Effect of Warmed Humidified CO2 on Peritoneum During Laparotomy

Peritoneal Inflammation Clinical Trial

Official title:

Effect of Intraoperative Humidified CO2 Insufflation in Open Laparotomy Colorectal Surgery Patients: a Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02975947
• Other study ID #: HREC/12/CRGH/196
• Status: Completed
• Phase: N/A
• First received: November 2, 2016
• Last updated: November 23, 2016
• Start date: August 2013
• Est. completion date: June 2016

Study information

• Verified date: November 2016
• Source: Concord Repatriation General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Human Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adults above age 18.

• Elective patients.

• Pathologies: colorectal carcinoma, polyposis syndromes, diverticular diseases, prolapses, and patients with inflammatory bowel disease undergoing elective resection.

• For colorectal carcinoma, all patients whether they are having curative or palliative surgery will be included.

• Patients undergoing open elective colectomy, with or without stoma formation/ bowel anastomosis.

Exclusion Criteria:

• Patients undergoing acute surgery (emergency surgery).

• Patients undergoing Laparoscopic colectomy (multiport, single incision and also hand assisted) as all these patients receive heated humidified CO2.

• For COPD patients, the exclusion criteria would be patients: (1) On home oxygen, (2) Type 2 respiratory failure (CO2 retainers) (3) FEV1<1L, or FEV1/FVC <50% of predicted

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Inflammation
• Peritoneal Inflammation
• Peritoneum; Injury
• Peritonitis

Intervention

Device:
• Humidified, warmed CO2 insufflation of open peritoneum using Fisher & Paykel's HUMIGARD (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand)
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.
• Standard heating
Standard intraoperative warming measures including heated blankets, heating with forced warmed air, warming of fluids, and insulation of limbs and head

Locations

Country	Name	City	State
Australia	Concord Repatriation General Hospital	Sydney	New South Wales

Sponsors (1)

Lead Sponsor	Collaborator
Concord Repatriation General Hospital

Country where clinical trial is conducted

Australia, 

References & Publications (23)

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. — View Citation

Brokelman WJ, Holmdahl L, Bergström 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. — View Citation

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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. — View Citation

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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. — View Citation

Insler SR, Sessler DI. Perioperative thermoregulation and temperature monitoring. Anesthesiol Clin. 2006 Dec;24(4):823-37. Review. — View Citation

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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. — View 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. — View 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. — View Citation

Persson M, van der Linden J. Can wound desiccation be averted during cardiac surgery? An experimental study. Anesth Analg. 2005 Feb;100(2):315-20. — View 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. — View 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. — View Citation

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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. — View Citation

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Inflammatory cytokine level in the peritoneal biopsy samples	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	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)	No
Primary	Intraoperative temperature at 30 minutes from start of operation	Temperature readings during the operation will be taken. Both core body temperature (esophageal) and intraperitoneal temperature will be measured.	30 minutes from start of operation	No
Primary	Intraoperative temperature at 60 minutes from start of operation	Temperature readings during the operation will be taken. Both core body temperature (esophageal) and intraperitoneal temperature will be measured.	60 minutes from start of operation	No
Secondary	Postoperative Analgesia requirement for pain	Postoperative pain as measured by MEDD (Morphine Equivalent Daily Dose)	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	No
Secondary	Length of in-patient hospital stay	number of days patient stayed postoperatively in hospital	duration of hospital stay, an expected average of 1 week	No
Secondary	Anastomotic leaks	The occurrence of anastomotic leak in the 6 months after the surgery	6 months	No