Surgical aspects in treatment of inflammatory bowel disease · Chapter 7 The Management of...
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Surgical Aspects in the Treatment of Inflammatory Bowel Diseaseusama ahmed ali
Surgical aspects in the treatment of
inflammatory bowel disease
Usama Ahmed Ali
Surgical aspects in the treatment of inflammatory bowel disease
PhD thesis, Utrecht University, The Netherlands
© U. Ahmed Ali, Utrecht, The Netherlands, 2019
Copyright of the published articles has been transferred to the respective publishers. No
part of this thesis may be reproduced, stored or transmitted, in any form or by any means,
without prior permission of the author.
The research in this thesis was financially supported by a personal grant from the Utrecht
University, The Netherlands and the Research Fellowship Program of the Cleveland Clinic,
Cleveland, United States of America.
Publication of this thesis was financially supported by Chirurgische Fonds UMC Utrecht,
Applied Medical and Erbe Nederland B.V.
Cover illustration: Rosalia Simunovic, RosalisArts, webshop: www.etsy.com/shop/RosalisArt
Lay-out: Optima Grafische Communicatie, Rotterdam, The Netherlands
Printed by: Optima Grafische Communicatie, Rotterdam, The Netherlands
Surgical aspects in treatment of
inflammatory bowel disease
Chirurgische aspecten in de behandeling van inflammatoire darmziekte
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht
op gezag van de rector magnificus, prof.dr. H.R.B.M. Kummeling,
ingevolge het besluit van het college voor promoties in het openbaar
te verdedigen op vrijdag 29 maart 2019 des middags te 2.30 uur
door
Usama Ahmed Ali
geboren op 19 april 1983 te Tripoli, Libië
Promotoren: Prof. dr. R. van Hillegersberg
Prof. dr. C.J. van Laarhoven
Prof. dr. R.P. Kiran
For my lovely wife – Amasi – and adored son – Shahien
Table of conTenTs
Chapter 1 General introduction and outline of the thesis 11
PART I CURRENT OUTCOMES IN COLORECTAL SURGERY
Chapter 2 Update of complications and functional outcome of the ileal
pouch-anal anastomosis: overview of evidence and meta-analysis
of 96 observational studies.
International Journal of Colorectal Disease, 2012.
21
Chapter 3 Actual versus estimated length of stay after colorectal surgery -
which factors influence a deviation?
The American Journal of Surgery, 2013.
43
Chapter 4 Risk and Location of Cancer in Patients with Preoperative Colitis-
Associated Dysplasia Undergoing Proctocolectomy.
Annals of Surgery, 2014.
59
PART II OPTIMIZING SURGICAL TREATMENT FOR INFLAMMATORY
BOWEL DISEASE
Chapter 5 Open versus laparoscopic (assisted) ileal pouch-anal anastomosis
for ulcerative colitis and familial adenomatous polyposis.
The Cochrane Database of Systematic Reviews, 2009.
81
Chapter 6 Surgical treatment of Ulcerative colitis: Ileorectal vs. Ileal-pouch
anal anastomosis.
World Journal of Gastroenterology, 2014.
113
Chapter 7 The Management of Anastomotic Pouch Sinus After ileal-pouch-
anal anastomosis.
Diseases of the Colon & Rectum, 2012.
131
Chapter 8 Impact of preoperative immunosuppressive agents on
postoperative outcomes in Crohn’s disease.
Diseases of the Colon & Rectum, 2014.
147
Chapter 9 Ileal pouch-anal anastomosis with close rectal dissection using
automated vessel sealers for ulcerative colitis: a promising
alternative.
Digestive Surgery, 2011.
169
PART III SUMMARY AND CONCLUSIONS
Chapter 10 Summary 185
Chapter 11 Gained insights and future perspectives 195
Chapter 12 Nederlandse samenvatting (Dutch summary) 205
APPENDICES
Review committee 217
Acknowledgement 218
List of publications 221
Curriculum Vitae 227
1 General introduction
and outline of the thesis
Chapter 1 13
1General inTroducTion
Inflammatory bowel disease (IBD) includes a group of chronic, relapsing, inflammatory
disorders of the gastrointestinal tract. It mainly includes ulcerative colitis (UC) and Crohn’s
disease (CD), with indeterminate colitis as an intermediate form in which there is difficulty
in distinguishing between these two conditions. Although the etiology and pathogenesis
of IBD are still poorly understood, it is widely accepted that several genetic and environ-
mental factors are involved. Several dozen genes have been identified by genome-wide
association studies to increase the susceptibility to IBD.1 Similarly, several environmental
risk factors are associated with IBD such as smoking, composition of the intestinal flora,
past history of appendectomy, certain medication, diet and stress.2
UC and CD differ with regards to various characteristics.3 UC usually starts in the rectum
and can extend in a continuous pattern to involve the complete colon. It is limited to the
mucosa and sometimes the submucosa. On the other hand, CD often starts at the terminal
ileum and extends in an irregular fashion with so called ‘skip’ lesions. The inflammation is
often transmural and can involve any part of the gastrointestinal tract. IBD commonly af-
fects people at an early age, with around 25% of patients diagnosed in the first 2 decades
(mostly between 13 to 18 years).4,5 The incidence and prevalence of IBD are increasing
worldwide, with the highest reported incidence in Europe of 24.3 per 100,000 person-
years for UC and 12.7 per 100,000 person-years for CD, and a respective prevalence of
505 per 100,000 and 322 per 100,000.6 Both UC and CD are lifelong diseases with a
significant impact on quality of life, personal burden and costs for patients and society.7,8
Therapy in IBD is directed at resolving symptoms as effectively as possible and subsequently
maintaining symptom-free periods. Lifelong medical treatment is required and currently
forms the corner-stone of management, especially with the development of several bio-
logic therapies that have proven to be effective in the majority of patients. The use of
these agents has been shown to facilitate remission, improve quality of life, reduce steroid
dependency and delay surgery.9-11
For UC, indications for surgical treatment include acute pancolitis, failure of medical treat-
ment, patient’s preference and the presence of dysplasia or neoplasia.12 The gold standard
for surgical treatment is a total proctocolectomy in which the complete colon and rectum
are removed.13 This surgery provides relief of symptoms and eliminates the risk of develop-
ing colorectal cancer. To re-establish continuity of the intestinal tract usually a restorative
ileal pouch-anal anastomosis (IPAA) procedure is performed. In this procedure, the terminal
ileum is used to form a reservoir to replace the removed colon, and is then anastomosed
14 Chapter 1
to the anus.13 The IPAA is currently the surgical treatment of choice for UC due to its good
functional results and high patient satisfaction.13,14
In CD, however, surgery is not curative, since the disease can (and does) recur throughout
the intestinal tract. This combined with the good clinical outcome of newer immuno-
modulatory drugs, has limited the indications of surgery to those patients with symptoms
or complications that are intractability to medical management.15 The surgical goal in CD
is, therefore, to limit the resection of bowel as much as possible. Limited small-bowel
resections, especially ileocecal resections, are the most common procedures in CD.
Surgery for IBD has certain challenges, including a relatively young patient population,
diseases that are chronic and recurring in nature and a continuously changing balance
between medical and surgical interventions resulting in a selection of sicker patients to be
operated. In this thesis we will examine certain aspects of the surgical management of IBD
as outlined below.
ouTline of The Thesis
In the first part of the thesis we review the current state of important outcomes in IBD sur-
gery. First, in Chapter 2 we provide a comprehensive update of the postoperative morbidity
and functional outcome after restorative proctocolectomy by means of an IPAA procedure.
This procedure has been performed for several decades now; a period that encompasses
many medical and technical advances. We examine whether these developments were able
to improve the outcome of this procedure by performing a systematic review summarizing
outcomes after the year 2000 and compare these to previous outcomes. Subsequently, in
Chapter 3 we focus on the length of hospital stay in colorectal surgery and its impact on
cost of care. In this era of ever-increasing costs it is prudent to examine how costs can be
reduced most effectively. Therefore, we have studied factors affecting the difference be-
tween the actual length of hospital stay, which represents the costs made by the hospital,
versus the estimated length of stay, representing the reimbursed amount received from
insurance companies. By selectively targeting modifiable factors identified by such analysis,
an optimized effort can be undertaken to reduce the financial burden for hospitals. In
Chapter 4, we examine the topic of oncological outcome after proctocolecotmy in colitis
patients with dysplasia. We evaluate the correlation between the preoperative findings
at colonoscopic surveillance (in terms of grade, location and appearance of dysplasia)
and those of the pathohistological findings after proctocolectomy. By doing so we aim at
improving our ability to predict the presence and location of cancer in colitis patients with
dysplasia, and facilitate recommendations regarding the necessity and type of surgery.
Chapter 1 15
1In the second part, we examine several aspects of the surgical treatment of inflammatory
bowel disease. First, in Chapter 5 we compare the open versus laparoscopic approach for
performing a restorative proctocolectomy with IPAA. With the advancements of minimal-
invasive surgery the laparoscopic approach for this demanding operation has been increas-
ingly popular. In this systematic Cochrane review we evaluate the presumed benefits of the
laparoscopic approach in a direct comparison. Next, we examine a potential alternative to
the IPAA procedure. While IPAA allows for removal of all diseases tissue and offers good
long-term results, it remains a large and complex procedure. Certain patients might benefit
from a less invasive treatment such as a total colectomy with ileorectal anastomosis, with
less postoperative complications as a major presumed advantage. In Chapter 6, we review
the literature and examine the benefits and harms of both approaches. Subsequently, we
focus on the optimal management of an anastomotic pouch sinus, an uncommon but
serious postoperative complication after IPAA. In Chapter 7 we retrospectively examine
a large prospectively collected database, identify all patients with this complication, and
map the received treatment and its outcome. Based on this, we provide recommenda-
tions on how best to manage this challenging complication. In Chapter 8, we evaluate
the impact of preoperative immunosuppressive agents on outcomes of surgery in CD.
While immunosuppressive agents are essential in the management of this disease, their
safety in the preoperative period is controversial. In this extensive systematic review and
meta-analysis, we examine the effect of various common immunosuppressive agents on
postoperative complications, especially infectious complications. Finally, in Chapter 9,
we examine whether a change in the way the IPAA procedure is performed might affect
postoperative outcome. In a pilot study, the close rectal dissection technique is attempted
instead of the more common total mesorectal excision approach. Safety, feasibility and
potential benefits are evaluated.
16 Chapter 1
references
1. Barrett JC, Hansoul S, Nicolae DL, Cho
JH, Duerr RH, Rioux JD, Brant SR, et al.
Genome-wide association defines more
than 30 distinct susceptibility loci for
crohn’s disease. Nature genetics. 2008; 40:
955-62.
2. Ye Y, Pang Z, Chen W, Ju S, Zhou C. The
epidemiology and risk factors of inflamma-
tory bowel disease. International journal of
clinical and experimental medicine. 2015; 8:
22529-42.
3. Price AB, Morson BC. Inflammatory bowel
disease: The surgical pathology of crohn’s
disease and ulcerative colitis. Human pa-
thology. 1975; 6: 7-29.
4. Benchimol EI, Fortinsky KJ, Gozdyra P, Van
den Heuvel M, Van Limbergen J, Griffiths
AM. Epidemiology of pediatric inflamma-
tory bowel disease: A systematic review of
international trends. Inflammatory bowel
diseases. 2011; 17: 423-39.
5. Mir-Madjlessi SH, Michener WM, Farmer
RG. Course and prognosis of idiopathic
ulcerative proctosigmoiditis in young pa-
tients. Journal of pediatric gastroenterology
and nutrition. 1986; 5: 571-5.
6. Molodecky NA, Soon IS, Rabi DM, Ghali
WA, Ferris M, Chernoff G, Benchimol EI, et
al. Increasing incidence and prevalence of
the inflammatory bowel diseases with time,
based on systematic review. Gastroenterol-
ogy. 2012; 142: 46-54.e42; quiz e30.
7. Kawalec P. Indirect costs of inflammatory
bowel diseases: Crohn’s disease and ulcer-
ative colitis. A systematic review. Archives of
medical science: AMS. 2016; 12: 295-302.
8. Floyd DN, Langham S, Severac HC,
Levesque BG. The economic and quality-
of-life burden of crohn’s disease in europe
and the united states, 2000 to 2013: A
systematic review. Digestive diseases and
sciences. 2015; 60: 299-312.
9. D’Haens GR. Top-down therapy for ibd:
Rationale and requisite evidence. Nature
reviews. Gastroenterology & hepatology.
2010; 7: 86-92.
10. Ford AC, Sandborn WJ, Khan KJ, Hanauer
SB, Talley NJ, Moayyedi P. Efficacy of bio-
logical therapies in inflammatory bowel dis-
ease: Systematic review and meta-analysis.
The American journal of gastroenterology.
2011; 106: 644-59, quiz 60.
11. Archer R, Tappenden P, Ren S, Martyn-St
James M, Harvey R, Basarir H, Stevens J,
et al. Infliximab, adalimumab and golim-
umab for treating moderately to severely
active ulcerative colitis after the failure of
conventional therapy (including a review
of ta140 and ta262): Clinical effectiveness
systematic review and economic model.
Health technology assessment (Winchester,
England). 2016; 20: 1-326.
12. Cohen JL, Strong SA, Hyman NH, Buie WD,
Dunn GD, Ko CY, Fleshner PR, et al. Practice
parameters for the surgical treatment of
ulcerative colitis. Diseases of the colon and
rectum. 2005; 48: 1997-2009.
13. Fazio VW, Ziv Y, Church JM, Oakley JR,
Lavery IC, Milsom JW, Schroeder TK. Ileal
pouch-anal anastomoses complications and
function in 1005 patients. Annals of sur-
gery. 1995; 222: 120-7.
14. Hueting WE, Buskens E, van der Tweel I,
Gooszen HG, van Laarhoven CJ. Results
and complications after ileal pouch anal
anastomosis: A meta-analysis of 43 obser-
vational studies comprising 9,317 patients.
Digestive surgery. 2005; 22: 69-79.
15. Seifarth C, Kreis ME, Grone J. Indications
and specific surgical techniques in crohn’s
disease. Viszeralmedizin. 2015; 31: 273-9.
Part I
Current outComes In ColoreCtal surgery
S. de Zeeuw1
U. Ahmed Ali1
R.A.R.T. Donders2
W.E. Hueting3
F. Keus1
C.J.H.M. van Laarhoven1
1 Department of Surgery, Radboud University Medical Centre, Nijmegen2 Department of Epidemiology, Biostatistics and HTA, Radboud University Medical Centre,
Nijmegen3 Department of Surgery, Diakonessenhuis, Leiden
2 update of complications and
functional outcome of the
ileal pouch-anal anastomosis:
overview of evidence and meta-
analysis of 96 observational
studies
International Journal of Colorectal Disease, 2012.
22 Chapter 2
absTracT
backgroundThe ileal pouch-anal anastomosis (IPAA) is the procedure of choice for the surgical treat-
ment of ulcerative colitis and familial adenomatous polyposis, since its introduction over
30 years ago. We aim at providing a comprehensive update of the outcome of the IPAA
over the past decades.
MethodsA systematic review with an extensive search in PubMed, EMBASE and The Cochrane
Library was conducted. All studies published after 2000 reporting on complications or
functional outcome after a primary open IPAA procedure for UC or FAP were selected.
Study characteristics, functional outcome and complications were extracted. A review
with similar methodology conducted 10-years earlier was used to evaluate developments
in outcome over time. Pooled estimates were compared using a random-effects logistic
meta-analyzing technique. Analyses focusing on the effect of time of study conductance,
centralization and variation in surgical techniques were performed.
resultsFifty three studies including 14,966 patients were included. Pooled rate of pouch failure
and pelvic sepsis were 4.3% (95% CI 3.5 – 6.3) and 7.5% (95% CI 6.1 – 9.1), respectively.
Compared to studies published before 2000, a reduction of 2.5% was observed in the
pouch failure rate (p = 0,0038). Analysis on the effect of the time of study conductance
confirmed a decline in pouch failure. Functional outcome remained stable over time, with
a 24-hour defecation frequency of 5.9 (95% CI 5.0 to 6.9). Technical surgery aspects did
not have an important effect on outcome.
conclusionThis review provides up to date outcome estimates of the IPAA procedure that can be
useful as reference values for practice and research. It is also shows a reduction in pouch
failure over time.
Chapter 2 23
2
inTroducTion
Restorative proctocolectomy by means of an ileal pouch-anal anastomosis (IPAA) is the
procedure of choice for the surgical treatment of ulcerative colitis (UC) and familial ad-
enomatous polyposis (FAP). The IPAA procedure generally results in acceptable long-term
functional outcomes and improvement of quality of life. It is, however, associated with
substantial morbidity with complications up to 50% of patients1. Since its introduction in
1978, the IPAA procedure has continuously been subjected to attempts of improvements
in technique.2 Additionally, much has been achieved in improving the peri-operative care.
Centralization of complex surgery has been a recent development in many countries. All
these developments may have resulted in improved outcomes.
A large number of observational studies have reported outcomes of the IPAA procedure,
most commonly from a selected group of patients in one hospital. This review aims to
provide an overview of the available evidence and to evaluate the effect of the continuous
developments on outcomes. Previously, a systematic review summarizing complications
and functional results after an IPAA procedure in studies published until 2000 was con-
ducted. This current systematic review provides an update regarding the outcomes of the
IPAA procedure and uses the combined data set of both reviews to analyze changes in the
outcomes of the IPAA procedure.
MeThods
This systematic review aims to provide an overview regarding the outcomes of the open
IPAA procedure. Additionally, it evaluates the effect of development of practice on the
most important outcomes over time.
search strategyA systematic literature search with predefined search terms was carried out in 4 electronic
databases: MEDLINE (1-1-2000 to 1-1-2010), EMBASE (1-1-2000 to 1-1-2010), and the
Cochrane Library (Issue 1, 2010)) (Figure 1). Two authors (SZ and UAA) independently
performed the selection of the publications according to inclusion criteria. Disagreements
were discussed with a third reviewer (FK). Additional relevant studies were looked for by
cross-reference checking of all included studies. Language restrictions were not applied.
24 Chapter 2
selection of studies
Inclusion criteria
Title and abstract of all identified publications (prospective and retrospective and observa-
tional and comparison studies) were screened according to the following inclusion criteria:
the study population consists of adult patients with established UC or FAP undergoing a
primary IPAA procedure; the intervention is a clearly documented open IPAA procedure in
an elective setting with or without a diverting ileostomy and irrespective of the number of
stages of the operation; the study reports at least one of the primary outcomes reported
below; the study includes a consecutive series with a minimal sample size of 50 patients.
10301 studies from search
terms
236 studies extracted by title
94 studies read by two
authors
53 studies included for meta-
analysis
58 studies < 50 patients
4 studies with morbus Crohn as population
21 studies with other outcome measures
12 studies with patients < 18 years
47 studies with laparoscopic surgery
Figure 1. Flow-chart of study selection resulting in the 54 included studies
Chapter 2 25
2
Exclusion criteria
Studies were excluded from this systematic review if they included children (<18 years) or
primarily elderly patients (> 65 years). Studies were excluded as well when the IPAA was
performed for other indications than UC or FAP (e.g. Morbus Crohn) or when a second-
ary IPAA was performed (e.g. after ileo-rectal anastomosis). Studies were also excluded
when there was selective outcome reporting, i.e. studies focusing on one parameter (e.g.
pouchitits) without reporting of any additional outcomes.
outcomes of interest and definitionsPrimary outcomes were pouch failure, pelvic sepsis, and severe day incontinence. Second-
ary outcomes included other complications (stricture, fistula, small bowel obstruction,
pouchitis, and sexual dysfunction) and parameters of functional outcome (defecation
frequency and incontinence). Table 1 shows the definitions of all outcomes.
Table 1. Definition of outcomes
Pouch failure Pouch excision or a nonfunctioning pouch at 12 months after IPAA
Pelvic sepsis Pelvic abscess, anastomotic leakage or dehiscence, pelvic/perineal wound infection
Fistula Any pouch-related fistula
Stricture Anastomotic fibrosis necessitating dilatation
Mild fecal incontinence Soiling, spotting in underwear
Severe fecal incontinence Regularly severe leakage or fecal loss passive fecal incontinence
data extractionAfter assessment for eligibility, two authors (SZ and UAA) independently extracted the fol-
lowing data if available: numbers of patients, patient characteristics, dates of start and end
of the inclusion period, duration of follow-up, variations in surgical technique, numbers
and type of complications, and parameters of pouch functional outcome. Authors were
contacted when data were missing. One author provided updated unpublished informa-
tion.3 Double publications describing identical populations were considered as one study.
data of studies published until 2000Previously, a systematic review was performed summarizing complications and functional
results after an IPAA procedure in studies published until 20004. For time-frame analyses
regarding the development of clinical practice and its effect on outcomes, data from both
reviews were combined. Both reviews were conducted with similar methodology, and the
full data set from the previous review was available.
26 Chapter 2
statistical analysisRelevant study characteristics and outcomes were extracted and presented for each study
individually. Outcomes were subsequently pooled and cumulative probabilities were calcu-
lated with 95% confidence intervals (95% CI). Data was pooled using a random-effects
model, based on the Restricted Maximum Likelihood (REML) estimator in order to incorpo-
rate the heterogeneity between studies. Pooled results of this review (all studies published
since 2000) were compared with pooled results of the previously published review (all stud-
ies published before 2000) by analyzing the complete set in one random-effects model and
incorporating a dummy variable that coded for period. The Knapp and Hartung adjustment
was used to obtain estimates and confidence intervals.5 Additionally, analysis focusing on
the effect of time of study conductance, centralization, and variation in techniques were
performed using linear regression and one-way ANOVA as appropriate. Data management
and statistical analyses were conducted using SPSS (version 15) and R Statistical Software
(R Development Core Team, version 2.11.1) with the metafor package.6,7
resulTs
selection processThe search resulted in a total of 10,301 hits. Initial selections based on titles identified 236
potentially relevant articles. Further selections based on abstracts excluded 142 studies.
The full-text of the remaining 94 studies was evaluated. Finally, a total of 53 studies with
14,966 patients were included (Figure 1).
description of identified studiesThe most important characteristics of the included studies are presented in Table 2. Most
studies were retrospective cohort studies (70%). The median sample size was 127 (range
50 to 2490) over a median inclusion periods of 12 years (range 4 to 30). A diverting
ileostomy was used in 79% (range 5 – 100%) of all the IPAA procedures. A handsewn
anastomosis was used in 40% of the procedures (range 0 – 100%). Median duration of
follow-up was 75 months (range 6 – 180). 31 studies mentioned postoperative mortality
with a median of 0% (range 0 – 2.9%).
Chapter 2 27
2
Table 2. Characteristics of studies and selected outcomes following IPAA in the 54 included studies published since 2000
Author Year of
pub.
Inclusion period
No. of patients
FU(mnt)
Age Gender(%
female)
Typeof
disease
Handsewn anastomo-
sis (%)
Withdivertingileostoma
(%)
Fonkalsrud8 2000 1993-1997 77 34.5 50 UC 57.1 100
Karlbom9 2000 1983-1996 168 29 32 39.3 UC 58.9 70.8
Seidel10 2000 1985-1996 55 31.2 45.5 Both
Simchuk11 2000 1987-1996 114 38 43.9 Both 100
Gullberg12 2001 1990-1995 86 72 34.1 45.3 Both 2.3 10.5
Barton13 2001 1983-2000 110 30 36.8 Both 100 100
Heuschen14 2001 1991-2000 171 30 36.7 45.6 UC 100 66.7
Regimbeau15 2001 1984-1998 172 60 36 47.1 Both 100 100
Blumberg16 2001 1982-1995 145 34 49 Both 15.2
Dayton17 2002 1982-2001 644 79 37.2 39.4 UC
Rossi18 2002 1989-2000 75 40 33.3 Both 54.7 100
Bullard19 2002 1980-1992 154 151 34 44.2 Both 64
Gignoux20 2002 1993-1998 84 22 33 42.9 Both 100
Mukhtar21 2002 1990-1997 50 35 44 Both 2 98
Rudolph22 2002 1991-1999 71 47 38 56 UC 84.5
Carmon23 2003 1990-2001 77 51 38 55.8 UC 72.7
Teixeira24 2003 1986-2000 80 108 50 UC 11.3 77.5
Michelassi25 2003 1987-2002 391 37 33.7 44.2 Both 29.9 65
Holubar26 2003 51 85 42.1 51 UC 70.6
Fowler27 2003 1984-2001 106 40 50 Both 39.4 41.3
Parc28 2004 1983-1990 110 175 26.5 43.6 FAP 100
Lin29 2004 1985-2002 61 60 37 54 Both 67.2
Hueting30 2004 1989-2000 111 42 35.4 68.5 UC
Gosselink31 2004 1989-2001 127 56 36 42.5 UC 21.6
Krausz32 2005 1984-2004 174 64 34.1 47.7 Both 54 87.4
Hallberg33 2005 1990-1997 100 53 32 39 UC 17
Swenson34 2005 1995-2003 54 22 35 35.2 57.4
Chapman35 2005 1981-2000 2002 121 33.5 46.6 Both 5
Kok Sun Ho36 2005 1989-2001 330 32 59.1 UC
Ikeuchi37 2005 1999-2003 242 32.1 50.8 UC 100 38
Arai38 2005 1993-2003 296 53 33.8 43.2 UC 96.3 55.4
Araki39 2006 1998-2003 220 34.5 46.8 Both 47.3
Rickard40 2006 1982-2002 516 33 45.2 Both 32.4 88
Bednarz41 2007 1994-2005 108 60 50 Both 18.5 100
Berndtsson42 2007 1982-1995 370 180 34 45.7 UC
Gualdrini43 2007 1987-2005 391 45.6 35.4 51.7 Both
28 Chapter 2
outcomes
Complications
Data on complications were available from all 53 studies. We found a pooled incidence of
pouch failure of 4.3% (95% CI 3.5 – 6.3) (Figure 2). A sensitivity analysis including only
studies with minimal follow-up of 5 years showed a pouch failure rate of 4.7%. The pooled
incidence of pelvic sepsis was 7.5% (95% CI 6.1 – 9.1) (Figure 3). Pooled incidence rates
for other important complications are presented in Table 3.
Functional results
Data on functional results after IPAA were available from 26 studies including 5,321
patients. The pooled incidence of mild and severe fecal incontinence during the day was
14.3% (CI 7.3 – 25.9) and 6.1% (2.9 – 12.3), respectively (Table 3). Mean defecation
frequency was 5.9 (4.9 – 6.7) per 24 hours with a mean nighttime frequency of 1.5 (1.0
– 2.1).
Table 2. (continued)
Author Year of
pub.
Inclusion period
No. of patients
FU(mnt)
Age Gender(%
female)
Typeof
disease
Handsewn anastomo-
sis (%)
Withdivertingileostoma
(%)
Kiran44 2008 2016 180 37.7 43.9 Both 15.4 85.9
Tulchinsky3 2008 1986-2005 211 124.6 35.4 58.3 UC 16.5 79
Walker45 2008 1987-2004 178 84 31 44.9 Both 6.7 100
Ferrante46 2008 1990-2004 173 78 39 38.7 UC 2.3 85
Leal47 2008 1984-2006 69 82 29.6 59.4 FAP 100 100
Zarate48 2008 1984-2006 107 34.4 57 Both 12.1 100
Pinto49 2009 2001-2008 66 21.1 52.8 66.7 Both 18.2 100
Leowardi50 2009 1988-1996 197 147.6 33 45.2 UC 100 100
Norwood51 2009 1997-2007 107 77 38 45.8 Both 99
Loftus52 2009 2001-2005 237 5.9 38.9 45 UC
Tekkis53 2009 1976-2006 2491 74.4 35.9 47.9 Both 33.3 67.3
Scarpa54 2009 1984-2004 58 136 38 34.5 UC 0
Wasmuth55 2009 1984-2006 304 120 34.4 38.8 Both 40.1 84
Andersson56 2009 1984-2003 110 144 35 45.5 Both 47.3
Fichera57 2009 2002-2007 106 24.8 36.9 42.2 UC 71.6
Rink2 2009 1990-2002 131 85 33 46.6 UC 84
Pricolo58 2009 1991-2008 312 36 46.8 Both 8
Chapter 2 29
2
Comparison with studies published before 2000
The previous review of studies published before 2000 identified 43 studies with a total of
9,317 patients.4 Median duration of follow-up was 36.7 months (range 12-99). Detailed
discussion of the characteristics of these studies is published elsewhere.4
We compared incidences of the most important complications reported in studies pub-
lished prior to 2000 versus the incidences reported in studies published since 2000 (Table
3). Pouch failure decreased between the two time periods from 6.8% to 4.3% (p=0.0038).
Pelvic sepsis showed a decrease from 9.5% to 7.4 (p=0.1284). Other complications and the
functional results showed no significant differences between the two groups of studies.
0 10 20 30 40
Percentage
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2009200920092009200920092009200920082008200820082008200820072007200720052005200520052005200420042003200320032003200320022002200220022002200220012001200120012001200020002000
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582491107197107
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3.8] 14.0] 9.6]
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21.5] 10.7] 16.3] 9.7] 5.1] 4.9] 6.8] 7.8]
14.7] 6.3] 3.1] 4.8] 7.0] 7.5]
10.4] 12.1] 6.2] 9.6]
13.6] 5.6] 8.3] 9.4]
17.6] 14.6] 8.0]
12.4] 8.9] 2.7] 7.1] 6.8] 9.8]
12.7] 8.8] 7.8]
15.6] 12.2]
,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
0.7 4.0 1.4 5.1 0.9 6.7 1.411.3 2.0 3.0 2.7 0.5 0.7 4.8 3.3 8.3 0.1 0.3 1.2 4.9 0.2 3.1 3.2 0.1 1.4 0.0 1.9 0.2 0.0 3.8 1.0 0.2 4.0 0.2 0.7 1.0 1.2 2.8 3.1 0.6 0.9 1.8 4.1
[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[
1.6 7.6 3.8 7.6 3.4 7.7 3.715.7 4.7 7.2 5.2 1.7 1.9 5.7 5.111.1 0.9 1.0 2.4 5.9 1.1 5.7 6.3 0.9 3.8 0.0 3.3 1.2 0.0 8.5 4.0 1.2 7.1 1.3 1.4 2.8 2.9 5.3 6.4 2.3 2.6 5.5 7.1
5.3], 3.5[ 4.3RE Model
Author Year Study Size
Figure 2. Proportions of pouch failure following an IPAA procedure in studies published since 2000The size of the dot correlates with the population size of the study. The lines represent the 95% CI.The pooled incidence of all studies is 4.3%.
30 Chapter 2
The effect of time of study conductance on iPaa outcomesResults of both reviews were combined to analyze the effect of time of study conductance
on the outcomes of the IPAA procedure. For this, the relationship between the median
year of inclusion of each study and the outcomes observed in that study was evaluated.
Regression analysis showed that studies with an earlier median year of inclusion have a
higher rate of pouch failure than studies with a more recent median year of inclusion
(p<0,001). Figure 4 is a scatter-plot depicting this relationship. In a sensitivity analysis
excluding the 5 studies with a pouch failure rate of >12.5%, the relationship remained
statistically significant (p=0.009). Additionally, we categorized the median year of inclusion
of all studies (published before and after 2000) into four interquartile ranges (IQR) in order
to evaluate the median rate of pouch failure over these four time periods. Figure 5 shows
0 10 20 30 40
Percentage
PricoloRinkFichera AnderssonWasmuthScarpaTekkisLoftusNorwoodPintoZarateLealWalkerKiranGualdriniBednarzRickardArakiAraiIkeuchiChapmanSwensonHallbergKrauszGosselinkHuetingParcLinFowlerHolubarMichelassiTeixeiraCarmonMukhtarGignouxRossiDaytonBlumbergRegimbeauHeuschenBartonGullbergSimchukSeidelKarlbomFonkalsrud
2009200920092009200920092009200920092009200820082008200820072007200620062005200520052005200520052004200420042003200320032003200320032002200220022002200120012001200120012000200020002000
312131106110304
582491
237107
66107
69178
2016391108516220296242
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174127111110
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644145172171110
86114
55168
77
2.5] 5.9]
20.0] 11.6] 24.9] 12.8] 13.1] 32.1] 22.0] 11.3] 10.7] 19.8] 9.4] 6.6]
27.5] 6.3] 7.1]
12.6] 7.8]
14.4] 8.2]
15.9] 22.0] 14.5] 13.1] 23.3] 6.2]
14.2] 12.0] 12.6] 10.8] 17.2] 9.8]
19.5] 15.0] 16.7] 6.0]
14.8] 13.3] 25.9] 6.2]
18.9] 11.2] 24.4] 12.9] 8.6]
,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
0.2 0.4 7.3 2.5
15.9 0.9
10.621.0 8.6 0.8 2.0 4.9 2.7 4.6
19.1 0.1 3.3 5.2 2.8 6.7 6.0 1.8 7.7 5.7 3.7 9.7 0.1 1.6 2.6 0.3 5.4 4.2 0.7 3.0 3.2 3.6 2.9 5.3 4.9
14.1 0.1 5.5 2.4 6.2 4.5 0.2
[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[
0.6 1.5
12.3 5.5
20.1 3.4
11.826.214.0 3.0 4.7
10.1 5.1 5.5
23.0 0.9 4.8 8.2 4.7 9.9 7.0 5.6
13.3 9.2 7.1
15.3 0.9 4.9 5.7 2.0 7.7 8.8 2.6 8.0 7.1 8.0 4.2 9.0 8.1
19.3 0.9
10.5 5.3
12.7 7.7 1.3
9.1], 6.1[ 7.5RE Model
Author Year Study Size
Figure 3. Proportions of pelvic sepsis following an IPAA procedure in studies published since 2000The size of the dot correlates with the population size of the study. The lines represent the 95% CI.The pooled incidence of all studies is 7.5%.
Chapter 2 31
2
a consecutive decline in the pouch failure rate over these time periods (p=0.005, one-way
ANOVA analysis).
centralization: trends over timeThe median inclusion rate for all studies was 14 patients per year (range from 2.9 to 105).
We evaluated the effect of time of study conductance (median year of inclusion) on the
inclusion rate (Figure 6). The figure shows that between 1991 and 2000 an increase was
seen in studies from centers including less than 1 patient per month, from 8 studies (30%)
before 1991 to 23 studies (46%) between 1991 and 2000. It also shows that there are not
yet enough studies available that have been conducted after 2000 to draw conclusions
Table 3. Pooled incidences of complications and functional outcome following an IPAA procedures in studies published since 2000 compared to studies published before 2000
Since 2000 Before 2000P-
valueNo. of studies
No. of patients
Pooled incidences
No. of studies
No. of patients
Pooled incidences
Complications % (95% CI) % (95%CI)
Pouch failure 43 13249 4.3 (3.5–5.3) 39 8877 6.8 (5.8–8.4) 0.004
Pouch failure: FU > 5 yrs
22 9873 4.7 (3.4–6.4) 11 3198 8.5 (5.4–13.2)
Pelvic sepsis 46 13450 7.5 (6.1–9.1) 41 9082 9.5 (8.2–10.9) NS
Fistula 38 12398 4.5 (3.5–5.7) 30 5120 5.5 (4.3–7.0) NS
Stricture 35 12219 10.7 (8.2–13.8) 28 5185 9.2 (6.8–12.4) NS
Pouchitis 39 12685 26.8 (21.0–33.5) 33 7289 18.8 (15.7–22.4) NS
Sexual dysfunction
13 6131 3.0 (1.7–5.2) 21 5112 3.6 (2.7–4.7) NS
Small bowel obstr.
34 11895 11.4 (9.1–14.1) 27 5853 13.1 (11.0–15.7) NS
Fecal incontinence
%(95%CI) % (95%CI)
Mild day incont. 21 6988 14.3 (7.3–25.9) 31 4313 17.0 (12.8–22.2) NS
Severe day incont.
13 3718 6.1 (2.9–12.3) 27 3914 3.7 (2.8–4.8) NS
Mild night incont.
9 5423 17.3 (4.7–46.8) 17 2582 13.1 (9.5–17.9) NS
Severe night incont.
10 3614 7.6 (2.5–21.3) 9 1271 4.5 (3.0–6.7) NS
Frequency mean(95%CI) mean (95%CI)
Frequency day 26 5321 5.7 (4.9–6.7) 13 2277 5.2 (4.0–6.7) NS
Frequency night 22 7117 1.5 (1.0–2.1) 20 2950 1.0 (0.6–1.6) NS
Frequency 24 h 26 5132 5.9 (5.0–6.9) 20 3547 5.2 (4.4–6.1) NS
CI: confidence interval; FU: Follow-up period; Yrs: years
32 Chapter 2
Figure 4. Scatter plot depicting the median year of inclusion and the rate of pouch failure of studies included in both reviews
Figure 5. Error-bar chart depicting the median rate of pouch failure compared to the median year of inclusion (divided into interquartile ranges)
Chapter 2 33
2
about the current situation. Analysis of the effect of the inclusion rate on the outcomes of
the IPAA did not show any benefit on the outcomes of the IPAA.
Technical aspects of the iPaaOverall, 43 out of 78 studies (55%) used a protective ileostomy as a routine part of the IPAA
procedure (routine use defined as ileostomy performed in more than 80% of patients). The
percentage has decreased from almost 70% (16 out of 23) in studies conducted between
1980 and 1990, to 47% (21 out of 44) in studies conducted after 1990. The number of
studies performing an ileostomy in less than 50% of patients increased from 11% to 32%
over the same periods. The rate of ileostomy was not associated with any of the outcomes
of the IPAA. Type of anastomosis (handsewn vs. stapled) was only available from 31 studies
published since 2000 (the previous review did not register this characteristic). Fifteen stud-
ies (48%) still performed a handsewn anastomosis in more than 50% of patients. There
were no differences in functional outcome or complications between studies performing
different types of anastomosis.
Figure 6. Relationship between moment of study conductance (median year of inclusion) and inclu-sion rate of patients, divided in the past three decades
34 Chapter 2
discussion
The open IPAA operation is the most common surgical reconstruction procedure in patients
with UC and FAP. Randomized trials on IPAA are rare1 due to low incidences as well as the
complexity of patient selection and the intervention. Therefore, most studies are retro-
spective case-series. Estimates of the outcomes of the IPAA procedure vary considerably.
Acceptable complication and functional outcome rates are, therefore, difficult to set. This
systematic review provides up to date and reliable incidences of important outcomes of the
IPAA procedure, that could provide a reference values for these outcomes. Additionally, this
review may provide insights in changes of practice over time and their effects on outcomes.
Several important finding are provided. First, it shows that the rate of pouch failure after
an IPAA procedure has declined continuously over time. This decline was larger in the
earlier period of the IPAA, but seems to continue over time. Secondly, a large proportion
of studies with this complex type of surgery are conducted in centers that include less than
one patient per month. Thirdly, the functional outcome of the IPAA seems not to improve
over time, despite several developments in surgical technique and peri-operative care. This
may represent an intrinsic limitation of the IPAA technique regarding functional outcome.
This review has some limitations. First, many of the included studies are retrospective
cohort series, which may limit the reliability of the results. However, the overwhelming
majority of the evidence in this field consists of this type of studies. This review provides
an overview of this evidence, thereby increases its utility for clinicians and researchers.
Moreover, the statistical techniques used are rather conservative to allow for incorporation
of the heterogeneity of the studies.
Second, publication bias is a factor that should be taken into consideration. For this purpose,
we excluded series with less than 50 patients. Studies with a small sample size do not only
increase heterogeneity of results, but are also more subject to publication bias; i.e. small
studies with ‘unfavorable’ results are less likely to get published. By introducing a threshold
we aimed to prevent including small studies with overestimated intervention effects.
Finally, the lack of individual patient data limits the analyses that could be performed.
For example, many studies report a cohort in which several types of operative techniques
have been used (e.g. several types of anastomses). This prohibits analyzing the effect of
variations in technique on a patient level, since only aggregate outcomes of the complete
cohorts are available. Collecting individual patient data of these large numbers of studies,
especially considering the dated studies, is not feasible. We, therefore, limited our analyses
to factors that could be analyzed reliably on an aggregate level.
Chapter 2 35
2
Many factors may have contributed to the reduction of the rate of pouch failure observed.
The additional analyses in this review were unable to pinpoint factors responsible for the
observed reduction in pouch failure. This is probably caused by the lack of individual pa-
tient data (as discussed above) and we believe that general improvements in care over the
past decades, and the increased experience of surgeons with this approach are the most
important factors contributing to this finding.
Another explanation that could be considered is the variation in the surgical techniques
that have been introduced and sometimes largely employed over the last decades. Such
variations include the various types of pouches used and the use of the double-stapled
anastomosis. The routinely constructed deviating ileostoma does not seem to improve
the frequency of postoperative complications, but only their severity. Despite comparative
studies and several large meta-analyses published previously, none of these variations in
technique could be identified as factors associated with the reduction of postoperative
complications, including pouch failure.59,60 This is in line with the findings in this review.
Fewer studies reported on other outcomes, which decreased the power of the analyses
concerning these other outcomes. Secondly, it could be that the observed decrease in the
rate of pouch failure may be, at least in part, a result of smaller decreases in various other
postoperative complications. Complications like pelvic sepsis, fistulae and strictures could
all result in pouch failure, provided they were severe enough. Smaller decreases in these
outcomes can be difficult to show statistically. Overall, however, they may have caused the
observed substantial decrease in pouch failure rate.
Recently, discussions on the relation between volume of complex surgical interventions
and outcomes have gained wide attention.61-64 Certain complex surgical interventions have
been centralized in high volume hospitals with improved outcomes.65-68 Centralization still
has to be reflected in the data in the years to come. Therefore, this review was unable to
evaluate the potential influence of this development on current practice. However, in the
period from 1991 to 2000 nearly 50% of studies were performed in ‘low inclusion rate’
centers (including less than 1 patient per month). This is a substantial increase from the
30% observed in the period from1980 to 1990. Taking into account that we only included
series of 50 patients or more (Figure 1), may mean that the true proportion of studies
conducted in such ‘low inclusion rate’ centers may be much higher. With the repeatedly
established relationship between volume and outcome in several fields of surgery, this is a
troublesome observation. Centralization of the complex IPAA procedure may offer a way
to further improve outcomes in future.
36 Chapter 2
Finally, we found no statistically significant differences in pooled estimates of the func-
tional outcome over time. There were also no differences in functional outcomes between
various surgical factors studied in this review. This is in agreement with findings in literature
showing no benefits in terms of functional outcome of technical developments of the
IPAA procedure, like type of anastomosis69 or laparoscopic approach.1 In most patients,
however, functional outcome of the IPAA is considered to be highly satisfactorily, allowing
for an acceptable quality of life and social functioning.70,71 Therefore, reducing complica-
tions, especially severe complications like pelvic sepsis and pouch failure, seems to be a
more important goal for future surgical developments.
conclusions
This systematic review and meta-analysis summarizes the available evidence and provides
up to date estimates for complications and functional outcome after an IPAA procedure
that can be useful as reference values for practice and research. It also shows a reduction
in pouch failure over time in patients operated on using the IPAA procedure. The functional
results remain unchanged over time and between various operative factors.
