Secondary Peritonitis and Intra-Abdominal Sepsis: An Increasingly Global Disease in Search of Better Systemic Therapies

Abstract

Secondary peritonitis and intra-abdominal sepsis are a global health problem. The life-threatening systemic insult that results from intra-abdominal sepsis has been extensively studied and remains somewhat poorly understood. While local surgical therapy for perforation of the abdominal viscera is an age-old therapy, systemic therapies to control the subsequent systemic inflammatory response are scarce. Advancements in critical care have led to improved outcomes in secondary peritonitis. The understanding of the effect of secondary peritonitis on the human microbiome is an evolving field and has yielded potential therapeutic targets. This review of secondary peritonitis discusses the history, classification, pathophysiology, diagnosis, treatment, and future directions of the management of secondary peritonitis. Ongoing clinical studies in the treatment of secondary peritonitis and the open abdomen are discussed.

Overview

Although there are different classifications of peritonitis, secondary peritonitis, typically originating from a breach in the gastrointestinal tract, is a global problem as it may manifest as intra-abdominal sepsis (IAS). Sepsis has been recognized as life-threatening organ dysfunction caused by a dysregulated host response to infection. IAS is particularly challenging as the focus of the disease occurs within a semi-rigid container within which inflammation from the primary disease and subsequent therapies also cause abnormal intra-cavitary pressures. In addition to the primary inflammation, there may be additional compartment pathophysiology, both potentiating physical and humoral consequences for the entire patient. Furthermore, as the gut containing the human microbiome is within this compartment, the primary disease, intra-abdominal hypertension (IAH), and systemic vasomotor changes quickly induce a pathological gut microflora or dysbiome with multiple, but still poorly understood consequences for the host. It is the clinicians’ challenge to make the diagnosis and assess both the therapies require not only to correct or mitigate the primary pathology (source control) but also to assess the patient’s response and to appropriately support organ function and manage sepsis. In addition to formal laparotomy, there is now an array of less invasive techniques to potentially address the primary pathology, such that great skill and experience are required for every unique patient. There are less options, however, to address the most severe septic cases resulting from secondary peritoneal pathologies, with no pharmacologic therapies whatsoever, and only critical care support. Leaving the abdominal cavity open to allow better peritoneal drainage of inflammatory ascites and to mitigate IAH is a therapeutic adjunct that is increasingly being used and is applicable in any healthcare setting, even in the developing world if critical care is offered. However, the evidence to clearly support this strategy is lacking, constituting the basis of the closed or open after source control laparotomy (COOL) trial (www.coolstudy.ca) being currently conducted on a Global Basis.

Peritonitis: History and Definition

Peritonitis has been life-threatening and ominous throughout the history of the human race. References to peritonitis can be found as far back as the ancient Egyptians (1). Peritonitis is the inflammation of the peritoneum. “Défence musculaire” or abdominal rigidity is a clinical finding in abdominal palpation with involuntary contraction of abdominal muscles. Peritonism is generalized rigidity of the abdomen. These findings are suggestive of intra-abdominal issues, yet sensitivity/specificity is poor. Nociceptive stimuli on the peritoneal lining cause activation of visceral afferent pathways that activate a reflex loop to the abdominal wall musculature. The result is the splinting of the abdominal wall using the abdominal skeletal muscle in response to viscerosomatic pain (2). While the origins of the peritoneal irritants that result in peritonitis are many, it is frequently a sign of catastrophe and if left untreated, brings a grim prognosis.

Classification of Peritonitis

Clinically, peritonitis can be localized or isolated to a certain sector of the abdomen. A classic example of localized peritonitis would be the localized tenderness at McBurney’s point in the diagnosis of appendicitis. As irritants disseminate throughout the peritoneal cavity, peritonitis becomes diffuse. The classification of peritonitis as localized versus diffuse is clinically helpful. With very few exceptions, patients presenting with diffuse peritonitis require immediate surgical exploration, while those with localized clinical signs are often able to undergo further evaluation.

Although the focus of this review is on secondary peritonitis, it is important to appreciate that peritonitis, in general, can be further classified into primary, secondary, and potentially tertiary etiologies. Each of these diagnoses have typical clinical presentations and scenarios that accompany them. In the practical setting, however, multiple nuances must be taken into account. At all times, it should be clarified that while “peritonitis” defines the clinical findings, IAS with its association with sepsis and organ failure is what kills the patient. Conceptual frameworks in understanding the incredibly complex and rapidly changing aspects of the inflammatory response to IAS that kills the patient have included the concepts where an acute pro-inflammatory response becomes supplanted by a mixed anti-inflammatory response with balanced pro and anti-inflammatory biomediators. This is followed by an anergic, compensatory anti-inflammatory response syndrome (CARS) leaving the host susceptible to secondary infectious complications (3).

