1. A 64-year-old renal transplant recipient. Excellent kidney function on Sirolimus (Rapamune) and steroids. He presented to the general surgical team with early sigmoid adenocarcinoma requiring. The surgeon advised curative left hemicolectomy.
- What is your peri-operative management?
- How would you manage his immunosuppression?
- Would your management differ if he was on Tac and steroids?
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*What is your peri-operative management?
Cardiac evaluation
Evaluation by nephrologist
Increase dose of steroid peri-operative
*How would you manage his immunosuppression?
Stop sirolumus and add tacrolimus with increase corticosteroid dose.
*Would your management differ if he was on Tac and steroids?
Cardiac and nephrologist evaluation
Increase corticosteroid dose
We can return to sirolumis after complete wound healing and another immunosuppressive agent
References
↵Kahan BD: Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: A randomized multicenter study. The Rapamune US Study Group. The Lancet356 :194– 202,2000
↵Podder H, Stepkowski SM, Napoli KL, Clark J, Verani RR, Chou T-C, Kahan B: Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol12 :1059– 1071,2001Abstract/FREE Full
↵Mota A, Arias M, Taskinen EI, Paavonen T, Brault Y, Legendre C, Claesson K, Castagneto M, Campistol JM, Hutchison B, Burke JT, Yilmax S, Hayry P, Neylan JF; for the Rapamune Maintenance Regimen Trial: Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant4 :953– 961,2004CrossRef
↵McTaggart RA, Gottlieb D, Brooks J, Bacchetti P, Roberts JP, Tomlanovich S, Feng S: Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am J Transplant3 :416– 423,2003CrossRef
1- What is your peri-operative management?
1- doubling steroid dose in the 1st few days of the operation.
2- adequate fluid balance and avoiding nephrotoxic agents.
3- serial follow-up of renal chemistry.
4- involvement of an experienced nephrologist
2- How would you manage his immunosuppression?
3- Would your management differ if he was on Tac and steroids?
1- doubling steroid dose as previously mentioned.
2- conversion to Sirolimus/everolimus after full wound healing to add the extra anti-proliferative effect.
This patient is a post renal transplant patient posted for hemicolectomy under general anesthesia is a major surgery. He is a high risk candidate. He needs pre operative fitness in the form of routine work up, i.e renal function test, liver function test, complete hemogram, HbA1c, Serology, RT PCR COVID in this pandemic, urine routine. He also needs cardiology fitness including ECG and 2D Echo. Lipid profile needs assessment as he has been on sirolimus and this may contribute to the overall cardiovascular risk. Urine routine assessment to rule out urinary tract infection and proteinuria needs an assessment. Proteinuria also could be a side effect of sirolimus therapy too.
What is your peri-operative management?
1-Stop sirolimus 1 week before surgery and start tacrolimus and should have level prep
2- give hydrocortisone stress dose at the day of operation then 2nd day oral prednisone
3-ensure good hydration
4- ensure coverage with broad spectrum antibiotics
4- Resume sirolimus after ensuring wound healing
How would you manage his immunosuppression?
Would your management differ if he was on Tac and steroids
1-hydrocortisone stress dose +tacrolimus same dose but may require uncertain surgeries to be IV
But can be shifted to sirolimus after wound healing due to anti proliferation effect on malignancy
There is not strong evidence for use of mTORI as antineoplastic in colon cancer. The use of mTORI is beneficial in skin cancer specifically Kaposi sarcoma. Therefore I wound wont change Tacrolimus to mTORI in colon cancer. The other important point is high risk of rejection when mTORI is used.
1) Full lab : CBC, s. electro;ytes, KFT , LFT, INR , Bleeding profile
2) Handling steroids: sfit to stress dose hydrocortisone 100mg / 8hours , resume oral 27 hours postoperative
3) Handling immune suppression: withhold sirolimus (m-tor are well known of their antiproliferative effect and impaired wound healing), replaced by tacrolimus, then consider reintroduction post operative afte 2-4 weeks
4) Preparing packed RBC units for Bl,Tx if needed
5) Fasting 10 to 12 hours starting at the night before to surgery +/- enema
withhold sirolimus (m-tor are well known of their antiproliferative effect and impaired wound healing), replaced by tacrolimus, then consider reintroduction post operative afte 2-4 weeks
shfit to stress dose hydrocortisone 100mg / 8hours , resume oral 27 hours postoperative
· shfit to stress dose hydrocortisone 100mg / 8hours , resume oral 27 hours postoperative
· continue on taceolimus and may consider shifting to sirolimus/evrolimus post operative considering their benefits in malignancy as an antiproliferative drugs.
Perioperative preparations :
Anemia ,electrolytes imbalance, Sepsis, dehydration ,Bowel preparation, DVT prophylaxis.
Liver , kidney , sepsis parameters labs , coagulation profile , serum albumin and full blood count .
Immunosuppression:
Discontinue sirolimus 5-10 days before surgery to avoid impaired wound healing , wound dehiscence , use steroids as hydrocortisone 100 mg / 8 hrs in the first 24 hrs then half of the dose the 2nd day and then oral prednisolone .
start tacrolimus 5-7 days prior to surgery and follow up the trough level , the decision of reintroducing of sirolimus after the surgery or tacrolimus should be individualized .
If the patient is on FK and steroids: same precautions , while he will continue on tacrolimus .
What is your peri-operative management?
Malignancy is one of the most common complication in solid organ transplant patients as a result of immune suppression plus patient risk factor like advance age and smoking
Management of malignancy in SOT and keeping the transplanted organ sometimes is something difficult to achieve as the main treatment for malignancy to decrease or stop immune suppressive medications
So you should assess risks and benefits of each decision and discuss with your patient to be ready to accept all results.
In heart and lung transplantation the decision is easier because you can never risk graft loss but in kidney transplant you still have other modalities on which patient can survive
CNI increase risk of malignancy as it increase TNF beta.
mTor has antiproliferative effect which is well established in treatment of NMSC post transplant but the effect on others types of malignancy still need more prospective cohort randomized controlled studies.
Also mTOR delay tissue healing because of its inhibitory effect on angiogenesis and its antiproliferative effect
In this patient perioperative management:
1/10 days preoperative i will shift mTOR to tacrolimus targeting trough level 5ng/dl and to be reintroduce after 4w or after wound healing
2/stress dose steroids 100mg hydrocortisone/8h preoperative and half dose day1 postoperative then recontinue his preoperative oral dose
3/iv fluids and avoid prolonged fasting without affording sufficient iv fluids maintenance
4/avoid NSAID intake and use parecetamol and narcotics for pain killer
5/antibiotics prophylaxis and preferred group are cephalosporins.
How would you manage his immunosuppression?
CNI increase risk of malignancy as it increase TNF beta.
mTor has antiproliferative effect which is well established in treatment of NMSC post transplant but the effect on others types of malignancy still need more prospective cohort randomized controlled studies and also it delay tissue healing.
As this patient has adenocarcinoma decreasing immune suppressive medications is mandatory. the 1st drug to be stopped or decreased is MMF if the patient is recieving it because you need to keep your patient on dual medications to decrease immune suppression medications and MMF can’t be used alone with steroids.
In such case i would prefer to shift mTOR to tacrolimus 10-15 days preoperative targeting trough level 5 ng/dl and continue 3-4w post operative or till achieve good tissue healing then reevaluate the current graft status and pathology of resected malignancy and discuss with the oncologist the risk of recurrence then discuss with the patient and mostly i will reintroduce mTOR again.
Would your management differ if he was on Tac and steroids?
CNI increase risk of malignancy as it increase TNF beta.
mTor has antiproliferative effect which is well established in treatment of NMSC post transplant but the effect on others types of malignancy still need more prospective cohort randomized controlled studies also risk of rejection is higher with mTOR inhibiors as it weaker drugs
Immunological risk of the patient, graft statusŘŚrisk of rejection vs risk of recurrence and the pathology results of the resected tumor
All these factors should be considered and discussed with the patient and tailor your medications either keeping tacrolimus and targeting lower level with close screening of recurrence or shifting to mTOR after 4w or complete tissue healing
1-Full evaluation by nephrologist ( good hydration perioperatively, , avoid nephrotoxic medications, avoiding hypotension during the procedure, and, monitoring of renal function test.
2- cardiac evaluation with risk stratifications.
3- perioperative antibiotics prophylaxis.
4- Might need the transplant surgeon to be around during procedure, because, it might injure the transplanted ureter.
How would you manage his immunosuppression?
Switch sirolimus to tacrolimus a week preoperative, because sirolimus delays wound healing by inhibiting nitric oxide & VEGF.
Monitor the therapeutic level of tacrolimus.
