- ICH GCP
- Rejestr badań klinicznych w USA
- Badanie kliniczne NCT02746432
Insulin Therapy Reduce Post-Operative Inflammatory Response After Curative Colorectal Cancer Resection: Randomization Controlled Trial
Research Problem:
Surgical stress induces inflammation and postoperative immuno-suppression, which are risk.
factors for both post-operative complication and possible disease recurrence. Colorectal cancer is in the top 5 malignancies in the Kingdome and the highest incidence in males. Recurrent disease locally or distally occurs in 35% of patients and is the leading cause of death in these patients. Despite the new era of laparoscopic surgery, still surgical stress is present and equally traumatic to the conventional open colorectal resection, earlier studies showed no major differences in post-operative inflammatory and immunological reactions. The previous studies revealed the anti-inflammatory effects of the hyper-insulinimic euglycemic therapy. Benefits observed in both major liver resection and in cardiac surgery. The anti-inflammatory effect reduced the surgical stress and postoperative inflammation.
The hypothesis is "Can intraoperative hyper-insulinimic euglycemic infusion reduce post operative inflammation and immunomodulation in colon cancer patients undergoing a curative surgery?"
Research methodology Triple blinded randomized controlled study with estimated sample size of 144 patients of non-metastatic colorectal cancer patients operated at King Saud University Medical city with a confirmed diagnosis of colon adenocarcinoma. Patients Consented will undergo computer randomization to receive intraoperative hyper-insulinimic normoglycemic infusion (experimental) or standardized insulin sliding scale and saline (control). A common preoperative and postoperative pathway with standardized management and pain control in both groups.
Outcomes will be measured via a battery of laboratory test consist of routine labs, inflammatory markers and immunological markers to be repeated at fixed timed intervals. All patients will be followed by regularly for 5 years.
Research objectives
Primary outcomes to examine:
- The anti-inflammatory effects of intraoperative hyper-insulinimic euglycemic therapy in patients undergoing colorectal cancer surgery.
- The immunomodulatory effect of intraoperative hyper-insulinimic euglycemic infusion
Secondary outcomes:
- Thirty days post-operative morbidity.
- Overall survival rate.
- Disease-free survival rate.
Przegląd badań
Status
Warunki
Interwencja / Leczenie
Szczegółowy opis
Aim & hypothesis:
The aim is to investigate the effect of the same protocol in colorectal surgery and to further delineate the effect on perioperative inflammation, immunosuppression and clinical outcome. This is an original approach, as this protocol was never used in bowel surgery.
The hypothesis predicts a reduced inflammation and resulting immunomodulation due to the anti-inflammatory effect of hyper-insulinmic euglycimic infusion, and improved postoperative morbidity and oncological outcome.
Study Design and Participants:
With the approval of the ethics board at King Saud University Medical city (KSUMC) a triple blinded randomized controlled study of operable resectable CRC patients of consented to be randomized to receive hyperinsulinimic normoglycemic protocol (experimental) or standardized insulin sliding scale (control).
Sample Size estimation:
72 patients per group( total of 144) was calculated to be sufficient to detect a reduction in disease recurrence from 35 to 20 percent, with α=0•05 and power of 0.8.
Randomization:
Computer generated randomization
Blinding:
Triple blinded study. Patient to be kept blinded to which group he/she will be assigned to. An independent anesthesia team will manage the infusion and will not be involved in the patient care or the study analysis. Research assistant will collect all the data and samples and will be blinded to the therapy. Patients' follow up by primary surgeons will also be blinded to the intervention. Analysis to be done in blinded groups A & B.
Intervention:
Intraoperative Intravenous insulin and glucose. The anasthesia will be asked to prepare an insulin bag containing 1000 units in 1 liter normal saline , another bag of dextrose 20 % with 30 mmol KPO4/ liter will be supplied from the pharmacy.
