<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02975947</url>
  </required_header>
  <id_info>
    <org_study_id>HREC/12/CRGH/196</org_study_id>
    <nct_id>NCT02975947</nct_id>
  </id_info>
  <brief_title>Effect of Warmed Humidified CO2 on Peritoneum During Laparotomy</brief_title>
  <official_title>Effect of Intraoperative Humidified CO2 Insufflation in Open Laparotomy Colorectal Surgery Patients: a Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Concord Repatriation General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Concord Repatriation General Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The operating theatre is deliberately made to be cold and dry to prevent bacteria from&#xD;
      growing. The problem with this is that during open abdominal surgery, the intestine and the&#xD;
      overlying peritoneum is exposed to cold dry air. Surgeons try to stop the bowel/peritoneum&#xD;
      from drying by applying warmed saline packs periodically to the bowel. However, this is not&#xD;
      always possible. Sometimes, the surgeon has to perform an important component of the&#xD;
      procedure (attach bowel/blood vessels together etc) and the bowel/peritoneum visibly dries.&#xD;
      When bowel/peritoneum dries damage occurs, inducing inflammation. Inflamed bowel/peritoneum&#xD;
      causes the bowel to stick together and form adhesions. Bowel adhesions can cause bowel&#xD;
      obstruction. This vicious cycle is repeated when the patient undergoes repetitive open&#xD;
      abdominal operations.&#xD;
&#xD;
      This study aimed to be the first human study to:&#xD;
&#xD;
        1. Demonstrate that peritoneal inflammation occurs during open abdominal surgery and also&#xD;
           to demonstrate that pro-inflammatory cells (polymorphs, macrophages) are activated&#xD;
           during the progress of the operation. This study aims to show that mRNA(using Q-PCR) is&#xD;
           increased for pro-inflammatory cytokines. This study also aim to show that&#xD;
           proinflammatory cytokines (Interleukin(IL)-1,2,6,9,10, and TNF by ELISA/confirmed using&#xD;
           Western Blotting) are elevated during the course of the operation.&#xD;
&#xD;
        2. Demonstrate that the mechanism of bowel/peritoneal inflammation is causally related to&#xD;
           the bowel/peritoneum drying (dessication).&#xD;
&#xD;
      This study will attempt to prove this by using humidified, warmed carbon dioxide gas which&#xD;
      will warm and moisten the peritoneum/bowel. It is proposed that this will arrest the&#xD;
      peritoneal injury and the inflammation. The investigators will attain peritoneal samples&#xD;
      during open colorectal operations. The investigators will obtain samples at the beginning and&#xD;
      end of the operation. This study design is a randomized controlled trial, where half the&#xD;
      patients will receive humidified, warmed carbon dioxide gas during surgery, and the other&#xD;
      half will get standard open surgery without carbon dioxide. 40 patients will be recruited in&#xD;
      this study. Half (20) will get CO2, and other half (20) will get standard open surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Forty patients undergoing open colorectal surgery will be recruited in this randomized&#xD;
      controlled trial.&#xD;
&#xD;
      The study group will receive warmed (37°C), humidified (98% RH) carbon dioxide. The delivered&#xD;
      gas will be defined by the United States Pharmacopeia and National Formulary, which requires&#xD;
      impurity of less than 200 parts per million, including water vapour. This medical grade CO2&#xD;
      will be warmed to 37°C and humidified to 98% RH using humidification system. The sterility of&#xD;
      the system will be assessed regularly as per protocol.&#xD;
&#xD;
      The control group will receive no gas insufflation into the open laparotomy wound. This is&#xD;
      current standard practice for all patients undergoing open laparotomy for colorectal&#xD;
      resection.&#xD;
&#xD;
      The device that will be used for insufflation of sterile, humidified, warmed CO2 is the&#xD;
      Fisher &amp; Paykel's HUMIGARD (Fisher &amp; Paykel Healthcare Ltd, Auckland, New Zealand).&#xD;
&#xD;
      It consists of a bacterial filter and a humidification chamber filed with 180mL sterile&#xD;
      water, positioned on a humidifier controller that includes an integrated temperature and flow&#xD;
      sensor. The outlet of the humidification chamber is connected to a thermally insulated&#xD;
      2.5m-long heated insufflation tube that maintains temperature and humidity of the gas to its&#xD;
      outlet. The warm and humidified CO2 enters a gas diffuser (ST300DF VITA-diffuserTM, Cardia&#xD;
      Innovation AB, Stockholm, Sweden) consisting of a 25cm-long polyvinylchloride tube (inner&#xD;
      diameter of 2.5mm) with polyurethane foam at its end. The cylindrical polyurethane foam tip&#xD;
      diverts the gas jet in multiple directions via the many small paths inside the foam. The gas&#xD;
      is thus uniformly distributed and the large diffuser surface area greatly reduces the&#xD;
      velocity of the outflow. Thus the system delivers humidified CO2 at 100% relative humidity&#xD;
      and 37C to the surgical wound. The gas diffuser will be positioned inside the open abdominal&#xD;
      wound cavity (in the right cranial quadrant) at a depth of approximately 4cm from the skin as&#xD;
      soon as the abdominal wall retraction has been done. The insufflation of warm humidified CO2&#xD;
      will then start and continue until the abdominal wall retractors are removed and abdominal&#xD;
      wall is commenced to be closed.&#xD;
