Inflammatory bowel disease: perioperative pharmacological considerations.

Mayo Clin Proc. • August 2011;86(8):748-757 • doi:10.4065/mcp.2011.0074 • www.mayoclinicproceedings.com748
Inflammatory Bowel DIsease
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revIew
From the Department of Hospital Medicine (A.K., M.A.), Department of Pedi-
atric Gastroenterology, Children’s Hospital (F.M.), Digestive Disease Institute
(B.S.), Cleveland Clinic, Cleveland, OH; and Department of Medicine (A.A.)
and Department of Gastroenterology (A.J.), MetroHealth Medical Center,
Cleveland, OH.
Individual reprints of this article are not available. Address correspondence
to Ajay Kumar, MD, MRCP, at his current affiliation: Chief, Division of Hospital
Medicine, Hartford Hospital, 80 Seymour St, Hartford, CT 06102 (drajaykumar
@gmail.com).
© 2011 Mayo Foundation for Medical Education and Research
The perioperative management of patients with Crohn disease (CD) and ulcerative colitis (UC) requires a mul-
tifaceted approach involving both traditional and disease-
specific considerations. As is true of any surgical patient,
a thorough preoperative evaluation is crucial. Of note, the
proportion of older patients among those with inflammatory
bowel disease (IBD) is increasing, with a consequent in-
crease in the complexity of comorbid conditions that would
require perioperative care. Recent data have shown worse
outcomes among elderly patients treated with certain im-
munosuppressant agents such as anti–tumor necrosis factor
(TNF) compared with a younger population.
Substantial morbidity is associated with IBD, especially
among malnourished patients, those aged 60 to 80 years,
those requiring emergency surgery, those with fistulizing
disease, and those treated at low-volume surgical centers.
The perioperative morbidity is associated as well with
the nature of the surgical procedure: a total proctocolec-
Inflammatory Bowel Disease:
Perioperative Pharmacological Considerations
Ajay Kumar, MD, MRCP; Moises Auron, MD; Ashish Aneja, MD; Franziska Mohr, MD;
Alok Jain, MD, MRCP; and Bo Shen, MD
The perioperative management of patients with inflammatory
bowel disease is challenging given the altered immune system
that results from a variety of biologic and immunomodulator thera-
pies. Clinicians are often faced with challenges and complicated
equations when deciding on the type and dose of medication. To
understand the effect of these medications and review the evi-
dence regarding the management of these medications in the
perioperative setting, a PubMed-based literature search (Janu-
ary 1, 1960, through April 1, 2011) was conducted using the fol-
lowing search terms: perioperative management, risk, outcome,
inflammatory bowel disease, ulcerative colitis, Crohn’s disease,
aminosalicylates, glucocorticoids, purine analogues, cyclosporine,
methotrexate, biologic therapy, infliximab, and thromboembolism.
The 414 articles identified were manually sorted to exclude those
that did not address perioperative risk, outcomes, and medica-
tions in the abstracts, yielding 84 articles for review. Additional
references were obtained from the citations within the retrieved
articles. This review surveys the findings of the selected articles
and presents guidelines and resources for perioperative medica-
tion management for patients with inflammatory bowel disease
undergoing surgery.
Mayo Clin Proc. 2011;86(8):748-757
ACTH = adrenocorticotropic hormone; 5-ASA = 5-aminosalicylic acid;
CD = Crohn disease; CI = confidence interval; DVT = deep venous throm-
bosis; GI = gastrointestinal; HPA = hypo thalamic-pituitary-adrenal;
IBD = inflammatory bowel disease; LMWH = low-molecular-weight hep-
arin; OR = odds ratio; PE = pulmonary embolism; TNF = tumor necrosis
factor; TPC = total proctocolectomy; UC = ulcerative colitis; VTE =
venous thromboembolism
tomy (TPC) with J pouch may result in higher postopera-
tive infection rates than TPC with an ileostomy; a stric-
tureplasty or stoma revision may have a decreased rate of
postoperative cardiopulmonary or infectious complications
compared with a complicated resection for fistulizing dis-
ease. Laparoscopic surgery also has been consistently as-
sociated with decreased postoperative length of stay and
complication rate.1,2
One of the factors with the greatest effect on medical
and surgical outcomes is the long-term immunosuppres-
sant therapy that makes patients susceptible to infections
and poor wound healing.3
The advent of immunomodulators and biological agents
poses new challenges for practicing physicians, who are
increasingly faced with making clinical recommendations
with little evidence to support their decision. This review
focuses on recommendations for perioperative manage-
ment of immunosuppressant and immunomodulator agents
in patients with IBD.
TIMING AND TyPE OF SURGERy
Patients undergoing urgent IBD-related surgery are at
additional risk of cardiac complications. Various factors
limit optimization of preoperative management of car-
diovascular risk in such patients. Mangano4 showed that
cardiac complications were 2 to 5 times more likely to
occur with emergent IBD and non–IBD-related surgical
procedures than elective operations. Such increased risk
might be expected, given the fact that these patients had
chronically debilitating disease conditions.
