2. Acute severe colitis- Do`s and Don`ts Dr.S Sebastian

3. Hendriksen C, Kreiner S, Binder V. Gut 1985;26:158-163.
Disease Severity at Presentation
100
Severe Activity (9%) 80 60
Moderate Activity (71%)
Patients with UC (%) 40
Slide 6
The prognosis of UC including survival, colectomy rate, activity of disease, and working capacity was estimated from a follow-up study of 783 patients with UC comprising all patients from the county of Copenhagen. The period of observation ranged from 1 to 18 years with a mean of 6.7 years. The following observations were made:
The survival rate of woman did not differ from that of the general population.
At diagnosis, men over age 40 had a slight excess mortality rate in the first 2 years after diagnosis.
Colon cancer was seen in only 7 of 783 patients. Annual risk was 0.07%.
The colectomy rate was 9.6% in first year of diagnosis.
After 10 years, the colectomy rate was 23%.
After 18 years, the colectomy rate was 31%.
At 3 years after diagnosis, the capacity to work including those with colectomy was not different from that of the general population.
The study also indicated that, at any given time,
50% of those with UC were without symptoms,
30% had low disease activity, and
20% had moderate to high disease activity.
Within 10 years of diagnosis, 97% of patients experienced at least one relapse.
References
Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis – based on results from a regional patient group from the county of Copenhagen. Gut 1985; 26: 20
Mild Activity (20%)
Disease Activity
Hendriksen C, Kreiner S, Binder V. Gut 1985;26:

4. The Walking (working) Wounded

5. Sick Unto Colectomy !!!

6. Actor With Refractory Pan-colitis
Formerly in remission on AZA
15-20 BM/day
Progressive weight loss

7. Key aspects …. Assessing and managing the disease daily
Assessing and managing risks daily
Joint care with colorectal surgery
`Individualised care`

8. Aims of medical management…
Achieve remission
Avoid colectomy, if possible
Avoid complications

9. Day 0- things to do Assessing severity of disease
Clarifying extend of disease
Ensuring no complications
Identifying reasons for failure of OPD treatment
Baseline tests
Starting treatment

10. 1. Clinical severity assessment
Mild
Less than 4 stools /day with or without blood
No systemic disturbance
Normal Plasma viscosity/ESR
Moderate
More than 4 stools/day
Minimal/ no systemic disturbance
Normal/ mild elevation in PV (<1.9) /ESR (<25)
Severe
More than 6 stools daily with blood
Evidence of systemic disturbance- fever,anemia, tachycardia
Plasma Viscosity >1.9 /ESR >30
Modified Truelove & Witts Criteria

11. CONSTRUCT TRIAL
COmparison of iNfliximab and cyclosporin in STeroid Resistant Ulcerative Colitis: a Trial
HTA funded- £1.6 milion
Propoposal 2003
Started Sep 2010
First results expected in 2014

12. What tests to do
FBC
CRP
BCP Mg
AXR
Stool culture
Stool C Difficle

13. Infection and Flare up of UC
Infections contribute in 14-16% of flare ups of UC
Steadily increasing concern in IBD patients
Retrospective studies- higher C Diff rates than other hospitalized patients
Roderman et al Cli Gastro Hepatol 2007
Issa M et al Clin Gastro Hepatol 2007
Prevalence 39.4/1000
? Selection bias

14. C Difficile in IBD
May not have clear history of antibiotic use/hospitalization
Community acquired C diff does not have a better prognosis
Risk of toxic megacolon 2-3%
No for increase in hypervirulent strain in IBD cohort
Predictors of higher risk
Females
Colonic involvement
Winter and spring months
Multiple immunomodulators

15. National survey (US) of C difficile
Nguyen et al Am J Gastro 2008
Prevalence
UC 37.3/1000
Crohns 10.9/1000
Non IBD 4.8/1000
Incidence doubled in 7yrs
Greater Mortality in UC (OR 3.79, CI ) but not in Crohn`s (OR 1.66, CI )
45-65% increase in duration of stay and costs

16. Recommendation…
All patients needing admission for flare up should have stool C difficile and Stool cultures in the work up algorithm
If C diff negative may need to recheck again if lack of response to treatment