Switch oral prednisolone to IV hydrocortisone once the patient starts NPO till he can tolerate orally postoperative, then continue on oral prednisolone as before.
Continue again on sirolimus after a month post-operative.
Would your management differ if he was on Tac and steroids?
Continue the same medications & add MMF
Switch tacrolimus to sirolimus a month post-operative.
What is your peri-operative management?
Evaluate her clinical condition including cardiovascular status, volume status and make sure he had no sepsis
How would you manage his immunosuppression?
Switch mTOR to MMF and predinsilone to hydrocortisone
Then went back to mTOR after healing of the wound
Would your management differ if he was on Tac and steroids?
I will keep it in a low level till the operation end and the wound healed then introduce mTOR
1-full lab
– cvs work up
-anathesia consultation
2-icrease corticosteroid dose as patient is highly stressed
– keep serolimus as it has anti neoplastic effect
3-yes I will convert tac to mtor as it has anti neoplastic effect
also use proper AB as patient immunocompramissed and highly suseptable for infection
also may need to stop serlimus for one week as it deteriorate wound healing then use it again
Q1: she needs an assessment of cardiovascular system before operations and laboratory tests include CBC, PLT, Biochemistry, coagulation tests
Anesthesia consultation
Suitable hydration
Avoidance of nephrotoxic drugs prescription.
Parenteral hydrocortisone 100 mg IV Q8h preoperatively then tapering the dose to past regular dose.
Using antibiotics prophylaxis : preferably first generation cephalosporin and avoid using antibiotic which increases CNIs levels because she need to switch to CNIs and safe one such as ciprofloxacin ,clindamycin or azithromycin if indicated.
Q2: stop sirolimus 2 weeks before surgery and start tacrolimus instead of it and continue for 1-3 months post operations.
Q3: If this patients was reciting tacrolimus, switch it to sirolimus 1-3 months after surgery.
How would you manage his immunosuppression?
Stop Sirolimus 5-10 days prior to surgery because sirolimus had poor wound healing. We can give TAC .
steroid showed be used in stress dose ( hydrocortisone 100mg IV on the day of surgery ,then the dose is reduced to 50 mg 8 hourly and restart oral prednisolone from post-operative day 2. After 2 -3 month we can shift to sirolimus .
Would your management differ if he was on Tac and steroids? I will keep TAC in acceptable level steroid used in stress dose ,add MMF .Then I will shift to sirolimus after 2-3 months
Regarding this patient with history of kidney transplant on sirolimus and steroid for pre- operative recommendations:
CBC and RFT monitoring regularly and keeping him in good hydration state pre and post op. with proper antibiotics coverage.
Keeping him on minimum dose of steroids due to its side effects related to infection and delay wound healing.
For sirolimus the patient who has elective surgery it’s better to discontinue using sirolimus one week before operation and continue using MMF ,CNI or azathioprine then return to sirolimus after wound healing and this is because of it’s side effects that affecting wound healing like interference with fibrogenesis and wound healing ,impaired of granulation of the wound and may cause ulcer formation with wound dehiscen and lymphoceles, in case of urgent operation sirolimus must be stopped immediately before operation.
If he is on Tac and steroid I will keep him on same regimen and after complete wound healing switched to sirolimus.
Reference
Handbook of kidney transplantation ( 6 ed.).Gabriel M. Danovitch.
What is your peri-operative management?
How would you manage his immunosuppression?
to dc rapamune once they decided to go for OR (rapmune has long half life, and to be shifted to cni achiveing lowest accepted level for her.
Would your management differ if he was on Tac and steroids?
no it will not be changed.
reffence
Transplant International ISSN 0934-0874nsplant International ISSN 0934-0874
Journal compilation
2009 European Society for Organ TranEuropean Society for Organ Transplant
The use of sirolimus is associated with many perioperative complications including poor wound healing and lymphocele , so it is wise to switch sirolimus to another immunosuppression drug ( CNI , MMF ) 7 days before the surgery return to sirulimus after 2 -3 months.
If the patient is on TAC and steroids we can proceed with surgery , and to convert him to sirolimus after 2-3 months to reduce the risk of tumor recurrence.
Reference :
Gabriel M. Danovitch, Handbook of Kidney Transplantation SIXTH EDITION
1-Peri-operative management:
planned left hemicolectomy for patient on IS consisting of mTOR inhibitor .
. General system review and general lab testing
.Holding Sirolimus 5-10 days before surgery to prevent wound healing affection.
. Replacement of sirolimus by Tac orally or IV according to allowed route of adminstration.In addition, suitable broad spectrum antibiotic prophylaxis is given.
2-Sirolimus to be resumed within 1-3 months considering wound condition.
3-Hydrocortisone given as stress dosing ;100 mg iv 8 hourly on surgery day to be 50 mg postoperatively then orally for 1-3 months and then shifting to sirolimus for its anti tumor effect
.
References:
Campistol J., Cockwell P., Diekmann F., et al Practical recommendations for early use of m-TOR inhibitors (sirolimus) in renal transplantation .Transplant International. 2009.
2.Managing his immunosuppression
3. Would my management differ if he was on Tac and steroids?
REFERENCES
Campistol JM. Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation. Transplant International. Vol 22, Iss 7. 2009
1. This patient has taken prednisolone as maintenance. Given that colectomy is a major surgery, it is suggested that the patient should receive 100 mg hydrocortisone at the time of surgery followed by 50 mg thrice a day for 24 hours, and then continue his usual prednisolone dose.
2. Rapamune should be held for one week prior to surgery and switched to Tacrolimus, because of the increased risk for delayed wound healing and wound dehiscence. When the surgical incision has healed, Tacrolimus should be discontinued and Rapamune restart.
When the patient can not take oral tacrolimus, an intravenous dose equal to one-third to one-forth of the oral daily dose or sublingual tacrolimus one-second of the oral dose can be administered.
3. If the patient was on tacrolimus, after healing of the surgical incision, tacrolimus should be switched to mTOR inhibitors (sirolimus or everolimus).
Evidences for my suggestions:
Tacrolimus increases the level of TGF-β and thereby promotes tumor progression and metastasis.
mTOR inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis.
Several mechanisms have been identified for mTOR inhibitor–mediated tumor inhibition. Specifically, mTOR inhibitors can induce apoptosis in a cell type–specific fashion (inhibition of P70S6K, thereby decreasing cell proliferation). It can also induce cell death in B-cell lymphoma lines, phosphatase and tensin homolog-lacking human tumors, and dendritic cells, possibly through p53 activation and reduction in the cyclin and surviving levels, and inhibition of IL-10.
opposite son some cancers (PTLD, skin cancers including BCC/SCC/Kaposi etc.) that have a link to immune suppressive treatment colon ca (as it has similar incidence to non-transplant patients) has same incidence. while on CNI’s we may think to shift to antiproliferative and mTOR preferably.
as response to second question I will leave the sirolimus as it is because of excellent renal function. steroid should be increased as tress dose perisurgicaly but such low dose when lowerd to 5 mg postoperatively unless there is remarkable wound problem can be continued. one option could be shifting to tacrolimus especially because of interference with wound healing known for antiproliferatives and mTORs. because of cancer we may return to previous regimen of the patient
I could not find consensus for such case but :
I will prefer tacrolimus and steroid after surgery (here no specific relation to this time of cancer I think)
so If patient was on Tac and steroid I would have continued. same may not apply in case of dermatological cancer. I could be afraid for replacing more potent regimen (including Tac) except for obligatory reasons.
From an oncologic view ,managing Colon tumor in Transplant Recipients isn’t different from non-transplant patients. It involves surgery and chemotherapy.
Pre- operative
1. Patient education & counseling about patient expectation in the pre- and postoperative phases of his surgery.
2. Address modifiable risk factors like smoking & alcohol, anemia(1–1.5 g iv iron if needed or packed RBC transfusion to keep Hb near 13), and nutrition ( Oral high calorific drinks plus specific nutrients such as arginine, glutamine, nucleotides and omega-3 fatty acids )
3. Prevent postoperative nausea & vomiting Risk factors are similar past history , female gender, non smokers, volatile anesthetic agents, nitrous oxide use, and use of too much opioid intra-operatively .use a two drug combination of anti emetic according to ERAS society guidelines if there are 1-2 risk factors and use of 2-3 antiemetic if there are more than 2 risk factors ( D2 antagonists, 5HT3 antagonists, and dexamethasone at a single dose of 8 mg )
4. Give Prophylactic intravenous antibiotics within 60 minutes prior to surgery according to the local hospital policy( metronidazole combined plus a third generation cephalosporin or ciprofloxacin for penicillin-allergic patients). Skin decontamination with iodine containing solutions or better chlorhexidine alcohol solutions , pre-operative antiseptic showers and avoid abdominal Hair shaving and clip it instead just prior to surgery.