The perioperative medication management in patients
with IBD will vary depending on the clinical situation of
the patient (UC vs CD; elective vs emergent surgery).

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Inflammatory Bowel DIsease
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In patients with UC, gastrointestinal (GI) surgery,
most commonly elective TPC with ileoanal anastomosis,
would be the recommended approach. However, emer-
gency surgery can be required, especially in the setting
of fulminant colitis with no opportunity for preopera-
tive optimization. Patients with UC who have previously
undergone proctocolectomy and require surgery will no
longer require immunosuppressant therapy, allowing for
more straightforward perioperative medication manage-
ment. Similarly, for patients with CD, clinical decision
making will depend on whether procedures are elective
(eg, strictureplasty) or emergent (eg, alleviation of small
bowel obstruction).
Perioperative morbidity is also associated with the na-
ture of the surgical procedure: a TPC with J pouch may
result in higher rates of postoperative infection than a
TPC with an ileostomy; a strictureplasty or stoma revi-
sion may have a decreased rate of postoperative cardio-
pulmonary or infectious complications compared with
a complicated resection for fistulizing disease.5 Lap-
aroscopic surgery has been consistently associated with
decreased postoperative length of stay and complication
rate.1,2 Staged procedures also result in decreased short-
term complications.6,7
The perioperative management of medication will not
differ between patients with IBD undergoing GI vs non-GI
surgeries (eg, orthopedic procedures) because, regardless
of the type of procedure, the adequate control of IBD is
paramount given its systemic implications.
Most of these patients who undergo surgery understand
that it carries a perioperative cardiac risk but have recon-
ciled themselves to the fact that the anticipated morbidity
and mortality from not operating overrides that risk. Be-
cause most surgical procedures in these patients are intra-
peritoneal and are traditionally classified into the interme-
diate-risk category, case-by-case evaluation of risk factors
should determine the use of perioperative β-blockers.8-10
Given the morbidity associated with the underlying dis-
ease, these patients may require emergency surgery, which
poses the additional risk of postoperative complications
and blood loss.11
One of the most important aspects of the perioperative
care of patients with IBD, the correct and efficient manage-
ment of medications, is summarized in Table 1 and dis-
cussed in detail in the section that follows.
PERIOPERATIVE MANAGEMENT OF
MEDICATIONS USED IN IBD
AminosAlicylAtes
5-Aminosalicylic acid (5-ASA) agents remain the main-
stay of therapy for the induction of remission in mild to
moderately active UC12 and for the maintenance of remis-
sion in UC and possible CD.13 Sulfasalazine, the prototype
aminosalicylate, was developed to deliver both an antibac-
terial agent (sulfapyridine) and an anti-inflammatory agent
(5-ASA, mesalamine, or mesalazine); the 5-ASA com-
ponent of sulfasalazine is primarily responsible for the
therapeutic benefit. It is poorly absorbed in the colon and
partially absorbed in the small intestine. Several sulfa-free
aminosalicylates have been developed in recent years14 to
target specific GI sites based on the assumption that the ef-
fects of 5-ASA are topical and not systemic. Sulfasalazine
and mesalamine have multiple anti-inflammatory effects,
including the inhibition of the arachidonic acid pathway
along the cyclooxygenase, lipoxygenase, and platelet ag-
gregation factor systems. These drugs are primarily elimi-
nated by the kidneys. Important adverse effects include
hypersensitivity reactions, bone marrow suppression,
pneumonitis, pancreatitis, and hemolytic anemia. These
compounds have a short half-life (6-10 hours) and are ex-
tensively metabolized. There is a paucity of clinical data
for perioperative use of these medications.
In patients in whom decreased glomerular filtration is
more likely (age, >65 years; American Society of Anes-
thesiologists physical status score, IV or V; revised cardiac
risk index score, >2; chronic heart disease), a reasonable
approach in the perioperative phase is to discontinue sul-
fasalazine and mesalamine a day before surgery with re-
sumption 3 days after surgery.15
Patients undergoing proctocolectomy will not require
postoperative resumption of these agents.