Primary Peritonitis

Primary peritonitis is defined as spontaneous bacterial seeding of the peritoneal cavity. Spontaneous bacterial peritonitis (SBP) requires the presence of a bacterial medium within the peritoneal cavity. More specifically, ascites in the setting of cirrhosis or peritoneal dialysate in end-stage renal disease create a bacterial culture medium which can progress to a disseminated infection once the medium is seeded. In hospitalized cirrhotic patients, the overall prevalence of bacterial infections is 32%–34%, a quarter of which is made up of patients with SBP (4). Once infected, the 1-year recurrence risk without prophylaxis happens at a rate of 20%–24% (5). Patients undergoing peritoneal dialysis suffer from SBP once every 2 years on average (6).

The main mechanism by which ascitic fluid becomes infected is dependent upon the background cause of ascitic fluid. This is reflected in the microbiology of the infected fluid. Usually, SBP infection consists of a single, dominant bacterial species. Cirrhotic ascites is most commonly seeded with gram negative or enterococcus species via bacterial translocation from the gut. Patients with indwelling peritoneal dialysis catheters are more likely to become infected with staphylococcus, pseudomonas, or pneumococcus species via direct spread of skin flora through the catheter itself or inoculation during breaks in sterility during dialysate change (6).

Mainstays of primary peritonitis include rapid institution of systemic antibiotics, with tailoring of antibiotics once the cultures have been speciated. In the case of recurrent infection, prophylactic antibiotics may be administered. More severe cases of non-resolving or recurrent peritonitis in patients with indwelling peritoneal catheters may necessitate a transition to hemodialysis and/or removal of infected peritoneal dialysis catheters. Finally, secondary peritonitis must always be considered as a possible etiology for the seeding of peritoneal fluid.

Secondary Peritonitis and IAS

Secondary peritonitis is defined as the irritation of the abdominal peritoneal lining caused by direct contact with a peritoneal contaminant (7). It occurs most commonly from a physical or functional disruption of the integrity of the gastrointestinal tract, and thus the bacterial contribution to secondary peritonitis is commonly polymicrobial. While gastrointestinal perforation causes direct spillage, secondary peritonitis can also be seen due to ischemic gut, volvulus, or blood in the peritoneal cavity secondary to trauma. It will be emphasized throughout this review that although “peritonitis” is the physical finding that unifies a wide range of pathologies within the abdominal compartment, the actual significance and implications for morbidity and mortality generally correlate with the potential of the inciting condition to IAS.

Tertiary Peritonitis and the Human Dysbiome

Tertiary peritonitis is poorly defined, misunderstood, and potentially historical. It was defined most recently in 2005 as “peritonitis that persists or recurs ⩾48 h following apparently successful management of primary or secondary peritonitis” (8). It has been associated with an observed shift from gram negative and enteric bacteria to nosocomial microbes such as Enterobacter, Enterococcus, Acetinobacter, Citrobacter, Pseudomonas, and fungal species (9). The clinical sequelae of tertiary peritonitis are grave and often deadly, with a mortality rate quoted as 30%–64% in some populations (10, 11). Clinically, it is most often suspected in cases of prolonged SIRS response and shock following effective management of the inciting pathology causing secondary peritonitis. Often, the diagnosis was made following repeated trips to the operating room on the suspicion of failed management of secondary peritonitis.

The effective treatment of tertiary peritonitis is multifaceted, although it has been described as representing the limit of surgical treatment of severe secondary peritonitis (11, 12). Patients suffering from tertiary peritonitis are often comorbid, malnourished, and metabolically deranged. Physiologic support often entails intensive care unit admission, administration of broad-spectrum antibiotics, and ensuring source control. However, pathogens cultured from the peritoneal cavity may be more of a symptom than a cause of critical illness (11). Cross-sectional imaging should confirm the absence of intra-abdominal abscess, anastomotic leakage, or failure of primary repairs that can be dealt with surgically. Unfortunately, by its very definition, there is no evident focus. Typically, only serosanguinous fluid upon reoperation is found in which selected microorganisms can be cultured (11).

It should be noted that the classic descriptions of tertiary peritonitis date from well before the critical importance of the human microbiome and consequences of pathological dysbiome in critical illness were understood. To our knowledge, the observations and theories related to tertiary peritonitis have NOT been updated to incorporate neither the modern understanding of the dysbiome nor the concept of the CARS syndrome. Dysbiosis defines a quantitate and functional change in the intestinal microbiota that alters immune responses, destabilizes intestinal homeostasis, and is associated with overgrowth of pathobionts (13). During critical illness/injury, there is a catastrophic loss of microbial diversity and induction of a state of severe dysbiosis (14). The loss of normal microbial diversity is met with overrepresentation by potentially pathogenic organisms, which combined with loss of gut barrier integrity, yielding a greater potential to translocate to extra-intestinal sites (15). It stands to reason that the risk factors and clinical setting, wherein tertiary peritonitis was previously described, will be almost certainly conditions in which a critically ill patient will have a radically pathological dysbiosis and likely CARS. In this case, further untargeted broad-spectrum antibiotic therapies could be disastrous. This opinion remains speculation as no good data exists, but does represent an area we think deserves urgent study and comprehensive overview of the different theoretical models.