5. Mechanical bowel preparation that include oral antibiotics will decrease infection , anastomotic leak rate, ileus and major morbidity
6. Pre-operative fasting & fluid management keep patient in euvolemic state (according to ERAS patient can to drink clear fluids up to two hours before surgery with a light meal six hours before. Carbohydrate loading drinks in the preceding evening and 2 hours before induction has been shown to reduce can decrease the catabolic response to surgery , insulin requirements, episodes of hyperglycemia, time to flatus, hospital stay and increase gastric emptying
Intra-operative
1. Anesthesia: avoid benzodiazepines , use short acting general anesthetic agents and use minimal intra-operative opioids( propofol for induction and fentanyl, alfentanil, sufentanil or remifentanil infusions ) .it is better to use opiate free anesthesia .
2. avoid hypothermia through assessment every 5 minutes by nasopharyngeal or esophageal probe . if detected :use warm & humidified anesthetic gasses, warm IV fluids and irrigation fluids, warming devices, and pre-warmed blankets.
3. Analgesia: Thoracic epidural(T7-T10) analgesia is superior to systemic opioids in open colorectal surgery . in laparoscopic surgery use Transversus abdominis plane (TAP) blocks (associated with fewer use of opioid , earlier flatus passage and bowel movements ) . to decrease the post operative pain, another approach can be used which is a single intrathecal injection of opioids .furthermore, Local wound infiltration of the fascia and dermis is used with the above measures
Post-operative
1. Early mobilizationto decrease the risk of DVT, atelectasis, and decreased muscle mass .
2. Postoperative analgesiawith Regular acetaminophen, non-steroidal anti-inflammatories (NSAIDS) and gabapentinoids. Use short acting opioid analgesia ( miniumum or better avoid ) only for breakthrough pain
3. Drains/tubes through Orogastric tubes for gastric decompression and increasing operative space . remove Foley catheters early
4. IV fluids and nutrition liquids are allowed on the first evening and then early starting of low residue diet as tolerated , if iv fluid are needed avoid excessive saline volumes in fear of hyperchloremic acidosis and interstitial fluid overload.
5. Avoiding post-operative ileus through . Limiting perioperative opioid use through multimodal pain regimens, early mobilization, avoiding routine use of nasogastric tubes and abdominal drains, early removal of Foley catheter to encourage mobilization, and careful perioperative fluid and electrolyte managements1
Chemotherapy
First we need to do HBV screening as this can reactivate with chemotherapy ending with fulminant hepatitis. chemotherapy includes combinations of 5-fluorouracil, oxaliplatin, leucovorin, and irinotecan .biologic drugs like bevacizumab can be added . all of these have no major drug interactions with CNI, mTOR inhibitors, and MMF.2
How would you manage his immunosuppression?
Sirolimus is associated with impaired wound healing in a dose-dependent manner. It reduces expression of vascular endothelial growth factor (VEGF) and nitric oxide (NO), and inhibits smooth muscle cells and fibroblast proliferation, and matrix deposition. So I would stop sirolimus during the first week post-transplantation. The half life of sirolimus is long so I would stop it 5 -10 days prior to surgery and resuming it after1-3 months. 3
Regarding steroid, the usual dose will be used plus hydrocortisone 50 mg iv before incision. Then 25 mg TDS for 24 hr then the daily dose 4
· Would your management differ if he was on Tac and steroids?
I will add MMF as it has anti-colon cancer effect ( inhibit the adhesion of colon cancer cells to intestinal epithelial cells)2 . I will keep tacrolimus on the minimum acceptable trough level and I will shift it into sirolimus after 1-3 month. 3
1-Kearney, D., Liska, D., Holubar, S.,Preoperative instructions and postoperative care in the 21 century ,Annals of Laparoscopic and Endoscopic Surgery}, Vol 4 (August 2019)
2-Prenner S, Levitsky J. Comprehensive Review on Colorectal Cancer and Transplant. Am J Transplant. 2017 Nov;17(11):2761-2774. doi: 10.1111/ajt.14340. Epub 2017 Oct 4. PMID: 28471512
3-Campistol, Josep & Cockwell, Paul & Diekmann, Fritz & Donati, Donato & Guirado, Luis & Herlenius, Gustaf & Mousa, Dujanah & Pratschke, Johann & Ruiz, Juan. (2009). Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation. Transplant international : official journal of the European Society for Organ Transplantation. 22. 681-7. 10.1111/j.1432-2277.2009.00858.x.
4-Melanie M. Liu,Andrea B., Reidy, Siavosh Saatee, Charles D. Collard, Perioperative Steroid Management: Approaches Based on Current Evidence ,Anesthesiology July 2017, Vol. 127, 166–172.
What is your peri-operative management ?
General management:
Fitness evaluation , specially cardiovascular assessment .
Basic laboratory investigation .
Basic kidney transplant recipient investigation .
Pre-operative surgical evaluation including bowel preparation Pre-operative antibiotic prophylaxis , post-operative DVT prophylaxis and care of wound site to prevent wound infections.
Special consideration for hydration and avoidance of harm drugs
Intra-operative episodes of hypotension and bleeding showed be recorded .
How would you mange his immunosuppressant ?
– with hold Sirolimus 5-10 days prior to surgery to avoid effects of sirolimus on wound healing.
– use CNI ( tacrolimus ) instead of sirolimus.
-steroid showed be used in stress dose ( hydrocortisone 100mg IV on the day of surgery ,then the dose is reduced to 50 mg 8 hourly and restart oral prednisolone from post-operative day 2.
In the post operative period ;
There are 2 ways to further manage immunosuppression:
First way is continue tacrolimus for 1-3 months and change back to sirolimus. Another way is to shift back to sirolimus in 5 days and continue with oral steroids.
Would your management differ if he was on TAC and steroid ?
In the pre-operative and the immediate post operative period ,tacrolimus should be continued and steroid should be given in a stress dose .
Later on after wound healing TAC can be switched to sirolimus to decrease risk of developing cancer.
References;
Kaplan, B., Qazi, Y. and Wellen, J., 2014. Strategies for the management of adverse events associated with mTOR inhibitors. Transplantation Reviews, 28(3), pp.126-133.
Tiong, H., Flechner, S., Zhou, L., Wee, A., Mastroianni, B., Savas, K., Goldfarb, D., Derweesh, I. and Modlin, C., 2009. A Systematic Approach to Minimizing Wound Problems for De Novo Sirolimus-Treated Kidney Transplant Recipients. Transplantation, 87(2), pp.296-302.
▪︎What is your peri-operative management?
Pre-operative investigations include routine blood tests ,cbc , liver function ,kidney function And trough level of immunosuppression.
Full cardiac evaluation , coagulation profile.
Full Anaesthesia assessment.
Laparoscopic surgery if possible would be better than open surgery
laparoscopic surgery for advanced rectal cancer is better in terms of blood loss, length of hospital stay, and wound infection than open surgery, and thus is considered useful for high-risk cases.
▪︎How would you manage his immunosuppression?
– 5 days Befor surgery stop sirolimus and shift to tacrolimus as sirolimus was associated with significantly higher wound complications and delay in wound healing
after wound healing and post operative 1 month Sirolimus is better to be used again.
-With introduction of MMF
-Steroids changed to stress dose 100 mg /8 h
The day of surgery and to half dose the day after then continued as long as the patient in NPO the tapering to the oral maintenance dose
mTOR inhibitors have been shown to induce apoptosis in colon cancer cells and have been studied in colon cancer trials as part of a chemotherapeutic regimen 1.
Based on the potential beneficial effects of mTOR inhibitors and tumor-promoting mechanisms of CNI, a strategy of changing immunosuppression to an mTOR-based regimen might be beneficial 2 .
MMF has also been shown to have antitumor effects against colon cancer and may also be a better option than CNI and azathioprine in patients with an active cancer 3 .
▪︎Would your management differ if he was on Tac and steroids?
The same for steroid
But no change in TACROLIMUS befor surgery
With shift after one month to sirolimus.
1He K, Zheng X, Li M, Zhang L, Yu J. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation. Oncogene 2016; 35: 148–157.
2 Epailly E, Albanell J, Andreassen A, et al. Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: Practical clinical management questions. Clin Transplant 2011; 25: E475–E486.
3 Engl T, Makarevic J, Relja B, et al. Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: Impact on tumor recurrence and malignancy. BMC Cancer 2005; 5: 4.
