SECONDARY PERITONITIS – ASSESSMENT OF SEVERITY AND

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, Finland

Adjunct Professor Panu Mentula, M.D., Ph.D.

Abdominal Center


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


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


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


(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.


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.


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


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.


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-


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


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.


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


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


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.


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.


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


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.


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


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,


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


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


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


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,


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.


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


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.


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.


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


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.


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.


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


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


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


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


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.


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


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).


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.


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.


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


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


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


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


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


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


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


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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SECONDARY PERITONITIS – ASSESSMENT OF SEVERITY AND