&#xD;
      Calculation of Power: The investigators estimated sample size of 40 patients for 80% power&#xD;
      using the literatures' reported standard deviation of levels of 3-chlorotyrosine (which is&#xD;
      one of the study's primary biochemical markers of inflammation)&#xD;
&#xD;
      ANALYSIS OF BIOCHEMICAL AND MOLECULAR MARKERS: Where acquired, samples of the human tissue&#xD;
      obtained (above) will be homogenised and assigned to biochemistry and molecular analyses.&#xD;
      Total RNA will be extracted using a commercial kit, converted to cloned DNA and then probed&#xD;
      for various pro-inflammatory genes. Where a change in gene regulation is noted, the&#xD;
      investigators will assess the corresponding change in protein level using a combined approach&#xD;
      consisting of multiplex ELISA to quantify changes in protein levels and further confirmation&#xD;
      with Western blotting using corresponding specific antibodies.&#xD;
&#xD;
      STATISTICAL ANALYSIS: Statistical analysis will be performed using SPSS for Windows version&#xD;
      18.0 GradPack (IBM, New York, USA). Non-parametric continuous variables will be tested using&#xD;
      Mann-Whitney U tests and parametric continuous variable will be tested using t-test/ANOVA.&#xD;
      Categorical variables will be tested using Fisher exact test.&#xD;
&#xD;
      OUTCOME AND STUDY END POINT:&#xD;
&#xD;
      The study will involve both clinical and laboratory based work, and the outcomes are as&#xD;
      follows.&#xD;
&#xD;
        1. Laboratory based work:&#xD;
&#xD;
           From each patient, 4 samples will be taken and hence 160 samples will be analysed.&#xD;
&#xD;
           From each sample, the investigators will analyse the activation of pro-inflammatory&#xD;
           cells (polymorphs, macrophages), level of messenger RNA.&#xD;
&#xD;
           The investigators will analyse level of (pro)inflammatory cytokines-- IL1,2,6,9,10, and&#xD;
           TNF.&#xD;
&#xD;
           The investigators will assess the relationship between time (duration of operation) and&#xD;
           the inflammatory markers.&#xD;
&#xD;
           The study will aim to prove that prove that as duration of operation increase, the&#xD;
           extent of in inflammation the intestine's surface increases, and that this process can&#xD;
           be mitigated by using humidified warmed carbon dioxide gas.&#xD;
&#xD;
        2. Clinical based work:&#xD;
&#xD;
      The study will see whether use of humidified, warmed carbon dioxide gas results in:&#xD;
&#xD;
        -  Better core body temperature control&#xD;
&#xD;
        -  Less postoperative pain&#xD;
&#xD;
        -  Shorter hospital stay&#xD;
&#xD;
        -  Less risk of complications, including wound infection, anastomotic leaks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2013</start_date>
  <completion_date type="Actual">June 2016</completion_date>
  <primary_completion_date type="Actual">June 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Inflammatory cytokine level in the peritoneal biopsy samples</measure>
    <time_frame>At the moment of time when: (1) peritoneal cavity is being opened, (2) when peritoneal cavity is being closed (expected average of 2 hours after peritoneal cavity is first opened)</time_frame>
    <description>Peritoneal samples will be taken when the peritoneal cavity is being opened (at beginning of operation), and also when the peritoneal cavity is being closed (at end of the operation). The change in the level of inflammatory cytokines in between these two time points will be measured</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Intraoperative temperature at 30 minutes from start of operation</measure>
    <time_frame>30 minutes from start of operation</time_frame>
    <description>Temperature readings during the operation will be taken. Both core body temperature (esophageal) and intraperitoneal temperature will be measured.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Intraoperative temperature at 60 minutes from start of operation</measure>
    <time_frame>60 minutes from start of operation</time_frame>
    <description>Temperature readings during the operation will be taken. Both core body temperature (esophageal) and intraperitoneal temperature will be measured.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Postoperative Analgesia requirement for pain</measure>
    <time_frame>Time from when the patient is moved out of operating theater to when the patient is no longer an inpatient in the hospital ward (discharged), with an expected average of 1 week</time_frame>
    <description>Postoperative pain as measured by MEDD (Morphine Equivalent Daily Dose)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of in-patient hospital stay</measure>
    <time_frame>duration of hospital stay, an expected average of 1 week</time_frame>
    <description>number of days patient stayed postoperatively in hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anastomotic leaks</measure>
    <time_frame>6 months</time_frame>
    <description>The occurrence of anastomotic leak in the 6 months after the surgery</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Peritoneal Inflammation</condition>
  <condition>Peritoneum; Injury</condition>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard intraoperative warming measures including heated blankets, heating with forced warmed air, warming of fluids, and insulation of limbs and head.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Study Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The study group will receive warmed (37°C), humidified (98% RH) carbon dioxide delivered into the open peritoneal cavity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Humidified, warmed CO2 insufflation of open peritoneum using Fisher &amp; Paykel's HUMIGARD (Fisher &amp; Paykel Healthcare Ltd, Auckland, New Zealand)</intervention_name>