Preoperative anesthesia evaluation is needed in concordance with surgical and trasnplanation team to assess his cardiac and respiratory fitness along with the graft function
Pre- and postoperative laboratory blood findings need to be evaluated including routine labCBC , KFT,bleeding profile to minimize intra- and postoperative complications
Perioperative evaluation should consider that he is chronically immunosuppressed, with increased risk for any surgical complication, particularly infectious.
Multiple trials demonstrated that minimally invasive surgery gives better short-term outcomes than open colorectal surgery concerning less intraoperative bleeding, postoperative pain, and hospital stay, as well as a lower incidence of infection and same as on long-term outcomes
The immunosuppression has great effect on wound healing and infection , specially in the immediate post-transplant period.
immunosuppression can also interfere with the drug interactions, adverse effects, wound healing, and postoperative complications
Sirolimus need to be replaced by tacrolimus because sirolimus has a significantly higher surgical wound complication rate and after proper wound healing and case stabilisation Sirolimus can be reused with close monitoring of graft function.
Tacrolimus and steroids can be continued and dosent need to be changed in the immediate postoperative period but latter on Tac can be substituted with Sirolimus due to the latter anticarcinogenic effect in such a case
Reference
Debrito SR etal . Outcomes Following Colorectal Resection in Kidney Transplant Recipients. J Gastrointest Surg. 2018 Sep; 22(9): 1603–1610.
Alasari S etal. Minimally Invasive Colorectal Resection in Kidney Transplant Recipients: Technical Tips, Short- and Long-Term Outcomes. Int Sch Res Notices. 2014; 2014: 254612.
Peri-operative management includes:
1- Anaesthesia and surgical risk assessment.
2- General surgeon or bowel surgeon team should co-ordinate with the transplant team or any intra-operative surgical issues.
3- Pre-operative investigations and preparations, like group and save, routine blood tests.
4- Intra-operative: maintain hemodynamic, monitor blood loss and replace adequately, surgical procedure techniques, sutures are better for wound healing compared to Staples.
5- Post-Operative:
Input/output chart, IV fluids, IV prophylactic antibiotics according to the local guidelines, post-operative surgical care (wound, drains, stoma, VTE prophylaxis) as per the surgical team plan and protocol.
6- Change of oral immunosuppression to IV as long as the patient is not taking orally will be discussed on immunosuppression management.
a- Steroids: IV Hydrocortisone 100mg tds on the day of surgery, from second day onwards till oral intake is permitted give IV hydrocortisone 50mg tds. Once oral intake started, switch to oral prednisolone.
b- Sirolimus (Rapamune): Stop Sirolimus 5-10 before this elective operation, continue holding Sirolimus post-operatively for 1- 3 months.
c- Introduction of CNIs instead of Sirolimus: Tacrolimus is available as oral, SL, IV. Cyclosporine is available as oral and IV. IV dose is one third of oral dose. SL Tacrolimus dose is half of oral dose. IV cyclosporine dose is given as infusion over 4 hours twice daily, IV Tacrolimus is infusion over 24 hours. IV or oral preparation depends on surgical team permission to start oral or not. Continue CNI for 1-3 months post operatively.
7- Sirolimus tends to delay wound healing that is why it is usually stopped before surgical intervention, restart Sirolimus once wound healing is satisfactory within 1-3 months post-operative.
I will keep steroids in the same regimen as mentioned earlier,
I will continue on Tacrolimus till satisfactory wound healing either oral or IV as mentioned earlier, However I should highly consider switching the patient to Sirolimus which has an anti-proliferative effect to minimize the chance of malignancy recurrence.
References:
1- Handbook of transplantation, Danovitch, Chapter 6.
Peri-operative management :
Cardiac fitness of the patient has to be assessed, along with fitness for anaesthesia. Evaluation of graft function, check for infection has to be done. Symptoms or signs of infection may be present which need to be evaluated appropriately, such as fever, rash, malaise, fatigue, night sweats, breathlessness, sudden bloating, edema, changes in urine or stool frequency or color or presence of blood in urine or stool, abdominal pain etc.
IV antibiotics may be given as prophylactic measure. Ceftriaxone is commonly used.
Lab investigation such as CBC, CRP, electrolytes, LFT, RFT, blood coagulation tests, urine tests if needed, CXR, ECG and echo will be done.
Increase in steroid dose may be considered as part of peri-operative management. Sirolimus should be stopped one week prior to date of surgery and replaced with tacrolimus. Sirolimus will be restarted 4-8 weeks postoperatively.
Management of immunosuppression :
Sirolimus would be stopped one week before the surgery, and replaced with tacrolimus. Post operatively once wound healing has been established and the patient has stabilized, Sirolimus can be restarted. This is because there is important evidence that suggests that Sirolimus impairs wound healing. This is demonstrated through diminished expression of VEGF and nitric oxide in wound.
Management difference if patient was on tac and steroids :
Tacrolimus levels might be increased by antibiotics like erythromycin.
Tac will be replaced by Sirolimus 4-8 weeks post surgery since mTOR inhibitors have anti-cancer features.
Ref :
Schäffer M, Schier R, Napirei M, Michalski S, Traska T, Viebahn R. Sirolimus impairs wound healing. Langenbecks Arch Surg. 2007 May;392(3):297-303. doi: 10.1007/s00423-007-0174-5. Epub 2007 Mar 24. PMID: 17384960.
Bowman LJ, Brennan DC. The role of tacrolimus in renal transplantation. Expert Opin Pharmacother. 2008 Mar;9(4):635-43. doi: 10.1517/14656566.9.4.635. PMID: 18312164.
Dental, J et al. Sirolimus for secondary prevention of skin cancer in kidney transplant recipients : 5 year results. Journal of clinical oncology. Volume 35 issue 25.
Reynold I. Lopez-Soler, Panpan Chen, Lakshmi Nair, Ashar Ata, Sunil Patel, David J. Conti,
Sirolimus use improves cancer-free survival following transplantation: A single center 12-year analysis,
Transplantation Reports,
Volume 5, Issue 2,
2020,
100040, https://doi.org/10.1016/j.tpr.2020.100040.
What is your peri-operative management?
I need to assess the patient surgical risk (cardiac risk need Echo, wound healing need BMI as obesity is a major risk for wound healing, post-surgical history if any, infection risk: patient on immunosuppression need antibiotic with close observation to signs of infection)
Basal management:
· like investigations (CBC, u/e/c/ urine R/E/ FBS/ Blood group and crossmatch….)
· INPUT-OUTPUT Chart
· IV fluid
· IV antibiotic prophylaxis (abdominal surgery Ceftriaxone+ Flagyl)
· Discus with the surgeon about closed suction retroperitoneal drain / good surgical technique including non-absorbable sutures in the fascia, preferable with an interrupted technique.
· Wound support for a longer period of time including the use of skin sutures for 3 weeks to ensure the wound edges are sealed
· Suture rather than staples
How would you manage his immunosuppression?
If the BMI > 32 I will stop sirolimus and replace it with tacrolimus 10 days before the patient goes surgery, then return it back after patient stabilization and wound healing
If BMI < 32 I will not stop sirolimus
Steroid, I will increase it to stress does in the day of surgery 100 mg 8 hrly, which will decrease 2nd day to 50% till return him to oral dose days later.
Would your management differ if he was on Tac and steroids?
Steroid, same as mentioned above
Tacrolimus will be replaced by sirolimus as it has an anti-proliferative effect as well, as the patient is 64 yrs, he will need less immunosuppression
What is the relation between Sirolimus and wound healing? That is a very important point here.
it cause delayed wound healing
All patients using immunosuppressive medications are at risk of postoperative wound infection.(1)
Being mTOR inhibitor, I may change it to tacrolimus , to avoid risk of delayed wound healing. and once wound has healed, switch back to mTOR inhibitor.
Yes, i may increase steroid dose preoperatively and keep patient on tacrolimus for fear of delayed wound healing then , shift tacrolimus to mTOR inhibitor medications.
references:
1 – Haubner F, Ohmann E, Pohl F, Strutz J, Gassner HG. Wound healing after radiation therapy: review of the literature. Radiat Oncol. 2012 Sep 24;7:162. doi: 10.1186/1748-717X-7-162. PMID: 23006548; PMCID: PMC3504517.
2- Uptodate.com last login Dec 2021
Good, How does Sirolimus prevent healing? any ideas ( clue – VGEF; nitric oxide)
What is your peri-operative management?
preoperative evaluation by the anesthesiologist should include: evaluation of the graft function, presence of infection, function of other organ systems.
A thorough review of systems along with a physical examination is essential in this popula- tion. Findings such as recent weight gain, edema, dyspnea, sweats, malaise, fever, rashes, abdominal pain, abnormal breath sounds on auscultation, and changes in stool or urine out- put are some of the potential signs and symptoms of infection or rejection.
The following investigations should be available preoperatively.
