Post on 12-Mar-2022
Abdominal Center
Helsinki University Hospital
Doctoral Programme in Clinical Research
Faculty of Medicine
University of Helsinki
SSECONDARY PERITONITIS –
ASSESSMENT OF SEVERITY AND
MANAGEMENT OF OPEN ABDOMEN
Matt i Tolonen
ACADEMIC DISSERTATION
To be presented, with the permission of the Faculty of Medicine of the University of
Helsinki, for public examination in Lecture Room 2, Biomedicum Helsinki 1, on
October 4 2019, at 12 noon.
Helsinki 2019
Supervisors Professor Ari Leppäniemi, M.D., Ph.D.
Abdominal Center
Helsinki University Hospital
Helsinki, Finland
Adjunct Professor Panu Mentula, M.D., Ph.D.
Abdominal Center
Helsinki University Hospital
Helsinki, Finland
Reviewers Adjunct Professor Arto Rantala, M.D., Ph.D.
Division of Digestive Surgery and Urology
Turku University Hospital
Turku, Finland
Adjunct Professor Juha Saarnio, M.D., Ph.D.
Department of Surgery
Oulu University Hospital
Oulu, Finland
Opponent Professor Ronald V. Maier, M.D., F.A.C.S., F.R.C.S. Ed
(Hon.), FCSHK (Hon.)
Department of Surgery
Harborview Medical Center
University of Washington
Seattle, Washington, USA
The Faculty of Medicine uses the Urkund system (plagiarism recognition) to examine all doctoral dissertations.
ISBN 978-951-51-5132-2 (paperback)
ISBN 978-951-51-5133-9 (PDF)
Unigrafia
Helsinki 2019
TTABLE OF CONTENTS
ABSTRACT………………………………………………………………………………………6
TIIVISTELMÄ.………………………………………………………………………………...8
LIST OF ORIGINAL PUBLICATIONS……………………………………………..…10
ABBREVIATIONS.…………………………………………………………………………..11
1. INTRODUCTION.………………………………………………………………………..13
2. REVIEW OF THE LITERATURE……………………………………………………16
2.1 Definitions and classifications……………………………………………16
2.2 Etiology, pathogenesis, and microbiology……….…………………..18
2.2.1 Etiology………………………………………………………………………………18
2.2.2 Pathogenesis……………………………………………………………………….19
2.2.3 Microbiology……………………………………………………………………….19
2.3 Inflammatory response.……………………………………………..…….22
2.4 Diagnosis of secondary peritonitis……………………………………..23
2.4.1 Clinical presentation………………………………………………….………..23
2.4.2 Initial evaluation…………………………………………………………………24
2.4.3 Clinical examination……………….…………………………………………..24
2.4.4 Initial assessment of organ dysfunctions..…………….…….………..25
2.4.5 Laboratory tests…………………………………………………………….……26
2.4.6 Imaging studies………………………………………………………….……….27
2.5 Management of secondary peritonitis.………………………………..31
2.5.1 Initial resuscitation………………………….…………………………….…….31
2.5.2 Antimicrobial treatment………………………………………………..…….32
2.5.3 Source control……………………………………………………………………..33
2.5.4 Intraoperative peritoneal lavage and drainage……….……………36
2.5.5 Sepsis………………………………………………………………………………….37
2.5.6 Relaparotomy strategy………………………………………………………..37
2.5.7 Damage control…………………………………………………………………..38
2.5.8 Open abdomen………………………………………………………….………..38
2.5.9 Wound………………………………………………………………………….…….42
2.6 Outcome……………………….…………………………………………………42
2.6.1 Grading complications………………………………………………….……..42
2.6.2 Mortality rates……………………………………………………………….…..44
2.6.3 Organ dysfunctions………………………………………………………..……44
2.6.4 Other prognostic factors…………………………………………………..….45
2.6.5 Scoring systems…………………………………………………………….…….46
3. AIMS OF THE STUDY……………………….…………………….…………….…….51
4. MATERIALS AND METHODS……………………….………………………...…..52
4.1 Study hospital……………………….…………………….………………..….52
4.2 Study design……………………….…………………….……………………..52
4.3 Patients…………………..…….…………………….…………………….…...52
4.4 Data collection………………………….…………………….…………….…54
4.5 Definitions……………………….…………………….………………..……..54
4.6 Surgical methods…………………………….…………………….…………56
4.7 Intra-abdominal view (IAV)…..…………….…………………….……..56
4.8 Cytokines……………………….…………………….……………….………..57
4.9 Statistical analysis………………………….…………………….…..……..58
4.10 Ethical approval and study permissions……………………………59
5. RESULTS……………………….…………………….…………………….…………..…60
5.1 Study I………………………….…………………….…………………….…....61
5.1.1 Patient characteristics………………………..………………………………..61
5.1.2 Intraoperative data…………………………..…………………………………61
5.1.3 Postoperative data and outcome…………………………………………..61
5.1.4 Uni- and multivariable analyses…………………..……………….……..62
5.1.5 Subgroup analyses…………………………..……………..…………………..62
5.2 Study II…………………………………………………………………………...64
5.2.1 Patient characteristics………………………..………………………………..64
5.2.2 Open abdomen……………………………..…………………………………….64
5.2.3 Comparison between survivors and non-survivors………………..65
5.3. Study III…………………………………………………………………….…..66
5.3.1 Patient characteristics……………………………..……………………..……66
5.3.2 Univariable analysis……………………………..……………………….……66
5.3.3 Multivariable analysis and the Intra-Abdominal View Score.…69
5.3.4 Subgroup analysis………………………………..…………………………….70
5.4. Study IV………………………………………………………………………….71
5.4.1 Patient characteristics…………………..…………………..…………….…..71
5.4.2 Cytokines…………………..…………………..…..……………..…………..….71
6. DISCUSSION………………………….…..……………………………………………..74
6.1 Selection of outcomes……………………………….……………………...74
6.2 Mortality and morbidity…………………………….………………..……75
6.3 Preoperative disease severity assessment……………………….….76
6.4 Intra-abdominal view and intraoperative disease severity
assessment………………………………………….………………………………..76
6.5 Open abdomen…………………………….…………………………..………77
6.6 Cytokines…………………………….…………………..………………..……78
6.7 Strengths and limitations of the study………………………..………79
6.8 Future prospects……………………………….…………………………….80
7. CONCLUSIONS………………………….……………………….……………………..82
7.1 Study I……………………………….……………………….…………………..82
7.2 Study II……………………………….……………………….…………………82
7.3. Study III…………………………….……………………….……………..…..82
7.4. Study IV…………………………….……………………….……………..…..83
ACKNOWLEDGMENTS……..…………………………….………………………..…..84
REFERENCES………………………..…………………………………..………………….87
ORIGINAL PUBLICATIONS………………………..……………………………..….105
AABSTRACT
Background. Intra-abdominal infections are the second most common etiology for
sepsis. Secondary peritonitis results from a breach in the gastrointestinal tract. The
contents spilled into the peritoneum cause a local inflammation response,
characterized by the release of various cytokines. The inflammation may further
advance into systemic circulation and cause sepsis with associated organ
dysfunctions and a high risk of death with a need for intensive care unit
management, referred to as severe complicated intra-abdominal sepsis (SCIAS).
Other identified risk factors include advanced age, poor functional status, severe
comorbidities, immunosuppression, and prolonged delays in management. The
intra-abdominal view (IAV) has traditionally been classified as local or diffuse,
noting also the appearance of the exudate. However, various other findings in the
IAV may emerge during the operation such as bowel dilatation, peritoneal redness,
other exudates, and various degrees of fibrin coverage. Severely ill patients may
require multiple operations and occasionally the abdomen cannot be closed in the
index operation due to swelling, intra-abdominal hypertension, or fascial defect.
Open abdomen (OA) management with a temporary abdominal closure device has
been proposed as an effective treatment in these situations. However, OA
management entails some risks for the patient, most importantly the inability to
close the abdomen in subsequent operations and the development of
enteroatmospheric fistulas.
Aims. The pre- and intraoperative prognostic factors for SCIAS and mortality as
well as the applicability of vacuum-assisted wound closure and mesh-mediated
fascial traction (VAWCM) in the management of OA were evaluated.
Patients and methods. Studies I and II were retrospective studies and the data
were collected from electronic patient records of Helsinki University Hospital. Study
I comprised all consecutive patients with a diffuse secondary peritonitis in 2012-
2013. Study II consisted of all consecutive patients with a diffuse peritonitis and OA
managed with VAWCM during 2008-2016. The patients with a secondary peritonitis
for Studies III and IV were prospectively recruited during 2016-2018. Preoperative
blood samples for cytokine analyses were obtained and the operating surgeon filled
out a paper form to describe the IAV.
Results. In Study I, 223 patients were analyzed. The independent preoperative risk
factors for SCIAS or mortality were septic shock, chronic kidney insufficiency, severe
sepsis, and pre-existing cardiovascular disease. Patients lacking these risk factors
had no mortality. In Study II, 41 patients were analyzed. Delayed primary fascial
closure rate among survivors was 92% (n = 33). Enteroatmospheric fistulas
developed in three patients (7%), one of which was caused by OA. In Study III,
including 283 patients, independent risk factors for SCIAS or mortality in the IAV
were fecal or bile exudate, diffuse peritonitis, diffuse substantial redness of the
peritoneum, and a non-appendicular source of infection. Based on these results an
IAV score was developed and it correlated significantly with several outcomes. In
Study IV, consisting of 131 patients, various cytokines were associated with the IAV,
IAV score, and organ dysfunctions. Interleukin-8 was the most competent marker
associated with all the variables assessed here.
Conclusions. The risk for the development of SCIAS or death can be preoperatively
effectively predicted based on readily available risk factors. The most important risk
factors are sepsis-related organ dysfunctions and pre-existing chronic kidney
insufficiency or cardiovascular disease. Patients without these risk factors had no
mortality. Various preoperative circulating cytokine levels are associated with the
IAV and outcome. Interleukin-8 showed the best overall performance. In IAV, the
extent of peritonitis, diffuse substantial redness of the peritoneum, type of exudate,
and source of infection correlate independently with SCIAS or mortality. A high IAV
score is associated with various outcomes, including mortality and organ
dysfunctions. The IAV provides a rough estimate of the magnitude of the systemic
inflammatory response and the IAV score serves as a simple method to quantify the
response. Surgeons’ perception of the IAV is important and it should be documented
in detail. Combining components of the IAV and cytokine measurements into
comprehensive scoring systems could provide additional value in prognosis
assessment of individual patients. The VAWCM technique in the management of OA
in patients with peritonitis is highly effective with acceptable complication rates.
8
Taustat. Vatsaontelon infektiot ovat toiseksi yleisin syy sepsikselle. Sekundaarinen
vatsakalvotulehdus johtuu mahasuolikanavan puhkeamasta. Vatsakalvolle päässyt
erite aiheuttaa paikallisen inflammaatioreaktion, missä vapautuu useita sytokiineja.
Inflammaatio voi edetä systeemiseen verenkiertoon aiheuttaen sepsiksen sekä siihen
liittyviä elinhäiriöitä, joihin liittyy tehohoidon tarve ja suuri kuolemanriski. Myös
korkea ikä, heikko toimintakyky, vakavat oheissairaudet, immunosuppressio ja
pitkät viiveet hoidossa ovat tunnistettu riskitekijöiksi kuolemalle. Näkymä
vatsaontelossa on perinteisesti luokiteltu paikalliseksi tai yleistyneeksi tulehdukseksi
sekä vatsaonteloeritteen mukaan. Leikkauksissa nähdään kuitenkin muitakin
löydöksiä, kuten suoliston laajenemista, vatsakalvon punoitusta, erilaisia eritteitä
sekä monenasteisia fibriinikatteita. Vaikeimmin sairaat potilaat voivat tarvita useita
leikkauksia ja ajoittain vatsaonteloa ei saada suljettua ensimmäisessä leikkauksessa
turvotuksen, vatsaontelon ylipaineen tai faskiapuutoksen vuoksi. Avomahahoitoa on
käytetty tällaisissa tilanteissa väliaikaisen vatsaontelon sulkulaitteen kanssa.
Avomahahoitoon liittyy kuitenkin riskejä, tärkeimpinä kykenemättömyys lopulta
sulkea vatsaontelo sekä enteroatmosfäärisen fistelin kehittyminen.
Tavoitteet. Tämän tutkimuksen tavoitteina oli tutkia elinhäiriöiden ja kuoleman
riskitekijöitä ennen leikkausta ja leikkauksen aikana sekä verkkoavusteisen
alipainesidoksen käyttöä avomahahoidossa.
Potilaat ja menetelmät. Osatyöt I-II olivat takautuvia, potilaiden tiedot kerättiin
Helsingin yliopistollisen sairaalan sähköisistä potilaskertomusjärjestelmistä.
Osatyössä I kerättiin kaikki peräkkäiset yleistynyttä vatsakalvotulehdusta
sairastaneet potilaat vuosilta 2012-2013. Osatyöhön II kerättiin kaikki perättäiset
potilaat vuosilta 2008-2016, joilla oli yleistynyt vatsakalvotulehdus sekä
avomahahoito, jota hoidettiin verkkoavusteisella alipainesidoksella. Osatöissä III-IV
vatsakalvotulehduspotilaat rekrytoitiin etenevästi vuosina 2016-2018. Sytokiineja
tutkittiin ennen leikkausta otetuista verinäytteistä ja leikkaava kirurgi täytti
vatsaontelonäkymän kaavakkeen.
TTIIVISTELMÄ
Tulokset. Osatyössä I analysoitiin 223 potilasta. Septinen sokki, krooninen
munuaisten vajaatoiminta, vakava sepsis sekä olemassa oleva sydänverisuonisairaus
olivat ennen leikkausta todettavia itsenäisiä riskitekijöitä tehohoitoon joutumiselle
tai kuolemalle. Potilailla, joilla ei ollut mitään näistä riskitekijöistä, ei esiintynyt
kuolleisuutta. Osatyössä II analysoitiin 41 potilasta. Vatsaontelon viivästetty sulku
onnistui 92%:lla (n = 33) eloonjääneistä. Enteroatmosfäärinen fisteli kehittyi
kolmelle (7%) potilaalle, mistä yksi oli avomahahoidon aiheuttama. Osatyössä III
tutkittiin 283 potilasta, vatsaontelonäkymän itsenäiset riskitekijät tehohoitoon
joutumiselle tai kuolemalle olivat fekaalinen tai sappea sisältävä erite, yleistynyt
vatsakalvotulehdus, vatsakalvon yleistynyt voimakas punoitus sekä ei-
umpilisäkelähtöinen tulehduksen lähde. Näiden tulosten perusteella luotiin
vatsaontelonäkymän pisteytys, mikä korreloi merkitsevästi useiden hoitotuloksen
vastemuuttujien suhteen. Osatyö IV koostui 131 potilaasta, useat sytokiinit
assosioituivat vatsaontelonäkymään, sen pisteytykseen sekä elinhäiriöihin.
Inteleukiini-8 assosioitui parhaiten kaikkien tutkittujen vastemuuttujien osalta.
Johtopäätökset. Tehohoidon tarvetta tai kuolemanriskiä voidaan ennustaa
tehokkaasti jo ennen leikkausta käyttämällä tietoja olemassa olevista riskitekijöistä.
Tärkeimmät riskitekijät ovat sepsikseen liittyvät elinhäiriöt sekä olemassa olevat
krooninen munuaisten vajaatoiminta tai sydänverisuonisairaus. Ilman näitä
riskitekijöitä kuolleisuutta ei tutkimusaineistossa esiintynyt. Useat ennen leikkausta
verestä mitattavat sytokiinipitoisuudet assosioituvat vatsaontelonäkymään sekä
sairauden vakavuuteen. Interleukiini-8 toimi sytokiineista parhaiten.
Vatsaontelonäkymässä vatsakalvotulehduksen laajuus, runsas laaja-alainen
punoitus, eritteen laatu ja tulehduksen lähde korreloivat itsenäisesti tehohoidon
tarpeeseen tai kuolemaan. Korkeat pisteet vatsaontelonäkymästä ennustavat useita
hoidon vastemuuttujia, mukaan lukien kuolleisuutta ja elinhäiriöiden kehittymistä.
Vatsaontelonäkymä tarjoaa karkean arvion systeemisestä sytokiinivasteesta ja
pisteytys toimii yksinkertaisena tapana määrittää vatsaontelonäkymä.
Vatsaontelonäkymä on tärkeä ja kirurgin tulee kirjata se yksityiskohtaisesti.
Vatsaontelonäkymän osien ja sytokiinitasojen yhdistäminen kattaviin
pisteytysjärjestelmiin voisi tuoda lisäarvoa yksittäisen potilaan ennusteen
arviointiin. Verkkoavusteinen alipainesidos vatsakalvotulehduspotilaan
avomahahoidossa toimii erinomaisesti ja hyväksyttävissä olevin komplikaatioriskein.
LLIST OF ORIGINAL PUBLICATIONS
This thesis is based on the following articles, which are referred to in the text by
Roman numerals I-IV:
I. Tolonen M, Sallinen V, Mentula P, Leppäniemi A. Preoperative prognostic
factors for severe diffuse secondary peritonitis: a retrospective study.
Langenbecks Arch Surg. 2016; 401: 611-7.