    <description>The study group will receive warmed (37°C), humidified (98% RH) carbon dioxide into the open peritoneal cavity using the Fisher &amp; Paykel's HUMIGARD system (Fisher &amp; Paykel Healthcare Ltd, Auckland, New Zealand). This will create a local atmosphere of 100% carbon dioxide (warmed, humidified) in the open peritoneal cavity.</description>
    <arm_group_label>Study Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Standard heating</intervention_name>
    <description>Standard intraoperative warming measures including heated blankets, heating with forced warmed air, warming of fluids, and insulation of limbs and head</description>
    <arm_group_label>Control Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults above age 18.&#xD;
&#xD;
          -  Elective patients.&#xD;
&#xD;
          -  Pathologies: colorectal carcinoma, polyposis syndromes, diverticular diseases,&#xD;
             prolapses, and patients with inflammatory bowel disease undergoing elective resection.&#xD;
&#xD;
          -  For colorectal carcinoma, all patients whether they are having curative or palliative&#xD;
             surgery will be included.&#xD;
&#xD;
          -  Patients undergoing open elective colectomy, with or without stoma formation/ bowel&#xD;
             anastomosis.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients undergoing acute surgery (emergency surgery).&#xD;
&#xD;
          -  Patients undergoing Laparoscopic colectomy (multiport, single incision and also hand&#xD;
             assisted) as all these patients receive heated humidified CO2.&#xD;
&#xD;
          -  For COPD patients, the exclusion criteria would be patients: (1) On home oxygen, (2)&#xD;
             Type 2 respiratory failure (CO2 retainers) (3) FEV1&lt;1L, or FEV1/FVC &lt;50% of predicted&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Concord Repatriation General Hospital</name>
      <address>
        <city>Sydney</city>
        <state>New South Wales</state>
        <zip>2138</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <results_reference>
    <citation>Persson M, van der Linden J. Intraoperative CO2 insufflation can decrease the risk of surgical site infection. Med Hypotheses. 2008;71(1):8-13. doi: 10.1016/j.mehy.2007.12.016. Epub 2008 Mar 4.</citation>
    <PMID>18304752</PMID>
  </results_reference>
  <results_reference>
    <citation>Persson M, van der Linden J. Can wound desiccation be averted during cardiac surgery? An experimental study. Anesth Analg. 2005 Feb;100(2):315-320. doi: 10.1213/01.ANE.0000140243.97570.DE.</citation>
    <PMID>15673849</PMID>
  </results_reference>
  <results_reference>
    <citation>Persson M, Elmqvist H, van der Linden J. Topical humidified carbon dioxide to keep the open surgical wound warm: the greenhouse effect revisited. Anesthesiology. 2004 Oct;101(4):945-9. doi: 10.1097/00000542-200410000-00020.</citation>
    <PMID>15448528</PMID>
  </results_reference>
  <results_reference>
    <citation>Persson M, Svenarud P, Flock JI, van der Linden J. Carbon dioxide inhibits the growth rate of Staphylococcus aureus at body temperature. Surg Endosc. 2005 Jan;19(1):91-4. doi: 10.1007/s00464-003-9334-z. Epub 2004 Nov 11.</citation>
    <PMID>15529188</PMID>
  </results_reference>
  <results_reference>
    <citation>Persson M, van der Linden J. Wound ventilation with ultraclean air for prevention of direct airborne contamination during surgery. Infect Control Hosp Epidemiol. 2004 Apr;25(4):297-301. doi: 10.1086/502395.</citation>
    <PMID>15108726</PMID>
  </results_reference>
  <results_reference>
    <citation>Svenarud P, Persson M, Van Der Linden J. Efficiency of a gas diffuser and influence of suction in carbon dioxide deairing of a cardiothoracic wound cavity model. J Thorac Cardiovasc Surg. 2003 May;125(5):1043-9. doi: 10.1067/mtc.2003.50.</citation>
    <PMID>12771877</PMID>
  </results_reference>
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    <citation>Svenarud P, Persson M, van der Linden J. Intermittent or continuous carbon dioxide insufflation for de-airing of the cardiothoracic wound cavity? An experimental study with a new gas-diffuser. Anesth Analg. 2003 Feb;96(2):321-7, table of contents. doi: 10.1097/00000539-200302000-00005.</citation>
    <PMID>12538172</PMID>
  </results_reference>
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    <citation>Hannenberg AA, Sessler DI. Improving perioperative temperature management. Anesth Analg. 2008 Nov;107(5):1454-7. doi: 10.1213/ane.0b013e318181f6f2. No abstract available.</citation>
    <PMID>18931198</PMID>
  </results_reference>
  <results_reference>
    <citation>Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008 Aug;109(2):318-38. doi: 10.1097/ALN.0b013e31817f6d76.</citation>
    <PMID>18648241</PMID>
  </results_reference>
  <results_reference>
    <citation>Insler SR, Sessler DI. Perioperative thermoregulation and temperature monitoring. Anesthesiol Clin. 2006 Dec;24(4):823-37. doi: 10.1016/j.atc.2006.09.001.</citation>
    <PMID>17342966</PMID>
  </results_reference>
  <results_reference>
    <citation>Sessler DI. Non-pharmacologic prevention of surgical wound infection. Anesthesiol Clin. 2006 Jun;24(2):279-97. doi: 10.1016/j.atc.2006.01.005.</citation>
    <PMID>16927930</PMID>
  </results_reference>
  <results_reference>
    <citation>Binda MM, Koninckx PR. Prevention of adhesion formation in a laparoscopic mouse model should combine local treatment with peritoneal cavity conditioning. Hum Reprod. 2009 Jun;24(6):1473-9. doi: 10.1093/humrep/dep053. Epub 2009 Mar 3.</citation>