In the Experimental therapy group, after obtaining a baseline preoperative blood glucose value, 2 U/kg bolus of insulin to be administered IV followed by an infusion of 2 mU/ kg/min. Ten minutes after starting the insulin infusion, and when the blood glucose is <6.1 mmol /L (110 mg /dL), dextrose 20% supplemented with phosphate (30 mmol/L ) is administered. In the operating room, blood glucose levels were measured every 15 minutes, and the dextrose infusion rate will be adjusted to maintain arterial glycemia between 3.5 and 6.1 mmol/L (63-110 mg/dL), according to this protocol. If Blood Glucose mg/dl Action <63 Stop insulin infusion.Give Dextrose 20% 10 ml recheck level in 10 minutes 63.0 - 110 Maintain current infusion rate 111 - 143 144 - 180 Increase infusion by 2 unit/hour >180 Increase infusion by 3 unit/hour
The blood glucose will be measured hourly for 24 hours in the ICU, and the dextrose infusion rate was modified by the attending nurse according to this protocol (attached).
Regarding the safety of the patient on the hyperinsulinemia arms glucocheck every 5-10 minutes using an arterial line. Ongoing dextrose 20% + KPO4 supplementation when glucocheck drops less than 110 and will be titrated aimed to maintain a glucocheck 63-110. If at any point of time patient reached sever hypoglycemia defined as 32.3 (1.8) or below the insulin drip will be stopped and the patient will be considered a dropout of the study. Resuscitation with dextrose and KPO4 will continue to achieve eu-glycemia again. An international expert in the insulin clamp will be conducting the first patients to assure the local team experience for extra assurance.
Glucose Level mg/dl 20% Dextrose infusion + 30 meq Kcl <63 + 15 ml/h & 20ml bolus & Call MD 63-74 +10 ml/h & 10 ml bolus 75-81 + 5ml/h 82-98 Maintain the rate 99-110 - 5ml/h 111-116 -10ml/h >126 - 50% of the current rate & Call MD
In the standard therapy group, blood glucose measurements will be performed before the induction of anesthesia,every 30 minutes during surgery, and hourly in the ICU for 24 hours. If the blood glucose was >6.1 mmol /L (110 mg /dL), an insulin infusion of 1 U/ h was started. This was then titrated according to the sliding scale (Attached), aiming at a blood glucose between 3.5 and 6.1 mmol / L (63-110 mg/dL) during surgery and 3.5 and 7.9 mmol /L (63-143 mg /dL) after surgery A common preoperative and postoperative pathway with standardized management and pain control to be implemented in both groups. In diabetic patients, the administration of oral hypoglycemic drugs will be discontinued 24 hours before surgery. If patients received insulin, the daily dose will be held the evening before surgery, and subcutaneous insulin will be administered using a sliding scale. Arterial blood glucose concentrations measured using the glucocheck. Human insulin to be administered using the concentration 100 U of insulin in 100 mL normal saline.
Assessments:
Baseline preoperative investigations, 2 hours into surgery and a day 1 post operative, day 3, day 5, and 1 month postoperative assessment consisting of : Routine lab work
- CBC differential,
- Urea & electrolytes.
- Liver function test. Inflammatory assessment
- TNF-alpha,
- IL-8,
- IL-6
- IL-10
- IL-1β
- IL-18
- IFNγ
- MIP1α
- MMP-8
- TGF beta
- C-reactive protein The cytokines analysis will be done using suspension bead array immunoassay with a Luminex 200 X-map instrument (Luminex Corp, Austin, TX, USA). Analysis of the cytokines was carried out using a Milliplex human cytokine kit following manufacturer's specifications (MPXHCYTO-60k, Millipore Corp, Bilerica, MA, USA). All samples were analyzed in duplicate and the kit had a sensitivity of 0.4 pg/mL. Concentrations were calculated from the standard curve generated by the MasterPlex QT 4.0 analysis software (MiraiBio Inc, Alameda, CA, USA). Immunomodulation Quantity and activity of CD4, CD8, T-Cells T-cell profile
- Activation
- Proliferation
- Functionality (Intracellular cytokines profile). NK-Cells Profile
- Proliferation
- Activation *The degree of perioperative inflammation is a dynamic process that differs according to the time. The number of lab test is intended to build a curve describing the patient inflammatory response and the effect of insulin on it. The cytokines analysis will be done at the research lab, and only very few test will be sent to the hospital lab. The amount of blood taken will be limited to the tests, in the OR the bloods are taken from a dedicated line to prevent any discard.