An Egalitarian Challenge: A Universal Overview of Secondary Peritonitis

Secondary peritonitis respects the principles of egalitarianism, as it remains a potential threat to the health of all humans of all age groups, race, and socioeconomics, no matter how healthy. Globally, the cumulative burden of all pathology causing peritonitis is tremendous. Affecting both the developing and developed world alike, secondary peritonitis is a tremendous source of lost life, livelihood, and resources. Using data from the Global Burden of Disease Study (15, 16), Stewart et al. reported an estimated 896,000 deaths, 20 million years of life lost, and 25 million disability adjusted life years lost per year related to just 11 emergency general surgical conditions (17). The magnitude of DALYs lost to this illness is likewise staggering (18). The overall all-cause incidence of secondary peritonitis is difficult to gauge, but large-scale epidemiologic studies show secondary peritonitis accounts for 1% of all hospital visits and is the second leading cause of sepsis worldwide (19). Diffuse peritonitis in any form is a poor prognostic indicator, with mortalities as high as 20% in some studies (20). As many patients with secondary peritonitis present in extremis and require long ICU stays, the economic burden of secondary peritonitis is devastating.

Secondary Peritonitis and IAS Beyond Earth

Technically, secondary peritonitis is actually more than a global challenge, it is a truly universal one. One of the greatest medical challenges for manned exploration beyond our planet is acute surgical emergencies, such as appendicitis and cholecystitis, which may still occur in healthy, intensively screened astronauts for whom therapies will be extremely limited (21). Although the actual numbers of humans potentially affected by secondary peritonitis while traveling beyond low Earth’s orbit is few at the moment, addressing such questions relates to deriving improved therapies for earth. For example, terrestrial resource constrained environments with little or no options for transfer to further definitive care. Thus, solutions for space may spin-off solutions for earth. Very briefly, there are many challenges concerning secondary peritonitis in space, including an immunosuppressed patient with space-induced physiologic de-adaptations to cardiovascular stress, increased virulence and antibiotic resistance of space-borne pathogens, extreme limitations in diagnostic, treatment, and supportive capabilities, and especially a space-induced primary dysbiosis even before a secondary peritonitis occurs (22).

Importance and Global Impact of Secondary Peritonitis on the Earth Surface

Common etiologies of abdominal sepsis in the developed world included ruptured appendicitis, cholecystitis, perforated gastrointestinal cancers, and diverticular disease. With expedient access to elective surgical services, screening programs, and preventive medication (i.e. proton pump inhibitors), the outcomes of patients with abdominal sepsis has steadily improved in the developed world (23). However, despite remarkable gains in many areas of global health, provision of global surgery in low- and middle-income countries (LMICs) has stagnated or regressed. Case-fatality rates remain high for common, easily treatable conditions including appendicitis and hernia (24). Thus, it is not surprising that global surgery has been described as the “neglected stepchild of global health” (25). Although this has sometimes been assumed to be due to the costliness of surgery, in fact, surgery can be a highly cost-effective means of preventing disability adjusted life years, being on financial par with better-recognized and funded interventions such as HIV anti-retrovirals, malaria prevention, and diarrhea treatment (26). The Lancet Commission on Global surgery thus concluded that surgery is an “indivisible, indispensable part of health care and that surgical and anesthesia care should be an integral component of a national health system in countries at all levels of development” (24). Thus, treatments for secondary peritonitis that are applicable to all parts of the globe especially bear consideration.

This consideration is critical. Even in developed nations, a significant proportion of the population lives distant from surgical care. Time to intervention is a proven predictor of outcome in secondary peritonitis (27). Studies from developed nations with relatively expedient access to surgical services demonstrate mortality rates at 10.5% (23). Patients with prolonged IAS are more likely to present with severe metabolic compromise and exhaustion. This leads to prolonged ICU stays, open abdomens (OAs), and overall poorer outcomes. LMICs have been shown to have low numbers of surgeons per unit population, which is reflected in the dismal outcomes of even basic surgical pathologies in these underserved populations. This is compounded by the increased incidence of predisposing pathologies such as H. pylori, tuberculosis, and other infectious etiologies (17, 26, 27). More specifically, the poorest 2 billion people in the world have increased risk factors, disparities in access to care, and poorer outcomes in nearly every recorded surgical pathology. Thus, proven economical, cost-effective, and logistically simple therapies are especially needed to address the causes of secondary peritonitis in these parts of the world.