Article HigHligHts
• Aminosalicylates (sulfasalazine and mesalamine)
should be discontinued 1 day before surgery with re-
sumption 3 days after surgery, especially in patients
with susceptibility for decreased glomerular filtration
• For patients receiving glucocorticoids, the most rel-
evant issue is to ensure adequate stress glucocorticoid
supplementation if required
• Purine analogues (6-mercaptopurine/azathioprine)
should be withheld on the day of surgery and resumed
in the first 3 postoperative days when oral medications
are resumed, if renal function remains normal
• Cyclosporine should be continued in the preoperative
and immediate postoperative period, given the existing
evidence
• Methotrexate should be discontinued 1 week before
surgery until at least 1 week after surgery in patients
with a history of infectious complications and resumed
after successful wound healing
• Immunomodulator therapy with anti–tumor necrosis
factor agents should be continued in the perioperative
setting

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Inflammatory Bowel DIsease
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glucocorticoids
Glucocorticoid use is common in IBD. The most relevant
approach in the perioperative period is to ensure that ad-
equate stress glucocorticoid supplementation is given. In
patients with IBD, especially patients with active Crohn
disease, glucocorticoids are highly effective in induc-
ing clinical remission. However, the therapeutic role of
glucocorticoids in the treatment of IBD is primarily to
decrease the intensity of inflammation because they are
ineffective in maintaining remission or healing mucosal
lesions. Long-term use of glucocorticoids is associated
with dependency as well as clinical relapses. In addition,
long-term glucocorticoid use is associated with osteope-
nia and osteoporosis, glucose intolerance and diabetes
mellitus, increased intraocular pressure and glaucoma,
and severe infections.16
Adequate glucose control must be established in these
patients in the perioperative setting because uncontrolled
hyperglycemia is associated with worse outcome, includ-
ing poor wound healing and increased infections.
The increased likelihood of infectious complications
was demonstrated in the TREAT (The Crohn's Therapy,
Resource, Evaluation, and Assessment Tool) registry, in
which glucocorticoid use was an independent factor asso-
ciated with serious infections (odds ratio [OR], 2.21; 95%
confidence interval [CI], 1.46-3.34; P<.001).17 In a series
of 100 patients with IBD who developed opportunistic in-
fections, Toruner et al18 found that glucocorticoid use was
significantly associated with the development of opportu-
nistic infections (OR, 3.4; 95% CI, 1.8-6.2). In this series,
in multivariate analysis, the risk for opportunistic infection
increased substantially with the use of a single immuno-
suppressant (OR, 2.9; 95% CI, 1.5-5.3) vs a combination of
2 or 3 immunosuppressants (OR, 14.5; 95% CI, 4.9-43.0).
In an epidemiologic study in Olmsted County, Minneso-
ta, glucocorticoid dependence at 1 year was found in 28%
of patients with CD and 22% of patients with UC.19
The strategy to minimize adverse effects related to glu-
cocorticoids in patients with IBD is to use the lowest effec-
tive dose to induce remission in patients with moderately to
severely active CD and acute severe colitis,16,20 along with
the early use of other immunosuppressant glucocorticoid-
sparing agents and biologic therapy.
In a 1952 article, Fraser et al21 first reported iatrogenic
adrenal insufficiency due to preoperative glucocorticoid
withdrawal in a surgical patient. The publication of similar
findings in a case report the following year led to recommen-
dations for high-dose or “stress-dose” glucocorticoids in the
perioperative period.22 Since then, the overall practice has
evolved, and currently the doses of glucocorticoid replace-
ment are lower than initially espoused because of concerns
about the adverse effects of glucocorticoids, including im-
paired wound healing, elevated risk of infections, GI bleed-
ing, and hyperglycemia.23 The entire practice of “stress-
dose” glucocorticoid replacement, even in its current form,
has been questioned by some investigators.22-25 In a recent
study, Bruewer et al26 found that patients receiving high-dose
and prolonged preoperative systemic glucocorticoid therapy
who underwent bowel resection for CD experienced no more
postoperative complications than did control patients.
In a series from the University of Tokyo, which ana-
lyzed data on all patients with UC from 1963 to 1994,
those receiving high-dose glucocorticoids were more like-
ly to undergo colectomy because they were more likely to
have a refractory disease and to experience postoperative
complications.27
Surgical stress is a potent stimulant of the hypothalam-
ic-pituitary-adrenal (HPA) axis. Stress acts by stimulating
the release of corticotropin-releasing hormone and argi-
nine vasopressin that in turn causes adrenocorticotropic
hormone (ACTH) release. In surgical patients, the highest
ACTH levels are noted during the immediate postopera-
tive recovery period and are likely triggered by trauma
and pain. Elevated levels of ACTH are also seen during
extubation and reversal of anesthesia and at the time of
surgical incision.27-29 Epidural or local anesthesia does not
appear to stimulate the HPA axis.30 In addition, plasma
ACTH response during surgery is attenuated by opiate
drugs.28 Substantial variation exists in the degree of en-
dogenous glucocorticoid release in response to surgical
TABle 1. Medication Management During the Perioperative Perioda
Drug Recommendation for practice Evidence levelb
Glucocorticoids Continue; administer stress dose (see Table 2)
5-ASA Discontinue on day of surgery and resume 3 days after surgery if normal renal function C
Azathioprine, 6-MP Discontinue on day of surgery and resume 3 days after surgery if normal renal function B, C
Methotrexate Continue, unless previous poor wound healing or postoperative infections B, C
Cyclosporine Continue but carefully monitor for opportunistic infectious complications B, C
Infliximab Continue without interruption B
a 5-ASA = 5-aminosalicylic acid; 6-MP = 6-mercaptopurine.
b Evidence level A = multiple populations evaluated (trials and clinical registries), multiple randomized clinical trials, or meta-
analysis; evidence level B = limited populations evaluated; data derived from a single randomized trial or nonrandomized studies;
evidence Level C = very limited populations evaluated or consensus opinion of experts, case studies, or standards of care.