    <PMID>19258346</PMID>
  </results_reference>
  <results_reference>
    <citation>Tsuchiya M, Sato EF, Inoue M, Asada A. Open abdominal surgery increases intraoperative oxidative stress: can it be prevented? Anesth Analg. 2008 Dec;107(6):1946-52. doi: 10.1213/ane.0b013e318187c96b.</citation>
    <PMID>19020142</PMID>
  </results_reference>
  <results_reference>
    <citation>Peng Y, Zheng M, Ye Q, Chen X, Yu B, Liu B. Heated and humidified CO2 prevents hypothermia, peritoneal injury, and intra-abdominal adhesions during prolonged laparoscopic insufflations. J Surg Res. 2009 Jan;151(1):40-7. doi: 10.1016/j.jss.2008.03.039. Epub 2008 Apr 23.</citation>
    <PMID>18639246</PMID>
  </results_reference>
  <results_reference>
    <citation>Brokelman WJ, Holmdahl L, Bergstrom M, Falk P, Klinkenbijl JH, Reijnen MM. Heating of carbon dioxide during insufflation alters the peritoneal fibrinolytic response to laparoscopic surgery : A clinical trial. Surg Endosc. 2008 May;22(5):1232-6. doi: 10.1007/s00464-007-9597-x. Epub 2007 Oct 18.</citation>
    <PMID>17943363</PMID>
  </results_reference>
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    <citation>Ivarsson ML, Bergstrom M, Eriksson E, Risberg B, Holmdahl L. Tissue markers as predictors of postoperative adhesions. Br J Surg. 1998 Nov;85(11):1549-54. doi: 10.1046/j.1365-2168.1998.00859.x.</citation>
    <PMID>9823923</PMID>
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    <citation>Moehrlen U, Ziegler U, Boneberg E, Reichmann E, Gitzelmann CA, Meuli M, Hamacher J. Impact of carbon dioxide versus air pneumoperitoneum on peritoneal cell migration and cell fate. Surg Endosc. 2006 Oct;20(10):1607-13. doi: 10.1007/s00464-005-0775-4. Epub 2006 Jul 3.</citation>
    <PMID>16823647</PMID>
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    <citation>Erikoglu M, Yol S, Avunduk MC, Erdemli E, Can A. Electron-microscopic alterations of the peritoneum after both cold and heated carbon dioxide pneumoperitoneum. J Surg Res. 2005 May 1;125(1):73-7. doi: 10.1016/j.jss.2004.11.029.</citation>
    <PMID>15836853</PMID>
  </results_reference>
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    <citation>Enfors SO, Molin G. The influence of high concentrations of carbon dioxide on the germination of bacterial spores. J Appl Bacteriol. 1978 Oct;45(2):279-85. doi: 10.1111/j.1365-2672.1978.tb04223.x. No abstract available.</citation>
    <PMID>31348</PMID>
  </results_reference>
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    <citation>Ott DE. Correction of laparoscopic insufflation hypothermia. J Laparoendosc Surg. 1991 Aug;1(4):183-6. doi: 10.1089/lps.1991.1.183.</citation>
    <PMID>1834266</PMID>
  </results_reference>
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    <citation>Frank SM, Beattie C, Christopherson R, Norris EJ, Perler BA, Williams GM, Gottlieb SO. Unintentional hypothermia is associated with postoperative myocardial ischemia. The Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology. 1993 Mar;78(3):468-76. doi: 10.1097/00000542-199303000-00010.</citation>
    <PMID>8457047</PMID>
  </results_reference>
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    <citation>Schmied H, Kurz A, Sessler DI, Kozek S, Reiter A. Mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty. Lancet. 1996 Feb 3;347(8997):289-92. doi: 10.1016/s0140-6736(96)90466-3.</citation>
    <PMID>8569362</PMID>
  </results_reference>
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    <citation>Hazebroek EJ, Schreve MA, Visser P, De Bruin RW, Marquet RL, Bonjer HJ. Impact of temperature and humidity of carbon dioxide pneumoperitoneum on body temperature and peritoneal morphology. J Laparoendosc Adv Surg Tech A. 2002 Oct;12(5):355-64. doi: 10.1089/109264202320884108.</citation>
    <PMID>12470410</PMID>
  </results_reference>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>November 2, 2016</study_first_submitted>
  <study_first_submitted_qc>November 23, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 29, 2016</study_first_posted>
  <last_update_submitted>November 23, 2016</last_update_submitted>
  <last_update_submitted_qc>November 23, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 29, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Concord Repatriation General Hospital</investigator_affiliation>
    <investigator_full_name>Dr Ju Yong Cheong</investigator_full_name>
    <investigator_title>Doctor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peritonitis</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>March 9, 2022</submitted>
    <returned>June 6, 2022</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02975947
org study id: HREC/12/CRGH/196
nct id: NCT02975947
lead sponsor: 
has dmc: No
The operating theatre is deliberately made to be cold and dry to prevent bacteria from
      growing. The problem with this is that during open abdominal surgery, the intestine and the
      overlying peritoneum is exposed to cold dry air. Surgeons try to stop the bowel/peritoneum
      from drying by applying warmed saline packs periodically to the bowel. However, this is not
      always possible. Sometimes, the surgeon has to perform an important component of the
      procedure (attach bowel/blood vessels together etc) and the bowel/peritoneum visibly dries.
      When bowel/peritoneum dries damage occurs, inducing inflammation. Inflamed bowel/peritoneum
      causes the bowel to stick together and form adhesions. Bowel adhesions can cause bowel
      obstruction. This vicious cycle is repeated when the patient undergoes repetitive open
      abdominal operations.

