and increase in PH the bacterial count in the more distal portions of the small bowel and terminal ileum, can reach up to 10⁸ organisms per gram of contents.²³ A more diverse microflora is present in those areas, with aerobic and facultative anaerobic gram negative bacilli. The latter are particularly present in the terminal ileum.²³

In the colon, slow motility and very low oxidation-reduction potentials create the perfect environment for bacterial proliferation. Making this section of the GI tract the most important site of microbial colonization in humans. Approximately 10¹⁰ to 10¹¹ microorganisms are present per gram of contents and 99.9% are obligate anaerobic organisms.^23,24 Enterobacteriaceae species are the most common pathogens in SBP. This condition is treated with extended-spectrum cephalosporin and quinolone. However, in nosocomial-acquired SPB the resistance to cephalosporin and quinolone is very common (23–50%), and the prevalence of methicillin-resistant staphylococcus aureus (MRSA) is alarmingly high (27%).²⁵ This is a worrisome pattern of change, since patients with multidrug-resistant bacteria have four times higher risk of death than those without.²⁶ Moreover, approximately 5–15% of patients with SBP and infected ascites, have a perforated viscus as the source of the infection. Treatment of those patients with antibiotics alone, frequently results in 100% mortality. However, patients with SBP who undergo unnecessary laparotomy also have high mortality rates; approximately 80%. Therefore, precise indication for surgical intervention is of utmost importance in SBP patients.^27,28

As expected, microorganisms from resident GI bacterial flora are involved in secondary peritonitis. Although stool cultures are usually polymicrobial, cultures from peritoneal collections of patients with IAIs from secondary peritonitis generate a predictable microbiological pattern. Escherichia coli and Klebsiella pneumonia are responsible for most community-acquired IAIs. Pseudomonas aeruginosa and Acinetobacter baumannii are the most common causative pathogens of hospital-acquired IAIs.²⁹ There is also a recent increase in prevalence of multidrug-resistant Enterobacteriaceae species that produce extended-spectrum β-lactamases (ESBL) and carbapenemases. Data from the study for monitoring Antimicrobial Resistance trends (SmARt) surveillance program showed that, in North America, 6.8% of E. coli and isolates from IAIs are ESBL-positive, but resistance to carbapenems is uncommon.29 Intra-abdominal fluid cultures from septic ICU patients with GI tract perforation showed aerobic gram-negative bacteria in 52.9% of abdominal fluid samples, of which 45% were E. coli²² In that study, the incidence of aerobic gram-negative bacteria was 68.8% in colorectal perforation and 77.8% in perforated acute appendicitis.²² The incidence of anaerobic bacteria was the same in the latter. Candida was cultured in 20% of the patients with GI perforation. The prevalence of aerobic gram-negative bacteria decreased over time after surgical treatment and antibiotic therapy, from 52.9–6.7% in the first culture after 4 weeks. Whereas, the incidence of gram-positive bacteria increased from 42.5–86.7% in the same period.²² Therefore, antimicrobial coverage should be modified over time to provide adequate coverage if patient improvement is not as evolving as expected, and surgical intervention may also be considered.

Clinical Manifestations and Physical Examination

Abdominal pain is the hallmark symptom of patients with IAIs, and was the main reason for 8 million emergency department visits in the United States in 2006; making it the most common complaint in that hospital setting.³⁰ Fever, tachycardia and tachypnea are frequently associated with IAIs. Non-specific findings, such as, loss of appetite, diarrhea, nausea, and abdominal distention are also common, and are reported in up to 30% of cases of IAIs. Underestimation of those complaints may lead to delay in diagnosis.³¹ Clinical manifestations of IAIs can be obscure in the elderly, children, and in patients who cannot inform appropriately. Moreover, the effects of analgesia, and sedation also hinder the diagnosis, particularly in ICU patients.⁴ Past medical history often provides valuable clues for the diagnosis. For example, primary peritonitis should be considered in a septic patient with known cirrhosis. History of recent abdominal surgery should prompt the suspicion for bowel obstruction, abscess, anastomotic leak, and less frequently, unrecognized bowel injury.⁶ Undetected abdominal wall hernias can cause delayed diagnosis. A patient with multiple cardiovascular risk factors who rapidly deteriorates, despite adequate therapy may have intestinal ischemia, and the onset of new organ dysfunction is commonly linked to abdominal sepsis in that context. From a surgical perspective, acute abdomens are generally classified as —

Acute abdomens caused by inflammatory processes and GI perforations are most frequently associated with IAIs. However, prolonged time interval between the onset of the symptoms and the diagnosis will ultimately lead to IAIs regardless of the primary cause.31,32 But for the most part, IAIs originated from acute abdominal conditions other than inflammatory processes and perforated viscus, are usually linked to delayed diagnosis resulting in sepsis and poor outcome. The most common sources of IAIs in inflammatory acute abdomens are appendicitis, cholecystitis, non-perforated diverticulitis, acute pancreatitis, and any condition that leads to intra-abdominal abscess formation. IAIs from GI perforations usually result from complications of diverticulitis and appendicitis, advanced GI cancer, and peptic ulcer disease.³²

The most important elements in the assessment of pain caused by IAIs are —

1.  Location

2.  Nature

3.  Triggering and alleviating factors

Infectious processes that cause pain in the left and right upper quadrants typically originate from the liver, biliary tract, and the kidneys. However, sub-phrenic abscess, a typical long ascending inflamed appendix, and intrathoracic conditions can present with pain in those regions.^31,32 Inflammatory processes located in the sub-phrenic areas can irritate the phrenic nerves and produce referred pain in the supraclavicular fossa (Kehr’s sign).

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