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stress. Important factors that may influence this variation in-
clude concomitant medication use, antecedent illnesses, and
age. In general, patients receiving 5 mg or less of prednisone
each day, alternate-day glucocorticoids, or any dose of glu-
cocorticoids for less than 3 weeks are not considered to have
a suppressed HPA axis and do not require “stress-dose” glu-
cocorticoids.31-34 In contrast, patients receiving less than 20
mg/d of prednisone (or its equivalent) for more than 3 weeks
or with features of Cushing syndrome should be assumed to
have a suppressed HPA axis and considered for “stress-dose”
glucocorticoid supplementation perioperatively. For patients
receiving between 5 and 10 mg of prednisone or its equiva-
lent for more than 3 weeks, a clinical prediction rule can-
not be implemented because, in this subset of patients, the
HPA axis may or may not be suppressed. Generally speak-
ing, rather than subjecting these patients to a corticotropin
stimulation test, which may not reliably predict HPA axis
suppression, it may be prudent to provide glucocorticoid
supplementation in these patients. However, the administra-
tion of glucocorticoids in any patient who has been receiving
prednisone doses of more than 5 mg/d for more than 1 week
in the 6 to 12 months before surgery appears unnecessary.
The physician performing the preoperative assessment
should bear in mind that patients receiving long-term high-
dose inhaled or topical glucocorticoids for various condi-
tions may have a suppressed HPA axis and may be candi-
dates for “stress-dose” glucocorticoids. Although a healthy
person is estimated to secrete between 20 and 30 mg of
cortisol a day,35 the requirement for patients undergoing a
surgical procedure, while varying according to the degree
of expected stress, rarely exceeds 200 mg of cortisol secre-
tion in 24 hours.22 Currently, expert consensus favors opti-
mizing the glucocorticoid replacement dose to the magni-
tude of stress posed by the surgery.
Patients receiving glucocorticoid therapy should receive
their daily requirement throughout the perioperative peri-
od, along with supplementation as outlined in Table 2.36,37
Purine AnAlogues (6-mercAPtoPurine/AzAtHioPrine)
These agents have been widely used as glucocorticoid-
sparing agents for maintenance of remission. Both agents
are oxidized or methylated in erythrocytes or the liver. The
perioperative use of immunomodulators such as purine
analogues does not affect surgical outcomes or morbid-
ity. Early complications after proctocolectomy with ileal
pouch-anal anastomosis were not found in patients using
azathioprine/6-mercaptopurine but were observed in pa-
tients receiving high-dose glucocorticoids in a study by
Mahadevan et al.38 However, potential concerns related to
purine analogues are pancreatitis, leukopenia, hepatitis,
and bone marrow suppression.
Azathioprine is known to be antagonistic to neuromus-
cular blocking agents. Dretchen et al39 described a reversal
of neuromuscular blockage produced by d-tubocurarine
but an increase of the neuromuscular blockade produced
by succinylcholine. The effects of azathioprine on neuro-
muscular transmission are considered to be secondary to
inhibition of phosphodiesterase in the motor nerve termi-
nal. Gramstad40 suggested that the initial dose of neuro-
muscular blocking drugs in renal transplant patients should
be increased in the presence of azathioprine (atracurium
by 37%, vecuronium by 20%, and pancuronium by 45%).
In this study, the atracurium dose was unaffected by re-
nal function, whereas dose requirements for vecuronium
TABle 2. Glucocorticoid Management During the Perioperative Period
Minor surgical stress Moderate surgical stress Major surgical stress
Axis suppression (hernia) (articular replacement) (CABG)
No Daily dose Daily dose Daily dose
PDN <5 mg/d No supplementation No supplementation No supplementation
Glucocorticoids <3 wk
Negative corticotropin test
Documented or suspected Daily dose Hydrocortisone Hydrocortisone
PDN >10 mg/d for >3 wk No supplementation 50 mg IV (induction) 100 mg IV (induction)
Cushingoid 25 mg IV every 8 h 50 mg IV every 8 h
Positive corticotropin test for 24-48 h for 24 h
25 mg IV every 8 h
for 24-48 h
Unknown Daily dose Positive corticotropin test Hydrocortisone
PDN 5-10 mg ≥3 wk No supplementation Hydrocortisone 100 mg IV (induction)
50 mg IV (induction) 50 mg IV every 8 h
25 mg IV every 8 h for 24 h
for 24-48 h 25 mg IV every 8 h
for 24-48 h
CABG = coronary artery bypass grafting; IV= intravenously; PDN = prednisone.