      This study aimed to be the first human study to:

        1. Demonstrate that peritoneal inflammation occurs during open abdominal surgery and also
           to demonstrate that pro-inflammatory cells (polymorphs, macrophages) are activated
           during the progress of the operation. This study aims to show that mRNA(using Q-PCR) is
           increased for pro-inflammatory cytokines. This study also aim to show that
           proinflammatory cytokines (Interleukin(IL)-1,2,6,9,10, and TNF by ELISA/confirmed using
           Western Blotting) are elevated during the course of the operation.

        2. Demonstrate that the mechanism of bowel/peritoneal inflammation is causally related to
           the bowel/peritoneum drying (dessication).

      This study will attempt to prove this by using humidified, warmed carbon dioxide gas which
      will warm and moisten the peritoneum/bowel. It is proposed that this will arrest the
      peritoneal injury and the inflammation. The investigators will attain peritoneal samples
      during open colorectal operations. The investigators will obtain samples at the beginning and
      end of the operation. This study design is a randomized controlled trial, where half the
      patients will receive humidified, warmed carbon dioxide gas during surgery, and the other
      half will get standard open surgery without carbon dioxide. 40 patients will be recruited in
      this study. Half (20) will get CO2, and other half (20) will get standard open surgery.
Forty patients undergoing open colorectal surgery will be recruited in this randomized
      controlled trial.

