Acute Severe Colitis (ASC)

Definition

• PUCAI > 65

Management

• Admission to hospital
• R/o Infection
• Gastrointestinal PCR panel (Stool Cx if PCR unavailable)
• C Diff toxin A & B PCR (1 stool sample is sufficient unless PCR is unavailable)
• PO Vancomycin should be started in severe cases or patients who failed outpatient PO steroids while awaiting C diff results
  
• Dose: 10mg/kg (up to 125-250 4x/day)
  
• Hospitalized UC patients with C difficile had fewer reported readmissions and a shorter length of hospital stay when treated with oral vancomycin compared with metronidazole
• In adults a flex sig might be performed upon admission to r/o CMV colitis. In pediatric patients, flex sig to r/o CMV colitis should be performed if a patient is not responding to IV steroids after 3 days
• Obtain mucosal biopsies for H&E and immunohistochemistry for CMV
• Note: positive PCR for CMV in the absence of inclusion bodies or positive staining is insufficient to diagnose CMV
• Treat CMV with ganciclovir 5 mg/kg twice daily for 21 days
• If patient is not responding within a few days, consult ID
• If responding, switch to oral Valganciclovir after several days of positive response
• Abdominal Plain Film to r/o megacolon
• Megacolon is defined as
• Transverse colon diameter >5.6cm or 4cm in children <10yrs
• Signs of systemic toxicity
• Fever
• Tachycardia (>2 SD above median for age)
  
• Dehydration
• Electrolyte disturbance
• Altered level of consciousness
• Hypotension/shock
• Note: steroids may mask peritoneal signs
• Initial management of Toxic megacolon
• NPO/Bowel rest
  
• IV fluids
• Consultation with Surgeon
• Empiric Antibiotics
• Consider NG tube, rectal decompression, positional changes
• Risk factors for toxic megacolon:
• CMV or C difficile infection, hypokalemia, hypomagnesemia, and the use of anticholinergics, antidepressants, loperamide, and opioids
• IV Steroids
• IV methylprednisolone 1mg/kg/day (up to 40mg/day)
• No benefit to continuous infusion or divided dosing
• Increased doses up to 1.5mg/kg/day (60mg/day) once daily or divided BID should be considered for more severe cases or patients who failed PO steroids prior to admission
• Return to lower dosing once response has been observed
• Methylprednisolone is preferred to hydrocortisone
  
• 2/3 of patients not responding to outpatient PO steroids will respond to IV steroids
• Labs
• CBC, CMP, Mg, CRP
• Consider Blood Transfusion for Hgb <8
• Defer IV Iron infusions during acute hospitalization
• Patients should be discharged with Iron supplement
• GI PCR
• C Diff toxin A&B PCR
• If patient biologic naive, consider TB testing, Hep B,
  
• Consider TMPT, Cholesterol/Lipids for 2nd line therapies
  
• Pain Management
  
• Tylenol
• Heat Packs
• Avoid NSAIDs
• Consider Celecoxib (check dosing) The data are conflicting regarding selective COX-2 inhibitors, but low doses and short treatment duration appear to be safe in UC
• Ketamine has been used to minimize opioid/NSAID use
• Opioids should be used as a last resort and with caution and close monitoring given risk of facilitating megacolon
• Bowel perforation or megacolon should be considered in case of severe or escalating abdominal pain or acute decompensation
• Nutrition
• Regular Diet
• Enteral feeding is contraindicated in cases of toxic megacolon or when surgery is imminent (NPO, consider PPN or TPN)
• Enteral polymeric nutrition had a similar remission rate and need for colectomy as compared with TPN, but a higher increase of serum albumin fewer adverse events, and fewer postoperative infections
• No evidence that special diets confer any benefit
• Studies have shown no benefit for bowel rest
  