Adapted from Med Clin North Am,36 with permission from Elsevier and Perioperative Medicine: Just the Facts,37
with permission from McGraw-Hill.

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and pancuronium were reduced by 23.2% and 61.5%, re-
spectively, compared with patients not taking azathioprine.
These findings suggest a transient antagonism of neuro-
muscular blockade in the presence of azathioprine.
Aberra et al41 performed a retrospective cohort study in
159 patients with IBD who underwent elective bowel sur-
gery, including 56 patients receiving glucocorticoids alone,
52 receiving 6-mercaptopurine/azathioprine with or with-
out glucocorticoids, and 51 patients receiving neither glu-
cocorticoids nor 6-mercaptopurine/azathioprine. The rate
of postoperative infectious complications was not found
to be significantly higher in the group receiving gluco-
corticoids or a combination of glucocorticoids and purine
analogues. In an animal study conducted by Brokowski et
al,42 the regeneration of a ureter and renal pelvis from a
transected and anastomosed strip of the ureteral wall was
not associated with any adverse effect on wound healing in
dogs receiving prednisone and azathioprine.
In a study by Colombel et al,43 the rate of postoperative
complications was not increased in 207 patients with CD
who underwent intra-abdominal surgery while receiving
glucocorticoids or immunosuppressive therapy with aza-
thioprine, 6-mercaptopurine, methotrexate, or infliximab.
Myrelid et al44 reported an 8% risk of postoperative
intra-abdominal septic complications in 343 consecutive
patients undergoing surgery for CD. Overall, thiopurine
therapy was associated with an increased risk of intra-ab-
dominal septic complications (16% vs 6% without therapy;
P=.044). The use of thiopurines was associated with a 24%
risk of septic complications in patients who had known risk
factors (both preoperative intra-abdominal sepsis and use
of colo-colonic anastomosis), 13% in patients with only 1
of these risk factors, and only 4% in patients with none of
these risk factors (P<.001).
A potential association between the use of thiopurines
and myelotoxicity has been reported.45 It has been recom-
mended, on the basis of weak evidence and physiologic
considerations, that thiopurines be stopped on the day of
surgery and resumed 3 days afterward because of their re-
nal elimination and potential for toxic metabolite accumu-
lation.46 However, the incidence rate of severe myelotoxic-
ity is less than 1% per patient and year of treatment, and
the mortality risk is less than 0.1%47; therefore, although
a theoretical risk for perioperative myelotoxicity exists, it
is almost negligible. Therefore, our recommendation is to
withhold thiopurines on the day of surgery and, if renal
function remains normal, to resume within the first 3 post-
operative days when oral medications are resumed.
cyclosPorine
This potent immunosuppressive agent has been used in pa-
tients with glucocorticoid-refractory UC as rescue therapy
before colectomy and occasionally in patients with CD. Cy-
closporine, a potent inhibitor of T cells that is metabolized
in the liver by CYP3A, is primarily excreted in bile; how-
ever, 6% of the drug is eliminated unchanged in urine. Ma-
jor adverse effects include nephrotoxicity, seizures, and op-
portunistic infections. The mortality rate with opportunistic
infections can be as high as 3.5%48; hence, patients receiving
cyclosporine and glucocorticoid therapy should be carefully
monitored for any signs of infection. These patients should
also receive due consideration for Pneumocystis jiroveci
prophylaxis with trimethoprim-sulfamethoxazole.
Preoperative cyclosporine has not been shown to have
any detrimental effects during or after surgery. In a small
case series of 25 patients, Pinna-Pintor et al49 found no
increased postoperative complications in patients treated
with intravenous or oral cyclosporine. These findings were
consistent with previous studies.50,51
We recommend careful observation of patients receiv-
ing cyclosporine for deterioration in renal function and op-
portunistic infections. At the same time, cyclosporine lev-
els ought to be carefully monitored. Current clinical data
are inadequate to support the discontinuation of this drug
before and immediately after surgery.
metHotrexAte
Methotrexate competitively inhibits the enzyme dihydro-
folate reductase, impairing DNA synthesis and therefore
cellular replication. Evidence to support its use in UC is
minimal.52 Methotrexate is excreted by the kidneys, and
patients with renal impairment require dose adjustment.
Major adverse effects include thrombocytopenia (up to
10%), pneumonitis, and hepatotoxicity. Perioperative con-
siderations include, but are not limited to, an increase in in-
fectious complications; in the setting of renal impairment,
a toxic buildup of its metabolites can lead to bone marrow
suppression.53,54 In a 1997 study of a population of patients
undergoing elective orthopedic surgery for rheumatoid
arthritis, Bridges and Moreland55 found increased periop-
erative complications in a small number of patients. Mul-
tiple subsequent studies in patients undergoing orthopedic
surgery have suggested an increased risk of postoperative
complications, consisting mainly of infections.56-58 Gren-
nan et al59 published a retrospective study of 388 patients
with rheumatoid arthritis who underwent surgery while re-
ceiving methotrexate and concluded that continuation of
methotrexate does not increase the risk of either infections
or surgical complications in patients within one year of
elective orthopedic surgery. Most studies have not specifi-
cally addressed the effect of methotrexate in the periopera-
tive period on renal function.