Chapter 2 37
2
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U. Ahmed Ali
T. Dunne
B. Gurland
J.D. Vogel
R.P. Kiran
Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
3 actual versus estimated lenGth
of stay after colorectal
surGery – which factors
influence a deviation?
The American Journal of Surgery, 2013.
44 Chapter 3
absTracT
backgroundDue to increasing health costs, reimbursement has shifted from a fee-for-service to fixed
reimbursement schemes, such as the Diagnosis Related Groups (DRG). Studying the devia-
tions of actual outcome compared to those expected based on such scheme provides more
insights in costs and identifies potential target for saving. This study determines factors
associated with deviation in length of hospital stay (LOS) from that determined by DRG.
MethodsCohort study from a prospectively collected database including consecutive patients oper-
ated in a high-volume colorectal surgery department in 2009.
resultsFor 1,461 included patients, average expected and actual LOS were 8.17 (IQR 4.7-11.9)
and 8.31 (IQR 4-10) days, respectively. The most prominent factors associated with an
increase of LOS from expected were parenteral nutrition (5.11 days), emergency room
admittance (3.67) and ileus (3.45) (all p≤0.001). Other independently associated factors
included blood transfusion, anastomotic leak, sepsis, pulmonary embolism and surgeon.
Patients with a higher severity-illness-index and postoperative intensive care stay had a
lower than expected LOS.
conclusionsIdentifying predictors of deviation of LOS offers an opportunity to identify maximally cost-
effective targets for hospital cost savings. We identified multiple factors that may serve as
targets for specific cost savings measures. DRG related outcomes also offer a tool to more
accurately compare results from hospitals with different case-mix.
Chapter 3 45
3
inTroducTion
Colorectal surgical procedures carry an increased risk of certain complications, like post-
operative ileus and anastomotic leakage. These complications are known risk factors for
prolonged hospital stay.1-4 Studies have looked at the influence of these factors on the
absolute length of hospital stay5-7 (LOS), but correlating these differences with deviation
from what is expected by risk estimation models, like the Diagnosis Related Groups (DRG),
is yet to be done. DRG is a classification system intended to relate the type of patients a
hospital treats to the costs incurred by the hospital.8 In the United States DRG is used to
determine hospital payment for Medicare patients.9 Other similar systems exist around the
world.10-12
The DRG offers an estimation of the expected LOS based on preoperative patient charac-
teristics, type of surgery and postoperative complications. Trying to predict deviation from
this estimate has certain advantages. Such analysis offers insights to physicians and depart-
ments to which factors result in the greatest increase in cost. This allows for prioritization
of research and management goals.13-16 As an example, a previous study from our group
showed that mean direct hospital costs were significantly lower for laparoscopic compared
to open colectomy, although DRG classifications (and thus payment to hospitals) were
similar.17 Additionally, the DRG classification offers a reference value that is more reliable
than absolute LOS alone. Since the DRG classification corrects for the complexity of patient
population (i.e. case-mix), results can be better interpreted across different sources and are
thus more generalizable. Therefore, the aim of this study was to evaluate factors associated
with deviation of actual LOS from expected based on the DRG classification.
MaTerials and MeThods
study populationAfter study approval by the institutional review board (IRB), all consecutive patients oper-
ated on from January 12th to December 17th 2009 in the Department of Colorectal Surgery
at the Cleveland Clinic were included. Patients were selected based on procedural codes
for colorectal surgical procedures. Patients had to be 18 years or older. No exclusion criteria
were used.
study variablesClinical and administrative data respectively were obtained from the prospectively col-
lected clinical “Outcomes database” and departmental financial records. Clinical data col-
lected included patient characteristics, medical history, co-morbidities, smoking, laboratory
46 Chapter 3
profiles, operative details and postoperative outcome (actual LOS and 30 day-postoperative
complications). Patients were accrued into the database on the day of discharge. A prede-
termined dataset was collected, including diagnosis, laboratory tests, surgical details and
in-hospital complications. Anastomotic leak was defined as any clinically evident leak or
extravasation of contrast from the anastomosis detected by radiology studies. Prolonged
postoperative ileus was defined as absence of gastrointestinal function for longer than 5
days or the need for placement of a nasogastric tube. Other complications were also based
on specific definitions. All patients were contacted after discharge to obtain a complete
30-day follow-up. Administrative data included DRG classification, expected LOS, severity
of illness index (from 1 to 4 indicating respectively, minor, moderate, major, or extreme
severity of illness )8,18, and source of admittance (i.e. clinic referral, emergency room or
transfer).
data and statistical analysisDifference between actual and expected LOS was calculated for all patients. Variables
univariatly associated with deviation of LOS were included in a multivariate model. The
Wilcoxon rank sum test, Kruskal-Wallis test and the Spearman correlation test were used
for univariate analysis as appropriate. Linear regression analysis with forward stepwise
inclusion was used for the multivariate model. A p-value of 0.05 was used as cut-off point
for statistical significance.
resulTs
A total of 1,461 patients with a mean age of 50 (±18) years, and with 755 (52%) males
were included (Table 1). Stoma takedown was the indication for surgery in 361 (25%)
patients, cancer in 257 (18%), Crohn’s disease in 204 (14%) and ulcerative colitis in 200
(14%) patients. Patients were coded to 76 different surgical procedures. Most frequently
performed operations were enterostomy closure, laparoscopic and open partial colectomy,
exploratory laparotomy and laparoscopic total colectomy. About 1196 (82%) patients were
assigned to five distinct DRG codes (Table 1). The average expected LOS based on the DRG
classification was 8.17 (interquartile range 4.7 to 11.9) days, while the average actual
LOS was 8.31 (interquartile range 4 to 10) days. The average actual LOS was higher than
expected by 0.14 (interquartile range -2.2 to 1.8) days per patient. Actual hospital stay was
shorter than or equal to expected in 804 (55%) patients, and longer than expected in the
remaining 657 (45%). The proportion of patients that stayed at least five, seven or 10 days
longer than expected was 136 (9.3%), 91 (6.2%) and 41 (2.8%), respectively.
Chapter 3 47
3
Table 1. Patient characteristics
Characteristics Result
Age (years) [mean (SD)] 50 (18)
Sex (males) [n (%)] 755 (52%)
BMI [mean (SD)] 26.3 (6.2)
Expected LOS (days) [mean (SD)] 8.17 (4.97)
Actual LOS (days) [mean (SD)] 8.31 (6.58)
Actual - Expected LOS (days) [mean (SD)] 0.14 (4.69)
Diagnosis / Indication of surgery [n (%)]
Stoma removal 361 (25%)
Cancer 257 (18%)
Crohn’s disease 204 (14%)
Ulcerative colitis 200 (14%)
Diverticulitis 93 (6%)
Polyp 58 (4%)
Other 288 (20%)
ASA classification [n (%)]
1. No disturbance 31 (2%)
2. Mild disturbance 828 (57%)
3. Moderate disturbance 541 (37%)
4. Severe disturbance 58 (4%)
Surgical procedure [n (%)]
Closure enterostomy 339 (23%)
Laparoscopic partial colectomy 253 (17%)
Partial colectomy 152 (10%)
Exploratory laparotomy 88 (6%)
Laparoscopic total colectomy 79 (5%)
Adominoperineal resection 66 (5%)
Ileal pouch anal anastomosis 59 (4%)
Other 425 (29%)
DRG codes [n (%)]
Major bowel procedure w CC (330) 476 (33%)
Major bowel procedure w/o CC (331) 245 (17%)
Major bowel procedure w MCC (329) 238 (16%)
Minor bowel procedure w/o CC (346) 131 (9%)
Minor bowel procedure w CC (345) 106 (7%)
Rectal resection w CC (333) 42 (3%)
Other 223 (15%)
ASA: American Society of Anesthesiologists. BMI: body mass index. (M)CC: (major) complications and comor-bidites. LOS: length of hospital stay.
48 Chapter 3
Table 2. Univariate analysis of preoperative and intra-operative factors potentially associated with differences between actual and expected length of hospital stay
N n (%)* P-value
General characteristics
Sex (males) 1461 755 (52%) 0.54
Age at surgery 1455 - 0.74
BMI 1450 - 0.61
Diagnosis** 1458 - <0.001
ASA classification 1460 - 0.59
Preoperative characteristics
Diabetes 1460 120 (8%) 0.10
COPD 1460 24 (2%) 0.35
Dialysis 1460 9 (1%) 0.77
Smoking (current smokers) 1460 280 (19%) 0.046
Creatinine levels 1458 - 0.54
Albumin levels 1037 - 0.96
White blood count 1458 - 0.01
Hematocrit 1457 - 0.76
Platelet count 1457 - 0.41
History of chemotherapy 1460 61 (4%) 0.22
History of pelvic radiation 1460 43 (3%) 0.007
Surgical details
Surgical procedure 1460 - 0.01
Surgical approach‡ 1460 - <0.001
Operative time 1461 - 0.08
Type of intestinal anastomosis§ 1442 - 0.09
Creation of stoma 1459 597 (41%) 0.07
Blood transfusions (intra-operative) 1457 163 (11%) 0.74
Intra-operative complications
Any complication 1461 197 (13%) 0.56
Small bowel puncture or laceration 1460 158 (11%) 0.05
ASA: American Society of Anesthesiologists. BMI: body mass index. COPD: chronic obstructive pulmonary disease.* Number of patients with a certain characteristic (for dichotomous factors only).** Diagnosis of cancer was associated with an increase in LOS from expected; while diverticulitis and ulcerative colitis were associated with a decrease in LOS from expected.‡ Surgical approach is classified as open, laparoscopic, hand-assisted, or converted. Open surgery and conver-sion were associated with increase LOS from expected, laparoscopic and hand-assisted were associated with a decrease from expected.§ Type of intestinal anastomosis is classified as stapled anastomosis, hand sewn anastomosis, other techniques or no anastomosis.
Chapter 3 49
3
risk factors for deviation of hospital stayPreoperative and postoperative factors that were univariably associated with deviation
of LOS from expected are shown in Table 2 and Table 3, respectively. Diagnosis, type of
surgical approach (laparoscopic, open or hand-assisted), postoperative parenteral nutri-
tion, multiple postoperative complications, DRG classification and severity of illness were
all strongly associated with deviation from expected LOS (p<0.001). Additionally, other
factors showed sufficient association to be included in multivariate analysis. On multivari-
ate analysis, diagnosis, surgeon, postoperative recovery unit, use of parenteral nutrition,
several postoperative complications, DRG classification, source of admittance and severity
of illness were independently associated with deviation of LOS from expected (Table 4).
Postoperative factors were generally more strongly associated with a deviation of LOS than
preoperative factors. Need for parenteral nutrition, prolonged ileus, elevated creatinine
(serum creatinine >1 mg/dL), need for blood transfusions and anastomotic leaks were each
Table 3. Univariate analysis of administrative and postoperative factors potentially associated with difference between actual and expected length of hospital stay
N n (%)* P-value
Administrative characteristics
DRG Code 1461 - <0.001
Admitting Source** 1461 - 0.001
Severity of illness index‡ 1461 - <0.001
Postoperative recovery
Initial postoperative facility§ 1459 - 0.01
Need for parenteral nutrition 1460 181 (12%) <0.001
Postoperative complications
Urinary tract infection 1459 42 (3%) 0.002
Pulmonary embolism / DVT 1460 43 (3%) 0.001
Prolonged ileus 1460 223 (15%) <0.001
Blood transfusion 1460 268 (18%) 0.003
New arrhythmias 1460 38 (3%) 0.85
Deep SSI (organ space) 1460 103 (7%) <0.001
Wound infection 1459 139 (10%) 0.001
Anastomotic leak 1461 43 (3%) <0.001
Elevated creatinine (>1 mg/dL) 1460 53 (4%) 0.002
Sepsis 1460 113 (8%) <0.001
DRG: Diagnosis related groups. DVT: deep venous thrombosis. SSI: surgical site infection.* Number of patients with a certain characteristic (for dichotomous factors only).** Admitting source scored as outpatient clinic referral, emergency room, transfers from other hospital, trans-fers from other health care facility or unknown.‡ Severity of illness index classified into four categories minor, moderate, major and extreme severity.§ Initial postoperative facility classified as regular ward, post-aneasthesia care unit (overnight stay), intensive care unit.
50 Chapter 3
Table 4. Independent factors associated with differences between actual and expected length of hospital stay
N / n (%)* Estimate (SE)** P-value
General characteristics
Diagnosis
- Ulcerative colitis 200 (14%) -0.77 (0.30) 0.010
Surgical details
Surgeon‡ 1461 up to ± 1.25 0.017
Postoperative recovery
Initial postoperative facility 0.04
- Regular nursing ward 1386 (95%) Ref.
- ICU 59 (4%) -1.25 (0.60) 0.04
- PACU overnight admission 14 (1%) 1.17 (1.04) 0.27
Use of parenteral nutrition 181 (12%) 5.11 (0.37) <0.001
Postoperative complications
DVT/PE 43 (3%) 1.90 (0.62) 0.002
Prolonged ileus 223 (15%) 3.45 (0.30) <0.001
Blood transfusion (postoperatively) 268 (18%) 2.26 (0.31) <0.001
Wound infection 139 (10%) 0.79 (0.37) 0.03
Elevated creatinine (>1 mg/dL) 53 (4%) 2.49 (0.58) <0.001
Anastomotic leak 43 (3%) 2.15 (0.65) 0.001
Sepsis 113 (8%) 1.97 (0.44) <0.01
Administrative characteristics
DRG
- Rectal resection with CC (code 333) 42 (3%) 1.38 (0.60) 0.02
Admitting Source <0.001
- Outpatient clinic 1305 (89%) Ref.
- Emergency room 58 (4%) 3.67 (0.53) <0.001
- Other hospital 86 (6%) 1.32 (0.48) 0.006
- Other health care facility 10 (1%) -1.10 (1.22) 0.36
Severity <0.001
- Minor 417 (29%) Ref.
- Moderate 593 (41%) -1.06 (0.25) <0.001
- Major 282 (19%) -4.57 (0.34) <0.001
- Extreme 169 (12%) -7.56 (0.48) <0.001
CC: complications and co-morbidities. SE: standard error. SSI: surgical site infection.* For continuous outcomes, the number of patients valid for analysis. For dichotomous factors, number and percentage of patients with a certain characteristic.** The estimate indicates the covariate-adjusted deviation in days of LOS from expected for the respective factor compared to the deviation in the group not having the factor (or reference group in case of categorical variables).‡ Different surgeons were responsible for a deviation of up to ±1.25 days from the mean deviation of LOS observed in this cohort.
Chapter 3 51
3
associated with an increase of LOS of over 2 days from expected, compared to not having
these complications (Table 4). Additionally, sepsis, venous thromboembolism and wound
infections were independently associated with increases of LOS from expected.
Patients admitted from the emergency room and from other hospitals had an LOS that was
longer than expected by 3.67 (0.52) and 1.32 (0.48) days, respectively, compared to pa-
tients admitted through clinic referral. Of the 58 patients admitted through the emergency
room, only 3 (5%) had previous surgery in our department. Different surgeons were also
independently associated with a deviation of LOS from expected of up to ±1.25 days from
the mean deviation of LOS observed for all surgeons. Patients with increasing severity of ill-
ness had a shorter than expected LOS. Actual LOS for moderate, major and extreme sever-
ity was -1.06 (0.53), -4.57 (0.34) and -7.65 (0.48) days shorter than expected, respectively,
compared to minor severity. Patients admitted to the ICU as the initial postoperative facility
also stayed shorter than expected by -1.25 (1.04) days, compared to those discharged to
the regular nursing floor.
In order to evaluate whether the use of laparoscopic surgery was responsible for LOS
differences amongst surgeons, data were also specifically examined for patients who
underwent laparoscopic surgery (n=315). For these patients, the influence of surgeon was
not statistically significant, both in univariate and multivariate analysis. When data was
further scrutinized, there was however a large variation between different surgeons. Most
of this variation was between surgeons who regularly performed laparoscopic surgery and
those who did not. Of a total of 12 surgeons, 5 had performed less than 10 laparoscopic
surgeries each, while 7 performed over 20 laparoscopic surgeries during the study period.
When the 7 surgeons with over 20 laparoscopic surgeons were analyzed (patients n=292),
only a variation of about ±0.5 LOS days was observed.
discussion
This study examined the difference between actual and expected LOS based on the DRG
classification in a large colorectal surgical department. Overall, the DRG accurately indi-
cated the actual LOS with an average difference of 0.14 days (interquartile range -2.2
to 1.8). We did identify several important factors that were associated with significant
deviation of LOS from expected. In this regard, postoperative complications were found to
be more influential than pre- or intra-operative risk factors. Thorough examination of the
identified factors is necessary in order to evaluate potential ways of reducing their burden
on patients’ health and hospital costs.
52 Chapter 3
The need for parenteral nutrition and admittance from the emergency room resulted in the
largest increases from expected with an average covariate-adjusted increase of 5.1 and 3.5
days, respectively. Parenteral nutrition has previously been associated with postoperative
morbidity, due to hyperglycemia and infectious complications.19-21 A consequent reduction
in parenteral nutrition use in some disciplines demonstrated decreased complications and
hospital resource utilization.22 At our institution, parenteral nutrition is only administered
when necessitated by the patient’s condition. In the postoperative phase, our policy is
to initiate parenteral nutrition in patients with delayed recovery of gastrointestinal func-
tion or to continue this until the re-establishment of an adequate and consistent oral
intake that can maintain nutrition can be ascertained when patients on this preoperatively
undergo surgery. It is, therefore, likely a surrogate of protracted recovery. Consequently,
directly influencing this factor is probably difficult. A potential limitation of this study
is that we were unable to separate out if the timing of TPN, whether preoperative or
postoperative, influenced its associated with outcomes in terms of LOS. Although, it may
be expected that certain diagnoses, such as inflammatory bowel disease may be expected
to have an increased use of preoperative parenteral nutrition, in a post-hoc analysis, no
associations were seen between these diagnoses and longer than expected LOS. Further,
postoperative parenteral nutrition remained an important factor on multivariate analysis
even when accounting for both diagnosis and ileus. Thus, these results indirectly suggest
that preoperative parenteral nutrition may have had a limited influence, although this
may also have been due to the relatively low number of patients receiving the therapy
preoperatively in our study.
In a similar way, emergency room admittance is not an easy target for care providers to
reduce LOS. In tertiary centers serving a large urban area, emergency admittance is known
to contribute to increased LOS and expenses.23,24 The increased severity of patients present-
ing in the emergency room and time needed to perform tests that are routinely performed
outside the hospital are factors that may lead to increased LOS.24
Prolonged ileus was the postoperative complication associated with the largest increase in
LOS, averaging more than 3 days from expected. Due to the nature of colorectal surgery,
prolonged ileus is a fairly common complication.1,5 It also is particularly difficult to prevent.
We previously showed that two of the three independent predictors of ileus were unmodi-
fiable (i.e. age and previous abdominal surgery).1 The third factor (preoperative narcotics)
is a potential target for LOS reduction. A recent double-blind randomized trial showed that
a short course of systemic lidocaine postoperatively was successful in improving gastroin-
testinal motility and shortening of the LOS compared to placebo.25 Another double-blind
randomized trial showed that intravenous Ketorolac was able to reduce the rate of post-
operative ileus in patients undergoing laparoscopic colon surgery.16 The study also showed
Chapter 3 53
3
“promise in reducing hospital stay”, although the outcome was not statistically significant,
probably due to relatively small sample size (n=44).16
Other complications, like elevated creatinine, need for blood transfusion, anastomotic
leak, sepsis and deep-venous thrombosis were also associated with a substantial increase
in LOS. These postoperative complications are known for their deleterious influence on
clinical outcome, and several studies have investigated factors contributing to their occur-
rence.26-32 Our study highlights the importance of addressing these specific factors from a
cost perspective. Measures aimed at reducing these complications has the largest potential
impact for hospitals reimbursed through a DRG based system. Therefore, departments and
hospitals can prioritize and select their goals in a more informed manner.
Another potential factor that emerged was the role of the individual surgeon. Surgeon had
an important influence on deviation of LOS of up to ±1.25 days compared to the mean of all
surgeons. This suggests that modifiable factors likely exist and further supports a strategy of
identifying and targeting potential factors that influence outcomes and LOS based on best
evidence. Enhanced recovery (fast-track) programs may offer a way of reducing differences
in LOS between care providers. Such programs help decrease variations in care by different
physicians and have shown to reduce LOS.33-37 Although our patients are managed using
standardized care pathways, individual variations exist amongst surgeons for preoperative
and postoperative care and decisions in addition to any potential intra-operative differ-
ences. While the inclusion of a large group of patients undergoing different operations by
several surgeons serves the current aim of the study well, these very factors limit our ability
to study the specific role of surgeon on outcome. In particular, such factors as experience,
certain variations in pre and postoperative care decisions amongst surgeons, and other
specific factors such as surgical technique were not recorded. While the use of laparo-
scopic surgery seemed to minimize the influence of surgeon on LOS, differences amongst
surgeons persisted, with surgeons who regularly performed laparoscopic surgery tending
to have a lower variation in LOS than those who performed laparoscopy less commonly.
Future studies that prospectively collect such differences in pre-, intra-, and post-operative
factors between surgeons and their influence on LOS may help elucidate the reasons for
these differences in LOS.
Patients with severe illness and those initially admitted to ICU after surgery, i.e. patients
identified as potential high risk for complications, stayed at our hospital shorter than ex-
pected. The DRG classification allocates a larger margin of fluctuation in the expected LOS for
severe patients, which may in part be responsible for these results. In a post-hoc analysis, we
observed a strong relation between the presence of preoperative co-morbidities and direct
postoperative admittance to ICU. First, we found a highly significant association between
54 Chapter 3
ASA classification and rate of ICU admittance, with 0%, 1.2%, 5.0% and 36% of patients
being directly admitted to ICU for ASA 1, 2, 3 and 4, respectively (p<0.001). We also found
a significant association between direct postoperative ICU admittance and preoperative
work-up for co-morbidities, including having had a cardiac consult (p<0.001) or stress test
(p<0.001). These results suggest that admittance directly to ICU was indeed highly associated
with presence of known preoperative co-morbid states, and thus supports the explanation
that DRG classification currently may overestimate the length of stay in patients with such co-
morbidities. These results also suggests that our department performed better than expected
in this complex category of patients. This is in line with previous evidence showing that
tertiary high volume centers generally perform better than lower volume centers.5,38
In addition to identifying factors that are important for LOS and costs, this study also pro-
vides a potential way for comparing results from various institutions more reliably. Rhodes
et al. have shown that patient mix is probably the most important factor in determining
LOS.7 Schoetz et al. warned against accepting rigid criteria for length of stay for patients
undergoing colorectal surgery, since differences in clinical characteristics can require dif-
ferences in approach.39 Although the DRG can not explain individual patient variation of
LOS and thus is not suitable for detailed subgroup analysis7, it does provide a more reliable
way for comparing the overall LOS between different hospital. For example, in the study by
Faiz et al. comparing LOS after colorectal surgery in various English NHS hospitals, it was
observed that wide variation existed in the rates of prolonged stay at all levels of hospital
volume.5 Correlating such findings to a case-mix adjusted expectation can provide insight
whether these variations were mainly driven by differences in the patients case-mix or
more so by different practices between hospitals.
A potential limitation of this study is the retrospective nature of the analysis. Thus, some
potentially relevant factors identified in previous studies, such as delays time of presenta-
tion and socioeconomic status of patients, were not available for this analysis.5,6 Despite
this drawbacks, this study measures the relative effect of co-morbidities and complications
on LOS, providing another dimension to the importance of reduction of these events on
health costs not previously provided by estimates of absolute LOS alone.
conclusion
Identifying predictors of deviation of LOS offers an opportunity to identify maximally cost-
effective targets for hospital cost savings. We identified multiple factors that may serve as
targets for specific cost savings measures. DRG related outcomes also offer a tool to more
accurately compare results from hospitals with different case-mix.
Chapter 3 55
3
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M, Jarnagin WR, DeMatteo RP, Tuorto S,
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30. Ondrula DP, Nelson RL, Prasad ML, Coyle
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31. Ortega-Deballon P, Radais F, Facy O, d’Athis
P, Masson D, Charles PE, Cheynel N, et al.
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32. Stender MT, Nielsen TS, Frokjaer JB, Larsen
TB, Lundbye-Christensen S, Thorlacius-
Ussing O. High preoperative prevalence
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33. Lovely JK, Maxson PM, Jacob AK, Cima RR,
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invasive colorectal surgery. Br.J Surg. 2011.
34. Lee Y, Fleming FJ, Deeb AP, Gunzler D,
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Dis. 2011.
35. Feroci F, Kroning KC, Lenzi E, Moraldi
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within a fast-track program enhances the
Chapter 3 57
3
short-term results after elective surgery for
resectable colorectal cancer. Surg Endosc.
2011; 25: 2919-25.
36. Muller S, Zalunardo MP, Hubner M, Clavien
PA, Demartines N. A fast-track program
reduces complications and length of
hospital stay after open colonic surgery.
Gastroenterology. 2009; 136: 842-47.
37. Kehlet H. Fast-track colorectal surgery.
Lancet. 2008; 371: 791-93.
38. Mehta RH, Liang L, Karve AM, Hernandez
AF, Rumsfeld JS, Fonarow GC, Peterson ED.
Association of patient case-mix adjustment,
hospital process performance rankings, and
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2008; 300: 1897-903.
39. Schoetz DJ, Jr., Bockler M, Rosenblatt MS,
Malhotra S, Roberts PL, Murray JJ, Coller
JA, et al. “Ideal” length of stay after col-
ectomy: Whose ideal? Dis Colon Rectum.
1997; 40: 806-10.
R.P. Kiran
U. Ahmed Ali
P.J. Nisar
W. Khoury
J. Gu
B. Shen*
F.H. Remzi
J.P. Hammel
I.C. Lavery
V.W. Fazio
J.R. Goldblum**
Departments of Colorectal Surgery, *Gastroenterology and **Anatomic Pathology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
4 risk and location of cancer
in patients with preoperative
colitis-associated dysplasia
underGoinG proctocolectomy
Annals of Surgery, 2014.
60 Chapter 4
absTracT
backgroundThe ability to predict the presence and location of cancer in colitis patients with dysplasia
is essential to facilitate recommendations regarding the necessity and type of surgery. The
aim of this study is to evaluate the influence of preoperative dysplasia grade, appearance
and site on risk and location of cancer in patients with colitis.
MethodsUlcerative and indeterminate colitis patients who underwent proctocolectomy for dysplasia
were retrospectively selected. Patient characteristics and findings at colonoscopic surveil-
lance were associated with findings on the surgical specimen by regression analysis.
resultsFrom 1984-2007, 348 proctocolectomy specimens with preoperative dysplasia showed
cancer in 51 (15%) and dysplasia in 172 (49%) cases. Patients with preoperative high-
grade dysplasia (HGD) had cancer in 29% compared to 3% in LGD (p<0.001). Patients with
preoperative dysplasia-associated lesion/mass (DALM) had cancer in 25% compared to 8%
in flat dysplasia (p<0.001). In LGD with DALM, the risk of cancer was not significantly
higher that in flat LGD (7% vs. 2%, p=0.3), but risk of cancer or HGD showed a a three-
fold increase (29% vs. 9%, p=0.015). On multivariate analysis, HGD, DALM and disease
duration were independent risk factors for postoperative cancer. In patients with isolated
colonic dysplasia above the sigmoid level, postoperative rectal involvement was limited.
conclusionsRisk of cancer for patients with HGD or DALM is substantial. Despite low risk of cancer
in patients with flat LGD, threshold for surgery should be low given the high prevalence
of postoperative pathologic findings. Only in selected cases, colonoscopic surveillance
after discussion of associated risks may be acceptable, provided high patient compliance.
Surgery remains the only modality that can eliminate the risk of cancer. The location of
preoperative dysplasia may allow for the clarification of the need for proctectomy especially
in the poor risk surgical patient.
Chapter 4 61
4
inTroducTion
Cancer in inflammatory bowel disease (IBD), is thought to develop through a sequence of
chronic inflammation, dysplasia and cancer.1-3 There is, however, significant variation in
the reported rates of progression.4-9 Dysplasia, especially high-grade dysplasia (HGD) and
dysplasia-associated lesions or masses (DALM) on colonoscopy, are associated with a high
risk of concomitant cancer of up to 58%.10-12 The correlation between low-grade dysplasia
(LGD) and cancer, on the other hand, is less clear. The reported risk of synchronous cancer
varies between 0 and 19%, and progression rates to HGD or cancer range between 0.5
and 54%.6-8,13-15 Considering these contrasting results, treatment strategies for patients
with LGD remain controversial, including either a low threshold for surgery or medical
management with close colonoscopic surveillance.6,9,12,13,16
Correlation of the type and location of dysplasia on colonoscopy with the type and site of
pathological findings in the resected specimen is not well studied. Such knowledge can
help guide decision-making regarding the optimal surgical procedure.17 For patients with
HGD or colorectal cancer, a total proctocolectomy has been widely adopted as the preferred
surgical treatment.18,19 However, whether less extensive resections are a safe alternative in
selected cases and whether removal of the anorectal mucosa should be routinely added in
patients with dysplasia are not clear.20
The aims of this study are to assess the frequency and location of dysplasia and cancer in proc-
tocolectomy specimens in patients diagnosed with preoperative dysplasia, and to identify risk
factors associated with the presence of colorectal cancer and HGD, in an attempt to provide
physicians with better estimates of risk and to aid decision making in this complex disease.
PaTienTs and MeThods
study populationPatients with ulcerative or indeterminate colitis undergoing proctocolectomy for preopera-
tive dysplasia at our institution from 1984-2007 were identified. Patients undergoing an
ileal pouch anal anastomosis were retrospectively identified from a prospective institutional
review board (IRB) approved pouch database. Patients undergoing total proctocolectomy
with end ileostomy were identified by searching the pathology database, hospital bill-
ing records and operating lists in our department. Additional data was collected from
endoscopy, pathology reports and patient charts. Presence of dysplasia was determined
from preoperative endoscopic and histopathology reports. Patients with lesions classified
as indefinite for dysplasia (IND) were included, while non-dysplastic lesions were excluded.
62 Chapter 4
study variables and definitionsPatient and disease characteristics including age, gender, diagnoses, duration and extent of
disease, primary sclerosing cholangitis (PSC) and surgical details were evaluated. In order to
assess whether control of colitis was associated with cancer risk, the presence or absence
of symptoms as a risk factor was also assessed. Symptomatic colitis was defined as the
presence of active disease with symptoms of diarrhea or rectal bleeding in the preoperative
period. PSC was defined as the presence of intra- or extra- hepatic bile duct abnormalities
in the form of beading, duct ectasia, and stricturing of the intra- or extrahepatic bile ducts
documented in the medical record from endoscopic retrograde cholangiopancreatography,
magnetic resonance cholangiopancreatography, and/or liver biopsy. Preoperative dyspla-
sia was classified according to grade (LGD, HGD and IND), appearance (flat, DALM or
adenoma-like lesions (ALM)) and focality (unifocal or multifocal).21 DALM was defined as
any mass or plaque-like lesion within inflamed areas of the colorectal mucosa, and ALM
as any mass that has the appearance of sporadic adenomas in non-inflamed areas of the
colon or rectum.22 As part of the standard preoperative workflow at our hospital, before
the confirmation or rejection of a diagnosis of dysplasia, all histopathology slides includ-
ing biopsies from colonoscopies performed elsewhere, are examined by two experienced
gastrointestinal pathologists and the findings discussed until an agreement is reached.
Location of dysplasia was classified as rectal, colonic or both (colonic and rectal). The
last 15 cm above the anal verge was considered to be the rectum. Colonic location was
categorized into cecum, ascending, transverse, descending and sigmoid colon. Postopera-
tive lesions located in colonic segments adjacent to preoperative dysplasia location were
considered to be in the same segment due to the potential limitation of endoscopy in
accurately identifying colonic segments. Dysplasia surveillance in our IBD Clinic has fol-
lowed the initial American College of Gastroenterology (ACG) Practicing Guidelines since
1997.23 After 8-10 years of colitis, patients typically underwent surveillance colonoscopy
every 1- 3 years with multiple biopsies from each segment of the colon and rectum with a
total minimum of 32 tissue samples. For polypoid or mass lesions, additional biopsies were
taken. The practice pattern before the publication of the ACG guideline varied amongst
gastroenterologists. Chromoendoscopy is occasionally used, but is not considered routine
practice in our clinic. As expected, equipment has improved gradually, with newer scopes
that allowed the use of narrow band imaging acquired in 2008. However, there was no
major change in how the surveillance was performed until 2008.
study outcomesThe main study outcome was histopathology of the colectomy specimen, which was classi-
fied as dysplasia (HGD, LGD or IND), cancer or neither. Colectomy specimens were handled
in a standardized manner. Sections taken from the proximal and distal surgical margin,
Chapter 4 63
4
every 10 cm throughout the specimen and from any gross lesions. Additional sections were
taken from the area of preoperative dysplasia.
data and statistical analysisCorrelations between grade, appearance and site of dysplasia and postoperative findings
were examined. Factors associated with the finding of cancer and cancer or HGD in the
surgical specimen were assessed by univariate and multivariate analysis. Risk factors evalu-
ated included age, gender, diagnoses, grade, appearance and multifocality of preoperative
dysplasia, duration of disease, symptomatic disease, extent of colitis and PSC. Categorical
variables were summarized as numbers and percentages, and quantitative variables as
means and standard deviations (SD) or medians with inter-quartile ranges (IQR), according
to normality. Univariate associations were analyzed by Chi-square, Wilcoxon rank sum,
Kruskal-Wallis tests and logistic regression, as appropriate. Logistic regression with step-
wise backward selection of variables was used for the multivariate models.
resulTs
Patient population and overall findingsWe included 348 (235 male) colitis patients diagnosed with preoperative dysplasia. Dyspla-
sia was the primary indication for surgery in 291 (83%) patients, and a secondary indication
in 57 (17%). Median age at surgery was 46 (IQR 38 to 57) years and median duration of
disease was 14.6 (IQR 8.7 to 20.9) years. Overall, 282 (81%) patients had ulcerative colitis
and 66 (19%) indeterminate colitis on final pathology. Three hundred thirty two (95%)
patients underwent restorative proctocolectomy, while 16 (5%) patients underwent total
proctocolectomy (TPC) with end ileostomy. The most common reasons for TPC with end
ileostomy were sphincter impairment, incontinence, older age and patient choice. Disease
was symptomatic in 282 (81%) patients and PSC diagnosed in 60 (17%) patients. Divided
into three equal periods (1984 – 1992, 1992 – 2000 and 2000 – 2007), the numbers of
operated patients were 71 (20%), 143 (41%) and 134 (39%) patients, respectively.
Postoperative pathology showed colorectal cancer in 51 (15%) patients, dysplasia in 172
(49%) and no cancer or dysplasia in the remaining 125 (36%). Of the 51 patients with
cancer, 11 (22%) had intramucosal adenocarcinoma, 17 (35%) had stage I disease, 9
(18%) had stage II, 11 (22%) had stage III, with the stage not well documented in 3
patient. Dysplasia on final pathology was graded as HGD in 100 (58%) patients, LGD in 59
(34%) and IND in 13 (8%).
64 Chapter 4
Preoperative dysplasia and postoperative findingsPreoperative dysplasia was HGD in 159 (46%), LGD in 136 (39%) and IND in 53 (15%)
patients (Table 1). Symptomatic disease, DALM appearance and multifocal dysplasia were
more frequently seen in patients with HGD (Table 1). Patients with HGD had a 29% risk of
malignancy in the surgical specimen, compared to 3% in patients with LGD (p<0.001). The
risk of HGD in the proctocolectomy specimen was 49% in patients with preoperative HGD,
compared to 12% for patients with preoperative LGD or IND (p<0.001).
In 316 (91%) patients, the appearance of dysplasia during endoscopy was documented.
Dysplasia was flat in 118 (37%) patients, appeared as DALM in 149 (47%) and as ALM
in the remaining 49 (16%) patients. Preoperative HGD and multifocal dysplasia were
significantly more common in DALM. Cancer on final pathology was significantly more
Table 1. Patient characteristics and pathological outcome by preoperative dysplasia grade
High GradeDysplasia(N=159)
Low Grade Dysplasia(N=136)
Indefinite for Dysplasia
(N=53)
P-value
Age in years (median-IQR) 46 (38 - 58) 45 (37 - 56) 47 (37 - 58) 0.5
Gender (male) 112 (70%) 89 (65%) 34 (64%) 0.6
Duration of disease in years (median-IQR)
15.5 (10.0 – 21.3) 13.8 (8.4 – 21.9) 11.7 (7.0 – 20.0) 0.1
Symptomatic disease 134 (84%) 102 (75%) 46 (87)% 0.05
Primary sclerosing cholangitis 35 (22%) 18 (13%) 7 (13%) 0.1
Extent of Disease
0.4
Pancolitis 120 (76%) 88 (65%) 38 (72%)
Left sided colitis 16 (10%) 22 (16%) 9 (16%)
Proctitis / Proctosigmoiditis 6 (4%) 9 (7%) 3 (6%)
Other / inactive 17 (11%) 17 (13%) 3 (6%)
Appearance of dysplasia
<0.001Flat 36 (23%) 56 (41%) 26 (49%)
DALM 95 (60%) 42 (31%) 12 (23%)
ALM 18 (11%) 23 (17%) 8 (15%)
Multifocal dysplasia 94 (59%) 46 (34%) 12 (23%) <0.001
Final pathology
Cancer 46 (29%) 4 (3%) 1 (2%) <0.001
HGD 78 (49%) 16 (12%) 6 (12%) <0.001
LGD 9 (6%) 46 (34%) 4 (8%) <0.001
Indefinite for dysplasia 3 (2%) 5 (4%) 5 (9%) 0.04
No dysplasia or cancer 23 (15%) 65 (48%) 36 (70%) <0.001
ALM: adenoma like mass. DALM: dysplasia associated lesion or mass. IQR: Interquartile range. HGD: high grade dysplasia. LGD: low grade dysplasia.
Chapter 4 65
4
frequent in DALM compared to flat dysplasia and ALM (25%, 8%, 0.4%, respectively,
p<0.001). Postoperative HGD was also more common in DALM compared to other types
of dysplasia appearance (41%, 19% and 29%, respectively, p<0.001). In flat dysplasia,
multifocality was not associated with a higher risk of cancer (12% vs. 4%, p=0.2), but it
was significantly associated with the risk of cancer or HGD (37% vs. 19%, p=0.03).
For patients with LGD and HGD, characteristics of patients and pathological outcome for
flat dysplasia, DALM and ALM are presented in Table 2. Risk of cancer in both flat and
DALM HGD (22% and 35%, respectively) was significantly higher than either flat or DALM
LGD (2% and 7%, respectively) (p<0.001). Patients with preoperative LGD with DALM
had a much higher risk of having pathological findings in the postoperative specimen
(p<0.001) compared to patients with flat LGD or ALM. The risk for cancer and/or HGD
was significantly higher in patients with LGD with DALM compared with flat LGD (29% vs.
9% patients, p=0.015). In flat LGD, multifocal dysplasia was not associated with cancer
risk (5% vs. 0%, p=0.4). For patients with HGD, extent of disease was greater in flat and
DALM dysplasia when compared to ALM. Risk of cancer was highest in DALM HGD (35%),
followed by flat HGD (22%) and ALM (6%) (p=0.08).
site of preoperative dysplasiaFor 336 patients with available data, 201 (58%) patients had dysplasia limited to the
colon, 82 (24%) had rectal dysplasia and 53 (15%) had colonic and rectal dysplasia (Table
3). Preoperative HGD and DALM were more frequent with combined colonic and rectal
dysplasia. Risk of cancer on final pathology was highest in the combined colonic and rectal
dysplasia group. For 215 patients, the exact location of both preoperative and postopera-
tive dysplasia within the colon was available (Table 3). Despite a high rate of concordance
between the location of preoperative and postoperative pathological findings, postopera-
tive lesions (dysplasia or cancer) were present in remote segments that were not similar or
adjacent to the segment of preoperative dysplasia in 11% (24 / 215) of patients. In patients
with preoperative dysplasia limited to the colon (n=201), rectal dysplasia on final pathology
was present in 13 (7%) patients and rectal cancer was seen in three patients (1.5%). When
only patients with colonic involvement above the level of the sigmoid were assessed, the
rates of rectal dysplasia and cancer were 3% (3/98) and 0% (0/98), respectively.
In patients with preoperative dysplasia limited to the colon (n=201), 41 (20%) had a muco-
sectomy with a handsewn anastomosis. None of these patients had evidence of dysplasia
in the mucosectomy specimen. On the other hand, of the 135 patients with rectal dysplasia
preoperatively, 56 (41%) patients underwent mucosectomy and handsewn anastomosis.
Nine (16%) of these patients had evidence of dysplasia in the mucosectomy specimen;
HGD was seen in 4 (7%) patients, LGD in 3 (5%) and indefinite dysplasia in 2 (4%). The
66 Chapter 4
Tab
le 2
. Pat
ien
t ch
arac
teri
stic
s an
d p
ath
olo
gic
al o
utc
om
e b
y p
reo
per
ativ
e d
ysp
lasi
a ap
pea
ran
ce
Low
gra
de
dys
pla
sia
Hig
h g
rad
e d
ysp
lasi
a
Flat
(N=
56)
DA
LM(N
=42
)A
LM(N
=23
)P-
valu
eFl
at(N
=36
)D
ALM
(N=
95)
ALM
(N=
18)
P-va
lue
Ag
e in
yea
rs (
med
ian
-IQ
R)
45 (3
7-54
)47
(40-
57)
42 (3
5–57
)0.
746
(34–
54)
45 (3
8–57
)62
(43–
73)
0.01
Gen
der
(m
ale)
32 (5
7%)
35 (8
3%)
13 (5
7%)
0.01
26 (7
1%)
68 (7
2%)
14 (7
8%)
0.9
Du
rati
on
of
dis
ease
in y
ears
(m
edia
n-I
QR
)13
.0(8
.9–1
9.7)
16.2
(7.8
-29.
8)10
.8(5
.1–2
0.7)
0.3
15.5
(10.
0–22
.6)
15.8
(10.
2–21
.9)
14.9
(8.9
–17.
1)0.
5
Sym
pto
mat
ic d
isea
se42
(75%
)29
(69%
)20
(87%
)0.
331
(86%
)83
(88%
)11
(61%
)0.
6
Prim
ary
scle
rosi
ng
ch
ola
ng
itis
9 (1
6%)
5 (1
2%)
2 (9
%)
0.6
4 (1
1%)
24 (2
5%)
3 (1
7%)
0.2
Exte
nt
of
Dis
ease
0.03
0.2
Panc
oliti
s45
(81%
)20
(48%
)14
(61%
)29
(81%
)73
(77%
)11
(61%
)
Left
sid
ed c
oliti
s4
(7%
)11
(26%
)4
(17%
)2
(6%
)8
(8%
)5
(28%
)
Proc
titis
/ Pr
octo
sigm
oidi
tis2
(4%
)3
(7%
)3
(13%
)3
(8%
)1
(1%
)1
(6%
)
Oth
er /
inac
tive
5 (9
%)
8 (1
9%)
2 (9
%)
2 (6
%)
13 (1
4%)
1 (6
%)
Mu
ltif
oca
l dys
pla
sia
21 (3
8%)
19 (4
5%)
6 (2
6%)
0.3
21 (5
8%)
60 (6
3%)
9 (5
0%)
0.6
Fin
al p
ath
olo
gy
Can
cer
1 (2
%)
3 (7
%)
0 (0
%)
0.2
8 (2
2%)
34 (3
5%)
1 (6
%)
0.08
HG
D4
(7%
)9
(21%
)3
(13%
)0.
