1. Treating the Challenging Inpatient with Complicated IBD: Case Studies
Peter D.R. Higgins, MD, PhD, MSc
University of Michigan

2. Today’s Cases 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

3. Complicated Crohn’s DIsease
CASE 1
Complicated Crohn’s DIsease

4. 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.

5. Long arrows: Active inflammatory TI stricture
Short yellow arrow: retroperitoneal abscess cavity medial to the cecum

6. Coronal images
Long arrows: Active inflammatory TI stricture
Short yellow arrows: retroperitoneal abscess cavity medial to the cecum

7. 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.

8. Options? 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…

9. Medical Therapies Anti-TNF Systemic steroids Topical steroids
Entocort
Immunomodulators
Methotrexate
Azathioprine
Abscess fertilizers

10. 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

11. 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% N=55
Goal is generally to get patient to ELECTIVE surgery
Nguyen, Sandborn, et al. CGH 2012: 400-4

12. 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”

13. Treating the challenging inpatient with complicated IBD: Case studies
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

14. 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

15. 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.

16. Sigmoid Colon
Rectum

17. Case 2 (cont'd)

18. 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

19. 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

20. 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.

21. In-Hospital Management and Birth Outcomes in Pregnancy in 2 Tertiary Care Centers (Mount Sinai, NYC, Chicago)
Time period : 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.
Average weight (g)
p<0.0001
p<0.0001
Reddy et al. 2008

22. 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

23. Severe ulcerative colitis
CASE 3
Severe ulcerative colitis

24. 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

25. Admitted 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

26. 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….

27. 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

28. 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:

29. Pain in Crohn’s Disease
Case 4
Pain in Crohn’s Disease
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

30. 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.

31. 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

32. Possible Reasons for Recurrent IBD Symptoms (Pain, Diarrhea)
Flare
Stricture, Abscess
Infection (e.g. C. diff, CMV)
Bacterial overgrowth
Narcotic Bowel Syndrome
IBS

33. Case 2 (cont'd) Workup Laboratory: CBC, CRP, calprotectin normal
CT-abdomen with oral contrast: Normal, no dilated loops, no abscess
Upper-GI endoscopy and colonoscopy:

35. Possible Reasons for Recurrent IBD Symptoms (Pain, Diarrhea)
Flare
Stricture, Abscess
Infection (e.g. C. diff, CMV)
Bacterial overgrowth
Narcotic Bowel Syndrome
IBS

36. 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

37. 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

38. 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 ………..
Grunkemeier et al. 2007

39. Detoxification Protocol for Narcotic Bowel Syndrome (2)
Effective communication with the patient is essential.
Explanation of rationale/benefit of stopping the narcotics
Explanation of the withdrawal program.
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

40. Detoxification Protocol for Narcotic Bowel Syndrome (3)
Start of TCA (e.g. desipramine, mg/qhs) or SNRI (e.g. duloxetine 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 g bid
Grunkemeier et al. 2007

41. Narcotics discontinued
Outcome after Discontinuation of Narcotics in IBD
Narcotics discontinued
n=22
Narcotics continued
n=17
Medically adherent
100 %
53 %
Surgically adherent
94 %
Mod/severe pain
27 %
82 %
None/mild clinical symptoms
80 %
24 %
Hanson et al. 2009