II. Tolonen M, Mentula P, Sallinen V, Rasilainen S, Bäcklund M, Leppäniemi A.
Open abdomen with vacuum-assisted wound closure and mesh-mediated
fascial traction in patients with complicated diffuse secondary peritonitis: A
single-center 8-year experience. J Trauma Acute Care Surg. 2017; 82: 1100-
1105
III. Tolonen M, Sallinen V, Leppäniemi A, Bäcklund M, Mentula P. The role of the
intra-abdominal view in complicated intra-abdominal infections. World J
Emerg Surg. 2019; 14: 15
IV. Tolonen M, Kuuliala K, Kuuliala A, Leppäniemi A, Kylänpää M-L, Sallinen V,
Puolakkainen P, Mentula P. The Association Between Intraabdominal View
and Systemic Cytokine Response in Complicated Intraabdominal infections. J
Surg Res. 2019; 244: 436-443
AABBREVIATIONS
AKI Acute kidney injury
APACHE The Acute Physiology and Chronic Health Evaluation
ASA American Society of Anesthesiologists
AUROC Area under the ROC curve
CA Community-acquired
CARS Compensatory anti-inflammatory response syndrome
CCI Charlson Comorbidity Index
CCIn Comprehensive Complication Index
CD Clavien-Dindo
CI Confidence interval
cIAI Complicated IAI
CT Computed tomography
DAMP Danger-associated molecular pattern
DCS Damage control surgery
DPFC Delayed primary fascial closure
EAF Enteroatmospheric fistula
ESAS Emergency Surgery Acuity Score
ESBLp Extended-spectrum beta-lactamase producer
GI Gastrointestinal
HA Hospital-acquired
HGF Hepatocyte growth factor
IAI Intra-abdominal infection
IAS Intra-abdominal sepsis
IAV Intra-abdominal view
ICU Intensive care unit
IL Interleukin
IQR Interquartile range
MAP Mean arterial pressure
MARS Mixed antagonist response syndrome
MCP Macrophage chemoattractant protein
MDRO Multidrug-resistant organism
MIF Macrophage (migration) inhibitory factor
MPI Mannheim Peritonitis Index
MRI Magnetic resonance imaging
MRSA Methicillin-resistant Staphylococcus aureus
NEWS National Early Warning Score
NPWT Negative pressure wound therapy
OA Open abdomen
OR Odds ratio
PAMP Pathogen-associated molecular pattern
PIRO Predisposition, Infection, Response, and Organ Dysfunction
PRR Pattern recognition receptors
qSOFA Quick SOFA
RCT Randomized controlled trial
ROC Receiver operating characteristic
SCIAS Severe complicated IAS
SIRS Systemic inflammatory response syndrome
SOFA Sequential Organ Failure Assessment
SSI Surgical site infection
TAC Temporary abdominal closure
TNF-a Tumor necrosis factor alpha
US Ultrasound
VAWCM Vacuum-assisted wound closure and mesh-mediated fascial
traction
WSES World Society of Emergency Surgery
WSESSSS WSES Sepsis Severity Score
Introduction
11. INTRODUCTION
Intra-abdominal infections (IAIs) are a worldwide challenge. An intra-abdominal
source of infection is the second most common etiology for sepsis, and it is possibly
associated with the highest mortality1,2. Secondary peritonitis results from a
perforation in the gastrointestinal (GI) tract and a direct contamination of the
peritoneal cavity by spillage from the perforated or necrotic organ3,4. The infection is
local in about 55% of patients, with or without abscess formation, and diffuse in 45%
of patients5. The most common source of infection is appendiceal perforation,
followed by colonic, gastroduodenal, and small bowel perforations4. Incidence of
patients with secondary peritonitis undergoing operative treatment has been
estimated at 9.3 per 1000 emergency room admissions in the USA6.
Mortality in secondary peritonitis is usually reported to be 6-10% in unselected
patient cohorts5-7. Sepsis with organ dysfunctions is the most critical determinant of
survival, and the number of dysfunctioning organ systems correlates with
mortality3,4,6,8-10. Organ dysfunctions are present in 11-15% of patients, and roughly
half of these patients are suffering from septic shock, with associated mortalities of
21-40% and 37-70%, respectively5-9,11,12.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated
host response to infection11. In secondary peritonitis, the bacteria spilled into the
peritoneal cavity cause a local inflammatory response, which may rapidly progress to
systemic infection and sepsis. The initial local response is characterized by activation
of the innate immune system, molecules released from injured mesothelial cells, and
production of pro- and anti-inflammatory cytokines4,13. Serum levels of various
cytokines have been shown to be associated with development of acute organ
dysfunctions and mortality14. In this thesis, we studied the association between
various relevant cytokines and the components of the intra-abdominal findings,
development of organ dysfunctions, and mortality (Study IV).
Besides organ dysfunctions, there are other risk factors associated with adverse
outcomes. Patient-related risk factors include increasing age, poor nutritional or
Introduction
functional status, immunosuppressive medications, malignant diseases, and various
other comorbidities6,9,12,15.
Disease-related variables have also been identified as independent risk factors, and
diffuse peritonitis has worse prognosis than local infections6,12,16,17. Fecal peritonitis
has been considered more severe than other exudates16. Acute appendicitis as the
source of the infection has a far better prognosis than other sources4,6,12. There is
large variety in the intra-abdominal view (IAV) of patients with a secondary
peritonitis, yet the prognostic value of what a surgeon sees in the abdomen has
seldom been evaluated in the current literature. In this thesis, we systemically
analyzed the components of the IAV and their association with death or the
development of severe complicated intra-abdominal sepsis (SCIAS), which was
defined as intensive care unit (ICU) admission due to acute organ dysfunctions.
Based on the results, an IAV score was created (Study III).
Management-related risk factors include delayed or inadequate source control,
postoperative complications, and inadequate empiric antimicrobial
treatment12,16,18,19. Attempts have been made to create comprehensive scoring
systems to predict the outcome, yet at present these systems work more as research
tools than as clinical prognostic tools3.
In this thesis, readily available preoperative risk factors for a severe outcome, i.e.
ICU admission or death, in patients with diffuse secondary peritonitis were
investigated (Study I). The goal was to enhance the early recognition of patients at
high risk for severe outcome.
The management principles of secondary peritonitis are initial resuscitation, broad-
spectrum systemic empiric antimicrobial medication, timely source control,
peritoneal lavage with evacuation of infectious material, and restoration of GI
function20,21. Principles of resuscitation and sepsis management follow the current
sepsis guidelines21. Source control can be achieved with open or laparoscopic surgery
in most cases. Also, treatment without definitive source control can be considered in
selected stable patients most commonly suffering from diverticulitis or appendiceal
abscesses. Well-defined and localized abscesses can be drained using ultrasound- or
Introduction
computed tomography-guided drainage, small abscesses with antimicrobial
treatment only3,22.
Some complicated or critically ill patients need several operations. Open abdomen
(OA) management with negative pressure wound therapy (NPWT) has recently been
used and studied in these patients. A few animal and human studies even indicate
that OA with NPWT management enhances the resolution of organ dysfunctions and
lowers mortality23,24. Yet, currently no strong recommendations can be made
regarding OA’s role in the management of secondary peritonitis25-29. Management of
OA entails some inherent risks. Most importantly, an inability to close the abdomen
will result in the development of massive hernias and increase the risk of the dreaded
enteroatmospheric fistulas (EAFs). Combining NPWT with a continuous fascial
traction method promotes delayed primary fascial closure (DPFC) rates together
with the lowest reported EAF rates30-32. In this thesis, we evaluated the results of the
OA and NPWT combined with mesh-mediated fascial traction in patients with
secondary peritonitis (Study II).
Review of the literature
22. REVIEW OF THE LITERATURE
2.1 DEFINITIONS AND CLASSIFICATIONS
Intra-abdominal infection (IAI)
IAIs are a diverse collection of diseases. IAI is broadly defined as any intra-
abdominal infectious process with or without peritoneal inflammation15. IAIs are
further classified as uncomplicated or complicated based on the extent of the
infection.
Uncomplicated IAI
Uncomplicated IAIs are defined as intramural inflammation of the GI tract without
anatomic disruption33. These may develop into complicated IAIs. If an
uncomplicated IAI is treated by removing the affected organ, antibiotics are not
needed beyond surgical prophylaxis and severe forms of the disease are virtually
non-existent3,15.
Complicated IAI
Complicated IAI (cIAI) develops when the infection extends beyond the diseased
organ into the peritoneal cavity33.
Primary peritonitis
Primary peritonitis is also referred to as spontaneous bacterial peritonitis. There is
no identifiable breach in the GI tract. These infections are usually monobacterial and
the current hypothesis is that the infection occurs via bacterial translocation34.
Usually, a predisposing factor is present, the most common being peritoneal dialysis
catheter or liver cirrhosis with ascites. Primary peritonitis does not warrant surgical
care3.
Secondary peritonitis
Secondary peritonitis is the most common form of a cIAI. It results from loss of
integrity in the GI tract and direct contamination of the peritoneal cavity by spillage
Review of the literature
from the affected organ3. The infection may be local, with or without abscess
formation, or diffuse.
Tertiary peritonitis
The definition of tertiary peritonitis is not well established, although it has gained
acceptance as a distinct entity. Some authors define it as a secondary peritonitis that
persists for more than 48 hours after appropriate source control4,33. In a recent
multidisciplinary specialist consensus conference executive summary, this definition
was questioned. Tertiary peritonitis was considered to be an evolution and
complication of secondary peritonitis. The terms ongoing peritonitis and persistent
peritonitis were suggested to better reflect that this is not a different disease, instead
representing longer lasting secondary peritonitis with more selected, less virulent,
and resistant pathogens3. It is more common among critically ill or
immunocompromised patients33.
Intra-abdominal sepsis
Intra-abdominal sepsis (IAS) is defined as an IAI that results in sepsis or septic
shock as defined by the current sepsis definition guidelines. Sepsis is now defined as
a life-threatening organ dysfunction caused by a dysregulated host response to
infection11,15,33. The term severe complicated IAS (SCIAS) has been proposed in a
recent randomized controlled trial (RCT) protocol to describe both sepsis and cIAI
resulting from a disruption in the GI tract8,35.
Other definitions
Another differentiation used with IAIs is community- (CA) or hospital-acquired (HA)
IAI. This differentiation is useful especially in predicting the likelihood of multidrug-
resistant organisms (MDROs) causing the infection. Postoperative peritonitis is
included in the HA-IAI3,15. Healthcare-associated infection (HCAI) is another term
for infections acquired while receiving healthcare. Within IAIs, it includes all HA-
IAIs as well as infections in patients receiving intravenous therapy, wound care, or
nursing care at home during the last 30 days, attended to in a hospital in the
previous 30 days, hospitalized for two or more days during the previous 90 days, or
residing in a nursing home or long-term care facility36. However, these definitions
have varied across published articles37. Most publications regarding IAIs have used
Review of the literature
the CA/HA-IAI definitions, and therefore, HCAI is not well known in the concept of
IAIs.
Classification of intra-abdominal findings in secondary peritonitis
In secondary peritonitis, the intra-abdominal findings have been classified in
different peritonitis-specific prognostic scoring systems. The commonly used
Mannheim Peritonitis Index (MPI) distinguishes the extent of peritonitis (local or
abscess and diffuse generalized peritonitis) as well as the type of exudate (clear,
cloudy/purulent, or fecal)16. The diverticulitis-specific classic Hinchey classification
differentiates pericolic abscess, distant abscess, purulent, and fecal peritonitis17. The
globally validated World Society of Emergency Surgery (WSES) Sepsis Severity Score
(WSESSSS) for patients with cIAIs takes into account colonic non-diverticular
perforation, small bowel perforation, diverticular diffuse peritonitis, and post-
operative diffuse peritonitis12.
22.2 ETIOLOGY, PATHOGENESIS AND MICROBIOLOGY
2.2.1 Etiology
A breach in the GI -tract is caused by organ inflammation, necrosis, trauma,
distension, tumor, anastomotic dehiscence, or iatrogenic damage. The most common
organs as the source of the infection in secondary peritonitis were recently
summarized in a review article by Ross et al.4. This data was based on three large
studies: Anaya et al. 2003 (81 hospitals, State of Washington, USA, 11202 patients)6,
Gauzit et al. 2009 (66 French hospitals, France, 841 patients)38, and Sartelli et al.
2014 (68 hospitals worldwide, 1898 patients)5. Between these studies, there was
variability in the inclusion criteria as well as in the classification of the perforated
organ, and therefore, the results are not directly comparable. The most common
source of the infection was appendiceal perforation (31-50%), followed by colonic
(15-32%), gastroduodenal (8-18%), and small bowel (7-13%) perforations. Perforated
cholecystitis as an etiology was reported in 0.9% of patients in the study by Anaya et
al. and in 14.6% by Sartelli et al.5,6. Gauzit et al. reported biliary tract perforations
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(5.8%) as an etiology38. Perforation of the gallbladder freely to the abdomen is a rare
condition, as are perforations of any part of the biliary tract. Typical cholecystitis is
usually covered by the omentum, possible perforations tend to occur towards the
liver, and when this condition should be defined as secondary peritonitis remains
debatable. Postoperative peritonitis accounts for about 15% of all etiologies. The
most common reason for postoperative peritonitis is anastomotic dehiscence, but
iatrogenic lesions also occur5.
22.2.2 Pathogenesis
The peritoneum, a single layer of mesothelial cells of mesodermal origin, is
characterized by apical microvilli, fragility, and high turnover. It rests on a basal
membrane and a bed of connective tissue beneath the abdominal musculature. The
abdominal cavity is covered by the parietal peritoneum, which turns into the visceral
peritoneum to cover the abdominal viscera. The total surface of the peritoneum is
approximately 1.7 m2. It provides entry for the lymphatic vessels, blood, and nerves.
Under normal conditions, between the peritoneal surfaces there is a narrow space
called the peritoneal cavity, which contains about 50 ml of yellow sterile peritoneal
fluid produced by the mesothelial cells from plasma transudate and reabsorbed by
the peritoneum. This environment provides response to mechanical stress and allows
the organs to slide on one another. Also, the exchange of nutrients, growth factors,
cytokines, chemokines, leukocytes, and pathogen removal occurs via the peritoneal
fluid. Large particles and bacteria are cleared through the lymphatic channels
between the mesothelial cells, which are concentrated on the diaphragmatic surface.
This mechanism works as a pathway for peritoneal infections, especially uncontained
diffuse peritonitis, to rapidly progress to systemic infection, bacteremia, and sepsis.
In abscess formation the inflammatory response (Section 2.3) produces fibrinogen
on the inflamed organ and can create a mesh that reduces and blocks reabsorption of
peritoneal fluid. Also, the omentum adheres to the inflamed organ assisting in
abscess formation by delivering inflammatory mediators and cells4,39,40.
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22.2.3 Microbiology
Labricciosa et al. published a secondary analysis in 2018 combining two prospective
studies with cIAI patients. This study included 2152 patients from 68 European
centers and 1898 patients from 68 facilities worldwide41. Intraperitoneal
microbiological cultures were obtained from 2529 patients; 1954 cultures (77.3%)
were CA-cIAIs and 575 (22.7%) HA-cIAIs. Cultures were positive in 1986 patients
(78.5%) and contained a total of 3534 isolated micro-organisms. Isolated micro-
organisms according to the source of infection are presented in Table 1. The most
frequent micro-organisms were Escherichia coli (33.6%), Enterococcus faecalis
(9.1%), Klebsiella pneumoniae (7.5%), Bacteroides species (spp.) (6.4%),
Streptococcus spp. (5.7%), and Candida albicans (5.2%).
MDROs were cultured in 347 samples (9.8%) from 276 patients (13.9%). The most
common MDROs were Escherichia coli extended-spectrum beta-lactamase producer
(ESBLp), Klebsiella pneumoniae ESBLp, and methicillin-resistant Staphylococcus
aureus (MRSA) (Table 1). In the univariable analysis, patients with MDROs were
more likely to have inadequate empiric antimicrobial therapy, longer duration of
antimicrobial therapy, higher number of isolated micro-organisms, admission to
ICU, higher chance of reoperations, longer hospital stay, and higher in-hospital
mortality. In the multivariable analysis, the independent risk factors for MDRO
infections were HA-cIAI, preceding antimicrobial therapy, leukocytosis or
leucopenia, inadequate source control, and pre-existent severe cardiovascular
disease. The risk for MDRO infection was the highest in Eastern Mediterranean and
South-East Asian regions.
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TTable 1. Isolated micro-organisms from peritoneal fluid of patients with complicated intra-abdominal infections and proportion of MDROs with MDRO resistance pattern. IIsolated micro-
organisms MDROs of isolated micro-organism
MDRO resistance pattern
Gram-negative bacteria n, (%) n, (%)
Escherichia coli 1186 (33.6) 155 (13.1) ESBLp
Klebsiella pneumoniae 266 (7.5) 69 (25.9) / 11 (4.1)
ESBLp / ESBLp and carbapenems
Pseudomonas aeruginosa 160 (4.5) 8 (5.0) carbapenems
Enterobacter spp. 126 (3.6)
Acinetobacter baumannii 42 (1.2) 17 (40.5) carbapenems
Klebsiella oxytoca 11 (0.3) 2 (18.2) ESBLp
Gram-posit ive bacteria n, (%) n, (%)
Enterococcus faecalis 323 (9.1) 19 (5.9) glycopeptides
Streptococcus spp. 200 (5.7)
Enterococcus faecium 149 (4.2) 14 (9.4) glycopeptides
Staphylococcus aureus 108 (3.1) 32 (29.6) methicillin
Anaerobic bacteria n, (%) n, (%)
Bacteroides spp. 225 (6.4) 7 (3.1) metronidazole
Clostridium spp. 37 (1.0) 1 (2.7) metronidazole
Fungi n, (%) n, (%)
Candida albicans 183 (5.2) 4 (2.2) fluconatzole
Other Candica spp. 52 (1.5) 8 (5.4) fluconatzole
Modified from Labricciosa et al. 201841 Abbreviations: MDRO = multi-drug resistant organism, ESBLp = extended-spectrum beta-lactamase producing, spp. = species
A European study, as a part of the worldwide Study for Monitoring Antimicrobial
Resistance Trends (SMART), with 3030 clinical isolates from 13 countries and 43
hospitals was published in 2011 by Hawser et al.42. This study focused on Gram-
negative bacilli and the most commonly isolated species were Escherichia coli
(49.3%), Klebsiella pneumoniae (10.5%), and Pseudomonas aeruginosa (8.6%).
ESBL positivity was found in 11.6% of Escherichia coli, 17.9% of Klebsiella
pneumoniae, 5.5% of Proteus mirabilis, and 4.5% of Klebsiella oxytoca. Of the
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countries involved in the study, Turkey, Greece, and Portugal tended to have higher
resistance among Escherichia coli than Lithuania, Estonia, and France.
The role of intra-abdominal candidasis as an independent risk factor for mortality
has been investigated in several retrospective studies. Montravers et al. in 2006
concluded in a case-control study that Candida species appeared to be an
independent risk factor for mortality in nosocomial peritonitis43. In later studies, this
has not been confirmed. Yet, early treatment of Candida peritonitis is considered
essential, although differentiating true infection from colonization is difficult44-47.
The relationship between the bacterial species and hospital mortality in patients with
cIAIs was evaluated by Claridge et al. in 201448. There were 323 non-appendicitis
cIAI patients with 8.7% mortality. Clostridium infection was identified as an
independent risk factor for death, whereas Streptococcus infection was predictive of
better survival. Shah et al. investigated in 2016 whether polymicrobial cIAIs had
worse outcomes than monomicrobial cIAIs49. Their results did not support this
hypothesis.