17. North East 25%, Yorkshire and Humber 45%
IBD audit-Stool Culture & CDT
UK Median 45%
North East 25%, Yorkshire and Humber 45% 17

18. VTE in IBD Complication in IBD 0.7 to 7.7 % Extensive, unusual sites
Increased mortality and morbidity

19. VTE Time trend analysis
Age adjusted VTE
per1000 admissions

20. Cumulative risk of VTE

21. Recommendation….
All IBD patients admitted to hospital should have VTE prophylaxis

22. North East 55%, Yorkshire and Humber 75%
% Prophylactic heparin - UC
UK Median 60%
North East 55%, Yorkshire and Humber 75% 22

23. Clarifying extend…
Why important
How to clarify
Safety of endoscopy

24. Ensure no complications…
Examine
look for distension, peritonism
Abd X-ray

25. Identifying reasons for failure
Natural course of disease
Non compliance
Infection
Proximal constipation
Suboptimal mucosal drug concentration
Co-existent IBS
Inaccurate diagnosis

26. What treatment to start
IV steroids
DVT prophylaxis
K replacement
Mg replacement
Nutritional management
Individualised management
Based on factors identified for failure
Patient preferences

27. Drugs to avoid Anti diarrhoeals Codeine Tramadol NSAIDs
Anti-cholinergics

28. What to look for every day
Stool chart
Abdominal pain, tenderness, distention
Temp
Bloods- CRP,FBC, Mg+, K+
See results !!!
Decide repeat AXR needed
drug card !

29. Acute abdominal pain in a colitic
Examine !!
Look for peritonism
Abdo x-ray
Avoid bowel paralytics
Analgesia-pethidine
Seek help

30. Case …. 47 yr old with known pancolitis on oral mesalazine
Admitted via AAU for uncontrolled flare up despite oral steroids
Stools > 10/day, Blood+++, abdominal pain
CP 113, WCC 16,Platelets 497, Alb 27, K 2.9
Started on IV steroids

31. Case …ctd 24hrs later- Diarrhoea settled but increasing pain
Review by SHO- Tramadol IM
Review by gastro
Repeat AXR

32. What is toxic megacolon?
Non obstructive colonic dilatation in the presence of toxic colitis
Jalan Criteria
Radiographic evidence of colonic dilatation ( Transverse >6cm)
3 of 4: Fever, tachycardia, anaemia, leucocytosis
1 of : hypotension, altered mentation, electrolyte imbalance
Not exclusive to UC but can occur with infective, ischemic or radiation colitis
Jalan KN. Gastroenterology. 1969; 57: 68.

33. Toxic megacolon in IBD Lifetime risk in UC- 1-2.5%
2-5% of severe attacks of UC needing admission develop megacolon.
Risk factors
Extensive active disease
Abrupt discontinuation of steroids/5-ASA
Use of loperamide, anticholinergics, opiates
Hypokalemia particularly after steroids

34. Toxic megacolon in IBD….
Perforation leads to mortality up to 20%
Signs of peritonism may be masked by steroids
Suspect micro perforation of increasing pain
Serial x-rays
Liaise with/ transfer care to gastroenterology and surgery

35. Drug therapy in acute severe colitis

36. Steroids-old dog still the `best`
Overall response 67% (95%CI 65-69)
Colectomy rate 29% (95% CI 28-31)
Mortality 1% (95 % CI )
How to improve response without compromising safety?
Turner D et al 2007

37. Rescue therapies in 2009 Infliximab Cyclosporine/tacrolimus Adacolumn
Vizilizumab
Choice will depend on center expertise with drug choices and availability of expert surgical support
Greatly tempered by pt preference
Averaged preferences support the use of medical interventions, 1/3 of individuals may benefit most from proceeding directly to colectomy