The degree of perioperative inflammation is a dynamic process that differs according to the time . The number of lab test are intended to build a curve describing the patient inflammatory response and the effect of insulin on it.
Postoperative morbidity Postoperative events is defined and graded as per attached tables . non-infectious morbidity:
Morbidity Description Hyperglycemia >10 mmol/L Hypoglycemia <2 mmol/L PONV ( post operative nausea and vomiting) Persistent beyond day 2 postoperative Bleeding Requiring surgical intervention Or Hemoglobin drop >4 mg/dL Cardiac event Symptomatic arrhythmia Blood troponin >0.5, with ECG changes Pleural effusion Tapping required for patient relief Abdominal Ascites: dyspnea or leaking through abdominal wall Acute renal failure Serum creatinine >2 x upper limit of normal Anastomotic Leak Radiological luminal contrast extravasation Clinical finding of localized or generalized peritonitis Feculent drainage from drains Need for urgent intervention
Infectious morbidity:
Morbidity Description Pneumonia Pneumonic or atelactic changes on chest radiographs with positive sputum culture Wound infection Erythema and indurations associated with positive bacterial culture Intra-abdominal Collection of pus in the abdomen with or without necrotic material Abscess associated with a positive bacterial culture Urinary tract infection Urinary symptoms with urine culture positive for bacterial growth >105 colony forming units/ml Central line sepsis Positive culture of the catheter tip >15 colony forming units in the presence of febrile episode.
Leakage Grading according to International study group of rectal cancer (ISREC)
Grade Type of leak A Anastomotic leakage requiring no active therapeutic intervention. B Anastomotic leakage requiring active therapeutic intervention but manageable without laparotomy.
C Anastomotic leakage requiring Laparotomy.
Overall Morbidity grading Full Scale Grades Definition Grade I: Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions.
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics and electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside.
Grade II: Requiring pharmacological treatment with drugs other than such allowed for grade I complications.
Blood transfusions and total parenteral nutrition are also included. Grade III: Requiring surgical, endoscopic or radiological intervention Grade III-a: intervention not under general anesthesia Grade III-b: intervention under general anesthesia Grade IV: Life-threatening complication (including CNS complications)‡ requiring IC/ICU-management Grade IV-a: single organ dysfunction (including dialysis) Grade IV-b: multi organ dysfunction Grade V: Death of a patient Suffix 'd': If the patients suffers from a complication at the time of discharge, the suffix "d" (for 'disability') is added to the respective grade of complication. This label indicates the need for a follow-up to fully evaluate the complication.
Survival outcomes:
As per the guidelines all our patients will undergo a routine colonoscopy at 1 year and then after depending on the results, also a CT scan at 1 year, and 3 years and 5 years.
Data privacy and management:
In cardiac surgery it was mainly directed towards postoperative complication only and graft survival. In liver resection the main outcome was postoperative liver dysfunction and the micro mechanism were related to glycogen storage that might have been the cause for earlier and faster hepatic recovery. In our study, it's the first time to correlate it with anastomotic leak mainly and oncological outcomes. The use of this therapy has not made it to the clinical side because more studies are needed to confirm its efficacy.
Typ studiów
Zapisy (Oczekiwany)
Faza
- Faza 4
Kontakty i lokalizacje
Lokalizacje studiów
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Riyadh, Arabia Saudyjska, 7805
- King Saud University Medical City
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Kryteria uczestnictwa
Kryteria kwalifikacji
Wiek uprawniający do nauki
Akceptuje zdrowych ochotników
Płeć kwalifikująca się do nauki
Opis
Inclusion Criteria:
- Age > 18 years
- Documented CRC by histopathology
Exclusion Criteria:
- Patient not consenting to the study or refused.
- Metastatic disease at the time of diagnosis.
- Contraindications to insulin
- Pregnancy
Plan studiów
Jak projektuje się badanie?
Szczegóły projektu
- Główny cel: Inny
- Przydział: Randomizowane
- Model interwencyjny: Przydział równoległy
- Maskowanie: Poczwórny
Broń i interwencje
Grupa uczestników / Arm |
Interwencja / Leczenie |
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Brak interwencji: Control group
Routine intra operative saline infusion to be administered.pre-operation
and timed assessment lab set to be obtained.