22.3 INFLAMMATORY RESPONSE
A breach in the GI -tract results in the appearance of inflammatory stimuli at the
mesothelial surface. The stimulus leads to an early activation of cellular components
and plasmatic systems in the peritoneum by pattern recognition receptors (PRRs) of
the innate immune system. The PRRs detect pathogen- and danger-associated
molecular patterns derived from microbes and host tissues, respectively50.
Proinflammatory, regulatory, and chemotactic cytokines are first released by injured
mesothelial cells and especially by local macrophages with absorption and lymphatic
drainage of the bacterial material as well as phagocytosis. The local response attracts
neutrophils and they arrive within two to four hours. The local response may be able
to contain the source of contamination with the production of fibrin by the
coagulation cascade and attracting the omentum to cover the source of infection. The
systemic inflammatory response is dependent on the host’s ability to contain the
source of contamination4,13.
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In case of gross contamination or impaired host defensive capabilities, the local
response is not able to manage the source of infection and it may spread to the
systemic circulation, causing sepsis with associated organ dysfunctions. At this point,
the combined infectious and inflammatory process may continue as a life-
threatening dysregulated host response to infection despite adequate surgical
control, clearance of the infection, and proper antibiotics4,13. The current concept is
that both pro- and anti-inflammatory cytokines are elevated early in sepsis, resulting
in the co-existence of systemic inflammatory response syndrome (SIRS) and
compensatory anti-inflammatory response syndrome (CARS), creating a mixed
antagonist response syndrome (MARS). The CARS becomes predominant after early
SIRS, especially as sepsis severity increases. Therefore, septic patients are in an
immunosuppressive state and prone to further infections13,51,52.
Various inflammatory mediators have been investigated in IAS. In a systematic
review by Xiao et al., 182 studies were analyzed53. Of cytokines, proinflammatory
interleukin-6 has been the most extensively researched. The inflammatory
mediators play a critical role in sepsis, and studies have shown correlations with
various cytokines and organ dysfunctions as well as with mortality. Yet, currently
there is no consensus on the use of cytokine measurements in clinical work. This is
most likely due to the lack of rapid and automated measurements as well as missing
cut-off points for interpretation53. Serum levels of cytokines have shown a better
correlation with outcome than intraperitoneal cytokine levels14.
22.4 DIAGNOSIS OF SECONDARY PERITONITIS
2.4.1 Clinical presentation
Acute abdominal pain is the most typical reason for seeking medical attention by
patients with secondary peritonitis. Patients usually lie still and avoid moving since it
often propagates the pain. Innervation of the parietal and visceral peritoneum is
distinct. Innervation of the parietal peritoneum derives from phrenic, thoraco-
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abdominal, subcostal, and lumbosacral nerves. Innervation of the visceral
peritoneum, in turn, is not as clearly understood, but it seems to occur through the
splanchnic nerves and the celiac and mesenteric plexuses. Therefore, peritonitis in
the parietal peritoneum is experienced more locally, sharply, and constantly. If
parietal peritonitis is close to the superficial muscles, palpation of the abdomen may
show rigidity and guarding of the muscles. Guarding is also commonly referred to as
”defénce musculaire” or merely ”defénce”. By contrast, peritonitis only in the visceral
peritoneum presents as a more blunt, less localized discomfort and pain in an area
corresponding to the associated afferent nerves4,39,40. Any intra-abdominal
inflammatory process may result in paralytic ileus, which presents as abdominal
distention, obstipation, and vomiting15. These often lead to dehydration with possible
hypotension. Other symptoms may occur if organ dysfunctions due to sepsis develop.
These include respiratory insufficiency, hypotension, and altered mental status11.
22.4.2 Init ial evaluation
Every patient with acute abdominal pain should initially be evaluated in a rapid and
focused manner to assess the severity of the patient’s clinical condition. Those with
compromised organ functions or suspicion of fast deterioration should be identified
and triaged. A swift clinical examination is done, including abdominal rigidity
assessment. If suspicion of IAS arises, fluid resuscitation, organ function support,
and monitoring should be initiated without delay. Blood cultures as well as
laboratory tests should be obtained and empiric antibiotics started. The first decision
to make is whether to proceed to immediate surgery or whether the patient can
tolerate a delay for diagnostic imaging studies4,54. When ileus is suspected, a
nasogastric tube should be placed to avoid emesis and aspiration of gastric contents.
2.4.3 Clinical examination
The clinical examination of all patients with acute abdominal pain follows the same
principles. Thorough patient medical, surgical, and social history should be sought.
The acute pain history often suggests further examinations; time and mode of onset,
progression, previous episodes, severity, region, radiation, and quality of pain need
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to be assessed. Also, positional changes of pain, and alleviating and provoking factors
are important. Other symptoms, concerning especially the GI -tract and the
urogenital tract, should be examined. Abdominal examination includes inspection,
auscultation, percussion, and palpation of the abdomen as well as palpation of the
femoral pulses and a rectal examination. Special attention should be paid to the
location of the pain in palpation, abdominal guarding, and signs of hernia.
Provocative tests for specific diagnoses may be used54,55.
The diagnostic accuracy of the abdominal auscultation has been questioned in
several small studies56-59. Therefore, caution must be taken in the interpretation of
auscultation. Pain relief with opioids prior to clinical examination has been shown
not to deteriorate the accuracy of the physician’s ability to evaluate the clinical
status60,61. Reliability of the abdominal palpation in obese, immunosuppressed, or
elderly patients, and in those with impaired consciousness may be diminished62-65.
Care should be taken not to overestimate the role of the abdominal palpation,
especially in these patient groups. All abdominal complaints with signs of infection
warrant further diagnostic studies.
22.4.4 Init ial assessment of organ dysfunctions
Organ dysfunctions are by far the most important prognostic factor for all patients
with sepsis, and cIAIs are the second most common etiology for sepsis1,8,11. Sepsis-
related organ dysfunctions develop as a continuum from the onset of infection. The
organ systems that should be observed are respiration, circulation, mentation,
diuresis, coagulation, and hepatic function11. An important assessment point is
during the initial evaluation in a hospital when the vital functions are measured. The
number and the nature of organ dysfunctions in the emergency department
assessment predict mortality well10,66. Different scoring systems are discussed in
detail in Section 2.6. In the emergency department setting, the National Early
Warning Score (NEWS), developed in 2012 by the Royal College of Physicians in the
United Kingdom, seems currently to have the best performance as a screening tool to
predict mortality and ICU admission67-71. The NEWS was updated to NEWS2 (Figure
1) in 2017, but doubts have been raised whether the now version is actually superior
to the original NEWS67,72.
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FFigure 1. The NEWS scoring system with thresholds and triggers. Reproduced with permission from: the Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardizing the assessment of acute-illness severity in the NHS. Updated report of a working party. London: RCP, 2017. Abbreviations: Sp02 = peripheral capillary oxygen saturation, CVPU = Confusion, Voice, Pain, Unresponsive Notes: SpO2 Scale 2 is used only if target range is 88-92%, e.g. in hypercapnic respiratory failure. Consciousness score only if new onset of confusion.
2.4.5 Laboratory tests
There are a variety of laboratory tests with a well-established role in diagnosis of
specific pathologies in the abdomen, such as pancreatitis, cholangitis, and
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appendicitis. However, in secondary peritonitis, no disease-specific laboratory tests
exist and they have a limited role in the diagnostic process4. The commonly used
laboratory tests for inflammation, such as white blood cell count and C-reactive
protein (CRP), lack specificity4. Also, CRP levels rise with a delay of 6-8 hours,
peaking at 48 hours, and therefore CRP may not be elevated in the primary
evaluation early after the onset of the disease73. Serum lactate acts as a marker of
systemic hypoperfusion and is independently associated with mortality in patients
with surgical sepsis. It has also been suggested for inclusion in mortality-predicting
scoring systems74,75. However, it must be noted that lactate entering the portal
circulation into the liver is cleared in large quantities via gluconeogenesis and the
Cori cycle4. Procalcitonin levels in emergency department have shown to correlate
with the severity of sepsis76. To summarize, laboratory tests in secondary peritonitis
are too unspecific as diagnostic tools, but are helpful in assessing disease severity.
2.4.6 Imaging studies
Historically, the decision to operate on suspected secondary peritonitis has been a
clinical diagnosis. Still, the latest guidelines and reviews suggest that patients with
convincing clinical findings of secondary peritonitis do not need imaging. These
findings include local or diffuse abdominal rigidity and instable hemodynamics or
sepsis-related organ dysfunctions. Imaging studies are considered not to alter the
need for the immediate laparotomy, merely resulting to unnecessary delay and
possibly impaired prognosis3,4,39,77. However, in the case of suspicion of an acute
mesenteric ischemia, a computed tomography angiography is recommended prior to
operation in order to guide the vascular intervention78-80. Also, occasionally, rapid
onset acute pancreatitis may mimic secondary peritonitis and it should be ruled out
since early operation provides no advantages for the patient. In decision-making
about whether to proceed to the operating room or request further imaging, local
circumstances and the delay associated with the chosen imaging study must be taken
into account.
Computed tomography (CT) with intravenous contrast media is the golden
standard of abdominal imaging in stable patients with suspected secondary
peritonitis, as well as in selected unstable patients4,62,77. Common signs of cIAI are
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free fluid and air in the abdominal cavity, along with peritoneal thickening as a sign
of peritonitis. CT has the best-reported sensitivity and specificity, and other
strengths include rapid imaging, wide availability, and operator independency.
Additionally, both surgeons and radiologists are experienced in the interpretation of
the images. Drawbacks include exposure to ionizing radiation and the preferred use
of iodinated contrast media4,81,82. A RCT by Ng et al. in 2002 compared early CT and
standard practice with 120 participants and concluded that the CT missed
significantly fewer severe diagnoses and it might reduce hospital stay and inpatient
mortality83. Another RCT by Lehtimäki et al. in 2013 with 254 patients stated that
the CT should not replace clinical judgment as the first-line diagnostic tool since this
strategy only provides more expenses and overuse of hospital resources without
clinical benefit84. A large Dutch study with 1021 patients presenting with acute
abdominal non-traumatic pain concluded that the preferred imaging strategy was
ultrasound first and CT only if needed. This strategy resulted in the best sensitivity
with lower exposure to radiation81. Allergic reactions may hinder the use of a contrast
media. Intravenous contrast use in CT has been linked to acute kidney injury (AKI),
but the latest meta-analysis based on observational studies with more than 100 000
patients found no evidence to support this relationship. It is more likely that other
patient- and disease related factors contribute to the development of the AKI85.
However, it must be noted that there are no RCTs with septic patients at substantial
risk for an AKI. The use of an oral contrast medium in CT for acute abdominal pain
has a wide variation in clinical practice. It may have several disadvantages: causing
delay, being cumbersome for patients who do not tolerate enteral feeding, possible
adverse events related to the contrast itself, and inability to provide more accurate
diagnosis. Current data do not support the routine use of an oral contrast agent86.
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FFigure 2. Computed tomography scans.
A. Diverticulitis perforation with free air in the abdominal cavity. B. Free air and fluid as signs of gastrointestinal perforation in the abdomen.
Plain abdominal radiography has historically been used as a routine
examination in patients with abdominal pain. Indications have thereafter been
limited to suspected bowel obstruction, bowel perforation, and foreign bodies. In all
of these scenarios, CT provides superior information on the associated pathologies
with much better sensitivity and specificity. Advances in CT technology and
individualization of the imaging protocols have also brought the levels of radiation
exposure to levels comparable with plain abdominal radiography87,88. Several
guidelines and reviews conclude that there is no place for plain abdominal
radiography in the workup of adult patients with acute abdominal pain presenting in
the emergency department88-90. When there is no CT available, plain abdominal
radiography may be considered.
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Figure 3. Chest radiography showing free air below the diaphragm as a sign of pneumoperitoneum.
Ultrasound (US) provides many advantages over the other imaging studies. It
augments the physical examination and is portable, quick to perform, ionizing
radiation-free, contrast-free, safe in pregnancy, and relatively specific. Disadvantages
include high dependence on operator skill, limited visibility especially dependent on
the body habitus and abdominal gas, and inferior sensitivity relative to the CT4,81.
Guidelines recommend the use of US especially in the right upper quadrant pain as
the first line of imaging89,90. Also, a staged approach has been proposed in unselected
patients with abdominal pain or suspected appendicitis, with the US first and the CT
only if the US is inconclusive81,91.
Magnetic resonance imaging (MRI) also offers many advantages. There is no
ionizing radiation, contrast media is not needed, it is operator-independent, and
results in some diagnoses of similar sensitivity and specificity to the CT. The
limitations include slowness, less familiar interpretation for radiologists and
especially surgeons, high cost, limited availability, and incompatibility issues with
some cardiac pacemakers and orthopedic implants4,89,90. In appendicitis, especially
in pregnancy, and in diverticulitis, MRI has showed good accuracy89. MRI does not
have an established role in the diagnostics of suspected secondary peritonitis, with
the exception of pregnant patients89,90,92.
Diagnostic bedside laparoscopy has been used especially in critically ill
patients as a minimally invasive diagnostic bedside tool. Research data are scarce
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and the study settings are not comparable with current diagnostic modalities. This
method has not gained large acceptance in clinical practice89,93,94.
22.5 MANAGEMENT OF SECONDARY PERITONITIS
2.5.1 Init ial resuscitation
If signs of sepsis or septic shock emerge in the patient’s initial evaluation, fluid
resuscitation should begin immediately. Resuscitation in sepsis or septic shock
follows the same principles regardless of the etiology. Therefore, the resuscitation in
patients with an IAS follows the current guidelines of sepsis management21,62,95.
Balanced crystalloids are the preferred initial fluid and the resuscitation should begin
with 30 ml/kg within the first three hours. Additional fluid administration should be
guided by a frequent reassessment of the hemodynamic status. Dynamic variables
are primarily recommended to predict the response to the fluids, with an initial
target mean arterial pressure (MAP) of 65 mmHg and normalized lactate levels. In
IAS patients, intra-abdominal pressure should be monitored and abdominal
perfusion pressure estimated. An early goal-directed therapy, including central
venous pressure and central venous oxygen saturation measurements, was
introduced in 2001 with intriguing results96. In three later high-quality large
multicenter studies, this approach was challenged since it did not provide any
survival benefit97-99. The most important tissue perfusion measurement is the MAP.
In addition to balanced crystalloids or saline, albumin may be used to replace the
intravascular volume, when substantial amounts of liquids are needed. Hydroxyethyl
starches should not be used due to the high suspicion of increased risk of death as
well as the need for renal replacement therapy21. If vasoactive medications are
needed to sustain the MAP at the target level of >65 mmHg, the first-choice
vasopressor is norepinephrine. An arterial catheter should be placed to monitor the
MAP. Norepinephrine may be combined with vasopressin or epinephrine to decrease
the norepinephrine dosage. Dopamine as an alternative to norepinephrine should
only be used in highly selected patients21. The early actions in patients with a
suspected sepsis are summarized in Table 2.
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TTable 2. The sepsis six. 1. Deliver high-flow oxygen to keep saturations > 94% 2. Take blood cultures and consider source control 3. Administer empiric intravenous antibiotics 4. Start intravenous fluid resuscitation 5. Measure serial blood lactate levels 6. Monitor urine output All within one hour Modified from Daniels et al.100
2.5.2 Antimicrobial treatment
Intravenous antimicrobials should be initiated as soon as possible, preferably within
one hour, after recognition of patients with suspected sepsis or septic shock. Each
hour in delay has been shown to have an adverse effect on organ dysfunctions and to
increase mortality21. Two sets of blood cultures for microbiologic samples should be
obtained prior to initiating antimicrobial treatment21. In IAS, empiric broad-
spectrum antimicrobials to cover all likely pathogens should be chosen. Special
attention should be paid to the probability of MDROs (see Section 2.2.3) when
selecting the empiric antimicrobial agents. The decision should also be based on local
incidence of MDROs, their sensitivity patterns, and local guidelines4,41,62,101.
Inappropriate initial empiric antimicrobial therapy has been associated with adverse
outcomes and higher mortality in patients with secondary peritonitis102,103. The
empiric therapy should be narrowed down once the infectious pathogens and their
sensitivities have been established from the blood and the intraperitoneal cultures.
For SCIAS, with adequate source control, 7-10 days of antimicrobial treatment is
generally sufficient, unless there are exceptional treatment requirements for the
pathogens or the patient21. In the case of a rapid clinical resolution, shorter courses
of antibiotics may be considered. Procalcitonin levels may aid in decision-making for
discontinuation of antibiotics21.
Shorter durations of antimicrobials in cIAIs have been recently studied. Sawyer et al.
published a multicenter RCT in 2015, with 518 cIAI patients and adequate source
control, for fixed 4±1 days versus two days after the resolution of fever, leukocytosis,
and ileus (maximum 10 days of therapy). No differences emerged in outcomes104. In
this study, there were some issues in adherence to the protocol and the number of
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septic patients was not reported. Another RCT in 2008 compared three versus five or
more days of Ertapenem in 111 non-septic CA-IAI patients and found no differences
in clinical outcomes105. In a recent systematic review comparing shorter (3-5 days)
versus longer duration of antimicrobial treatment, no differences in outcomes were
observed in patients with secondary peritonitis106.
2.5.3 Source control
Source control is defined as all measures taken to discontinue the ongoing
contamination and to eliminate the source of the infection. Timing and adequacy of
the source control are essential parts of the management of secondary peritonitis3.
Failed or late source control has been recognized as an independent risk factor for
adverse outcome3,107-109.
The Surviving Sepsis Guidelines state that in patients with sepsis or septic shock
requiring source control it should be implemented as soon as medically and
logistically possible after the diagnosis is made21. The urgency is dependent of the
anatomical and physiological severity of the secondary peritonitis. In contained local
infections without sepsis, it is probably safe to postpone surgery for up to 24 hours as
long as conservative treatment is given3. In patients with sepsis or septic shock, it
remains to be determined whether some patients would benefit from a short period
of resuscitation prior to operation, although this has been suggested4. On the other
hand, resuscitative means can be carried out while preparing for surgery and during
the operation3,21. In patients with septic shock, a delay seems to be a critical factor for
increasing mortality. Therefore, unnecessary delays should be avoided by all possible
means108. Also, in perforated peptic ulcer, surgical delay has been shown to be a
critical determinant for increasing mortality107.
