Treating the Challenging Inpatient
with Complicated IBD: Case Studies
Peter D.R. Higgins, MD, PhD, MSc
University of Michigan
Today’s Cases
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Difficult inpatients
The kind that are NOT eligible for clinical trials
Limited, if any, RCT data available
There are frequently NO right answers
Management through general principles, art,
analogy, and a bit of science
CASE 1
COMPLICATED CROHN’S DISEASE
Case 1: Crohn’s Disease
• 23 year old male with CD x 4 years
• Ileal and segmental colonic location
• Failed 5-ASA x 8m, Aza x 3 years, now referred after
starting IFX monotherapy x 4m
• Slowly worsening RLQ pain, fevers x 2 months
• CT Scan ordered
• Admitted with CRP 4.3, ESR 78,
Albumin 2.2, Prealbumin 3 after scan result.
Long arrows: Active inflammatory TI stricture
Short yellow arrow: retroperitoneal abscess cavity medial to the cecum
Coronal images
Long arrows: Active inflammatory TI stricture
Short yellow arrows: retroperitoneal abscess cavity medial to the cecum
Consultant Notes
• Radiology: 2.6 cm abscess medial to cecum,
adjacent to long (15 cm) TI stricture with active
inflammation. Unable to drain safely. Upstream SB
dilated to 3.6 cm.
• Surgery: No emergent indication for surgery.
Recommend maximize medical therapy to eliminate
inflammation and eradicate all infection before
elective surgery. Follow up in surgery clinic in 8
weeks.
Options?
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Continue anti-TNF?
What are the anti-inflammatory options?
Anti-microbial therapy?
Surgical therapy?
Will this situation recur?
Will this damaged bowel be responsive to therapy?
Discuss…
Medical Therapies
• Anti-TNF
• Systemic steroids
• Topical steroids
– Entocort
• Immunomodulators
– Methotrexate
– Azathioprine
Abscess fertilizers
Anti-microbial therapy
• Drainage
– Would be optimal, not always possible
– 60-84% can be drained in case series with 2+ attempts
• Antibiotics
– Cover gut bugs broadly
– Consider iv for best bioavailability
– Consider early re-image (3-5d) if incomplete drainage
– Long term, re-image in 4-6 weeks
Waljee, Chapter 135, Advanced Therapy of IBD text, ed. Bayless and Hanauer
Feagins, Kane, et al, CGH 2011:842
Is Surgery Avoidable?
• Usually not
• Penet rating complications occur close to strictures
– Increased pressure within and upstream
– Inflammation weakens walls
• Likely to recur unless stricture fixed
– There are exceptions – inflammatory strictures
– Can you drain and start anti-TNF? 31% recur @5y N=55
• Goal is generally to get patient to ELECTIVE surgery
Nguyen, Sandborn, et al. CGH 2012: 400-4
Goals for pre-op visit
• Eradicate infection
• Control mucosal inflammation
– Even better, control transmural inflammation
– Limit/reduce length of resection
• “neoadjuvant” anti-TNF therapy?
• Prevent new fistulas, abscesses
• Boost nutritional status – Prealb, Alb
• Boost functional status – “Pre-hab”
Treating the challenging inpatient with
complicated IBD: Case studies
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Case 2
27 yo female patient, hospitalized for refractory ulcerative colitis
PMHx: Diagnosis of ulcerative pancolitis 2.5 years ago
• Initial therapy with steroids and 5-ASA without improvement, start of
infliximab.
• Allergic reaction with shortness of breath, chest pain during maintenance
therapy
• Start of 6-MP, remission for 18 months until 3 weeks before
hospitalization.
• 2 weeks before hospitalization start of oral steroids (40 mg prednisolone)
without success
Case 2 (cont'd)
Time of consult:
• 8-10 bloody bowel movements/day, no fever
• Physical exam: Abdomen soft, non-tender
• Medication: Start of 60 mg methylprednisolone iv yesterday.
Labs:
WBC 11.9 x10 9th/L, HGB 8.9 g/dl, platelets 550,000 x10 9th/L,
CRP 9.4 mg/dl.
Sigmoid Colon
Rectum
Case 2 (cont'd)
Case 2 (cont'd)
Therapeutic options in the setting of no response to
steroids in active UC and pregnancy:
• Infliximab
• Adalimumab
• Golimumab
• Cyclosporine
• Colectomy with ileostomy
Cyclosporine Therapy of UC in Pregnancy
3 case reports, 3 case series with 2, 5 and 8 patients
8 patients
• 7-Pan-UC
• 1 Left sided UC
Pregnancy week 6-27
Iv cyclosporine for 5-17 days (1 patient
oral), then switch to oral cyclosporine
(2 patients + AZA
• 7/8 patients with response to therapy.