116
(44%
)50
(52%
)11
(61%
)0.
5
LGD
18 (3
2%)
22 (5
2%)
4 (1
7%)
0.01
3 (8
%)
3 (3
%)
1 (6
%)
0.5
Inde
finite
for
dys
plas
ia3
(5%
)1
(2%
)0
(0%
)0.
41
(3%
)1
(1%
)1
(6%
)0.
4
No
dysp
lasi
a or
can
cer
30 (5
4%)
7 (1
7%)
16 (7
0%)
<0.
001
8 (2
2%)
9 (1
0%)
4 (2
2%)
0.03
ALM
: Ade
nom
a lik
e le
sion
. DA
LM: d
yspl
asia
ass
ocia
ted
lesi
on o
r m
ass.
IQR:
Inte
rqua
rtile
ran
ge.H
GD
: hig
h gr
ade
dysp
lasi
a. L
GD
: low
gra
de d
yspl
asia
.
Chapter 4 67
4
Table 3. Patient characteristics and pathological outcome by location of preoperative dysplasia
Colonicdysplasia(n=201)
Rectaldysplasia
(n=82)
Colonic & Rectal dysplasia
(n=53)P-value
Age at Surgery- years[median (IQR)]
46 (38 - 56) 49 (40 - 59) 45 (34 - 54) 0.2
Gender (male) 134 (67%) 55 (67%) 40 (76%) 0.5
Duration of Disease- years [median (IQR)]
15.3 (9.4 - 22.0) 15.4 (9.0 - 22.3) 13.3 (8.0 - 18.4) 0.2
Symptomatic disease 172 (86%) 55 (67%) 45 (85%) 0.001
Primary sclerosing cholangitis 36 (18%) 7 (9%) 14 (26%) 0.02
Extent of Disease
0.01
Pancolitis 145 (72%) 50 (61%) 42 (79%)
Left sided colitis 24 (12%) 15 (18%) 6 (11%)
Proctitis / Proctosigmoiditis 7 (4%) 10 (12%) 0 (0%)
Other / inactive 25 (12%) 7 (9%) 5 (10%)
Preoperative dysplasia Grade
0.008HGD 85 (42%) 37 (45%) 37 (70%)
LGD 86 (43%) 31 (38%) 13 (25%)
Indefinite 30 (15%) 14 (17%) 3 (6%)
Appearance of dysplasia
<0.001Flat 82 (41%) 26 (32%) 9 (17%)
DALM 68 (34%) 45 (55%) 36 (68%)
ALM 36 (18%) 9 (11%) 4 (8%)
Multifocal dysplasia 88 (44%) 11 (13%) 53 (100%) <0.001
Pouch Anastomosis Type <0.001
Handsewn 41 (20%) 31 (38%) 25 (47%)
Final pathology
Cancer 30 (15%) 7 (9%) 14 (26%) 0.02
HGD 55 (27%) 24 (29%) 20 (38%) 0.3
LGD 35 (17%) 15 (18%) 9 (17%) 1.0
Indefinite for dysplasia 8 (4%) 3 (4%) 1 (2%) 0.8
No dysplastic changes 73 (36%) 33 (40%) 9 (17%) 0.04
Postoperative site related to preoperative site*
117 (97%) 50 (100%) 43 (100%) 0.2
Presence of remote postoperative dysplasia sites*
19 (16%) 1 (2%) 4 (9%) 0.03
68 Chapter 4
four patients with HGD in the mucosectomy specimen also had HGD in the preoperative
colonoscopy biopsies. Details of the location of preoperative dysplasia within the rectum
were available in 45 patients (lower rectum:13, mid rectum: 12, upper rectum: 20). In
patients with dysplasia in the lower rectum, eight patients (7 with HGD and 1 with LGD)
underwent mucosectomy and handsewn anastomosis. Two (25%) patients had evidence
of dysplasia (1 HGD and 1 LGD) in the mucosectomy specimen. In patients with dysplasia
of the mid rectum, 6 patients (3 with HGD, 2 with LGD and 1 indefinite for dysplasia)
underwent mucosectomy and handsewn anastomosis. The mucosectomy specimen of
one (16%) patient showed lesions indefinite for dyplasia. In patients with dysplasia in the
upper rectum, 4 patients (2 with HGD, 2 with LGD) underwernt mucosectomy. One (25%)
patient with LGD preoperatively had LGD in the mucosectomy specimen.
risk factors for postoperative cancer and dysplasiaUnivariate analysis of factors associated with the presence of cancer in the colectomy
specimen in patients with preoperative dysplasia is shown in Figure 1. Presence of can-
cer in the colectomy was significantly associated with duration of disease, symptomatic
disease, presence of preoperative HGD, DALM, multifocal dysplasia and combined colon
and rectum site of dysplasia. These factors were included in a multivariate analysis (Table
4). Disease duration, HGD and DALM were found to be independent predictive factors for
cancer in this model.
Factors associated with the presence of cancer or HGD in the colectomy specimen were also
analyzed (Figure 2). There was a significant association for this outcome with symptomatic
Table 3. (continued)
Colonicdysplasia(n=201)
Rectaldysplasia
(n=82)
Colonic & Rectal dysplasia
(n=53)P-value
Site of postoperative pathological findings**
<0.001
Cecum 45 (22%) 0 (0%) 12 (23%)
Ascending 35 (17%) 0 (0%) 11 (21%)
Transverse 47 (23%) 1 (1%) 15 (28%)
Descending 41 (20%) 1 (1%) 19 (36%)
Sigmoid 54 (27%) 3 (4%) 22 (43%)
Rectum 13 (7%) 47 (57%) 35 (66%)
ALM: adenoma like mass. DALM: dysplasia associated lesion or mass. IQR: Interquartile range.HGD: high grade dysplasia. LGD: low grade dysplasia.* Percentages are based on patients in which the exact location of dysplasia is documented both pre- and postoperatively (n =215).** Some patients had multiple lesions in different locations, while others did not have any pathological findings. Percentages are of total number of patients.
Chapter 4 69
4
Figure 1. Factors associated with cancer in patients with colitis undergoing proctocolectomy for dysplasia
Figure 2. Factors associated with cancer and/or dysplasia in patients with colitis undergoing procto-colectomy for dysplasia
70 Chapter 4
disease, extensive inflammation (i.e. pancolitis), preoperative HGD, DALM, multifocality
and combined colon and rectum site dysplasia. There was also a trend towards an as-
sociation with duration of disease, but it did not reach statistical significance (p=0.1).
Multivariate analysis identified HGD and DALM as independent predictive factors for this
outcome (Table 4).
Table 4. Multivariate analysis for risk factors of cancer and high grade dysplasia in patients with preoperative dysplasia
Multivariate analysisOdds ratio
(95% Confidence interval)P-value
Risk factors for cancer
Dysplasia grade
<0.001- LGD 1.32 (0.14 - 12.54)
- HGD 12.09 (1.57 - 93.19)
DALM 3.08 (1.39 – 6.80) 0.005
Duration of disease (10 years) 1.53 (1.05 - 2.25) 0.03
Symptomatic disease 2.71 (0.85 - 8.58) 0.09
Risk factors for cancer or high grade dysplasia
Dysplasia grade
<0.001- LGD 1.13 (0.41 – 3.13)
- HGD 20.80 (7.77 – 55.67)
DALM 3.87 (2.10 – 7.14) <0.001
DALM: dysplasia associated lesion or mass. HGD: high grade dysplasia. LGD: low grade dysplasia
discussion
Optimal management of IBD patients with dysplasia on colonoscopy is important. In this
study, synchronous colorectal cancer was present in 15% of patients with colitis who
underwent restorative proctocolectomy for dysplasia. Patients with HGD and DALM had
a higher risk of cancer than patients with LGD and flat dysplasia, respectively. Multivari-
ate analysis additionally identified duration of disease as an independent risk factor for
cancer. This study also identified certain relationships between the location of preoperative
dysplasia and the postoperative location of pathological findings, which could be used to
clarify the need for proctectomy especially in the poor risk surgical patient.
Given the high risk of cancer, our findings support surgery in all patients with HGD. This
approach is supported by previous results and is in accordance with the ACG practice
guidelines.16,18,24,25 We found that the risk of cancer is further increased depending upon
additional factors such as duration of disease and the presence of DALM, consistent with
previous reports.1-3,12,26,27 For patients with preoperative LGD, cancer was detected in only
Chapter 4 71
4
3% of proctocolectomy specimens. The risk for either cancer or HGD was 15%. Patients
with LGD appearing as DALM had a higher rate of cancer (7%) compared to patients
with flat LGD (2%), but this difference was not statistically significant. When the risk for
postoperative cancer and HGD was considered, patients with LGD appearing as DALM
compared to flat LGD had a three-fold increase in risk from 9% to 29% (p=0.015). These
results suggest that the presence of DALM, even in the setting of LGD, is a sufficient
argument to support prophylactic surgical treatment. This position is also supported by
other current evidence and guidelines.16,18,24,28
Whether surgery should be undertaken in flat LGD is a matter of continued controversy,
considering the variability in the reported cancer risk.6,12,13 Current ACG guidelines prompt
consideration of surgery in patients with flat LGD to prevent progression to a higher grade
of neoplasia.16 However, the Medical Position Statement by the American Gastroentero-
logical Association (AGA) finds that current evidence is insufficient to either advice for
or against colectomy for flat LGD.25,29 These unclear recommendations leave much room
for debate. In this study we have shown that the risk of cancer in flat LGD is 2%, which
is at the lower end of the range (0 to 20%) previously reported.6,13-15 Without further
specification, however, these results make it difficult to decide for or against surgery. It is,
therefore, important to take other factors into account that might aid in this decision. This
study shows that about 1 in 10 patients with flat LGD had either cancer or HGD at the time
of diagnosis. In addition, 53% of patients with LGD had pathological findings of dysplasia
or cancer in the surgical specimen. These findings support a low threshold for surgery in
all patients with LGD, since this is the only treatment modality that can eliminate the risk
of cancer. Presence of other factors associated with cancer, like long duration of disease,
should also further tip the balance towards surgery. Other factors that could be taken into
account include multifocal dysplasia and extensive disease (i.e. pancolitis), which were uni-
variately associated with malignant change in our study. PSC and family history have also
been shown to be associated with increased risk of cancer in other reports.1,2,28 When none
of these factors are present, both surgery and a conservative approach may be considered,
the choice being individualized based on an informed discussion with the patient. The
high 5-year progression rates of up to 54% from LGD to HGD or cancer reported in several
studies is a further ongoing important consideration in favour of surgery.7,8,15,28
Considering the presence of dysplasia and cancer in segments adjacent to and remote
from the preoperative location, total proctocolectomy (+/- restoration of intestinal continu-
ity) is the ideal procedure for most patients undergoing surgery. Patients with isolated
colonic dysplasia without sigmoid involvement had low rates of rectal dysplasia (3%) and
rectal cancer (0%). Thus, colectomy with rectal preservation may obviate some of the risks
of a pelvic dissection when such patients have significant co-morbidity but require surgery.
72 Chapter 4
Select patients unwilling to have a permanent stoma and unsuitable for restorative surgery
may also be candidates for this approach, especially if the cancer risk or other conditions
preclude a strategy of surveillance alone.
Additionally, in patients with isolated colonic dysplasia who underwent mucosectomy
(n=41), none of the mucosectomy specimens showed dysplastic changes. Given the poor
functional outcomes for patients after mucosectomy and handsewn anastomosis30,31 and
also the small chance of finding cancer or dysplasia in the rectum or mucosectomy speci-
men, patients with isolated colonic dysplasia may safely be offered a stapled anastomosis.
In patients with preoperative rectal dysplasia, the risk of cancer or dysplasia in the rectum
is considerable (about 60%). In these patients, a proctocolectomy is virtually always the
management of choice. The type of anastomosis, however, is still a matter of controversy.
In series with long-term follow-up, dysplasia and cancer in the anal transitional zone after
stapled pouch surgery has been found to be infrequent.32-34 Dysplasia mostly developed
in the first two to three years, if at all, and often disappeared on repeated biopsies. None
of the series found cancer in the anal transition zone with a follow-up of 10 years or
more. These findings, combined with several reports of worse functional outcomes after
mucosectomy with handsewn anastomosis, support the use of a stapled approach in most
patients, especially when concerns regarding sphincter function exist. In selected cases,
like the presence of dysplasia near the anal transitional zone or if patients are considered
high risk for cancer for other reasons, mucosectomy may be considered.
When considering trends over time in our series, there was an increase in the number of
patients operated on for dysplasia in the later parts compared to the earlier parts of the
study. Reasons for this could be several, such as an increased awareness of the risk of
cancer, more standardized surveillance, increased incidence and prevalence of ulcerative
colitis and lower threshold for surgery due to advances in the field.
This study has some limitations. The study is retrospective, which limits the availability of
certain data. This was especially the case for some variables on preoperative colonoscopy,
which were not always well documented (e.g. exact location and size of lesions). Another
limitation is that this cohort only included patients who had proctocolectomy. This provides
a reliable reference test for the presence of cancer, in the form of complete pathological
examination of colon and rectum. On the other hand, it might introduce a certain degree
of selection bias. First, some patients with dysplasia may have been managed medically by
their physicians and not referred for surgery. Since HGD is widely considered an absolute
indication for surgery,16,23,25 we expect that this selection bias is limited in patients with
HGD. With LGD there is the possibility that physicians may have advised some patients not
to undergo surgery, since controversy still exists about this decision. Such referral bias is
Chapter 4 73
4
expected to occur more often in patients with fewer risk factors for cancer, and less often
in patients with factors that might increase this risk (e.g. prolonged severe disease, family
history, etc). In these latter patients, the decision to refer to surgery will probably have
been made more promptly. Therefore, if this referral bias has influenced our study, it would
probably have skewed our population to include patients with LGD judged as having a
greater risk of cancer. Although this should be taken into consideration when evaluating
results, we should recognize that the observed risk of cancer in LGD patients in this study
is actually in the lower range of that reported in the literature (3% vs. 0% to 20%).
The strength of this study is the inclusion of patients with a complete pathological evalu-
ation of the colon and rectum. This clearly provides the most reliable way of assessing the
presence of any synchronous pathological findings. The detailed review of all data and the
classification of endoscopic and pathologic findings based on current standard definitions
is also a strength. Some controversy in the literature on the topic relates to the constantly
changing definitions of these findings. Thus, our ability to classify and correlate the preop-
erative and final pathology findings based on uniform, standard definitions, is a particular
strength of this study. Finally, this study has a large sample size, with the total numbers of
patients with LGD (n=136) and LGD and DALM (n=42) being greater than even a previous
meta-analysis7, where the corresponding numbers of patients used to calculate the risk of
synchronous cancer were 98 and 31 respectively. Thus, the large numbers of patients in
the current study provide data that are less susceptible for over- and underestimation. The
study hence provides reliable estimates of cancer risk after proctocolectomy for colitis pa-
tients with dysplasia based on a consideration of patient, disease and endoscopic factors.
This information aids decision-making for clinicians and patients alike facing the dilemma
of choosing the optimal management strategy in area of controversy but great clinical
importance.
In conclusion, the presence of HGD or DALM should favour surgical intervention as the
treatment of choice. Despite a low risk of cancer in patients with flat LGD, the threshold
for surgery should be low given the high likelihood of finding dysplasia or cancer in the
postoperative pathology and hence the potential further ongoing risk of cancer. A detailed
discussion of associated risks and consideration of factors potentially increasing the risk
of cancer especially in the context of the beneficial effect of surgery in control of colitis
and thus reducing symptoms are important steps in decision-making. The specific medical
condition of the patient, especially duration of disease, severity and extent of disease,
multifocal dysplasia, family history and perioperative risk along with the risk of future
cancer based on current findings are additional factors that should be taken into con-
sideration in this decision. In most patients, especially if other factors that are associated
with risk of cancer are present, surgery should be considered. In selected cases without
74 Chapter 4
such factors, colonoscopic surveillance after discussion of associated risks may be accept-
able, provided high patient compliance can be assured. The location of dysplasia, whether
colonic or rectal, may further clarify the optimal surgical approach in individual patients.
Total proctocolectomy and restorative pouch surgery is currently the gold standard for
surgical management. Isolated colonic dysplasia without sigmoid involvement may allow
for subtotal colectomy in selected poor risk surgical patients. A stapled anastomosis may
be safely undertaken in patients with isolated colonic dysplasia and the majority of patients
with rectal dysplasia. Mucosectomy and hand-sewn anastomosis should be reserved for
specific circumstances as determined on a case by case basis.
Chapter 4 75
4
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30. Kirat HT, Remzi FH, Kiran RP, Fazio VW.
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31. Lovegrove RE, Constantinides VA, Heriot
AG, Athanasiou T, Darzi A, Remzi FH, Nich-
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analysis of 4183 patients. Ann Surg. 2006;
244: 18-26.
32. Remzi FH, Fazio VW, Delaney CP, Preen
M, Ormsby A, Bast J, O’Riordain MG, et
al. Dysplasia of the anal transitional zone
after ileal pouch-anal anastomosis: Results
of prospective evaluation after a minimum
of ten years. Dis Colon Rectum. 2003; 46:
6-13.
33. O’Riordain MG, Fazio VW, Lavery IC, Remzi
F, Fabbri N, Meneu J, Goldblum J, et al.
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2000; 43: 1660-65.
34. Coull DB, Lee FD, Henderson AP, Anderson
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Part II
oPtImIzIng surgICal treatment for Inflammatory bowel dIsease
U. Ahmed Ali1
F. Keus2
J.T. Heikens3
W.A. Bemelman4
S.V. Berdah5
H.G. Gooszen1
C.J.H.M. van Laarhoven6
1Department of Surgery, University Medical Center Utrecht, Utrecht, Netherlands2Department of Surgery, Diakonessenhuis, Utrecht, Netherlands3Department of Surgery, St Elisabeth Hospital, Tilburg, Netherlands4Department of Surgery, Academic Medical Centre, Amsterdam, Amsterdam, Netherlands5Department of Digestive Surgery, Hôpital Nord - Marseille, Marseille, France6Department of Surgery, Radboud University Medical Center, Nijmegen, Netherlands
5 open versus laparoscopic
(assisted) ileal pouch-anal
anastomosis for ulcerative
colitis and familial adenomatous
polyposis
Cochrane Database of Systematic Reviews, 2009.
82 Chapter 5
absTracT
backgroundRestorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the main surgi-
cal treatment for patients with ulcerative colitis (UC) and familial adenomatous polyposis
(FAP). With the advancements of minimal-invasive surgery this demanding operation is
increasingly being performed laparoscopically. Our objective is to perform a systematic
review to compare the beneficial and harmful effects of laparoscopic versus open IPAA for
patients with UC and FAP.
MethodsWe searched The Cochrane IBD/FBD Group Specialized Trial Register (April 2007), The
Cochrane Library (Issue 1, 2007), MEDLINE (1990 to April 2007), EMBASE (1990 to April
2007), ISI Web of Knowledge (1990 to April 2007) and the web casts of the American
Society of Colon and Rectal Surgeons (ASCRS) (up to 2006) for all trials comparing open
versus laparoscopic IPAA. All trials in patients with UC or FAP comparing any kind of lapa-
roscopic IPAA versus open IPAA. The methodological quality of included trials was evalu-
ated. Analysis of RCTs and non-RCTs was performed separately. Sensitivity and subgroup
analyses were performed if appropriate.
resultsEleven trials included 607 patients of whom 253 (41%) in the laparoscopic IPAA group.
Only one of the included trials was a randomized controlled trial. There were no signifi-
cant differences in mortality or complications between the two groups. Reoperation and
readmission rates were not significantly different. Operative time was significantly longer
in the laparoscopic group both in the RCT and meta-analysis of non-RCTs (weighted mean
difference (WMD) 91 minutes; 95% Confidence Interval (CI) 53 to 130). There were no sig-
nificant differences between the two groups regarding postoperative recovery parameters.
Sensitivity analysis using imputed data showed slightly improved postoperative recovery in
the laparoscopic group. Total incision length was significantly shorter in the laparoscopic
group, while two trials evaluating cosmesis found significantly higher cosmesis scores in
the laparoscopic group. Other long-term outcomes were poorly reported.
conclusionsThe laparoscopic IPAA is a feasible and safe procedure. Short-term advantages of the
laparoscopic approach seem to be limited and their clinical significance is arguable. Large
high-quality trials focusing on differences regarding specific postoperative complications,
cosmesis, quality of life and costs are needed.
Chapter 5 83
5
inTroducTion
Ulcerative colitis (UC) is an inflammatory disease of the large intestine of uncertain etiology
characterized by recurring episodes of inflammation primarily involving the mucosal layer
and occasionally the submucosa of the colon. The estimated incidence of UC is 8.7/100.000
in Europe.1 Whereas medical treatment is the mainstream for the management of UC, sev-
eral evidence-based indications for surgical treatment have been identified, including acute
pancolitis, intractability to medical treatment and the presence of dysplasia or neoplasia.2
Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease, character-
ized by the development of hundreds to thousands of adenomatous polyps in the colon
and rectum of affected individuals leading to cancer at young age, if left untreated. The
incidence is around 2 per million and the prevalence is around 40 per million.3,4 Because of
the inevitable development of cancer in this disease, colectomy is warranted for all patients
with FAP at a certain point of their disease.
Both UC and FAP are limited to the colon and rectum. Therefore, proctocolectomy pro-
vides relief of symptoms and eliminates the risk of developing colorectal cancer. Since its
introduction in 1978 the restorative ileal pouch-anal anastomosis (IPAA) has gained wide
acceptance in the surgical treatment of patients with UC and FAP.5 The open IPAA has
become the standard surgical approach for UC and FAP, due to its good functional results
and high patient satisfaction.6-9
Over the past decades laparoscopic techniques have evolved rapidly and large bowel resec-
tions were increasingly being performed laparoscopically. The first laparoscopic-assisted
restorative proctocolectomy with IPAA (LA-IPAA) was described in 1992,10 and technical
feasibility of this procedure has been shown repeatedly.11-14 Reduced post-operative pain
quicker recovery and superior cosmetic results are presumed advantages of the LA-IPAA
over the open IPAA. However, reports have shown inconsistent results. Early reports tend
to be skeptical with respect to the benefits of the LA-IPAA,15-17 while recent studies tend to
show more favorable results of the laparoscopic technique.18-20
As patients with UC and FAP requiring surgery generally are young, active and highly
motivated individuals, minimal-invasive surgery may especially be appealing in this group
of patients.12 Cosmesis and patients’ satisfaction could therefore play important role in the
choice between these two approaches. However, possible benefits regarding these items
are of secondary importance compared to primary outcomes of surgery, like postoperative
morbidity and mortality. To be able to compare both techniques in a satisfactory manner a
systematic evaluation of the benefits and harms of open versus LA-IPAA is needed.
84 Chapter 5
MeThods
objectivesTo study whether laparoscopic and open IPAA for UC and FAP are different in terms of
primary (mortality and complications) and secondary outcomes (operative time, hospital
stay, convalescence, cosmesis, functional outcome and quality of life). If data were present,
differences in other secondary outcomes were compared as well.
criteria for considering studies for this review
Types of studies
Due to the paucity of randomized clinical trials, non- randomized controlled clinical trials
comparing open IPAA versus LA-IPAA were also included in this review. Trials were included
if they performed a direct comparison of open IPAA versus LA-IPAA, irrespectively of ran-
domization, prospective data collection, number of patients or language of the article.
Types of participants
Studies including patients with UC or FAP who underwent an IPAA procedure were in-
cluded. If studies sporadically included patients with other diseases, they were included
as long as the main population consisted of UC or FAP patients. Studies including mainly
patients with other diseases were excluded, unless they presented the data for the UC and
FAP patients separately. When multiple studies have overlapping patient populations, only
the most recent publication was included in the review.
Types of interventions
Studies comparing any type of open IPAA to any type of LA-IPAA were included. The
following classification of the surgical procedures (based on intention-to-treat) was used:
• 'LaparoscopicIPAA'includedthoseproceduresstartedasalaparoscopicprocedure,with
creation of any kind of pneumoperitoneum (by Veress needle or open introduction) or
mechanicalabdominalwalllift,irrespectiveofthenumberoftrocarsused.'Laparoscopic-
assistedIPAA'includedthoseproceduresinwhichanadditionalsmallincisionlaparotomy
was used (e.g. Pfannenstiel or subumbilical midline incision) to facilitate the laparoscopic
IPAA procedure.
• Inallothercasesthesurgicalinterventionwasclassifiedas'openIPAA'.
Types of outcome measures
Primary outcome measures were mortality and complications (except minor complications).
Secondary outcome measures were all other outcomes assessed in the comparison of the
two operative techniques. These included minor complications, operative time, operative
Chapter 5 85
5
blood loss, time to bowel movement, time to regular diet, hospital stay, readmission rate,
reoperation rate, incision length, cosmesis, functional outcome (fecal and sexual function)
and costs.
Complications were classified into the following categories:
• Intraoperativecomplications:allcomplicationsoccurringanddetected intraoperatively,
like small bowel perforation and severe intraoperative bleeding.
• Procedurespecificcomplications:pouchfailure,pelvicsepsis,pouchfistula,anastomotic
leakage and strictures.
• Severe postoperative complications: e.g. intra-abdominal abscesses, bleeding, sepsis,
burst abdomen (Platzbauch) and myocardial infarction.
• Mildpostoperativecomplications:e.g.includingprolongedileus,woundinfections,uri-
nary tract infections, urinary retention, pleural effusion, late incisional hernia, and deep
venous thrombosis. Other postoperative complications were categorized appropriately at
first encounter.
• Totalcomplications:thetotalnumberofallcomplicationsperstudy.
The following definitions were used for the procedure specific complications:
• Pouchfailure:pouchexcisionoranon-functioningpouchat12monthsafterIPAApro-
cedure.
• Pelvicsepsis:pelvicabscess,anastomoticleakageordehiscenceorpelvic/perinealwound
infection.
• Pouchfistula:anypouchrelatedfistula.
• Stricture:anastomoticfibrosisnecessitatingdilatation.
Functional outcome was assessed using the following items:
• Defecationfrequency:timesofdefecationperday,nightorper24hours.
• Mildfecalincontinence:soilingorspottinginunderwear.
• Severefecalincontinence:regularlysevereleakageorfecallossorpassivefecalinconti-
nence.
• Urgefecal incontinence: inability todeferdefecationmorethan15minutesafterfirst
urge.
• Sexualdysfunction:retrogradeejaculation,erectiondisorderordyspareunia.
search methods for identification of studiesWe have searched the following databases:
• TheCochraneIBD/FBDGroupSpecializedTrialRegister(NonMEDLINERecords)
• TheCochraneLibrary(includingTheCochraneDatabaseofSystematicReviews,Database
of Abstracts
86 Chapter 5
• ofReviewsofEffects(DARE),TheCochraneCentralRegisterofControlledTrials(CEN-
TRAL), Health
• TechnologyAssessment (HTA)Database,NHSEconomicEvaluationDatabase) (Issue1,
2007)
• MEDLINE(1990toApril2007)
• EMBASE(1990toApril2007)
• ISIWebofKnowledge(WebofScience)(1990toApril2007)
• WebcastsoftheannualmeetingsoftheAmericanSocietyofColonandRectalSurgeons
(ASCRS)
Since the LA-IPAA was not described before 1992 the search was started from the year
1990. As a fall-safe strategy we pre-specified that if any eligible article published before
1992 was to be found, the search would have been expanded to start from 1985. During
the search no eligible articles prior to 1992 were found, thus the search remained un-
changed. References of included trials and relevant reviews encountered during the search
were searched manually. Finally, all authors of included trials were requested for additional
information on any published, unpublished or ongoing trials.
data collection and analysisThe review was conducted according to the pre-specified protocol and the recommenda-
tions from the Cochrane Handbook for Systematic Reviews of Interventions.21,22
Selection of studies
Titles of all retrieved articles were first screened by UAA or FK and all obviously irrelevant
reports were excluded. Subsequently, abstracts of selected articles were reviewed by both
UAA and FK independently and differences were resolved by discussion with CVL, if neces-
sary. In case of any uncertainty, articles were always selected for the subsequent step.
Finally, the full-text of all selected articles was reviewed by UAA and FK independently to
determine the eligibility of the article for this review.
Extraction of data
Two reviewers (UAA and FK or JH) independently extracted all relevant data. For each study
patient characteristics, study characteristics, data needed for the methodological quality
assessment of the study and the primary and secondary outcomes were extracted according
to availability. Data regarding patient characteristics included number of patients in each
group, age, gender, BMI and diagnoses of included patients. Data regarding study charac-
teristics included study design, sample size information, inclusion and exclusion criteria of
the study, follow-up period, loss to follow-up, surgical experience and information regarding
surgical techniques. Individual authors were contacted if any essential data were missing.
Chapter 5 87
5
assessment of methodological quality of included studiesIn this review both randomized controlled trials (RCTs) and non- randomized controlled
trials (non-RCTs) were included. For both types a different assessment method was chosen.
Assessment of methodological quality of randomized clinical trials
Based on the available empirical evidence we assessed the methodological quality of RCTs
using the following items.22-25
– Generation of the allocation sequence
• Adequate, if the allocation sequence was generated by a computer or random
number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing
dice was considered as adequate if a person who was not otherwise involved in the
recruitment of participants performed the procedure.
• Unclear,ifthetrialwasdescribedasrandomized,butthemethodusedforgeneration
of the allocation sequence was not described.
• Inadequate,ifasysteminvolvingdates,names,oradmittancenumberswasusedfor
the allocation of patients.
– Allocation concealment
• Adequate, iftheallocationofpatients involvedacentral independentunit,on-site
locked computer, or sealed envelopes.
• Unclear,ifthetrialwasdescribedasrandomized,butthemethodusedtoconcealthe
allocation was not described.
• Inadequate,iftheallocationsequencewasknowntotheinvestigatorswhoassigned
participants or if the study was quasi- randomized.
– Blinding
• Adequate,ifthetrialwasdescribed(atleast)asblindtoparticipantsorassessorsand
the method of blinding was described. We are well aware that it is very difficult to
properly blind trials comparing surgical treatments, therefore one level of blinding
was considered adequate.
• Unclear,ifthetrialwasdescribedas(double)blind,butthemethodofblindingwas
not described.
• Notperformed,ifthetrialwasnotblinded.
– Follow-up
• Adequate,ifthenumbersandreasonsfordropoutsandwithdrawalsinallinterven-
tion groups were described or if it was specified that there were no dropouts or
withdrawals.
• Unclear,ifthereportgavetheimpressionthattherehadbeennodropoutsorwith-
drawals, but this was not specifically stated.
• Inadequate, if thenumberor reasons fordropoutsandwithdrawalswerenotde-
scribed.
88 Chapter 5
Assessment of methodological quality of non- randomized clinical trials
Quality assessment for non- randomized clinical trials is a complex topic and is generally
considered to be an area of ongoing research (Cochrane Handbook of Systematic Reviews
of Interventions, section 6.8).22 In an extensive review of this topic investigators reviewed
193 tools for quality assessment in literature,26 and concluded that based on quality and
design of these tools only 6 tools were suitable for use in systematic reviews. They also
concluded that all 6 tools needed some type of modification before being fully suitable for
that purpose.
In this review we used a modification of the Methodological Index for Non-Randomized
Studies (MINORS).27 This tool is one of the few validated and tested methods specifically
developed for the assessment of quality of non- randomized trials. To adhere to the guide-
lines of the Cochrane Handbook the following modifications were applied:
• Fourofthe12itemsoftheMINORSweredisregardedinthequalityassessment,because
these items related to the applicability, reporting quality, and precision of the results,
rather than the validity of the assessed trials.
• Everyitemwasusedindependentlytodistinguishbetweenhighandlowqualitytrials,
rather than using the sum score of this list. The draw-backs of using summary scores
are the decreased transparency to readers of the review and the evidence showing that
different scales could results in contradicting results when applied in the same review.28
The modified MINORS list is outlined in Table 1. Every study was assessed using this method
by UAA and JH independently. Discrepancies were solved by consensus discussion with a
third reviewer, CVL, if necessary.
statistical analysisData from RCTs and non-RCT were analyzed separately. With adequate data available
statistical analysis of binary data was conducted using relative risks (RR) as the summary
statistic. Trials with zero events in both arms were excluded from meta-analyses. However,
a sensitivity analysis using risk differences (RD) was performed with inclusion of these trials,
and in case of inconsistency the results of this sensitivity analysis were reported.
For continuous outcomes weighted mean differences (WMD) were used as the summary
statistic. Authors, however, often presented their results in medians with ranges due to
suspicion of skewed data, while means with their standard deviations (SD) are needed
for meta-analysis. Authors were contacted for additional data if necessary. Additionally,
sensitivity analyses imputing data for missing means and standard deviations (calculated
from available medians and ranges) were performed.29
Chapter 5 89
5
Heterogeneity was calculated using Higgins chi-square (χ²) test and quantified by mea-
suring I².30 A χ²-test with a P-value of <0.10 was considered to indicate the presence
of heterogeneity, while an I²>50% was considered to suggest a marked inconsistency
in effect between studies. The fixed-effect model was only used if no heterogeneity was
present. In all other cases the random-effects model was used. If excessive heterogeneity
was present, data were re-checked first. If heterogeneity persisted, subgroup or sensitivity
analyses were used to explore its causes. When adequate reasons were present extreme
outliers were excluded in sensitivity analyses. In situations of excessive heterogeneity that
could not be explained, we refrained from reporting a pooled estimate.
Bias detection
Funnel plots were used to provide a visual assessment of whether treatment estimates
were associated with study size. This may help identify the presence of publication or other
type of biases.31-33
Table 1. Modified Methodological Index for Non-Randomized Studies (MINORS)
Item*
1. Inclusion of consecutive patients: all patients potentially fit for inclusion (satisfying the criteria for inclusion) have been included in the study during the study period (no exclusion or details about the reasons for exclusion).
2. Prospective collection of data: data were collected according to a protocol established before the beginning of the study.
3. Unbiased assessment of the study endpoint: blind evaluation of objective endpoints and double-blind evaluation of subjective endpoints. Otherwise the reasons for not blinding should be stated.
4. Follow-up period appropriate to the aim of the study: the follow-up should be sufficiently long to allow the assessment of the main endpoint and possible adverse events.
5. Loss to follow up less than 5%^: all patients should be included in the follow up. Otherwise, the proportion lost to follow up should not exceed the proportion experiencing the major endpoint; or if the numbers and reasons for dropouts and withdrawals in all intervention groups were described.
6. An adequate control group: having a gold standard diagnostic test or therapeutic intervention recognized as the optimal intervention according to the available published data
7. Contemporary groups: control and studied group should be managed during the same time period (no historical comparison).
8. Baseline equivalence of groups **: the groups should be similar regarding the criteria other than the studied endpoints, i.e. absence of confounding factors that could bias the interpretation of the results.
* Items were scored ‘adequate’ if condition was satisfied, ‘inadequate’ if condition was not satisfied and ‘un-clear’ if information regarding item was not reported.^ Measured at time of discharge, since most trials only followed patients until discharge.** In this review baselines of the two groups should be equivalent regarding age, gender, BMI and distribution of diagnoses (UC/FAP).
90 Chapter 5
Subgroup and sensitivity analyses
Subgroup analyses were performed according to the methodological quality of the in-
cluded trials:
• ForRCTs:adequatecomparedtounclear/inadequateregardingthefourqualitycriteria
used to assess the methodological quality of RCTs.
• For non-RCTs: adequate compared to unclear/inadequate regarding each item of the
modified MINORS list on which the studies differed.
Furthermore, causes of heterogeneity were explored by performing sensitivity analysis
based on surgical technique and other factors that may explain heterogeneity.
Statistical analysis was conducted using the statistical package (RevMan Analyses v. 5.0.16)
provided by The Cochrane Collaboration and was performed by UAA, FK and CVL.
resulTs
description of studies
Search and trial identification
The systematic search was conducted in The Cochrane IBD/FBD Group Specialized Trial
Register (Non-MEDLINE Records) (931 records, 0 selected), The Cochrane Library, Issue
1, 2007 (649 hits, 5 selected), The National Library of Medicine (MEDLINE) via PubMed
(4455 hits, 117 selected), Exerpta Medica via EMBASE (6830 hits, 503 selected), ISI Web
of Knowledge (1573 hits, 54 selected), and web casts of the annual meetings of the
American Society of Colon and Rectal Surgeons (ASCRS) (all published web cast until 2006,
2 selected).
Altogether, the search resulted in 14,438 hits. The first selection was performed based on
the titles of publications and all clearly irrelevant publications were excluded. A total of
679 hits were considered possibly relevant based on their titles. After correction for dupli-
cates, 590 publications remained. The abstracts of these 590 publications were reviewed
independently by two reviewers (UAA and FK). Differences between UAA and FK were
discussed with CVL. A total of 552 publications could be rejected based on their abstracts.
Eventually, 37 publications were selected for full-text review.
From the selected 37, eleven publications were included, and one protocol of an ongoing
RCT was identified.34 A cross-reference search was performed of all included publications as
well as five reviews considered relevant to our review.35-39 This resulted in the identification
Chapter 5 91
5
of one additional publication.40 Consequently, 12 publications were finally included in this
review. A flow-chart of the selection process is provided in Figure 1.
Figure 1. Flow-chart of the selection process
Of these 12 publications, two described the short- and long-term outcomes of a partially
overlapping patient population (Larson 2005; Larson 2006).19,41 These publications were
considered to be two distinct trials, but data of only one of these two publications was
used in any single meta-analysis to prevent double reporting of patients. Two other pub-
lications (Maartense 2004; Polle 2007) described the short- and long-term outcomes of
the same trial.42,43 These two publications were considered one trial and data was handled
accordingly. In summary, 12 publications, describing 11 trials were included in this review.
92 Chapter 5
Finally, two publications were translated from French and Japanese (Berdah 2004; Otani
2001).44,45 Additional information on methodology was obtained regarding seven out of
11 trials and additional data (i.e. individual patient data) was obtained from two trials
(Berdah 2004; Maartense 2004).42,44
Patient characteristics
The 11 trials included 607 patients, of whom 253 (41%) in the laparoscopic and 354 (59%)
in the open IPAA group. A total of 516 (85%) patients suffered from UC and 89 (15%)
from FAP. Two studies exclusively included patients with UC,40,45 whereas all other studies
included both UC and FAP patients. None of the studies presented results of UC and FAP
patients separately. Baseline characteristics of included patients are shown in Table 2.
Trial designs
Of the 11 included trials, only one was a randomized controlled trial.42 Four of the 10
non- randomized trials collected their data prospectively. The other 6 had retrospectively
data-collection or did not clearly specify this aspect. Ten trials had a mono-center design,
and one trial was conducted in two centers.42 Characteristics of the included trials are
shown in Table 3.
Surgical interventions
The types of performed surgical interventions varied between the included trials. Eight
trials compared the laparoscopic-assisted IPAA (LA-IPAA) with the conventional open IPAA.
The other three trials compared slightly different types of procedures: one trial (Brown
2001) compared the LA-IPAA with a mini-open IPAA46, another trial (Maartense 2004)
compared the laparoscopic hand-assisted IPAA (HA-IPAA) with the conventional open
IPAA,42 and yet another trial (Larson 2006) compared a combined group of LA-IPAA and
HA-IPAA with the conventional open IPAA. We considered all trials comparing procedures
using a laparoscopic technique versus open IPAA.
The HA-IPAA differs from the LA-IPAA in that the accessory incision is performed at the
start of the operation and covered with an air sealed hand-port. Through this hand-port
manual assistance could be provided during the different stages of the operation. In gen-
eral, HA-IPAA and LA-IPAA were performed using a small Pfannenstiel incision, facilitating
open rectum resection and open creation of a J-pouch by means of a double-stapling
technique to construct the ileal pouch-anal anastomosis.
Outcome measures
Primary outcome measures, mortality and complications, were well reported. Due to
the brief follow-up period in most trials mainly short-term complications were reported.
Chapter 5 93
5
Tab
le 2
. Pat
ien
ts’ c
har
acte
rist
ics
of
incl
ud
ed s
tud
ies
Tria
l
NA
ge
Gen
der
(M
:F)
BM
ID
iag
no
sis
(UC
:FA
P)
LA-IP
AA
/O
pen
IPA
ALA
-IPA
AO
pen
IPA
ALA
-IPA
AO
pen
IPA
ALA
-IPA
AO
pen
IPA
ALA
-IPA
AO
pen
IPA
A
Ara
ki 2
00140
21/1
127
.2(8
.1)^
31.1
(11.
2)^
8:13
2:09
31.2
(4.5
)^33
.1(4
.8)^
21:0
011
:00
Berd
ah 2
00444
12/1
232
(16-
60)
31 (2
1-58
)6:
066:
0624
(17-
29)
22 (2
0-26
)11
:01
11:0
1
Brow
n 20
0146
13/1
332
(16-
69)
29 (1
5-59
)4:
085:
08-
-2:
9 +
1 o
ther
6:07
Dun
ker
2001
4715
/17
30.6
(7.1
) ^*
39.2
(8.4
) ^*
4:11
9:08
23.6
(4.6
) ^24
.5 (3
.2)
14:0
114
:03
Has
him
oto
2001
4811
/13
30.0
(19-
47)
30.0
(18-
49)
4:07
7:06
--
6:05
6:07
Lars
on 2
00519
33/3
328
(18-
56)
27 (1
7-56
)6:
276:
2721
.7 (1
7-31
)22
.3 (1
8-33
)31
:02:
0031
:02:
00
Lars
on 2
00641
100/
200
32 (1
7-66
)32
(17-
64)
40:6
080
:120
22.4
(17-
34)
23 (1
6-32
)98
:02:
0019
1:09
:00
Maa
rten
se 2
00442
30/3
029
(16-
57)*
35 (1
6-57
)*9:
2115
:15
22.6
(18.
1-34
.7)
23.3
(17.
2-34
.2)
20:1
020
:10
Mar
cello
200
02020
/20
25 (1
2-61
)26
(9-6
1)15
:05
15:0
524
(18-
32)
24 (1
8-30
)13
:07
13:0
7
Ota
ni 2
00145
10/1
830
.2(1
1.8)
^39
.6(1
7.7)
^-
--
-10
:00
18:0
0
Schm
itt 1
99417
22/2
031
(12-
59)
34 (1
7-64
)11
:11
11:0
9-
-16
:5 +
1 o
ther
15:0
5
* si
gnifi
cant
diff
eren
ce; ^
mea
n (S
D).
IPA
A: i
leal
pou
ch-a
nal a
nast
omos
is; L
A-IP
AA
: lap
aros
copi
c (a
ssis
ted)
IPA
A; M
: mal
e; F
: fem
ale;
UC
: ulc
erat
ive
colit
is; F
AP:
fam
ilial
ade
nom
atou
s po
lypo
sis.
