984078 SJS Secondary Peritonitis and Intra-abdominal SepsisClements et al.

Review Article
SJS
SCANDINAVIAN
JOURNAL OF SURGERY

Scandinavian Journal of Surgery

Secondary peritonitis and intra- 2021, Vol. 110(2) 139­–149

© The Finnish Surgical Society 2021

abdominal sepsis: An increasingly

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DOI: 10.1177/1457496920984078
https://doi.org/10.1177/1457496920984078

global disease in search of better journals.sagepub.com/home/sjs

systemic therapies

T. W. Clements1, M. Tolonen2, C. G. Ball1 and A. W. Kirkpatrick1,3

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.

Keywords
Peritonitis, secondary peritonitis, intra-abdominal sepsis, human microbiome, pathobiome, multiple organ dysfunction
syndrome
Date received: 2 October 2020; accepted: 7 December 2020

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 mani-
fest as intra-abdominal sepsis (IAS). Sepsis has been recog-
nized 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 dis-
ease, intra-abdominal hypertension (IAH), and systemic
vasomotor changes quickly induce a pathological gut micro-
flora 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
1FoothillsMedical Centre, Department of Critical Care Medicine and
Surgery, Cumming School of Medicine, University of Calgary, Calgary,
AB, Canada
2HUS Helsinki University Hospital, Helsinki, Finland
3Canadian Forces Medical Services, University of Calgary, Calgary, AB,
Canada
Corresponding author:
A. W. Kirkpatrick, CD, MD, MHSc, FRCSC, FACS, Foothills Medical
Centre, Department of Critical Care Medicine and Surgery, Cumming
School of Medicine, University of Calgary, 1403—29 Street NW,
Calgary, Canada, AB T2N 2T9.
Email: Andrew.Kirkpatrick@albertahealthservices.ca
140 Scandinavian Journal of Surgery 110(2)
for every unique patient. There are less options, however, to
address the most severe septic cases resulting from second-
ary 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 criti-
cal 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 through-
out 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 stim-
uli on the peritoneal lining cause activation of visceral affer-
ent pathways that activate a reflex loop to the abdominal
wall musculature. The result is the splinting of the abdomi-
nal 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 cer-
tain 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 dissemi-
nate 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 immedi-
ate surgical exploration, while those with localized clinical
signs are often able to undergo further evaluation.
Although the focus of this review is on secondary perito-
nitis, it is important to appreciate that peritonitis, in general,
can be further classified into primary, secondary, and poten-
tially tertiary etiologies. Each of these diagnoses have typi-
cal 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 biomedi-
ators. 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 seed-
ing 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 hospi-
talized 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 perito-
neal dialysis catheters are more likely to become infected
with staphylococcus, pseudomonas, or pneumococcus spe-
cies 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 infec-
tion, prophylactic antibiotics may be administered. More
severe cases of non-resolving or recurrent peritonitis in
patients with indwelling peritoneal catheters may necessi-
tate 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 abdomi-
nal 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 peritoni-
tis is commonly polymicrobial. While gastrointestinal perfo-
ration causes direct spillage, secondary peritonitis can also be
seen due to ischemic gut, volvulus, or blood in the peritoneal
Clements et al. 141
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 mor-
tality 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 oper-
ating room on the suspicion of failed management of second-
ary peritonitis.
The effective treatment of tertiary peritonitis is multifac-
eted, 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 admis-
sion, 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, anasto-
motic 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 microorgan-
isms 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 knowl-
edge, the observations and theories related to tertiary perito-
nitis 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 micro-
bial 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 anti-
biotic 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 egalitarian-
ism, 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 peri-
tonitis 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 second-
ary 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 great-
est medical challenges for manned exploration beyond our
planet is acute surgical emergencies, such as appendicitis
and cholecystitis, which may still occur in healthy, inten-
sively 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 ther-
apies 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
142 Scandinavian Journal of Surgery 110(2)
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 capabili-
ties, 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, perfo-
rated gastrointestinal cancers, and diverticular disease. With
expedient access to elective surgical services, screening pro-
grams, and preventive medication (i.e. proton pump inhibi-
tors), 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, pro-
vision of global surgery in low- and middle-income coun-
tries (LMICs) has stagnated or regressed. Case-fatality rates
remain high for common, easily treatable conditions includ-
ing 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 some-
times been assumed to be due to the costliness of surgery, in
fact, surgery can be a highly cost-effective means of prevent-
ing 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 con-
cluded 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 sec-
ondary 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 devel-
oped 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 pro-
longed 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 dis-
mal 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 infec-
tion 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 con-
trol, and inappropriate antibiotic administration play a role
(28, 29). Once a patient meets criteria for septic shock, car-
diovascular 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-destruc-
tion initiated by the primary pathology (31, 32). Organ dys-
function 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 circu-
lator, 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 lac-
tate 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 forma-
tion, 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 rela-
tively recent recognition of microbial ecological shift in the
Clements et al. 143
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 world-
wide. 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 infec-
tions 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 molecu-
lar patterns (PAMPs) are generated. In the case of trauma, pan-
creatitis, 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 extracellu-
lar traps, promoting degranulation, release of leukocyte-acti-
vating cytokines (CD40L), augmenting leukocyte adhesion,
and even directly killing invading pathogens (36). Secondary
peritonitis, being a surgical disease, primes the infected, phys-
iologically exhausted patient for massive systemic inflamma-
tory 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 sec-
ondary 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 ini-
tiation 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 inter-
vention 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 inflamma-
tory cytokine from the peritoneal cavity prevents its lym-
phatic 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
144 Scandinavian Journal of Surgery 110(2)