• Electrolyte imbalance (Hypokalemia and Hypomagnesemia can promote colonic dilation)
• Monitor I&O's
• IV fluids if not maintaining adequate hydration
• Thromboprophylaxis
• Although lower than adults, Studies suggest that the risk for VTE complications is increased also in children with ASC
• Use anticoagulation in Adolescents with at least 1 risk factor
• Use anticoagulation in Prepubertal children with at least 2 risk factors
• Risk factors:
• Smoking
• Oral contraceptives
• Complete immobilization
• Central venous catheters (including PICC line)
• Obesity
• Concurrent significant infection (eg, respiratory, urinary, skin, and intra-abdominal)
• Known prothrombotic disorder
• Previous VTE
• Family history of VTE
• Prophylax with subcutaneous enoxaparin 1mg/kg/day (100 IU/kg/day) in one daily dose
• Monitoring with anti-Xa activity is not usually required unless patient has significant renal impairment
• Ambulation, adequate hydration, removing indwelling catheters/lines should be encouraged
• Discontinue 5-ASA (Mesalamine) po and pr preparations during admission
• May consider reintroduction after significant improvement in clinical condition
• Note: There have been case reports of exacerbation of colitis symptoms in patients with mesalamine intolerance (2-10% of patients)
• Antibiotics
• Antibiotics are not routinely recommended in children with ASC at admission, except for starting empiric Vanc while waiting for C Diff results (as noted above)
• Consider starting empiric antibiotics if sepsis or bacterial infection is suspected while awaiting culture results
• Salvage Antibiotic Therapy
• At least one study showed that the use of an oral wide-spectrum antibiotic cocktail (including metronidazole, amoxicillin, doxycycline and—in hospitalized patients—vancomycin) in children with moderate-to-severe UC, refractory to multiple immunosuppressants, was effective in 47% of patients. Another study, the PRASCO trial showed greater improvement in PUCAI score on day 5 with IV steroids and antibiotics vs IV steroids alone.
  
• Current recommendations for usage include steroid refractory disease, failure of outpatient PO steroids, more severe course, or awaiting colectomy
  
• Antibiotic Regimen:
• Vancomycin 250 mg × 4/day (children younger than 8 years of age, 125 mg × 4/day)
• Amoxicillin 50 mg/kg/day divided into 3 doses (up to 500 mg × 3/day)
• Metronidazole 5 mg/Kg × 3/day (up to 250 mg × 3/day)
• Doxycycline 2 mg/kg × 2/day (up to 100 mg × 2/day)
  
• children < 7 yrs of age: ciprofloxacin 10 mg/Kg × 2/day; up to 250 mg × 2/day)
• children < 2yrs or known allergy to one of the drugs: oral gentamicin (2.5 mg/Kg × 3/day)
• Discontinue antibiotics if no improvement noted in 4-7 days

• Monitoring

• PUCAI score at days 3 and 5 is the best validated predictive and decision-making tool in children with ASC
• Day 0,1,3,5
• PUCAI Score
• Day 3
• PUCAI <45, continue steroids - follow recommendations for discharge
• PUCAI >45
• Start planning for second line therapy between days 3-5
• Second line therapy should be started day 5 if PUCAI >65 on IV steroids
• Flex Sig to r/o CMV
• Surgery Consult
  
• Day 5
• PUCAI <65, continue IV steroids for 2-5 more days. Make decision based on response to IV Steroids regarding starting a second line therapy
  
• A PUCAI > 70 points on day 5 was associated with IVCS failure with a specificity of 100%, PPV of 100%, sensitivity of 35%, and NPV of 79%, indicating that response is highly unlikely in the presence of PUCAI > 70

• Second Line therapies (See table below)
  

• Clinical guidelines for adults recommend that second-line therapy should be initiated if no response to IVCS is achieved within 3 to 10 days after initiation as further steroid treatment in non-responding patients is associated with complications
• Infliximab is recommended as second-line therapy in anti-TNF naive children failing IV steroids
• Consider intensification or accelerated induction regimen (10mg/kg at 0,1,4 wks)
• In patients who respond to infliximab, the addition of an immunomodulator is recommended for 6mo
  