Pathophysiology of Secondary Peritonitis and IAS

Sepsis and septic shock

From a practical patient-orientated perspective, peritonitis most warrants consideration as marker of impending IAS. For example, even severe peritoneal irritation from blood emanating from a ruptured physiologic ovulation (Mittelschmerz) is uncomfortable, but not life-threatening as not associated with IAS. However, intrabdominal infection is the second most common cause of sepsis (27). Complicating the high incidence of IAS is high mortality estimated from 7.6% to 36.0% (23). Multiple factors have been shown to worsen prognosis in secondary peritonitis. Candidal infection, severe organ dysfunction (SOFA ⩾ 7), severe pre-existing comorbidities, inadequate source control, and inappropriate antibiotic administration play a role (28, 29). Once a patient meets criteria for septic shock, cardiovascular instability, sepsis-associated coagulopathy, and worsening organ failure drive mortality rates to over 50%, or even 80% in the developing world (30).

In 2016, definitions for sepsis and septic shock were revised. The Third International Consensus Definitions defines sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, emphasizing the critical concept to appreciate is the host’s self-destruction initiated by the primary pathology (31, 32). Organ dysfunction was defined by an increase in a sequential organ failure assessment (SOFA) score of 2 or more. Previous definitions of sepsis based on SIRS criteria in the presence of an infectious source were abandoned as being too focused on patient inflammatory response. Septic shock is defined as a “subset of sepsis in which particularly profound circulator, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone” (31, 32). This is recognized by the need for vasopressors to maintain adequate mean arterial pressure, and a serum lactate level > 2mmol/L after adequate resuscitation. Host response as manifested by sepsis and septic shock greatly dictates the management of intrabdominal infection. Decisions on gastrointestinal reconstruction, stoma formation, or damage control hinge on the metabolic/physiologic status of the patient. Thus, a “deeper dive” into the basic mechanisms of this dysregulated systematic self-destruction is warranted.

Microbial Factors

The microbiology of secondary peritonitis is evolving. The relatively recent recognition of microbial ecological shift in the setting of critical illness has led to increased understanding of the drivers of multi-organ failure (MOF). In addition, multi-drug resistant organisms have become commonplace worldwide. The Complicated intra-abdominal infections worldwide (CIAOW) study elucidated the increasing incidence of resistant organisms (27). Extended spectrum beta-lactamase (ESBL) producing Escherichia coli incidence nearly tripled worldwide from 2002 to 2008 (7). Klebsiella pneumoniae resistance is nearly 20%. Enterococci species, some of the most common pathogens isolated in nosocomial sepsis, have shown increasing resistance. Pseudomonas infection has been identified as an independent risk factor for mortality (33). Candidal infection likewise has been shown to drastically increase mortality in critically injured patients (34). As resistance patterns increase, the role of resistant organisms plays a larger and larger role in the outcomes of critically ill patients with abdominal sepsis. Thus, we believe all surgeons should support the Global Alliance for Infections in Surgery, which aims to include and educate all professionals involved in the battle against infections in surgery (35).

Inflammatory Cytokines

The dysregulated immune response is the pathophysiologic driver that results in the end-organ effects of sepsis. In the presence of infection, microbial pathogen-associated molecular patterns (PAMPs) are generated. In the case of trauma, pancreatitis, or other non-infectious insults, systemic inflammatory responses can be generated by the recognition of damage-associated molecular patterns (DAMPs). These inflammatory mediators activate toll-like receptors (TLRs) on sentinel cells of the immune system. These macrophages and dendritic cells initiate the inflammatory cascade responsible for the adverse end-organ effects of sepsis. Via activation from neutrophils, platelets have multiple immune functions in various immune pathways including inducing release of neutrophil extracellular traps, promoting degranulation, release of leukocyte-activating cytokines (CD40L), augmenting leukocyte adhesion, and even directly killing invading pathogens (36). Secondary peritonitis, being a surgical disease, primes the infected, physiologically exhausted patient for massive systemic inflammatory response with a combination of massive intraperitoneal bacterial burden, and invasive surgery for source control.

TLRs are pattern-recognition receptors expressed on endothelial and immune cells which are instrumental to the inflammatory response. Protein kinase cascades are activated within these cells, propagating the production of pro and anti-inflammatory cytokines. Specifically, IL-6, IL-8, IL-1/β, IL-10, MCP-1, TNF-α, Thromboxane A2, HMGB1, and thrombin are all among noted downstream effectors and cytokines produced by the TLR pathways. Intra-abdominal contamination and secondary peritonitis provide an ongoing source of PAMPs (via spillage of enteric content) and DAMPs (via direct damage to abdominal viscera and organs). This “Motor of Multisystem Organ Failure” provides ongoing cytokine fuel to the raging systemic response (37). For example, TNF-α and IL-1 are important pro-inflammatory cytokines. Each of these has been shown to induce vascular permeability, resulting in pulmonary edema and hemorrhage (38). IL-6 is a key molecule in the initiation of the fever response, activation of lymphocytes, and also plays a role in hematopoiesis. However, it has also been shown to induce myocardial depression (38). IL-12, interferon-γ, and macrophage migration inhibitor factor (MIF) all have roles in the upregulation of the immune system and likewise have described deleterious end-organ effects in sepsis. This again demonstrates that septic shock is more than just severe infection. The host response is paramount in the reaction of every patient facing septic insult, with a remarkable variance in host response based partially on sex, age, and especially genetics.