1. Laboratory parameters:
a. Complete blood count (to rule out bone marrow suppression)
b. Electrolytes
c. Renal function tests
d. Liver function tests
e. Coagulation tests
2. Chest radiograph
3. Electrocardiogram
4. Echocardiography
How would you manage his immunosuppression?
100 mg of hydrocortisone is given intravenously every eight hours perioperatively, and the dose is slowly reduced (but not the frequency) until the patient can be switched to his or her regular doses of oral medications.
The relatively long half-life of sirolimus necessitates that the drug is discontinued 5–10 days before planned major surgery in order to avoid any postsurgery complications such as impaired wound-healing so sirolimus Change to CNI(TAG)
we would recommend re-starting siroli mus treatment after 1–3 months post operation
Would your management differ if he was on Tac and steroids?
after 1–3 months post operation We can change from TAG to sirolimus because of its antineoplastic effect of sirolimus.
Reference
1-Josep M. Campistol, Paul Cockwell .Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation.
Transplant International
Volume 22, Issue 7 p. 681-687. 04 June 2009
https://doi.org/10.1111/j.1432-2277.2009.00858.x
Citations: 28
2-Katarina Tomulić Brusich and Ivana Acan. Anesthetic Considerations in Transplant Recipients for Nontransplant Surgery.
http://dx.doi.org/10.5772/intechopen.74329. Organ Donation and Transplantation – Current Status and Future Challenges.2018
3-up to date 2021
Good reply, you covered most of it. Try to be more systematic in future. I know it is probably a lack of a comma but your starting statement “preoperative evaluation by the anesthesiologist should include: evaluation of the graft function, presence of infection, function of other organ systems” is misleading as an anesthesiologist will not evaluate graft fn etc.
1- Perioperative management plan :
This patient will undergo elective major surgery, so need careful clinical assessment including
a- Cardiac assessment as CVD are common among transplant recipient.
b- Assess risk of postoperative complications including
· Impaired wound healing ( common with both steroid and sirolimus) , that has both modifiable risk factors as BMI and Steroid dose and non modifiable ones as age and race .
· Increase risk of infection : coverage with antibiotic .
c- Assess the risk of VTE and the need for prophylactic anticoagulant.
d- Close monitoring of graft function .
e- Surgical intervention techniques :
Careful closure of the wound to allowe better healing , keep the drains in place till obtain acceptable flow.
II- for IS medications
· Steroid : due to the high risk of incidence of adrenocortical insuffiency in these patients, it is recommended to shift to high dose IV steroid starting with induction of anesthesia either
Hydrocortisone ( or equivelant) 10 mg / h and have the dose the second day after operation or use hydrocortisone 100 mg /8 h and decrease the dose but not the interval when the patient is stable then swich back to his maintenance dose .
· Sirolimus:
As sirolimus is associated with significant risk for impaired wound healing so it should be discontinued one week preoperative and replaced with Tac , to be resumed 1-3 month after surgery. Sirolimus is the prefared maintance IS in patient with cancer as it has antineoplastic action through inhibiting angiogenesis and VEGF secretion.
III- If the patient was on Tac :
More caution showed be given to drug – drug interaction as
· Antibiotic : eryhromycin will incease Tac level.
· Anesthetic agents as nenzodiazepines : need dose modifications as Tac increase their blood level.
1- Campistol, Josep M et al. “Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation.” Transplant international : official journal of the European Society for Organ Transplantation vol. 22,7 (2009): 681-7. doi:10.1111/j.1432-2277.2009.00858.x
2- UpToDate : Shapiro R ., Kidney transplantation in adults: Nontransplant surgery in the kidney transplant recipient. Topic 7317 Version 22.0
Why should we recommence sirolimus after 1-3 months in this case. Case of say diverticular perforation, can we start sirolimus after 1 week. ( Clue is in the question)
Dear all, what possible patient factors and new medications may affect your post-operative decision on maintenance IS?
This is a patient on dual immunosuppression of mTOR inhibitor and steroid. He is planned for an elective major surgery.
The peri-operative management includes general management for left hemicolectomy and specific management with respect to transplant recipient status.
General management:
1) Pre-operative evaluation including cardiovascular assessment, laboratory parameters like complete blood counts, renal function tests, liver function tests etc.
2) Pre-operative bowel preparation
3) Arrangement of blood products
4) Discussion about the treatment outcomes with the patient/ family members
5) Pre-operative antibiotic prophylaxis: Covering gram negative and anaerobic organisms – ceftazidime with metronidazole.
6) Post-operative DVT prophylaxis.
7) Care of wound site to prevent wound infections.
Transplant specific management:
1) Management of immunosuppression:
a) Stress dose of hydrocortisone – 100 mg intravenous 8 hourly on the day of surgery, reduce dose to 50 mg 8 hourly on post-operative day 1 and restart oral prednisolone from post-operative day 2 (if orally allowed). This helps in taking care of the secondary adrenal insufficiency.
b) Stop Sirolimus 5-10 days prior to the surgery: This helps in avoiding the side effects of sirolimus like poor wound healing and wound dehiscence.
c) CNI (Tacrolimus) introduction in place of sirolimus: Oral Tacrolimus initially and intravenous tacrolimus when patient is kept nil per orally (usually on day of surgery and first post-operative day). Restart oral tacrolimus once patient is allowed oral intake.
d) In post-operative period, there are 2 ways to further manage immunosuppression: First way is continue tacrolimus for 1-3 months and change back to sirolimus. Another way is to shift back to sirolimus in 5 days and continue with oral steroids. (1)
If the wound is fine and there are no surgical complications, I would like to re-introduce sirolimus after 5 days post-surgery in place of tacrolimus.
The management of immunosuppression in this patient would include:
a) Stress dose of hydrocortisone – 100 mg intravenous 8 hourly on the day of surgery, reduce dose to 50 mg 8 hourly on post-operative day 1 and restart oral prednisolone from post-operative day 2 (if orally allowed). This helps in taking care of the secondary adrenal insufficiency.
b) Stop Sirolimus 5-10 days prior to the surgery: This helps in avoiding the side effects of sirolimus like poor wound healing and wound dehiscence.
c) CNI (Tacrolimus) introduction in place of sirolimus: Oral Tacrolimus initially and intravenous tacrolimus when patient is kept nil per orally (usually on day of surgery and first post-operative day). Restart oral tacrolimus once patient is allowed oral intake.
d) In post-operative period, there are 2 ways to further manage immunosuppression: First way is continue tacrolimus for 1-3 months and change back to sirolimus. Another way is to shift back to sirolimus in 5 days and continue with oral steroids. (1)
If the wound is fine and there are no surgical complications, I would like to re-introduce sirolimus after 5 days post-surgery in place of tacrolimus.
If the patient was on Tacrolimus and steroids:
a) Stress dose of hydrocortisone – 100 mg intravenous 8 hourly on the day of surgery, reduce dose to 50 mg 8 hourly on post-operative day 1 and restart oral prednisolone from post-operative day 2 (if orally allowed). This helps in taking care of the secondary adrenal insufficiency.
b) Continue oral Tacrolimus initially and intravenous tacrolimus when patient is kept nil per orally (usually on day of surgery and first post-operative day). Restart oral tacrolimus once patient is allowed oral intake.
c) Shift to mTOR inhibitors: Continue tacrolimus for 1-3 months and change to sirolimus as they have been found to be associated with anti-tumor properties. (2)
References:
1) Campistol JM, Cockwell P, Diekmann F, et al. Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation. Transpl Int. 2009;22:681-687.
2) Prenner S, Levitsky J. Comprehensive Review on Colorectal Cancer and Transplant. Am J Transplant 2017;17:2761-2774.
Good and practical response.
Do you think it’s always mandatory to stop mTOR inhibitors?
As per the article by Campistol et al, it is recommended that mTOR inhibitors be stopped prior to a surgical intervention. In view of wound related complications seen with mTOR inhibitors, it is a prudent approach and I think it is a sensible thing to do, especially if it is for 2 to 3 weeks.
In minor elective surgery or a laparoscopic surgery without risk factors (like African-American race, concomitant steroids, Thymoglobulin induction, overweight patient etc), mTOR inhibitors need not be stopped.
Your reply “if the wound is fine and there are no surgical complications, I would like to re-introduce sirolimus after 5 days post-surgery in place of tacrolimus“. Our case is Ca sigmoid, would you give Rapamune along with chemotherapy?
No. In case of concomitant chemotherapy, it is imperative to stop sirolimus for 1-3 months, as per the article by Campistol et al
What is your peri-operative management?