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Eksperymentalny: Intervention group.Hyper insulinemic euglycemic clamp
After obtaining a baseline preoperative lab set blood glucose value, 2 U/kg bolus of insulin to be administered IV followed by an infusion of 2 U/ kg/min.fiver
- Ten minutes after starting the insulin (Human regular insulin) ) infusion, and when the blood glucose is <6.1 mmol /L (110 mg /dL).
an Infusion of dextrose 20% supplemented with pottasium phosphate (30 mmol/L ) to be administered.
In the operating room, blood glucose levels were measured every 5-15 minutes, and the dextrose infusion rate was adjusted to maintain arterial glycemia between 3.5 and 6.1 mmol/L (63-110 mg/dL).
timed intra operative lab assessment to be obtained.
|
After obtaining a baseline preoperative lab set blood glucose value, 2 U/kg bolus of insulin (Human regular insulin) to be administered IV followed by an infusion of 2 U/ kg/min.fiver
- Ten minutes after starting the insulin infusion, and when the blood glucose is <6.1 mmol /L (110 mg /dL).
an Infusion of dextrose 20% supplemented with pottasium phosphate (30 mmol/L ) to be administered.
In the operating room, blood glucose levels were measured every 5-15 minutes, and the dextrose infusion rate was adjusted to maintain arterial glycemia between 3.5 and 6.1 mmol/L (63-110 mg/dL).
timed intra operative lab assessment to be obtained.
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Co mierzy badanie?
Podstawowe miary wyniku
Miara wyniku |
Opis środka |
Ramy czasowe |
---|---|---|
The anti-inflammatory effects of intraoperative hyper-insulinimic euglycemic therapy in patients undergoing colorectal cancer surgery.
Ramy czasowe: 1 month
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effect on Inflamatory profile namely levels of Tnf- Alpha , IL-8 , IL-6 , IL-10 , IL-1B,IL-18 , IFNγ, MIp1-Alpha , MMP-8 , TGF Beta , CRP
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1 month
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Miary wyników drugorzędnych
Miara wyniku |
Opis środka |
Ramy czasowe |
---|---|---|
The immunomodulatory effect of intraoperative hyper-insulinimic euglycemic infusion.
Ramy czasowe: 1 month
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Change of CD4 , CD8 & T-cell , Quantity and activity
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1 month
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Inne miary wyników
Miara wyniku |
Ramy czasowe |
---|---|
Ogólny wskaźnik przeżycia
Ramy czasowe: 5 lat
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5 lat
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Wskaźnik przeżycia wolnego od choroby
Ramy czasowe: 5 lat
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5 lat
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Thirty days post-operative morbidity
Ramy czasowe: 30 days
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30 days
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Thirty days post-operative mortality
Ramy czasowe: 30 days
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30 days
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Współpracownicy i badacze
Sponsor
Publikacje i pomocne linki
Publikacje ogólne
- Basse L, Jakobsen DH, Bardram L, Billesbolle P, Lund C, Mogensen T, Rosenberg J, Kehlet H. Functional recovery after open versus laparoscopic colonic resection: a randomized, blinded study. Ann Surg. 2005 Mar;241(3):416-23. doi: 10.1097/01.sla.0000154149.85506.36.
- Ogawa K, Hirai M, Katsube T, Murayama M, Hamaguchi K, Shimakawa T, Naritake Y, Hosokawa T, Kajiwara T. Suppression of cellular immunity by surgical stress. Surgery. 2000 Mar;127(3):329-36. doi: 10.1067/msy.2000.103498. Erratum In: Surgery 2000 Jun;127(6):613.
- Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108. doi: 10.3322/canjclin.55.2.74.
- Oberhofer D, Rumenjak V, Lazic J, Vucic N. [Inflammatory indicators in patients after surgery of the large intestine]. Acta Med Croatica. 2006 Dec;60(5):429-33. Croatian.
