984078

research-article2020
SJS0010.1177/1457496920984078Secondary Peritonitis and Intra-abdominal SepsisT. W. Clements, et al.

Review Article
SJS
SCANDINAVIAN
JOURNAL OF SURGERY

Secondary Peritonitis and Intra-Abdominal

Sepsis: An Increasingly Global Disease in
Search of Better Systemic Therapies

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

1Foothills
Medical 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

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.
Key words: Peritonitis; secondary peritonitis; intra-abdominal sepsis; human microbiome; pathobiome;
multiple organ dysfunction syndrome

Overview
Although there are different classifications of peritoni-
tis, 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 con-
tainer within which inflammation from the primary
disease and subsequent therapies also cause abnormal

Correspondence:
A. W. Kirkpatrick, CD, MD, MHSc, FRCSC, FACS
Foothills Medical Centre
Department of Critical Care Medicine and Surgery Scandinavian Journal of Surgery
Cumming School of Medicine 1­–11
University of Calgary © The Finnish Surgical Society 2021
Article reuse guidelines:
1403—29 Street NW sagepub.com/journals-permissions
Calgary, Canada DOI: 10.1177/1457496920984078
https://doi.org/10.1177/1457496920984078
AB T2N 2T9 journals.sagepub.com/home/sjs
Email: Andrew.Kirkpatrick@albertahealthservices.ca
2 T. W. Clements, et al.
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 micro-
biome is within this compartment, the primary dis-
ease, intra-abdominal hypertension (IAH), and
systemic vasomotor changes quickly induce a patho-
logical 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 appropri-
ately 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 experi-
ence are required for every unique patient. There are
less options, however, to address the most severe sep-
tic cases resulting from secondary peritoneal patholo-
gies, 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 thera-
peutic adjunct that is increasingly being used and is
applicable in any healthcare setting, even in the devel-
oping 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 vis-
ceral 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 catas-
trophe 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, sec-
ondary, and potentially tertiary etiologies. Each of
these diagnoses have typical clinical presentations and
scenarios that accompany them. In the practical set-
ting, 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 suscepti-
ble 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 infec-
tion once the medium is seeded. In hospitalized cir-
rhotic 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 dialy-
sis 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 microbiol-
ogy of the infected fluid. Usually, SBP infection con-
sists 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 dial-
ysis 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 infection, prophylactic antibiotics
may be administered. More severe cases of non-resolv-
ing 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 Intra-abdominal Sepsis
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 com-
monly from a physical or functional disruption of the
integrity of the gastrointestinal tract, and thus the bacte-
rial 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 signifi-
cance and implications for morbidity and mortality gen-
erally 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 fol-
lowing 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 pro-
longed SIRS response and shock following effective
management of the inciting pathology causing second-
ary peritonitis. Often, the diagnosis was made follow-
ing 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 repre-
senting the limit of surgical treatment of severe sec-
ondary peritonitis (11, 12). Patients suffering from
tertiary peritonitis are often comorbid, malnourished,
and metabolically deranged. Physiologic support
often entails intensive care unit admission, adminis-
tration 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 cul-
tured (11).
It should be noted that the classic descriptions of
tertiary peritonitis date from well before the critical
importance of the human microbiome and conse-
quences 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
3
CARS syndrome. Dysbiosis defines a quantitate and
functional change in the intestinal microbiota that
alters immune responses, destabilizes intestinal home-
ostasis, and is associated with overgrowth of pathobi-
onts (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 set-
ting, 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 untar-
geted 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 egali-
tarianism, as it remains a potential threat to the health
of all humans of all age groups, race, and socioeco-
nomics, no matter how healthy. Globally, the cumula-
tive burden of all pathology causing peritonitis is
tremendous. Affecting both the developing and devel-
oped world alike, secondary peritonitis is a tremen-
dous 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 dis-
ability 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 sec-
ondary 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 perito-
nitis 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 sec-
ondary peritonitis while traveling beyond low Earth’s
orbit is few at the moment, addressing such questions
4 T. W. Clements, et al.
relates to deriving improved therapies for earth. For
example, terrestrial resource constrained environ-
ments 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 chal-
lenges 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 diag-
nostic, 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 devel-
oped world included ruptured appendicitis, cholecys-
titis, 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 pre-
venting disability adjusted life years, being on finan-
cial par with better-recognized and funded
interventions such as HIV anti-retrovirals, malaria pre-
vention, 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, treat-
ments 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 peritoni-