The Abdominal Inflammatory Reservoir and Inflammatory Lymph Flow

In the presence of secondary peritonitis, the abdominal cavity is a rich reservoir of inflammatory cytokines. Abdominal visceral damage, peritoneal irritation, and intrabdominal contamination are all potent triggers for systemic cytokine response. IL-6, IL-8, TNF-α, and IL-1β have all been shown to occur in high concentration in inflammatory ascites after abdominal visceral insult (39). Translocation of inflammatory cytokine from ascitic fluid into the systemic circulation has been demonstrated to occur via mesenteric lymph channels (40). The phrenic or diaphragmatic lymph system is also responsible for up to 70%–80% of fluid reabsorption from the abdominal cavity (41). Mesenteric and phrenic lymph channels eventually empty into the cisterna chyla, leading to the thoracic duct and systemic circulation. Disruption of this inflammatory flow may blunt the systemic inflammatory response, and ameliorate acute respiratory distress syndrome (ARDS) and MOF in animal models (42, 43). The peritoneal cavity and inflammatory ascites have become a target for intervention to blunt the systemic effects of intraperitoneal injury. Multiple studies have been performed testing the clinical effects of removing or diluting inflammatory ascites in the metabolically exhausted septic patient. The premise of these studies is that the removal of inflammatory cytokine from the peritoneal cavity prevents its lymphatic uptake and subsequent systemic circulation.

The Pathophysiology of Secondary Peritonitis Confounded by IAH

IAH is a ubiquitous feature of critical illness/injury. IAH is operationally defined as a sustained or pathologic intra-abdominal pressure (IAP) reading ⩾ 12 mm Hg. The abdominal compartment syndrome (ACS) is defined as IAP >20 mm Hg in the context of new organ failure. As the grade of IAH increases and persists in the first 14 days, so too does the risk of 28 and 90 day mortality (44). IAH and ACS are far more common in emergency cases, with secondary peritonitis making up a large proportion of these cases (44). Once a patient progresses to ACS, the mortality of this group of patients has been seen as high as 75.9%, with untreated or missed ACS having a mortality rate near 100% (44). Unfortunately, its influence is often minimized or ignored. However, it can be conceptualized as equating to “ischemia” and malperfusion of the viscera within the abdominal compartment and beyond (15).

Secondary peritonitis itself and especially subsequent therapies involving fluid resuscitation are significant risk factors for ACS, and thus some degree of IAH likely accompanies the majority of closed abdomens after diffuse peritonitis. Management of IAH is targeted toward each of these features. Early operative control of enteric spillage and bleeding is paramount. Intraluminal fluid should be aggressively drained with both gastric and rectal drainage. Detectable ascites is drained via percutaneous drainage. IAH induces profound effects that have adverse effects widely beyond the abdominal cavity that may be broadly considered physical and humoral.

Physical and Humoral Effects of IAH

IAH causes mechanical derangements of all organs within the abdominal cavity and beyond through polycompartment interactions. These derangements include well described respiratory compromise including worsening pulmonary edema and ARDS, cardiovascular, gastrointestinal, renal, and even central nervous system effects. What is less appreciated are the humoral effects of IAH, which reduces blood flow to the intestinal mucosa, causing increased permeability of the intestinal mucosal barrier (45). Locally, this causes irreversible mitochondrial damage and necrosis of the gut mucosa. Systemically, increased bacterial translocation and systemic endotoxemia are observed. Unsurprisingly, IAH, ACS, and loss of intestinal barrier function increase release of DAMPs and PAMPs into the systemic circulation. The resultant massive release of pro-inflammatory cytokines drives multi-system organ failure (MSOF), even after source control is achieved (46). Clinically, the common biochemical markers used in infection (white cell counts, platelet levels, and c-reactive protein levels) do not seem to correlate with the actual level of circulating cytokines. The importance and difficulty in controlling the shock resultant from secondary peritonitis and IAH cannot be overstated. Advances in the understanding of the drivers of shock, early source control, awareness and avoidance of IAH/ACS, and appropriate anti-microbial therapy all represents advancements in critical care which have improved the outcomes in sepsis and secondary peritonitis.

If a patient is to progress to overt ACS despite conservative treatment, decompressive laparotomy with temporary abdominal closure is indicated. What is not well understood, however, is what to do about lesser degrees of IAH that contribute to ischemia and likely catalyze MOF, which are below the threshold for formal laparotomy.