too does the risk of 28 and 90 day mortality (44). IAH and contribute to ischemia and likely catalyze MOF, which are
ACS are far more common in emergency cases, with sec- below the threshold for formal laparotomy.
ondary peritonitis making up a large proportion of these
cases (44). Once a patient progresses to ACS, the mortality The human microbiome and the
of this group of patients has been seen as high as 75.9%,
with untreated or missed ACS having a mortality rate
induction of a dysbiome in critical
near 100% (44). Unfortunately, its influence is often illness
minimized or ignored. However, it can be conceptualized as A full understanding of the implications and consequences
equating to “ischemia” and malperfusion of the viscera of secondary peritonitis is also immensely complicated by
within the abdominal compartment and beyond (15). the fact that the intraperitoneal inflammation occurs within
Secondary peritonitis itself and especially subsequent the body cavity containing the human microbiome. A fact,
therapies involving fluid resuscitation are significant risk not yet fully understood or appreciated, is that humans are
factors for ACS, and thus some degree of IAH likely accom- super-organisms, living in symbiosis with their microbi-
panies the majority of closed abdomens after diffuse perito- omes, the genetic diversity of which dwarfs that of the
nitis. Management of IAH is targeted toward each of these human host (47). There may be 150-fold more bacterial
features. Early operative control of enteric spillage and genetic material in the human–microbiome commensal
bleeding is paramount. Intraluminal fluid should be aggres- (14), such that humans are more accurately classified as
sively drained with both gastric and rectal drainage. symbionts with their microbial constituents, upon whom the
Detectable ascites is drained via percutaneous drainage. human’s health depends (14). At homeostasis, immune cells
IAH induces profound effects that have adverse effects within the Peyers patches of the gut constantly sample intra-
widely beyond the abdominal cavity that may be broadly luminal antigens and potentiate an immune response within
considered physical and humoral. gut-associated lymphoid tissues. In the absence of intestinal
pathology, bacteroides and firmicutes species are common.
Derangements in microbial balance may have a profound
Physical and humoral effects of IAH influence on the immune function of the gut, and in turn the
IAH causes mechanical derangements of all organs within overall response of the patient. Multiple hypotheses have
the abdominal cavity and beyond through polycompartment been formulated to explain the role of the digestive tract in
interactions. These derangements include well described res- the immunologic response to intra-abdominal injury (IAI).
piratory compromise including worsening pulmonary edema An interesting avenue currently being explored involves the
and ARDS, cardiovascular, gastrointestinal, renal, and even role of pancreatic proteases that disrupt the protective intes-
central nervous system effects. What is less appreciated are tinal mucus layer, allowing downstream organ dysfunction.
the humoral effects of IAH, which reduces blood flow to the It is remarkable that while the CRASH-II trial found sur-
intestinal mucosa, causing increased permeability of the vival differences with therapy, there was no difference in
intestinal mucosal barrier (45). Locally, this causes irreversi- bleeding between treatment groups suggesting another
ble mitochondrial damage and necrosis of the gut mucosa. potential biological effect, which might involve gut mucosal
Systemically, increased bacterial translocation and systemic stabilization (48, 49). Nonetheless, bacterial translocation
endotoxemia are observed. Unsurprisingly, IAH, ACS, and through the portal system was long been a favored mecha-
loss of intestinal barrier function increase release of DAMPs nism of systemic insult in abdominal pathology, but this
and PAMPs into the systemic circulation. The resultant mas- theory now has been superseded by the gut-lymph hypoth-
sive release of pro-inflammatory cytokines drives multi-­ esis, as systemic sepsis from intra-abdominal sources hap-
system organ failure (MSOF), even after source control is pens in the absence of clear bacterial translocation (50). The
achieved (46). Clinically, the common biochemical markers gut-lymph hypothesis postulates that biomediators travel
used in infection (white cell counts, platelet levels, and through the mesenteric lymph system to cause remote injury
c-reactive protein levels) do not seem to correlate with the (14). Intestinal epithelial apoptosis and epithelial hyperper-
actual level of circulating cytokines. The importance and dif- meability have also been implicated in the propagation of
ficulty in controlling the shock resultant from secondary peri- MOF in abdominal sepsis.
tonitis and IAH cannot be overstated. Advances in the Injury to the viscera can have a profound effect on the
understanding of the drivers of shock, early source control, existing microbiome. The normal, healthy microbiome rep-
awareness and avoidance of IAH/ACS, and appropriate anti- resents the most important host barrier to intestinal micro-
microbial therapy all represents advancements in critical care bial pathogenesis (51). Interactions between normal,
which have improved the outcomes in sepsis and secondary non-virulent gut bacteria, and potential pathogens are
peritonitis. largely responsible for preventing host infection and
If a patient is to progress to overt ACS despite conserva- immune response to otherwise pathogenic bacteria that con-
tive treatment, decompressive laparotomy with temporary stantly exist in the gut. Sudden injury to the gut causes rapid
abdominal closure is indicated. What is not well understood, ecological collapse of the normal, protective intestinal
however, is what to do about lesser degrees of IAH that microflora. For example, Lactobacilli have been shown to
Clements et al. 145
decrease by nearly 90% (52). In place of these “good” bac-
teria, 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 bacte-