Most patients with secondary peritonitis should undergo surgical source control.
Open surgical technique, usually midline laparotomy (Figure 4), is the preferred
approach in the most severe cases. The positioning and length of the incision should
be tailored to the suspected diagnosis. Source control can be achieved by organ
resection, direct closure of the perforation, or exteriorization of the perforation as an
ostomy. Other routine measures are evacuation of the infectious material,
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debridement of the necrotic or infected tissue, peritoneal lavage, restoration of GI
function, and drainage of the abdomen. However, there are specific circumstances in
which other surgical methods can be safely applied3,77.
FFigure 4. Full-length midline laparotomy provides excellent exposure of the abdomen.
Laparoscopy (Figure 5) has gained wide acceptance as a primary mean of diagnosing
the exact source of the secondary peritonitis and treating applicable diseases. It has
become the preferred surgical method for appendicitis and cholecystitis110,111.
Generally, laparoscopy offers less postoperative pain, less wound infections, and
faster recovery from the operation. Anatomical circumstances, surgeon’s experience,
and patient’s ability to tolerate the pneumoperitoneum must be considered when
choosing the surgical method3,62. Also, the surgical method must not compromise the
source control and other surgical principles. In unstable patients, laparoscopy should
be avoided due to the likely adverse changes in cardiovascular and pulmonary
physiology112. A recent meta-analysis comparing perioperative outcomes of
laparoscopy versus open surgery in acute perforated gastroduodenal ulcers stated
that the laparoscopic approach resulted in modest benefits, less early postoperative
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pain, and fewer wound infections. Other clinical outcomes showed no significant
differences113.
FFigure 5. Laparoscopy image from an operation for a perforated peptic ulcer.
Treatment without definitive source control has been considered applicable in
selected stable patients with secondary peritonitis. Laparoscopic lavage, instead of
resection, has been proposed as an adequate treatment in selected patients for
diverticulitis with purulent peritonitis. There are three RCTs addressing this matter
with inconsistent conclusions114-116. A meta-analysis was recently published,
comprising data from these three RCTs as well as from four comparative studies. The
meta-analysis concludes that laparoscopic lavage is associated with a threefold
greater risk of persistent peritonitis, intra-abdominal abscesses, and need for
emergency surgery relative to colonic resection117. Well-localized and well-defined
abscesses may be percutaneously drained using US- or CT-guided drainage. Most
commonly, patients with small diverticulitis- or appendicitis-related abscesses are
treated with antibiotics only. Larger abscesses (>3-6 cm) are preferably drained3,22.
One RCT, with a single experienced surgeon, showed that laparoscopic surgery is
safe and feasible as a primary treatment for appendiceal abscesses. It had a higher
rate of uneventful recovery than conservative initial management118. Conservative
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treatment in perforated peptic ulcer in selected patients has also been studied, with
promising results, but it has not gained much popularity among surgeons119,120
2.5.4 Intraoperative peritoneal lavage and drainage
During the initial operation for a secondary peritonitis intraoperative peritoneal
lavage has been traditionally performed to irrigate and reduce peritoneal
contamination (Figure 6). Different fluids have been applied, including antibiotics,
sterile saline, water, and antiseptics. The amounts of the liquid used are not
standardized, some surgeons lavage until the liquid is clear and some use up to 30
liters. The rationale is to physically clean the infected abdomen, washing away
bacteria and exudate. The benefit of intraoperative peritoneal lavage is highly
unsubstantiated in the current literature121-123.
Figure 6. Intraoperative peritoneal lavage.
Another commonly used approach largely lacking in evidence is draining of the
abdomen after surgery for secondary peritonitis. The rationale is to empty the
abdominal cavity of residual infectious material, detect bleeding or anastomotic
complications early, to evacuate ascites in selected patients, or to enable the creation
Review of the literature
of a controlled fistula in situations where source control cannot be achieved.
Duration of drainage varies among clinicians, conditions, and patients. Despite the
lack of evidence, most surgeons choose to drain the abdomen at the end of the
operation for diffuse secondary peritonitis4,62. Routine drainage after an operation
for appendicitis and cholecystitis has been studied; the results do not support the
routine use of drainage124-126.
22.5.5 Sepsis
Patients suffering from sepsis-related organ dysfunctions should be treated in the
ICU. Sepsis treatment follows the same principles regardless of the etiology. The
current sepsis management guidelines are followed in patients with an IAS21. If
hemodynamic stability is not achieved with adequate fluid resuscitation and
vasopressors, intravenous hydrocortisone is suggested. Mechanical ventilation,
sedation, and renal replacement therapy are used when appropriate. Blood glucose is
managed following a strict protocol. Venous thromboembolism prophylaxis,
preferably a low-molecular-weight heparin, should be administered when there are
no contraindications. In patients with risk factors for GI bleeding, stress ulcer
prophylaxis should be given. Early enteral feeding is recommended when plausible.
Post-pyloric feeding tubes can be used in the case of gastroparesis. In feeding
intolerance, prokinetic agents should be used21.
2.5.6 Relaparotomy strategy
Some patients develop persisting symptoms regardless of attempts to achieve source
control. It is a common problem for clinicians to decide which patients might benefit
from a relaparotomy. There are two different approaches to this matter:
relaparotomy on-demand and planned relaparotomy3. Van Ruler et al. published a
RCT in 2007, in which they compared planned versus on-demand relaparotomy
strategies in patients with severe secondary peritonitis. A total of 223 patients were
randomized. This study concluded that on-demand relaparotomy had similar results
to planned ralaparotomy regarding mortality and morbidity. The on-demand
strategy resulted in a substantial reduction of laparotomies, health care utilization,
Review of the literature
and medical costs127. Planned relaparotomy is not recommended as a general
strategy3. The decision to perform a relaparotomy is considered case-by-case.
Continuous monitoring is essential and a CT scan can be used to give additional
information on intra-abdominal status. Kiewiet et al. published a scoring system in
2013 to aid in decision-making128. OA can be considered as a third strategy for
relaparotomy29.
2.5.7 Damage control
The term ”damage control” for abdominal trauma was introduced by Rotondo et al.
in 1993129. Damage control surgery (DCS) strategy constitutes an abbreviated
laparotomy with initial temporary control for hemorrhage and contamination,
leaving the abdomen open, restoration of homeostasis in the ICU, and after 1-2 days
a definitive repair of the organ defects and restoration of GI function when the
patient’s physiology is more favorable. DCS has been used in cases with a severe
physiological derangement of the patient. The rationale is to avoid an extensive and
prolonged initial operation that the patient might not tolerate. This is done to escape,
or preferably avoid, the notorious lethal triad of coagulopathy, hypothermia, and
metabolic acidosis29,130. The first damage control maneuver, liver packing to control
traumatic bleeding, was published in 1908 by Pringle131. DCS has been accepted as a
preferred treatment strategy in selected trauma patients. In non-traumatic
abdominal emergencies, case series publications of DCS have increased in the 21st
century130. Most DCS publications in secondary peritonitis address diverticular
perforations. The reported benefit in DCS is to perform a deferred primary
anastomosis in improved patients, as opposed to a diversion procedure132-134.
Currently, there are no RCTs published and the possible benefits of DCS, as well as
patient selection criteria, in secondary peritonitis remain unclear29,130,135-138. A single
retrospective study of 74 patients with perforated diverticulitis, managed with DCS
strategy, concluded that the macroscopic signs of an ongoing peritonitis in
relaparotomy predicted a worse outcome139.
Review of the literature
2.5.8 Open abdomen
Open abdomen (OA), also referred to as laparostomy, management is used in various
severe abdominal conditions25,26. The most common indications include abdominal
compartment syndrome, DCS strategy, inability to close the abdomen, and inability
to obtain a definitive source control27,28,140. OA classification, developed with the
support of the World Society of the Abdominal Compartment Syndrome, was
developed in 2009 and amended in 2016 (Table 3)140,141.
Table 3. Open abdomen classification. 1A Clean, no fixation 1B Contaminated, no fixation 1C Enteric leak, no fixation 2A Clean, developing fixation 2B Contaminated, developing fixation 2C Enteric leak, developing fixation 3A Clean, frozen abdomen 3B Contaminated, frozen abdomen 3C Established enteroatmospheric fistula, frozen abdomen Modified from Björck et al.140 OA is controlled with a temporary abdominal closure (TAC) device. Although
commonly used in severe conditions, OA is a non-anatomic situation with many
potential side-effects. Inability to close the abdomen will result in the development of
massive hernias, frozen abdomen, and prolonged OA treatment time, which
increases the likelihood of the dreaded EAFs27,30. There are several TAC options but
NPWT has shown the best results26,27,32,142. Further, combining NPWT with
continuous fascial traction, most commonly mesh-mediated (Figure 7), seems to
yield the best results regarding the highest DPFC rates as well as the lowest EAF
rates30-32. Other reported options for applying continuous fascial traction include
retention sutures and narrowing technique143-146.
The use of OA and NPWT as a method to improve recovery from organ dysfunctions
and to lower mortality in secondary peritonitis was further propagated by a porcine
model study by Kubiak et al. in 2010. This study showed remarkable improvement in
organ dysfunctions with NPWT compared with closed fascia23. Possible mechanisms
are a more efficient removal of the inflammatory ascites and lowering of intra-
abdominal pressure. In 2015, Kirkpatrick et al. published a RCT comparing two
Review of the literature
different TACs in 45 patients with IAS or trauma. The TACs were a commercial
NPWT device and a less effective NPWT method called the Barker’s vacuum pack. A
significant difference was present in mortality, which could not be explained by
improved peritoneal fluid drainage, fascial closure rates, or markers of systemic
inflammation24. Whether OA and NPWT, in cases where direct fascial closure is
possible, are efficient in improving the resolution of organ dysfunctions and lowering
mortality, without an unacceptable increase in OA-related complications, remains
unknown. However, recruiting has started for an international multicenter RCT to
address this issue. The study protocol and the inclusion criteria have been
published8,35.
Another method aiming at reducing the inflammation and facilitating OA closure is
direct peritoneal resuscitation. In this method, peritoneal dialysis or hypertonic
solutions are continuously administered and removed in the abdominal cavity. The
results in human studies are promising, albeit preliminary147. A similar philosophy is
used in NPWT combined with abdominal instillation therapy. In this technique, the
instillation fluid is delivered via the NPWT device. NPWT with instillation has also
only been evaluated in retrospective case studies148. At this time, neither of these
techniques do not have an established role in the management of OA27.
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FFigure 7. Open abdomen management by vacuum-assisted wound closure with mesh-mediated fascial traction (VAWCM). A: The intra-abdominal fenestrated plastic sheet is placed to cover and protect the viscera. B: A shaped polypropylene mesh is sutured to the fascial edges. C: Mesh in place. D: Shaped perforated foam is set to cover the wound. E: After occlusive adhesive drapes are set airtight, a hole is made for vacuum suction. F: Vacuum is applied. G: In reoperation the mesh is cut from the midline and the dressings are changed. H: After the dressings have been changed, the cut midline of the mesh is tightened by suturing in order to provide fascial traction.
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22.5.9 Wound
Postoperative wound complications are common after laparotomy for secondary
peritonitis. The most common complications are surgical site infection (SSI), seroma
or hematoma formation, and wound dehiscence149. After closure of the fascia, the
options are to leave the wound open with or without NPWT or to close the wound
with or without NPWT. In a three-armed RCT by Lozano-Balderas et al. in 2017, 81
patients with contaminated or infected wounds were randomized to primary closure,
delayed primary closure (wound open at least seven days), or NPWT changed every
48 hours followed by delayed closure150. The corresponding SSI rates were 37%, 17%,
and 0%. Another RCT by Duttaroy et al. in 2009 compared dirty abdominal wounds
of 77 patients151. The groups were primary skin closure and open wound with saline
dressings followed by delayed primary closure. There were significantly lower rates
of superficial SSI (42.5% vs. 2.7%) and fascial dehiscence (25% vs. 1%) with initial
open wound management. Complete incision healing time, length of stay, and short-
term cosmetic appearance were also superior in open wound management. Seamon
et al. studied retrospectively the skin closure techniques of 503 trauma patients with
transmural enteric injuries in 2013152. In the multivariable analysis, primary skin
closure increased the risk of superficial SSIs nine fold and fascial dehiscence six fold,
compared with leaving the skin open primarily. In a recent meta-analysis of nine
studies and 1266 patients, the use of prophylactic NPWT in closed laparotomy
wounds for both elective and emergency surgery was investigated. The results
showed that NPWT does reduce the incidence of SSIs (12.4% and 27.1%,
respectively), but not seroma or wound dehiscence rates149.
2.6 OUTCOME
2.6.1 Grading complications
The most commonly used grading system for postoperative surgical complications is
the Clavien-Dindo (CD) classification, published in 2004153. It was revised and
validated five years later (Table 4)154. However, the CD classification was developed
Review of the literature
using elective surgical patients. Therefore, the applicability of this classification is
questionable in the emergency surgery setting. Emergency surgery accounts for
about 11% of all surgeries, yet it represents 47% of mortalities and 28% of surgical
complications155. This discrepancy in reporting complications for emergency surgery
patients was addressed by Mentula et al. in 2014. The study concludes that the CD
classification can be used in emergency surgery patients, but the preoperative organ
dysfunctions should not be graded as class IV complications156. In 2013, a new
continuous scale called the Comprehensive Complication Index (CCIn) was
published157. The same group who developed the CD classification presented the
CCIn. The main difference is that instead of reporting only the worst complication,
the CCIn combines all complications into a continuous scale, therefore providing
additional value in the reporting of complications158.
TTable 4. Classification of surgical complications. Grade I Any deviation from the normal postoperative course without the need for
pharmacological treatment or surgical, endoscopic, and radiological interventions. Acceptable therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics, and electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside.
Grade II Requiring pharmacological treatment with drugs other than such allowed for grade I complications. Blood transfusions and total parenteral nutrition are also included.
Grade III Requiring surgical, endoscopic, or radiological intervention
Grade IIIa Intervention not under general anesthesia
Grade IIIb Intervention under general anesthesia
Grade IV Life-threatening complication (including CNS complications)‡ requiring IC/ICU-management
Grade IVa Single-organ dysfunction (including dialysis)
Grade IVb Multi-organ dysfunction
Grade V Death of patient
Suffix “d” If the patient suffers from a complication at the time of discharge, the suffix “d” (for ‘disability’) is added to the respective grade of complication. This label indicates the need for a follow-up to fully evaluate the complication.
‡ brain hemorrhage, ischemic stroke, subarachnoidal bleeding, but excluding transient ischemic attacks (TIA); CNS; Central nervous system; IC: Intermediate care; ICU: Intensive care unit www.surgicalcomplication.info. Reprinted with permission from Clavien et al.154.
Review of the literature
22.6.2 Mortal i ty rates
Anaya et al. evaluated 11202 patients with a secondary peritonitis from 81 hospitals
in the State of Washington in 1997-2000. The mortality in the entire cohort was 6%6.
Sartelli et al. published a worldwide cohort study with 1898 patients collected during
a six-month period in 2012-2013. The overall mortality was 10%5. A very similar
study by the same author collected 2152 patients from Europe in 2012. In this study
the overall mortality was 8%7. Gauzit et al. investigated prospectively 841 patients
from 66 French hospitals in 2005 suffering from non-postoperative secondary
peritonitis, with an overall mortality of 15% (Table 5)38.
2.6.3 Organ dysfunctions
Organ dysfunctions represent the most important prognostic factor for death in
patients with secondary peritonitis3,4,8,9. The number of organ dysfunctions also
correlates dramatically with mortality6,9,10. In secondary peritonitis, the proportion
of patients with organ dysfunctions is usually reported to be 11-17% in unselected
patients, roughly half of whom are suffering from septic shock5-9. Generally, reported
mortality in patients with organ dysfunctions rises to 20-34%6,8,9,12. When septic
shock is present, the reported mortality is 38-68% (Table 5)8,9,11,12.
Review of the literature
Table 5. Mortality and organ dysfunctions. First author and publication year
Anaya 2003 Sartelli 2015 Posadas-Calleja 2018
Number of patients 11202 4533 905
Data collection years 1997-2000 2014-2015 2005-2010
Patient setting Secondary peritonitis Complicated intra-abdominal infection
Intra-abdominal sepsis
Geographical region State of Washington, USA
Worldwide Calgary, Alberta, Canada
n (%) n (%) n (%) Overall mortality 686 / 11202 (6) 416 / 4533 (9) 193 / 905 (21)
Mortality, no organ dysfunctions
263 / 9968 (3) 103 / 3742 (3) 26 / 317 (8)
Mortality, organ dysfunctions
423 / 1234* (34) 157 / 561 (28) 29 / 248 (12)
Mortality, septic shock 140 / 367** (38) 156 / 230 (68) 138 / 340 (41) *all organ dysfunctions **septic shock not mentioned, this number is for cardiovascular organ dysfunction
Modified from Anaya et al.6, Sartelli et al.12, and Posadas-Calleja et al.9.
2.6.4 Other prognostic factors
Along with organ dysfunctions, there are a variety of other independent prognostic
factors. These factors have been identified in multivariable analyses in different
studies with various viewpoints and setups. Predisposing patient-related factors
include increasing age, poor nutritional or functional status, immunosuppression,
malignant diseases, and a large variety of comorbidities6,9,12,15,16,19,159,160. Patients with
chronic organ insufficiencies or diminished physiological reserves are more prone to
developing acute organ dysfunctions. Leukopenia and hypothermia as acute findings
have also been shown to be independent risk factors for mortality at nearly the same
magnitude as acute organ dysfunctions9.
In addition to patient-related factors, peritonitis itself possesses factors with
different risk profiles. Diffuse peritonitis compared with local peritonitis has been
recognized as an independent risk factor for death6,12,16,17. HA-cIAIs have worse
prognosis than CA-cIAIs12. Postoperative peritonitis tends to have a more severe
Review of the literature
course of disease (Figure 8)12,161. The type of exudate has an effect on mortality; fecal
peritonitis has been considered to have the worst outcome16. Mortality related to
acute appendicitis is much lower than that for other diagnoses4-6,162. Small bowel
perforations, on the other hand, tend to have the highest mortalities4,6,12. A few
studies have found microbiological findings to correlate with outcome. Infections
with Enterococcus and clostridium species have been linked to impaired
prognosis15,48,159.
Furthermore, management-related risk factors have been shown to be important.