• Calcineurine inhibitors (Tacrolimus and Cyclosporin) can be considered as alternative second line therapies
• Note: these medications are used as rescue medicines to bridge to long term therapy (Biologic, Azathioprine, etc)
  
• Second line therapy response is judges by PUCAI, CRP, and Albumin (anticipate drop of 20pts with 2nd line therapy)
• Corticosteroids should be weaned when initiating second line therapies
• Colectomy must be discussed when starting second line therapies in case of failure
• Steroid refractory ASC increases risk for colectomy within one year

Second line therapies

Discharge Recommendations

• Patients should begin discharge planning when the PUCAI is <35
• Prefer to discharge patients when they have achieved remission (PUCAI < 10)
• In the adult literature there is evidence that achieving complete clinical remission (⩽3 stools/day with no visible blood) during the index hospital admission improves long-term outcome and delays the need for colectomy
• Thiopurine maintenance is generally recommended after ASC responsive to IV steroids
• Could consider Mesalamine if patient was mesalamine naive prior to admission
• If patient was responsive to Infliximab as second line therapy, it should be continued as maintenance after discharge
• Discharge Criteria
• PUCAI downtrending below 35
• Stable vitals
• Adequate PO nutrition
• Stable H/H
• Improving CRP and Albumin
• Toleration of Oral meds, if applicable
• Tolerating discontinuation of Pain medications 24hrs prior to discharge
• Convert IV steroids (Methylprenisolone) to PO prednisone
• 1mg methylprednisolone = 1.23mg of prednisone
• e.g. 40mg IV Steroids = 50mg PO prednisone
• Thiopurines may take up to 10-14wks to reach full therapeutic effect
• Cyclosporine or tacrolimus should be weaned within several months as a bridge to Thiopurine or other maintenance meds (vedolizumab)
• PJP prophylaxis with trimethoprim-sulfamethoxazole should be considered for triple immunosuppression which includes anti-TNF or a calcineurin inhibitor plus 2 other immunosuppressants, mainly steroids. Trimethoprim-sulfamethoxazole dosing: 450 mg/m² twice daily for 3 days each week, (maximum daily dose 1.92 g) either consecutive or alternate day dosing (note 480 mg of trimethoprim-sulfamethoxazole consists of trimethoprim 80 mg and sulfamethoxazole 400 mg)
• PO Iron supplements if Hgb >10 (Consider Iron infusion if Hgb <10 at discharge)
• Follow up re-evaluation within 2-3wks

• Post pediatric ASC discharge, 49% of initial IVCS responders lost clinical response despite maintenance mesalamine or thiopurine therapy during the subsequent 1 year and 14% became steroid dependent

Expert consensus steroid tapering algorithm

(doses are in mg/day prednisone equivalent): the goal is to discontinue steroids by week 10

Avoid steroid dependency by timely escalation of maintenance therapy when needed. The risk for exacerbation is smaller with prednisone doses >20 mg, but
the risk for adverse events is then higher thus a more rapid tapering to 20 mg is desired. Shortening each stage from 7 to 5 days or any other tapering
modification may be considered individually since many factors come into play when weaning off steroids. Consider the possibility of adrenal insufficiency,
even many months after tapering off steroids.

First 2 to 3 weeks: start prednisone at 1 mg/kg up to 40 mg once daily (after discharge from acute severe colitis admission, the dose may be as high as 60 mg/
day; see part 2 of these guidelines). If there is no significant improvement (ie, PUCAI decrease of <20 points) after 7 to 14 days, or an increase in PUCAI  20
points at any time, then escalate treatment after excluding other causes for steroid-refractory disease (see text and Figs. 2 and 3).