Concern has been raised about the potential interaction
between nitrous oxide used for anesthesia and methotrex-

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ate. A substantial interaction between nitrous oxide–based
anesthesia and methotrexate in cancer patients undergoing
surgery has been demonstrated by in vivo studies. Accord-
ing to these studies, patients who receive methotrexate dur-
ing the immediate postoperative period (within 6 hours)
after nitrous oxide–based anesthesia often develop severe
bone marrow depression and mucositis.60 However, no
quantitative data for dose-effect interactions are available
regarding the combined toxic effects of methotrexate and
nitrous oxide.
Most published trials have included patients receiving
low dosages of methotrexate (5-10 mg weekly). Only a
paucity of data supports the currently recommended dosag-
es of 15 mg weekly with escalation to 20 to 30 mg weekly
depending on clinical response and tolerability.61,62
Existing data do not suggest a significant increase in the
risk of perioperative infections or impaired wound healing.
Given the lack of data, in patients with a history of previous
or severe septic complications, it may be reasonable to dis-
continue methotrexate 1 week before surgery and resume
it no sooner than 1 week after or when the wound has suc-
cessfully healed. The risks vs the benefits of discontinuation
should be discussed with the patient, and the potential for
flare of the disease should be weighed against the potential
of poor wound healing or infectious complications.63
Biologic tHerAPy
Treatment for IBD has entered an era of biologic response
modifiers. One such agent, infliximab, a chimeric mono-
clonal antibody targeting TNF-α, is the first drug approved
by the US Food and Drug Administration for the treatment
of CD. Its role in the treatment of refractory CD is well
established,64,65 and current data support its use in patients
with moderately to severely active UC who have had an in-
adequate response to conventional therapy.66 Infliximab has
a long half-life of 8.0 to 9.5 days and has its own unique
adverse effect profile. Several adverse effects have been re-
ported for TNF-α–blocking agents, including reactivation
of tuberculosis; an increased risk of sepsis, pneumonia, and
fatal and opportunistic infections (eg, invasive fungal infec-
tions, listeriosis, Pneumocystis infections); reactivation of
chronic hepatitis B in carriers; worsened chronic heart fail-
ure; optic neuritis; demyelination reactions; bone-marrow
toxicity infusion reactions; acute and delayed hypersen-
sitivity reactions; and formation of anti–double-stranded
DNA.67-70
Despite its potent immunosuppressive effects, preopera-
tive use of infliximab does not seem to increase postopera-
tive complications in patients with UC or CD. In a cohort
of 314 patients with CD, 40 of whom received 1 or more
infusions of infliximab before intestinal resection, Mar-
chal et al71 found no increase in postoperative infections
or prolongation of hospital stay after infliximab infusion.
In a study by Jarnerot et al72 using infliximab as rescue
therapy in patients with moderately severe UC, 7 patients
who received infliximab underwent colectomy without any
increase in the postoperative complication rate. On the
basis of their retrospective study of 277 patients with CD
who received infliximab within 8 weeks of surgery and 4
weeks after surgery in addition to other immunomodula-
tors, Colombel et al43 concluded that infliximab is safe in
the perioperative setting. A 30-day postoperative follow-up
showed no increase in septic and nonseptic complications.
In a cohort study by Kunitake et al73 of 413 patients
with IBD who underwent abdominal surgery, the rate of
postoperative complications was similar in the 100 patients
who had received infliximab 12 weeks or less before sur-
gery vs those who had not.
Bordeianou et al74 compared 44 patients with UC and
symptoms of unremitting disease who were taking inflix-
imab before TPC or a subtotal colectomy with 127 patients
who were not using infliximab. The outcomes in both
groups were similar: rate of emergent surgery (4.5% vs
0.4%; P=.98), rate of subtotal colectomy (19.2% vs 18.0%;
P=.99), or rate of ileoanal J pouch reconstruction (53.8%
vs 62.0%; P=.98). The authors concluded that infliximab
contributed no increased surgical morbidity in patients
with UC.
Kraemer et al75 found that 16 of 19 patients who re-
ceived 5 mg/kg of infliximab perioperatively during sched-
uled anal reconstructive surgery for complicated fistulizing
anal CD had a favorable outcome, findings similar to those
of other studies in the same population. In the TREAT
registry study evaluating 6290 patients, Lichtenstein et al76
found that infliximab was not independently associated with
increased risk after adjustment for corticosteroid use and
disease severity; however, both corticosteroids and disease
severity were associated with adverse outcomes. In a recent
study by Gainsbury et al,77 infliximab was not associated
with increased risk of short-term postoperative complica-
tions after proctocolectomy and ileoanal anastomosis.