94 Chapter 5
Tab
le 3
. Ch
arac
teri
stic
s o
f in
clu
ded
stu
die
s
Tria
lN
Cas
es/C
ontr
ols
Des
ign
Mat
chin
g^
Follo
w-u
p
per
iod
Loss
to
Fo
llow
-up
LA-IP
AA
Loss
to
Fo
llow
-up
Ope
n IP
AA
Co
nve
rsio
n r
ate
(%)
Ara
ki 2
00140
21/1
1R,
NR
-D
/C0
0-
Berd
ah 2
00444
12/1
2P,
NR
1,2,
3,4
> 3
yea
rs0
03/
12 (2
5%)
Brow
n 20
0146
12/1
3R,
NR
-D
/C0
00/
12 (0
%)
Dun
ker
2001
4715
/17
R, N
R4,
5,8
Mea
n 16
mon
th0
00/
15 (0
%)
Has
him
oto
2001
4811
/13
R, N
R-
D/C
00
0/11
(0%
)
Lars
on 2
00519
33/3
3P,
NR
1,2,
3,4,
6>
12
mon
ths
4N
/A-
Lars
on 2
00641
100/
200
P+R,
NR
1,2,
3,5,
690
day
s0
06/
100
(6%
)
Maa
rten
se 2
00442
30/3
0RC
T-
30 d
ays
2/30
(6,6
%)
3/30
(10%
)0/
30 (0
%)
Mar
cello
200
02020
/20
P, N
R1,
2,3,
4,7
D/C
00
0/20
(%)
Ota
ni 2
00145
10/1
8N
S, N
R-
D/C
00
-
Schm
itt 1
99417
22/2
0P,
NR
1,2,
4D
/C0
0-
Tota
ls25
3/35
4*9/
200
(4.5
%)
* La
rson
200
5 w
as n
ot a
dded
up
to t
he t
otal
of
patie
nts
to a
void
dup
licat
ion
patie
nt d
uplic
atio
n.^
1:
age;
2:
gend
er;
3: B
MI;
4: d
iagn
osis
; 5:
ope
rativ
e te
chni
que;
6:
date
of
oper
atio
n; 7
: se
verit
y of
dis
ease
; 8:
dur
atio
n of
fol
low
-up.
Eac
h nu
mbe
r in
dica
tes
that
the
stu
dy
had
activ
ely
mat
ched
bet
wee
n th
e tw
o gr
oups
reg
ardi
ng t
hat
item
.IP
AA
: ile
al p
ouch
-ana
l ana
stom
osis
; LA
-IPA
A:
lapa
rosc
opic
(as
sist
ed)
IPA
A;
R: r
etro
spec
tive;
P:
pros
pect
ive;
P+
R: p
rosp
ectiv
e fo
r th
e LA
-IPA
A g
roup
, an
d re
tros
pect
ive
for
the
open
-IPA
A g
roup
; NS:
not
spe
cifie
d; N
R: n
on-r
ando
miz
ed t
rial;
RCT:
ran
dom
ized
con
trol
led
tria
l; N
/A: n
ot a
pplic
able
; D/C
: unt
il di
scha
rge.
Chapter 5 95
5
Long-term outcomes were reported by 4 trials only (Berdah 2004; Dunker 2001; Larson
2005; Maartense 2004).19,42,44,47
Secondary outcomes were reported variably. Based on availability of data, meta-analysis
was performed for complications, operative time, blood loss, time to bowel movement,
time to regular diet, hospital stay, re-operation rate and incision length. Cosmesis, func-
tional outcome and costs were reviewed without meta-analysis.
risk of bias in included studiesSince only one RCT was identified all trials, including the RCT, were assessed using the
modified MINORS. Differences were identified regarding three items only:
• Prospective collectionofdata:five trials (45%) scored 'adequate'and six trials (55%)
scored'unclear/inadequate'.
• Contemporarygroupsofcasesandcontrols:seventrials(64%)scored'adequate'and
fourtrials(36%)scored'unclear/inadequate'.
• Baselineequivalenceofgroups:seventrials(64%)scored'adequate'andthefourtrials
(36%)scored'inadequate'.
Only three trials, including the RCT, scored adequate for these three items. Detailed meth-
odological assessment of trials is listed in Table 4.
Table 4. Methodological assessment of included studies
Trial
Item 1Con-
secutive patients
Item 2Prospec-
tive design
Item 3Assess-ment of
out-comes
Item 4FU-
period
Item 5Loss to
FU< 5%
Item 6Ad-
equate control group
Item 7Contem-porary control group
Item 8Baseline equiva-lence
Araki 200140 A U I A A A I A
Berdah 200444 A A I A A A A A
Brown 200146 A I I A A A I A
Dunker 200147 A I I A A A A I
Hashimoto 200148 A I I A A A I I
Larson 200519 A A I A A A A A
Larson 200641 A I I A A A A A
Maartense 200442 A A I A A A A A
Marcello 200020 A A I A A A A A
Otani 200145 A U I A A A U I
Schmitt 199417 A A I A A A A I
A: Adequate; I: Inadequate; U: Unclear
96 Chapter 5
effects of interventionsMeta-analysis of RCTs was not feasible, since only one RCT was identified. Results of this
RCT are presented in Table 5. When adequate data were available, a meta-analysis of
the non- randomized trials was performed. In this meta-analysis five comparisons were
conducted. In three comparisons trials were subdivided into subgroups of high- and low-
quality trials based on the three methodological quality criteria. In the fourth comparison
trials meeting all three methodological criteria (highest-quality trials) were set against all
other trials. The fifth comparison contained additional sensitivity analyses. The findings of
the RCT as well as the results of the meta-analysis of non-RCTs are discussed below.
No significant differences were observed regarding mortality, intra-operative complications,
procedure specific complications, severe complications, minor complications, readmission
and reoperation rate in any of the performed comparisons.
Table 5. Reported outcomes by Maartense 2004 (RCT)
OutcomeLA-IPAA(N=30)
Open IPAA(N=30)
P-value*
Mortality 0 (0%) 0 (0%) NS
Intraoperative complications 1 (3%) 1 (3%) NS
Procedure specific complications 4 (13%) 6 (20%) NS
Severe postoperative complications 0 (0%) 2 (7%) NS
Mild postoperative complications 9 (30%) 7 (23%) NS
Total complications 14 (47%) 16 (53%) NS
Operative time 214 (149 - 400) 133 ( 97 - 260) p<0.001
Blood loss 263 (75–1200) 300 (50–800) p=0.98
Time to regulat diet 6 (4 - 19) 7 (4 - 15) 0.6
Hospital stay 10 (5 - 13) 11 (6 - 28) 0.767
Readmission 5/23* (22%) 3/23* (13%) NS
Reoperation 5 (17%) 5 (17%) NS
N (%) / Median (range)* Only reported in a sub-group of patients (N=23).IPAA: ileal pouch-anal anastomosis; LA-IPAA: laparoscopic (assisted) IPAA. NS = not statistically significant.
Mortality
Mortality was not reported in two trials (Hashimoto 2001; Otani 2001).45,48 In the nine
trials reporting mortality a total of 232 patients and 323 patients were included in the
laparoscopic and the open group, respectively. Eight trials reported zero mortality in both
groups. With one death in the open group by one trial (Araki 2001), there was no statisti-
cally significant difference.40
Chapter 5 97
5
Intraoperative complications
Intraoperative complications were reported by 5 trials including 130 and 230 patients in
the laparoscopic and open groups, respectively. The RCT and one additional trial reported
one intraoperative complication in each group, while three trials reported zero intraopera-
tive complications. No significant differences were observed between the two groups.
Procedure specific complications
Procedure specific complications were reported in 8 trials, with 2 trials reporting zero
complications. The RCT reported 4/30 (13%) and 6/30 (20%) complications in the
laparoscopic and open group, respectively (not statistically significant). Five non-RCTs were
pooled showing 6/132 (4.5%) procedure specific complications in the laparoscopic group
and 6/224 (2.7%) in the open group. Differences were not statistically significant (Relative
risk (RR) 0.81; 95% confidence interval (CI) 0.32 to 2.02). Heterogeneity was not present.
Severe complications
Severe complications were reported in 9 trials, with 3 trials reporting zero complications.
The RCT reported 0/30 (0%) and 2/30 (7%) severe complications in the laparoscopic and
open group, respectively (not statistically significant). Five non-RCTs were pooled showing
8/157 (5.1%) severe complications in the laparoscopic group and 20/258 (7.8%) in the
open group. Differences were not statistically significant (RR 0.65; 95% CI 0.29 to 1.48).
Heterogeneity was not present.
Minor complications
Minor complications were reported in 9 trials. The RCT reported 9/30 (30%) and 7/30
(23%) minor complications in the laparoscopic and open group, respectively (not statisti-
cally significant). Eight non-RCTs were pooled. There were 59/213 (27.7%) minor compli-
cations in the laparoscopic group and 83/306 (27.1%) in the open group. Differences were
not statistically significant (RR 1.05; 95% CI 0.78 to 1.41). No significant heterogeneity
was present.
Total complications
Total complications consisted of the sum of all complications in the aforementioned cat-
egories. The RCT showed 14/30 (47%) and 16/30 (53%) total complications in the laparo-
scopic and open group, respectively (not statistically significant). Eight non-RCTs with 213
patients in the laparoscopic group and 306 patients in the open group were pooled. A total
of 80 (37.6%) complications in the laparoscopic group and 127 (41.5%) in the open group
were observed. There were no significant differences between the two groups (RR 0.91;
95% CI 0.73 to 1.14) (Figure 2). No heterogeneity was observed between the studies. In a
funnel plot on total complications we did not find arguments for bias (Figure 3).
98 Chapter 5
Operative time
Operative time was reported in 10 trials, but only five provided data in means with their
standard-deviations. Both the RCT and the pooled non-RCTs showed a significantly longer
operative time for the laparoscopic procedure. The RCT showed an increase in the median
operative time from 133 (range 97 to 260) for the open IPAA to 214 (range 149 to 400)
Figure 2. Meta-analysis total complications
Figure 3. Funnel plot of trials reporting total complications, including 95% confidence interval lines. There are no indications for bias.
Chapter 5 99
5
for the laparoscopic approach (p=<0.001). The meta-analysis of four non-RCTs included 58
patients in each group and showed a significantly longer operative time in the laparoscopic
group (weighted mean difference (WMD) 92 minutes; 95% CI 53 to 130). The random-
effects model was used, since substantial heterogeneity was present (χ² 11.02 (p=0.01),
I² 73%).
Sensitivity analysis imputing data for missing values included 223 and 324 patients in the
laparoscopic and open groups, respectively, and confirmed the findings of the primary
meta-analysis (WMD 82 minutes; 95% CI 60 to 105). Heterogeneity remained significant
(χ² 36.30 (p<0.0001), I² 75.2%). Further exploring of data in subgroup analyses did not
identify clear causes for the observed heterogeneity.
Blood loss
Operative blood loss was reported by five trials. The RCT reported no difference between
the two groups with a median blood loss of 263 mL (range 75 to 1200) in the laparoscopic
and 300 mL (range 50 to 800) in the open group (p=0.98). Two non-RCTs provided data
in means and SDs and were pooled. The meta-analysis included 31 and 29 patients in the
laparoscopic and open groups, respectively. There was no significant difference in blood
loss between the two techniques (WMD -99 mL; 95% CI -261 to 64). As heterogeneity was
present, the random-effects model was applied (χ² 2.70 (p<0.10), I² 63.0%). A sensitivity
analysis imputing data for two more trials included 62 patients in each group and did show
a significant reduction in blood loss using the laparoscopic technique (WMD -138 mL; 95%
CI -235 to -41). Adding these two extra trials reduced heterogeneity significantly (χ² 4.57
(p<0.21), I² 34.4%).
Time to bowel movement
Time to bowel movement was reported by three non-RCTs. All trials found a significant
shorter time to bowel movement in the laparoscopic group. Data of only one trial was
provided in means and standard-deviations (Araki 2001).40 Therefore, only pooled data
from a sensitivity analysis imputing data for means and SD from the two other trials was
available. This analysis included 141 and 231 patients in the laparoscopic and open group,
respectively, and showed a significant shorter time to bowel movement in the laparoscopic
Figure 4. Sensitivity analysis time to bowel movement (days) with imputed data
100 Chapter 5
group (WMD -1.96 days; 95% CI -3.45 to -0.46) (Figure 4). The random-effects model was
used, since heterogeneity was present (χ² 6.74 (p=0.03), I² =70%).
Time to regular diet
Time to regular diet was reported by six trials. The RCT showed a median of 6 days (range
4 to 19) in the laparoscopic and 7 days (range 4-15) in the open group (p=0.6). Only two
non-RCTs including 25 and 35 patients in the laparoscopic and open groups, respectively,
provided data in means and standard-deviations. No significant difference between both
groups was found when pooling these trials (WMD -2.72 days, 95% CI -8.33 to 2.88).
A sensitivity analysis with imputed data including three additional trials, with a total of 148
patients in the laparoscopic and 261 patients in the open group, did result in a significant
difference in favor of the laparoscopic group (WMD -1.47 days; 95% CI -2.25 to -0.69)
(Figure 5). No significant heterogeneity was present.
Figure 5. Sensitivity analysis time to regular diet (days) with imputed data
Hospital stay
Hospital stay was reported by 9 trials. The RCT showed no significant difference between
the two groups, with a median stay of 10 days (range 5 to 13) in the laparoscopic and 11
days (range 6-28) in the open group. Four non-RCTs, including 48 patients in the laparo-
scopic and 40 in the open group, presented data in means with SD. Pooling these trials
showed a significantly shorter hospital stay for the laparoscopic procedure compared to the
open technique (WMD -2.66 days; 95% CI -4.28, -1.04). No heterogeneity was present.
A sensitivity analysis using imputed data included five additional trials, with a total of 213
patients in the laparoscopic and 306 in the open group. This sensitivity analysis, showed a
significant shorter hospital stay for the laparoscopic group as well (WMD -2.12 days; 95%
CI -3.12 to -1.12) (Figure 6). The random-effects model was used, since heterogeneity was
present (χ² 12.33 (p=0.09), I² 43%).
Chapter 5 101
5
Figure 6. Sensitivity analysis duration of hospital stay (days) with imputed data
Readmission rate
Readmission rate was reported by two trials. The RCT reported 5/23 (22%) and 3/23 (13%)
readmissions in the laparoscopic and open group, respectively. Larson 2006 found 21/100
(21%) readmissions in the laparoscopic and 44/200 (22%) in the open group.41 Both stud-
ies showed no significant difference between the two groups.
Reoperation rate
Re-operation rate was reported by seven trials. The RCT reported 5/30 (17%) reoperations
in both groups (not statistically significant). Six non-RCTs were pooled. There were 7/172
(4.0%) reoperations in the laparoscopic and 16/275 (5.8%) in the open group. Differences
were not statistically significant (RR 0.74; 95% CI 0.32 to 1.71). No significant heterogene-
ity was present.
Incision length
Incision length was reported by two studies (Brown 2001, Dunker 2001).46,47 Both studies
showed a significant smaller incision length for the laparoscopic group. Since only one
trial provided means and SDs, no meta-analysis was performed. Sensitivity analysis with
imputed data, including 27 patients in the laparoscopic and 30 patients in the open group,
showed a significantly shorter incision in the laparoscopic group as well (WMD -7.79 cm;
95% CI -9.68 to -5.9). There was no heterogeneity present.
Cosmesis
Cosmesis scores were reported by two trials (Dunker 2001; Maartense 2004).42,47 Both
studies used the same cosmesis scale and both showed significantly higher cosmesis scores
in the laparoscopic group. The RCT showed a significant increase from a mean of 14.7
points in the open group to 18.5 in the laparoscopic groups (SD not reported, p=0.01).
Dunker 2001 reported an increase from a mean of 16 (4.6) points in the open to 19.8 (4.6)
in the laparoscopic group (p=0.03).47
102 Chapter 5
Functional outcome
Defecation frequency
Defecation frequency was reported by four trials. However, pooling data was not possible
due to inconsistencies in reporting of results. All available data of these four trials are
presented in Table 6. The defecation frequency was reported by three trials (1 RCT and 2
non-RCTs) per day and night separately, all with a follow-up period of at least 12 months.
One trial (Otani 2001) reported the defecation frequency per 24 hours at discharge.45 No
significant differences were reported between the two groups by any of the four trials. Two
sensitivity analyses imputing missing data for non-RCTs reporting the defecation frequency
per day and night separately, showed no significant differences as well.
Table 6. Available data for defecation frequency and costs
OUTCOME N LA-IPAA Open IPAA
DefecationFrequency
TrialLA-IPAA /
Open-IPAAMean/Median
(SD/Range)Mean/Median
(SD/Range)P-value*
- during the day Dunker 200147 15/17 5.70 (1.30) 6.30 (2.00) NS
Larson 200519 33/33 7 (3-14) 6 (3-12) 0.23*
Maartense 200442 22/23 6.09 (2.29) 5.35 (1.82) 0.161
- during the night Dunker 200147 15/17 1.0 (0.7) 1.3 (0.7) NS
Larson 200519 33/33 1 (1-5) 2 (1-4) 0.86*
Maartense 200442 22/23 2.14 (1.91) 1.78 (1.41) 0.371
- per 24 hours Otani 200145 10/18 8.00 (2.3) 11.00 (1.0) NS
Costs (Euros) TrialLA-IPAA /
Open-IPAAMean (SD) Mean (SD) P-value*
operative costs Maartense 200442 30/30 3467 (291) 1756 (171) 0.001
overall costs Maartense 200442 30/30 18,733 (8667) 16,830 (8626) 0.095
* As provided by author.IPAA: ileal pouch-anal anastomosis; LA-IPAA: laparoscopic (assisted) IPAA
Fecal incontinence
Four trials reported on this outcome. Every study used its own classification for fecal incon-
tinence and pooling results was not possible. None of the four trials found any significant
difference between the two groups regarding daytime continence, overnight continence,
soiling, urge incontinence, or any of the used measure of fecal continence.
Sexual function
Sexual function was reported by three trials. All trials measured and reported sexual
function differently. None of these trials identified a significant difference between the
laparoscopic and open group regarding this outcome as well.
Chapter 5 103
5
Costs
Only one trial (Maartense 2004) reported on differences in costs between the laparoscopic
and open IPAA (Table 6).42 Operative costs were significantly higher in the laparoscopic
group. However, when the overall total costs (including costs for hospital stay, relaparoto-
mies and readmission, etc.) were analyzed no significant difference was found.
discussion
This systematic review evaluating differences between laparoscopic and open IPAA
procedures shows several important findings. First, only one randomized trial has been
conducted so far on LA-IPAA versus open IPAA. Therefore, lower level evidence had to be
included in this review with consequently an increased risk for introducing bias. Second,
no significant differences were found in the primary outcome measures: mortality and
complications. Also readmission and reoperation rates were not significantly different.
Third, laparoscopic IPAA is associated with a significantly longer operative time. Fourth,
presumed short-term benefits of the LA-IPAA regarding convalescence could not be con-
firmed reliably. Fifth, follow-up periods of most studies were inappropriate for evaluation
of long-term outcomes.
This review has encountered several methodological problems. First, by including non-
randomized studies the risk for bias and its influence on false conclusions is considerable.26
Non-randomized trials have a higher risk of bias, due to lack of standardized protocols,
unclear methodology, high risk of selection bias and inability to match for all confounders.
Moreover, the methodological quality of most included trials was moderate or poor. For
example, only 3 out of the 10 non- randomized trials collected their data prospectively and
had a sufficient level of base-line equivalence between the two groups. However, these
lower level evidence studies are the best we have so far. While future research is obviously
needed, we hope that by reviewing this evidence systematically we can provide clinicians
with a balanced understanding of the present evidence and its possible implications.
Methodological quality assessment of non- randomized trials has proved to be problematic
as well. Contrary to RCTs, little evidence exists regarding important items in the method-
ological assessment of non- randomized trials. Moreover, few validated scales and lists
exist for this purpose and there is no consensus regarding the tool of choice. The MINORS
index, chosen for its validation and simplicity, proved to have its own shortcomings as well.
It was liable to confuse the validity of trials with other items like quality of reporting and
precision of results, and it used a summary score to indicate the overall quality of trials.
Both properties have important drawback and their use is discouraged by the Cochrane
104 Chapter 5
guidelines.22 The applied modifications did solve these problems, but they also may have
undermined the validity of the scale. Empirical evidence regarding methodological criteria
influencing reliability of the results of non- randomized trials is needed for better assess-
ment of this type of trials.
Another problem that faced this review was the paucity of data regarding several out-
comes. This was caused by the relatively small number of available trials, but also by the
small numbers of patients in every trial and the limited amount of data suitable for meta-
analysis. Especially the latter point was of considerable importance. For several continuous
outcomes less than half of the available trials could be included in the meta-analysis. This
could undermine the reliability of results, as illustrated by the inconsistent results of the
meta-analysis and the sensitivity analysis with imputed data, seen in several outcomes.
Additionally, most trials had a short follow-up period, usually until discharge, which made
it difficult to evaluate important long-term outcomes, like functional outcome and quality
of life.
During the conduct of this review another meta-analysis comparing open versus laparo-
scopic IPAA was published.49 General conclusions of this meta-analysis were quite similar to
ours, although there were some important differences. First, the search strategy performed
was less extensive and limits were applied for ‘study type’ in PubMed. This resulted in
failure to identify two relevant trials.44,45 Secondly, this meta-analysis included just over
half the numbers of patients included in our meta-analysis (329 compared to 607), mainly
due to a large trial which was published recently.41 Also, two trials were included in this
meta-analysis that were excluded by us for having partial overlap in patients with other
included trials.14,50 The last important difference is that the authors imputed means and
standard deviations using medians and ranges in their meta-analyses without specification
in the methods section. Some of their findings were therefore partly based on imputed
data and may very well be biased.
The absence in this review of differences between the open and laparoscopic IPAA con-
sidering the primary outcomes, mortality and complications, suggests that the LA-IPAA is
a feasible and safe procedure. This is in accordance to the results of several relative large
series of LA-IPAA published recently.12,51 However we have to emphasize that the number
of included patients is rather low to be able to detect all clinically relevant differences.
Especially detailed evaluation of individual complications, like wound infections or late
incisional hernia that may benefit from a minimal invasive approach, is not possible based
on the available data.
Chapter 5 105
5
Regarding postoperative recovery, this review could not reliable identify clinically significant
benefits of the laparoscopic approach. Hospital stay was shorter for the laparoscopic ap-
proach in both the meta-analysis of non-RCTs (WMD -2.7 days) and the sensitivity analysis
with imputed data (WMD -2.1 days). However, this was not supported by the result of
the RCT. One explanation could be that the RCT used a hand-assisted approach for the
laparoscopic IPAA, while most other trials used a laparoscopic-assisted approach. Sensitiv-
ity analyses imputing missing data also suggested that the laparoscopic technique was
associated with less blood loss, time to bowel movement and time to regular diet. As
proved by these inconsistent findings, more data is needed before a final word could be
said regarding this matter.
A point worth considering is that the clinical relevance of such relatively small benefits
regarding the postoperative recovery remains questionable. With a complex operation like
the IPAA a one or a two day reduction of hospital stay is not likely to be decisive in the
choice of operative technique. Neither will be a slightly faster normalization of bowel func-
tion or return to normal diet. Especially with the increased implementation of ‘fast-track’
perioperative care programs, the differences between open and laparoscopic techniques
could diminish even further. ‘Fast-track’ programs have already been applied in a wide
variety of colonic operations and results seem to confirm their ability to accelerate recovery,
reduce morbidity and shorten hospital stay.52 In time, implementation of such programs
even in complex procedures, like the IPAA, seems likely. Therefore, future studies compar-
ing open and laparoscopic IPAA should probably focus on other clinically more relevant
outcomes, like specific complications, costs and long-term outcomes.
One of the most relevant long-term outcomes is maybe the cosmetic result of surgery and
its impact in this predominately young group of patients. In this review, two trials showed
a significantly shorter incision in the laparoscopic IPAA. Also, two trials reported results
of cosmesis and body image. Both trials observed significantly higher scores regarding
cosmesis in the laparoscopic group. Additionally, in the long-term follow-up of the only
RCT body image scores in female patients were found to be significantly higher in the
laparoscopic group.42 These results suggest that the shorter incision of the laparoscopic
approach is associated with long-lasting benefits in the perception of patients of their
own body, which could be an interesting argument in favor of the laparoscopic technique.
While these results need conformation from other trials, the social and psychological
impact could be significant. With an ever increasing patient’s awareness a smaller scar and
improved cosmesis could be important factor in guiding the choice of operative technique
in clinical practice.
106 Chapter 5
Costs also play an important role when evaluating new operative techniques, since fear of
increased costs could be a strong motive against their implementation. In this review only
one trial reported on costs and found no significant differences when the overall costs,
including admission, complications and readmission, were evaluated.42 The costs of the
laparoscopic procedure was, however, significantly higher than the open technique. Trials
comparing costs of other types of colonic surgery give contradicting results: some trials
show no differences in costs between laparoscopic and open approaches,53 while others
show results favoring the laparoscopic approach.54 It is therefore not possible to draw
reliable conclusion from these studies and future research is required to resolve this issue
as well.
In this context the ongoing LapCon-Pouch Trial is an important step in the right direction.34
This single-center, patient blinded trial will randomize 160 patients into two groups: a
totally laparoscopic IPAA group and a conventional open IPAA group. This trial will be the
largest randomized clinical trial and will have the largest number of total laparoscopic IPAA
patients included in any report so far. It will have the power to answer several interesting
question and with a follow-up period of 12 month more light could be shed on important
long-term outcomes. While the sample-size is not large enough to resolve all issues, it
should be noted that for a relatively infrequent operation as the IPAA a sample of this size
is substantial. It is therefore to be hoped that other high-volume centers will follow the
example of this trial and that in the near future a meta-analysis based solely on RCTs would
become feasible.
conclusions
implications for practiceThe laparoscopic IPAA is a safe procedure that could be performed successfully in centers
experienced in laparoscopic and restorative pouch surgery. The laparoscopic approach
seems to be associated with some short-term advantages regarding postoperative recov-
ery, but these advantages seem to be limited and their clinical significance is arguable. For
a complex operation like the IPAA other outcomes, like specific complications, long-term
functional outcome, cosmesis and costs are more likely to influence the choice of the
operative technique. This review have shown that for cosmesis there are some data favor-
ing the laparoscopic approach, but that the evidence is still inconclusive and more research
is needed before a general recommendation can be made. There is also some evidence that
costs, a crucial item in today’s health care, may not become a decisive item in the decision
between open and laparoscopic IPAA.
Chapter 5 107
5
implications for researchHigh volume colorectal surgical centers should include patients scheduled for laparoscopic
IPAA in high-quality RCTs with sufficiently long follow-up to be able to reliable assess
differences in relevant long-term outcomes. The focus of these trials should be specific
postoperative complications, cosmesis, quality of life and costs. Trials should provide data
suitable for meta-analysis in there published publications, or at least make it readily available
upon request. There is need for empirical evidence to guide the process of methodological
quality assessment of non- randomized controlled trials.
108 Chapter 5
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Chapter 5 111
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D. Scoglio1
U. Ahmed Ali2
A. Fichera1
1Department of Surgery, University of Washington Medical Center, Seattle, Washington, USA2Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
6 surGical treatment of ulcerative
colitis: ileorectal vs. ileal
pouch-anal anastomosis
World Journal of Gastroenterology, 2014.
114 Chapter 6
absTracT
backgroundTotal proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the current gold stan-
dard in the surgical treatment of ulcerative colitis (UC) refractory to medical management.
However, it remains a procedure of significant magnitude and complications. colectomy
with ileorectal anastomosis (IRA) might offer an alternative with good long-term functional
results in a selected group of patients.
MethodsA review of literature is performed to compare the recent evidence on IRA vs. IPAA. Studies
including adult patients with UC and describing postoperative outcomes of IRA in terms of
morbidity, mortality, functional outcome and risk of cancer were identified and discussed.
resultsThe overall mortality was comparable after IRA (0 and 4.0%) versus IPAA (0 and 2.9%).
Overall morbidity for IRA was between 8% and 28%, which was lower than for IPAA
(15% to 63%). Failure of the reservoir was higher after IRA with a rate of 7% to 16% after
5-years, compared to 4.7% for IPAA. The risk of cancer was higher after IRA, with a rate
of 0 to 8% compared to <0.5% for IPAA, and a cumulative risk of cancer after 20 years
of 6% to 14% for IRA compared to 4.2% for the IPAA. Functional results seemed to be
better after IRA with lower frequency of bowel movements and less night-time seepage.
conclusionIPAA is the preferred approach for most patients with UC given its curative nature and
lower risk of failure and cancer. Nonetheless, patients with higher surgical risk with mild
rectal involvement and no evidence of dysplasia or cancer at the time of intervention might
benefit from the good functional outcomes of an IRA procedure. Patients should be aware
of the risk of recurrent disease and cancer, and be compliant with surveillance.
Chapter 6 115
6
inTroducTion
The main goals of surgical treatment for ulcerative colitis (UC) are not only to alleviate
symptoms and minimize cancer risk but also to obtain good functional outcomes and
improve quality of life. Until the 1950s total proctocolectomy with end-ileostomy (TPC)
was the only available procedure for UC patients failing medical management.
In the 1940s reports of subtotal colectomy with ileorectal anastomosis (IRA) as an alterna-
tive to TPC in selected patients were first published.1 During the 1950s and 1960s, Aylett
became the leading proponent of this procedure describing it as a way to avoid a permanent
stoma.2 At that time IRA represented a valid alternative to TPC in high selected patients
with minimal rectal inflammation. It was a less invasive operation, performed in one stage
and not requiring pelvic dissection with the associated risk of sexual dysfunction.3-5
In 1978, Parks et al. described an ileal pouch-anal anastomosis (IPAA).6 Since then, IPAA
has become the procedure of choice for patients affected by UC with excellent long-term
functional results, low risk of persistent cuff inflammation or neoplastic degeneration in
the retained rectum.7,8 Consequently, many surgeons have abandoned IRA in favor of IPAA
and TPC has remained an option for patients not candidates for IPAA. The counterargu-
ment is that IPAA, as a major procedure, carries its own risks including anastomotic failure
and pelvic sepsis that could result in poor pouch function, pouchitis and infertility in young
women, as well as pelvic nerve damage and portal vein thrombosis.3-5,9,10 In addition few
cases of cancer have been reported arising not only in the anal transitional zone but also
in the pouch itself.7,8
Interestingly, recent series of selected UC patients undergoing IRA showed long-term func-
tional results similar to IPAA.11-14 The aim of the current study was to review and compare
the most recent literature on IRA and IPAA as it pertains to postoperative morbidity and
mortality, failure rates, functional outcomes and cancer risk. It will help surgeons to provide
a tailored treatment for UC patients.
MeThods
literature search and study selectionTo identify relevant studies on the IRA procedure, we searched PubMed with predefined
search terms ‘ileorectal anastomosis ulcerative colitis’ on December, 2013. A total of 218
hits were identified and were screened by DS. For postoperative outcomes after IPAA in
terms of morbidity and mortality, a recent systematic review performed by the authors
116 Chapter 6
was used. For risk of cancer an additional search of PubMed with the terms pouch (pouch
ulcerative colitis AND cancer [tiab]) was performed, yielding 46 hits that were screened by
UAA.
Inclusion criteria were cohort studies including adult patients with UC and describing
postoperative outcomes of IRA in terms of morbidity, mortality, functional outcome and
risk of cancer. Exclusion criteria were case-reports, studies including a majority of patients
with other diseases than UC, mixed series with other interventions in which IRA results
were not presented separately and studies not reporting on relevant outcomes, written in
a language other than English, or presented in abstract form only.
study outcomesStudy outcomes were morbidity, especially serious procedure specific postoperative com-
plications such as pouch failure and anastomotic leak, morbidity, functional outcome and
long-term risk of cancer. Secondary outcomes included individual complications depending
on available data.
data extraction and analysisTitles and abstracts of all retrieved records, and subsequently full-text articles, were
examined by a single author (DS or UAA). The following data, were appropriate, were
extracted: inclusion period, sample size, duration of follow-up, reported outcomes and
results, including estimated cumulative risk of cancer if available.
Study characteristics and reported outcomes are discussed in a narrative review. Relevant
figure on study outcomes are presented in tables for ease of comparison. Due to difference
in indication between the two procedures, the study populations are quite different. This
combined with paucity of data on IRA A, did not allow for a meaningful (comparative)
meta-analysis of the procedures.
resulTs
ileorectal anastomosisUC begins in the rectum and extends proximally in a continuous fashion. The severity of
the disease also seems to be higher distally with the exception of fulminant pancolitis.
However, distal disease is sometimes alleviated by topical treatment and patients with mini-
mal rectal involvement and no dysplastic changes in the rectum could be considered for
IRA. Furthermore, an adequate rectal compliance and a normal anal sphincters function are
critical for good long-term results. These functions can easily be assessed by digital rectal
Chapter 6 117
6
examination but more accurately by rigid/flexible proctoscopy and manometry. Patients
with poor sphincter function, severe rectal disease, and non-distensible rectum should not
be offered an IRA. On the contrary, patients with colitis associated colorectal cancer and
advanced metastatic disease may benefit from an IRA because of their short life expectancy
and the palliative nature of their treatment.
Several studies have shown IRA for UC to be safe, with low postoperative morbidity and
mortality.11,13,15-17 During the years, overall morbidity has been reported between 8% and
28% and mortality between 0 and 4% (Table 1). Most studies focused their attention
on postoperative complications such as small bowel obstruction, anastomotic leak and
abdominal abscess. The fatal events were due to anastomotic leak (with subsequent sepsis)
and a pulmonary embolism.
Table 1. Morbidity and mortality after ileorectal anastomosis
Study Period N° Anastomotic leak (%)
Proctitis (%)
Need for proctectomy
(%)
Overall Morbidity
(%)
Mortality (%)
da Luz Moreira11 1971-2006 86 2.3 28 53 8 0
Leijonmarck13 1955-1984 51 3.9 45 57 16 4
Pastore15 1974-1990 48 4.4 10 17 23 0
Börjesson16 1997-2003 32 3.1 9.3 12 28 0
Grundfest17 1957-1977 89 9.1 11 21 16 0
Elton18 1990-1999 18 5.6 11 17 22 0
Andersson19 1992-2006 105 2.8 8.6 13 12 0
Lepistö20 1978-2000 20 - 45 35 - -
Oakley21 1960-1982 288 - 41 55 - -
The majority of published data has included mainly primary anastomosis with leak rates
ranging from 2% to 9%.11,13,15-19,22 Diverting ileostomies have been utilized in selective
cases at the surgeon discretion. Turnbull et al. suggested that preservation of grossly
involved recto-sigmoid colon was the main cause of IRA failure.23 In his opinion an anasto-
mosis at 6cm or less above peritoneal reflection improved rectal inflammation during the
first months and reduced the likelihood of IRA failure.
IRA does not involve extensive pelvic dissection, unlike IPAA, minimizing the risk of sexual
and urinary dysfunction. Hence, higher fertility rates may be expected in IRA patients com-
pared to IPAA although definitive studies providing evidence for better fertility rates in UC
patients are lacking. Thus, colectomy with IRA could be considered when treating women
in their reproductive age.22 Some authors have shown acceptable long-term success rate
after IRA.2,11,13,15,18,20 Aylett et al. reported on a total of 300 cases operated on over a
118 Chapter 6
ten-year period with only 7% failure rates.2 Lepistö et al. and Pastore et al. reported a
cumulative probability of having a functioning IRA at five years of 84%.15,20 Elton et al. had
88% success in their 18 patients, but the follow-up in that study was shorter.18 Ten year cu-
mulative success (69%) in Lepistö’s series was higher than reported by Leijonmarck (51%)
in 1990.13,20 At 20-years the current probability of having a functioning IRA has ranged
between 46 and 69 percent.22 A recent study compared 22 IRA with 66 IPAA patients
matched for age, gender, and follow-up time, including IRAs performed in the past 25
years showed a cumulative probability of having a functioning IRA at 5, 10, 15 and 20 years
of 81, 74, 56 and 46 percent respectively in accordance with previously published work.11
In terms of functional results, the da Luz Moreira’s series reported six bowel movements
per day (range 2-11), 1/22 (5%) night-time seepage and 15/22 (68%) reporting frequent
urgency.11 Leijonmarck et al. showed four bowel movements per day and none during
the night, with 100% of continence (25% of patients are on antidiarrheal medication),
after a mean follow-up of 13 years.13 Elton et al. had no significant difference between
preoperative and 1-year postoperative stool frequency, 11/12 patients had no problems
with continence, and three were using antidiarrheal medication.18 Pastore et al. described
a median number of six bowel movements per day (range 2-20).15 The median number of
nocturnal bowel movements was 1 (range 0-10) and three patients had more than eight
daily stools with frequent soiling and urgency. At the time of follow-up, anti-diarrheal
medications were taken by 53.3% of patients, whereas 31.3% required low doses of
systemic or topical steroids. More than 90% of patients considered that their health status
had improved after the operation. Quality of life was improved in 84%.
All the studies above showed that IRA is a safe procedure with an acceptable function
and quality of life, but unfortunately it is not necessarily a definitive operation, especially
for young patients. Specifically, Andersson et al. reported an estimated cumulative failure
rate of 10.1% and 24.1% respectively at 5 and 10 years.19 In his series Leijonmarck et al.
had 57% of failure after 13-year follow-up.13 Pastore et al. suggested that time between
IRA and additional surgery in his series was 3.9 ± 4.7 years.15 In da Luz Moreira’s series, 38
patients (44%) continued to have a functioned IRA after a median follow-up of 11 years
(range 1-30 years).11 The rectum was resected in 46 (53%) of 86 patients and the median
follow-up between IRA and completion proctectomy was 10 years (range 1-33 years).
The main indication for proctectomy is recurrent proctitis refractory to medical manage-
ment, followed by dysplasia or cancer, and the development of Crohn’s disease.11,13,15-21
The options for these patients include IPAA, Brooke ileostomy, or a continent ileostomy
(Kock pouch). Very Often IPAA can be safely performed in the majority of these patients
thus preserving bowel continuity and avoiding permanent fecal diversion.11
Chapter 6 119
6
Cancer risk after IRA
Mucosal dysplasia is a premalignant pathological state associated with long standing UC.24
Dysplasia in general is considered an indication for surgery in UC, even though this para-
digm is rapidly changing. Epithelial dysplasia of the colon and rectum was graded as mild,
moderate, or severe depending on whether the upper one-third, upper two-third, or entire
glands displayed nuclear anisocytosis and hyperchromatism, as well as loss of nuclear po-
larity and the normal goblet cell configuration of colonic mucosa. Since dysplastic changes
were often patchy, only the highest degree of dysplasia was considered. Johnson et al. has
shown in 1983 that the probability of developing rectal adenocarcinoma after a diagnosis
of mild or severe dysplasia in IRA patients reached 42% at nine years from diagnosis.25
The rate of dysplasia and cancer, in patients with UC, increases with time and leaving the
rectum in place contributes to the increased risk. The overall cumulative probability of
rectal dysplasia in the retained rectum increases from 9% at 10 years to 25% at 20 years.11
The overall incidence of rectal cancer after an IRA varies in the literature based on length
of follow-up, ranging from 0 to 18%. Grundfest et al. reported on four patients who
developed carcinoma of the rectum during their study period (4.8% at 8-year follow-up),
although he estimated the risk of rectal cancer to be 13% at more than 25 years of follow-
up.17 Oakley et al. found nine patients with rectal cancer in the stump (3.1%) at an 8-year
follow-up while Andersson et al. showed an overall risk of cancer of 1.9% at a 5.4-year
follow-up.19,21 However, some series reported higher rates of degeneration as Baker et al.
who described, in 1978, a cumulative cancer risk of 6% after 20 years rising to 18% after
35 years in a series of 374 unselected patients.26 In da Luz Moreira’s series, the cumulative
probability of developing dysplasia and cancer was 7, 9, 20 and 25% and 0, 2, 5 and 14%
at 5, 10, 15 and 20 years respectively.11 On the other hand, Leijonmarck et al. and Lepistö
et al. have reported no case of cancer in more recent series at 13 and 18-year follow-up,
respectively.13,20 Pastore et al. showed a cumulative probability of remaining free of cancer
around 85.5% at 12 years (95%CI: 57.7-100).15
Most patients who develop rectal cancer in the retained rectum presented at an advanced
stage (stage III-IV) suggesting the possibility of a more aggressive biology and making
close surveillance imperative.11,27 For instance, in Baker’s study 62% of patients who had
developed rectal cancer died within three years of diagnosis. Johnson et al. reported a total
of 10 rectal cancers, 8 of which had either nodal or distant metastases.27 The patients in
the series reported by Oakley et al. fared better, with just 2 of 9 patients with rectal cancer
dying over a 22-year time period.21 Rectal biopsies taken from multiple sites every 6 to 12
months are advised following IRA in UC patients. If dysplasia is found, completion proctec-
tomy is indicated. Patients with long standing UC who are not able or willing to undergo
surveillance should not be offered an IRA. It is also important to emphasize that colectomy
with IRA should not be offered to patients with preexisting dysplasia or cancer due to the
120 Chapter 6
increased risk of further neoplastic degeneration.28 In addition, the presence of dysplasia or
cancer in the resected colon should cause particular concern about the fate of the remain-
ing rectum suggesting that a completion proctectomy would be indicated in these cases.
In fact, Oakley et al. reported on five surviving patients who had cancer in their colonic
specimens; three of the five were found on follow-up to have cancer or severe dysplasia in
the rectal remnant.12 Grundfest et al. described nine patients with a colitis-associated colon
cancer or severe dysplasia who underwent subtotal colectomy, eight of whom survived; of
the eight, five developed severe dysplasia or cancer in the retained rectum.17
ileal Pouch-anal anastomosisRestorative proctocolectomy with IPAA is currently the procedure of choice for the surgical
treatment of UC. The main reason for its popularity is its avoidance of a permanent stoma
with stable functional results and good quality of life. In over 30 years of its existence,
the IPAA has undergone several refinements in the quest of achieving optimal results.
Examples include different shapes of the pouch, different anastomotic techniques, use of
defunctioning ileostomy and various dissection methods.29-31 Surgeons have also obtained
greater experience and familiarity with the technique, which has also benefited outcomes.
A large body of literature exists on the outcomes of IPAA. Most studies, however, are
retrospective cohorts reporting outcomes from a single institution. Due to large variations
between studies, an overview is needed for reliably assessment of the IPAA outcomes. A
meta-analysis of 43 observational studies, all published before 2000, has provided pooled
estimates of complications and functional outcomes after IPAA.32 This meta-analysis showed
a pouch failure risk of 6.8% (95%CI: 5.4-8.4), increasing to 8.5% (95%CI: 5.4-13.2) when
only patients with a minimal follow-up of 5 years were considered.32 Other pouch related
complications were also studied. Pelvic sepsis and pouch fistulas, both major postoperative
complications, were observed in 9.5% (95%CI: 8.2-10.9) and 5.5% (95%CI: 4.3-7.0),
respectively. Sexual dysfunction was present in 3.4% (95%CI: 2.7-4.7), while pouchitis was
reported in 18.8% (95%CI: 15.7-22.4).