      The study group will receive warmed (37°C), humidified (98% RH) carbon dioxide. The delivered
      gas will be defined by the United States Pharmacopeia and National Formulary, which requires
      impurity of less than 200 parts per million, including water vapour. This medical grade CO2
      will be warmed to 37°C and humidified to 98% RH using humidification system. The sterility of
      the system will be assessed regularly as per protocol.

      The control group will receive no gas insufflation into the open laparotomy wound. This is
      current standard practice for all patients undergoing open laparotomy for colorectal
      resection.

      The device that will be used for insufflation of sterile, humidified, warmed CO2 is the
      Fisher & Paykel's HUMIGARD (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand).

      It consists of a bacterial filter and a humidification chamber filed with 180mL sterile
      water, positioned on a humidifier controller that includes an integrated temperature and flow
      sensor. The outlet of the humidification chamber is connected to a thermally insulated
      2.5m-long heated insufflation tube that maintains temperature and humidity of the gas to its
      outlet. The warm and humidified CO2 enters a gas diffuser (ST300DF VITA-diffuserTM, Cardia
      Innovation AB, Stockholm, Sweden) consisting of a 25cm-long polyvinylchloride tube (inner
      diameter of 2.5mm) with polyurethane foam at its end. The cylindrical polyurethane foam tip
      diverts the gas jet in multiple directions via the many small paths inside the foam. The gas
      is thus uniformly distributed and the large diffuser surface area greatly reduces the
      velocity of the outflow. Thus the system delivers humidified CO2 at 100% relative humidity
      and 37C to the surgical wound. The gas diffuser will be positioned inside the open abdominal
      wound cavity (in the right cranial quadrant) at a depth of approximately 4cm from the skin as
      soon as the abdominal wall retraction has been done. The insufflation of warm humidified CO2
      will then start and continue until the abdominal wall retractors are removed and abdominal
      wall is commenced to be closed.

      Calculation of Power: The investigators estimated sample size of 40 patients for 80% power
      using the literatures' reported standard deviation of levels of 3-chlorotyrosine (which is
      one of the study's primary biochemical markers of inflammation)

      ANALYSIS OF BIOCHEMICAL AND MOLECULAR MARKERS: Where acquired, samples of the human tissue
      obtained (above) will be homogenised and assigned to biochemistry and molecular analyses.
      Total RNA will be extracted using a commercial kit, converted to cloned DNA and then probed
      for various pro-inflammatory genes. Where a change in gene regulation is noted, the
      investigators will assess the corresponding change in protein level using a combined approach
      consisting of multiplex ELISA to quantify changes in protein levels and further confirmation
      with Western blotting using corresponding specific antibodies.