tis (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 num-
bers of surgeons per unit population, which is reflected
in the dismal outcomes of even basic surgical patholo-
gies in these underserved populations. This is com-
pounded 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 logisti-
cally 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, peri-
tonitis most warrants consideration as marker of
impending IAS. For example, even severe peritoneal
irritation from blood emanating from a ruptured
physiologic ovulation (Mittelschmerz) is uncomforta-
ble, 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 mor-
tality 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 pathol-
ogy (31, 32). Organ dysfunction was defined by an
increase in a sequential organ failure assessment
(SOFA) score of 2 or more. Previous definitions of sep-
sis based on SIRS criteria in the presence of an infec-
tious 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 man-
agement of intrabdominal infection. Decisions on gas-
trointestinal 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
 Secondary Peritonitis and Intra-abdominal Sepsis
(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) produc-
ing Escherichia coli incidence nearly tripled worldwide
from 2002 to 2008 (7). Klebsiella pneumoniae resistance is
nearly 20%. Enterococci species, some of the most com-
mon 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 dras-
tically increase mortality in critically injured patients (34).
As resistance patterns increase, the role of resistant organ-
isms 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 edu-
cate all professionals involved in the battle against infec-
tions in surgery (35).
Inflammatory Cytokines
The dysregulated immune response is the pathophysi-
ologic 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-infec-
tious 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 respon-
sible for the adverse end-organ effects of sepsis. Via acti-
vation from neutrophils, platelets have multiple immune
functions in various immune pathways including
inducing release of neutrophil extracellular traps, pro-
moting 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 mas-
sive systemic inflammatory response with a combina-
tion 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 peritoni-
tis 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 vascu-
lar permeability, resulting in pulmonary edema and hem-
orrhage (38). IL-6 is a key molecule in the initiation of the
5
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 like-
wise have described deleterious end-organ effects in sep-
sis. 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 abdomi-
nal 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 sys-
temic circulation has been demonstrated to occur via
mesenteric lymph channels (40). The phrenic or dia-
phragmatic lymph system is also responsible for up
to 70%–80% of fluid reabsorption from the abdomi-
nal cavity (41). Mesenteric and phrenic lymph chan-
nels 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 intraperi-
toneal 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 perito-
neal cavity prevents its lymphatic uptake and subse-
quent 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 patho-
logic 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 perito-
nitis 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
6 T. W. Clements, et al.
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 subse-
quent therapies involving fluid resuscitation are sig-
nificant risk factors for ACS, and thus some degree of
IAH likely accompanies the majority of closed abdo-
mens 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 poly-
compartment interactions. These derangements include
well described respiratory compromise including wors-
ening 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 sys-
temic endotoxemia are observed. Unsurprisingly, IAH,
ACS, and loss of intestinal barrier function increase
release of DAMPs and PAMPs into the systemic circula-
tion. 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 circulat-
ing cytokines. The importance and difficulty in control-
ling the shock resultant from secondary peritonitis and
IAH cannot be overstated. Advances in the understand-
ing of the drivers of shock, early source control, aware-
ness and avoidance of IAH/ACS, and appropriate
anti-microbial therapy all represents advancements in
critical care which have improved the outcomes in sep-
sis and secondary peritonitis.
If a patient is to progress to overt ACS despite con-
servative 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 for-
mal laparotomy.
The Human Microbiome and
The Induction of a Dysbiome in
Critical Illness
A full understanding of the implications and conse-
quences of secondary peritonitis is also immensely
complicated by the fact that the intraperitoneal inflam-
mation 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 tis-
sues. 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 poten-
tial biological effect, which might involve gut mucosal
stabilization (48, 49). Nonetheless, bacterial transloca-
tion 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 mes-
enteric lymph system to cause remote injury (14).
Intestinal epithelial apoptosis and epithelial hyperper-
meability have also been implicated in the propaga-
tion of MOF in abdominal sepsis.
Injury to the viscera can have a profound effect on
the existing microbiome. The normal, healthy microbi-
ome represents the most important host barrier to
intestinal microbial pathogenesis (51). Interactions
between normal, non-virulent gut bacteria, and poten-
tial 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 col-
lapse 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
 Secondary Peritonitis and Intra-abdominal Sepsis
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 ana-
tomic 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 imme-
diate complications.
Secondary peritonitis is typically a clinical diagno-
sis, although multiple adjuncts help to refine the opti-
mal 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 peritoni-
tis requires immediate intervention without unneces-