A recent meta-analysis, including 53 studies published after 2000, showed significant
improvements in some but not all of these complications.33 The overall rate of pouch
failure was significantly reduced to 4.3% (95%CI: 3.5-5.3), and pouch failure after at least
5 years of follow-up was 4.7% (95%CI: 3.4-6.4). An trends towards improvement was also
seen in other complications, although differences were not statistically significant. Pelvic
sepsis, pouch fistula and sexual dysfunction were reported in 7.5% (95%CI: 6.1-9.1),
4.5% (95%CI: 3.5-5.7) and 3.0% (95%CI: 1.7-5.2) of patients. The only complication
showing a substantial increase was pouchitis, with a rate of 26.8% (95%CI: 21.0-33.5).
Chapter 6 121
6
Thus it seems that the rate of complications after IPAA has declined over time (Table 2).
The authors of the meta-analyses have noticed that the decline was largest in the earlier
period of the IPAA, but seems to have continued over time. Nonetheless, IPAA remains a
complex surgery with substantial risk of morbidity. Unfortunately, these reviews did not
provide estimates of the overall morbidity since large variations exists in definition between
studies. In a recent review comparing laparoscopic to open IPAA, we observed an overall
morbidity rate after open IPAA ranging from 15% to 63%, with a total of 127 events in
306 patients (42%).34 Severe postoperative complications were reported by 6 studies with
rates ranging from 5% to 27%, with a total 28 events in 269 patients (14%).34 The high
rate of pouchitis is also worrisome, since this complication can affect functional outcomes,
quality of life and might also increase risk of dysplasia in the pouch.35,36 It should be noted
that the meta-analyses discussed above did not distinguish between acute and chronic
pouchitis, which is an important distinction in terms of course and health implications.35-37
Table 2. Morbidity and moratlity after ileal pouch-anal anastomsosis
Study(Period)
N ofstudies
N ofpatients
Pelvic sepsis(%, 95%CI)
Pouch failure(%, 95%CI)
Pouchitis(%, 95%CI)
Mortality(%, range)
Heuting 2005(Studies<2000)32
43 9,317 9.5 (8.2–10.9) 6.8 (5.8–8.4) 18.8 (15.7–22.4) -
De Zeeuw 2012(Studies ≥2000)33
53 14,966 7.5 (6.1–9.1) 4.3 (3.5–5.3) 26.8 (21.0–33.5) 0 (0 – 2.9)
CI: confidence interval.
Functional outcomes after IPAA were similar in studies published before and after 2000.33
Average frequency of bowel movements per 24 hours was 5.9 (95%CI: 5.0-6.9), of which
1.5 (95%CI: 1.0-2.1) overnight. Mild and severe faecal incontinence were reported in
14.3% (7.3-25.9) and 6.1% (2.9-12.3) of patients, respectively. The authors conclude that
functional outcomes of IPAA may be determined by an intrinsic limitation of the IPAA
procedure, rather than growing expertise or technical refinement. This is in line with other
studies showing no improvement in functional outcomes based on technical developments,
such as type of anastomosis or laparoscopic approach.34,37 However, most patients consider
the functional outcome after IPAA to be highly satisfactory, with good quality of life and
social functionality that are comparable to those in a healthy reference population.38,39
As expected, achieving these adequate quality of life scores was highly correlated with
achieving of good functional outcomes.40
Cancer risk after IPAA
The IPAA has as an important advantage the removal of the whole colon and virtually the
entire rectum as part of the procedure. This minimizes chances of colon and rectal cancer
in this high-risk population. A proctocolectomy should be considered almost mandatory
122 Chapter 6
when dysplasia is present. Even when only low-grade dysplasia has been identified by colo-
noscopy, the risk remains substantial. In such patients, studies show a risk of concomitant
cancer or high-grade dysplasia of 15% and a 5-year progression rate of up to 54% if not
operated on.28,41
When a double-stapled approach for IPAA is used, a mucosal remnant at the anal transition
zone (ATZ) is left in place. The risk of cancer in this area is a matter of controversy. In three
series with long-term follow-up focused on this outcome, dysplasia and cancer in the anal
transitional zone after stapled pouch surgery was found to be infrequent.7,42,43 Dysplasia
was observed in 8/178 (4.4%), 7/210 (3.3%) and 0/135 (0%) after at least 10 years of
follow-up. In most of these cases, dysplasia developed in the first 2 to 3 years and often
disappeared on repeated biopsies. None of the series found cancer in the ATZ after such
prolonged follow-up. These data strongly emphasize the extent to which IPAA minimizes
the risk of cancer.
The best evidence regarding the development of dysplasia and adenocarcinoma after IPAA
can be obtained from a recent study from the Cleveland Clinic, in which 3,203 patients
undergoing an IPAA from 1984 to 2009 were analysed.44 Cumulative incidences for pouch
neoplasia at 5, 10, 15, 20, and 25 years were 0.9%, 1.3%, 1.9%, 4.2%, and 5.1%, re-
spectively. Overall, 23 patients (0.72%) developed dysplasia, while 11 (0.36%) developed
adenocarcinoma of the pouch and/or the ATZ. Risk factors for pouch neoplasia were also
evaluated. Preoperative established cancer (hazard ratios (HR) 13.43, 95%CI: 3.96-45.53,
p<0.001) or dysplasia (HR 3.62, 95%CI: 1.59-8.23, p=0.002) were the only independent
factors associated with increased risk of pouch neoplasia. Mucosectomy did not protect
against this risk, and the rate of pouch cancer was actually higher after mucosectomy with
a rate of 1.3% (6/451) compared to 0.3% (9/2734) after the double-stapled approach. The
authors concluded that the risk for neoplasia in patients with UC and IPAA is small, and
that it is mainly determined by the presence of preoperative dysplasia or cancer.
Additionally, in a review of literature, 26 published case reports were identified between
1984 and 2008.45 Certain observations from this review are noteworthy. First, of the 26
carcinomas, 14 (52%) arose from rectal mucosa or from the anal transition zone, while
6 (23%) were from ileal pouch mucosa. Second, adenocarcinomas developed after
mucosectomy in 17 patients, and after a double-stapled approach in 8 patients (1 case
not reported). Also worth noting, the indication for the IPAA was due to neoplasia in 19
patients (9 cancers and 10 dysplasia) and non-neoplasia in 6 patients. The median time for
development of pouch lesions was the shortest in patients operated on for cancer (median
3 years), compared to a median of 6.5 in the other patients. This review is in line with
results from the above mentioned study, and further establishes the following conclusions:
Chapter 6 123
6
1) the low number of reported cases, 2) cancer can develop both after mucosectomy
or double-stapled approach, 3) the close relationship between surgery for neoplasia and
development of cancer.
The review was not able to estimate the incidence of cancer after IPAA, since the total
number of IPAA cases was not stated in most case reports. Branco et al. did publish their
own case as part of this review, which was the first case they observed in a cohort of 520
patients (0.2%) from 1978 to 2008.45 This percentage is also in line with the Cleveland
study.44
Despite this seemingly small risk, surveillance of selected patients has been recommended
by some authors.46,47 This approach might especially be important in UC patients with
dysplasia or cancer present at time of surgery, or patients with retained rectal mucosa and
active inflammation (i.e. cuffitis). Also the presence of chronic pouchitis might be a valid
indication for surveillance, since this has been associated with increased risk of low-grade
dysplasia (odds ratio 13.48, P < 0.02), as well as high-grade dysplasia (3/66 vs 0/210,
p=0.01).36 An overview of the current evidence on the risk of cancer after IRA vs. IPAA is
presented in Table 3.
Table 3. Risk of cancer after ileorectal vs. ileal pouch-anal anastomosis in ulcerative colitis
Ileorectalanastomosis
Period N Follow-up average (years)
Overall cancerrate (%)
Estimated cumulative risk after 20 years (%)
da Luz Moreira11 1971-2006 86 9 8 14
Leijonmarck13 1955-1984 51 13 0 -
Pastore15 1974-1990 48 6.3 2 14.3*
Börjesson16 1997-2003 32 3.5 0 -
Grundfest17 1957-1977 89 8 4.8 5 ± 3.5
Elton18 1990-1999 18 2.6 - -
Andersson19 1992-2006 105 5.4 - 2.1
Lepistö20 1978-2000 20 18 0 -
Oakley21 1960-1982 288 8.2 3.1 -
Baker26 1952-1976 374 >10 5.9 6 ± 2
ileal pouch-analanastomosis
Period N Follow-up average (years)
Overall cancerrate (%)
Estimated cumulative risk after 20 years (%)
Kariv44 1984-2009 3,203 ±12 0.4 4%
Branco45 1978-2008 520 ±15 0.2 -
* Cumulative risk at 12 years (rather than 20).
124 Chapter 6
conclusion
In the current era IPAA is the preferred approach for patients with UC requiring surgical
treatment. The removal of all diseased mucosa and the lower risk of cancer after IPAA
compared to IRA are the main advantages of this technique (Table 4). Therefore, IPAA
should certainly be performed when the rectum is actively involved in the disease or when
dysplasia or cancer are present in any part of the colon or rectum. Nonetheless, there is
still a role for IRA and TPC for selected patients and for patients not candidates for IPAA.
Total abdominal colectomy with IRA is justified in UC patients with normal anal sphincters
tone without severe perineal disease, and spared and distensible rectum with no evidence
of dysplasia or cancer at the time of intervention. It can be also proposed to young women
as a possible interim procedure based on concerns for infertility after IPAA.
The risk of cancer is of particular concern in the comparison between these two tech-
niques. Current evidence shows a large variation in the reported rates of cancer after IRA
from 0% to 8%. For IPAA, this risk is much smaller, and two large series have shown a rate
of cancer of about 0.3%. Few studies have calculated the cumulative risk of cancer as well.
Similarly, estimated cumulative risk of cancer after 20 years was higher after IRA (6% to
14%) compared to IPAA (4.2%) (Table 4).
Therefore, every patient undergoing IRA should be informed about the risk of recurrent
proctitis and cancer in long standing disease. They have to fully understand the need for
meticulous surveillance and agree to comply with at least yearly endoscopy with rectal
Table 4. Main advantages and disadvantages of ileorectal anastomosis (IRA) and ileal pouch-anal anastomosis (IPAA)
IRA IPAA
Advantages Easier operation Lower risk of cancer
Lower overall morbidity No need for medical therapy
Lower risk of urinary and sexual dysfunction Less urgency
Fewer bowel movements per day
Better continence
Disadvantages Need for maintenance therapy Major operation
Risk of recurrent/persistent disease Risk of postoperative complications
Higher risk of neoplastic degeneration Pouchitis
Need for strict surveillance
More dietary and work restrictions
Chapter 6 125
6
biopsies. Unless these conditions are met, patients should not be offered an IRA. Also,
patients with widely metastatic colorectal cancer may benefit from an IRA as a palliative
procedure.
Functional results seem to be better after IRA with lower frequency of bowel movements
and less night-time seepage but with more urgency compared to patients with an IPAA.
The overall quality of life is similar, although the IRA group has significantly more dietary
and work restrictions.11 Finally, TPC still remains the procedure of choice in patients with
impaired anal sphincter function and high-risk of pouch failure.
126 Chapter 6
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8; discussion 78.
U. Ahmed Ali
B. Shen*
F.H. Remzi
R.P. Kiran
Departments of Colorectal Surgery and *Gastroenterology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
7 the manaGement of anastomotic
pouch sinus after ileal pouch-
anal anastomosis (ipaa)
Diseases of the Colon & Rectum, 2012.
132 Chapter 7
absTracT
backgroundAnastomotic sinus is a relatively uncommon complication after an ileal pouch anal anasto-
mosis (IPAA). Disease course is poorly defined and management can be challenging. The
aim of this study is to evaluate frequency, management and outcome of this complication.
MethodsWe performed a retrospective designed cohort study from a prospectively collected
database of a high volume specialized Colorectal Surgery department. Patients with an
anastomotic sinus after pouch surgery from 1997 to 2009 were included. Management
and outcomes of these patients were evaluated. Main endpoints were the rates of sinus
healing and pouch failure.
resultsFrom 2286 patients who underwent an IPAA procedure, 45 (2.0%) patients were identified
with an anastomotic pouch sinus. There were 32 (71%) males, and the mean age was 40
(±13) years. The pouch sinus was initially managed by observation in 23 (51%) patients,
drainage of the sinus in 9 (20%), unroofing of the sinus tract in 8 (18%), sinus closure in 3
(7%) and a diverting ileostomy in 2 (4%). In 28 patients (62%), subsequent treatment was
necessary. Sinus healing was achieved in 27 (60%) patients, whereas 15 (33%) eventually
developed pouch failure. Of the treatment modalities applied, a strategy with observation
as initial treatment was the most successful with a healing rate of 65%. The healing rate
was significantly lower in symptomatic patients compared to asymptomatic patients (30%
vs. 84%, p=0.001). Pouch failure was also higher (45% vs. 24%, p=0.14). No other factors
associated with healing rate or pouch failure were identified.
conclusionAnastomotic pouch sinuses after pouch surgery are associated with a high rate of pouch
failure. Symptomatic presentation is a significant predictor for low healing rates and is
associated with a high risk of pouch failure. Observation and watchful monitoring is the
initial treatment of choice when permitted by the patient’s condition.
Chapter 7 133
7
inTroducTion
In an ileal pouch anal anastomosis (IPAA) procedure, the integrity of the anastomosis is an
important determinant of the long-term viability of the constructed pouch. Anastomotic
leak and fistulae are well known complications that could threaten the structure of the
anastomosis and are important predictors of pouch failure.1,2 An anastomotic sinus of
the pouch is a less known condition that occurs in 2.8 to 8% of patients undergoing an
IPAA procedure.3-5 It is thought to be a special form of anastomotic leak in which the leak
is confined to a blind-ending track.3-5 The clinical impact of an anastomotic sinus of the
pouch can be significant. It can delay ileostomy closure when shown in the precedent
Gastrografin enema and require prolonged evaluation and follow-up. It also can require
intervention aimed at facilitating the closure of the sinus, with added costs and burden to
the patient and health system. Furthermore, it has the potential to eventually cause pouch
failure, resulting in major surgical interventions such as pouch revision, redo pouches or
pouch excision with hospital admission and significant potential morbidity.3,5 Addition-
ally, there have been previous reports of malignant changes occurring in various types of
fistulae, draining sinuses and chronic inflammatory tracts.6-9
The optimal management of anastomotic sinuses in an ileoanal pouch is not well known.
Many surgeons choose to delay ileostomy reversal and repeat the pouchogram at a later
time, hoping for eventual spontaneous resolution, which has been reported to occur in
approximately 40 to 50% of patients.3,10 Several surgical therapies have been described
for the management of patients with persistent sinuses including debridement, unroofing,
occlusive treatment with fibrin glue, pouch revision and redo pouch.3-5,10,11 Results of these
interventions vary greatly between reports, and large series are very scarce.5 In this study,
we set out to evaluate the frequency, management and outcome of anastomotic pouch
sinuses after IPAA in a specialized colorectal surgical center.
PaTienTs and MeThods
PatientsAll patients who underwent restorative proctocolectomy in the study period were included
in a prospective ileal pouch database. Patients who developed an anastomotic pouch sinus
after IPAA between 1997 and 2009 were identified from this prospectively maintained
institutional review board approved database.
134 Chapter 7
inclusion and exclusion criteriaPatients who had a primary or redo IPAA for ulcerative colitis or indeterminate colitis and
subsequently developed a pouch sinus were included.
surgical treatmentAt our institution, most patients undergo a double-stapled ileal J-pouch anastomosis
with a defunctioning loop ileostomy. The choice of operation is based on surgeon prefer-
ence, with the selective performance of a one-stage proctocolectomy and IPAA without
a defunctioning ostomy based on an individual patient’s circumstances.12 In the absence
of any specific concerns after surgery, we routinely perform a gastrografin enema just
before closure of the ileostomy to ensure integrity of the pouch anastomosis. In patients
with complications (e.g. pelvic sepsis or anastomotic leaks) other approaches, like exam
under anesthesia (EUA), pouchoscopy and concomitant closure of ileostomy if satisfactory
healing is deemed to have occurred, may be chosen by the surgeon. All ileostomy closures
were performed at our institution.
definition of a pouch sinus and diagnostic modalitiesA pouch sinus was defined as a blind-ending tract arising from the area of the pouch
anal anastomosis. All pouch sinuses were identified by imaging modalities (pouchogram)
or endoscopy or by examination under anesthesia (EUA) performed by an experienced
colorectal surgeon. Pouchograms were performed by means of Gastrografin enema.
study variablesData regarding patient demographics (age, gender and preoperative diagnosis), medical
and surgical history, diagnostic modality and management of the sinus were collected. Fac-
tors potentially influencing outcome of treatment were collected and analyzed. These were
pouch construction (primary pouch vs. redo pouch), history of postoperative anastomotic
leak or pelvic sepsis after IPAA, symptomatic presentation of sinus and time to ileostomy
closure (before vs. after ileostomy closure). The primary outcomes evaluated were sinus
healing and pouch failure. Healing was defined as complete healing of the sinus confirmed
by imaging (pouchogram), endoscopy or EUA. Pouch failure was defined as any condition
necessitating permanent diversion through an ileostomy or excision of the pouch. Thus,
patients who had successful redo of the pouch as part of the treatment with an eventually
healed sinus were considered to have developed pouch failure, although such a sinus was
deemed to have eventually healed from the standpoint of healing rates.
data and statistical analysisCategorical variables were summarized as frequencies and percentages. Quantitative vari-
ables were summarized by medians with ranges and mean with standard deviations (SD).
Chapter 7 135
7
The different treatment modalities and associated healing rate are presented and discussed.
The course of pouch sinuses diagnosed before ileostomy closure and those diagnosed after
ileostomy closure were compared. Statistical testing of categorical variables was performed
with a Chi-square test, with a p-value of 0.05 as cut-off point for statistical significance.
resulTs
Patients and characteristicsBetween 1997 and 2009, a total of 2286 patients underwent an IPAA procedure at the
Colorectal Surgical Department of the Cleveland Clinic. A total of 45 (2.0%) patients with a
chronic anastomotic pouch sinus were identified. The mean age of these patients at pouch
surgery was 40 (±13) years old, and 32 (71%) patients were male. Preoperative diagnosis
was ulcerative colitis in 41 (91%) patients and indeterminate colitis in 4 (9%). Final pathol-
ogy showed ulcerative colitis in 30 (67%), indeterminate colitis favoring ulcerative colitis in
7 (16%), indeterminate colitis in 7 (16%) and Crohn’s disease in 1 (2%) patient. At subse-
quent follow-up, mucosal apperance and histology acquired during pouch examination did
raise the suspicion of Crohn’s disease in 9 (20%) patients. Preoperatively, 26 (58%) patients
were on 1 or more immunomodulatory drugs. Thirty-five (78%) patients developed an
anastomotic pouch sinus after a primary IPAA procedure. The procedure was performed as
a 1-stage procedure in 1 patient, 2-stage procedure in 19 patients and a 3-stage procedure
in 15 patients. The remaining 10 (22%) developed the pouch sinus after a redo IPAA. A
double-stapled approach was used in 34 (76%) patients and handsewn anastomosis was
used in 11 (24%) patients. All but 2 patients (96%) had a defunctioning loop ileostomy.
Twenty-four (53%) patients had a previous anastomotic leak or pelvic abscess.
Twenty (44%) patients were asymptomatic at the time of diagnosis, while 25 (56%) pre-
sented with one or more symptoms. Symptoms in patients who were diverted included
fever, perianal / back pain and rectal drainage. Symptoms in patients who were not diverted
were fever, perianal / abdominal pain, pouchitis like symptoms (pain, urgency), severe
rectal burning, diarrhea, irritation and itching. A pouch sinus was noticed before closure of
the diverting ileostomy in 23 (51%) patients, and after closure of the diverting ileostomy
in the remaining 22 (49%) patients. All patients who developed a sinus after ileostomy
closure had normal pre-takedown evaluation. The median duration between IPAA surgery
and ileostomy closure was 5 months (IQR 3 to 8).
Anastomotic pouch sinus was initially diagnosed by endoscopy in 23 (51%) patients, Gas-
trografin enema in 15 (33%) patients and by exam under anesthesia (EUA) in the remaining
7 (16%) patients (Figure 1).13 Diagnosis was confirmed in all patients either by additional
136 Chapter 7
diagnostic modalities or by imaging modalities used for the treatment and follow-up of
patients. Of the 23 (51%) patients who were initially diagnosed with a pouch sinus on
pouchoscopy, all but 5 patients had this diagnosis confirmed by atleast one other form of
imaging. In 12 patients, the diagnosis was confirmed by a gastrografin enema. In these 12
patients, no discrepancies were seen between gastrografin enema and pouchoscopy. The
median duration between surgery and the initial diagnosis of the sinus was 6 months (IQR
2 to 22.5). In patients diagnosed with a sinus before ileostomy closure, the median dura-
tion from IPAA to diagnosis of the sinus was 2 months (IQR 2 to 3). For patients diagnosed
with a sinus after ileostomy closure this median duration was 22.5 (IQR 8 to 64) months.
ManagementThe initial management of a pouch sinus included watchful observation in 23 (51%) pa-
tients, drain placement in the sinus in 9 (20%) patients, unroofing of the sinus in 8 (18%)
patients, sinus closure in 3 (7%), construction of a diverting ileostomy in 2 (4%) patients
(Table 1). For patients undergoing observation as initial treatment, the first reassessment of
the sinus after its initial detection was performed after a median of 2 months (IQR 1 to 3.5
months). After initial treatment, 28 (62%) patients required additional treatments (Figure
2). These included unroofing of the sinus in 14 (50%) patients, drainage in 3 (11%), fibrin
glue in 2 (7%), sinus closure in 2 (7%), diversion in 5 (18%), pouch redo in 1 (4%) and
pouch excision in 1 (4%) patients. Nine (20%) patients required one more subsequent
treatment, including unroofing (x2), drainage (x1), fibrin glue (1x), diversion (x1), redo
pouch (x2) and pouch excision (x2).
Figure 1. Distal pouch sinus at the anastomosis on pouchoscopy (A) and pouchogram by means of a Gastrografin enema (B) (arrows)
Chapter 7 137
7
Table 1. Treatment patterns of anastomotic pouch sinus and associated rates of healing and pouch failure
Patterns of treatment NSinus Healed
n (%)Pouch failure
n (%)
Number of required treatments
Only 1 treatment 17 12 (71%) 5 (29%)
Two or more treatments 28 15 (54%) 10 (36%)
Initial treatment*
Observation 23 15 (65%) 5 (22%)
Drainage 9 5 (56%) 3 (33%)
Unroofing 8 4 (50%) 4 (50%)
Sinus closure 3 1 (33%) 2 (67%)
Diversion 2 2 (100%) 1 (50%)
* Healing and pouch failure rates represent the final outcome of patients after all interventions.
Sinus (n=45)
Observation (n=23)
Drainage (n=9)
- Unroofing (n=4) - Drainage (n=1) - Diversion (n=1) - Drainage &
unroofing (n=1) - Diversion & redo
pouch (n=1)
- Unroofing (n=4) - Diversion (n=2) - Improved, but not yet healed (n=2)
- Unroofing (n=1) - Sinus closure (n=1) - Fibrin glue (n=1)
- Unroofing (n=1) - Diversion (n=1) - Unroofing & redo pouch (n=1) - Fibrin glue & drainage (n=1) - Not healed (n=1)
- Unroofing (n=1) - Sinus closure & Diversion (n=1)
Diversion (n=2)
- Unroofing (n=1) - Drainage & Fibrin glue (n=1)
Unroofing (n=8)
- Redo pouch (n=1)
- Pouch excision (n=1) - Not helaed (n=3)
None
Sinus not healed or pouch failure.
Sinus healed after additional treatment.
Sinus healed after initial treatment.
Healed (n=7)
Sinus closure (n=3)
Healed (n=1) Healed (n=3) Healed (n=1) -
None
Figure 2. A diagram showing the treatment modalities applied for pouch sinus and the outcome of these treatments
138 Chapter 7
outcomesProven complete healing of the sinus was eventually achieved in 27 (60%) of patients
(Table 2). The median time from the diagnosis of the sinus to healing was 7.5 months
(IQR 2 to 28). In two patients substantial reduction of the size of the sinus was seen on
imaging, but the sinus was not yet completely healed. Two patients lacked recent imaging
to confirm healing of the sinus, although these patients had normally functioning pouches.
A total of 15 (33%) patients eventually had pouch failure.
The influence of various factors on the healing and pouch failure rates is presented (Table
2). The healing rate was slightly higher (63% vs. 50%, p=0.76) and pouch failure rate lower
(29% vs. 50%, p=0.21) in patients who underwent a primary IPAA procedure compared
to patients who developed a sinus after a redo IPAA procedure, respectively. Patients with
a history of an overt postoperative anastomotic leak or pelvic sepsis had similar healing
rate of the sinus (63% vs. 57%, p=0.49) and pouch failure rate (38% vs. 29%, p=0.53)
as patients without a history of these complications. Symptomatic sinus presentation was
significantly associated with a lower healing rate (30% vs. 84%, p=0.001), pouch failure
was higher but did not reach statistical significance (45% vs. 24%, p=0.14). Finally, pouch
sinuses noticed before closure of the ileostomy had a higher rate of healing (70% vs. 50%,
p=0.33) compared to sinuses noticed after closure of ileostomy, but pouch failure rates
were quite similar (30% vs. 36%, p=0.67). Eighteen patients had an incidental finding of a
sinus tract on preoperative investigation performed to ensure anastomotic integrity before
loop ileostomy closure. These were managed at the discretion of the operating surgeon by
Table 2. Evaluation of potential factors associated with healing and pouch failure in patients with an anastomotic pouch sinus
Potential risk factors NHealing rate
n (%)P-value
Pouch failuren (%)
P-value
All patients 45 27 (60%) - 15 (33%) -
Pouch construction
- Primary pouch 35 22 (63%)0.756
10 (29%)0.205
- Redo pouch 10 5 (50%) 5 (50%)
History of anastomotic leak or pelvic sepsis
- Yes 24 15 (63%)0.490
9 (38%)0.526
- No 21 12 (57%) 6 (29%)
Symptomatic sinus presentation
- Yes 20 6 (30%)0.001
9 (45%)0.138
- No 25 21 (84%) 6 (24%)
Time to ileostomy closure
- Before closure 23 16 (70%)0.334
7 (30%)0.673
- After closure 22 11 (50%) 8 (36%)
Chapter 7 139
7
means of observation in 10 (55%), drainage in 4 (22%), unroofing in 2 (11%), and sinus
closure in 2 (11%) patients. Healing rate was 83%, while pouch failure rate was 22% for
these patients.
Of the treatment modalities applied, a strategy with observation as initial treatment was
the most used treatment strategy (23 (51%) of patients), with a healing rate of 65%. In
treating asymptomatic patients all treatment modalities seemed more successful than in
symptomatic patients (Table 3). Observation resulted in higher healing rates for asymptom-
atic compared to symptomatic patients (79% vs. 44%, p=0.19, respectively). The use of
invasive treatment modalities was fairly similar in asymptomatic and symptomatic groups
of patients, but healing rates were generally higher in asymptomatic patients. Initial treat-
ment with drainage (100% vs. 20%, p=0.016) and unroofing (100% vs. 0%, p=0.005)
were both significantly associated with higher healing rates in asymptomatic patients as
when compared to symptomatic patients.
Table 3. Treatments and healing rates of anastomotic pouch sinus in patients with asymptomatic vs. symptomatic presentation
Patterns of treatment
N
Asymptomatic Symptomatic
P-valuen Healed n (%) n Healed n (%)
Number of treatments
Only 1 treatment 17 11 9 (82%) 6 3 (50%) 0.0793
Two or more treatments 28 14 12 (85%) 14 3 (21%) 0.012
Initial treatment*
Observation 23 14 11 (79%) 9 4 (44%) 0.188
Drainage 9 4 4 (100%) 5 1 (20%) 0.016
Unroofing 8 4 4 (100%) 4 0 (0%) 0.005
Sinus closure 3 2 1 (50%) 1 0 (0%) 0.386
Diversion 2 1 1 (100%) 1 1 (100%) -
* Healing and pouch failure rates represent the final outcome of patients after all interventions.
In treating patients diagnosed with pouch sinuses before vs. after ileostomy closure a
slight difference in the initial treatment modalities preferred was noted (Table 4). More
patients with sinuses diagnosed before ileostomy closure were treated with drainage (7
vs. 2 patients) and sinus closure (3 vs. 0 patients) compared to patients diagnosed after
ileostomy closure. On the other hand, unroofing was a more preferred initial treatment in
patients diagnosed with sinuses after ileostomy closure (6 out of 8 patients).
Observation was performed initially in an equal proportion of patients in both groups with
similar rates of success (Table 4). In patients where the pouch sinus was noticed before
diverting ileostomy closure, the ileostomy was closed after complete healing of the sinus
140 Chapter 7
in most patients. In 5 (22%) patients, however, the sinus was deemed acceptable enough
to allow closure of the ileostomy before complete healing. In all cases, the size of the sinus
was noted to be getting progressively smaller and the surgeons deemed the sinus small
enough to not pose a threat to the integrity of the anastomosis. Two of these patients had
an initial asymptomatic presentation, and both of them achieved complete healing. The 3
other patients had a symptomatic presentation initially; none of them achieved complete
healing after ileostomy closure, and all experienced pouch failure eventually. Of the 10
patients with a suspicion of Crohn’s disease, the sinus healed in 5 (50%) patients and 4
(40%) patients developed pouch failure.
discussion
An anastomotic pouch sinus is a relatively uncommon complication after IPAA. Its outcome
and consequences for treatment are not well studied. Only few reports have presented
outcomes of this condition in the last 15 years, most of which are relatively small (Table
5). Moreover, previous studies have typically presented the outcome of pouch sinuses in
highly selected populations based on patient presentation or type of treatment.3-5,11 There
is, therefore, a paucity of data regarding the treatment and outcome of pouch sinuses,
especially from large series. The present study has shown that pouch sinuses are associated
with pouch failure in about 33% of cases, making it an important risk factor for pouch
failure. This is comparable to the pouch failure rate of patients suffering from pouch-
related fistulae.1 We also showed that the risk for pouch failure was not equal across all
patients. Patients with an asymptomatic presentation tend to have a much better outcome
Table 4. Treatments and healing rates in patients diagnosed with an anastomotic pouch sinus before and after ileostomy closure
Patterns of treatment
N
Before IL closure After IL closure
P-valuen Healed n (%) n Healed n (%)
Number of treatments
Only 1 treatment 17 9 8 (89%) 8 4 (50%) 0.117
Two or more treatments 28 14 8 (57%) 14 5 (50%) 0.340
Initial treatment*
Observation 23 11 8 (73%) 12 7 (85%) 0.599
Drainage 9 7 5 (71%) 2 0 (0%) 0.073
Unroofing 8 2 2 (100%) 6 2 (33%) 0.102
Sinus closure 3 3 1 (33%) 0 - -
Diversion 2 0 - 2 2 (100%) -
IL: diverting ileostomy.* Healing and pouch failure rates represent the final outcome of patients after all interventions.
Chapter 7 141
7
in terms of healing of the sinus and preservation of a functional pouch. These findings
are important in that they can raise the alertness of physicians to this condition, provide
guidance in the treatment of its different presentations and help counsel patients.
The overall healing rate in this study was about 60%, which is lower than healing rates
reported in previous studies (Table 5). However, when only asymptomatic patients are
observed, the healing rate of 84% was fairly similar to previous reports. The improved out-
come of asymptomatic patients can potentially be explained by differences in the severity
of the condition. Smaller non-inflamed sinuses are more likely to present asymptomatically
than larger or inflamed sinuses. This could also explain the tendency of asymptomatic
sinuses to heal more often under conservative treatment. Another explanation could be
the effect of clinical symptoms on the choice of treatment. Severe clinical symptoms may
necessitate the abandonment of a conservative approach with the use of surgical interven-
tions earlier, with a potentially less favorable outcome.
The optimal treatment for anastomotic pouch sinuses is not well defined. Most surgeons
adapt a conservative wait-and-see strategy in which they observe the patient and repeat
imaging modalities at regular intervals to monitor the healing of the sinus.3,5 Results from
this study support this conservative approach, especially for asymptomatic patients. When
a conservative watchful waiting approach is not possible or insufficient to achieve complete
healing, other treatments may be applied. Several treatments have been described, includ-
ing drainage of the sinus, surgical closing of the sinus and permanent fecal diversion.3,11
There are no studies comparing these treatments, and all available evidence is descriptive.
In 1997, Whitlow et al. described a new method for treating pouch sinuses by unroof-
ing of the anastomosis, whereby the common wall between the sinus and the adjacent
bowel lumen (i.e. pouch) is divided.4 In 6 patients treated by this approach, all achieved
complete sinus healing by 12 months after surgery. In the current study, 8 patients were
Table 5. Studies describing the outcome of anastomotic pouch sinuses after ileal pouch anal anas-tomosis
Study N Selection criteria Initial treatments Healing rate
Akbari 20093 22Asymptomatic, before ileostomy
closureObservation
(± debridement)20/21 (95%)
Nyam 19975 41Asymptomatic, before ileostomy
closureObservation 40 / 41 (95%)
Swain 200411 7 Fibrin glue treatment Fibrin glue 7 / 7 (100%
Whitlow 19974 6 Unroofing as treatment Unroofing 6 / 6 (100%)
Current study 45Symptomatic and asymptomatic,
irrespective of ileostomy closure or type of treatment
Depending on patient condition and
presentation27 / 45 (60%)
EUA: exam under anesthesia
142 Chapter 7
treated with unroofing of the sinus as the initial treatment with 4 (50%) patients achieving
complete healing. All 4 patients had an asymptomatic presentation of the sinus. Addition-
ally, 14 patients underwent unroofing of the sinus as an additional treatment (9 after
observation, 3 after drainage, 1 after sinus closure and 1 after diversion). Seven patients
achieved complete healing of the sinus, 5 of which were asymptomatic. In all, 50% (11
of 22 patients) had healing. However, unroofing seems to be a promising treatment in
asymptomatic sinuses (81% (9 of 11 patients) healed), but results seem to be less favorable
in symptomatic patients (18% (2 of 11 patients) healed).
The use of fibrin glue for closure of pouch sinuses was also recently reported by Swain et
al.11 Only 3 patients were treated by this approach in our series, with 2 patients achieving
complete healing (Figure 2). With regards to transanal drainage of the sinuses, in total 12
patients had this treatment at any time and 8 (66%) patients eventually healed. Again,
healing rate in asymptomatic patients was much higher (100% (7 out of 7 patients))
compared to symptomatic patients (20% (1 out of 5 patients)). Treatments utilized before
or after ileostomy closure did not differ substantially (Table 4). In both groups, conservative
treatment was chosen first in the majority of patients with comparable success rates (73%
vs. 85% for before and after ileostomy closure, respectively). Some small differences did
exist (slightly greater use of drainage and sinus closure in the group that developed a
sinus before ileostomy closure, and greater use of unroofing of the sinus in the group
that developed a sinus after ileostomy closure), but these differences probably reflect an
individual physician’s choice in a particular patient. Diversion was performed in 8 out of
the 22 patients with a sinus diagnosed after ileostomy closure (Figure 2). In the major-
ity of cases, therefore, other treatment modalities were considered more appropriate in
this group of patients. This is understandable, since an anastomotic sinus, especially if
asymptomatic, may be a relatively small defect, which may not always justify a re-operation
for diversion. When other measures fail, a redo pouch is the ultimate surgical option in
the treatment of pouch sinuses. Three (1%) patients were treated with a redo pouch in
this series. Two (66%) of these patients achieved successful healing and had a functional
pouch. The third patient, unfortunately, did not benefit from this procedure and the new
pouch was eventually excised.
The current study includes prospectively collected information for a large cohort of patients
undergoing IPAA who developed pouch sinuses. Although it does have the disadvantages
of a retrospective design, the inclusion of a relatively large number of patients who have
varying presentations of this rare and complex condition may provide better information
that helps guide physicians faced with its management. The small numbers of patients
in the subgroups may have also led to a type II error, resulting in an insignificant p-value.
Nevertheless, the details of the outcomes with the various treatment strategies will provide
Chapter 7 143
7
information previously not clearly available. This may help patients and clinicians make
decisions when faced with the quandary of how best to manage this difficult condition.
Based on the results of this study, we propose the following algorithm for the management
of a sinus after IPAA. Sinuses detected in patients who have intestinal continuity restored
and are otherwise asymptomatic, are best left alone without intervention. When a pouch
sinus is incidentally encountered (e.g. on a Gastrografin enema) prior to ileostomy clo-
sure, we suggest delaying ileostomy closure for a few months until healing of the sinus is
demonstrated. Symptomatic sinuses and those that are defunctioned, but non-healing on
watchful waiting alone, may be managed by trans-anal drain placement, unroofing of the
sinus or injection of fibrin glue. Consideration may be given to simply closing the ileostomy
in selected asymptomatic patients with a small persistent sinus after due discussion with
the patient about the pros and cons of this approach. On the other hand, the creation of a
defunctioning ostomy may be considered in circumstances where eventual healing of the
sinus may be expected in patients who are not defunctioned. When attempts at healing
have failed or may not reasonably be anticipated due to the size or persistence of the sinus,
a redo IPAA may be considered in symptomatic patients and those with large sinuses.
conclusion
Anastomotic pouch sinuses after IPAA are associated with a high rate of pouch failure.
Symptomatic presentation is a significant predictor for low healing rates and is associated
with a high risk of pouch failure. Observation and watchful monitoring is the treatment of
choice when permitted by the patient’s condition. Optimal choice of subsequent treatment
is not well studied and comparative studies are needed.
144 Chapter 7
references
1. Nisar PJ, Kiran RP, Shen B, Remzi FH, Fazio
VW. Factors associated with ileoanal pouch
failure in patients developing early or late
pouch-related fistula. Dis.Colon Rectum.
2011; 54: 446-53.
2. Forbes SS, O’Connor BI, Victor JC, Cohen
Z, McLeod RS. Sepsis is a major predictor of
failure after ileal pouch-anal anastomosis.
Dis.Colon Rectum. 2009; 52: 1975-81.
3. Akbari RP, Madoff RD, Parker SC, Hager-
man G, Minami S, Bullard Dunn KM,
Mellgren AF. Anastomotic sinuses after
ileoanal pouch construction: Incidence,
management, and outcome. Dis.Colon
Rectum. 2009; 52: 452-55.
4. Whitlow CB, Opelka FG, Gathright JB,
Jr., Beck DE. Treatment of colorectal and
ileoanal anastomotic sinuses. Dis.Colon
Rectum. 1997; 40: 760-63.
5. Nyam DC, Wolff BG, Dozois RR, Pemberton
JH, Mathison SM. Does the presence of
a pre-ileostomy closure asymptomatic
pouch-anastomotic sinus tract affect the
success of ileal pouch-anal anastomosis?
J.Gastrointest.Surg. 1997; 1: 274-77.
6. Cruickshank AH, McConnel EM, Miller DG.
Malignancy in scars, chronic ulcers, and
sinuses. J.Clin.Pathol. 1963; 16: 573-80.
7. Gifford J, Saltzstein SL, Barone RM.
Adenocarcinoma occurring in association
with a chronic sinus tract and biliary fistula.
Cancer. 1981; 47: 2093-97.
8. McCune WS, Thistlethwaite JR. Fistula
cancer. Ann.Surg. 1959; 149: 815-20.
9. Skir I. Mucinous carcinoma associated with
fistulas of long-standing. Am.J.Surg. 1948;
75: 285-89.
10. Arumainayagam N, Chadwick M, Roe
A. The fate of anastomotic sinuses after
total mesorectal excision for rectal cancer.
Colorectal Dis. 2009; 11: 288-90.
11. Swain BT, Ellis CN. Fibrin glue treatment of
low rectal and pouch-anal anastomotic si-
nuses. Dis.Colon Rectum. 2004; 47: 253-55.
12. Remzi FH, Fazio VW, Gorgun E, Ooi BS,
Hammel J, Preen M, Church JM, et al. The
outcome after restorative proctocolectomy
with or without defunctioning ileostomy.
Dis Colon Rectum. 2006; 49: 470-77.
13. Tang L, Cai H, Moore L, Shen B. Evaluation
of endoscopic and imaging modalities in
the diagnosis of structural disorders of the
ileal pouch. Inflamm.Bowel Dis. 2010; 16:
1526-31.
U. Ahmed Ali1
S.T. Martin2
A.D. Rao3
R.P. Kiran3
1 Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands2 Department of Colorectal Surgery, St. Vincent’s University Hospital, Dublin, Ireland3 Division of Colorectal Surgery, Department of Surgery, Columbia University Medical Center, New York, USA
8 impact of preoperative
immunosuppressive aGents on
postoperative outcomes in
crohn’s disease
Diseases of the Colon & Rectum, 2014.
148 Chapter 8
absTracT
backgroundImmunosuppressive agents are essential in the management of Crohn’s disease. Their
safety before surgery is, however, still controversial. Therefore, this review aims to evalu-
ate whether preoperative use of immunosuppressive agents is associated with increased
postoperative complications.
MethodsA literature search of PubMed, EMBASE, and The Cochrane Library was undertaken. All
studies describing postoperative outcomes of patients undergoing bowel resections for
Crohn’s disease were included if they reported data comparing patients on preoperative
immunosuppressive agents to an appropriate control group. Main outcomes were overall
and infectious complications.
resultsTwenty-one eligible studies (20 retrospective and 1 prospective) with 6899 patients were
included. When individual studies were examined, only 2/14 (14%), 4/13 (31%) and 1/8
(13%) studies found an association between postoperative complications and preoperative
anti-tumor necrosis (TNF) agents, corticosteroids and thiopurines, respectively. In meta-
analysis, patients on anti-TNF agents (Relative Risk (RR) 1.29, 95% Confidence Interval
(CI) 1.07 to 1.55), and corticosteroids (RR 1.55, 95% CI 1.23 to 1.95) were found to have
a higher risk of postoperative infectious complications. The use of anti-TNF agents was
also significantly associated with wound infection (RR 1.62, 95% CI 1.12 to 2.34) and
septic shock (RR 1.81, 95% CI 1.03 to 3.17). There was no association between use of
thiopurines or combined immunomodulator drugs and postoperative complications.
conclusionsPatients with Crohn’s disease on preoperative immunosuppressive agents are at higher risk
for complications. Both corticosteroids and anti-TNFα agents may increase risk of infections
and septic shock. A preoperative drug free interval, when feasible, might be considered to
reduce the risk of infections. The adoption of any operative strategies that modify these
outcomes may additionally counter these risks.