First, I have to assess the risk factors for delayed wound healing or wound dehiscence such as
1. Diabetes mellitus
2. Advanced age
3. Obesity
4. Malnourishment
5. Anticoagulant use
6. Long surgery duration
7. MMF -was found to result in more wound healing problems than azathioprine
8. corticosteroids – known to impair the healing of surgical wounds
9. prior abdominal surgeries
Then, peri-operative management include:
1- Switch sirolimus to tacrolimus at least one week before surgery
· mTOR inhibitors block growth signals required for proliferation of endothelial cells and fibroblasts, thereby restricting fibrosis, which is a key factor in successful wound healing
· mTOR inhibitors also inhibit vascular endothelial growth factor (VEGF) and nitric oxide, which are mediators of angiogenesis, inflammation, and immune function in skin wounds
· Sirolimus has also been shown to disrupt skin T cell proliferation, migration, and production of growth factors
2- Will discuss with surgeon regarding surgical techniques that can minimize wound complications or improve wound healing
· placing closed-suction drains
· using subcutaneous sutures-nonabsorbable sutures in the fascia, preferably with an interrupted technique
· sealing or ligating lymphatic ducts
· performing prophylactic peritoneal fenestration
· avoiding extensive dissection
· Sutures rather than staples seem to be better tolerated- leave the sutures for 3 weeks to ensure the wound edges are sealed.
· if using staples, it can remain in place for 3 to 4 weeks to prevent skin dehiscence
·
3- Antibiotics prophylaxis prior to surgery- commonly used is cephalosporin such as cefuroxime, given prior to surgery
4- Switch prednisolone to IV hydrocortisone as patient is going for colonic surgery and I would expect the patient will not be able to tolerate orally soon after surgery.
How would you manage his immunosuppression?
1- Sirolimus will be switched to tacrolimus 1 week prior to surgery as I do not want to take risk of wound complications
2- I would switch tacrolimus back to sirolimus 10-15 days post-surgery as suggested by Manito N et al 2010, if the wound healed completely.
3- Switch prednisolone to IV hydrocortisone during surgery. Post-surgery, if patient able to tolerate orally, will change back to prednisolone
Would your management differ if he was on Tac and steroids?
Peri operative management will be similar. I would like to continue tacrolimus as it has low risk of cancer and no adverse event on wound healing. But I would suggest patient to switch to sirolimus after the wound has healed. Sirolimus has 30-50% reduction in risk of developing cancer.
References
Practical points, thank you
What is the differential effect of mTOR on VEGF?
Pre operative:
Elective colorectal surgery is clean-contaminated and has high rate of surgical site infection (SSI). Prophylactic antibiotic as recommended for general population with no need for coverage of opportunistic organisms, antibiotic prophylaxis reduces the rate of SSI
mechanical bowel preparation with oral antibiotic prophylaxis.
perioperative steroid augmentation to 25-75mg hydrocortisone for 24-48 hours
cardiac evaluation before anesthesia as immunosuppressed state is a cardiac risk factor.
post operative:
prophylaxis against venous thromboembolism as general population
Sirolimus should be switched to CNI based regimen (Tacrolimus and steroids)
Sirolimus is associated with high rate of wound complications and impaired wound healing as it inhibit fibroblasts and smooth muscle proliferation.
It should be re administered after surgery with waiting period of about 30 days after surgery to allow wound healing
Tacrolimus is associated with increased risk of malignancy.
It should be switched to mTORi after the surgery after wound healing is completed to avoid wound complications.
Whiting J. Perioperative concerns for transplant recipients undergoing nontransplant surgery. Surgical Clinics. 2006 Oct 1;86(5):1185-94.
Nashan B, Citterio F. Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature. Transplantation 2012.
Romagnoli J, Tagliaferri L, Acampora A, Bianchi V, D’Ambrosio V, D’Aviero A, Esposito I, Hohaus S, Iezzi R, Lancellotta V, Maiolo E. Management of the kidney transplant patient with cancer: report from a multidisciplinary consensus conference. Transplantation Reviews. 2021 Jul 1;35(3):100636.
Sprangers B, Nair V, Launay-Vacher V, Riella LV, Jhaveri KD. Risk factors associated with post–kidney transplant malignancies: an article from the Cancer-Kidney International Network. Clinical kidney journal. 2018 Jun;11(3):315-29.
del Toro LĂłpez MD, DĂaz JA, Balibrea JM, Benito N, Blasco AC, Esteve E, Horcajada JP, Mesa JD, Vázquez AM, Casares CM, Del Pozo JL. Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery. CirugĂa Española (English Edition). 2021 Jan 1;99(1):11-26.
Colorectal cancer after renal transplantation associated with long term use of Immunosuppressive medication ,incidence increased after first 10 years due to increase the TGB -beta expression especially with CNI (cyclosporine, tacrolimus) ,and its dose dependent based on report from animal studies, human case series (1,2). while Sirolimus associated with 40% reduction in overall malignancy ratio.
Other comorbid disease associated with increased risk of colorectal cancer like obesity, DM with hyper insulinoma and insulin resistance, both insulin like growth factor (IGF-1), IGF binding protein-3(IGFBP-3) were influences the CRC in cohort study from metanalysis review of 14 studies with 38% higher rate of CRC in IDDM (3) with increased cancer related mortality.
Cyclosporine and azathioprine maintenance immunosuppressive medications were associated with increased risk of proximal colon cancer compared with tacrolimus and MMF (5).
colorectal cancer mortality was 5-6times higher in post transplantation compared to general population (4)
References:
1-tacrolimus enhances transforming growth factor-beta1expressionand promotes tumor progression,Maluccio M,SharmaV,LagmanM,VyasS,Yang H,liB,Suthanthiran M.Transplantation 2003:76(3):597.
2–Colon and rectal cancer after renal transplantation, Manstein Kan 1, John S Gill, Sam M WisemanExpert Rev Anticancer Ther. 2008 Aug;8(8):1339-46.
3- IS diabetes mellitus an independent risk factor for colon cancer and rectal cancer?YuharaH,Steinmaus C,Cohen SE,Corley DA, TeiY,BufflerPA.
AmJ Gastroenterol.2011:106(11):1911.
4-Cancer mortality in kidney transplant recipients: An Australianand New Zealand population-based cohort study, 1980–2013Brenda M. Rosales1, Nicole De La Mata1, Claire M. Vajdic2, Patrick J. Kelly1, Kate Wyburn3,4and Angela C. Webster1,5.
5-Risk of colorectal cancer after solid organ transplantation in the United StatesM Safaeian, PhD1,*, HA Robbins, MSPH1,3, SI Berndt, PharmD, PhD1, CF Lynch, MD2, JF Fraumeni Jr., MD1, and EA Engels,MD, Am J Transplant. 2016 March ; 16(3): 960–967.
6-Woundhealingcomplications after kidney transplantion aprospective randomized comparism of sirolimus andtacrolimus,DeanPG,LundWJ,LassonTS,PrietoM,NYbergSL,..
Transplantation2004;77(10):1555.
What is your peri-operative management?
How would you manage his immunosuppression?
Sirolimus should be stopped 5-10 days before the planned surgery because of the relatively long half life of sirolimus, and to avoid the complications associated with sirolimus use such as wound infection, dehiscence and poor wound healing. one to three months post surgery, the patient can re use sirolimus, meanwhile corticosteroids and CNI cover can be used till the patient can return to sirolimus.
Would your management differ if he was on Tac and steroids?
In this case, I will change oral steroid to IV hydrocortisone and continue on CNI till 3 months post surgery and then I’ll change the CNI to sirolimus.
Reference:
Preoperative preparations of the patient are to correct:
1. Nutritional deficiency eg, hypoalbuminemia
2. Anaemia
3. electrolytes imbalance
4. weight loss
5.Sepesis and hypovolemia
6. Bowel preparation, parenteral antibiotics, and deep venous thrombosis prophylaxis.
Immunosuppressive agents:
-Discontinued sirolimus 5-10 days before surgery to avoid postsurgery complications such as impaired wound healing.
-use steroids as immunosuppressants so steroid adjusted according to the local guideline.
-1-3months post-surgery restarting sirolimus.
-Shift to IV tacrolimus with follow-up of trough level
-If the patient is on tacrolimus and steroid: continue on tacrolimus for 1-3 months then shift to sirolimus because sirolimus is blocked the activity of the mammalian target of rapamycin. The mammalian target of rapamycin is a protein kinase that regulates growth factors that stimulate growth and angiogenesis.
Reference :
Josep M. Campistol,Paul Cockwell,Fritz Diekmann,Donato Donati,Luis Guirado,Gustaf Herlenius,Dujanah Mousa,Johann Pratschke,Juan Carlos Ruiz San Millán. Practical recommendations for the early use of mTOR inhibitors (sirolimus) in renal transplantation.Transplant international. 04 June 2009.