A retrospective study of 389 patients with CD who un-
derwent ileocolonic resection at the Cleveland Clinic,
60 of whom received infliximab within 3 months before
surgery, found an increased rate of postoperative sepsis,
abscess, and readmissions in the patients who received
infliximab; the authors of this study suggested that these
complications might have been prevented by a divert-
ing stoma.78 Of these patients, those using infliximab
had an increased rate of early complications (OR, 3.54;
95% CI, 1.51-8.31; P=.004) or sepsis (OR, 13.8; 95% CI,
1.8-105.0; P=.011) and an increased need for a 3-stage
procedure (OR, 2.07; 95% CI, 1.18-3.63; P=.011), lead-
ing Mor et al79 to conclude that infliximab use has changed

Mayo Clin Proc. • August 2011;86(8):748-757 • doi:10.4065/mcp.2011.0074 • www.mayoclinicproceedings.com754
Inflammatory Bowel DIsease
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
the surgical approach to UC by increasing the number of
operations. However, in response to an invited editorial
comment, they acknowledged that 3-stage procedures are
safe in these patients.
In a multivariate analysis of 301 patients with UC who
underwent ileal pouch anal anastomosis, 47 of whom re-
ceived infliximab preoperatively, Selvasekar et al80 re-
ported that infliximab was the only factor independently
associated with infectious complications in this group of
patients.
Toruner et al18 described a substantial increase in the
risk for opportunistic infection in patients taking a combi-
nation of 2 or 3 immunosuppressants (OR, 14.5; 95% CI,
4.9-43) vs those taking a single immunosuppressant (OR,
2.9; 95% CI, 1.5-5.3).
A recent study by Cottone et al81 demonstrated a higher
risk of severe infections (11%), neoplasms (3%), and mor-
tality (10%) in patients older than 65 years who received
TNF inhibitor therapy than in younger patients or in pa-
tients of the same age who did not receive such treatment.
Although new anti-TNFα drugs (eg, adalimumab and
certolizumab pegol) are available for the treatment of CD,
no data regarding their use in the perioperative setting have
been reported. The safety profile of these medications ap-
pears to be similar to that of infliximab, especially for fistu-
lizing CD.82-88
Another recently introduced agent that has been ap-
proved for the management of moderate to severe CD is
natalizumab, a humanized monoclonal antibody against
the α4 integrin subunit that inhibits leukocyte adhesion and
migration to areas of inflammation. However, safety con-
cerns regarding its association with progressive multifocal
leukoencephalopathy have limited its use. Data regarding
its use in the perioperative setting are unavailable.
Most evidence suggests that infliximab can be used
safely in the perioperative period. Divergent data may re-
flect the higher burden of comorbidity (concomitant im-
munosuppressant use, increased severity of disease) in pa-
tients with adverse outcomes.
Practices being increasingly recommended to improve
outcome include staged surgeries with temporary divert-
ing stomas and the selection of 3- rather than 2-stage ileal
pouch anal anastomosis.7,89
In a recent review, Beddy et al5 questioned whether it
was justifiable to delay surgery in patients who have re-
cently been administered infliximab or to create a proxi-
mal diverting stoma purely to deliver biologic medications.
Currently, we do not recommend the discontinuation of
immunomodulator therapy with anti-TNF agents in the pe-
rioperative setting. However, the clinician should be aware
of all possible complications, including serious infections,
in surgical patients receiving these agents.
PerioPerAtive medicAtion And
tHromBoemBolic events in iBd
Patients with IBD have long been known to be at increased
risk of thromboembolism. In 1936, Bargen and Barker90
at Mayo Clinic reported that 18 of 1500 patients with UC
had evidence of extensive arterial and venous thrombosis.
Since then, the association of these complications with
IBD has been increasingly recognized. Thromboembolic
complications in the cerebral and retinal vasculature,91 the
portal vein, and peripheral arteries92 have been reported.
In a case series of IBD-related thromboembolism from
Mayo Clinic, the activity of disease and extent of colonic
involvement in patients with UC were found to be associ-
ated with increased risk; however, 87% of patients in this
study had another risk factor for venous thrombosis, such
as hospitalization, immobilization, malignancy, or recent
surgery.93 These risk factors are common in patients who
are undergoing surgery, and aggressive antivenous throm-
bosis prophylaxis should be considered in these patients.
However, no guidelines for venous thrombosis prophylaxis
specifically in IBD patients have been published. In a study
by O’Connor et al,94 the event rate of clinical thrombosis
after major abdominal and pelvic surgery for patients with
UC was noted to be similar to that in patients without UC
undergoing similar surgery. The authors of that study con-
cluded that standard prophylaxis in a patient with UC is
acceptable to reduce the occurrence of thrombotic events
in the perioperative period.