Chapter 8 149
8
inTroducTion
Crohn’s disease (CD) is a chronic, inflammatory disease of the gastrointestinal tract, char-
acterized by alternating periods of relapse and remission. Traditionally, medical treatment
consisted of aminosalicyclates, antibiotics, immunosuppressive and modulating agents
such as corticosteroids, thiopurines (6-mercaptopurine, azathioprine) and methotrexate.1,2
Recently, anti-tumor necrosis alpha (TNF) drugs have been used to induce and maintain
remission in moderate to severe CD.3,4 Increasingly, there is a vogue for “top-down” ap-
proach to the treatment of patients with moderate and severe colitis, with early treatment
with anti-TNF drugs followed by other immunomodulator drugs, if needed, with reported
superior clinical outcomes.5 The use of these agents has been shown to facilitate remission,
improve quality of life, reduce steroid dependency and delay surgery.4,6 Controversy regard-
ing the potential adverse effects of these agents on outcomes of surgery, however, exists.7,8
Data suggest that these agents may be independently associated with septic complications
in the post-operative period, when used as monotherapy or in combination.9-11 Previous
data from our institution implicated infliximab use in the 3 months preceding surgery in
the increased rates of post-operative sepsis, abscess and readmission,9 other reports do
not show any association between adverse septic complications after surgery and the use
of infliximab and/or steroids.12-16 In fact, one study has suggested improved outcomes for
patients receiving immunomodulating agents.17 The aim of this systematic review is to
determine whether pre-operative immunosuppression and/or the use of immunodulator
agents are associated with adverse outcomes following surgery in Corhn’s disease patients.
MaTerials and MeThods
study selectionA systematic literature search with predefined search terms was carried out in MEDLINE,
EMBASE and The Cochrane Library for articles published until February 20th, 2013 (Figure 1).
inclusion criteriaTitles and abstracts of all identified records were screened and selected according to the
following inclusion criteria: study population - adult patients with CD; intervention - bowel
resection procedures for CD; study period - published in 1990 or later; research question -
comparison of the effect of any preoperative immunosuppressive agent on the postopera-
tive outcomes of surgery; study outcomes – the study reported at least one of the outcome
measures listed below; publication - published as a full article in a peer-reviewed journal.
If studies reported a mix of patients that included CD, the study was only included if CD
was the most common disease reported. Studies were excluded if written in a language
150 Chapter 8
other English (only 1 Korean study was excluded due to language), or were presented in
abstract form only.
study outcomesPrimary outcomes were total overall complications and total infectious complications. In-
fectious complications included wound infections, wound dehiscence, anastomotic leaks,
(intra-abdominal) abscess, sepsis, pneumonia, peritonitis, bacteremia, and other compli-
cations thought to have an infectious etiology. Secondary outcomes included individual
complications depending on available data.
data extractionTitles and abstracts of all retrieved records, and subsequently full-text articles, were exam-
ined independently by 2 authors (UAA and SM). The following data were also extracted
independently by these two authors: inclusion period, population characteristics, study
design, reported outcomes and results. The time period in which the medications were
administered prior to surgery (drug window) for patients in the treatment group was also
extracted. Discrepancies were resolved by discussion and agreement. Accuracy of search
results and data extraction was independently assessed by a third investigator (ADR).
risk of confounding biasConsidering the high risk of confounding in non-randomized studies, we adapted a simple
system for evaluating the risk of confounding in studies included in our meta-analysis.
• Lowriskofconfoundingbias: studies thatpresenteddatabasedonmatchedanalysis
(matched for important confounders).
• Mediumriskofconfoundingbias:studiesthatdidnotcorrectforpotentialconfound-
ers, but presented complete baselines, with equal characteristics for important potential
confounders.
• Highriskofconfoundingbias:studiesthatdidnotcorrectforpotentialconfounders,and
did not present baseline characteristics or presented unequal baseline characteristics.
statistical analysisStudy characteristics and reported outcomes were presented. Outcomes reported by 2 or
more studies were pooled in meta-analyses. Pooled results were presented for all studies
(total group) and stratified for risk of confounding (low, medium and high groups). In
addition, meta-analysis of only the low and medium groups was presented. A sensitivity
analysis excluding studies with mixed populations of patients (i.e. studies that addition-
ally included patients with diagnoses other than Crohn’s disease) was also performed to
determine the influence of these data on the overall results.
Chapter 8 151
8
Meta-analysis results were presented as risk ratios (RRs) with 95% confidence intervals (CI).
Empirical evidence suggests that there is no difference in consistency across trials between
RR and OR when variations in control group event rates are present.18 This fact combined
with the possibility of overestimating a benefit when OR are used, have made us choose
RR.19 Statistical heterogeneity was defined as presence of variability in the intervention ef-
fects between studies, and is considered reflective of clinical or methodological differences.
Heterogeneity was calculated using Higgins χ²-test and quantified by the I² measure.20
I² values of 25%, 50%, and 75% are considered to represent low, moderate, and high
heterogeneity, respectively.20 For this review, a χ²-test with a p-value of < 0.05 or I² > 50%
were considered to indicate significant heterogeneity. The fixed-effect model using the
Mantel–Haenszel method was used if no significant heterogeneity was present. In cases of
significant heterogeneity, the random-effects model using DerSimonian and Laird method
was used, and this is indicated in the results. Non-randomized studies with zero events in
one arm were included in the analysis by adding a continuity correction of 0.5 to the cells
in the 2 × 2 table of that study. Review Manager (version 5) provided by The Cochrane
Collaboration was used for data management and statistical analyses.
resulTs
description of studiesA total of 2787 potentially eligible reports were identified by our search. Through a two
stage selection process (Figure 1), a total of 21 eligible studies were identified.9,12-17,21-34
These studies included a total of 6899 patients. The inclusion period in these studies
ranged from 1981 to 2010. All studies included CD patients, although 5 studies addi-
tionally included patients with other diagnoses. All but one study were retrospectively
designed. Fourteen studies reported data on the influence of anti-TNF alpha drugs, 13 on
the influence of corticosteroids, and 8 on the influence of thiopurines on postoperative
outcome. Additionally, 6 studies reported the outcome after the use of a combination of
immunosuppressive agents. One study (Page 2002), reported outcomes for patients <60
years and patients ≥60 years seperately.16 Data of both age groups were included (Page
2002a for patients <60 and Page 2002b for patients ≥60 years). Table 1 describes the most
important datapoints of the included studies.
Table 1 also presents the main conclusions of the individual studies. Individually, most
studies failed to find any significant association between preoperative immunosuppressive
agents and postoperative complications. Only 2 (14%) out of 14, 3 (31%) out of 14 and
152 Chapter 8
1 (13%) out of 8 studies found an association between postoperative complications and
preoperative anti-TNF agents, corticosteroid and thiopurines, respectively.
anti-Tumor necrosis factor (Tnf) agentsFourteen studies reported on the effect of preoperative anti-TNF agents on postoperative
outcomes, with a total of 5634 patients. Table 2 shows characteristics and results of these
studies. Most studies used a period of 3 months preoperatively as cut-off for including
patients into the anti-TNF group. Only 3 studies were matched (low risk of confounding),
while 4 others were not matched but had equivalent baseline characteristics (medium risk
of confounding). Meta-analysis showed no difference in total postoperative complication
rates between anti-TNF and no-TNF groups (Relative risk (RR) 1.16, 95% CI 0.97 to 1.40).
When only low and medium risk of confounding studies were included a trend towards
higher postoperative complications in the anti-TNF group was observed, but it did not
reach statistical significance (RR 1.35, 95% CI 1.00 to 1.83). Sensitivity analysis excluding
studies with other disease than Crohn’s disease also showed no difference between groups
Papers excluded by detailed review n=74 - Abstract only n=15 - Reviews n=14 - Letters & comments n=11 - Relevant outcomes not reported n=7 - Not focused on immunosuppressives n=7 - Duplicates n=6 - Not about Crohn’s Disease n=4 - Postoperative immunosuppressives n=3 - Published before 1990 n=2 - Focus on recurrence of disease n=1 - Case report n=1 - Other languages (Korean) n=1 - Not a surgical cohort n=1 - Animal study n=1
General Search Syntax: (immunosuppression OR immunosuppressive OR azathioprine OR Imuran OR cyclosporine OR 6-MP OR 6-mercaptopurine OR Puri-Nethol OR infliximab OR Remicade OR Humira OR adalimumab OR (anti AND TNF AND alpha) OR corticosteroids) AND (crohn's disease OR inflammatory bowel disease OR IBD) AND (Preoperative or “pre-operative” or postoperative or “post-operative” or perioperative or “peri-operative” or surgical complications or surgical outcome or surgical outcomes or postoperative complications)
Total (n=2787)
n=1077
n=36
Papers screened after search (n=2504)
Potentially relevant studies (n=95)
Papers excluded n=283 - Filtering double papers n=283 Papers excluded n=2409 - Clearly not relevant based on title and abstract n=2409
Studies included in review (n=21, 20 retrospective and 1
prospective)
n=1674 Medline (via PubMed)
EMBASE
The Cochrane Library
Figure 1. Flow chart of the selection process
Chapter 8 153
8
Tab
le 1
. Ch
arac
teri
stic
s an
d r
epo
rted
au
tho
r’s
con
clu
sio
ns
of
incl
ud
ed s
tud
ies
Stu
dy
IDC
ou
ntr
yPe
rio
dN
Dia
gn
ose
sSu
rgic
alin
terv
enti
on
Typ
eD
esig
n &
Dat
a co
llect
ion
Stu
die
d d
rug
sD
oes
Dru
g in
crea
se
com
plic
atio
ns?
Ab
erra
200
321U
SA19
92-2
000
159
CD
(55%
), U
CRs
.C
ohor
tR,
RC
S, T
hio
CS:
Yes
. Thi
o: N
o.
Ap
pau
200
89U
SA19
98-2
007
404
CD
Rs.
Coh
ort
R, R
a-TN
FIF
X: Y
es.
Baf
ford
201
212U
SA19
99-2
010
196
CD
Rs.,
Stom
.C
ohor
tR,
Pa-
TNF,
CS,
Thi
o, M
ixN
o.
Bru
ewer
200
313G
erm
any
1982
-200
039
7C
DRs
.C
ohor
tR,
RC
SN
o.
Can
edo
201
014U
SA20
00-2
008
225
CD
Rs.
Coh
ort
R, P
a-TN
F, T
hio
No.
Co
lom
bel
200
420U
SA19
98-2
001
270
CD
Rs.,
Stric
.C
ohor
tR,
Ra-
TNF,
CS,
Thi
oN
o.
El-H
uss
un
a 20
1223
Den
mar
k20
00-2
007
417
CD
Rs.
Coh
ort
R, R
a-TN
F, C
S, T
hio
CS:
Yes
. a-T
NF
& T
hio:
No.
Ind
ar 2
00924
USA
1999
-200
711
2C
DRs
., St
ric.,
Stom
.C
ohor
tR,
Ra-
TNF,
CS,
Any
No.
Kas
par
ek 2
01225
Ger
man
y20
01-2
008
168
CD
Rs.
Mat
ched
R, P
a-TN
FN
o.
Ku
nit
ake
2008
15U
SA19
93-2
007
413
CD
(45%
), U
C, I
CRs
., St
ric.
Coh
ort
R, R
a-TN
FN
o.
Mar
chal
200
426Be
lgiu
m19
98-2
002
79C
DRs
.M
atch
edR,
Ra-
TNF
No.
Mas
care
nh
as 2
01227
USA
2003
-201
093
CD
Rs.
Coh
ort
R, R
Any
No.
Myr
elid
200
928Sw
eden
1989
-200
234
3C
DRs
., St
ric.
Coh
ort
R, P
CS,
Thi
oC
S: N
o. T
hio:
Yes
.
Nas
ir 2
01029
USA
2005
-200
937
0C
DRs
.C
ohor
tR,
Pa-
TNF,
CS,
Thi
o, M
ixN
o.
No
rgar
d 2
01230
Den
mar
k20
00-2
010
2293
CD
Rs.
Coh
ort
R, R
a-TN
FN
o.
Pag
e 20
02a16
USA
1989
-199
910
5C
D (6
7%),
UC
Rs.
Coh
ort
R, R
CS,
Thi
oN
o.
Pag
e 20
02b
16U
SA19
89-1
999
105
CD
(67%
), U
CRs
.C
ohor
tR,
RC
S, T
hio
No.
Post
199
131G
erm
any
1981
-198
942
9C
DRs
., St
ric.,
Stom
.C
ohor
tR,
PC
SC
S: Y
es.
Riz
zo 2
01132
Italy
2004
-201
011
4C
D (7
6), U
CRs
.C
ohor
tR,
Ra-
TNF,
CS,
Thi
oC
S: Y
es. a
-TN
F: N
o.
Sam
pie
tro
200
933Ita
lly19
93-2
007
393
CD
Rs.
Coh
ort
P, P
CS,
Thi
o, M
ixN
o.
Tay
2003
17U
SA19
98-2
002
100
CD
Rs.,
Stric
.C
ohor
tR,
Ra-
TNF,
CS,
Mix
CS:
No.
Any
: Les
s co
mpl
icat
ions
.
Wat
erm
an 2
01334
Can
ada
2000
-201
047
3C
D (6
0%),
UC
, IC
Rs.
Mat
ched
R, P
a-TN
FN
o.
a-TN
F: a
nti-t
umor
nec
rosi
s fa
ctor
. C
D:
Cro
hn’s
dise
ase.
CS:
cor
ticos
tero
ids.
P:
pros
pect
ive.
R:
retr
ospe
ctiv
e. R
s.:
bow
el R
esec
tions
. St
ric.:
Stric
turo
plas
ty.
Stom
.: St
oma
plac
e-m
ent/
clos
ure.
Thi
o: T
hiop
urin
es. U
C: U
lcer
ativ
e co
litis
.
154 Chapter 8
Tab
le 2
. Po
sto
per
ativ
e o
utc
om
e in
pat
ien
ts w
ith
an
d w
ith
ou
t p
reo
per
ativ
e an
ti-t
um
or
nec
rosi
s fa
cto
r ag
ents
Stu
dy
IDD
rug
win
do
w
Ris
k o
f co
nfo
un
din
g
bia
s in
MA
a
N C
ases
vs. C
on
tro
ls
Tota
l co
m-
plic
atio
ns
(%)
Tota
l in
fec-
tio
us
com
-p
licat
ion
s(%
)
An
asto
mo
tic
leak
(%)
Intr
a-ab
do
min
al
Ab
sces
s(%
)
Wo
un
din
fect
ion
(%)
Sep
tic
sho
ck(%
)R
eop
erat
ion
(%)
Mo
rtal
ity
(%)
Kas
par
ek 2
01225
<3m
oLo
w (M
)48
vs.
48
56 v
s. 4
235
vs.
38
4 vs
. 13
6 vs
. 10
19 v
s. 1
5-
23 v
s. 2
1-
Mar
chal
200
426A
nyLo
w (M
)40
vs.
39
48 v
s. 3
835
vs.
18
0 vs
. 55
vs. 3
--
--
Wat
erm
an
2013
34<
6mo
Low
(M)
195
vs. 2
78-
20 v
s. 1
33
vs. 5
4 vs
. 510
vs.
42
vs. 1
4 vs
. 81
vs 0
.03
Ap
pau
200
89<
3mo
Med
ium
60 v
s. 3
29-
42 v
s. 1
910
vs.
410
vs.
4-
20 v
s. 1
08
vs. 3
2 vs
. 0
El-H
uss
un
a 20
1223
<3m
oM
ediu
m32
vs.
385
-9
vs. 1
3-
--
--
-
Riz
zo 2
01132
<3m
oM
ediu
m54
vs.
60
26 v
s. 1
717
vs.
13
7 vs
. 5-
--
-
Tay
2003
17<
8wks
Med
ium
22 v
s. 7
8-
14 v
s. 1
0-
--
--
-
Baf
ford
201
212<
3mo
Hig
h (B
NE)
35 v
s. 1
61-
20 v
s. 2
4-
--
--
-
Can
edo
201
014<
3mo
Hig
h (B
NE)
65 v
s. 7
5-
25 v
s. 1
73
vs. 1
3 vs
. 314
vs.
11
-3
vs. 3
0 vs
. 0
Co
lom
bel
20
0422
<2m
oH
igh
(BN
R)52
vs.
218
23 v
s. 2
317
vs.
20
--
--
--
Ind
ar 2
00924
<1m
oH
igh
(BN
R)17
vs.
95
35 v
s. 2
8-
--
--
--
Ku
nit
ake
2008
15<
3mo
Hig
h (B
NE)
101
vs. 3
1217
vs.
16
6 vs
. 10
3 vs
. 3-
--
-2
vs. 3
Nas
ir 2
01029
<2m
oH
igh
(BN
E)11
9 vs
. 251
30 v
s. 2
83
vs. 2
b-
--
--
-
No
rgar
d 2
01230
<3m
oH
igh
(BN
E)21
4 vs
. 207
9-
-4
vs. 3
--
-8
vs. 9
0.5
vs. 3
Out
com
e da
ta p
rese
nted
as
perc
enta
ges
of c
ases
(%) v
s. p
erce
ntag
es o
f co
ntro
ls (%
). M
A: m
eta-
anal
ysis
.a L
ow(M
): lo
w ri
sk b
ecau
se o
f app
ropr
iate
mat
chin
g. M
ediu
m: n
ot m
atch
ed, b
ut b
asel
ine
equi
vale
nt b
etw
een
grou
ps. H
igh(
BNE)
: Hig
h ris
k, b
asel
ine
not e
qual
bet
wee
n gr
oups
. H
igh(
BNR)
: hig
h ris
k, b
asel
ine
not
repo
rted
.b R
epor
ted
infe
ctio
us c
ompl
icat
ions
lim
ited
to m
ajor
abd
omin
al c
ompl
icat
ions
(abs
cess
es, l
eaks
).
Chapter 8 155
8
(RR 1.15, 95% 0.93 to 1.41). Infectious complications were significantly higher in the anti-
TNF groups (RR 1.29, 95% CI 1.07 to 1.55) (Figure 2). When studies were categorized ac-
cording to risk of confounding, the difference was significant in both the low and medium
risk of confounding groups (RR for low and medium risk of confounding 1.52, 95% CI
1.22 to 1.89). Results were consistent with sensitivity analysis excluding studies with other
patients than CD (RR 1.31, 96% 1.06 to 1.64). The rates of wound infection (RR 1.62,
95% CI 1.12 to 2.34) and septic shock (RR 1.81, 95% CI 1.03 to 3.17) were higher in the
a-TNF group compared to control (reported by three and two studies, respectively). Results
were consistent in the subgroup of only low and medium risk of confounding. In sensitivity
Study or Subgroup1.2.1 Low risk of confoundingKasparek 2012Marchal 2004Waterman 2013Subtotal (95% CI)Total eventsHeterogeneity: Chi² = 3.18, df = 2 (P = 0.20); I² = 37%Test for overall effect: Z = 2.28 (P = 0.02)
1.2.2 Medium risk of confoundingAppau 2008El-Hussuna 2012Rizzo 2011Tay 2003Subtotal (95% CI)Total eventsHeterogeneity: Chi² = 5.11, df = 3 (P = 0.16); I² = 41%Test for overall effect: Z = 3.05 (P = 0.002)
1.2.3 High risk of confoundingBaford 2012Canedo 2010Colombel 2004Kunitake 2008Nasir 2010Subtotal (95% CI)Total eventsHeterogeneity: Chi² = 3.70, df = 4 (P = 0.45); I² = 0%Test for overall effect: Z = 0.33 (P = 0.74)
Total (95% CI)Total eventsHeterogeneity: Chi² = 19.12, df = 11 (P = 0.06); I² = 42%Test for overall effect: Z = 2.68 (P = 0.007)
Events
171439
70
25393
40
716
964
42
152
Total
4840
195283
60325422
168
356552
101119372
823
Events
187
35
60
6149
88
126
38134332
5
131
317
Total
4839
278365
3293856078
852
16175
218312251
1017
2234
Weight
11.8%4.6%
18.9%35.4%
12.3%4.9%5.0%2.3%
24.6%
8.9%7.9%
10.9%10.3%
2.1%40.1%
100.0%
M-H, Fixed, 95% CI
0.94 [0.56, 1.60]1.95 [0.88, 4.31]1.59 [1.05, 2.41]1.42 [1.05, 1.92]
2.25 [1.54, 3.27]0.74 [0.24, 2.23]1.25 [0.52, 3.01]1.33 [0.38, 4.59]1.66 [1.20, 2.29]
0.85 [0.41, 1.74]1.42 [0.74, 2.73]0.88 [0.46, 1.68]0.58 [0.25, 1.35]1.69 [0.46, 6.17]0.94 [0.67, 1.32]
1.29 [1.07, 1.55]
Anti-TNF agents Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.1 0.2 0.5 1 2 5 10Favours anti-TNF agents Favours control
Figure 2. Meta-analysis of postoperative infectious complication with and without preoperative anti-tumor necrosis factor (TNF) agents
156 Chapter 8
Tab
le 3
. Po
sto
per
ativ
e o
utc
om
e in
pat
ien
ts w
ith
an
d w
ith
ou
t p
reo
per
ativ
e st
ero
id u
se
Stu
dy
IDD
rug
w
ind
ow
Ris
k o
f co
nfo
un
din
g
bia
s in
MA
b
N C
ases
vs.
C
on
tro
ls
Tota
l co
m-
plic
atio
ns
(%)
Tota
l in
fec-
tio
us
com
-p
licat
ion
s(%
)
An
asto
mo
tic
leak
(%)
Intr
a-ab
do
min
al
Ab
sces
s(%
)
Wo
un
d
infe
ctio
n(%
)
Sep
tic
sho
ck(%
)R
eop
erat
ion
(%)
Mo
rtal
ity
(%)
Bru
ewer
20
0313
a<
1mo
Med
ium
219
vs. 1
77-
11 v
s. 8
3 vs
. 25
vs. 3
--
3 vs
. 32
vs. 2
El-H
uss
un
a 20
1223
<1w
kM
ediu
m66
vs.
351
-20
vs.
11
--
--
--
Riz
zo 2
01132
NR
Med
ium
48 v
s. 6
625
vs.
18
17 v
s. 1
4-
--
--
-
Tay
2003
17N
RM
ediu
m50
vs.
50
-12
vs.
10
--
--
--
Ab
erra
200
321N
RH
igh
(BN
E)56
vs.
51
-29
vs.
65
vs. 0
5 vs
. 05
vs. 0
5 vs
. 4-
-
Baf
ford
201
212<
6wks
Hig
h (B
NE)
72 v
s. 1
24-
29 v
s. 1
9-
--
--
-
Co
lom
bel
20
0422
aN
RH
igh
(BN
R)77
vs.
193
27 v
s. 2
223
vs.
18
--
--
-
Ind
ar 2
00924
<1m
oH
igh
(BN
R)47
vs.
65
28 v
s. 3
1-
--
--
--
Myr
elid
200
928<
2wk
Hig
h (B
NR)
87 v
s. 2
569
vs. 7
--
--
--
Nas
ir 2
01029
NR
Hig
h (B
NE)
151
vs. 2
1928
vs.
29
1 vs
. 3-
--
--
Pag
e 20
02a16
NR
Hig
h (B
NR)
62 v
s. 1
321
vs.
15
--
--
-
Pag
e 20
02b
16N
RH
igh
(BN
R)26
vs.
442
vs.
75
--
--
--
-
Post
199
131N
RH
igh
(BN
R)26
5 vs
. 89
12 v
s. 7
6 vs
. 0-
--
--
-
Sam
pie
tro
20
0933
NR
Hig
h (B
NR)
165
vs. 2
733
vs. 7
--
--
--
-
Out
com
e da
ta p
rese
nted
as
perc
enta
ges
of c
ases
(%) v
s. p
erce
ntag
es o
f co
ntro
ls (%
). N
R: n
ot r
epor
ted.
MA
: met
a-an
alys
is.
a Th
ese
two
stud
ies
also
rep
orte
d a
sub-
grou
p an
alys
is b
etw
een
high
dos
e of
ste
roid
s vs
. no
ster
oids
.b
Low
(M):
low
risk
bec
ause
of a
ppro
pria
te m
atch
ing.
Med
ium
: not
mat
ched
, but
bas
elin
e eq
uiva
lent
bet
wee
n gr
oups
. Hig
h(BN
E): H
igh
risk,
bas
elin
e no
t equ
al b
etw
een
grou
ps.
Hig
h(BN
R): h
igh
risk,
bas
elin
e no
t re
port
ed.
Chapter 8 157
8
analysis excluding studies with diseases other than CD, the risk of wound infection was no
longer statistically significant (RR 1.29, 95% CI 0.68 to 2.44), but septic shock (reported
only by 1 study) remained statistically significant (Table 2). Other individual complications
showed no differences.
corticosteroidsWe identified 13 studies that reported on the effect of preoperative corticosteroids on
postoperative outcomes, with a total of 3510 patients (Table 3). Unfortunately, most
studies only reported data on total and infectious complications, but not on individual
complications. Studies often did not report the cut-off point in terms of the dose and
preoperative time period over which steroids were used. None of the studies were
matched, but 4 studies had equivalent baseline characteristics. Two studies reported a
subgroup analysis comparing patients on high-dose of preoperative corticosteroids vs. no
steroids.13,22 Breuwer 2003 reported on a subgroup of 73 patients receiving 20 mg or more
/ day of corticosteroids.13 Colombel 2004 reported on a subgroup of 43 patients with 40
mg or more /day.22 Although data of these subgroups are not presented in the table, we
performed an additional meta-analysis (i.e. sensitivity analysis) in which we substituted
the overall data of these studies with the data from these subgroups only. This allowed
us to evaluate whether an increased dose of steroids would affect our results (testing
consistency of results).
Meta-analysis showed no difference in total postoperative complication rates for patients
on corticosteroid vs. those not on steroids (RR 1.03, 95% CI 0.83 to 1.27). This was
consistent in our subgroup analysis of only low and medium risk of confounding and
sensitivity analysis excluding studies with other diseases than CD. The difference became
more pronounced when only patients on high-dose corticosteroids were included for the
two studies above, but did not reach significance (RR 1.12, 95% CI 0.74 to 1.68, I²=67%,
Random-effects model (REM)). The risk of infectious complications was significantly higher
in the corticosteroid group (RR 1.55, RR 95% CI 1.23 to 1.95) (Figure 3). These results were
consistent in the subgroup analysis of only low and medium risk of confounding studies
(RR 1.45, 95% CI 1.01 to 2.08), and in the sensitivity analysis excluding studies with
diseases other than CD (RR 1.45, 95% CI 1.13 to 1.87). The difference was greater when
only patients on high-dose corticosteroids were included (RR 1.67, 95% CI 1.31 to 2.13).
Data were insufficient to show differences in individual complications.
ThiopurinesEight studies reporting on the impact of preoperative thiopurines on postoperative out-
comes were included, with a total of 1934 patients (Table 4). Most studies only reported
on total and infectious complications, without reporting on individual complications. The
158 Chapter 8
timeframe for preoperative thiopurine use in these studies varied from 2 weeks to 3 months.
None of the studies were matched. None of the pooled outcomes showed a significant
difference between the two groups. The pooled RR estimates for total complications and
infectious postoperative complications were 0.97 (95% CI 0.69 to 1.36) and 1.23 (95% CI
0.66 to 2.29, I²=81%, REM), respectively.
Mixed immunosuppressive agentsSix studies compared postoperative outcomes of patients who were on a combination of
immunosuppressive agents preoperatively to those not taking these medications. They
included a total of 1264 patients (Table 5). Three studies included patients on any immu-
nosuppressive agents, including steroids and anti-TNF agents. One study (Nasir 2010) did
not include patients who were on anti-TNF agents and corticosteroids (i.e. only included
patients on other immunosuppressants).23 Two studies (Sampietero 2009 and Tay 2003)
Study or Subgroup4.3.1 Medium risk of confoundingBruewer 2003El-Hussuna 2012Rizzo 2011Tay 2003Subtotal (95% CI)Total eventsHeterogeneity: Chi² = 0.75, df = 3 (P = 0.86); I² = 0%Test for overall effect: Z = 2.01 (P = 0.04)
4.3.3 High risk of confoundingAberra 2003Baford 2012Colombel 2004Myrelid 2009Nasir 2010Post 1991Subtotal (95% CI)Total eventsHeterogeneity: Chi² = 9.07, df = 5 (P = 0.11); I² = 45%Test for overall effect: Z = 3.10 (P = 0.002)
Total (95% CI)Total eventsHeterogeneity: Chi² = 9.66, df = 9 (P = 0.38); I² = 7%Test for overall effect: Z = 3.67 (P = 0.0002)
Events
2413
86
51
162118
82
16
81
132
Total
219664850
383
56727787
151265708
1091
Events
1439
95
67
3243418
70
86
153
Total
177351
6650
644
51124193256219
89932
1576
Weight
16.1%12.8%
7.9%5.2%
42.0%
3.3%18.3%20.2%
9.5%5.9%0.8%
58.0%
100.0%
M-H, Fixed, 95% CI
1.39 [0.74, 2.60]1.77 [1.00, 3.13]1.22 [0.51, 2.94]1.20 [0.39, 3.68]1.45 [1.01, 2.08]
4.86 [1.50, 15.70]1.51 [0.91, 2.51]1.33 [0.80, 2.20]1.31 [0.59, 2.90]0.41 [0.09, 1.97]
11.17 [0.68, 184.22]1.62 [1.19, 2.19]
1.55 [1.23, 1.95]
Steroids Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.05 0.2 1 5 20Favours steroids Favours control
Figure 3. Meta-analysis of postoperative infectious complication with and without preoperative cor-ticosteroid
Chapter 8 159
8
Tab
le 4
. Po
sto
per
ativ
e o
utc
om
e in
pat
ien
ts w
ith
an
d w
ith
ou
t p
reo
per
ativ
e th
iop
uri
nes
Stu
dy
IDD
rug
w
ind
ow
Ris
k o
f co
nfo
un
din
g
bia
s in
MA
a
N C
ases
vs.
C
on
tro
ls
Tota
l co
m-
plic
atio
ns
(%)
Tota
l in
fec-
tio
us
com
-p
licat
ion
s(%
)
An
asto
mo
tic
leak
(%)
Intr
a-ab
do
min
al
Ab
sces
s(%
)
Wo
un
d
infe
ctio
n(%
)
Sep
tic
sho
ck(%
)R
eop
erat
ion
(%)
Mo
rtal
ity
(%)
El-H
uss
un
a 20
1223
<1m
oM
ediu
m16
6 vs
. 251
-10
vs.
14
--
--
--
Riz
zo 2
01132
NR
Med
ium
34 v
s. 8
015
vs.
24
9 vs
. 18
--
--
--
Ab
erra
200
321<
2wk
Hig
h (B
NE)
18 v
s. 5
1-
72 v
s. 6
6 vs
. 00
vs. 0
17 v
s. 0
6 vs
. 4-
-
Baf
ford
201
212<
3mo
Hig
h (B
NE)
69 v
s. 1
27-
13 v
s. 2
8-
--
--
-
Can
edo
201
014<
1mo
Hig
h (B
NE)
85 v
s. 7
5-
33 v
s. 1
75
vs. 1
7 vs
. 37
vs. 1
1-
8 vs
. 30
vs. 0
Co
lom
bel
20
0422
<1m
oH
igh
(BN
R)10
5 vs
. 165
25 v
. 22
19 v
s. 1
9-
--
--
-
Myr
elid
200
928<
6wk
Hig
h (B
NR)
51 v
s. 2
9210
vs.
6-
--
--
-
Pag
e 20
02a16
NR
Hig
h (B
NR)
20 v
s. 5
515
vs.
22
--
--
--
-
Pag
e 20
02b
16N
RH
igh
(BN
R)13
vs.
17
54 v
s. 4
1-
--
--
--
Out
com
e da
ta p
rese
nted
as
perc
enta
ges
of c
ases
(%) v
s. p
erce
ntag
es o
f co
ntro
ls (%
). N
R: n
ot r
epor
ted.
MA
: met
a-an
alys
is.
a M
ediu
m: n
ot m
atch
ed, b
ut b
asel
ine
equi
vale
nt b
etw
een
grou
ps. H
igh(
BNE)
: Hig
h ris
k, b
asel
ine
not
equa
l bet
wee
n gr
oups
. Hig
h(BN
R): h
igh
risk,
bas
elin
e no
t re
port
ed.
160 Chapter 8
Tab
le 5
. Po
sto
per
ativ
e o
utc
om
e in
pat
ien
ts w
ith
an
d w
ith
ou
t p
reo
per
ativ
e im
mu
no
sup
pre
ssiv
e d
rug
s in
co
mb
inat
ion
Stu
dy
IDD
rug
w
ind
ow
Ris
k o
f co
nfo
un
din
g
bia
s in
MA
a
N C
ases
vs.
C
on
tro
ls
Tota
l co
mp
licat
ion
s(%
)
Tota
l in
fect
iou
s co
mp
licat
ion
s(%
)
An
asto
mo
tic
leak
(%)
Intr
a-ab
do
min
al
Ab
sces
s(%
)
Wo
un
d
infe
ctio
n(%
)M
ort
alit
y(%
)
Baf
ford
201
212<
3mo
Hig
h (B
NE)
127
vs. 6
9-
24 v
s. 2
0-
--
-
Ind
ar 2
00924
<1m
oH
igh
(BN
R)69
vs.
43
32 v
s. 2
619
vs.
73
vs. 2
1 vs
03
vs 0
0 vs
. 0
Mas
care
nh
as 2
01227
<3m
oM
ediu
m19
vs.
74
21 v
s. 8
--
--
0 vs
. 0
Nas
ir 2
01029
bN
RH
igh
(BN
E)11
5 vs
. 255
25 v
s. 3
02
vs. 3
--
--
Sam
pie
tro
200
933 c
NR
Hig
h (B
NR)
60 v
s. 3
338
vs. 1
7-
--
--
Tay
2003
17 c
<2m
oM
ediu
m72
vs.
28
-6
vs 2
51
vs 1
13
vs 1
4-
-
Out
com
e da
ta p
rese
nted
as
perc
enta
ges
of c
ases
(%) v
s. p
erce
ntag
es o
f co
ntro
ls (%
). N
R: n
ot r
epor
ted.
MA
: met
a-an
alys
is.
a Med
ium
: not
mat
ched
, but
bas
elin
e eq
uiva
lent
bet
wee
n gr
oups
. Hig
h(BN
E): H
igh
risk,
bas
elin
e no
t eq
ual b
etw
een
grou
ps. H
igh(
BNR)
: hig
h ris
k, b
asel
ine
not
repo
rted
.b In
clud
ed a
ll im
mun
osup
pres
sive
age
nts
othe
r th
an a
nti-t
umur
nec
rosi
s fa
ctor
(TN
F) a
gent
s an
d st
eroi
dc In
clud
ed d
rugs
cla
ssifi
ed a
s im
mun
olog
ical
and
bio
logi
cal d
rugs
(exc
lude
d st
eroi
ds)
Chapter 8 161
8
only included drugs that they classified as immunologic and/or biologic drugs (effectively
excluding corticosteroids).17,33 None of the studies was matched, and only few reported
data on individual complications. None of the pooled outcomes showed a significant dif-
ference. The pooled RR estimates for total and infectious postoperative complications were
0.89 (95% CI 0.67 to 1.18) and 1.01 (95% CI 0.67 to 1.54), respectively.
discussion
This study provides a comprehensive review of the impact of immunosuppressive agents on
postoperative outcomes in CD, and identified several important findings. Firstly, patients
on preoperative anti-TNF agents or corticosteroids were at higher risk for developing post-
operative infectious complications. The use of anti-TNF agents was also significantly associ-
ated with individual infectious complications (i.e. wound infection and septic shock). For
corticosteroids, the available data also suggest a dose-related response to its deleterious
effect on postoperative complications. This review also provides a comprehensive review
on the state of current evidence on this topic, and identified several shortcomings of the
current studies relating to the study question.
Anti-TNF medication has become one of the most important and widely used medica-
tions in the treatment of CD.3,35 Its use in the preoperative period, however, has triggered
concerns among surgeons and gastroenterologists alike about a potential increased risk of
associated postoperative (infectious) complications.36 In earlier reviews that did not include
a meta-analysis, the conclusions tended to suggest the lack of any such association.36,37
One reason for this could be that the small sample size and methodological limitations of
these studies precluded their ability to detect potential differences in outcomes. As shown
in this review, only 2 (14%) out of 14 studies found an association between postoperative
complications and preoperative anti-TNF agents (Table 1). However, when meta-analysis
was performed, a clear increase in overall infectious complications as well as in several in-
dividual infectious complications was observed. As a significant proportion of patients with
CD undergo at least one surgical procedure in the course of the disease,38,39 these findings
are likely to be of great importance in clinical practice. Thus, when patients on anti-TNF
agents require surgery, a preoperative drug free interval, when feasible, is advisable and
might reduce the risk of septic complications. The adoption of specific operative strategies
that may reduce these risks or their effects, such as the use of a temporary ostomy, may
additionally be considered. The findings also support patient education and counseling of
potential adverse outcomes of these agents when patients undergo surgery.
162 Chapter 8
A recent review has similarly reported a significant increase in infectious complications
after anti-TNF treatment in CD patients.10 However, that review had several limitations and
based its results on only 6 out of the 12 studies that were included in our meta-analysis.
Four of these studies were published after their search, while two that were published
prior to the search were omitted. Most importantly, the review did not stratify studies
based on the risk of confounding. Given the heterogeneity and the high risk of confound-
ing in several studies, the findings of that review were inconclusive. The inclusion of a
greater number of studies and the consideration of the confounding risk allowed us to
identify potentially important differences in individual infectious complications, such as
wound infection. The association between immunosuppressive agents and delayed wound
healing and infection has been the topic of several in vitro and in-vivo studies, which
have suggested a strong pathophysiological basis for this phenomenon.8 In addition, septic
shock was found to be significantly associated with anti-TNF treatment in meta-analysis.
Although only two studies reported on this outcome, the severity of this complication war-
rants serious consideration of these results, and future research should focus on providing
more data on this outcome.
We also found an increased risk of postoperative infectious complications for CD patients
on corticosteroid. These deleterious effects of steroids on postoperative infectious compli-
cations are not specific to CD since previous studies have described such an association
in both general medical patients and patients with inflammatory bowel disease in gen-
eral.11,40 A further interesting finding of our study was that subgroup analyses suggested
a dose-effect relationship between preoperative corticosteroids and rates of infectious
complications. This suggests that lowering the dose of corticosteroids in anticipation of
surgery might decrease risk of complications in patients, when discontinuing the drug
is not possible. Finally, our findings suggest that based on current evidence, there is no
association between the use of thiopurines or other immunomodulatory drugs in combina-
tion on postoperative complications. This is in line with other reviews in the literature,7,37
although this review does include the largest number of studies and patients, and is cur-
rently the only review to combine current data on these medications into a meta-analysis.
Our review also highlights current limitations of the published data on this topic. Firstly,
most studies are underpowered, which does not allow the identification of potential im-
portant clinical differences. Similarly, most studies were non-randomized and unmatched,
thus leading to significant differences between baseline characteristics of the study groups.
Although some studies used regression to correct for baseline discrepancies, the inclusion
of many covariates in regression models could further decrease the power of these studies.
This might explain the failure of many of the studies to identify the differences that were
observed in this meta-analysis. Also, poor reporting of comparative data has proven to be a
Chapter 8 163
8
limitation to meta-analyses of secondary outcomes of interest; several important individual
complications, such as anastomotic leaks and pelvic and intra-abdominal abscesses that
might influence the decision for surgery. It may have also been interesting to study the
relation between the time of last drug administration and post-operative complications.
Most studies, however, did not aim to study this effect, and unfortunately the data were
therefore not suitable for this analysis.
Despite the continuing controversy on this clinically relevant topic, the quality of evidence
has essentially remained suboptimal over the last 20 years. It is likely that randomized studies
or large prospective cohort studies will remain a significant challenge due to the complexity
of the question at hand. The accumulation of data on all important confounding factors
and the use of a matched study design may allow for more appropriate interpretation of
results and allow meta-analyses. Performing meta-analysis with aggregate published data
is subject to certain limitations. For example, patients may have more than 1 complication,
and it is often difficult to determine the exact number of patients that had complica-
tions when different subgroups (e.g. mild and severe complications) are combined into
a single (total complications) group. In this regard, performing an individual patient data
meta-analysis confers certain advantages facilitating more accurate and powerful analyses,
adjustment for confounders and the opportunity for subgroup analyses. Performing an
individual patient data meta-analysis, however, is often limited by the resources, time and
cooperation required.41
The results of this review, which currently provides the best evidence on the topic, suggests
that patients with Crohn’s disease on immunosuppressive therapy in the peri-operative
period may have adverse postoperative outcomes.. We acknowledge that this review does
have some limitations. Firstly, five studies (24%) included patients with diagnoses other
than CD, e.g. ulcerative colitis and indeterminate colitis. We sought to overcome this by
including such studies if CD was the largest group of patients (in most cases >60% of
patients). In addition, the results of our sensitivity analysis excluding these five studies was
consistent with our main meta-analysis, adding to the robustness of our findings. Secondly,
there were differences between studies in regard to the definition of their endpoints.
Therefore, we focused on two major outcomes (i.e. total complications, and infectious
complications), and did not include other classifications that may have been introduced by
individual studies (e.g. major vs. minor, early vs. late). Under infectious complications we
included the outcomes reported by each study that were consistent with our definition.
Also, the retrospective nature of studies and the varying methods of analyses used alters
the robustness of the conclusions that can be derived. In this regard, the reliability of the
findings in this review are strengthened by the fact that we stratified results of studies
based on the risk of confounding, and showed consistent results in the low and medium
164 Chapter 8
risk of bias subgroup. In the subgroup of studies that had a high risk of confounding no
significant difference was observed for most comparisons. It seems, therefore, that studies
that correct well for potential confounding are more likely to find an association between
anti-TNF agents and postoperative complications. A similar pattern was recognized in an
earlier review of studies of anti-TNF agents and postoperative complications in patients
with ulcerative colitis.36 Authors of that review noticed that studies that specifically ad-
justed for disease severity were more likely to find a positive association between anti-TNF
drugs and postoperative complications.
In conclusion, this review suggests that CD patients on preoperative immunosuppressive
agents are at higher risk for complications. Both corticosteroids and anti-TNF agents may
increase risk of infections and septic shock. A preoperative drug free interval, when fea-
sible, is advisable and might reduce the risk of infections.
Chapter 8 165
8
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Aboul Nasr El Yafi FA, Belaiche J. Behaviour
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classification: Changing pattern over the
course of the disease. Gut. 2001; 49:
777-82.
39. Mekhjian HS, Switz DM, Watts HD,
Deren JJ, Katon RM, Beman FM. National
cooperative crohn’s disease study: Factors
determining recurrence of crohn’s disease
after surgery. Gastroenterology. 1979; 77:
907-13.
40. Stuck AE, Minder CE, Frey FJ. Risk of
infectious complications in patients taking
glucocorticosteroids. Rev Infect.Dis. 1989;
11: 954-63.
41. Lyman GH, Kuderer NM. The strengths
and limitations of meta-analyses based on
aggregate data. BMC Med Res Methodol.
2005; 5: 14.
S. de Zeeuw
U. Ahmed Ali
M.B.M. van der Kolk
C.J.H.M. van Laarhoven
Department of Surgery, Radboud University Medical Centre, Nijmegen
9 ileo-pouch anal anastomosis
with close-rectal dissection
usinG automated vessel
sealers for ulcerative colitis:
a promisinG alternative
Digestive Surgery, 2011.
170 Chapter 9
absTracT
backgroundDespite decennia of experience, the ileo pouch anal anastomosis for ulcerative colitis is
still associated with high complication rates. The development of automatic vessel sealers
has resulted in the revive of a promising surgical alternative to the conventional procedure:
the close rectal dissection. By preserving the mesorectal layer it is hypothesized that nerve-
related and other postoperative complications can be reduced.