rial symbiotes into virulent gut organisms. These microbes
interact with pattern recognition receptors expressed by
immune cells of the gut and activate the inflammatory cas-
cade (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 sur-
gical pathologies within the gut trigger changes in intestinal
microbial ecology, which has an effect on systemic inflam-
matory response.
Diagnosis of secondary peritonitis
and IAS
To ideally care for a patient suffering from secondary peri-
tonitis, the clinician has to both diagnose the anatomic prob-
lem 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 man-
agement of patients who do not require immediate explora-
tory 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 local-
ized 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 var-
ied as there are patients. An example is locally perforated
diverticulitis of the sigmoid colon. A macroperforation gen-
erating massive peritoneal irritation and profound systemic
reaction with overt vasomotor changes would be clinically
obvious requiring urgent laparotomy without further inves-
tigations. 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 pathol-
ogy and guide decisions regarding therapies.
Patients may present in various stages of hemodynamic
instability ranging from normal hemodynamics to decom-
pensated shock. Abdominal rigidity is a hallmark clinical
exam finding. Patients may present with leukocytosis, aci-
dosis, 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 abdo-
mens. When combined with relative lymphopenia, specific-
ity 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 diagno-
sis 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 ioniz-
ing 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 work-
horse 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 addi-
tion, management of diseases where percutaneous interven-
tions 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 treat-
ment of secondary peritonitis involves both managing the
primary anatomic cause and treating or supporting the
affected host. Ideal outcomes typically require a multi-dis-
ciplinary 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 manage-
ment of whatever is causative. The failure to obtain adequate
146 Scandinavian Journal of Surgery 110(2)
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 lapa-
rotomy. 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 diag-
nostic imaging studies to elucidate etiology, allowing for
minimally invasive, percutaneous, or conservative tech-
niques. Largely facilitated by advances in diagnostic imag-
ing, non-operative management of multiple different
etiologies of secondary peritonitis has become common.
Uncomplicated diverticulitis has been managed with antibi-
otics and bowel rest for decades. More recently, randomized
controlled as well as observational evidence has shown that
uncomplicated diverticulitis may be managed with observa-
tion alone (58). Broad spectrum antibiotic therapy was not
shown to significantly alter complications, recurrence, read-
mission, or need for surgery in patients with uncomplicated
diverticulitis (58). Antibiotics have also been advocated for
the treatment of uncomplicated appendicitis (59). This man-
agement 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 strat-
egies 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 manage-
ment 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 descrip-
tion 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 per-
missive hypotension and the use of vasoactive agents.
Although definitive scientific evidence is lacking, the mod-
ulation 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 con-
sider blocking or removing the mediators propagating pro-
gressive 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 exam-
ple, immunological monoclonal antibody therapies were
designed against TNF-α, IL-1, and MIF. However, antibod-
ies 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 biomedi-
ator 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 tech-
nique in severe sepsis has been suggested to offer early iden-
tification 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 gastroin-
testinal anastomoses (68). Despite the absence of compelling
evidence of efficacy, use of the OA after laparotomy for sep-
sis is increasing being recommended.(69–71] This includes
Clements et al. 147
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 peri-
tonitis (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 effi-
cient home-made system in mixed trauma/non-trauma
patients with OAs. However, they did not show any signifi-
cant 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 man-
agement 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 infus-
ing 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 dam-
age 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 seem-
ingly 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 per-
fect 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 adop-
tion without sound scientific evidence to base this upon.
Therefore, a multi-center multi-national prospective rand-
omized trial addressing this question in those requiring
source control laparotomies for severe complicated IAS has
recently launched globally (68). Although critical care ser-
vices are critically limited globally, employing the OA is
logistically possible even in rudimentary critical care set-
tings (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 ques-
tion 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 vul-
nerable patients (77).
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: A.W.K. is the Principle Investigator of the Closed or Open
after Laparotomy for Source Control in Severe Complicated IAS
(https://clinicaltrials.gov/ct2/show/NCT03163095). A.W.K. has
also consulted for the Zoll, Innovative Trauma Care, and SAM
Medical Corporations. The remaining authors declare no conflicts
of interest.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
A. W. Kirkpatrick https://orcid.org/0000-0002-1692-5919
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