Delayed or inadequate source control, postoperative surgical complications, and
inadequate empiric antibiotics have been recognized as independent risk factors for
mortality12,16,18,19. Also, dedicated emergency surgeons have been demonstrated to
reduce mortality in emergency general surgery163.
FFigure 8. Laparotomy for postoperative peritonitis.
2.6.5 Scoring systems
Review of the literature
There are multiple scoring systems used in assessing disease severity and prognosis
in patients with secondary peritonitis. Theoretically, the optimal scoring system
would address chronic physiology and performance capacity, medications, acute
physiology, and both disease- and treatment-specific factors.
A few scoring systems are specific to cIAIs, including the Mannheim Peritonitis
Index (MPI, Table 6)16 and the World Society of Emergency Surgery Sepsis Severity
Score (WSESSSS, Table 7)12. Emergency surgery-specific scoring systems include the
recently introduced Emergency Surgery Acuity Score (ESAS, Table 8)164, which is
also referred to as the Emergency Surgery Score (ESS)165, and the more user-friendly
abbreviated Physiological ESAS (PESAS)166. The ESAS/ESS seems promising, but
has not yet achieved an established role167.
Table 6. Mannheim Peritonitis Index (MPI) (range 0-47). Risk factor Score Age > 50 years 5 Female gender 5 Organ failure* 7 Malignancy 4 Preoperative duration of peritonitis > 24 hours 4 Origin of sepsis not colonic 4 Diffuse generalized peritonitis 6 Exudate -Clear 0 -Cloudy/purulent 6 -Fecal 12 Modified from Linder et al.16 Table 7. World Society of Emergency Surgery Sepsis Severity Score (WSESSSS) for patients with complicated intra-abdominal infections (range 0-18). Risk factor Score Clinical condition on admission -Severe sepsis (acute organ dysfunction) 3 -Septic shock 5 Healthcare associated infection 2 Origin of IAI -Colonic non-diverticular perforation 2 -Small bowel perforation 3 -Diverticular diffuse peritonitis 2 -Post-operative diffuse peritonitis 2 Delay in source control > 24 hours 3 Other risk factors -Age > 70 years 2 -Immunosuppression* 3 *chronic glucocorticoids, immunosuppressant agents, chemotherapy, lymphatic diseases, virus Modified from Sartelli et al.12
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TTable 8. Emergency Surgery Acuity Score (ESAS) (range 0-29). Demographics -Age > 60 years 2 -White race 1 -Transfer from outside emergency department 1 -Transfer from an acute care hospital inpatient facility
1
Comorbidities -Ascites 1
-BMI < 20 kg/m2 1
-Disseminated cancer 3 -Dyspnea 1 -Functional dependence 1 -History of COPD 1 -Hypertension 1 -Steroid use 1 -Ventilator requirement within 48 hours preoperatively
3
-Weight loss > 10% in the preceding 6 months 1 Laboratory values -Albumin < 3.0 U/L 1 -Alkaline phosphatase > 125 U/L 1 -Blood urea nitrogen > 40 mg/dL 1 -Creatinine > 1.2 mg/dL 2 -International normalized ratio > 1.5 1 -Platelets < 150 x 103/μL 1 -SGOT > 40 U/L 1 -Sodium >145 mg/dL 1 -WBC, x103/μL <4.5 1 >15 and ≤25 1 >25 2 Abbreviations: BMI = body mass index, COPD = chronic obstructive pulmonary disease, SGOT = serum glutamic oxaloacetic transaminase, WBC = white blood cells Modified from Sangji et al.164
Other commonly used scoring systems in IAI patients are applied to all kinds of
critically ill patients. The Acute Physiology and Chronic Health Evaluation
(APACHE-II)168, the Sequential Organ Failure Assessment (SOFA, Table 9)169, the
Portsmouth Physiological and Operative Severity Score for the enUmeration of
Mortality and morbidity (P-POSSUM)170, the Therapeutic Intervention Scoring
System (TISS-28)171, the National Early Warning Score (NEWS, Figure 1)72, the
Simplified Acute Physiology Score (SAPS-II)172, and the Predisposition, Infection,
Response, and Organ Dysfunction (PIRO)173 scores are the most widely used. A
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distinct PIRO score was recently derived for abdominal sepsis (PIRO model for intra-
abdominal sepsis, PIRO-IAS, Table 10)9.
Table 9. The Sequential Organ Failure Assessment (SOFA) score (range 0-24). 1 2 3 4 Respiration PaO2/FiO2, mmHg
<400 <300 <200* <100*
Coagulation Platelets x 103/mm3
<150 <100 <50 <20
Liver Bilirubin, mg/dL (μmol/l)
1.2 – 1.9 (20 – 32)
2.9 – 5.9 (33 – 101)
6.0 – 11.9 (102 – 204)
>12.0 (>204)
Cardiovascular Hypotension
MAP < 70 mmHg
Dopamine ≤ 5 or dobutamine**
Dopamine > 5 or (nor)epinephrine ≤0.1
Dopamine > 15 or (nor)epinephrine >0.1
Central nervous system Glasgow Coma Score
13 - 14 10 - 12 6 - 9 <6
Renal Creatinine, mg/dL (μmol/l) or urine output
1.2 – 1.9 (110 – 170)
2.0 – 3.4 (171 – 299)
3.5 – 4.9 (300 – 440) or <500 ml/day
>5.0 (>440) or <200 ml/day
*with respiratory support **adrenergic agents administered for at least one hour (doses μg/kg per minute) Modified from Vincent et al.169 Table 10. Predisposition, infection/injury, response, organ dysfunction (PIRO) model for intra-abdominal sepsis (PIRO-IAS) (range 0-8). Predisposition Age > 65 years 1 Comorbid conditions* 1 Response Leukopenia <4000 μL 1 Hypothermia <36 0C 1 Organ dysfunction** Cardiovascular 1 Respiratory 1 Renal 1 Central nervous system 1 *according to APACHE-II definitions (advanced liver cirrhosis, advanced cardiac insufficiency (NYHA-IV), severe chronic pulmonary disease, chronic dialysis, immunosuppression) **SOFA score ≥ 2 Modified from Posadas-Calleja et al.9
The current Sepsis-3 guidelines use the SOFA scoring system to define sepsis11. In
these guidelines, a bedside screening tool called the quick SOFA (qSOFA) was also
introduced. It includes three variables: respiratory rate ≥ 22/min, altered mentation,
and systolic blood pressure ≤ 100 mmHg. The qSOFA has proven to be specific, but
lacks sensitivity, and therefore, it is not optimal for its intended use8,68,70,75,174.
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A recent study tested various scoring systems (APACHE-II, MPI, sepsis-3 definition,
qSOFA, WSESSSS, PIRO-IAS, and SOFA) and their ability to predict severe cIAI or
30-day mortality in patients with diffuse secondary peritonitis8. This study was done
to establish the inclusion criteria for a multicenter international RCT35. Overall, the
best results were achieved with PIRO-IAS and the lowest predictive values for MPI.
However, no one scoring system worked satisfyingly, and for RCT purposes a
combination of scores was chosen.
PIRO-IAS score was tested in the derivation study with 905 IAS patients, and it
outperformed the APACHE-II and the SOFA scores9. NEWS has been proposed to be
a useful tool in the early detection of organ dysfunctions67-70. Currently, the typical
role of the different scoring systems is more as a research tool than for guiding
individual patient management3.
Aims of the study
33. AIMS OF THE STUDY
This thesis aimed at assessing the severity and management of open abdomen in
patients with secondary peritonitis. Specific aims of Studies I-IV are listed below.
I:
To analyze the readily available preoperative risk factors for severe diffuse secondary
peritonitis.
II:
To evaluate mortality and major morbidity, i.e. the delayed primary fascial closure
and the enteroatmospheric fistulae rate, in patients with diffuse secondary
peritonitis treated using an open abdomen and a vacuum-assisted wound closure
with mesh-mediated fascial traction.
III:
To systemically analyze the components of the intra-abdominal view and their
association with severe complicated intra-abdominal sepsis or mortality in patients
with complicated intra-abdominal infection.
IV:
To analyze the association between eight relevant blood plasma cytokines and
components of the intra-abdominal view, development of organ dysfunctions, and
mortality.
Materials and methods
44. MATERIALS AND METHODS
4.1 STUDY HOSPITAL
The study hospital in all studies presented in this thesis was Helsinki University
Hospital, Meilahti Tower Hospital. Meilahti Tower Hospital is an academic center
that serves as both a secondary and a tertiary referral center for adult (16 years or
older) patients. It serves a population of approximately 1.7 million. Meilahti Tower
Hospital provides continuous emergency care with approximately 30 000 emergency
clinic visits. About 5000 emergency surgeries are performed annually, approximately
2200 of which are abdominal emergency operations. Of surgical specialties,
gastrointestinal, vascular, urologic, cardiothoracic, and oral and maxillofacial are
represented in Meilahti Tower Hospital. In Finland, all organ transplantations in
adult patients are performed at this hospital.
4.2 STUDY DESIGN
Studies I and II were retrospective studies. Studies III and IV were prospective
studies.
4.3 PATIENTS
Study I:
The electronic operating room log was browsed for all abdominal emergency
surgeries during a two-year study period between January 1, 2012 and December 31,
2013. Cases with secondary peritonitis were further examined to identify all
consecutive adult (18 years or older) patients with diffuse secondary peritonitis.
Patients with appendicitis or cholecystitis as the source of the infection were not
collected due to the better prognosis and the straightforward management protocols.
There were 227 patients identified during the study period. Four patients were
Materials and methods
further excluded from the final study cohort since at the time of onset of secondary
peritonitis they were already admitted to the ICU due to another diagnosis (two
patients with severe pancreatitis and two patients with an early postoperative phase,
one after lung transplantation and the other after an operation for a ruptured
abdominal aortic aneurysm). The final study cohort consisted of 223 patients with
diffuse secondary peritonitis.
Study II:
The vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM)
method for the management of OA was first used in the study hospital on July 4,
2008. This was the beginning of the study period. The study period ended eight years
later on July 4, 2016. The operating room database was searched with the Nordic
Classification of Surgical Procedures (NCSP) for OA (JAH30, JAH33) and NPWT
(TQW11) -related codes. The individual electronic patient records were further
viewed to identify all adult (18 years or older) patients with ongoing diffuse
secondary peritonitis, OA, and VAWCM. Patients with other underlying diagnoses
for OA and VAWCM managements were excluded. The other diagnoses were severe
pancreatitis (n = 59), ruptured abdominal aortic aneurysm (n = 48), trauma (n = 14),
acute mesenteric ischemia (n = 14), other GI diagnosis (n = 37), other vascular
diagnosis (n = 18), and fascial dehiscence (n = 41). The final study cohort consisted
of 41 patients with diffuse secondary peritonitis managed with OA and VAWCM.
Study III:
The study period for this prospective study was two years from March 31, 2016, to
March 31, 2018. Inclusion criteria were adult (18 years or older) patients undergoing
operative management for cIAI due to a breach in the GI tract, i.e. secondary
peritonitis. Patients with a diagnosis of acute pancreatitis, trauma, or acute
mesenteric ischemia were not recruited to the study. The electronic operating room
log was manually browsed to identify the total number of eligible patients during the
study period. There were 657 patients operated on with a diagnosis of cIAI in the
study period. The reasons for not recruiting patients to this study were failure to
attempt recruiting (n = 165), declined or infeasible informed consent (n = 72), cIAI
not suspected preoperatively (n=117), and incompletely filled research form (n = 20).
Materials and methods
The final study cohort consisted of 283 eligible patients with a properly filled IAV
form.
Study IV:
The cytokine measurements in patients for Study IV were collected from a subgroup
of patients in Study III. The study cohort comprised patients from whom
preoperative informed consent and blood samples were collected preoperatively. A
total of 131 patients were included in the study cohort. During the study period there
were 16 patients with suspected cIAI, but another diagnosis was confirmed in the
operation. These patients’ cytokine analyses were used as disease controls. The
diagnoses for the control group patients were uncomplicated appendicitis (n = 6),
colon necrosis without peritoneal contamination (n = 2), uncomplicated cholecystitis
(n =2), small bowel obstruction (n = 2), uncomplicated small bowel diverticulitis (n =
1), and an exploratory operation for three patients without diagnostic findings and
with an uneventful recovery.
44.4 DATA COLLECTION
In Studies I and II, all data were collected from the electronic medical records used
in the study hospital. Studies III and IV also include data from the IAV paper sheet
form filled out by the operating surgeon (Section 4.7).
4.5 DEFINITIONS
Comorbidities were addressed in Studies I-III according to the Charlson
Comorbidity Index (CCI)172. Physical status was classified in Study I according to
the American Society of Anesthesiologists (ASA) classification used during the study
years 2012-2013. Immunosuppression was classified according to the WSESSSS
definition (immunosuppressive medication, chronic use of glucocorticoids,
chemotherapy within 30 days, or lymphatic disease) in Studies III and IV12.
Materials and methods
Sepsis was classified according to the Sepsis-2 definitions in Studies I and II176. The
Sepsis-3 definitions were published in 2016 and used accordingly in Studies III and
IV11. The SIRS and the concept of severe sepsis were removed from the new
definitions (Table 11). The SOFA score was used in all studies to assess the combined
severity of sepsis-related organ dysfunctions in ICU patients169. In Study I, extended
criteria were used to address the preoperative organ dysfunctions in the emergency
room. If noninvasive ventilation was used, pulse oximetry saturation below 90% or
respiratory rate constantly over 25 per minute was used to define respiratory organ
dysfunction. Similarly, AKI was defined as over 50% rise in baseline plasma
creatinine or hourly urine output less than 0.5 ml/kg after fluid resuscitation. When
MAP was not invasively measured, the equation [(2 x diastolic blood pressure) +
systolic blood pressure] / 3 was used to estimate MAP.
TTable 11. A simplified comparison of Sepsis-2 and Sepsis-3 definitions. Sepsis Infection and ≥ 2 SIRS
criteria Infection and SOFA score ≥ 2
Severe sepsis Sepsis with organ dysfunction
-
Septic shock Sepsis and refractory hypotension
Sepsis and vasopressor to maintain MAP > 65 mmHg and lactate > 2 mmol/l
Abbreviations: SIRS = systemic inflammatory response syndrome, SOFA = Sequential Organ Failure Assessment, MAP = mean arterial pressure Modified from Levy et al.172 and Singer et al.11
Comprehensive scoring systems were used in all studies. The APACHE-II in
Studies I, III, and IV, MPI in all studies, and WSESSSS in studies III and IV12,16,168.
The CD classification was used in Study III to define surgical complications153.
Only new-onset organ dysfunctions or complications that significantly contributed to
the worsening of preoperative organ dysfunctions were classified as grade IV
complications156. There was some variability in reporting of outcomes. In Study I,
severe peritonitis was defined as a composite outcome of either ICU admission or
30-day mortality. In Study III, a composite outcome of SCIAS (ICU admission due to
acute organ dysfunctions) or 30-day mortality was used to define the severe
peritonitis.
Materials and methods
44.6 SURGICAL METHODS
In Studies I, III, and IV, all patients were treated according to the operating
surgeon’s preference based on individual assessment. The same is true for Study II,
yet in this study the results of the VAWCM method constituted the essential research
question. The VAWCM method was first published and presented in detail (first
referred to as vacuum and mesh-mediated fascial traction, VACM) by Petersson et al.
in 2007177. Briefly, a commercial NPWT system designed for the management of OA
was used. Two different systems were used, in the early study period Vacuum-
Assisted Closure (VAC©, KCI, San Antonio, TX, USA), and after 2012 predominantly
the ABThera™ (KCI, San Antonio, TX, USA). The procedure is shown in Figure 7. A
perforated polyethylene sheet was placed deep to cover the viscera following the
suturing of a polypropylene mesh to the fascial edges with a running 0 monofilament
suture. The polyurethane sponge, occlusive adhesive drapes, and continuous
pressure to 125 mmHg are placed as in the routine procedure. In the first
reoperation, after 48 hours, the mesh is cut in the midline, the intra-abdominal sheet
is changed, and the mesh is tightened by suturing the midline back together with a 0
monofilament, creating fascial traction towards the midline. The procedure is
repeated every 2-3 days, and when fascial closure is deemed possible, the mesh is
removed, and the fascia is closed. If the fascial edges seized to approximate,
adjunctive methods, such as the subcutaneous component separation, were used178.
In some patients, a Bogotá bag, i.e. a sterile plastic sheet sutured to the margins of
the skin, was used in the index operation, and the VAWCM was used in subsequent
operations.
4.7 INTRA-ABDOMINAL VIEW (IAV)
Studies III and IV focused on the role of the IAV in patients with cIAI. Data from the
IAV were collected on a paper form (Figure 9) by the operating surgeon. The
abdomen was divided into six regions: right and left upper supramesocolic areas,
right and left lower and paracolic areas, mid-abdomen small bowel area, and pelvic
Materials and methods
area (below the promontorium). The type of exudate in each area was recorded as
clear, purulent, fecal, or bile. The operating surgeon evaluated subjectively the
amount of fibrin and redness in each area as none, mild, or substantial. In addition,
the localization of the infection in the peritoneum was recorded by area as parietal
and/or visceral, excluding the pelvic area where there is no parietal peritoneum.
Bowel dilatation was also recorded as small and/or large bowel dilatation. The
peritonitis was classified as fecal or bile peritonitis, if any area contained fecal or bile
exudate, respectively. If both were present, the peritonitis was classified according to
the predominant exudate.
FFigure 9. Intra-abdominal view on paper form.
4.8 CYTOKINES
Cytokine analyses were performed in Study IV. We chose eight different relevant
cytokines for analysis; hepatocyte growth factor (HGF), macrophage (migration)
inhibitory factor (MIF), interleukin-1 beta (IL-1β), IL-6, IL-8, IL-10, macrophage
Materials and methods
chemoattractant protein 1 (MCP-1), and tumor necrosis factor alpha (TNF-a). Once
the decision to operate was made, blood samples (6ml, EDTA tube) were drawn from
the patients preoperatively. The plasma was separated from the blood and the
samples were frozen to -70°C and stored. The cytokine levels were determined using
Bio-Plex Pro Human Cytokine Assay (Bio-Rad Laboratories, Hercules, CA, USA)
according to the manufacturer’s instructions. The Bio-Plex 200 System was used to
analyze the samples, and Bio-Plex Manager 6.0 software (Bio-Rad) was used to
calculate the results. Results are reported as pg/mL.