MethodsAll patients with ulcerative colitis with indication for restorative proctocolectomy at our
institution during the pilot study underwent the close-rectal pouch procedure with tempo-
rary diverting ileostomy. Standardized clinical history, anorectal physiology measurements,
endoscopic and histological examination were carried out before and after surgery.
resultsThe procedure was technically successful in all 10 patients, with a median age of 41 years
and a median postoperative follow-up period of 16 months. There were no cases of pelvic
sepsis and bladder- or sexual dysfunction. The median daytime defecation frequency was
6.0. Endoscopic and histological examination showed no abnormalities. Anorectal physiol-
ogy supported the good functional results.
conclusionThe preliminary results of the close-rectal pouch procedure are promising, with good
functional results and a low complication rate after one year.
Chapter 9 171
9
inTroducTion
Surgery is an essential modality in the treatment of ulcerative colitis (UC). In UC the most
common surgical indication is severe refractory colitis. The side effects associated with
chronic medical therapy, in particular corticosteroids, are another reason for patients and
doctors to seek a more definitive solution. Eventually, up to 30% of all UC patients will
undergo surgery after 10 years of disease onset.1,2
The ability to restore the oral-anal continuity has been an important mile stone in the
surgical management of UC.3 Two surgical restorative options gained wide acceptance.
The ileorectal anastomosis (IRA) proved useful in certain patient subgroups, mainly in UC
patients with mild proctitis. The downside is the residual rectal mucosa, and the associated
risk of malignant degeneration. The second option, the restorative proctocolectomy by
means of an ileo pouch anal anastomosis (IPAA) progressed to be the gold standard for
restorative surgery for the majority of UC patients.3
Despite decennia of experience, the IPAA is still associated with high complication rates.
The adoption of the double-stapled approach for the anastomosis by most surgeons
have arguable resulted in an improvement in functional results.4 Studies regarding the
routine use of a defunctioning ileostomy did not show any reliable differences in terms
of complication rate5, especially pelvic sepsis. The use of an ileostomy therefore remains a
matter of surgeon’s preference and experience.6 Currently, major complications still pose
an important challenge for restorative surgery. Pelvic sepsis occurs in up to 12% of all
cases7-10, sexual dysfunction in 4%11, and the rate of pouch failure varies up to 8%.10,11
The close rectal or perimuscular dissection (CRD)12 has been first described in 1972. Despite
promising preliminary results, the technique was found to be laborious and few surgeons
adopted it. With the development of the electrothermal bipolar vessel sealer (EBVS) and
ultrasound dissection13 the technique has been substantially simplified. Several series have
since shown that this technique is safe and promising.14-18 The main distinction of the CRD
technique is in the way the dissection of the rectum is performed. In this technique the
rectum is dissected through the nonanatomic perimuscular plane in an effort to avoid dam-
age to the pelvic autonomic nerves, which lie immediately outside the mesorectal plane.
This is hypothesized to reduce nerve-related postoperative complications like sexual dys-
function. In addition, with the preservation of the mesorectal fat it is hypothesized that
there will be less room in the pelvis for postoperative hematoma or fluid collections. This
can reduce the risk of subsequent infection and abscess formation in the deep pelvis.
Finally, in case of a potential leakage of the anastomosis, the mesorectal fat can help
172 Chapter 9
contain such leakage, protecting the remainder of the pelvis and potentially avoiding pelvic
sepsis. The goal of this pilot study is to evaluate whether the CR-IPAA is a safe procedure
that could potentially reduce the complication rate, especially in terms of pelvic sepsis and
autonomic nerve damage.
MaTerials and MeThods
ethics and patient selectionThe medical ethics committee of the Radboud University Nijmegen Medical Centre ap-
proved this study. Ten patients, all with UC, with an indication for surgical treatment by
means of an IPAA procedure during this pilot study, were suitable candidates for the study.
Written informed consent was obtained before inclusion of any patient.
surgical techniquePatients were admitted to the hospital one day before surgery to undergo preoperative
assessment and preparations. Antibiotic prophylaxis were administrated to all patients im-
mediately before surgery. The patient was placed in the lithotomy position. The procedure
was performed through a pfannenstiel or a low midline incision. (Laparoscopic) subtotal
colectomy with end ileostomy was in most cases performed as a staged procedure prior
to proctectomy and IPAA. This was the case for both elective and acute (e.g. toxic mega
colon) procedures. During the pouch formation, the rectum was dissected according to
the CRD technique.12 The dissection was conducted circulair to the mesorectum, in the
nonanatomic perimuscular plane, thereby preserving the mesorectum fat layer just outside
the rectum. The dissection was aided by electrothermal bipolar vessel sealer (Ligasure®,
Covidien, USA). Subsequently, a J-pouch was constructed from the distal ileum in a con-
ventional manner. The anastomosis was performed as a stapled pouch-anal anastomosis.
Because the mesorectal thickness is minimized to almost zero at the level of the pelvic floor,
the pouch-anal anastomosis is at the same level and identical to the anastomosis of the
conventional IPAA procedure. A diverting ileostomy was performed routinely in all patients.
Oro-anal continuity was restored approximately three months after clinical and radiological
assessment of a healed pouch and pouch-anal anastomosis.
follow-upPatients were seen in the outpatient clinic at 3 weeks and 3, 6 and 12 months after surgery.
At every visit a standardized history was taken, with emphasis on defecation frequency and
level of continence. Any complications were recorded. Pelvic sepsis was defined as a pelvic
abscess, anastomotic leakage or dehiscence or a pelvic or perineal wound infection.
Chapter 9 173
9
functional resultsDefecation frequency and questions about incontinence were scored. Physical examination
was performed, including inspection of the anus and digital rectal examination. There were
four question addressing sexual and bladder dysfunction (Table 1).
Table 1. Questions regarding sexual and bladder dysfunction
Bladder dysfunction Do you experience any problems with urination?
Sexual dysfunction for women Do you experience pain during sexual intercourse?
Sexual dysfunction for menDo you experience a problem with getting an erection?
Do you suffer from retrograde ejaculation?
anorectal physiologyEvaluation of anorectal function was performed preoperatively, and one year postopera-
tive. Anal sphincter pressure was measured by circular 4-channel low compliance water
fusion manometry (Mui scientific, Mississauga, ON, Canada). Volume capacity was mea-
sured by means of balloon distention. All measurements were performed in the left supine
position.19-21
endoscopy and pathologyEndoscopy was performed at three months and one year to evaluate the pouch mucosa,
inflammatory activity and to take multiple biopsies. The proctocolectomy specimens were
processed for histopathology to examine the dissection planes and confirm the diagnosis
colitis ulcerosa. Biopsies of the mucosa, taken at endoscopy, were processed for detailed
routine histopathological evaluation.
Mesorectal evaluationTo support the close-rectal dissection principle, we performed MRI scans pre- and post-
operatively. To our knowledge, there is no objective measurement for the volume of the
mesorectum. Mesorectum is mobile and adapts its shape to every change in rectum or
pouch volume. Therefore, we determined the presence of the mesorectum at three levels
on the MRI scans.
statistical analysisDescriptive statistics were used to summarize patient demographics, clinical data, surgical
details, morbidity and fecal incontinence. Continuous data were tested using the paired-
t-test and otherwise the Wilcoxon signed-rank test was used. Statistical significance was
considered when p<0.05. SPSS® version 16.0 (SPSS, Chicago, Illinois, USA) was used for
all statistical analysis.
174 Chapter 9
resulTs
All patients referred to our institution for an IPAA procedure during the study period con-
sented to participate in this study and were thus included. In total 10 consecutive patients
underwent an IPAA procedure with CRD dissection. The group consisted of six men and four
women, all diagnosed with UC. Six of ten suffered severe colitis (Mayo score of 3 points22),
the other patients suffered medical refractory mild to moderate colitis. Half of the patients
were operated on in an acute stage (e.g. toxic colitis). None of the subtotal colectomy
specimens showed evidence of dysplasia. The median age at surgery was 41 years (range
21 to 53). Surgical data and pre-operative medication specifications are listed in Table 2.
Table 2. Surgical data of the patient population (N=10)
Characteristic N (%)
Immunmodulating medication before colectomy 5 (50%)
Immunomodulating medication before pouch construction 0 (0%)
Referred after first-stage surgery in other hospital 5 (50%)
Stages:- Two-stage procedure- Three-stage procedure
9 (90%)1 (10%)
surgical parametersThe procedure was technically successful in all patients. The median surgical time was
247 minutes (range 133 to 332). The median blood loss was 425 ml (range 200 to 900).
Hospital stay was median 9 days (range 6 to 16 days). The median interval to closure of the
ileostomy was 4.5 months.
follow-upAll patients completed the direct postoperative follow-up. The median follow-up period
was 16 months (range 7 to 37).
Postoperative complicationsOne patient who developed a 5 cm presacral abscess one month postoperatively, which
was drained radiologically. This patient suffered minimal systemic symptoms and recovery
was uneventful. Five patients had minor complications. Two patients had a gastroparesis,
for which conservative treatment was sufficient. Three infectious complications occurred
in three patients: two urinary tract infections and one pulmonary infection, all could be
treated with antibiotics. None of the patients suffered bladder- or sexual dysfunction
preoperatively and postoperatively there were no cases of bladder dysfunction or sexual
dysfunction.
Chapter 9 175
9
functional resultsThe recorded daily defecation frequency was a median of 6.0 in all patients (range 3 to
8.5). The median nocturnal frequency after one year was 1.5 (range 0.5 to 3.5). Three
patients recorded occasionally nocturnal soiling. Passive and urge incontinence was not
reported.
anorectal physiologyAnorectal manometry was performed in all patients to objectively assess the anorectal
function. For the seven patient with at least one year follow-up the preoperative and
one year follow-up manometry results were compared. The maximal tolerated volume
increased from 68 ml (preoperative rectum measurements) to a median of 193 ml after
one year (postoperative pouch measurement) (p=0,03). First sense and first urge volumes
also increased significantly after one year (p=0.01 and p=0.02). All the results are shown
in Table 3.
Table 3. Pre- and postoperative anal sphincter manometry and reservoir function
Referencevalues
Medianpreoperative
values (range)
Medianpostoperative value
at 1 year (range) p-value
Anal sphincter
Maximal resting pressure (mm Hg) 43–89 60 (30–70) 60 (23–90) 0.63
Maximal squeeze pressure (mm Hg) 58–122 123 (38–225) 129 (38–360) 0.89
Reservoir function
First sense volume (ml) 35 30 (9–40) (rectum) 50 (15–200) (pouch) 0.01
First urge volume (ml) 80–120 43 (24–60) (rectum) 73 (60–200) (pouch) 0.02
Maximal tolerated volume (ml) 200 68 (27–80) (rectum) 193 (82–203) (pouch) 0.03
endoscopy and pathologyEndoscopy results after 1 year revealed signs of inflammation in the two patients. One
patient had symptoms of pouchitis at the moment of endoscopy. Microscopic examination
of the proctocolectomy specimens confirmed the diagnosis of UC in all patients. Histo-
pathology confirmed the diagnosis pouchitis on the basis of the biopsies taken in two
patients. No dysplasia or carcinoma was present in any specimen or at follow-up.
Mesorectal evaluationAll postoperative MRI scans showed the presence of vital mesorectum tissue in situ. This
supports the principle of close-rectal dissection. Figure 1 presents the MRI scans of a pa-
tient, showing the mesorectum at three levels in the pelvis, preoperatively and 6 months
after surgery. This indicates the presence of viable mesorectum postoperative comparable
to preoperative without any objective differences in volume.
176 Chapter 9
discussion
The surgical principles of the IPAA technique, originate from the total mesorectal excision
(TME). The TME technique is based on oncological principles for rectal carcinomas. The
TME removes the entire rectum including the mesorectum.23 In patients with oncological
diseased rectums the mesorectum has to be removed because of possible lymphatic in-
volvement. This is where the discrepancy comes in: the proctectomy for UC is no oncologic
surgery. There is no reason to go along with the TME principle. The CRD is a well known
“old” technique, but used to be too laborious to gain support.12 It leaves the mesorectum
in situ. With the advent of the automated vessel sealers, the CRD has gained renewed
interest.
This pilot study aimed to assess to the feasibility and evaluate the potential of the CR-IPAA
with automated vessel sealers to offer an alternative for the conventional IPAA. Several
important findings have been made. First, the new CR-IPAA technique is a safe proce-
dure, which could easily be learned and performed with the aid of the new technical
Figure 1. Comparison of the mesorectum preoperatively surrounding the rectum versus postopera-tively surrounding the ileo-anal pouchArrows indicate the mesorectum. Very low in the pelvis, just above the anal sphincter, there is physically no mesorectum in situ. At middle-high and high levels in the pelvis the mesorectum is shown. There are no objec-tive differences in mesorectum volume.
Chapter 9 177
9
developments like the electrothermal bipolar vessel sealer or ultrasound dissection. This
straight forward technique is reflected in a short operative time and with low blood loss,
comparable to the open IPAA procedure.24
In addition, the theoretical advantage of more space after mesorectal excision for the
pouch doesn’t seem to last: the defecation frequency after CR-IPAA remains the same
compared to the IPAA after TME principles. The mesorectum seems to function as a kind
of “communicating vessel” together with the pouch in the pelvis. The MRI scans confirm
this theory.
This pilot study showed a promising tendency regarding pelvic-related postoperative
complications. Only one of the patients developed a retropouch-localised abscess, without
systemic sign of infection and therefore no pelvic sepsis This is in line with the hypothesis
that the remnant mesorectum can protect against pelvic sepsis if there is an anastomotic
leakage: symptoms will be minimized. Pre-operative high dose steroid use has a negative
influences on the morbidity.25 Therefore we performed so many three-stage procedures.
The immunomodulating medication could be reduced after the first stage.
In addition, there were no signs of autonomic nerve damage in the ten patients: no sexual
dysfunction and bladder dysfunction was reported. This also contributes to the hypothesis
that the close-rectal dissection protects against nerve damage.
The functional outcome at one year follow-up after the CR-IPAA was comparable to
that of the conventional IPAA observed in literature. In an extensive review about the
long-term outcome of the conventional IPAA, Hueting et al.11 observed that an average
daytime frequency of 5.2 and nocturnal frequency of 1.0 was achieved. Tekkis et al.10
reported a daytime frequency of 5 and nocturnal frequency of 1.0. Whether in the long
term the retained mesorectum will hamper the reservoir function of the pouch needs to
be researched.
First sense, first urge and maximum tolerated volume of the pouch are closely related to
functional outcome.26 Therefore, the significantly increased volumes of these parameters
in our population support a good functional outcome. Our results of maximal anal rest-
ing pressure are comparable to a study of Selvaggi et al, while the maximum tolerated
volume of Selvaggi seems to be higher.27 But the functional results in terms of defecation
frequency are comparable. Anorectal manometry measurements should only be used as
a contribution to the overall results. Defecation frequency and continence are the most
important parameters in terms of functional results.
178 Chapter 9
A limitation of this pilot study is the small sample size. A larger study with long-term
follow-up will be needed to reliably assess the hypothesized benefits of the CR-IPAA. There
are twelve studies reporting to have used the close-rectal dissection technique.14-18,28-34
One study34 has a population with both close-rectal and total mesorectal excision, so
the results of this study cannot be analyzed. But the five largest studies, with over 100
patients, show contradictory results: Rink et al.18 and Berry et al.14 show a very low leakage
rate and no autonomic nerve damage respectively, due to the close-rectal dissection. But
Jarvinen et al.15, Araki et al.28 and Régimbeau et al.33 present a normal leakage rate and
sexual dysfunction percentage, comparable to the conventional technique. The reason for
these varying results can be different use of technique: partial versus complete and circular
close-rectal dissection. None of the studies specify the technique. Another reason for the
difference in results is the use of conventional versus new diathermic instruments.
However, with the recent developed automated vessel sealers, the traditional laborious
close-rectal IPAA technique has been greatly simplified. The circular close rectal dissection
with automated vessel sealers is technically easy, comes along with minimal blood loss and
a vital, dry mesorectal bedding, which shows in these 10 patient to function as a shield in
case of pelvic sepsis and protects the autonomic nerves.
conclusion
Given the ease of the CRD technique, the absence of oncological arguments and potential
advantages on complications, the question should be raised whether the CR-IPAA should
replace the TME technique in case of an IPAA for UC patients. Results so far of the CR-IPAA
need further investigation to substantiate potential benefits of this technique in a large
well conducted trial.
Chapter 9 179
9
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Part III
summary and ConClusIons
10 summary
Chapter 10 187
10
suMMary
The first part of this thesis focusses on evaluating the current state of important outcomes
in inflammatory bowel disease (IBD) surgery. First, we evaluated the contemporary out-
comes of the ileal pouch-anal anastomosis (IPAA) procure in terms of complications and
functional outcome (Chapter 2). This treatment of choice in patient with ulcerative colitis
(UC) has been performed for over 30 years, a period encompassing various improvements
in surgical equipment and perioperative care, as well as fine-tuning of surgical technique.
We performed an extensive review of literature and identified 53 observational studies
from the year 2000 onwards. Results were compared to a previously performed systematic
review with similar methodology describing the results of 43 studies published before
2000. This allowed for comparison of pooled estimates of a large and representative
sample from both eras with a total of 24,283 included patients.
We found a pooled rate of pouch failure of 4.3% (95% CI 3.5 to 6.3) for studies published
after 2000, which was 2.5% less than the rate before 2000 (p=0.004). An additional
time-effect analysis confirmed a decline in pouch failure over time. The rate of pelvic
sepsis was 7.5% (95% CI 6.1 – 9.1) and 9.5 (8.2–10.9) in the periods after and before
2000, respectively, but the difference was not statistically significant. Functional outcome
remained stable over time, with a 24-hour defecation frequency of 5.9 (95% CI 5.0 to
6.9). Variations in the technical aspects of the operations, such as routine use of ileostomy,
did not have an important effect on outcome. Thus, after decennia of experience with the
IPAA, the rate of certain severe complications such as pouch failure and pelvic sepsis seem
to have declined, but functional outcomes did not improve. The estimates provided by this
review can be useful as reference values for practice and research.
Secondly, we examined the length of hospital stay after colorectal surgery from a hospital
cost-perspective. In countries all over the world a shift has been observed in reimburse-
ment schemes for health care. Instead of the traditional fee-for-service scheme, countries
are adapting the fixed reimbursement scheme, such as the Diagnosis Related Groups (DRG)
in the USA and the ‘Diagnose-Behandelcombinatie’ (DBC) in the Netherlands. In these
schemes, patients are assigned to predetermined groups based on diagnosis, received
treatments and several other characteristics (e.g. co-morbidities or occurrence of certain
complications). Hospitals are reimbursed a certain fixed amount per patient based on the
group he or she is assigned to. For each group, an estimate of the expected hospital stay
is used to calculate this fixed reimbursement.
In contrary to the usual approach in which the absolute hospital stay is studied, we exam-
ined which factors are responsible for the largest deviation of the actual versus estimated
188 Chapter 10
hospital stay, and thus for the largest financial burden for hospitals (Chapter 3). A total of
1,461 patients were included in this single-department consecutive cohort. The average
expected and actual hospital stay were virtually equal, being 8.17 (IQR 4.7-11.9) and 8.31
(IQR 4.0-10.0) days, respectively. As hypothesized, certain factors were associated with
a large difference between the actual and expected length of stay. Parenteral nutrition
showed the largest deviation with an increase of about 5.1 days. Other factors showing
significant increases were emergency room admittance (3.67), ileus (3.45), blood transfu-
sion (2.3), anastomotic leak (2.2), sepsis (2.0) and venous thrombosis (1.9 days). While not
all factors are modifiable, some of them form a potential target for cost-savings measures.
The next step will be to examine hospital policies regarding factors showing large increases
and attempt to modify them were possible to effectuate the largest possible savings.
In the final chapter of part I, we examine the risk of cancer in colitis patients diagnosed
with dysplasia at colonoscopic surveillance. The aim of the study is to utilize the informa-
tion available preoperatively, such as patient characteristics and findings at colonoscopic
surveillance, to predict the presence and location of cancer in such patients. For this, we
identified 348 patients with colitis that underwent a proctocolectomy due to dysplasia in a
period of over 20 years (Chapter 4). Pathohistological examination showed the presence
of cancer in 51 (15%) patients, while some degree of dysplasia was observed in about
50% of patients. In patients with high-grade dysplasia preoperatively, the risk of cancer
was 29%. The presence of dysplasia-associated lesions or masses (DALM) preoperatively
was also associated with high risk of cancer of about 25%. These results were confirmed
by multivariate analysis in which high-grade dysplasia, DALM and disease duration were
independent risk factors for postoperative cancer. These results support surgical manage-
ment by a proctocolecotmy in virtually all patients with either high-grade dysplasia or
DALM during preoperative surveillance.
Patients with low-grade dysplasia (LGD) without DALM (i.e. flat LGD) had a relatively low
risk of cancer (2%) and a moderate risk of high-grade dysplasia (7%). Management of
these patients is challenging since it entails a balance between the small but present risk
of cancer and the risk of morbidity and mortality associated with surgery. This paper helps
physicians inform their patients more accurately and thus allows for better shared-decision
making. In regard to the location of histopathological findings, we observed that dysplasia
and cancer can be present in segments adjacent to and remote from the preoperative
location. This also supports the choice for a total proctocolectomy (+/- restoration of intes-
tinal continuity) for most patients. Patients with isolated colonic dysplasia without sigmoid
involvement had low rates of rectal dysplasia (3%) and rectal cancer (0%). Therefore, in
selected patients with a high-risk of morbidity a colectomy with rectal preservation may
obviate some of the risks of a pelvic dissection and provide an acceptable alternative.
Chapter 10 189
10
In part II, we evaluate various aspects of the surgical treatment of IBD aiming at optimizing
these treatments and findings ways to improve patients’ outcomes. First, we compare the
upcoming laparoscopic approach for the IPAA procedure with the established open ap-
proach. With the advancements of minimal-invasive surgery this demanding operation has
been increasingly performed laparoscopically. We evaluated the presumed benefits of the
laparoscopic approach in a systematic Cochrane review (Chapter 5). Eleven comparative
trials (including 607 patients) were included, of which only 1 was randomized. Analysis
showed no significant differences in complications or functional outcomes. Operative time
was significantly longer in the laparoscopic approach by about 1.5 hours. In regard to post-
operative recovery parameters, no significant differences were seen when only published
data suitable for meta-analysis (i.e. means and standard deviations) were used. However,
when all available published data were used to impute the missing measures, a significant
reduction in time-to-bowel movement (-1.96 days), time-to-regular diet (-1.30 days) and
hospital stay (-1.88 days) were observed. Total incision length was significantly shorter in
the laparoscopic group, while two trials evaluating cosmesis found significantly improved
cosmesis scores in the laparoscopic group. While more research is required, this review did
show that the laparoscopic IPAA is a feasible and safe procedure that has the potential for
quicker postoperative recovery. Moreover, cosmesis and body image were superior in the
laparoscopic group, which can be important in this young, active and highly motivated
patient group.
While IPAA is the treatment of choice for most patients, certain patients might benefit
from a less invasive procedure to reduce the operative morbidity. In such patients, a total
proctocolectomy with end-ileostomy is possible, but it does not allow for restoring the
continuity of the intestinal tract. In certain cases, a subtotal colectomy with ileorectal
anastomosis (IRA) might offer a valid alternative. IRA offers a one stage procedure that
does not require pelvic dissection, potentially reducing surgical morbidity and avoiding
the associated risk of sexual dysfunction. In order to examine whether these proposed
benefits are supported by evidence, we performed a narrative review comparing the IRA
to the IPAA procedure (Chapter 6). Overall morbidity was less after IRA, ranging from 8%
to 28%, compared to 15% to 63% after IPAA. Severe postoperative complications, except
for reservoir failure, were lower after IRA. Anastomotic leak, for example, was reported
between the 2.3 and 9.1% after IRA (weighted average of 4.5%), compared to an average
pelvic sepsis rate of 7.5% (95% CI 6.1 to 9.1) after IPAA. Rate of sexual dysfunction was
low after IPAA (around 3%), but this complication was virtually non-existent after IRA.
The overall mortality was comparable after IRA (0 and 4.0%) versus IPAA (0 and 2.9%).
Failure of the reservoir was higher after IRA with a reported frequency after 5-years of 7%
to 16%, compared to an average of 4.7% for IPAA. The risk of cancer was also higher
after IRA with reported frequency between 0 to 8% compared to <0.5% for IPAA, and
190 Chapter 10
an estimated cumulative risk of cancer after 20 years of 6% to 14% for IRA compared
to 4.2% for the IPAA approach. Functional results seemed to be better after IRA with
lower frequency of bowel movements and less night-time seepage, but with more urgency
compared to patients with an IPAA.
Thus, current evidence supports IPAA as the preferred approach for patients with UC
requiring surgical treatment. The definitive nature of the procedure with low risk of failure
and removal of all diseased mucosa with lower risk of cancer are the main advantages of
this technique. Nonetheless, there might be a role for IRA in selected patients. Patients
with higher surgical risk with mild rectal involvement and no evidence of dysplasia or
cancer at the time of intervention might benefit from the good functional outcomes of
an IRA procedure. These patients should, however, be aware about the risk of recurrent
proctitis and cancer in long standing disease, and have to fully understand the need for
meticulous surveillance. Unless these conditions are met, patients should not be offered an
IRA. Finally, patients not suitable for IPAA or with widely metastatic colorectal cancer may
also benefit from an IRA procedure.
Subsequently, we focused on the optimal management of an anastomotic pouch sinus.
This serious complication after IPAA is challenging to treat and carries a high risk of pouch
failure. Due to its relative infrequency, its course and optimal management are not well
defined. Therefore, we set out to evaluate the frequency, management and outcome of
anastomotic pouch sinus in a large prospectively collected database encompassing 2,286
patients that have underwent an IPAA procedure (Chapter 7). A total of 45 (2.0%) patients
were diagnosed with an anastomotic pouch sinus confirmed by imaging or examination
under anaesthesia. The pouch sinus was initially managed by observation in 23 (51%)
patients. Other treatment modalities included transrectal drainage, unroofing of the sinus
tract, sinus closure or diverting of the fecal stream. Healing rate after initial treatment
alone was low (26%). In 28 patients (62%), subsequent treatment was necessary. Eventu-
ally, sinus healing was achieved in 27 (60%) patients, whereas 15 (33%) developed pouch
failure. When examining factors influencing the rate of healing only symptomatic presenta-
tion was associated with worsened outcomes. The healing rate was significantly lower in
those patients compared to asymptomatic patients (30% vs. 84%, p=0.001). Pouch failure
tended to higher as well (45% vs. 24%, p=0.14). Of the treatments applied, a strategy
with observation as initial treatment was the most successful with a healing rate of 65%.
Based on findings in this study as well as a review of literature, we proposed an algo-
rithm for management of a pouch sinus after IPAA. Observation and watchful waiting
are recommended in asymptomatic patients or patients with incidentally encountered
sinuses (e.g. on a Gastrografin enema) prior to ileostomy closure (with delay of ileostomy
Chapter 10 191
10
close). Symptomatic sinuses and those that are defunctioned but non-healing on watchful
waiting alone, may be managed by trans-anal drain placement, unroofing of the sinus or
injection of fibrin glue. No clear evidence exists to favour one approach over the other,
and experience of the treating physician should be guiding. A defunctioning ostomy may
be considered in circumstances where eventual healing of the sinus may be expected in
patients who are not defunctioned. When attempts at healing have failed or may not
reasonably be anticipated due to the size or persistence of the sinus, a redo IPAA may be
considered.
Next we evaluated the impact of immunosuppressive agents in patients with CD that are
undergoing surgery. While such agents have become a corner-stone in the management
of CD, their impact on postoperative complication, especially infectious complications,
has been a topic of concern. To gain more insight into this potentially harmful effect, we
performed a systematic review including comparative studies on this topic (Chapter 8).
A total of 21 comparative studies including 6,899 patients were identified. We analysed
data separately for anti-tumor necrosis factor (TNF) agents (14 studies), corticosteroids (14
studies), thiopurines (9 studies) and mixed immunosuppressive agents (6 studies).
In meta-analysis, patients receiving anti-TNF agents and corticosteroids before surgery were
found to have a higher risk of postoperative infectious complications with a RR of 1.29
(95% CI 1.07 to 1.55) and 1.55 (95% CI 1.23 to 1.95), respectively. These results were
consistent in sensitivity analysis of studies with the highest methodological quality. Suf-
ficient data to compare individual complications were only present in the anti-TNF group,
which should a significant increase in rates of wound infection (RR 1.62, 95% CI 1.12 to
2.34) and septic shock (RR 1.81, 95% CI 1.03 to 3.17) when these drugs are administered
within 3 months of surgery. For corticosteroids, the risk of infectious complications was
greater when only patients on high-dose corticosteroids were included (RR 1.67, 95%
CI 1.31 to 2.13). Based on the limited data available, no association was seen between
use of thiopurines (RR 1.23 (95% CI 0.66 to 2.29) or combined immunomodulator drugs
(RR 1.01 (95% CI 0.67 to 1.54) and infectious postoperative complications. Overall, this
review shows that certain commonly used immunosuppressive agents do increase risk of
infectious postoperative complications, and that this should be considered when informing
patients and making decisions regarding the optimal timing of surgery.
Finally, we examined a variation in the way the pelvic dissection is performed during the IPAA
procedure. Pelvic dissection is most commonly performed according to the total mesorectal
excision (TME) principles, in which both the rectum and mesorectum are excised en-bloc.
This technique is the golden-standard for oncological resection, but is not strictly necessary
in benign disease. An alternative is the close-rectal dissection, which has been proposed
192 Chapter 10
in the 1970’s but was too laborious given the technical equipment at that time. In this
technique the rectum is dissected through the nonanatomic perimuscular plane, thereby
preserving the mesorectal fat layer that is just outside the rectum. Hypothesized benefits
include preservation of the pelvic autonomic nerves (responsible for sexual dysfunction)
and allowing for less room in the pelvis for postoperative hematoma or fluid collections,
potentially reducing the risk pelvic infectious complication. Due to developments in surgi-
cal equipment, especially electrothermal bipolar vessel sealer and ultrasound dissection,
this technique has been substantially simplified.
To examine the feasibility and evaluate potential benefits, we performed a pilot study
including 10 consecutive patients with UC undergoing an IPAA procedure (Chapter 9).
The procedure was technically successful in all patients. After a median follow-up of 16
months, no cases of pelvic sepsis or bladder- or sexual dysfunction were observed. The me-
dian daytime defecation frequency was 6.0, and anorectal physiological testing supported
the good functional results. Thus, results of the close-rectal pouch procedure in the current
era are promising, and support further comparative research to validate and quantify the
potential benefits of this technique.
11 Gained insiGhts and
future perspectives
Chapter 11 197
11
inTroducTion
In the preceding chapters, findings from several studies on the surgical treatment of in-
flammatory bowel disease (IBD) have been presented. In this final chapter, we present a
topic based discussion of the most important gained insights and future perspective based
on the entirety of the thesis.
role and alTernaTives of The ileal Pouch-anal anasToMosis (iPaa)
Based on current evidence, the IPAA is considered the current gold-standard for the treat-
ment of patients with ulcerative colitis (UC). An important finding from our thesis was
the stagnation (or stability) of functional outcomes after the IPAA procedure even after
3 decades of experience (Chapter 2). This probably represents an intrinsic limitation of
the IPAA procedure, which could be used to counsel patients and also to set accurate
expectations of outcomes in scientific research. We also showed that the laparoscopic ap-
proach has shown short-term advantages when compared to the open approach in terms
of postoperative recovery and cosmesis (Chapter 5). This combined with the increased
experience in laparoscopic colorectal surgery, has resulted in the laparoscopic IPAA to be-
come the preferred treatment modality by both physicians and patients. We also showed
promising results of a technical modification of the IPAA procedure (Chapter 9). This so
called close-rectal dissection (CRD) has been revived due to recent technical advances in
surgical instrumentation making it easier and safer. While only 10 patients were included
in this pilot study, results show that this alternative is feasible, safe and was associated with
promising results in regard to postoperative complications. A recent RCT confirmed the
hypothesized benefits of the CRD approach.1 In this RCT including 59 patients, the CRD
approach led to a lower severe complication rate (2 of 28 (7%) vs. 10 of 31 (32%)) and
better short-term quality of life than the traditional approach.
While the (laparoscopic) IPAA is suitable for most patients with UC, certain subgroups can
be identified in which an alternative approach such as the ileorectal anastomosis (IRA) is
beneficial. Due to unequal target populations, direct comparison between these two pro-
cedures was not feasible. A narrative approach in which all relevant evidence is presented
was performed, with focus on risk of postoperative complications and cancer as important
determinates in the choice between the two interventions (Chapter 6). This has resulted in
concrete recommendations to guide selection of patients for each procedure. Patients with
higher surgical risk with mild rectal involvement and no evidence of dysplasia or cancer
at the time of intervention might benefit from the good functional outcomes of an IRA
198 Chapter 11
procedure. It can be also proposed to young women as a possible interim procedure based
on concerns for infertility after IPAA. Patients should be aware of the risk of recurrent
disease and cancer, and be compliant with surveillance.
In regard to the increased risk of cancer in patients with UC, this thesis have shown that
patients with high-grade dysplasia or dysplasia-associated lesion/mass on colonoscopic
surveillance have a high risk of synchronize colon carcinoma, and should undergo a proc-
tocolectomy (Chapter 4). Management of patients with flat low-grade dysplasia (LGD),
on the other hand, is particularly challenging. In our study we have shown that the risk
of cancer in flat LGD is 2%, which is at the lower end of the range reported by previous
studies (i.e. 0 to 20%).2-4 Triggered by the large variation reported in literature, the Position
Statement by the American Gastroenterological Association (AGA) states that current evi-
dence is insufficient to either advice for or against colectomy for flat LGD.5,6 We propose an
individualized approach in which surgery should be considered in patients with additional
risk factors for cancer as identified in literature. Such risk factors included young age, long
duration of disease, multifocal dysplasia especially if located distally, extensive disease (e.g.
pancolitis) and positive family history.7,8 In other cases, colonoscopic surveillance after dis-
cussion of associated risks is acceptable, provided high patient compliance can be assured.
Future research, especially longitudinal cohort studies aiming at reliably identifying the
rate and predictors of progression of flat LGD to advanced neoplasia is needed to further
fine-tune these recommendations.
PrevenTion and ManaGeMenT of coMPlicaTions afTer ibd surGery
Given the increased importance of immunosuppressive agents in the treatment of Crohn’s
disease (CD), we evaluated their effect on postoperative complications (Chapter 8). We
were able to show an increase in overall infectious complications for certain commonly
used immunosuppressive agents. While not a substitute for well-designed and performed
studies, the synthesis of all available evidence into meta-analyses with consideration of
the risk of bias allowed us to identify these potentially important differences. We feel that
this review provides sufficient evidence to advice a preoperative drug free interval when
feasible to reduce the risk of infectious complications. The adoption of specific operative
strategies that may reduce these risks or their effects, such as the use of a temporary
ostomy, may additionally be considered in high risk patients.
For studying uncommon postoperative complications, such as anastomotic pouch sinuses
after IPAA, large surgical registries are indispensable. Using such database we were able
Chapter 11 199
11
for the first time to present the full spectrum of incidence, presentation, treatment and
outcomes of this complication (Chapter 7). These findings are important in that they can
raise the alertness of physicians to this condition, provide guidance in the treatment of its
different presentations and help counsel patients. This study shows that observation was
the preferred initial management for pouch sinuses with reasonable healing rates. When
this treatment strategy fails, several other options as well as their success rates have been
presented. No superior method was identified, and choice of treatment should rely on
availability and experience of the treating physician.
challenGes in surGical research MeThodoloGy
Finding the ideal timing to perform randomized trials for innovative surgical treatments
is challenging.9 RCTs should be done as early as possible after introduction of a new
intervention to reduce the possibility that the new innovation becomes widely adopted
and strong preferences of physicians or patients hinders delivery of the allocated interven-
tion. However, randomization needs to be sufficiently delayed until the surgical team is
adequately prepared, the new procedure is considered safe and feasible, and the learn-
ing curve has been passed.10 This combined with the cost, ethical and organisational
restraints of performing RCTs makes surgeons often prefer non-randomized studies or
(even worse) historic comparison of cohorts over time. This challenge is clearly illustrated
in our systematic review of open versus laparoscopic IPAA (Chapter 5). Only one RCT was
identified comparing laparoscopic vs. open IPAA, compared to 10 non-randomized studies.
Moreover, it turned-out the second on-going RCT that was identified by our review had
to be stopped prematurely due to insufficient recruitment because of a marked patients’
preference in favour of the laparoscopic approach.11 The researchers were eventually only
able to recruit 42 out of the 160 intended patients.
This consequently results in two important challenges for the surgical field. First, given the
relatively short window in which RCTs can be conducted, performing RCTs as soon as pos-
sible should receive the highest priority of all innovating centres. Surgeons have to take the
initiative in discussing this limitation with ethical boards as well as governmental regulatory
and funding organisation in order to facilitate the conductance and funding of RCTs for
promising surgical innovations. Secondly, we need to find ways to deal with the suboptimal
body of evidence that will inevitably be produced. This has to be done in a way that
ensures maximal benefit of the available good quality evidence, without getting misled by
the potential biases of lower quality evidence. The Cochrane review performed in Chapter
5 of this thesis is an attempt in this direction, since it was one of the few Cochrane reviews
incorporating a meta-analysis of non-randomized trials at the time. It was also one of the
200 Chapter 11
first Cochrane reviews to incorporate imputed estimates of mean and standard deviation
when these were not published, but other data such as medians and ranges were available.
Currently, similar approaches are becoming more familiar. For example, the GRADE clas-
sification which is now part of all Cochrane reviews allows for non-randomized evidence to
be classified as moderate or even high quality, when studies are well performed and results
show certain signs that reinforces their reliability (e.g. a strong magnitude of effects or if
all plausible biases would reduce an apparent treatment effect).12
Finally, in relation to health costs research, by looking at clinical outcomes from the
perspective of disproportionate costs compared to the reimbursement received by the
hospital, we add a dimension that is often overlooked (Chapter 3). Results from such
approach can help guide policy making and prioritize research funding and efforts towards
targeting factors with the largest cost impact. A limitation of this approach is the fact that
regional and local differences between hospitals might make results of a study not directly
generalizable to other hospitals. Thus, each hospital has to perform their own analysis of
factors causing the most excessive costs. This same limitation, however, does come with
an unexpected advantage. Using this methodology of reporting outcomes offers a tool
to more accurately compare results of hospitals with different patient populations, since
outcomes are normalized based on the expected outcomes of that case-mix.
conclusions
The IPAA is the gold-standard treatment of patients with UC. Functional results after this
procedure has been stable for the last 30 years, suggesting no further improvement is to
be expected. The laparoscopic IPAA has been associated with improved convalescence and
cosmetics and have become the preferred method. Performing an IPAA procedure using
a close-rectal dissection, rather than the usual total mesorectal excision (TME) method,
might reduce the risk of certain postoperative complications and increase the quality of
life. For specific patients an IRA might be a suitable alternative, although the risk of cancer
and proctitis should be taken into account. In regard to the risk of cancer, colitis patients
with high-grade dysplasia or dysplasia-associated lesion/mass on colonoscopic surveillance
have a high risk of synchronize colon carcinoma, and should undergo a proctocolectomy.
Patients with low-grade dysplasia need to undergo a personalized assessment in which
surgery should be considered in patients with additional risk factors for cancer.
Use of certain immunosuppressive agents prior to surgery in patients with CD, is associated
with an increase in overall infectious complications. Physicians should be aware of this
increased risk and a preoperative drug free interval when feasible is advised to reduce this
Chapter 11 201
11
risk. For the management of anastomotic pouch sinuses after IPAA, observation has been
shown to be the optimal initial management. If this fails, several options are available
with current evidence being insufficient to provide recommendations on their efficacy.
Therefore, the choice of treatment should rely on availability and experience of the treating
physician.
Performing randomized controlled trials in the field of surgery remains challenging. A
genuine effort to perform RCTs in the brief window of opportunity is important. Similarly
a collective initiative to reduce the financial and organization burden of surgical RCTs on
physicians and institutions is warranted. Finally, identification of clinical outcomes that
result in the largest disparity between costs incurred and the reimbursement received by
hospitals can help reduce health costs. Targeting these outcomes, if possible, to reduce
their occurrence can provide an efficient way to maximise health cost savings.
202 Chapter 11
references
1. Bartels SA, Gardenbroek TJ, Aarts M, Pon-
sioen CY, Tanis PJ, Buskens CJ, Bemelman
WA. Short-term morbidity and quality of
life from a randomized clinical trial of close
rectal dissection and total mesorectal exci-
sion in ileal pouch-anal anastomosis. The
British journal of surgery. 2015; 102: 281-7.
2. Befrits R, Ljung T, Jaramillo E, Rubio C. Low-
grade dysplasia in extensive, long-standing
inflammatory bowel disease: A follow-up
study. Diseases of the colon and rectum.
2002; 45: 615-20.
3. Lim CH, Axon AT. Low-grade dysplasia:
Nonsurgical treatment. Inflammatory
bowel diseases. 2003; 9: 270-2; discussion
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4. Lindberg B, Persson B, Veress B, Ingelman-
Sundberg H, Granqvist S. Twenty years’
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and malignant transformation. Scandina-
vian journal of gastroenterology. 1996; 31:
1195-204.
5. Farraye FA, Odze RD, Eaden J, Itzkowitz
SH. Aga technical review on the diagnosis
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6. Farraye FA, Odze RD, Eaden J, Itzkowitz SH,
McCabe RP, Dassopoulos T, Lewis JD, et
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neoplasia in inflammatory bowel disease.
Gastroenterology. 2010; 138: 738-45.
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BV, Nielsen NM, Frisch M. Decreasing risk
of colorectal cancer in patients with
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Gastroenterology. 2012; 143: 375-81.e1;
quiz e13-4.
8. Navaneethan U, Jegadeesan R, Gutierrez
NG, Venkatesh PG, Hammel JP, Shen B, Ki-
ran RP. Progression of low-grade dysplasia
to advanced neoplasia based on the loca-
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Crohn’s & colitis. 2013; 7: e684-91.
9. Ergina PL, Cook JA, Blazeby JM, Boutron
I, Clavien PA, Reeves BC, Seiler CM, et al.
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10. Barkun JS, Aronson JK, Feldman LS, Mad-
dern GJ, Strasberg SM, Altman DG, Barkun
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11. Schiessling S, Leowardi C, Kienle P, Antolovic
D, Knebel P, Bruckner T, Kadmon M, et al.
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12 nederlandse samenvattinG
(dutch summary)
Chapter 12 207
12
saMenvaTTinG
In het eerste deel van dit proefschrift wordt de huidige status van chirurgie van inflam-
matoire darmziekten (IBD) onderzocht. De ileo-anale anastomose met ileumreservoir (IPAA)
wordt ruim 30 jaar verricht en wordt gezien als de ‘gouden standaard’ voor de chirurgische
behandeling van patiënten met colitis ulcerosa. De invloeden op deze operatie van ontwik-
kelingen in de perioperatieve zorg en verfijning van chirurgische technieken worden in een
systematische review van de literatuur onderzocht (Hoofdstuk 2). Behandeluitkomsten in
53 observationele studies na het jaar 2000 werden vergeleken met de resultaten van 43
studies die gepubliceerd waren voor het jaar 2000.