38. Cyclosporin A First drug proven in steroid failures
Response rate of CsA %
Rapid response
Short half life
Check cholesterol and magnesium
2mg/Kg sufficient
Before treatment with IV CSA was initiated all patients were treated with IV glucocorticosteroids (minimum, 40 mg methylprednisolone/day). Patients were considered for CSA if their clinical condition did not improve after 5–7 days of IV steroid treatment or when there was a subjective or objective deterioration in their condition. Patients received CSA at a dose of 4 mg/kg/day or 2 mg/kg/day as a continuous IV infusion for a total of 7 days. The conditions of all patients were assessed daily by the treating physician and the consulting surgeon and when patients failed to improve after 7–10 days or when their medical condition worsened, they were scheduled for immediate colectomy. During IV treatment, CSA blood levels were kept between 250 and 450 ng/mL (4 mg/kg) or between 150 and 250 ng/mL (2 mg/kg). Patients who had a response were switched to oral treatment with Neoral (Novartis, Basel, Switzerland) at an initial dose of 8 mg/kg/day and the dose was adjusted to blood levels between 150 and 250 ng/mL. Intravenous glucocorticosteroids were continued at stable doses during IV CSA treatment. Those patients who achieved a response to IV CSA were switched to a tapering dose of oral glucocorticosteroids. CSA was continued in responders for a total of 3 months. Patients who already were taking azathioprine or 6-mercaptopurine were continued at their current levels. Those patients not taking azathioprine or 6- mercaptopurine were started at a dose of 2.5 mg/kg and 1.5 mg/kg, respectively, at the time of response to CSA during their hospitalization, if they had no known intolerance.
Lightiger NEJM 2004
Van Assche G. Gastro (4);

39. CsA Long Term Results Oxford; 76 pt retrospective series
All severe UC, got steroids or CsA
56 (74%) initial remission
At 12 months
65% of CsA remitters had 1+ flare
At 84 months, 58% had colectomy
AZA did not effect rates in subgroup analysis.
Several European tertiary center series
68-88% colectomy rates within 7 years
Moskowitz 2006; Campbell 2003, 2005

40. IV Cyclosporine: Major Toxicity
Hypertension 25%
Renal insufficiency 23%
Infection 20%
Seizures 3%
Deaths 2%
Anaphylaxis 1% 4

41. ACT1 Patient Population
Subjects with:
Moderately to severely active ulcerative colitis (UC):
Mayo score  6 points (on 12 point scale)
Endoscopy subscore  2 points
Subjects must meet at least 1 of the following criteria:
Current treatment with ≥ 1 of the following:
Oral corticosteroids, 6‑mercaptopurine (6- MP), or azathioprine (AZA)
Have failed to successfully taper, tolerate, or respond to corticosteroids within the past 18 months
Have failed to tolerate or respond to 6-MP or AZA within the previous 5 years
The inclusion criteria included:
1. Evidence of moderate-to-severe disease, indicated by a Mayo score of 6 to 12 points, with an endoscopic subscore of at least 2.
The Mayo score is an assessment of ulcerative colitis activity, the total Mayo score ranging from 0 to 12 points, higher scores indicating more severe disease. The Mayo score is a composite of four measurements including stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and physician's global assessment .
2. AND either concurrent treatment with corticosteroids, azathioprine and/or 6-MP OR failure to tolerate or respond to at least one of the aforementioned therapies.

42. ACT 1 vs Real Life
Clinical series % have colectomy within 3 months
Elective surgery in INF patients safe but what about emergency surgery?
Scottish survey 2/23 died, 3 have fungal sepsis
Possibly better response in moderate and less severe scenario ACT, Jarnerot et al
More worrying- patients having steroids, then cyclosporine then infliximab and then death!
Cannot recommend combination therapy to avoid colectomy

43. IFX RISK FOR SUBSEQUENT COLECTOMY?
Mayo Clinic report
IFX patients had more postop. complication after tac/ipaa than non-INFX
However, more AZT and high-dose steroids in INFX group
MGH review
All IBD (413/156UC) patients with surgery
assessed IFX exposure within 3 months;
compared postop outcomes
No sig. diff in death, leak, infection
no diff in infection controlling for UC/CD, steroids, preop infection.
OR for IFX =2.5, p0.14.
Selvasekar 2007; Kunitake 2008

44. IFX RISK FOR SUBSEQUENT COLECTOMY?
Cleveland Clinic (n=523)
IFX-treated/matched controls who underwent proctocolectomy
Postoperative complications and rate of three- stage procedures compared
adjusted OR of early complication for the IFX group was 3.54
OR of sepsis was 13.8 for the IFX group
OR for late complication was 2.19 for the IFX group
OR for three-stage procedures was 2.07 in the IFX group
Mor 2008