sary further delay. Stable patients with more localized
tenderness are amenable to workup with diagnostic
imaging. Every intra-abdominal organ has the poten-
tial 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 investi-
gations. However, the same anatomic perforation in
an anergic host with little systemic reaction might
require advanced imaging to detect. A microperfora-
tion 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 hemody-
namic instability ranging from normal hemodynamics
to decompensated shock. Abdominal rigidity is a hall-
mark 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 surgi-
cal 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 investi-
gation ordered. However, leukocytosis is an insensi-
tive (53.5%) and relatively non-specific (73.7%) finding
in acute abdomens. When combined with relative
lymphopenia, specificity is increased (89.2%), but sen-
sitivity suffers (47.8%) (54). CRP, largely considered an
overly sensitive test, also fails to correlate with posi-
tive intra-abdominal pathology on computerized
tomography (CT) scanning of the abdomen (54).
7
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 radia-
tion (19, 55). While by no means an alternative to
cross-sectional imaging, ultrasound can be effectively
applied at the bedside by clinicians to augment con-
vincing history or physical exam findings and we
believe should be further adopted by practicing sur-
geons.
Enhanced CT has largely become the diagnostic
workhorse of the modern workup of peritonitis. In the
stable patient with an acute abdomen, CT scans inter-
preted by consultant radiologist are able to yield a cor-
rect 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 dis-
eases where percutaneous interventions abound, like
diverticulitis, have been revolutionized by accurate
cross-sectional imaging. The old adage of a 10% nega-
tive 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 man-
aging the primary anatomic cause and treating or sup-
porting the affected host. Ideal outcomes typically
require a multi-disciplinary endeavor, involving sur-
geons, 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 opera-
tive intervention in secondary peritonitis remain con-
stant; 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 recon-
struction 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 man-
agement of multiple different etiologies of secondary
peritonitis has become common. Uncomplicated
8 T. W. Clements, et al.
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 man-
aged 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 recur-
rence 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 perfo-
rated 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 diverticuli-
tis, 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 lap-
aroscopic 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, appen-
dicitis, or other gastrointestinal perforation can be suc-
cessfully 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 sug-
gested that formation of anastomosis is safe in even
the most critically injured patient. Currently, the
debate between fecal diversion and primary anasto-
mosis 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 hospi-
tal stay, duration of operation, wound infection rates,
and overall complication rate (65). The majority of
operative management decisions in secondary perito-
nitis are evolving from being etiology dependent to
more reflecting physiology and host response.
Managing the Host Response
Although the breach in the gastrointestinal tract initi-
ates the disease, progressive organ failure is the ulti-
mate 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 resusci-
tation has greatly fallen out of favor, replaced by per-
missive 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 crit-
ically ill, in our opinion.
Beyond general supportive care, it is appealing to
consider blocking or removing the mediators propa-
gating progressive organ damage. Increased recogni-
tion 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 mon-
oclonal antibody therapies were designed against
TNF-α, IL-1, and MIF. However, antibodies against
these cytokines failed to show any meaningful mortal-
ity 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 possibil-
ity. 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 cav-
ity open, with some form of negative peritoneal pres-
sure device. Such a technique in severe sepsis has been
suggested to offer early identification and increased
drainage of any residual infection, control any persis-
tent source of infection, more effective removal of bio-
mediator-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 rec-
ognized 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 impor-
tant option in the treatment of severe peritonitis (71), a
position reaffirmed in 2018, although the lack of evi-
dence was again emphasized (72).
Kirkpatrick et  al. (73) demonstrated in a rand-
omized controlled trial (RCT) that intraperitoneal neg-
ative 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 intraperito-
neal 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
 Secondary Peritonitis and Intra-abdominal Sepsis
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 ventila-
tion, 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 sys-
temic 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 abro-
gates systemic sepsis and post-peritonitis multiple
organ failure, then this may be a truly impactful surgi-
cal strategy. We are therefore hopeful that this collabo-
ration both answers a critical question in the
management of secondary peritonitis/IAS, as well as
lays a collaborative framework to continue to defi-
nitely answer critical questions for some of the world’s
most vulnerable patients (77).
Declaration of conflicting interests
The author(s) declared the following potential conflicts of
interest with respect to the research, authorship, and/or pub-
lication 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.
9
ORCID iD
A. W. Kirkpatrick https://orcid.org/0000-0002-1692-5919
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Received: October 2, 2020
Accepted: December 7, 2020