• One patient after 17 days switch to IFX with response (later on Dx of CD)
• 7/8 pregnancies conducted to term.
• 1 death at week 22 (cyclosporine started week 10; mother with protein-S
defect).
• Two newborns premature.
Branche et al. 2009
Surgical management of Therapy Refractory UC
in Pregnancy
11 case reports with 1 or 2 patients, 4 case series with 4, 5, 7 and 9 patients
Case series before 2000 , especially around the 1970’s significant mortality of
mothers or infants
Case series Mayo 2006 (Dozois et al. 2006):
• 5 patients with UC.
• All with subtotal colectomy at first (1), second (3) and third trimester (1)
• No complications after surgery or during delivery.
In-Hospital Management and Birth Outcomes in Pregnancy in 2
Tertiary Care Centers (Mount Sinai, NYC, Chicago)
Time period 1989-2001: 11 patients with UC, 6 patients with CD, 1 patient with IC
• Hospitalization and treatment with hydrocortisone n=18, cyclosporine n=5, start of
6-MP/AZA n=3.
• 15 pat. 83% response to medical therapy, 3 (17%) colectomy. 1 patient in
cyclosporine group spontaneous abortion week 15.
38.7
Flare IBD (n=10)
35
32
34
36
38
Gestation period (week)
40
p<0.0001
Control (n=41)
Average weight (g)
4000
p<0.0001
3018
3000
2000
2001
1000
0
Flare IBD
(n=10)
Control
(n=41)
Reddy et al. 2008
Outcome case UC pregnancy
• Start of cyclosporine 2 mg/kg bw . Aim trough level >200 <400 ng/ml.
Continuation of 6-MP Continuation of iv steroids
• Patient improved after 2 days with decrease of bowel movements.
Switch to oral steroid taper on day 3.
Switch on day 7 to oral cyclosporine (6 mg/kg body weight).
• Continuation of oral cyclosporine + 6-MP for 3 months, then
continuation of 6-MP only
• Uncomplicated vaginal delivery week 36, baby with normal weight
CASE 3
SEVERE ULCERATIVE COLITIS
Case 3: Severe Ulcerative Colitis
• 19 year old female with UC x 4 months
• 3 m on 5-ASA, various types and doses
• 1 m on Aza 2.5 mg/kg
– TPMT 13.2
• C diff infection found 3 weeks ago
– Flagyl x 10 days, better on days 5-10
– Then worsened
• 22 bloody BM daily, low-grade fevers
Admitted
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CDTOX negative
WBC 12.2, ESR 33, CRP 9.2
HR 95, BP 122/78
IV methylprednisolone 60 mg daily
Small improvements
Day 2 scope - severe UC, no CMV
End of day 3: 15 BM/day, CRP 6.9
Options?
• Prognosis?
• What are the rescue therapy options?
• How to dose/frequency of dosing?
– Where will drug go? How to monitor levels?
• Implications of surgery on fertility?
• What are long-term risks/benefits?
• Discuss….
An Extreme Paucity of Data…
• A fair amount of trial and error
– Trial and failure, learn from your mistakes
• IFX can leak out of colon into stool in surprisingly
large amounts
• CRP is invariably high, and falls with therapy
• Retrospectively developed prognostic indices help
– If steroids are not working by day 3, will not work
• In the CYSIF trial, IFX ~ Cyclo at 90 days
What Various IBD Centers Do
• Operate at Day 4
• Rescue with Cyclosporine (decreasing)
• Rescue with IFX
– Dose high (10 mg/kg)
– Dose often (5 mg/kg q 72h until CRP <1)
– Hybrids of these
• UM protocol:
http://www.med.umich.edu/ibd/docs/UMSevereUCPr
otocol.2.5.pdf
Case 4
Pain in Crohn’s Disease
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Case 4
40 yo female patient
• Diagnosis of Crohn‘s disease (CD) at age 24
Intermittent treatment with steroids and 5-ASA for 10 years
• CD flares up with severe colitis, steroid refractory. Initiation of infliximab
and 6-MP. Remission after 2nd infusion of infliximab.
• 3 months later diagnosis of fibromyalgia. No effects of pregabalin, start of
pain management by outside pain clinic.