Het falen van het ileumreservoir was gedaald van 6,8% (95% betrouwbaarheidsinterval
(BI) 5,8 tot 8,4) voor 2000 naar 4,3% (BI 3,5 tot 5,3) na 2000 (p=0,004). Er werd ook een
daling geconstateerd in het percentage van septische complicaties van 9,5% (BI 8,2 tot
10,9) naar 7,5% (BI 6,1 tot 9,1), maar dit verschil was niet statistisch significant. Functi-
onele uitkomsten waren gelijk in de tijd. Variaties in de operatieve procedure, zoals het
wel of niet aanleggen van een ontlastend stoma, hadden geen effect op deze uitkomsten.
Concluderend heeft in de afgelopen jaren een verfijning van de IPAA techniek gezorgd
voor een daling van de meest ernstige complicaties, zonder dat de functionele uitkomsten
verder verbeterden. Deze getallen kunnen als een graadmeter gebruikt worden voor de
huidige praktijk en wetenschappelijk onderzoek. De stabiele functionele uitkomsten repre-
senteren waarschijnlijk de biologische limiet dat het ileumreservoir kan realiseren.
Een ander actueel onderwerp is het bestuderen van de opnameduur na colorectale
chirurgie in het kader van kosteneffectiviteit. Wereldwijd is er een verschuiving gaande
van directe vergoedingen (‘fee-for-service’) naar geïntegreerde vergoedingen zoals het
DBC (Diagnose-Behandelcombinatie) systeem in Nederland. Een vergelijkbaar systeem in
de VS is de ‘Diagnosis Related Groups’ (DRG). Ziekenhuizen krijgen een vast bedrag per
patiënt afhankelijk van de diagnose, behandeling en een aantal andere karakteristieken
(bijvoorbeeld co-morbiditeiten en complicaties). Patiënten worden op basis van deze gege-
vens in groepen verdeeld. Bij iedere groep hoort een verwachte opnameduur waarop de
vergoeding is berekend.
In de meeste wetenschappelijke studies wordt de absolute opnameduur bestudeerd. In
onze studie werd gekeken naar de discrepantie tussen de verwachte opnameduur (o.b.v.
de DRG groep) en de daadwerkelijke opnameduur (Hoofdstuk 3). In totaal werden er
1.461 opeenvolgende patiënten die colorectale operaties hebben ondergaan geïncludeerd.
Overall was de gemiddelde verwachte en daadwerkelijke opnameduur voor de gehele
groep vrijwel gelijk, namelijk 8,17 (interkwartielbereik (IQR) 4,7 tot 11,9) en 8,31 (IQR 4,0
208 Chapter 12
tot 10) dagen, respectievelijk. Via multivariate analyse werden verschillende individuele
factoren nader onderzocht. De opnameduur werd vooral beïnvloed door het gebruik van
parenterale voeding (5,1 dagen langer dan verwacht). Andere factoren die grote verschil-
len lieten zien waren opname vanaf de spoedeisende hulp (3,7 dagen), ileus (3,5 dagen),
bloedtransfusie (2,3 dagen), naadlekkage (2,2 dagen), sepsis (2,0 dagen) en veneuze
trombose (1,9 dagen). Deze resultaten kunnen gebruikt worden om een prioritering aan
te brengen in de factoren waarnaar gekeken dient te worden om een maximale kosten-
besparing te realiseren. Een gedegen analyse op ziekenhuis- en afdelingsniveau zijn hierbij
essentieel om te kijken naar verbeterpunten in relevante protocollen en procedures (bijv.
omtrent parenterale voeding).
In Hoofdstuk 4, werd het risico op kanker bij patiënten met colitis ulcerosa waarbij
dysplasie is vastgesteld bij coloscopie onderzocht. Het doel was om te beoordelen of de
aanwezigheid en locatie van kanker voorspeld kan worden op basis van de coloscopie. Er
werden 348 patiënten met colitis ulcerosa geïncludeerd die een proctocolectomie had-
den ondergaan in verband met dysplasie. Pathologisch onderzoek liet kanker zien in 51
(15%) van de patiënten. In patiënten met hooggradig dysplasie was de kans op kanker
29%. De aanwezigheid van de zogenaamde met dysplasie samenhangende afwijking
of massa (‘dysplasia associated lesion or mass’ (DALM)) ging gepaard met een kans op
kanker van 25%. In multivariate analyse, waren hooggradig dysplasie, DALM en duur van
de ziekte onafhankelijke voorspellers voor de aanwezigheid van kanker. Deze resultaten
ondersteunen de keuze voor een resectie als standaardbehandeling voor patiënten met
deze afwijkingen.
Patiënten met laaggradige dysplasia zonder DALM hadden een relatief laag risico van
kanker (2%) en middelmatig risico op hooggradige dysplasie (7%). Behandeling van deze
patiënten is uitdagend, aangezien het risico van morbiditeit en mortaliteit van de operatie
gewogen dient te worden tegen het lage maar reële risico op kanker. Ten aanzien van de
locatie van de afwijkingen, werd aangetoond dat in het postoperatieve preparaat kanker
of dysplasie regelmatig gevonden wordt in andere delen van het colon dan waar de pre-
operatieve afwijking werd gezien. Daardoor blijft een proctocolectomie de operatie van
keuze voor de meeste patiënten. Bij patiënten met uitsluitend afwijkingen proximaal van
het sigmoïd bij de coloscopie, was de kans op rectale afwijkingen laag (i.e. 3% dysplasie
en 0% kanker). In geselecteerde patiënten met hoge operatierisico’s kan in deze groep
patiënten een subtotale colectomie overwogen worden om het complicatierisico’s bij een
rectumresectie te vermijden.
In het tweede deel van dit proefschrift, wordt nader in gegaan op het optimaliseren van
de chirurgische behandelingen bij IBD. Door de ontwikkeling van de minimaal-invasieve
Chapter 12 209
12
chirurgie wordt de IPAA steeds vaker laparoscopisch uitgevoerd. In Hoofdstuk 5, werd
in een systematische Cochrane review deze techniek onderzocht. Analyse van 11 verge-
lijkende studies met 607 patiënten liet geen verschil zien in complicaties en functionele
uitkomst. Operatietijd van de laparoscopische operatie was significant langer (gemiddeld
1,5 uur langer). Ten aanzien van het postoperatief herstel, werden er geen significante
verschillen gezien bij het analyseren van alleen de gepubliceerde resultaten die geschikt
waren voor meta-analyse. Echter, bij het includeren van alle gepubliceerde data en impu-
teren van ontbrekende parameters, werd een significante reductie gezien in tijd tot eerste
defecatie (−1,96 dagen), tijd tot normaal dieet (−1,3 dagen) en ziekenhuisverblijf (−1,88)
in de laparoscopische groep. Totale incisie lengte was significant korter en patiëntbeoorde-
ling van het cosmetisch aspect was significant beter in de laparoscopie groep. Deze review
laat zien dat de laparoscopische IPAA een veilig procedure is met potentie tot verbetering
van de postoperatieve uitkomsten. Het cosmetische voordeel kan bovendien zwaarwegend
zijn, gezien de voornamelijk jonge patiënten die voor deze operatie in aanmerking komen.
Bij hoog operatierisico patiënten kan een subtotale colectomie met ileorectale anastomose
(IRA) een alternatief bieden voor de IPAA. IRA is een operatie die geen dissectie vereist
in het kleine bekken, met potentieel een verminderd risico op chirurgische complicaties
en seksuele dysfunctie. Om te beoordelen of deze beoogde voordelen ook worden on-
dersteund door de literatuur, werd een review uitgevoerd waarbij de IRA en de IPAA met
elkaar werd vergeleken (Hoofdstuk 6). De totale morbiditeit was lager bij de IRA (8% tot
28%) vergeleken met de IPAA (15% tot 63%). Ernstige complicaties, zonder falen van
het reservoir, waren lager na de IRA. De kans op naadlekkage was tussen de 2,3% en
9,1% na de IRA (gewogen gemiddelde 4,5%), vergeleken met een gemiddelde kans van
7,5% (95% betrouwbaarheidsinterval van 6,1% tot 9,1%) voor de IPAA. Het percentage
seksuele dysfunctie was laag na de IPAA (rond 3%), maar deze complicatie werd niet ge-
rapporteerd na de IRA. De totale mortaliteit was vergelijkbaar tussen de IRA (0 tot 4%) en
de IPAA (0 tot 2,9%). Falen van het reservoir was hoger in de IRA groep, met 5 jaarsfalen
van 7% tot 16%, vergeleken met gemiddeld 4,7% na IPAA. De kans op maligniteit na
een IRA was ook hoger, met een incidentie van 0% tot 8% vergeleken met incidentie van
<0,5% voor de IPAA. Het cumulatieve risico op kanker na de IRA wordt geschat op 6% tot
14% vergeleken met 4,2% voor de IPAA. Functionele uitkomsten lijken beter te zijn na de
IRA, met lagere defecatiefrequentie en minder kans op lichte incontinentie. Kans op ‘urge
incontinentie’ is echter licht hoger bij de IRA vergeleken met de IPAA.
Deze resultaten ondersteunen de keuze voor de IPAA als voorkeursoperatie voor patiënten
met colitis ulcerosa. Het feit dat de IPAA een definitieve behandeling is met laag risico
op kanker is de voornaamste reden hiervoor. Desondanks kan de IRA soms nuttig zijn
in geselecteerde patiënten. Patiënten met een hoog operatierisico en weinig tot geen
210 Chapter 12
rectale betrokkenheid, kunnen voordeel hebben van de minder grote operatie en de goede
functionele resultaten na de IRA. Wel moeten ze goed worden voorgelicht over de kans
op het ontwikkelen van proctitis en kanker, en bereid zijn onder langdurige endoscopische
controles te blijven. Tenslotte, kan de IRA ook geschikt zijn voor patiënten die geen kandi-
daat zijn voor de IPAA of die reeds gemetastaseerde ziekte hebben.
Een ileumreservoir sinus na een IPAA operatie is een ernstige complicatie, die moeilijk te
behandelen is en een hoog risico heeft op pouchfalen. Om de incidentie, behandeling en
uitkomst beter in kaart te brengen, hebben we gekeken naar een grote cohort van 2.286
patiënten die een IPAA hebben ondergaan (Hoofdstuk 7). In totaal waren er 45 (2,0%)
patiënten die een ileumreservoir sinus ontwikkelden. In 23 (51%) patiënten werd de sinus
aanvankelijk conservatief behandeld. Bij de overige patiënten werd de sinus op verschil-
lende manieren behandelend, waaronder transrectale drainage, ‘deroofing’ van de sinus,
primair sluiten van de sinus en aanleggen van een deviërend stoma. Het genezingspercen-
tage na de initiële invasieve behandeling was laag (26%). Een vervolgbehandeling was bij
28 (62%) patiënten nodig. Dit resulteerde uiteindelijke in genezing bij 27 (60%) patiënten
en in falen van het ileumreservoir bij 15 (33%) patiënten. Het bestaan van klachten ten
tijde van presentatie was een belangrijke voorspellende factor voor het falen van behande-
ling met een genezingspercentage van slechts 30%, vergeleken met 84% bij patiënten
zonder klachten (p=0,001). Van de toegepaste behandelingen was observatie de meest
succesvolle initiële behandeling met genezing bij 65%.
Op basis van bevindingen in deze studie, gecombineerd met een review van de bestaande
literatuur, werd een behandelalgoritme opgesteld voor de behandeling van een ileumre-
servoir sinus na een IPAA procedure. Expectatief beleid wordt geadviseerd bij asymptomati-
sche patiënten als initiële behandeling. Bij patiënten met symptomen en patiënten die een
deviërend stoma hebben, kan een invasieve behandeling ingezet worden (i.e. drainage,
‘deroofing’ of primair sluiten). Er is onvoldoende bewijs om te bepalen welke van deze
behandelingen het beste is. De ervaring van de behandelende arts hoort hierbij leidend te
zijn. Het aanleggen van een deviërend stoma kan overwogen worden om de genezingskans
van de sinus te maximaliseren. Bij sinussen waarbij de verwachting op genezing klein is,
op basis van hun grootte en duur van bestaan, dient een redo-IPAA overwogen te worden.
In Hoofdstuk 8 werd het effect van immunosuppressiva op de operatierisico’s bij patiën-
ten met de ziekte van Crohn geëvalueerd. Immunosuppressiva vormen in de hedendaagse
geneeskunde de belangrijkste behandeling voor de ziekte van Crohn. Hun invloed op het
ontstaan van infectieuze complicaties bij een noodzaak tot een operatie blijft echter een
reden van zorg. Om meer inzicht hierin te krijgen, werd een systematische review ver-
richt. Er werden 21 vergelijkende studies met in totaal 6.899 patiënten geïdentificeerd.
Chapter 12 211
12
Postoperatieve resultaten bij gebruik van ‘anti-tumor necrosis factor’ (anti-TNF) (14 studies),
corticosteroïden (14 studies), thiopurines (9 studies) en gemengde immunosuppressiva (6
studies) werden afzonderlijk geanalyseerd.
Een meta-analyse liet een hogere kans zien op postoperatieve infectieuze complicaties bij
patiënten die voor de operatie anti-TNF (RR 1,29, 95% BI 1,07 tot 1,55) of corticosteroïden
(RR 1,55, 95% BI 1,23 tot 1,95) gebruikten. Sensitiviteitsanalyse van studies met hoge
kwaliteit bevestigde deze resultaten. Voor anti-TNF gebruik waren er voldoende data om
afzonderlijke complicaties te analyseren. Er werd een significante toename gezien in het
risico op wondinfecties (RR 1,62, 95% BI 1,12 tot 2,34) en septische shock (RR 1,81, 95%
BI 1,03 tot 3,17) bij gebruik van anti-TNF middelen binnen 3 maanden voor de operatie.
Bij corticosteroïden werd geconstateerd dat patiënten die een hogere dosering innamen,
een extra hoog risico hadden op infectieuze complicaties (RR 1,67, 95% BI 1,31 tot 2,13).
Er werd geen verband gezien tussen het optreden van infectieuze complicaties en gebruik
van thiopurines (RR 1,23, 95% BI 0,66 tot 2,29) of gemengde immunosuppressiva (RR
1,01, 95% BI 0,67 tot 1,54). Concluderend, laat deze review zien dat sommige veel ge-
bruikte immunosuppressiva een verhoogde kans geven op infectieuze complicaties, en dat
dit meegenomen moet worden bij het informeren van patiënten en bij het bepalen van het
optimale tijdstip voor een eventuele operatie.
In Hoofdstuk 9 worden de resultaten van een nieuwe technische variatie voor de rectale
dissectie bij een IPAA procedure beschreven. De dissectie in het kleine bekken wordt door-
gaans uitgevoerd volgens de ‘totale mesorectale excisie’ (TME), waarbij zowel het rectum
als mesorectum en-bloc worden gereseceerd. TME wordt gezien als de gouden standaard
voor oncologische resecties, maar is niet strikt noodzakelijk voor benigne aandoeningen.
Een alternatief hiervoor is het ‘close-rectal’ dissectie, waarbij de dissectie plaatsvindt dicht
op de wand van het rectum. Deze techniek werd voor het eerst in de jaren 70 voorgesteld,
maar werd toen als ‘te veeleisend’ ervaren. Het voordeel van deze techniek is het intact
houden van de mesorectale vetlaag rondom het rectum. Dit is de laag waarin de autonome
zenuwen lopen die o.a. verantwoordelijke zijn voor de blaas- en seksuele functie. De mo-
gelijke voordelen van het ‘close-rectal’ dissectie is het behoud van deze functies en het
minder radicaal uitruimen van het kleine bekken, waardoor er minder ruimte is voor stase
van bloed en vocht en hierdoor minder kans op infectieuze complicaties. Met de huidige
chirurgische instrumenten zoals elektrische en ultrasonische dissectoren is deze techniek
eenvoudiger geworden.
Om de haalbaarheid van deze dissectie te evalueren en om een inschatting te krijgen van
de potentiële voordelen, hebben we een pilot studie uitgevoerd bij 10 patiënten. Deze
patiënten ondergingen allen een IPAA in verband met colitis ulcerosa. De procedure was
212 Chapter 12
technisch gelukt in alle patiënten. Niemand ontwikkelde septische ontstekingen van het
kleine bekken. Na een mediane follow-up van 16 maanden, werden ook geen blaas- of
seksuele dysfunctie klachten waargenomen. De mediane defecatiefrequentie was 6,0 keer
per dag, en anorectale manometrie liet goede functionele resultaten zien. De resultaten
van deze dissectietechniek met de huidige beschikbare chirurgische instrumenten zijn zeer
bemoedigend. Grotere studies zijn nodig om de mogelijke voordelen beter te bestuderen.
aPPendICes
217
A
Appendices
review coMMiTTee
• Prof.dr.R.L.A.W.Bleys,DepartmentofAnatomy,UtrechtUniversity
• Prof.dr.G.J.Groen,DepartmentofAnesthesia,UniversityofGroningen
• Prof.dr.I.Q.Molenaar,DepartmentofSurgery,UtrechtUniversity
• Prof.dr.H.M.Verkooijen,DepartmentofRadiology,UtrechtUniversity
• Prof.dr.F.P.Vleggaar,DepartmentofGastroenterology,UtrechtUniversity
218 Appendices
acknowledGMenT
I would like to express my greatest appreciation to all the patients, their families, co-
authors, local investigators and colleagues that were involved in the studies included in this
thesis. Without you, this would not have been possible.
Prof. dr. van Laarhoven, dear Kees, it is with you that I took my first steps in research and had
the chance to build a solid and rich foundation. Our first article was a Cochrane review; a
challenging endeavor that proved to be highly rewarding. Several Cochrane reviews followed
and those form an important part of both PhD dissertations. You also supported me to fol-
low a course on Evidence-Based Medicine at the University of Oxford, a unique experience
that I cherish. This eventually evolved into completing this prestigious Master’s program, as
you yourself have done before. Thank you for your early recognition and encouragement.
Prof. dr. Kiran, dear Ravi, we only met shortly in Oxford, but there was an unmistakable
connection and appreciation. Your invitation to come to the Cleveland Clinic was an honor,
and working with you on a daily basis was a true reward. I have learned so much from
you about research, medicine and life. The greatest realization of all is that who you work
with is probably the greatest factor for success. Thank you for a wonderful experience, and
thank you for your trust, advice and wholehearted support.
Prof. dr. van Hillegersberg, dear Richard, our work together was brief, but your professional
career is an example for every researcher and physician. The devotion with which you devel-
oped the minimal invasive approach in upper gastrointestinal surgery has transformed the field
regionally and nationally. Thank you for your involvement and facilitation of this endeavor.
Dear review committee, professor Ronald Bleys, professor Gerbrand Groen, professor
Quitus Molenaar, professor Lenny Verkooijen, professor Frank Vleggaar, thank you for
reviewing and assessment of this thesis.
Dr. Keus, dear Erik, you helped me with my first steps in research and showed me how to turn
an idea into a publication. More importantly, you taught me the value of high quality research
and that it does not come easy: for our first Cochrane review we screened over 14,000 hits…
twice!! I really enjoyed our visit to the Cochrane group in Denmark and the discussions we
had there with Gluud and Wetterslev. Thank you for your company and support.
Drs. de Zeeuw, dear Sharonne, partner in the pouch research in Nijmegen. It was a pleasure
to work with you on all kinds of projects. Your contribution to this thesis is substantial. It is
unfortunate that our paths have split somewhere along the road. I can’t believe time went
219
A
Appendices
so fast and that you are now in your final year of residency. I wish you all the luck in the
world with your surgical career and lovely family.
Dr. Heikens, dear Joost, my companion to my first trip to Oxford! Thanks for the unforget-
table moments and many tips about research, surgery and life!
Dr. Fichera, dear Alessandro, it was an honor to work with you. Always upbeat and charm-
ing, but also always present for colleagues and patients. I learned a lot from you about
colorectal surgery and Italy (especially Juventus)! Thanks for having me in the team in
Seattle and for supervising one of the chapters of this thesis.
Dr. Scoglio, dear Danielle, thanks for your work on this thesis and the good (albeit short)
time we had together in Seattle.
Dear Dilara Khoshknabi, team mate in the cubicles of the Cleveland Clinic! I still remember
when we had to re-extract lost data of over 800 patients in less than a week! We were
unbeatable. Thank you for your unparalleled effort and great work ethic. It was a pleasure.
Dear Kathrina Allen, the busy bee of the Cleveland Clinic. Thank you for your help and
assistance in all matters during my stay in Cleveland.
Dear prof. dr. Groen, dear Gerbrand, it was always great to walk into your room at the
UMCU and just be surprised by the unexpected turns our conversations took. Thank you
for all the great stories and life lessons. Also, thank you for your passionate and amusing
way of teaching. I still remember your not so subtle hint for the C7 dermatome.
Dear prof. dr. Elkhammas, dear uncle Elmahdi, few people can even begin to compare
to your kindness, cheerful personality, especially in combination with your skills and ac-
complishments. I really enjoyed my time working with you and the transplant team at Ohio
State. Thank you for you hospitality, boundless support and especially the great BBQs we
had together in Columbus.
To my fellow researchers in the Cleveland Clinic, Awad Jarrar, Galal El Gazzaz and Faisal
Elagili. We had a blissful and memorable time together. Thank you immensely for being a
second family to me during my time there.
Dear Dr. Moayeri, dear Nizar, colleague, friend and paranimf. Thanks for your companion-
ship in computer science, medical school, student activities, research and trading cars. It is
always a pleasure to have you nearby.
220 Appendices
Friends for life, Khalid Annejar, Fatih Arslan, Mohamed Attrach, Mohamed Fathi and
Nicolas Schroten, thank you for your friendship and all the nice moments we had together.
My dear supervisors and fellow residents at the University Medical Center Utrecht and the
St. Antonius Hospital, thank you for being my extended family in the past four years.
Nobody has been more important to me in the pursuit of this thesis than my family:
First and foremost, I would like to thank my parents, whose love, support and guidance
have made me the person I am today. I would like to express my endless gratitude to my
father, Hadi, the person to whom I owe so much, not in the least my drive for knowledge,
perseverance and sense of responsibility. Thank you for putting our wellbeing and educa-
tion first, knowing that it has not always been easy. Circumstances might have increased
the distance between us, but I will never forget the blessed time we had together.
To my mother, the dearest person to my heart and greatest love of my life. You raised us
with unconditional love, boundless caring and infinite giving that are truly unmatched.
There is nothing we can say or do that can express the level of gratitude we owe you. May
God enable us to be the sons and daughters you hope for, and allow us to serve you in
every way that you desire.
My siblings, Iman, Inas, Isra, Inam and Anas, five unique personalities that have had a
profound impact on my life. Life has not always been easy, but we have stood the test time
and time again. Thank you all for being there, and thank you for keeping me honest when
needed! I wish you all the peace and happiness in the world.
My friend, companion and love, Amasi: thank you for your friendship, support and pa-
tience. I am grateful for all the joyful and blissful times together. I am even more grateful
for your limitless support through the demanding tasks of life, and the direly needed
consolation when (on occasion) things really go south. Thank you for bearing with my
flaws and imperfections all those years. Most importantly, thank you for making me feel at
home every day of my life.
My son, Shahien, the newest addition to our family. You might be too young to realize this,
but ‘oh God!’ you are one busy little fella! According to your grandmother the apple did
not fall far from the tree (and as you can see your father did eventually alright, so we have
good hope for you too!). We are truly blessed to have you. You bring an incredible amount
of joy to us: me, your mom, grandmother, aunts and uncle. We love you immensely.
221
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Appendices
lisT of PublicaTions
1. Van Dalen AHM, Ahmed Ali U, Murray AC, Kiran RP. Optimizing Patient Selection
for Laparoscopic and Open Colorectal Cancer Resections: A National Surgical Quality
Improvement Program–Matched Analysis.
The American Surgeon, February 2019.
2. Schepers NJ, Bakker OJ, Besselink MG, Ahmed Ali U, Bollen TL, Gooszen HG, van Sant-
voort HC, Bruno MJ, for the Dutch Pancreatitis Study Group. Impact of Characteristics of
Organ Failure and Infected Necrosis on Mortality in Necrotizing Pancreatitis.
Gut, June 2018.
3. Ahmed Ali U, ten Hove JR, Reiber BM, van der Sluis PC, Besselink MG. Sample Size of
Surgical Randomized Controlled Trials: a Lack of Improvement over Time.
Journal of Surgical Research. 2018 Aug;228:1-7.
4. Issa Y, van Santvoort HC, van Dieren S, Besselink MG, Boermeester MA, Ahmed Ali
U. Diagnosing Chronic Pancreatitis: Comparison and Evaluation of Different Diagnostic
Tools.
Pancreas. 2017 Oct;46(9):1158-1164.
5. Rijkers AP, Bakker OJ, Ahmed Ali U, Hagenaars JCJP, van Santvoort HC, Besselink MG,
Bollen TL, van Eijck CH; Dutch Pancreatitis Study Group. Risk of Pancreatic Cancer After
a Primary Episode of Acute Pancreatitis.
Pancreas. 2017 Sep;46(8):1018-1022.
6. Ahmed Ali U, Beata RM, ten Hove JR, MD; van der Sluis PC, Gooszen HG, Boermeester
MA, Besselink GH, Journal impact factor and methodological quality of surgical random-
ized controlled trials: a systematic reviewan empirical study.
Langenbecks Arch Surg. 2017 Nov;402(7):1015-1022.
7. Frima H, Hulsmans MH, Houwert RM, Ahmed Ali U, Verleisdonk EJ, Sommer C, van
Heijl M. End cap versus no end cap in intramedullary nailing for displaced midshaft
clavicle fractures: influence on implant-related irritation.
Eur J Trauma Emerg Surg. 2018 Feb;44(1):119-124.
8. van Rosmalen BV, Alldinger I, Cieslak KP, Wennink R, Clarke M, Ahmed Ali U, Besselink
MG. Worldwide trends in volume and quality of published protocols of randomized
controlled trials.
PLoS One. 2017 Mar 15;12(3).
9. Broeders JA, Ahmed Ali U, Fischer G. Systematic review and meta-analysis of random-
ized clinical trials (RCTs) comparing topical calcineurin inhibitors with topical corticoste-
roids for atopic dermatitis: A 15-year experience.
J Am Acad Dermatol. 2016 Aug;75(2):410-419.
222 Appendices
10. Houwert RM, Smeeing DP, Ahmed Ali U, Hietbrink F, Kruyt MC, van der Meijden OA.
Plate fixation or intramedullary fixation for midshaft clavicle fractures: a systematic
review and meta-analysis of randomized controlled trials and observational studies.
J Shoulder Elbow Surg. 2016 Jul;25(7):1195-203.
11. Ahmed Ali U, Issa Y, Hagenaars JC, Bakker OJ, van Goor H, Nieuwenhuijs VB, Bollen
TL, van Ramshorst B, Witteman BJ, Brink MA, Schaapherder AF, Dejong CH, Spanier BW,
Heisterkamp J, van der Harst E, van Eijck CH, Besselink MG, Gooszen HG, van Santvoort
HC, Boermeester MA; Dutch Pancreatitis Study Group. Risk of Recurrent Pancreatitis and
Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis.
Clin Gastroenterol Hepatol. 2016 May;14(5):738-46.
12. Broeders JA, Ahmed Ali U, Molyneux AJ, Poncyljusz W, Raymond J, White PM, Steinfort
B. Bioactive versus bare platinum coils for the endovascular treatment of intracranial
aneurysms: systematic review and meta-analysis of randomized clinical trials.
J Neurointerv Surg. 2016 Sep;8(9):898-908.
13. Ahmed Ali U, Pahlplatz JM, Nealon WH, van Goor H, Gooszen HG, Boermeester MA.
Endoscopic or surgical intervention for painful obstructive chronic pancreatitis.
Cochrane Database Syst Rev. 2015 Mar 19;(3):CD007884.
14. Ahmed Ali U, Issa Y, van Goor H, van Eijck CH, Nieuwenhuijs VB, Keulemans Y, Fock-
ens P, Busch OR, Drenth JP, Dejong CH, van Dullemen HM, van Hooft JE, Siersema PD,
Spanier BW, Poley JW, Poen AC, Timmer R, Seerden T, Tan AC, Thijs WJ, Witteman BJ,
Romkens TE, Roeterdink AJ, Gooszen HG, van Santvoort HC, Bruno MJ, Boermeester
MA; Dutch Pancreatitis Study Group. Dutch Chronic Pancreatitis Registry (CARE): design
and rationale of a nationwide prospective evaluation and follow-up.
Pancreatology. 2015 Jan-Feb;15(1):46-52.
15. Hollemans RA, Bollen TL, van Brunschot S, Bakker OJ, Ahmed Ali U, van Goor H, Boer-
meester MA, Gooszen HG, Besselink MG, van Santvoort HC; Dutch Pancreatitis Study
Group. Predicting Success of Catheter Drainage in Infected Necrotizing Pancreatitis.
Ann Surg. 2016 Apr;263(4):787-92.
16. Bakker OJ, van Brunschot S, van Santvoort HC, Besselink MG, Bollen TL, Boermeester
MA, Dejong CH, van Goor H, Bosscha K, Ahmed Ali U, Bouwense S, et al.; Dutch
Pancreatitis Study Group. Early versus on-demand nasoenteric tube feeding in acute
pancreatitis.
N Engl J Med. 2014 Nov 20;371(21):1983-93.
17. Scoglio D, Ahmed Ali U, Fichera A. Surgical treatment of ulcerative colitis: ileorectal vs
ileal pouch-anal anastomosis.
World J Gastroenterol. 2014 Oct 7;20(37):13211-8.
18. Ahmed Ali U, Dunne T, Gurland B, Vogel JD, Kiran RP. Actual versus estimated length
of stay after colorectal surgery - which factors influence a deviation?
Am J Surg. 2014 Oct;208(4):663-9.
223
A
Appendices
19. Ahmed Ali U, Boermeester MA. [Appraising the evidence for new treatments].
Ned Tijdschr Geneeskd. 2014;158:A7281.
20. Ahmed Ali U, Martin ST, Rao AD, Kiran RP. Impact of preoperative immunosuppressive
agents on postoperative outcomes in Crohn’s disease.
Dis Colon Rectum. 2014 May;57(5):663-74.
21. Bakker OJ, van Santvoort H, Besselink MG, Boermeester MA, van Eijck C, Dejong K,
van Goor H, Hofker S, Ahmed Ali U, Gooszen HG, Bollen TL; Dutch Pancreatitis Study
Group. Extrapancreatic necrosis without pancreatic parenchymal necrosis: a separate
entity in necrotising pancreatitis?
Gut. 2013 Oct;62(10):1475-80.
22. Bouwense SA, Ahmed Ali U, ten Broek R, Issa Y, van Eijck CH, Wilder-Smith OH, van
Goor H. Pain outcome after pancreatic surgery for pain of chronic pancreatitis: Relation
to altered central pain processing.
Br J Surg. 2013 Dec;100(13):1797-804
23. Issa Y, Ahmed Ali U, Bouwense SA, van Santvoort HC, van Goor H. Preoperative Opioid
Use And The Outcome Of Thoracoscopic Splanchnicectomy In Chronic Pancreatitis: A
Systematic Review.
Surg Endosc. 2014 Feb;28(2):405-12.
24. Ahmed Ali U, van der Sluis PC, Issa Y, AbouHabaga B, Gooszen HG, Flum DR, Algra
A, Besselink MG. Trends in worldwide volume and methodological quality of surgical
randomized controlled trials.
Ann Surg. 2013 Aug;258(2):199-207.
25. Besselink MG, Ahmed Ali U. Nederland wereldwijd koploper in kwaliteit van chirur-
gische RCTs.
Nederlands Tijdschrift voor Heelkunde. 2013 Jul;22(4):10-1.
26. Ahmed Ali U, Vogel JD. Safety of Surgical Resident Training.
Adv Surg. 2013;47:45-57. (Book chapter)
27. Kiran RP, Ahmed Ali U, Nisar PJ, Khoury W, Gu J, Shen B, Remzi FH, Hammel JP, Lavery
IC, Fazio VW, Goldblum JR. Risk and Location of Cancer in Patients with Preoperative
Colitis-Associated Dysplasia Undergoing Proctocolectomy.
Ann Surg. 2014 Feb;259(2):302-9.
28. Ahmed Ali U, Issa Y, Bruno MJ, van Goor H, van Santvoort H, Busch ORC, Dejong CHC,
Nieuwenhuijs VB, van Eijck CH, van Dullemen HM, Fockens P, Siersema PD, Gouma
DJ, MA Boermeester, et al. Early Surgery versus Optimal Current Step-up Practice for
Chronic Pancreatitis (ESCAPE): design and rationale of a randomized trial.
BMC Gastroenterol. 2013 Mar 18;13(1):49.
224 Appendices
29. Broeders JA, Roks DJ, Ahmed Ali U, Watson DI, Baigrie RJ, Cao Z, Hartmann J, Maddern
GJ. Laparoscopic Anterior 180-Degree Versus Nissen Fundoplication for Gastroesopha-
geal Reflux Disease Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Ann Surg. 2013 May;257(5):850-9.
30. Shapiro R, Ahmed Ali U, Lavery IC, Kiran RP. Endorectal ultrasound does not reliably
identify patients with uT3 rectal cancer who can avoid neoadjuvant chemoradiotherapy.
Int J Colorectal Dis. 2013 Feb; 28(7):993-1000.
31. Ahmed Ali U, Nieuwenhuijs VB, van Eijck CH, Gooszen HG, van Dam RM, Busch OR, Di-
jkgraaf MG, Mauritz FA, Jens S, Mast J, van Goor H, Boermeester MA; Dutch Pancreatitis
Study Group. Clinical outcome in relation to timing of surgery in chronic pancreatitis: a
nomogram to predict pain relief.
Arch Surg. 2012 Oct;147(10):925-32.
32. Kiran RP, Ahmed Ali U, Coffey JC, Vogel JD, Pokala N, Fazio VW. Impact of Resident
Participation in Surgical Operations on Postoperative Outcomes: National Surgical Qual-
ity Improvement Program.
Ann Surg. 2012 Sep;256(3):469-75.
33. Ahmed Ali U, Shen B, Remzi FH, Kiran RP. The Management of Anastomotic Pouch
Sinus After IPAA.
Dis Colon Rectum. 2012 May;55(5):541-8.
34. van Esch AA, Ahmed Ali U, van Goor H, Bruno MJ, Drenth JPH. Wide variation in
diagnostic and therapeutic strategies in chronic pancreatitis: A Dutch national survey.
Journal of the Pancreas. 2012 Jul 10;13(4):394-401.
35. de Zeeuw S, Ahmed Ali U, Donders RA, Hueting WE, Keus F, van Laarhoven CJ. Update
of complications and functional outcome of the ileo-pouch anal anastomosis: overview
of evidence and meta-analysis of 96 observational studies.
Int J Colorectal Dis. 2012 Apr;27(4):553.
36. Ahmed Ali U, Bruno MJ, Issa Y, Gooszen HG, Fockens P, Boermeester MA; Pancreatitis
Werkgroep Nederland. [Better pain management in chronic pancreatitis through early
surgery?].
Ned Tijdschr Geneeskd. 2012;156(5):A4469. Dutch.
37. Ahmed Ali U, Pahlplatz JM, Nealon WH, van Goor H, Gooszen HG, Boermeester MA.
Endoscopic or surgical intervention for painful obstructive chronic pancreatitis.
Cochrane Database Syst Rev. 2012 Jan 18;1:CD007884.
38. de Zeeuw S, Ahmed Ali U, van der Kolk MB, van Laarhoven KC. Ileal pouch anal anas-
tomosis with close rectal dissection using automated vessel sealers forulcerative colitis: a
promising alternative.
Dig Surg. 2011;28(5-6):345-51.
225
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Appendices
39. van Santvoort HC, Bakker OJ, Bollen TL, Besselink MG, Ahmed Ali U, SchrijverAM,
Boermeester MA, et al; Dutch Pancreatitis Study Group. A conservative and minimally
invasive approach to necrotizing pancreatitis improves outcome.
Gastroenterology. 2011 Oct;141(4):1254-63.
40. Broeders JA, Roks DJ, Ahmed Ali U, Draaisma WA, Smout AJ, Hazebroek EJ. Lapa-
roscopic anterior versus posterior fundoplication for gastroesophageal reflux disease:
systematic review and meta-analysis of randomized clinical trials.
Ann Surg. 2011 Jul;254(1):39-47.
41. Ahmed Ali U, Jens S, Busch OR, Keus F, van Goor H, Gooszen HG, Boermeester MA.
Antioxidants for pain in chronic pancreatitis.
Cochrane Database Syst Rev. 2014 Aug 21;(8):CD008945.
42. Bakker OJ, van Santvoort HC, van Brunschot S, Ahmed Ali U, Besselink MG,Boermeester
MA, et al; Dutch Pancreatitis Study Group. Pancreatitis, very early compared with normal
start of enteral feeding (PYTHON trial): design and rationale of a randomised controlled
multicenter trial.
Trials. 2011 Mar 10;12:73.
43. Broeders JA, Mauritz FA, Ahmed Ali U, Draaisma WA, Ruurda JP, Gooszen HG,Smout AJ,
Broeders IA, Hazebroek EJ. Systematic review and meta-analysis oflaparoscopic Nissen
(posterior total) versus Toupet (posterior partial) fundoplication for gastro-oesophageal
reflux disease.
Br J Surg. 2010 Sep;97(9):1318-30.
44. Besselink MG, van Santvoort HC, Renooij W, de Smet MB, Boermeester MA, FischerK,
Timmerman HM, Ahmed Ali U, Cirkel GA, et al; Dutch Acute Pancreatitis Study Group.
Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in
acute pancreatitis.
Ann Surg. 2009 Nov;250(5):712-9.
45. Ahmed Ali U, Keus F, Heikens JT, Bemelman WA, Berdah SV, Gooszen HG, vanLaar-
hoven CJ. Open versus laparoscopic (assisted) ileo pouch anal anastomosis for ulcerative
colitis and familial adenomatous polyposis.
Cochrane Database Syst Rev. 2009 Jan 21;(1): CD006267.
46. Keus F, Ahmed Ali U, Noordergraaf GJ, Roukema JA, Gooszen HG, van LaarhovenCJ.
Laparoscopic vs. small incision cholecystectomy: Implications for pulmonary function
and pain. A randomized clinical trial.
Acta Anaesthesiol Scand. 2008 Mar;52(3):363-73.
226 Appendices
collaborator47. van Santvoort HC, Besselink MG, Bakker OJ, Hofker HS, Boermeester MA, Dejong CH,
van Goor H, Schaapherder AF, van Eijck CH, Bollen TL, van Ramshorst B, Nieuwenhuijs
VB, Timmer R, Laméris JS, Kruyt PM, Manusama ER, van der Harst E, van der Schelling
GP, Karsten T, Hesselink EJ, van Laarhoven CJ, Rosman C, Bosscha K, de Wit RJ, Houdijk
AP, van Leeuwen MS, Buskens E, Gooszen HG; Dutch Pancreatitis Study Group. A step-
up approach or open necrosectomy for necrotizing pancreatitis.
N Engl J Med. 2010 Apr 22;362(16):1491-502.
48. van Santvoort HC, Besselink MG, de Vries AC, Boermeester MA, Fischer K, Bollen TL,
Cirkel GA, Schaapherder AF, Nieuwenhuijs VB, van Goor H, Dejong CH, van Eijck CH,
Witteman BJ, Weusten BL, van Laarhoven CJ, Wahab PJ, Tan AC, Schwartz MP, van der
Harst E, Cuesta MA, Siersema PD, Gooszen HG, van Erpecum KJ; Dutch Acute Pancre-
atitis Study Group. Early endoscopic retrograde cholangiopancreatography in predicted
severe acute biliary pancreatitis: a prospective multicenter study.
Ann Surg. 2009 Jul;250(1):68-75.
49. Besselink MG, van Santvoort HC, Buskens E, Boermeester MA, van Goor H, Timmerman
HM, Nieuwenhuijs VB, Bollen TL, van Ramshorst B, Witteman BJ, Rosman C, Ploeg RJ,
Brink MA, Schaapherder AF, Dejong CH, Wahab PJ, van Laarhoven CJ, van der Harst E,
van Eijck CH, Cuesta MA, Akkermans LM, Gooszen HG; Acute Pancreatitis Werkgroep
Nederland. [Probiotic prophylaxis in patients with predicted severe acute pancreatitis: a
randomised, double-blind, placebo-controlled trial].
Ned Tijdschr Geneeskd. 2008 Mar 22;152(12):685-96.
50. Besselink MG, van Santvoort HC, Buskens E, Boermeester MA, van Goor H, Timmerman
HM, Nieuwenhuijs VB, Bollen TL, van Ramshorst B, Witteman BJ, Rosman C, Ploeg RJ,
Brink MA, Schaapherder AF, Dejong CH, Wahab PJ, van Laarhoven CJ, van der Harst
E, van Eijck CH, Cuesta MA, Akkermans LM, Gooszen HG; Dutch Acute Pancreatitis
Study Group. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised,
double-blind, placebo-controlled trial.
Lancet. 2008 Feb 23;371(9613):651-659.
227
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Appendices
curriculuM viTae
Usama Ahmed Ali was born on 19 April 1983 in Tripoli,
Libya. Both his parents have their roots in Gherian (غريان) a
small mountain town 80 kilometers to the south of the Libyan
coast. He came with his family to the Netherlands at 9 years
of age to call Utrecht home for most of his subsequent life.
He graduated high-school from College De Klop in 2001, and
enrolled into a double-major in Medicine and Computer Sci-
ence at Utrecht University. He obtained a Bachelor›s degree in
Computer Science in 2006, followed by his Medical Degree in
2007. During his studies he participated in several scientific
projects, most notably on colorectal surgery with dr. Eric Keus and prof. dr. van Laarhoven.
After graduation, he commenced with his PhD program within the Dutch Pancreatitis Study
Group with the goal of initiating research on chronic pancreatitis under the supervision of
prof. dr. Boermeester and prof. dr. Gooszen. This resulted in setting-up and obtaining
grants for two long-term longitudinal projects, namely the CARE-national database and
the ESCAPE-randomized trial. While recruitment for both projects was ongoing, he crossed
the Atlantic to Columbus, Ohio in 2011 in chase of his love and by that time his spouse
Amasi Elbakush. There, he worked as a research fellow at the Department of Colorectal
Surgery of the Cleveland Clinic under supervision of prof. dr. Ravi Kiran. He then completed
his US Medical Licensing Exams and took a brief clinical training program at the University
of Washington in Seattle. In the meantime he read part-time for a Master’s degree on
Evidence-Based Medicine at the University of Oxford, which he obtained in 2012 with
distinction. Eventually he returned to his hometown Utrecht to start his General Surgery
residency, which he commenced in 2014 at the University Medical Center Utrecht. The two
research tracks he has engaged in, i.e. chronic pancreatitis and colorectal surgery, evolved
into the current two PhD dissertations.