After the first 2 to 3 weeks: PUCAI 15 to 30: consider keeping the dose stable (while prolonging the total course by 1 week); PUCAI > 35, increase steroids to
the dose of the previous 1 to 2 steps for 1 week and then re-start weaning more slowly; PUCAI > 60 or increase in PUCAI by 20 points at any time, escalate therapy

References:

Turner, D., Ruemmele, F. M., Orlanski‐Meyer, E., Griffiths, A. M., De Carpi, J. M., Bronsky, J., Veres, G., Aloi, M., Strisciuglio, C., Braegger, C. P., Assa, A., Romano, C., Hussey, S., Stanton, M., Pakarinen, M., De Ridder, L., Katsanos, K., Croft, N., Navas‐López, V., . . . Russell, R. K. (2018). Management of Paediatric Ulcerative Colitis, Part 1. Journal of Pediatric Gastroenterology and Nutrition, 67(2), 257–291. https://doi.org/10.1097/mpg.0000000000002035 https://onlinelibrary.wiley.com/doi/10.1097/MPG.0000000000002035

Turner, D., Travis, S. P. L., Griffiths, A. M., Ruemmele, F. M., Levine, A., Benchimol, E. I., Dubinsky, M., Alex, G., Baldassano, R. N., Langer, J. C., Shamberger, R., Hyams, J. S., Cucchiara, S., Bousvaros, A., Escher, J. C., Markowitz, J., Wilson, D. C., Van Assche, G., & Russell, R. K. (2011). Consensus for Managing Acute Severe Ulcerative colitis in Children: A Systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. The American Journal of Gastroenterology, 106(4), 574–588. https://doi.org/10.1038/ajg.2010.48 https://naspghan.org/files/documents/pdfs/training/curriculum-resources/inflammatory%20bowel%20disease_zeusdeleted_145_09092015100906/Consensus_for_Managing_Acute_Severe_Ulcerative_ECCo.pdf

Use of antibiotics (Antibiotic Salvage therapy / cocktail)
Dan Turner, Jason Bishai, Leah Reshef, Guila Abitbol, Gili Focht, Dana Marcus, Oren Ledder, Raffi Lev-Tzion, Esther Orlanski-Meyer, Baruch Yerushalmi, Marina Aloi, Anne M Griffiths, Lindsey Albenberg, Kaija-Leena Kolho, Amit Assa, Shlomi Cohen, Uri Gophna, Hera Vlamakis, Eberhard Lurz, Arie Levine, Antibiotic Cocktail for Pediatric Acute Severe Colitis and the Microbiome: The PRASCO Randomized Controlled Trial, Inflammatory Bowel Diseases, Volume 26, Issue 11, November 2020, Pages 1733–1742, https://doi.org/10.1093/ibd/izz298
https://academic.oup.com/ibdjournal/article/26/11/1733/5675351?login=false

Turner D, Levine A, Kolho KL, et al. Combination of oral antibiotics may be effective in severe pediatric ulcerative colitis: a preliminary report. J Crohns Colitis 2014; 8: 1464–1470. https://pubmed.ncbi.nlm.nih.gov/24958064/

Ciclosporin after infliximab failure in acute severe colitis
Weisshof R, Ollech JE, El Jurdi K, Yvellez OV, Cohen RD, Sakuraba A, Dalal S, Pekow J, Rubin DT. Ciclosporin Therapy After Infliximab Failure in Hospitalized Patients With Acute Severe Colitis is Effective and Safe. J Crohns Colitis. 2019 Sep 19;13(9):1105-1110. doi: 10.1093/ecco-jcc/jjz032. PMID: 30726894; PMCID: PMC7327272.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327272/

Tofacitinib in Acute Severe Colitis
Casper Steenholdt, Pernille Dige Ovesen, Jørn Brynskov, Jakob Benedict Seidelin, Tofacitinib for Acute Severe Ulcerative Colitis: A Systematic Review, Journal of Crohn's and Colitis, Volume 17, Issue 8, August 2023, Pages 1354–1363, https://doi.org/10.1093/ecco-jcc/jjad036
https://academic.oup.com/ecco-jcc/article/17/8/1354/7067135