The Human Microbiome and The Induction of a Dysbiome in Critical Illness

A full understanding of the implications and consequences of secondary peritonitis is also immensely complicated by the fact that the intraperitoneal inflammation occurs within the body cavity containing the human microbiome. A fact, not yet fully understood or appreciated, is that humans are super-organisms, living in symbiosis with their microbiomes, the genetic diversity of which dwarfs that of the human host (47). There may be 150-fold more bacterial genetic material in the human–microbiome commensal (14), such that humans are more accurately classified as symbionts with their microbial constituents, upon whom the human’s health depends (14). At homeostasis, immune cells within the Peyers patches of the gut constantly sample intraluminal antigens and potentiate an immune response within gut-associated lymphoid tissues. In the absence of intestinal pathology, bacteroides and firmicutes species are common. Derangements in microbial balance may have a profound influence on the immune function of the gut, and in turn the overall response of the patient. Multiple hypotheses have been formulated to explain the role of the digestive tract in the immunologic response to intra-abdominal injury (IAI). An interesting avenue currently being explored involves the role of pancreatic proteases that disrupt the protective intestinal mucus layer, allowing downstream organ dysfunction. It is remarkable that while the CRASH-II trial found survival differences with therapy, there was no difference in bleeding between treatment groups suggesting another potential biological effect, which might involve gut mucosal stabilization (48, 49). Nonetheless, bacterial translocation through the portal system was long been a favored mechanism of systemic insult in abdominal pathology, but this theory now has been superseded by the gut-lymph hypothesis, as systemic sepsis from intra-abdominal sources happens in the absence of clear bacterial translocation (50). The gut-lymph hypothesis postulates that biomediators travel through the mesenteric lymph system to cause remote injury (14). Intestinal epithelial apoptosis and epithelial hyperpermeability have also been implicated in the propagation of MOF in abdominal sepsis.

Injury to the viscera can have a profound effect on the existing microbiome. The normal, healthy microbiome represents the most important host barrier to intestinal microbial pathogenesis (51). Interactions between normal, non-virulent gut bacteria, and potential pathogens are largely responsible for preventing host infection and immune response to otherwise pathogenic bacteria that constantly exist in the gut. Sudden injury to the gut causes rapid ecological collapse of the normal, protective intestinal microflora. For example, Lactobacilli have been shown to decrease by nearly 90% (52). In place of these “good” bacteria, an inflammatory microbiome takes hold. Klebsiella, Escherichia, Enterococcus, Staphylococcus, and Candida species replicate and dominate the injured gut. While many of these bacteria are known as commensal organisms in the digestive system, injury to the gut also increases horizontal transmission of pathogenic genes, transforming these bacterial symbiotes into virulent gut organisms. These microbes interact with pattern recognition receptors expressed by immune cells of the gut and activate the inflammatory cascade (53). While a complete review of the effect of ecological shifts on gut microflora is beyond the scope of this review, there is strong and compelling evidence to suggest the surgical pathologies within the gut trigger changes in intestinal microbial ecology, which has an effect on systemic inflammatory response.

Diagnosis of Secondary Peritonitis and IAS

To ideally care for a patient suffering from secondary peritonitis, the clinician has to both diagnose the anatomic problem responsible, assess and risk stratify the degree of physiologic derangement and host response to the anatomic cause as well as any local or systemic progression of the inciting pathology, including immediate complications.

Secondary peritonitis is typically a clinical diagnosis, although multiple adjuncts help to refine the optimal management of patients who do not require immediate exploratory laparotomy. In the era of advanced imaging, clinical examination remains important. The unstable patient with diffuse peritonitis requires immediate intervention without unnecessary further delay. Stable patients with more localized tenderness are amenable to workup with diagnostic imaging. Every intra-abdominal organ has the potential to cause secondary peritonitis, with a plethora of pathologies listed for each organ. There are nuances as complex and varied as there are patients. An example is locally perforated diverticulitis of the sigmoid colon. A macroperforation generating massive peritoneal irritation and profound systemic reaction with overt vasomotor changes would be clinically obvious requiring urgent laparotomy without further investigations. However, the same anatomic perforation in an anergic host with little systemic reaction might require advanced imaging to detect. A microperforation of the same organ, with a profound host reaction, might require both diagnostic imaging for diagnosis and multiple biochemical/hematological tests to assess the host response to the pathology and guide decisions regarding therapies.

Patients may present in various stages of hemodynamic instability ranging from normal hemodynamics to decompensated shock. Abdominal rigidity is a hallmark clinical exam finding. Patients may present with leukocytosis, acidosis, and high lactate levels, but this is not mandatory for diagnosis. While the physical exam is an integral part of the evaluation of the surgical patient, commonly taught findings may be absent. Less than half of patients with an acute abdomen will present with generalized peritonitis (19). Localized peritonitis is much more common. Physical exams may be unreliable in the steroid-dependent, obtunded, or paralyzed patient. Biochemically, complete blood counts are likely the most common laboratory investigation ordered. However, leukocytosis is an insensitive (53.5%) and relatively non-specific (73.7%) finding in acute abdomens. When combined with relative lymphopenia, specificity is increased (89.2%), but sensitivity suffers (47.8%) (54). CRP, largely considered an overly sensitive test, also fails to correlate with positive intra-abdominal pathology on computerized tomography (CT) scanning of the abdomen (54). However, due to this sensitivity, if the symptoms have lasted for more than 24 h and CRP is normal, IAI is very unlikely as the cause of symptoms.