      STATISTICAL ANALYSIS: Statistical analysis will be performed using SPSS for Windows version
      18.0 GradPack (IBM, New York, USA). Non-parametric continuous variables will be tested using
      Mann-Whitney U tests and parametric continuous variable will be tested using t-test/ANOVA.
      Categorical variables will be tested using Fisher exact test.

      OUTCOME AND STUDY END POINT:

      The study will involve both clinical and laboratory based work, and the outcomes are as
      follows.

        1. Laboratory based work:

           From each patient, 4 samples will be taken and hence 160 samples will be analysed.

           From each sample, the investigators will analyse the activation of pro-inflammatory
           cells (polymorphs, macrophages), level of messenger RNA.

           The investigators will analyse level of (pro)inflammatory cytokines-- IL1,2,6,9,10, and
           TNF.

           The investigators will assess the relationship between time (duration of operation) and
           the inflammatory markers.

           The study will aim to prove that prove that as duration of operation increase, the
           extent of in inflammation the intestine's surface increases, and that this process can
           be mitigated by using humidified warmed carbon dioxide gas.

        2. Clinical based work:

      The study will see whether use of humidified, warmed carbon dioxide gas results in:

        -  Better core body temperature control

        -  Less postoperative pain

        -  Shorter hospital stay

        -  Less risk of complications, including wound infection, anastomotic leaks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Participant)
measure: Change in Inflammatory cytokine level in the peritoneal biopsy samples
time frame: At the moment of time when: (1) peritoneal cavity is being opened, (2) when peritoneal cavity is being closed (expected average of 2 hours after peritoneal cavity is first opened)
description: Peritoneal samples will be taken when the peritoneal cavity is being opened (at beginning of operation), and also when the peritoneal cavity is being closed (at end of the operation). The change in the level of inflammatory cytokines in between these two time points will be measured
measure: Intraoperative temperature at 30 minutes from start of operation
time frame: 30 minutes from start of operation
description: Temperature readings during the operation will be taken. Both core body temperature (esophageal) and intraperitoneal temperature will be measured.
measure: Intraoperative temperature at 60 minutes from start of operation
time frame: 60 minutes from start of operation
description: Temperature readings during the operation will be taken. Both core body temperature (esophageal) and intraperitoneal temperature will be measured.
measure: Postoperative Analgesia requirement for pain
time frame: Time from when the patient is moved out of operating theater to when the patient is no longer an inpatient in the hospital ward (discharged), with an expected average of 1 week
description: Postoperative pain as measured by MEDD (Morphine Equivalent Daily Dose)
measure: Length of in-patient hospital stay
time frame: duration of hospital stay, an expected average of 1 week
description: number of days patient stayed postoperatively in hospital
measure: Anastomotic leaks
time frame: 6 months
description: The occurrence of anastomotic leak in the 6 months after the surgery
arm group label: Control Group
arm group type: Active Comparator
description: Standard intraoperative warming measures including heated blankets, heating with forced warmed air, warming of fluids, and insulation of limbs and head.
arm group label: Study Group
arm group type: Experimental
description: The study group will receive warmed (37°C), humidified (98% RH) carbon dioxide delivered into the open peritoneal cavity.
intervention type: Device
intervention name: Humidified, warmed CO2 insufflation of open peritoneum using Fisher & Paykel's HUMIGARD (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand)
description: The study group will receive warmed (37°C), humidified (98% RH) carbon dioxide into the open peritoneal cavity using the Fisher & Paykel's HUMIGARD system (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand). This will create a local atmosphere of 100% carbon dioxide (warmed, humidified) in the open peritoneal cavity.
arm group label: Study Group
intervention type: Device
intervention name: Standard heating
description: Standard intraoperative warming measures including heated blankets, heating with forced warmed air, warming of fluids, and insulation of limbs and head
arm group label: Control Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Australia
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responsible party type: Principal Investigator
investigator affiliation: Concord Repatriation General Hospital
investigator full name: Dr Ju Yong Cheong
investigator title: Doctor
mesh term: Peritonitis
mesh term: Inflammation
sharing ipd: No
submitted: March 9, 2022
returned: June 6, 2022