45. IFX RISK FOR SUBSEQUENT COLECTOMY?
Cedars-Sinai
Chart review of pts undergoing IPAA or colectomy for refractory UC
17 patients failed IFX, 134 patients never treated with IFX
IPAA performed in 112 patients (74%) and subtotal colectomy in 39 patients (36%)
There were no deaths.
Postoperative complications in 43 patients (28%)
no statistically significant difference between IFX-treated (37%) and IFX-untreated patients (27%)
61 patients (40%) treated with preoperative CsA
5 patients also had IFX w/ 80%complication rate
29% in CsA only
Schluender 2007

46. Cyclosporin Vs Infliximab
Long experience
Trail and experience data
Short half life
Rapid onset
High short term toxicity
No increased risk post colectomy
Relatively short experience
Paucity of trial data
Longer half life
Rapid onset
Lower short term toxicity
Suggestion of increased risk post colectomy
Individualize patients
Consult with an IBD Physician

47. My take on infliximab data in severe acute colitis
Short term benefit in avoiding/delaying colectomy but with unknown but potential risks in those proceeding to surgery
NICE – For acute severe colitis as rescue therapy to avoid colectomy as an alternative to cyclosporine

48. Timing of colectomy in severe UC
The most taxing clinical judgement in UC
As therapeutic options increase do do the opportunity for medical indecision making
One death from complications of operating too late will negateball benefits of medical therapy
How to early stage those who need colectomy?

49. Predictive Factors of colectomy
Radiological
Colonic dilatation >5.5 cms – 75%
Mucosal islands on plain film – 75 %
3 or more small bowel loops of gas - 50%
stool frequency >12 on day 2 – 55%
Frequency >8 /day on day 3 – 85%
frequency >8 /day & CRP >45 mg/ on day 3 -85%
Frequency >4 and CRP >25 on day 3 – 75%
Albumin <30 before day 4 -55%
Genetic profile

50. What I Use? Travis Index On Day 3 after intensive treatment
Stool frequency >8/day or
Stool frequency 3-8/day CRP >45 mg/L
85% chance of colectomy within 6 months

51. No change in 50yrs !!! 116 patients Colectomy 33 (28%)
Howthorne, Travis
Gut 2002
116 patients
Colectomy 33 (28%)
Response 47 (41%)
Partial response 36 (28%)
1955 results (Trulove & Witts)
Remission 41%
Improved 27%
Worse 32%

52. Decision on Colectomy
Decision is a triangular decision between patient, gastroenterologist and surgeon
Daily review by an IBD physician, surgeon facilitates early decision making
Close liason with stoma therapist
Do not delay decision

53. Tenuous Balancing Act

54. A Century of Problems with Drugs
“If the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind, and all the worse for the fishes.”
Oliver Wendell Holmes
Medical Essays, “Comments and Counter”
Currents in Medical Science

55. Take home
Avoid the temptation to go on and on and on and ……..on medical treatment
Use objective indices to predict colectomy preferably by day 3
Joint decision by IBD specialist and IBD surgeon

56. Problem with decisions/indecision

57. Refractory UC and CMV: Culprit or Companion?
Detection of CMV genome is higher in IBD in general
Current systemic steroids related to CMV infection (p = 0.03); p=NS for severity, past Rx
Colectomy specimens (n=85) 20% stained positive
27% (15/55) of steroid-refractory
9% (6/68) positive PRE-op biopsies
NO post-op CMV in any of 85 (pouch bx)
High false negative retes on preop biopsies
1) Dimitroulia E et al IBD (9): Greek two center study
85 pts with IBD, 42 controls. 58 UC, 27 CD
Controls: Immunostain: None PCR +12% in blood, 2% in tissue;
UC Immunostain:
+ PCR associated with shorter duration of IBD
2) Maconi G et al Dig Liver Dis (6): Italian surgical series
77 consecutive resections for UC
55 steroid refractory 6 megacolon, 7 dysplasia/ cancer, 9 dysfunction

58. Final Points There is no “one size fits all” to IBD therapy
Therapy and decision making are tailored to the individual
Algorithms are based upon available evidence
Evidence is in constant flux
Success of algorithms depends upon optimization of each step of therapy and considerable judgment about each outcome
Skillful application of medical therapy makes all the difference in outcomes

59. Sick Unto Colectomy