Ultrasound imaging has a significant role in the diagnosis of the acute abdomen, especially in biliary, ovarian, and uterine pathology. It is often the initial diagnostic test of choice in children and pregnancy. Ultrasound has taken an increasingly prominent role in the diagnosis of appendicitis, while sensitivity is low (59%–78%), the specificity (73%–88%) can help augment the physical exam and avoid ionizing radiation (19, 55). While by no means an alternative to cross-sectional imaging, ultrasound can be effectively applied at the bedside by clinicians to augment convincing history or physical exam findings and we believe should be further adopted by practicing surgeons.

Enhanced CT has largely become the diagnostic workhorse of the modern workup of peritonitis. In the stable patient with an acute abdomen, CT scans interpreted by consultant radiologist are able to yield a correct diagnosis in >90% of cases (56). This is helpful not only in the decision to operate but also in planning surgical approach. In addition, management of diseases where percutaneous interventions abound, like diverticulitis, have been revolutionized by accurate cross-sectional imaging. The old adage of a 10% negative appendectomy rate has also been rendered near obsolete.

Treatment of Secondary Peritonitis and IAS

Akin to the dual responsibilities of diagnosis, optimal treatment of secondary peritonitis involves both managing the primary anatomic cause and treating or supporting the affected host. Ideal outcomes typically require a multi-disciplinary endeavor, involving surgeons, radiologists, and recognizing these are surgical diseases and the team should be surgeon-led.

Addressing the Macroscopic Physical Pathology: Source Control

It is critical to provide the earliest source control or management of whatever is causative. The failure to obtain adequate source control is an independent mortality predictor (57). The primary goals of operative intervention in secondary peritonitis remain constant; arrest of hemorrhage, control of contamination, and decisions regarding reconstruction or damage control are the basic tenants of the emergency laparotomy. Perforated or damaged viscera should be resected, or in very select cases, patched or repaired. Abscesses should be drained. If the decision for reconstruction is made, well perfused bowel ends should be brought together with airtight anastomoses.

Stable patients with localized disease may undergo diagnostic imaging studies to elucidate etiology, allowing for minimally invasive, percutaneous, or conservative techniques. Largely facilitated by advances in diagnostic imaging, non-operative management of multiple different etiologies of secondary peritonitis has become common. Uncomplicated diverticulitis has been managed with antibiotics and bowel rest for decades. More recently, randomized controlled as well as observational evidence has shown that uncomplicated diverticulitis may be managed with observation alone (58). Broad spectrum antibiotic therapy was not shown to significantly alter complications, recurrence, readmission, or need for surgery in patients with uncomplicated diverticulitis (58). Antibiotics have also been advocated for the treatment of uncomplicated appendicitis (59). This management has generated controversy, with recurrence rates at 1 year being over 20%, as well as higher rates of adverse events, longer hospital stays, and increased incidence of complicated appendicitis (60, 61). These management strategies depend on the body’s physiologic barriers to infection to establish source control. Laparoscopic interventions have become increasingly commonplace, such as for perforated duodenal and gastric ulcers. Laparoscopic Graham-patch repair may reduce hospital stay, as well as reduced post-operative pneumonia, cardiac events, and mortality (62). Laparoscopic lavage in diverticulitis, however, has an increased risk of reoperation and subsequent requirement for percutaneous drainage (63). Laparoscopic-assisted colon resections have gained acceptance. A recent Cochrane analysis of the subject showed that laparoscopic sigmoid resection in acute diverticulitis showed no difference between laparoscopic and open surgery with regards to mortality, anastomotic leak rates, or overall complications (64). Complications are now much more easily managed than previously, especially intra-abdominal abscesses. Intra-abdominal abscesses from diverticulitis, appendicitis, or other gastrointestinal perforation can be successfully treated in the stable patient with percutaneous drainage with or without antibiotic therapy, or even just with antibiotics alone.

Multiple questions still remain in the management of secondary peritonitis. Fecal diversion and stoma formation have long been considered the standard for destructive colonic pathology in critically ill patients. However, more recent retrospective literature has suggested that formation of anastomosis is safe in even the most critically injured patient. Currently, the debate between fecal diversion and primary anastomosis remains unanswered. Prophylactic surgical drainage after laparotomy is a common practice among acute care surgeons. Evidence for this practice is very scarce, but has demonstrated increased hospital stay, duration of operation, wound infection rates, and overall complication rate (65). The majority of operative management decisions in secondary peritonitis are evolving from being etiology dependent to more reflecting physiology and host response.