Maintain normovalemia.
Monitor Uop.
For corticosteroid:
Intravenous hydrocortisone 100mg every 8hr, till patient can resume oral intake.
Providing stress ulcer prophylaxis.
For patient on immunosuppression who cannot take oral medication conversion to
injection form is best option.
TAC. Injection to keep trough at 5- 8ng /ml.
MMF to injection form.
Cyclosporine also inject to keep trough level 50-100ng/ml.
Sirolimus change to TAC is better for 2-3 month then return to mTOR reduce risk of
delayed wound healing.
Preoperative Antibiotic:
Cefazolin + metronidazole, cefoxitin, cefotetan, ampicillin–sulbactam, ceftriaxone +
Metronidazole, ertapenem.
Alternative Agents in Patients with b-Lactam Allerg:
Clindamycin + aminoglycosides or aztreonam or fluoroquinolones-j metronidazole +
aminoglycosides or fluoroquilone.
If TAC:
Continue TAC with consideration to interaction with medication.
Tacrolimus has been associated with QT-interval prolongation or torsade’s de pointes.
Care should be taken with concomitant use of medicines that can also prolong the QT-
interval.
Anesthetic agents that may be used in the perioperative period that are known to, or
predicted to, prolong the QT-interval include:
*monitor ECG if concurrent use unavoidable; if risk factors for QT-prolongation are also
present (increasing age, female sex, cardiac disease, and some metabolic disturbances
e.g. hypokalemia) use greater caution.
References :
1- lists the wound classification criteria currently used by the CDC National Healthcare
Safety Network (NHSN) and Healthcare Infection Control Practices Advisory Committee
(HICPAC).
2-Transplant antirejection medication. UKCPA.
Regarding perioperative management:
As any colonic surgery ,the patient should have colonic preparation ( clearance) 1 day before surgery, to allow manipulation .
Antibiotics covering gram negative organisms should be administered 1 hour before incision
Being on long term steroids , we should guard against 2ry adrenal insufficiency using stress steroid doses with induction of anaesthesia
Regarding his immunosuppression, sirolimus is the best choice in case of malignancy
Some data suggest that sirolimus, suppresses the growth and proliferation of tumors in various animal models . Possible mechanisms of actions include inhibition of p70 S6K , interleukin-10 and cyclins.
Rapamycin is an effective inhibitor of human renal cancer metastasis.AULuan FL, Ding R, Sharma VK, Chon WJ, Lagman M, Suthanthiran MÂ SOKidney Int. 2003;63(3):917.Â
If he was on tacrolimus and steroids , I would shift him to mtor inhibitors after surgery ( in order for mtor I not to affect wound healing )
Tacrolimus appears to increase TGF-beta levels an effect clearly associated with tumor growth
Risk factors for malignancy in Japanese renal transplant recipients.AUImao T, Ichimaru N, Takahara S, Kokado Y, Okumi M, Imamura R, Namba Y, Isaka Y, Nonomura N, Okuyama AÂ SOCancer. 2007;109(10):2109.
Thankyou for addressing colonic surgery prophylaxis
you clearly mentioned the pros. and cons of mTOR versus CNI
so try to give a clear plan regarding IS if this patient is under your care.
In case he is on sirolimus and steroids , I would keep the same regimen , only stress dose of steroids at time of surgery
In case of tacrolimus and steroids , I will shift tacrolimus to sirolimus , 4-6 weeks after surgery to allow for proper wound healing
KTR is at higher risk for complications at time of surgery and post-op:
KTR on mTORi is at high risk at time of surgery to have wound-healing complications eg; wound healing impairement,lymphocele and incisional hernia
Measures to minimize wound-healing impairment in relation to the use of mTORi:
Peri-operative plan of management:
How would you manage his immunosuppression?
Would your management differ if he was on Tac and steroids?
The management will slightly differ, if being on TAC and steroid:
Thankyou for the organised answer
your final decision is to give low dose CNI until wound heals then shift back to mTOR
There is contradiction to that between the third and last paragraphs!
scenarios teaches everyone to take decisions so do it.
Peri-operative management:
Corticosteroids in immunosuppression protocol: Adrenal suppression related to the higher maintenance doses of steroids was common, requiring the administration of high perioperative doses of glucocorticoids. There are two regimens may be utilized in patients considered to have suppression of the hypothalamic-pituitary-adrenal axis:
One approach is to provide high doses of glucocorticoid starting at the time of induction of anaesthesia. A continuous infusion of 10 mg of hydrocortisone per hour or the equivalent amount of dexamethasone or prednisolone. The glucocorticoid dose can be reduced by 50 % the day after surgery, and the maintenance dose usually can be resumed in the second postoperative day.
The 2nd approach is parenteral hydrocortisone stress doses, 100 mg of hydrocortisone is given intravenously every eight hours perioperatively, and the dose is slowly reduced until the patient can be switched to his regular doses of oral medications.
Antibiotic prophylaxis, chronically immunosuppressed transplant patients considered at higher risk to develop infectious complications after surgical procedures. In the current scenario use of antibiotics covering gram negative bacteria and anaerobic bacteria will be recommended.
Clarithromycin and erythromycin (hepatic enzyme inhibitors) are predicted to increase the concentration of sirolimus. If concurrent use is highly indicated, increase the frequency of monitoring sirolimus concentrations.
Tissue integrity and wound healing:
Wound healing is generally slower in immunosuppressed patients, Some evidence suggests that sirolimus may lead to a higher incidence of adverse outcomes in wound healing. The mechanism of Sirolimus in delaying wound healing is inhibition of angiogenesis it reduces expression of vascular endothelial growth factor (VEGF) and nitric oxide and inhibits smooth muscle cells and fibroblast proliferation and matrix deposition.
How would you manage his immunosuppression? sirolimus should be discontinued 5-10 days prior to a planned surgery and depends on steroids as a main immunosuppressant and resume Sirolimus 1-3 months after surgery.
Would your management differ if he was on Tac and steroids?
Restart treatment in the immediate post-operative period. If the patient cannot take their usual oral medication post-operatively can be given by IV route of 0.01 to 0.02 mg/kg/day should be initiated as a continuous 24-hour infusion.
References:
Zhu J, Wu J, Frizell E, et al. Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis. Gastroenterology 1999; 117: 1198.
Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation 2005; 80(2 Suppl): S254.
V.good answer regarding surgery adrenal axis care infection prophylaxis
BUT in the IS management decision : are you going to keep him on high doses steroids only for 1-3 months before resuming mTORs. though that was covered in the last paragraph.
On eof most important complications of IS is malignancy, & it is the second leading cause of death in SOT recipients. There are several measures to reduce this risk( HPV vaccine, screening, & early detection). The risk factors of post transplant malignancy include:
The incidence of specific malignancy vary by geographical area as NMSC, PTLD are commonest types in Europe, North America, Australia, & New Zealand, while urotheral transitional cell, renal cell carcinoma & GI malignancy are common in non Western Asia & Middle East.
Renal transplant recipients 2-3 times increased risk of colorectal carcinoma higher than general population, & mean time of occurrence is 10.4 years. Colonic carcinoma occurs in first 12 months post transplantation considered as preexisted tumor. Surgery is the first choice of treatment. Screening of GI malignancy recommended for adults 45-75 years by fecal immuno chemical testing biannually, sigmoidoscopy every 5 years or colonoscopy every 10 years.
In major elective surgery including cancer surgery & because relatively long half life of sirolimus, it should be stopped 5-10 days before surgery & reintroduced after 1-3 months after surgery & increased the steroid dose. Peri operative steroid dose depends on pre operative dose & type of surgery. In major surgery 100 mg of IV hydrocortisone given every 8 hours on day of surgery & IV steroid maintained during surgery.
In first 1-3 months post operative period sirolimus replaced by CNI, after that sirolimus can be reintroduced.
References:
If the patient was on Tac & steroid, Tac replaced by sirolimus after 1-3 months post operative
welldone.
How would you manage his immunosuppression?
The patient will start IV fluid once he is NPO.
100 mg of hydrocortisone is given intravenously every eight hours perioperatively, and the dose is slowly reduced (but not the frequency) until the patient can be switched to his or her regular doses of oral medications. (some centres use one dose of hydrocortisone 100 mg on the day of the surgery, and shift the patient to his routine oral dose once he is able to take it orally). as steroids can delay wound healing.
-Routine antibiotic prophylaxis, either with a first-generation cephalosporin or, in the case of dental procedures, oral amoxicillin, is ordinarily sufficient in most cases. I will recommend adding metronidazole as a prophylactic for anaerobes.