Inherited risk factors for thrombosis, such as the fac-
tor V Leiden mutation, the G20210A mutation in the pro-
thrombin gene, and the homozygous C677T mutation in
the methylenetetrahydrofolate reductase gene, have not
been attributed to increased thrombosis in patients with
IBD.95 However, a thorough investigation of the coagula-
tion profile and genetic testing is advisable in younger IBD
patients with a first idiopathic thrombotic event.96
Hyperhomocysteinemia, which is considered a risk fac-
tor for arterial as well as venous thrombosis, has been found
to be more prevalent in patients with IBD97 but has not been
found to be a major contributory factor in the development
of venous or arterial thrombosis in patients with IBD.98
Using a large outpatient database (Manitoba Health da-
tabase), Bernstein et al99 demonstrated a 3-fold increased
risk of developing deep venous thrombosis (DVT) or pul-
monary embolism (PE) in patients with IBD, incidence
rates of 31.4 per 10,000 person-years for DVT and 10.3
per 10,000 person-years for PE in patients with CD, and
incidence rates of 30.0 per 10,000 person-years for DVT
and 19.8 per 10,000 person-years for PE in patients with
UC.99
In a more recent study among 13,756 patients with IBD
and 71,672 matched controls, Grainge et al100 found that

Mayo Clin Proc. • August 2011;86(8):748-757 • doi:10.4065/mcp.2011.0074 • www.mayoclinicproceedings.com 755
Inflammatory Bowel DIsease
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
139 patients and 165 controls developed venous throm-
boembolism (VTE); patients with IBD had a higher risk of
VTE compared with controls (hazard ratio, 3.4; 95% CI,
2.7-4.3; P<.001; absolute risk, 2.6 per 1000 person-years).
In the inpatient setting, Nguyen and Sam101 evaluated a
large national database of 522,704 discharges of non-IBD
patients compared with 73,197 discharges of patients with
CD and 43,645 discharges of patients with UC; the risk of
VTE was 1.5- to 1.8-fold higher among patients with vs
without IBD (P<.001). In patients with IBD, VTE risk was
higher among patients with UC or fistulizing CD.101
The Joint Commission National Quality Core measures
specifications include the appropriate use in patients under-
going general surgery of pharmacological VTE prophylax-
is, including unfractionated heparin, low-molecular-weight
heparin (LMWH), factor Xa inhibitor (fondaparinux), and
any pharmacological choice combined with a physical
measure (stockings or intermittent pneumatic compression
devices). Nonpharmacological prophylaxis is used in pa-
tients with a high risk of bleeding.102
No studies have specifically evaluated the potential ben-
efit of VTE prophylaxis in hospitalized or ambulatory pa-
tients with IBD. Studies to date do not support an increased
bleeding risk with moderate doses of anticoagulant medi-
cations in patients with active IBD.103
During the perioperative period, we recommend that
patients with IBD receive prophylaxis based on Ameri-
can College of Chest Physicians Evidence-Based Clini-
cal Practice Guidelines (8th Edition).104 However, a recent
study by Scarpa et al105 demonstrated that standard prophy-
lactic LMWH may be insufficient for VTE prophylaxis in
patients with IBD. In a series of patients undergoing major
colorectal surgery from 1999 until 2006, they demonstrated
an elevated risk of postoperative DVT in patients with UC
colitis (OR, 7.4; 95% CI, 1.4-44.4; P=.017) despite pro-
phylactic anticoagulation with 4000 IU/d of LMWH. The
rate of DVT in patients with UC was higher than in patients
with colorectal cancer (P=.009).
For patients undergoing open surgery, we recommend
prophylaxis with 5000 U of subcutaneous heparin 3 times
daily, 40 mg of subcutaneous enoxaparin once daily, or 2.5
to 5.0 mg of subcutaneous fondaparinux daily.
CONCLUSION
Perioperative physicians play a critical role in controlling
and standardizing the management of surgical patients re-
ceiving immunomodulator or immunosuppressant therapy.
However, sound research in this field has been limited, es-
pecially in the subgroup of patients with IBD.
Over the years, the management of patients receiving
glucocorticoids perioperatively has become fairly stan-
dardized. Guidelines for the management of patients re-
ceiving methotrexate have been based largely on findings
from orthopedic studies. Although the evidence on which
these recommendations are based is admittedly less than
robust, we recommend a conservative approach in patients
older than 65 years and in patients with renal impairment.
Azathioprine and 6-mercaptopurine use should be care-
fully monitored in patients at risk for toxicity. Cyclosporine
use poses a substantial risk of postoperative opportunistic
infections. Patients receiving cyclosporine therapy tend to
be much sicker and prone to an increased rate of opportu-
nistic infections.
With the exciting advent of biologic agents have come
new challenges. The experience in the perioperative use of
most of these agents is certainly not sufficient to make any
accurate predictions regarding their efficacy and safety;
however, the current level of evidence, although limited,
has been reassuring for the use of infliximab in the periop-
erative period.
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