Case 2 (cont'd)
• Now admission with increased diarrhea (8-10 BMs daily), non-bloody and
severe abdominal pain (10 out of 10).
• Previous medication before admission:
- For CD: Infliximab q 8 weeks, last infusion 4 weeks ago and 6-MP (1.2
mg/kg bodyweight).
- For fibromyalgia: Fentanyl patch 25 mcg/hr and
oxycodone/acetaminophen 7.5 mg/325 mg 3-4 tablets daily as needed.
• Physical exam: No fever, abdomen soft, diffusely tender on deep palpation,
no rebound tenderness.
• After admission: Patient is on hydromorphone 4 mg iv q 4 hours
Possible Reasons for Recurrent IBD Symptoms
(Pain, Diarrhea)
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Flare
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Stricture, Abscess
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Infection (e.g. C. diff, CMV)
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Bacterial overgrowth
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Narcotic Bowel Syndrome
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IBS
Case 2 (cont'd)
Workup
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Laboratory: CBC, CRP, calprotectin normal
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CT-abdomen with oral contrast: Normal, no dilated loops, no
abscess
• Upper-GI endoscopy and colonoscopy:
Possible Reasons for Recurrent IBD Symptoms
(Pain, Diarrhea)
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Flare
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Stricture, Abscess
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Infection (e.g. C. diff, CMV)
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Bacterial overgrowth
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Narcotic Bowel Syndrome
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IBS
Use of Narcotics in Hospitalizations for IBD
117 patients with IBD (exclusion of postoperative pat. (up to 1 month) and pat.
with abscesses.
• 70. 1% receiving pain medications at admission ( median 12 mg in first 24
hours, median daily later on 7.5 mg/day.
• 7.7 % PCA pump
Risk Factors for Inpatient Narcotic Use
Odds ration
95% confidence
interval [CI]
Narcotics prior to admission
5.4
1.5 – 19.0
Smoking
4.3
1.2 – 15.6
Psychiatric diagnosis
2.2
0.4 – 11.6
Long et al. 2012
Diagnostic Criteria for Narcotic Bowel Syndrome
Chronic or frequently recurring abdominal pain that is treated with
acute high-dose or chronic narcotics and all of the following:
• The pain worsens or incompletely resolves with continued or escalating
dosages of narcotics.
• There is marked worsening of pain when the narcotic dose wanes and
improvement when narcotics are re-instituted (soar and crash).
• There is a progression of the frequency, duration, and intensity of pain
episodes.
• The nature and intensity of the pain is not explained by a current or
previous GI diagnosis.
Grunkemeier et al. 2007
Detoxification Protocol for Narcotic Bowel Syndrome (1)
Reduction of morphine dose
Treatment of anxiety
Treatment of withdrawal symptoms
Start of medications for long term control of abdominal pain
Physician – Patient Relationship
Days 1
2
3
4
5
6
7
8
9
10………..
Grunkemeier et al. 2007
Detoxification Protocol for Narcotic Bowel Syndrome (2)
Effective communication with the patient is essential.
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Explanation of rationale/benefit of stopping the narcotics
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Explanation of the withdrawal program.
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Affirmation of the patient’s pain and an explanation of the underlying
pathophysiology of NBS (i.e. altered motility and/or visceral
hypersensitivity).
Total narcotic daily dose should be converted to morphine equivalents
using an appropriate calculator and the 24 hours total drug dose reduced
by 10-33% q 24 hours. In inpatients setting administration of morphine as
continuous infusion (not PRN).
Grunkemeier et al. 2007
Detoxification Protocol for Narcotic Bowel Syndrome (3)
• Start of TCA (e.g. desipramine, nortriptyline @25-150 mg/qhs) or SNRI
(e.g. duloxetine 30-90 mg. qd) for immediate and long terms pain control
and to help manage psychological comorbidities.
• Mirtazepine (15-30 mg. qhs) can be considered instead of or in addition to
a TCA or SNRI if nausea is a prominent feature.
• For withdrawal symptoms clonidine (start with 0.1 mg bid)
• For anxiety benzodiazepine (e.g. lorazepam 1 mg q 6 hours)
• For constipation e.g. PEG 3350 17 g bid
Grunkemeier et al. 2007
Outcome after Discontinuation of Narcotics in IBD
Narcotics discontinued
n=22
Medically adherent
Surgically adherent
100 %
100 %
Narcotics
continued
n=17
53 %
94 %
Mod/severe pain
None/mild clinical
symptoms
27 %
82 %
80 %
24 %
Hanson et al. 2009