44.9 STATISTICAL ANALYSIS
The statistical analyses in all studies were conducted by using the SPSS© Statistics
version 22 or 25 for Mac (IBM Corp©, Armonk, NY, USA). An exception was the
bootstrapping analysis in Study III, where R software (R foundation for Statistical
computing, Vienna, Austria. URL https://www.R-project.org/) was used. Numbers
and percentages were used to describe the categorical data. Mean with standard
deviation (SD) and median with interquartile range (IQR) summarized the
continuous data, according to normality of the data. The Shapiro-Wilk test was used
to test normality in the continuous variables together with the evaluation of the
skewness and histograms. In univariable analyses, to analyze the differences between
the groups in the categorical variables, Fischer’s exact test or Pearson’s chi-squared
test were used in Studies I and II as appropriate. The differences between the groups
for the normally distributed continuous variables were assessed with Student’s t-test
(Studies I and II). For the non-normally distributed continuous variables, Mann-
Whitney U-test (Studies II-IV), Kruskal-Wallis test (Study III), or Jonckheere-
Terpstra test (Study IV) was used as appropriate. The ordinal data in Study III were
tested with Mantel-Haenszel linear-by-linear association chi-squared test. The
nonparametric correlations between the continuous variables were analyzed using
Spearman’s rank correlation coefficient in Study III.
Binary logistic regression analyses were used in Studies I-III. In Study I, variables for
the multivariable analysis were chosen, after reclassification of some variables, from
Materials and methods
the univariable analysis when p-value was below 0.20, avoiding multicollinearity.
Both logistic regression and ordinal regression analyses were used in Study I. In
Study III, univariable analyses were performed using univariable logistic regression
for categorical variables. For binary logistic regression, different models were tested
and the model with the highest Nagelkerke R square was chosen. The goodness-of-fit
in multivariable models was tested with the Hosmer-Lemeshow test, and the model
performance was assessed with Nagelkerke R square (Studies I and III). In Study III,
the score was built according to the regression coefficients from the logistic
regression by an applicable multiplier and choosing the nearest integer.
Receiver operating characteristic (ROC) curves were plotted in Studies I and III. In
Study III, the area under the ROC curve (AUROC) was calculated for the scoring
system. Missing values were encountered in Study I; they were either considered to
be within the reference values or discarded, according to clinical rationale. Power
calculations were performed for Study III. The calculations were based on the
estimated prevalence of the primary outcome measure, which was SCIAS (ICU
admission due to acute organ dysfunctions) or mortality, and the applicability of an
appropriate multivariable analysis with seven variables. Therefore, a need for at least
49 patients with the primary outcome was estimated. Based on previous reports, we
estimated that 17% of all the patients would meet the primary composite outcome,
resulting in the need to recruit at least 288 patients. In all studies, two-tailed p-
values were reported and a p-value below 0.05 was considered significant. The odds
ratio (OR) values were presented with a 95% confidence interval (CI).
Bootstrapping for an optimism-adjusted area under curve calculation was used in
Study III to internally validate the logistic model.
44.10 ETHICAL APPROVAL AND STUDY PERMISSIONS
The Institutional Review Board approved all study protocols. The Helsinki University
Hospital Ethics Committee of Surgery approved the study design for Studies III and
IV. Written informed consent was obtained from all patients recruited for Studies III
Materials and methods
and IV. Studies I and II were retrospective observational studies, and thus, Ethics
Committee approval was not necessary.
Results
55. RESULTS
Patient characteristics, including intraoperative data and outcomes, from all studies
in this thesis are presented in Table 12. The OA patients from Study I are included in
Study II. The patients in Study IV are a subgroup of the patients in Study III.
Table 12. Patient characteristics in original studies. Study Study I Study II Study II I Study IV§
Patients Diffuse peritonit is
Diffuse peritonit is, OA+VAWCM
Secondary peritonit is
Secondary peritonit is
Years 2012-2013
2008-2016 2016-2018 2016-2018
n (%) n (%) n (%) n (%) Preoperative Total number of patients 223 41 283 131 Sex, male 119 (53) 23 (56) 132 (47) 62 (47) Age, years* 65 (53-74) 59 (50-68) 64 (49-74) 66 (53-77) Charlson Comorbidity Index* 2 (1-4) 2 (0-4) 1 (0-5) 2 (0-5) Malignant diseases -Local solid malignant tumor 26 (12) 9 (22) 35 (12) 18 (14) -Solid malignant tumor with metastasis or lymphoma
43 (19) 6 (15) 45 (16) 23 (18)
Preoperative sepsis classification** -Severe sepsis (organ dysfunctions) 46 (21) 9 (22) 60 (21) 33 (25) -Septic shock 58 (26) 22 (54) 19 (7) 6 (5) Intraoperative Source of infection -Gastroduodenal 61 (27) 3 (7) 32 (11) 15 (11) -Small bowel 40 (18) 15 (37) 30 (11) 14 (11) -Appendicitis n/a 0 (0) 109 (39) 43 (33) -Colorectal perforation 122 (55) 23 (56) 101 (36) 56 (43) Postoperative peritonitis 57 (26) 24 (59) 38 (13) 17 (13) Fecal exudate 52 (23) 21 (51) 85 (30) 38 (29) MPI* 28 (23-33) 33 (29-37) 26 (22-32) 27 (23-32) Open abdomen§§ 17 (8) 41 (100) 5 (2) 2 (2) Postoperative ICU admission 72 (32) 31 (76) 57 (20) 28 (21) -Peak SOFA score at ICU* 8 (5-10) 10 (7-13) 8 (6-10) 8 (6-10) -Length of ICU admission, days* 5 (3-8) 13 (7-15) 4 (3-9) 5 (3-9) Reoperations 56 (25) 41 (100) 36 (13) 17 (13) Length of hospital stay, days* 10 (6-21) 32 (24-44) 6 (3-11) 7 (4-12) ICU admission or 30-day mortality 93 (42) 31 (76) 71 (25) 35 (27) Mortal i ty Mortality, 30 days 33 (15) 12 (29) 29 (10) 13 (10) -If no preoperative organ dysfunctions
6 / 119 (5) 0 / 10 (0) 7 / 204 (3) 3 / 92 (3)
-If preoperative organ dysfunctions (but not shock)
10 / 46 (22) 3 / 9 (33) 16 / 60 (27) 10 / 33 (30)
-If preoperative septic shock 17 / 58 (29) 9 / 22 (41) 6 / 19 (32) 0 / 6 (0) -If ICU admission 12 / 72 (17) 12 / 31 (39) 15 / 57 (26) 6 / 28 (21) Mortality, 90 days 49 (22) 12 (29) 37 (13) 18 (14) *continuous variables are presented as median (interquartile range)
Results
**sepsis classification was different between Studies I/II and III/IV, seeSection 4.5 §Study III is a subgroup of Study IV §§open abdomen patients from Study I are included in Study II 5.1 STUDY I
5.1.1 Patient characterist ics
A total of 223 patients between the years 2012-2013 with diffuse secondary
peritonitis were analyzed. Patient characteristics are shown in Table 12. Briefly, 53%
(n = 119) of patients were male, and their mean age was 65 (IQR 53-74) years.
Malignant diseases were common; 36% (n = 81) were suffering from some form of a
malignant disease. The ASA class was 3 or higher in 78% (n = 174). According to the
Sepsis-2 definitions, 21% (n = 46) had severe sepsis, i.e. organ dysfunctions,
preoperatively. Septic shock was present in 26% (n= 58) of patients.
5.1.2 Intraoperative data
Most perforations (74%, n=164) were due to an underlying disease. Postoperative
complications were the reason for the perforation in 26% (n = 57). The most
common diagnoses resulting in GI tract perforation were peptic ulcer (n = 52, 23%),
colon diverticulitis (n = 44, 20%), anastomotic dehiscence (n = 37, 17%), iatrogenic
(n = 20, 9%), and tumor (n = 20, 9%). Colon perforations accounted for 55% (n=122)
of the sources, followed by gastroduodenal (27%, n = 61) and small bowel (18%, n =
40) perforations. Exudate was purulent in 74% (n = 166) and fecal in 23% (n =52).
Source control was considered adequate in 97% (n = 216), and in 10 cases (4%) an
OA was used in the primary operation. The mean MPI was 28 (IQR 23-33).
5.1.3 Postoperative data and outcome
Thirty-two percent (n = 72) of the patients were admitted to the ICU, with a median
stay of 5 days (IQR 3-8) and a median peak SOFA score of 8 (IQR 5-10). Among the
patients admitted to the ICU, 30-day mortality was 17% (12/72) and 90-day
Results
mortality 26% (19/72). ICU admission was refused immediately postoperatively for
24 patients (11%) due to underlying end-stage disease or poor functional capacity.
Reoperations were performed for 56 patients (25%), the vast majority (44/56, 79%)
of which were unplanned. In the whole study cohort, the overall 30-day mortality
was 15% (n = 33) and the 90-day mortality 22% (n=49).
5.1.4 Uni- and mult ivariable analyses
Several pre-existing conditions were significantly associated with severe peritonitis
in univariable analysis: age over 75 years, corticosteroid medication, anticoagulative
medication, various cardiovascular diseases, diabetes, and moderate or severe renal
insufficiency. Of preoperative laboratory tests, hemoglobin less than 100 g/l,
potassium outside reference values, creatinine over 100 μmol/l, blood glucose over 8
mmol/l, and lactate over 3 mmol/l showed significance. In addition, organ
dysfunctions and their related patient vital sign measurements showed significance.
A binary logistic regression analysis was conducted of preoperative risk factors for
the composite outcome of 30-day mortality or ICU admission, to describe severe
peritonitis (Table 13). The model contains pre-existing cardiovascular disease and
chronic kidney insufficiency as well as the sepsis classification. The Hosmer-
Lemeshow test significance 0.18 showed that the model had an adequate fit. The
Nagelkerke R square was 0.49 and the AUROC for this model was 0.87 (95% CI
0.82-0.92, p<0.001)
5.1.5 Subgroup analyses
A group of 24 patients (11%) were refused ICU admission and deemed too sick to
benefit from ICU treatment. In this group, 90-day mortality was 88% (21/24). The
median age was 74 (IQR 65-88) years, 21% (n = 5) were institutionalized, 42% (n =
10) had a metastatic malignant tumor or lymphoma, the median CCI was 5 (IQR 1-
6), the median MPI 32 (IQR 28-35), and severe sepsis was present in 29% (n = 7)
and septic shock in 54% (n = 13).
Results
When analyzing patients with none of the independent risk factors (n = 86), 7% (n =
6) were admitted to the ICU and no 30-day mortality occurred. Also, in patients who
did not need ICU level of care and had no limitations of treatment (n = 106) there
was no 30-day mortality.
To separately analyze patients receiving full level of care during the first three days of
hospitalization (n=190), a subgroup ordinal regression analysis was conducted
(Table 13). An ordinal regression model was used to emphasize mortality over ICU
admission as outcome with a three-step outcome (no ICU admission or mortality,
ICU admission, 30-day mortality). The 30-day mortality in this group was 5% (n =
9), and 33% (n = 62) of patients were admitted to the ICU. The independent risk
factors for the primary outcome, in descending OR order, were septic shock, severe
sepsis, metastatic malignant disease or lymphoma, and corticosteroid use. The
Hosmer-Lemeshow p-value was 0.066, and the Nagelkerke R square was 0.38. The
AUROC for ICU admission was 0.80 (95% CI 0.73-0.87, p<0.001), and the AUROC
for mortality was 0.91 (95% CI 0.85-0.97, p<0.001).
TTable 13. Multivariable analyses in Study I. Analysis Binary logistic
regression* Ordinal regression**
Cohort Full study cohort Subgroup*** Number of patients 223 190 Risk factor Outcome OR (95% CI) Outcome OR (95% CI) p-value Cardiovascular disease 2.58 (1.22-5.47) 0.014 Chronic kidney insufficiency
5.98 (1.56-22.86) 0.009
Corticosteroid use 2.98 (1.18-7.51) 0.021 Metastatic malignant disease or lymphoma
3.11 (1.34-7.20) 0.008
Preoperative sepsis classification
-No organ dysfunction Reference Reference -Severe sepsis 4.80 (2.10-10.65) 5.56 (2.39-12.89) <0.001 -Septic shock 37.94 (14.52-99.13) 11.89 (4.98-28.40) <0.001 *Method: forward LR, composite outcome: ICU admission or 30-day mortality **Weighted outcome, ordinal regression dependent (no ICU or mortality, ICU admission, 30-day mortality) ***Patients without limitations of treatment within three days of hospitalization
Results
55.2 STUDY II
5.2.1 Patient characterist ics
In this study, there were 41 patients with diffuse peritonitis, OA, and VAWCM. The
patient characteristics are shown in Table 12. Briefly, 56% (n =23) were male,
median age was 59 (IQR 50-68) years, and according to Sepsis-2 definitions, 22% (n
= 9) had severe sepsis and 54% (n = 22) septic shock. Malignant diseases were found
in 37% (n = 15) of patients.
Intraoperative findings show that 51% (n = 21) had fecal peritonitis with median MPI
of 33 (IQR 29-37). The most common etiology for the GI perforation was primary
colorectal perforation (37%, n = 15), followed by iatrogenic small bowel perforation
(24%, n = 10) and colorectal anastomotic dehiscence (22%, n = 9). The majority
(59%, n = 24) of patients suffered from postoperative peritonitis, which were caused
either by anastomotic dehiscence (n = 14) or iatrogenic small bowel perforation (n =
10).
Postoperatively, 76% (n = 31) of patients were admitted to ICU with a peak SOFA
score median of 10 (IQR 7-13) and a median ICU stay of 13 (IQR 7-15) days. Renal
replacement therapy was necessary for 35% (n = 11) of patients. The median hospital
stay was 32 (IQR 24-44) days and both 30- and 90-day mortality was 29% (n = 12).
5.2.2 Open abdomen
The data and the results regarding OA treatment are reported in Table 14. The OA
was used in the index operation for peritonitis in 66% (n = 27) of cases, and the rest
were left open after the unplanned relaparotomies with an ongoing peritonitis. The
most common indications for OA were prophylactic (37%, n = 15) and inability to
close due to swelling (37%, n = 15). The DPFC rate among survivors was 92% (n =
33/36). Subcutaneous component separation was used as an adjunct method in three
patients (5%) to achieve the DPFC.
Results
TTable 14. Open abdomen (OA) data (total n = 41). n (%) OA indication -Prophylactic 15 (37) -Inability to close due to swelling 15 (37) -Poor fascia or fascial defect 6 (15) -Preoperative abdominal compartment syndrome 2 (5) -Other 3 (7) OA closure -Direct fascial closure 30 (73) -Died with OA 5 (12) -Subcutaneous component separation and direct closure 3 (7) -Free skin transplant 2 (5) -Partial skin only closure 1 (2) OA results -OA duration, days 7 (5-10)* -OA dressing changes 2 (1-3)* -Enteroatmospheric fistula 3 (7) -DPFC among survivors (n = 36) 33 (92) *Continuous variables are presented as median (interquartile range) DPFC stands for delayed primary fascial closure
Altogether, there were three patients (7%) with an EAF. Two of these patients had an
iatrogenic small bowel perforation as the indication for relaparotomy and as the
source of peritonitis. The lesions were sutured in the relaparotomy but the sutures
did not hold during the OA treatment. In one of these two patients, a DPFC was
achieved with a drain and a controlled fistula. Only one patient developed an EAF
during OA treatment. There were three patients (7%) who did not reach the DPFC,
two of which had an EAF. Additionally, one patient had a defect in the upper part of
the fascia and a skin-only closure was performed in the upper part of the incision.
5.2.3 Comparison between survivors and non-survivors
Several variables were compared between survivors (71%, n = 29) and non-survivors
(29%, n = 12). The results are presented in Table 15. Non-survivors were significantly
more often over 60 years old and had more comorbidities (CCI > 2). All non-
survivors had preoperative organ dysfunctions as well as MPI over 31. In addition, a
prophylactic indication for OA was more often used in non-survivors, and non-
survivors suffered from more serious postoperative organ dysfunctions (peak SOFA
score >10 in ICU).
Results
TTable 15. Comparison between survivors (n = 29) and non-survivors (n = 12). Survivors,
n (%) Non-survivors, n (%)
p-value OR (95% CI)
Age > 60 years 9 (31) 10 (83) 0.002* 11.1 (2.0-61.4) CCI > 2 10 (34) 9 (75) 0.018* 5.7 (1.3-25.9) Preoperative organ dysfunctions
19 (31) 12 (100) 0.021 1.6 (1.2-2.2)
Postoperative peritonitis 19 (66) 5 (42) 0.184 0.4 (0.1-1.5) MPI > 31 14 (48) 12 (100) 0.001 1.9 (1.3-2.7) OA prophylactic indication 6 (21) 9 (75) 0.003 11.5 (2.4-56.2) Peak SOFA score in ICU > 10
5 (17) 8 (67) 0.027 5.6 (1.2-27.1)
*Chi-squared test (for others, Fischer’s exact test) Abbreviations: OR = odds ratio, CCI = Charlson Comorbidity Index, MPI = Mannheim Peritonitis Index, OA = open abdomen, SOFA = sequential organ failure assessment
5.3. STUDY III
5.3.1 Patient characterist ics
A total of 283 patients were included and analyzed. Patient characteristics are
presented in Table 12. Briefly, 47% (n =132) of patients were male and the median
age was 64 (IQR 49-74) years. Malignant diseases were present in 25% (n = 80) of
the patients. Sepsis was classified according to the Sepsis-3 definitions; sepsis was
present in 21% (n = 60) and septic shock in 7% (n = 19). The cIAI was hospital-
acquired in 22% (n = 62); the majority of these were postoperative cIAIs (n=38). The
most common sources for the cIAI were appendix (39%, n = 109) and colorectal
(36%, n = 101). The median MPI was 26 (IQR 22-32), WSESSSS 6 (IQR 3-9), and
APACHE-II score 9 (IQR 6-15).
Postoperatively, reoperations were performed for 13% (n = 36) of the patients.
Severe complications, i.e. CD > 3 were encountered in 34 patients (12%). Of the
patients, 20% (n = 57) were admitted to the ICU, with a median peak SOFA score of
8 (IQR 6-10). SCIAS or 30-day mortality was present in 25% (n = 71). Thirty-day
mortality was 10% (n = 29) and 90-day mortality 13% (n = 37).