Managing the Host Response

Although the breach in the gastrointestinal tract initiates the disease, progressive organ failure is the ultimate cause of death. Thus, how to best arrest or mitigate this progressive organ dysfunction is critical. The initial steps in managing the critically ill victim of IAS consist of the full gamut of resuscitation/critical care capabilities. While a full description is beyond the scope of this review, one critical concern regards fluid resuscitation. Thankfully, massive crystalloid resuscitation has greatly fallen out of favor, replaced by permissive hypotension and the use of vasoactive agents. Although definitive scientific evidence is lacking, the modulation of the “saline Tsunami” that characterized gross over-resuscitation in the recent past appears one of the most profound evolutions in the care of the critically ill, in our opinion.

Beyond general supportive care, it is appealing to consider blocking or removing the mediators propagating progressive organ damage. Increased recognition of inflammatory cytokines as the driver for organ dysfunction in sepsis has opened the door for new potential treatments of the systemic inflammatory response in sepsis. For example, immunological monoclonal antibody therapies were designed against TNF-α, IL-1, and MIF. However, antibodies against these cytokines failed to show any meaningful mortality outcomes (66, 67). Similarly, there have been 100 s of inconclusive trials attempting to manipulate or block single mediator molecules without success (68). Currently, there have been no human trials for these therapies, and their use remains only a future possibility. It thus appears that other modalities will be required to better address the systemic effects of IAS.

Another potential option to potentially mitigate biomediator spillage from the abdominal cavity into the systemic circulation is to leave the abdominal cavity open, with some form of negative peritoneal pressure device. Such a technique in severe sepsis has been suggested to offer early identification and increased drainage of any residual infection, control any persistent source of infection, more effective removal of biomediator-rich peritoneal fluid, effective avoidance of IAH, and to safely allow for delayed gastrointestinal anastomoses (68). Despite the absence of compelling evidence of efficacy, use of the OA after laparotomy for sepsis is increasing being recommended.(69–71] This includes consensus recommendations from recognized societies such as the World Society of the Abdominal Compartment Syndrome and the World Society of Emergency Surgery who stated that despite lack of high-quality data, OA use might be an important option in the treatment of severe peritonitis (71), a position reaffirmed in 2018, although the lack of evidence was again emphasized (72).

Kirkpatrick et al. (73) demonstrated in a randomized controlled trial (RCT) that intraperitoneal negative pressure therapy associated with a mortality benefit over a less efficient home-made system in mixed trauma/non-trauma patients with OAs. However, they did not show any significant difference in levels of biomediators.

Peritoneal lavage is employed in an attempt to “wash out” not only peritoneal contaminants, but also dilute and remove peritoneal cytokines. While most laparotomies will be irrigated at some point, interest is again being directed toward continuous intraperitoneal lavage which may be combined with negative pressure peritoneal wound management systems. The most current and largest (albeit non-randomized) experience with this technique using isotonic fluid infusion found increased complications during the OA period, but no differences in mortality, entero-atmospheric fistula, or opening time.

Direct peritoneal resuscitation is a related technique infusing hypertonic dialysate fluid continuously into the peritoneal cavity (74). The perceived mechanism of action relates to the hypertonicity of the fluid. Hyperosmolarity is believed to dilate the arterioles of the gut and improve visceral blood flow counteracting the intestinal ischemia (74). An RCT performed by Smith et al. (75) in traumatized patients undergoing damage control surgery with massive transfusions showed improved fascial closure, less ICU days, shorter ventilation, and non-significant trends in 30 day mortality. Despite these data, the technique of direct peritoneal resuscitation has seemingly not caught. Cytokines within the peritoneal cavity have a clear effect on the systemic response to abdominal sepsis. Disrupting the transmission of these intraperitoneal cytokines into systemic circulation may be beneficial, although the perfect mechanism to accomplish this has yet to be elucidated.

The closed or open after Laparotomy (Cool) for source control in severe complicated IAS Trial

Thus, although unexplained, significantly improved survival with more efficient OA management using safer temporary abdominal closure devices does seem to warrant continued studies, especially as there appears to be much clinical adoption without sound scientific evidence to base this upon. Therefore, a multi-center multi-national prospective randomized trial addressing this question in those requiring source control laparotomies for severe complicated IAS has recently launched globally (68). Although critical care services are critically limited globally, employing the OA is logistically possible even in rudimentary critical care settings (76). Thus, if this technique truly abrogates systemic sepsis and post-peritonitis multiple organ failure, then this may be a truly impactful surgical strategy. We are therefore hopeful that this collaboration both answers a critical question in the management of secondary peritonitis/IAS, as well as lays a collaborative framework to continue to definitely answer critical questions for some of the world’s most vulnerable patients (77).