–
Two macrolides, erythromycin and clarithromycin, should be avoided in patients being administered cyclosporine or tacrolimus as these antibiotics antagonize the CYP 3A4 enzyme system, leading to elevated levels of cyclosporine and tacrolimus.
– sirolimus may lead to a higher incidence of adverse outcomes in this setting. Perigraft fluid collections, superficial wound infections, and incisional hernias were reported.
So, I will recommend shifting the patient to tacrolimus for 1-2 weeks post-surgery, then return again to sirolimus.
No, I will not change the immunosuppressive, just I will keep tacrolimus in the lower range If the patient is known as low immunological risk. as the main benefit of mTOR in malignancy in skin cancer.
1-UpToDATE.
2-Dean PG, Lund WJ, Larson TS, et al. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus. Transplantation 2004; 77:1555.
What is your peri-operative management?
Kidney transplant recipients are at risk of several complications of infectious and non-infectious origin. Wound healing is well recognized adverse event of the use of m-TORi and is most common type of post-transplant surgical complication. This adverse event is associated with significant morbidity.
The mechanism of action of m-TORi involved targeting cell-cycle progression, inhibiting fibroblast proliferation and angiogenesis inhibition.
In addition to m-TORi, other factors increase the risk of mTOR inhibitor-associated wound-healing AEs are advanced age, diabetes, malnourishment, corticosteroid or anticoagulant use, high BMI, thymoglobulin induction, and long surgery duration.
In patients who require several surgeries, mTOR inhibitor therapy can be replaced with CNI to reduce the risk of wound-related AEs . In this case stop mTOR inhibitor therapy at least 1 week before surgery and resuming it 10 to 15 days after surgery.
Surgical techniques should be taken also in consideration as some techniques were reported to improve wound-healing outcomes in transplant recipients,. These techniques include include placing closed-suction drains, using subcutaneous sutures, sealing or ligating lymphatic ducts, performing prophylactic peritoneal fenestration, and avoiding extensive dissection; careful attention to surgical technique also is important. Staples, when used, can remain in place for 3 to 4 weeks to prevent skin dehiscence.
Post operatively, surgical wounds should be assessed frequently for signs of infections and dehiscence. From infection point of view, transplant patients are immunocompromised and at risk to develop post op wound infections, for this reason patients should receive antibiotic prophylaxis preoperatively.
Patients receiving steroids as a maintenance therapy should be maintained on a higher dose of steroids in the intravenous form, and should be started preoperatively as patients on chronic steroids are at higher risk of acute adrenal insufficiency caused by suppression of pituitary-adrenal axis due to surgery related stress.
How would you manage his immunosuppression?
Owing to the antiproliferative effect of mTORi, transplant recipients are converted to mTORi based immunosuppressive maintenance therapy, as CNI are more associated with the development of malignancies, especially in high risk patients receiving concomitantly r-ATG induction therapy.
In this low risk patient receiving mTORi based dual immunosuppression, continue sirolimus and steroids.
Would your management differ if he was on Tac and steroids
If patient was maintained on tacrolimus, I would shift the patient the patient into mTORi based regimen, but after reviewing the risk of rejection. As CNI free, mTORi based regimens are associated with worse renal outcomes. If the patient is at risk of rejection , I will keep tacrolimus with lower target level and adding everolimus to the combination with steroids.
References

UpTODate
Priscilla Ueno, Claudia Felipe, Alexandra Ferreira et al., MD1Wound Healing Complications in Kidney Transplant Recipients Receiving Everolimus. Transplantation. April 2017 V101,N 4
Mehrabi A, Fonouni H, Wente M, et al. Wound complications following kidney and liver transplantation. Clin Transplant. 2006;20:97–110. 2.
Nashan B, Citterio F. Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature. Transplantation. 2012;94:547–561
J.M. Campistol, P. Cockwell, F. Diekmann, et al.Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation. Transpl Int, 22 (2009), pp. 681-687
E. Roine, I.T. Bjork, O. Oyen. Targeting risk factors for impaired wound healing and wound complications after kidney transplantation. Transplant Proc, 42 (2010), pp. 2542-2546
Your perioperative IS plan in a case of hemicollectomy by oral sips of Sirolimus
with fear of wound dehesence due to mTORi
is there another option to cover the period of wound healing.
what would be your antibiotic suggestion?
The plan for immunosuppression is either to continue with sirolimus with caution so daily or BID dressing, local and systemic antibiotics, monitoring the healing process. the second option which i already mentioned is to stop sirolimus and shift to CNI one week before surgery and resume mtori 2 weeks after surgery to allow for better healing.
For antibiotic choice, the operation on colon is associated with risk of peritoneal contamination or seeding or bacteremia, so this is a high risk patient from infection point of view and could be associated with complication as colon perforation or stool leakage into the peritoneum. So my recommendation to cover gram negative and anaerobic infection with 3rd generation cephalosporin, carbapenem, B lactam with B lactamase inhibition.
What is your peri-operative management? And How would you manage his immunosuppression?
Corticosteroids
Patients that are on sirolimus and prednisolone alone as a maintenance therapy are usually maintained on a higher dose of steroids rendering them at high risk for suppression of pituitary-adrenal axis with subsequent increase in the probability of acute adrenal insufficiency due to stress-induced by surgery
So it is recommended to switch to intravenous hydrocortisone on the day of operation, 2 regimes are used:
Antibiotic prophylaxis
Wound healing
In summary, the recommended perioperative management include :
1. Increase the dose of corticosteroid on the day of operation followed by tapering
2. Continue on oral sirolimus on the day of operation with sips of water
3. Antibiotic prophylaxis
4. Gentle handling of tissues during operation
5. Putting skin staples for a longer period
Would your management differ if he was on Tac and steroids?
REFERANCES
1. Uptodate
2. Imao T, Ichimaru N, Takahara S, et al. Risk factors for malignancy in Japanese renal transplant recipients. Cancer 2007; 109:2109.
3. Huber S, Bruns CJ, Schmid G, et al. Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis. Kidney Int 2007; 71:771.
Some recommend holding sirolimus for 1 week before operation and shifting to tacrolimus and after healing of surgical wound patient can be shifted again to sirolimus
If the patient cannot take oral, switch to IV formulation.
Thankyou for the addition as you did not give up on mtors in this patient with malignancy.
perioperative management including and immunosuppression drugs:
1- keep good UOP and mange fluid status
2- control blood pressure
3- prophylactic antibiotic
4-pulse methylprednisolone
5- keep sirolimus as it has antitumor effect
yes, management will differ ..will shift from tac to sirolimus
Thankyou for trying please more details
1)What is your peri-operative management?
Tests to be done
ECG
Chest xray PA view
Urea,creat,electrolytes
Liver function tests
CBC
BSL R
Urine routine
PT-INR
Aptt
HIV,anti HCV, hbsag
Blood grouping and reserve 4 units of blood
Pre anaesthetic check up and any additional fitness needed from other department to be taken.
Iv fluid once patient NBM
Prophylactic antibiotics pre incision
Post op
Intake output’
Daily urea,creat,electrolyte,cbc
Stop sirolimus and shift to Tacrolimus oral 0.1mg/kg in divided doses 1 week prior .
How would you manage his immunosuppression?
Stop sirolimus 1 week prior to surgery and start tacrolimus 0.1mg/kg in BD dose and increase prednisolone to 1mg/kg and taper by 10 mg every 3 days.
Do tac level on 4th day after starting and adjust tacrolimus dose and repeat after 72 hrs if necessary.
On day of surgery in the morning oral tacrolimus and prednisolone dose.
Post surgery shift to iv tacrolimus and equivalent dose of hydrocortisone(equal to ongoing prednisolone dose).
Iv tacrolimus and also tapering dose of iv hydrocortisone till patient is not allowed oral feeding.
Once oral feed allowed shift to oral tacrolimus and repeat tac level after 72 hrs and adjust the dose .also shift to oral prednisolone and keep tapering by 10mg every 3 days ,then after 30mg taper by 5mg every 3 days and then after 20mg taper by 2.5mg every three days till baseline dose is achieved.
Restart sirolimus after 3 months and stop tacrolimus if graft function stable and no episode of rejection.
Would your management differ if he was on Tac and steroids?
On day of surgery in the morning oral tacrolimus and usual prednisolone dose.
Post surgery shift to iv tacrolimus and iv hydrocortisone 100mg iv 8hrly and decrease dose of hydrocortisone by 25% every day.
Iv tacrolimus and also tapering dose of iv hydrocortisone till patient is not allowed oral feeding.
Once oral feed allowed shift to oral tacrolimus and repeat tac level after 72 hrs and adjust the dose .also shift to oral prednisolone equivalent to ongoing hydrocortisone dose and taper to baseline dose.