Results
55.3.2 Univariable analysis
Univariable analysis was performed using univariable binary logistic regression, and
the outcome was a composite outcome of SCIAS or 30-day mortality (Table 16). Of
the perforated organs, the appendix as the source of the infection showed a much
less severe form of disease than the other sources. Regarding the extent of the
peritonitis, OR values started to rise when four or more out of six areas were
infected. In the bowel dilatation, a colon-only dilatation was significantly more likely
than the others to meet the primary outcome. Clear or purulent exudate was
associated with less severe disease than fecal or bile exudate. Fibrin analyses showed
that if substantial fibrin was found in five or more areas the probability of the
primary outcome was significantly higher. Substantial redness in four or more areas
had a more severe course of disease. The localization of the infection in the visceral
or the parietal and visceral peritoneum was not correlated with the primary outcome.
Table 16. Univariable binary logistic regression of components of the intra-abdominal view for the
primary outcome of severe complicated intra-abdominal sepsis (SCIAS) or 30-day mortality. Risk factor n (%) Outcome, n
(%) OR (95% CI) p-value B
Perforated organ -Appendix -Gallbladder -Colorectal -Gastroduodenal -Small bowel
109 (39) 11 (4) 101 (36) 32 (11) 30 (11)
5 (5) 4 (36) 37 (37) 12 (38) 13 (43)
reference 11.89 (2.60-54.42) 12.03 (4.49-32.18) 12.48 (3.96-39.33) 15.91 (5.03-50.33)
<0.001 0.001 <0.001 <0.001 <0.001
2.475 2.487 2.524 2.767
Non-appendiceal source*
174 (62) 66 (38) 12.71 (4.93-32.81) <0.001 2.542
Extent of peritonitis (areas) 1 2 3 4 5 6
30 (11) 47 (17) 29 (10) 32 (11) 32 (11) 113 (40)
4 (13) 7 (15) 1 (3) 8 (25) 7 (22) 44 (39)
reference 1.14 (0.30-4.28) 0.23 (0.02-2.21) 2.17 (.58-8.13) 1.82 (0.47-6.99) 4.15 (1.35-12.69)
0.001 0.849 0.204 0.252 0.383 0.013
0.129 -1.460 0.773 0.599 1.422
Diffuse peritonitis (≥4 areas)*
177 (63) 59 (33) 3.92 (1.99-7.71) <0.001 1.365
Bowel dilatation -No dilatation -Small bowel only -Colon only*
164 (58) 77 (27) 19 (7)
35 (21) 19 (25) 8 (42)
reference 1.21 (0.64-2.29) 2.68 (1.00-7.17)
0.097 0.563 0.050
0.188 0.986
Results
-Small bowel and colon
23 (8)
9 (39)
2.37 (0.95-5.93)
0.065
0.863
Type of exudate -Clear -Purulent -Fecal -Bile
16 (6) 160 (57) 85(30) 22 (8)
3 (19) 27 (17) 30 (35) 11 (52)
reference 0.88 (0.24-3.30) 2.36 (0.62-8.95) 4.33 (0.96-19.58)
0.001 0.849 0.206 0.057
-0.128 0.860 1.466
Fecal or bile* 107 (38) 41 (38) 3.02 (1.74-5.26) <0.001 1.106 Extent of fibrin (areas) 0 1 2 3 4 5 6
37 (13) 77 (27) 46 (16) 28 (10) 31 (11) 24 (9) 39 (14)
15 (41) 12 (16) 7 (15) 3 (11) 6 (19) 10 (42)
18 (46)
reference 0.27 (0.11-0.67) 0.26 (0.09-0.74) 0.18 (0.05-0.69) 0.35 (0.12-1.06) 1.05 (0.37-2.98) 1.26 (0.51-3.12)
<0.001 0.004 0.120 0.130 0.640 0.930 0.622
-1.306 -1.335 -1.737 -1.044 0.047 0.229
Extent of substantial fibrin (areas) 0 1 2 3 4 5 6
140 (49) 72 (25) 25 (9) 19 (7) 10 (4) 6 (2) 11 (4)
33 (24) 12 (17) 6 (24) 7 (37) 2 (20) 4 (67) 7 (64)
reference 0.65 (0.31-1.35) 1.02 (0.38-2.78) 1.89 (0.69-5.20) 0.81 (0.16-4.01) 6.49 (1.14-37.01) 5.67 (1.56-20.59)
0.016 0.246 0.963 0.216 0.797 0.035 0.008
-0.433 0.024 0.637 -0.210 1.869 1.736
Substantial fibrin ≥5 or more areas*
17 (6) 11 (65) 6.29 (2.2-17.73) <0.001 1.840
Extent of redness (areas) 0 1 2 3 4 5 6
17 (6) 41 (14) 55 (19) 32 (11) 32 (11) 27 (10) 78 (28)
8 (47) 6 (15) 7 (13) 3 (9) 7 (22) 7 (26) 33 (42)
reference 0.19 (0.05-0.70) 0.16 (0.05-0.57) 0.12 (0.03-0.53) 0.32 (0.09-1.12) 0.39 (0.11-1.42) 0.83 (0.29-2.37)
<0.001 0.012 0.004 0.006 0.074 0.155 0.720
-1.646 -1.808 -2.151 -1.155 -0.932 -1.192
Extent of substantial redness (areas) 0 1 2 3 4 5 6
125 (44) 73 (26) 34 (12) 21 (7) 9 (3) 3 (1)
26 (21) 10 (14) 10 (29) 5 (24) 5 (56) 2 (67)
reference 0.60 (0.27-1.34) 1.59 (0.68-3.73) 1.19 (0.40-3.55) 4.76 (1.19-18.99) 7.62 (0.66-87.29)
<0.001 0.214 0.290 0.755 0.027 0.103
-0.504 0.462 0.174 1.560 2.030
Results
18 (6)
13 (72)
9.90 (3.24-30.29)
<0.001
2.293
Substantial redness ≥4 or more areas*
30 (11) 20 (67) 7.92 (3.49-17.97) <0.001 2.070
Localization of infection non-parietal (only visceral)
49 (17) 11 (22) 0.84 (0.40-1.75) 0.639 -1.094
Method: enter *Included in multivariable analysis B stands for regression coefficient 5.3.3 Mult ivariable analysis and the Intra-Abdominal
View Score
A multivariable binary logistic regression analysis was conducted with the variables
chosen from univariable analysis (Table 17). Fecal or bile exudate, diffuse peritonitis,
substantial redness in four or more areas, and a non-appendiceal source of infection
were identified as the independent risk factors for a SCIAS or 30-day mortality. The
AUROC curve for this logistic model was 0.812 (95% CI 0.761-0.865). Internal
validation of the logistic model was performed with a bootstrapping method and the
optimism-adjusted AUROC for the logistic model was 0.802. The Hosmer-
Lemeshow goodness-of-fit test showed adequate fit with a significance of 0.36. The
Nagelkerke R square was 0.36.
Table 17. Multivariable binary logistic regression of the intra-abdominal view for primary outcome of severe complicated intra-abdominal sepsis (SCIAS) or 30-day mortality. Risk factor Outcome OR (95% CI) p-value B IAV
score Non-appendiceal source 11.20 (4.11-30.54) <0.001 2.416 3 Substantial redness (≥4 areas) 5.73 (2.12-15.44) 0.001 1.745 2 Diffuse peritonitis (≥4 areas) 2.15 (1.02-4.55) 0.045 0.767 1 Fecal or bile exudate 1.98 (1.05-3.73) 0.034 0.685 1 Method: forward LR Abbreviations: B = regression coefficient, IAV = Intra-abdominal view (Score = 1.3 x B to nearest integer)
Based on the regression coefficients of the multivariable analysis, an IAV score was
developed. The IAV score was further categorized as low (0-2, n = 102, 36%),
medium (3-5, n = 158, 56%), or high (6-7, n = 23, 8%). The IAV was shown to
correlate significantly with various outcomes (Table 18) and with the development of
organ dysfunctions (Table 19).
Results
TTable 18. Intra-abdominal view (IAV) score evaluation; low, middle and high scores with various outcomes. Outcome All patients Low score Medium
score High score p-value*
Mortality, 30 days, n (%) 29 (10) 1 (1) 22 (14) 6 (26) <0.001 ICU admission, n (%) 57 (20) 2 (2) 39 (25) 16 (70) <0.001 SCIAS or 30-day mortality, n (%)
71 (25) 3 (3) 50 (32) 17 (74) <0.001
Clavien-Dindo ≥3, n (%) 87 (31) 14 (14) 62 (39) 11 (48) <0.001 Length of stay, days** 6 (3-10) 3 (2-5) 8 (6-13) 10 (6-18) <0.001
*P-values are calculated using linear-by-linear association for dichotomous variables and Kruskal-Wallis Test for continuous variables **Continuous variables are presented as median (interquartile range) Abbreviations: SCIAS = severe complicated intra-abdominal sepsis Table 19. Correlations of the intra-abdominal view (IAV) score with pre- and postoperative organ dysfunctions (total n = 283). Preoperative organ dysfunctions
No, n (%) 204 (72)
Yes, n (%) 79 (28)
IAV score* 3 (1-4) 4 (4-5) p < 0.001 Postoperative SCIAS or death
No, n (%) 191 (94)
Yes, n (%) 13 (6)
No, n (%) 21 (27)
Yes, n (%) 58 (73)
IAV score* 3 (1-4) 4 (3-5) 3 (1-4) 5 (4-6) p = 0.008 p < 0.001 *IAV scores are presented as median (interquartile range) P-values are calculated with Mann-Whitney U-test
The AUROC for the IAV score in predicting the primary outcome was 0.81,
remaining unchanged from the original logistic model. The performance of the IAV
score was evaluated against that of the WSESSSS, APACHE-II score, and MPI by
comparing the AUROCs in ability to predict the primary outcome. The best-
performing score was APACHE-II, with an AUROC of 0.85 (95% CI 0.80-0.90,
p<0.001).
5.3.4 Subgroup analysis
Since patients with acute appendicitis have a much less severe course of the disease,
a subgroup analysis was performed with a cohort of a non-appendiceal source of
cIAI. The number of patients in this analysis was 174, of which 30% (n = 53) were
admitted to ICU, 16% (n = 27) died within 30-days, and 38% (n = 66) met the
Results
primary outcome. The results showed that substantial redness in ≥4 areas (OR 5.09,
95% CI 1.71-15.13, p 0.003, B 1.628) and fecal or bile exudate (OR 2.06, 95% CI 1.06-
4.03, p 0.034, B 0.725) were independently associated with the primary outcome.
Diffuse peritonitis (OR 2.14, 95% CI 0.97-4.72, p 0.059, B 0.761) had a non-
significant p-value. The Hosmer-Lemeshow test significance was 0.91 and the
Nagelkerke R square 0.19.
55.4. STUDY IV
5.4.1 Patient characterist ics
The study cohort consisted of 131 patients with cIAI and a successful preoperative
cytokine analysis. Patient characteristics are presented in Table 12. Briefly, median
age was 66 (IQR 53-77) years, 47% (n = 62) were male, and median CCI was 2 (IQR
2-5). Sepsis was present in 33 patients (25%) preoperatively and septic shock in 6
patients (5%). The most common source of cIAI was colorectal (n = 56, 43%),
followed by appendix (n = 43, 33%). Median MPI was 27 (IQR 23-32), WSESSSS 6
(IQR 3-9), and IAV score 4 (IQR 1-5). The patients were grouped according to their
IAV score into low (0-2 points, n = 39, 30%), medium (3-5 points, n = 82, 63%), and
high (6-7 points, n = 10, 8%) groups. Twenty-eight patients (21%) were admitted to
ICU and 30-day mortality was 10% (n =13).
5.4.2. Cytokines
P-values of associations with each cytokine and the components of the IAV are
presented in Table 20. IL-6, IL-8, and IL-10 were associated significantly with all
components of the IAV. MIF was npt significantly associated with any of the
components.
Results
TTable 20. Association of preoperative plasma cytokine levels and components of the intra-abdominal view. Cytokine Diffuse
peritonitis (≥ 4 areas)
Substantial redness (≥ 4 areas)
Substantial fibrin (≥ 4 areas)
Exudate fecal or bile
Non-appendiceal source
HGF 0.002 0.068 0.012 0.016 0.473 MIF 0.692 0.846 0.333 0.947 0.910 IL-1β <0.001 0.084 0.593 0.062 0.819 IL-6 <0.001 0.015 0.029 0.004 0.001 IL-8 <0.001 0.012 0.003 0.001 <0.001 IL-10 <0.001 0.039 0.004 0.002 0.014 MCP-1 <0.001 0.190 0.026 0.026 0.199 TNF <0.001 0.011 0.097 0.088 0.104 P-values are calculated with Mann-Whitney U-test P-values of associations between cytokines and the IAV score groups are presented in
Figure 10. IL-6, IL-8, and IL-10 as well as TNF were significantly associated with IAV
score groups.
Figure 10. Association of preoperative plasma cytokine levels with the Intra-Abdominal View Score. Group medians are shown as horizontal lines within boxes denoting the 25th to 75th percentiles. P-values are calculated with the Jonckheere-Terpstra test
Cytokine plasma levels were compared with cIAI patients and controls (Table 21).
MIF values were not different from controls, but all other cytokine levels were
significantly higher in cIAI patients. Cytokine levels of patients with
immunosuppression (n = 27, 21%) were compared with those of other patients, but
there no significant differences emerged between the groups (data not shown).
Lo Med Hi Lo Med Hi Lo Med Hi Lo Med Hi Lo Med Hi Lo Med Hi Lo Med Hi Lo Med Hi0,001
0,01
0,1
1
10
100
1000
10000
100000
1000000
Intra-abdominal view (IAV) score
Pla
sma
conc
entra
tion
(pg/
ml)
MIFHGF IL-1β IL-6 IL-8 IL-10 MCP-1 TNF
p=0.124 p=0.970 p=0.515 p<0.001 p<0.001 p=0.001 p=0.065 p=0.007
Results
Two different outcomes, development of postoperative organ dysfunctions or 30-day
mortality, were compared with plasma cytokine levels (Table 21). There were 96
patients with a non-severe course of disease (no ICU, no 30-day mortality) and 28
patients with postoperative organ dysfunctions requiring ICU admission. Significant
associations for organ dysfunctions were found in HGF, MIF, IL-6, IL-8, IL-10,
MCP-1, and TNF. With mortality alone, IL-8 and MIF showed significant
associations.
TTable 21. Cytokine plasma level association to controls, organ dysfunctions, and 30-day mortality. cIAI patients Controls p-value Cytokine n = 131, median (range) n = 16, median (range) HGF 1503.13 (938.27-2374.42) 509.78 (397.67-937.04) <0.001 MIF 4138.92 (2670.54-5824.68) 2984.72 (2455.38-3737.08) 0.136 IL-1β 0.64 (0.22-1.80) 0.14 (0.14-0.14) <0.001 IL-6 180.53 (60.75-932.20) 24.76 (8.40-68.78) <0.001 IL-8 32.79 (13.95-123.14) 5.19 (3.44-17.10) <0.001 IL-10 11.78 (3.76-35.57) 1.13 (0.12-6.71) <0.001 MCP-1 109.98 (49.37-295.81) 19.89 (16.22-45.40) <0.001 TNF 69.55 (36.03-180.74) 18.96 (15.77-32.81) <0.001 Outcome: organ dysfunctions Cytokine No, n = 96, median (IQR) Yes, n = 28, median (IQR) p-value HGF 1346.75 (857.14-2140.13) 2223.35 (1335.68-4719.91) 0.001 MIF 3794.50 (2418.70-4888.02) 5207.78 (3372.82-7109.43) 0.007 IL-1β 0.56 (0.22-1.46) 1.02 (0.22-2.46) 0.212 IL-6 133.32 (57.19-747.27) 469.22 (192.39-1911.47) 0.008 IL-8 26.06 (10.27-57.76) 138.17 (51.68-387.52) <0.001 IL-10 8.24 (2.83-21.74) 33.10 (12.43-81.13) <0.001 MCP-1 95.39 (48.83-284.04) 205.58 (73.38-833.07) 0.024 TNF 66.48 (34.05-159.57) 130.28 (63.41-215.19) 0.010 Outcome: 30-day mortality Cytokine No, n = 118, median (IQR) Yes, n = 13, median (IQR) p-value HGF 1481.23 (952.74-2297.39) 1698.54 (929.39-3045.29) 0.574 MIF 3961.17 (2644.27-5642.54) 5211.48 (4072.75-9028.90) 0.027 IL-1β 0.61 (0.22-1.80) 0.75 (0.22-1.93) 0.862 IL-6 187.61 (65.51-943.89) 154.11 (43.22-668.11) 0.614 IL-8 31.74 (12.27-110.43) 60.25 (39.36-246.25) 0.035 IL-10 11.20 (3.57-34.06) 20.54 (7.24-45.17) 0.346 MCP-1 113.71 (49.36-301.76) 82.01 (48.71-300.47) 0.569 TNF 70.85 (36.26-181.59) 69.55 (33.10-188.63) 0.979 P-values were calculated using Mann-Whitney U-test Cytokine levels are reported in pg/mL Abbreviations: IQR = interquartile range, SCIAS = severe complicated intra-abdominal sepsis
Discussion
66. DISCUSSION
6.1 SELECTION OF OUTCOMES
The most important determinants of development of sepsis or death are organ
dysfunctions4,5,8,9. Considering the definition of SCIAS and the current sepsis-3
definitions, this is not surprising since sepsis is defined by organ dysfunctions and
organ dysfunctions are the primary reason for ICU admission8,11,35. Organ
dysfunctions are a dynamic state; signs of preoperative organ dysfunctions may
resolve quickly after initial treatments, but usually they are more persistent and
require ICU management.
Using mortality as the primary outcome in different scoring systems has also some
aspects worth discussing. Dying from secondary peritonitis is multifactorial; the
recognized risk factors include comorbidities, medications, increasing age, poor
nutritional or functional status, organ dysfunctions, and the nature and management
of the secondary peritonitis, including postoperative complications.