- Galizia G, Gemei M, Orditura M, Romano C, Zamboli A, Castellano P, Mabilia A, Auricchio A, De Vita F, Del Vecchio L, Lieto E. Postoperative detection of circulating tumor cells predicts tumor recurrence in colorectal cancer patients. J Gastrointest Surg. 2013 Oct;17(10):1809-18. doi: 10.1007/s11605-013-2258-6. Epub 2013 Jun 28.
- Rahbari NN, Aigner M, Thorlund K, Mollberg N, Motschall E, Jensen K, Diener MK, Buchler MW, Koch M, Weitz J. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010 May;138(5):1714-26. doi: 10.1053/j.gastro.2010.01.008. Epub 2010 Jan 25.
- Law WL, Choi HK, Lee YM, Ho JW. The impact of postoperative complications on long-term outcomes following curative resection for colorectal cancer. Ann Surg Oncol. 2007 Sep;14(9):2559-66. doi: 10.1245/s10434-007-9434-4. Epub 2007 May 24.
- Deng HP, Chai JK. The effects and mechanisms of insulin on systemic inflammatory response and immune cells in severe trauma, burn injury, and sepsis. Int Immunopharmacol. 2009 Oct;9(11):1251-9. doi: 10.1016/j.intimp.2009.07.009. Epub 2009 Jul 30.
- Albacker T, Carvalho G, Schricker T, Lachapelle K. High-dose insulin therapy attenuates systemic inflammatory response in coronary artery bypass grafting patients. Ann Thorac Surg. 2008 Jul;86(1):20-7. doi: 10.1016/j.athoracsur.2008.03.046.
- Sato H, Carvalho G, Sato T, Bracco D, Codere-Maruyama T, Lattermann R, Hatzakorzian R, Matsukawa T, Schricker T. Perioperative tight glucose control with hyperinsulinemic-normoglycemic clamp technique in cardiac surgery. Nutrition. 2010 Nov-Dec;26(11-12):1122-9. doi: 10.1016/j.nut.2009.10.005. Epub 2010 Jan 25.
- Wu FP, Sietses C, von Blomberg BM, van Leeuwen PA, Meijer S, Cuesta MA. Systemic and peritoneal inflammatory response after laparoscopic or conventional colon resection in cancer patients: a prospective, randomized trial. Dis Colon Rectum. 2003 Feb;46(2):147-55. doi: 10.1007/s10350-004-6516-2.
- Sato H, Lattermann R, Carvalho G, Sato T, Metrakos P, Hassanain M, Matsukawa T, Schricker T. Perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) in patients undergoing major liver resection. Anesth Analg. 2010 Jun 1;110(6):1711-8. doi: 10.1213/ANE.0b013e3181d90087. Epub 2010 Apr 7.
- Khansari DN, Murgo AJ, Faith RE. Effects of stress on the immune system. Immunol Today. 1990 May;11(5):170-5. doi: 10.1016/0167-5699(90)90069-l.
- Law WL, Poon JT, Fan JK, Lo OS. Survival following laparoscopic versus open resection for colorectal cancer. Int J Colorectal Dis. 2012 Aug;27(8):1077-85. doi: 10.1007/s00384-012-1424-8. Epub 2012 Feb 9.
Daty zapisu na studia
Główne daty studiów
Rozpoczęcie studiów (Oczekiwany)
Zakończenie podstawowe (Oczekiwany)
Ukończenie studiów (Oczekiwany)
Daty rejestracji na studia
Pierwszy przesłany
Pierwszy przesłany, który spełnia kryteria kontroli jakości
Pierwszy wysłany (Oszacować)
Aktualizacje rekordów badań
Ostatnia wysłana aktualizacja (Rzeczywisty)
Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości
Ostatnia weryfikacja
Więcej informacji
Terminy związane z tym badaniem
Słowa kluczowe
Dodatkowe istotne warunki MeSH
Inne numery identyfikacyjne badania
- KSULDRCCRCMH001
Plan dla danych uczestnika indywidualnego (IPD)
Planujesz udostępniać dane poszczególnych uczestników (IPD)?
Informacje o lekach i urządzeniach, dokumenty badawcze
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Bada produkt urządzenia regulowany przez amerykańską FDA
produkt wyprodukowany i wyeksportowany z USA
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