ICU level of treatment is highly important in fighting organ dysfunctions. However,
ICU treatment is expensive and resources are limited. Due to the limited number of
ICU beds, patients without acute organ dysfunctions or exacerbation of existing
comorbidities are not admitted to the ICU. On the other hand, some patients are
refused ICU admission, due to poor functional status or terminal comorbidities,
which very likely accelerated their death. Therefore, using only death as an outcome
would result in highlighting the effect of terminal comorbidities and ICU admission
or refusal criteria, and these patients might not receive a full level of care. Excluding
patients with limitations of treatments from studies is another option. In this case,
however, it should be clearly stated that the results do not represent the entire
burden of the disease. For the reasons above, we chose a composite outcome of ICU
admission due to acute organ dysfunctions (=SCIAS) or 30-day mortality in Studies I
and III. This outcome represents all patients who have a severe course of disease. In
Study II, the patients were selected on the basis of receiving OA management, and
this method is very rarely applied to patients who do not receive a full level of care.
Discussion
66.2 MORTALITY AND MORBIDITY
The overall 30-day mortality in the included studies varied between 10% and 29%
depending on the patient cohort. Mortality in the patients with septic shock was 29-
41% in Studies I-III. Study IV had only six patients with septic shock and no
mortality. Mortality in patients with other organ dysfunctions was 22-33%. However,
the definitions of sepsis, severe sepsis, and septic shock varied between Studies II
and III, and therefore, the results are not entirely comparable. Patients with
persisting organ dysfunctions were admitted to the ICU, unless refused. The ICU
admission rates varied between studies from 20% to 76%. Mortality among patients
who were admitted to ICU was 17-39%. Of note, the patient cohort in Study II
represents a very complicated and severely ill group of patients with secondary
peritonitis.
The overall mortality results are comparable with the results from previous studies.
However, the proportion of patients with organ dysfunctions was higher in the
studies of this thesis (28-76%).5-7,38. Mortality in patients with sepsis (22-33%) or
septic shock (29-41%) is among the lowest reported6,9,11,12. However, ICU mortality
rates are strongly dependent on ICU admission and refusal criteria, rendering
comparisons unreliable.
According to the results of Study I, patients can be generalized into three different
groups. The first group, without a need for ICU level of care due to acute organ
dysfunctions and without sufficiently severe comorbidities for treatment limitations,
comprising about half of the patients, had no mortality. The second group,
approximately one-third of the patients, had a SCIAS and was treated with full level
of care with 17% mortality. The third group, about one-tenth of the patients,
comprising patients who were severely ill and refused ICU admission, had a 90-day
mortality of 88%. More than half of the deaths in this study belonged to the third
group. In conclusion, it seems that the battle between the physiological reserve and
the quantum of the physiological assault caused by the acute infection and the
inflammatory response is the most important determinant of whether a patient lives
or dies.
Discussion
66.3 PREOPERATIVE DISEASE SEVERITY ASSESSMENT
Decisions on triage need to be made early and with limited data of the patient. Delays
in resuscitation, antibiotics, and source control have been shown to increase
mortality in severely ill patients21,107,108. Therefore, assessing prognosis and
identifying patients at high risk for a SCIAS or mortality according to the
preoperative variables are important. Study I focused on preoperative risk factors in
patients with diffuse secondary peritonitis. Preoperative septic shock, severe sepsis,
pre-existing chronic kidney insufficiency, or cardiovascular diseases were identified
as independent risk factors for the primary outcome. In a subgroup analysis of
patients without treatment limitations during the first three days, the independent
risk factors were septic shock, severe sepsis, metastatic malignant tumor or
lymphoma, and corticosteroid use. These results highlight the crucial role of organ
dysfunctions and are also in line with the well-performing PIRO-IAS score9. The
WSESSSS model only recognizes immunosuppression as a meaningful comorbidity12.
MPI takes malignancies, but not other comorbidities, into account16. However, it is
likely that comorbidities have a role in the development of organ dysfunctions since
underlying insufficiencies in critical organs lower the reserves of these organs to
withstand further physiological stress. Advanced age, with varying cut-offs, has been
recognized as a risk factor in several studies and scoring systems9,12,16. In Study I, age
was not identified as an independent risk factor.
Patients with signs of organ dysfunctions and other risk factors for mortality should
be diagnosed and treated with high priority, avoiding delays. Also, these factors
should be taken into account in intraoperative decision-making. A safer surgical
method (e.g. ostomy instead of anastomosis) should be chosen, when plausible.
6.4 INTRA-ABDOMINAL VIEW AND INTRAOPERATIVE
DISEASE SEVERITY ASSESSMENT
Study III was a pioneer study of the role of the IAV in predicting SCIAS or mortality.
The independent risk factors recognized in this study were fecal or bile as exudate,
Discussion
diffuse peritonitis, diffuse substantial redness in the peritoneum and a non-
appendiceal source of infection.
The results were mostly expected. A previously completely unrecognized risk factor
was diffuse substantial redness in the peritoneum. This is logical since the stronger
the inflammatory response the more visible the redness of the peritoneum. The other
risk factors have been previously recognized. However, of the cIAI-specific scoring
systems, only the MPI takes the type of exudate into account.
The IAV score needs further external validation before wider application. The
AUROC of the IAV score is surprisingly high considering that it only accounts for the
IAV and does not include the most important recognized prognostic factors. The IAV
score also correlated well with the various other outcomes and the development of
organ dysfunctions. Levels of various circulating cytokines were associated with the
components of the IAV as well as the IAV score. These results showed that the IAV
offers a rough estimation of the cytokine response of a patient. The IAV score
provides a method for quantification of the IAV. It is likely that including more
components of the IAV in comprehensive scoring systems would provide better
prognostic models.
6.5 OPEN ABDOMEN
The results of this severely ill and surgically complicated patient group showed that
the VAWCM method yields good results in the management of OA. The main results
are in line with other studies and with current guidelines supporting the use of a
continuous fascial traction as an adjunct to the NPWT27,30,32. Mesh-mediated fascial
traction has gained more popularity than dynamic sutures or narrowing technique in
providing fascial traction32,143,144,146. There are various studies stating that peritonitis
as the indication for OA leads to worse DPFC rates than trauma179-181. When using
the VAWCM, DPFC rates have not been shown to be dependent on the underlying
disease177,182-187.
Discussion
In the whole study group there were three patients (7%) with an EAF. One of these
EAFs was clearly a complication of the OA treatment. The lowest EAF rates have
been achieved by using the NPWT with a fascial traction method32. EAFs are still an
issue in OA management and every measure should be taken to avoid this terrible
complication. Avoiding iatrogenic small bowel lesions, both in a mobile small bowel
as well as in the frozen abdomen, is of the utmost importance. In OA management,
meticulous and minimal bowel handling during dressing changes, stabilizing the
fascia with the mesh sutured to the fascial edges, avoiding unnecessary drains, and
placing the intra-abdominal dressings of the TAC to cover the whole viscera are the
key factors, as discussed by Pereboom and Hofker188.
In Study II, the recognized factors associated with mortality were in line with
previous studies6,9,12. Older patients, patients with more comorbidities, or patients
with more severe organ dysfunctions were more likely to die. Patients with a
prophylactic indication for the OA in Study II had a higher mortality than patients
with other indications. We hypothesize that this was because the OA was used as a
last resource in patients with profound organ dysfunctions.
66.6 CYTOKINES The results from Study IV show that preoperative levels of circulating cytokines were
associated with the components of the IAV, the IAV score, development of acute
organ dysfunctions, and mortality, and further, that the levels of cIAI patients can be
differentiated from the levels of other intra-abdominal diagnoses.
IL-8 showed the best overall performance and was, in fact, significantly associated in
all the variables assessed in Study IV. Previously, IL-6 has been the most studied
cytokine, with varying results for its efficacy in predicting outcome14,53. IL-8 attracts
and activates, together with MCP-1, polymorphonuclear granulocytes during the
early stages of cIAI. MCP-1 was associated with several components of the IAV and
organ dysfunctions, but not with mortality.
Discussion
Inflammatory cytokines TNF, IL-1β, and IL-6, and anti-inflammatory IL-10 were
also investigated. IL-6 and IL-10 were associated with all of the components of the
IAV score as well as with organ dysfunctions, but not with mortality only. These
results are in line with earlier studies showing an association with organ
dysfunctions in cIAI patients14,189,190. The findings also support the modern concept
that pro- and anti-inflammatory cytokines are elevated simultaneously in sepsis, and
hence, SIRS and CARS co-exist51,52. IL-1β only was associated with the presence of
diffuse peritonitis, however, the IL-1β levels were much lower than levels of other
cytokines, and it is likely that the sensitivity of the assay was not ideal for IL-1β
analyses.
Interestingly, MIF levels were not associated with any of the components of the IAV,
but were associated with both outcome variables. Previous studies have shown that
high circulating plasma MIF is associated with cellular damage and tissue injury
rather than with inflammatory processes191,192. This was also seen in the comparison
between cIAI patients and controls, where there were no differences between MIF
levels. Instead, all other cytokines showed very clear and significant differences. It is
worth noting that the levels of HGF, TNF, IL-1β, and MCP-1 did not even overlap. It
is possible that cytokine measurements can be used to differentiate infectious
processes from other intra-abdominal diseases.
66.7 STRENGTHS AND LIMITATIONS OF THE STUDY
Studies I and II were single-center retrospective studies with a limited number of
patients. The retrospective study design imposes some limitations such as missing
data points and possible inaccuracy of collected data. In Study I, the limited number
of patients might result in some infrequent risk factors not being statistically
significant. In Study II, the number of patients was small and there was no
comparison group available. The strength of these retrospective studies was that all
consecutive patients were included in the analyses, providing accurate data that
reflects the real burden of the disease in clinical work.
Discussion
Studies III and IV were prospective single-center studies. Less than half of the
recruitable patients were included in Study III. The evaluation of fibrin and redness
in the abdomen comprised a subjective statement from the operating surgeon, and
some interobserver variability is therefore likely. Also, the IAV score lacks external
validation and is not yet widely applicable. Preoperative cytokine level measurements
for Study IV were obtained from less than half of the patients from Study III.
Cytokines were measured at various time points after the onset of the disease. The
control group in Study IV was small and heterogeneous. IL-1β levels might have been
affected by a suboptimal assay.
66.8 FUTURE PROSPECTS
The current scoring systems are not sufficiently accurate for assessing prognosis and
guiding management of individual patients. An ideal system should be able to
distinguish patients developing organ dysfunctions and at high risk for mortality, in
the pre- and intraoperative phase, when triage and management decisions are being
made. The derivation phase of this system should include data on patient’s functional
status, comorbidities, medications, acute physiology, laboratory values, systemic
inflammation, intra-abdominal status, and probability of MDROs. Well-designed
high-volume multicenter studies are needed to address this matter.
Sepsis remains a major challenge worldwide, with substantial morbidity and
morbidity. All of the aspects of improving the prognosis warrant further attention.
The roles of OA and DCS are not yet established in severely ill patients. It is not well
defined which patients, if any, should be treated with these methods that include
reoperations, increased costs, and additional risks for complications. A multicenter
international RCT, Closed Or Open after Source Control Laparotomy for Severe
Complicated Intra-Abdominal Sepsis (the COOL trial) protocol has been published
and the study is now underway35. This study was designed to elucidate the role of OA
and its effect on organ dysfunctions and mortality in patients with SCIAS. The results
will most likely provide important additional information. The number of severely ill
patients with SCIAS per center is not sufficiently large for anyone to conduct this
Discussion
kind of study alone. Also, determination of the optimal TAC method to manage the
OA requires well-designed comparative studies.
Conclusions
77. CONCLUSIONS
7.1 STUDY I
The risk for a poor outcome can effectively be predicted by using readily available
preoperative risk factors. Acute organ dysfunctions, especially septic shock, have a
determinant role as risk factors. Pre-existing severe comorbidities and chronic use of
oral corticosteroids also act as independent risk factors. Patients without any of these
factors had no mortality. For patients refused intensive care unit (ICU) admission,
the mortality is extremely high. Therefore, ICU admission should be addressed
preoperatively in order to avoid futile operations.
7.2 STUDY II
The vacuum-assisted wound closure and mesh-mediated fascial traction - method is
effective in management of open abdomen in patients with diffuse secondary
peritonitis. Delayed primary fascial closure (DPFC) rates were similar to those of
other diagnoses and among the highest reported. The enteroatmospheric fistula
(EAF) numbers were low compared with other methods. DPFC was achieved in all
patients without a defect in fascia or an EAF.
7.3. STUDY III
The classification systems for patients with complicated intra-abdominal infections
(cIAIs) should include more data on the intra-abdominal view (IAV). The developed
IAV score may provide a simple method to classify patients with a cIAI. The IAV
score predicts various outcomes well and correlates with preoperative organ
dysfunctions as well as with the development of postoperative organ dysfunctions.
The IAV score needs to be externally validated prior to further utilization.
Conclusions
77.4. STUDY IV
Preoperative circulating cytokine levels are associated strongly with the IAV, IAV
score, and disease severity. Assessment of an individual patients immune-
inflammatory status could be improved with measurements of various cytokine
levels. In this study of cIAI patients, the best overall performance was found in
interleukin-8 levels, which were associated significantly with all measured variables.
Currently, cytokine analyses lack validated reference values and the analyses are not
routinely used in clinical medicine. The IAV offers an estimation of the magnitude of
the systemic cytokine response. The IAV score can provide a simple method for
quantification of the IAV, yet it needs further validation before wider use.
AACKNOWLEDGMENTS
This study was conducted at the Abdominal Center, Helsinki University Hospital
between 2013 and 2019. I am deeply grateful to all of the brilliant people who made it
possible.
The work was financially supported by the Martti I Turunen Foundation, the
Helsinki University Hospital Research Funds, the Mary and Georg Ehnrooth
Foundation, the Finnish Medical Foundation, and the Gastroenterological Research
Foundation. All funding is gratefully acknowledged.
I thank Professor Pauli Puolakkainen for creating a positive environment where
clinical work and scientific endeavors exist hand in hand without sacrificing leisure
time and family. Pauli has been very friendly and supportive since medical school.
My deepest gratitude belongs to my supervisors Professor Ari Leppäniemi and
Adjunct Professor Panu Mentula. Ari has been much more than a supervisor and my
boss as the Chief of Emergency Surgery. Ari has acted as my personal mentor, with
all of the positive associations, since he took me under his wing when I started
working in Helsinki in 2012. Despite his extremely busy schedule, Ari has always
found time to listen and guide me through joys and sorrows. Ari’s extensive
experience has been irreplaceable in this project. He has introduced me to dozens of
surgical scientists all around the world, enabling my involvement in many intriguing
international projects. Panu, my other supervisor and colleague, has devoted a
tremendous amount of time and effort in instructing me in clinical surgical science.
Panu has been the mastermind behind most study hypotheses and he is a true master
of biostatistics. His commitment to this project has been invaluable.
I am grateful to Adjunct Professor Ville Sallinen who acted, unofficially, as the third
supervisor in this thesis. Ville’s hands-on support, especially in the early stages of the
project, was critical. Thank you for your patience and friendship. I have joined the
vast group of colleagues admiring your progression as a scientific surgeon. I feel
privileged for having been taught by my supervisors. Together, we made a great
team. There is no doubt that I will continue to pursue a career as an academic
surgeon, thank you all for showing me the way and making it possible.
I also thank my other co-authors: Minna Bäcklund, Suvi Rasilainen, Krista Kuuliala,
Antti Kuuliala, and Leena Kylänpää. Minna, I truly appreciate the collaboration with
you and other intensivists for the benefit of our patients as well as science. Suvi, I’m
looking forward to working with you on multiple open abdomen projects. Krista and
Antti, the cytokine masters, thank you for sharing your wisdom and for all the work
that you did. Lennu, I’m sure we will continue working together on future academic
projects. Your highly competent leadership skills and profound kindness warrants
special mention.
I sincerely thank Adjunct Professors Juha Saarnio and Arto Rantala for reviewing
this dissertation. Your kind words and constructive comments and suggestions have
been most helpful. Thank you Professor Paulina Salminen and Adjunct Professor
Vesa Koivukangas for acting as the monitoring group during the development of this
thesis. Your feedback and reassuring comments made a difference. I am also very
grateful that you gave me the opportunity to lecture on topics of the studies in
various national congresses.
I am grateful to all of my colleagues at the Helsinki University Hospital. The
directors of the clinic, Esko Kemppainen, Leena Halme, and Jukka Sirén, have been
very kind and supportive in combining academic work with clinical surgery. I have
had the privilege of being trained by some wonderful experts in gastrointestinal
surgery. Special gratitude belongs to Päivi Siironen, Arto Kokkola, Anna Lepistö,
Laura Renkonen-Sinisalo, Lennu Kylänpää, Marianne Udd, Tom Scheinin, Olli
Kruuna, and Arno Nordin. I have trained with some outstanding peers and friends.
Thank you Henna Sammalkorpi, Tuure Saarinen, Johan Back, Laura Koskenvuo,
Anne Penttilä, Klas Linderborg, Mikael Laine, Hanna Lampela, Taija Korpela, and
many others for the exiting and enjoyable shared moments.
My gratitude is also owed to the great people at Jyväskylä Central Hospital, where I
did the early years of my surgical training. Professor Jukka-Pekka Mecklin was
extremely supportive and approachable, helping me to gain surgical confidence and
enjoy my time in Jyväskylä. The resident parties at your summer home were so much
fun and great for team spirit. Professor Ilmo Kellokumpu presented the beauty of
surgical craft in elective operations. Quite dissimilar I must say to the emergency
procedures that I ended up doing. Johanna Mrena showed patience and kindness in
guiding me during my early residency.
Without family and friends there would be no balance in life. I am forever grateful for
being able to spend my time with all of you magnificent, fun, inspiring, and caring
people. Thank you Äiti and Iskä. For everything. I have always felt safe and loved.
Thank you Ukki for showing me what true grit looks like. My dear talented, brilliant
brothers Antti and Pekka, I feel invincible with you at my side. Having such close
relationships with you and your families makes this world a better place for us all.
You have always had my back, love you bros! Tuoppi - my third brother, yet from
another mother. You are my best man, also literally speaking. I truly appreciate our
close friendship and the way we mirror our perceptions to each other.
My dear boys, Rasmus and Tuure, thank you for being you. You guys bring so much
joy and purpose to my life. My most heartfelt wish is to see you grow up happy, kind,
and confident.
The final words in this thesis are dedicated to my radiant wife. Laura, you are the
love of my life. You are my companion, a wonderful wife, the best imaginable mother
to our kids, and the heart and brain of our house. I am indebted to you for keeping
my priorities straight. It is easy to get carried away with work, yet one should never
forget that it is not where the most magical things in life take place.
Helsinki, March 2019
Matti Tolonen
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