Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00642005 |
| Other study ID # |
Laphumid |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
March 17, 2008 |
| Last updated |
March 10, 2014 |
| Start date |
April 2008 |
| Est. completion date |
August 2009 |
Study information
| Verified date |
March 2014 |
| Source |
University of Auckland, New Zealand |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
New Zealand: Health and Disability Ethics Committees |
| Study type |
Interventional
|
Clinical Trial Summary
Laparoscopic surgery allows surgeons to remove bowel via small incisions. To allow insertion
of a camera and instruments, cold and dry gas is blown into the abdominal cavity. This
project investigates the use of warmed, humidified gas in laparoscopic surgery. The
hypothesis is that this will result in less damage to internal surfaces, and shorten
recovery time. Previous studies have demonstrated positive outcomes in laparoscopic
gallbladder operations. The investigators plan to study patients undergoing laparoscopic
colon operations, as these operations are longer and the effect of humidification will be
magnified. The investigators will enroll 74 patients: 37 will have the operation with cold
dry gas, and 37 will have warm, humidified gas. The investigators will measure
intraoperative heat loss, postoperative pain, fatigue, nausea and vomiting, and time to
return of bowel function.
Description:
The key determinants of a return to normal activity after major colorectal surgery are pain
and fatigue. Our research group has an interest in enhancing perioperative care to reduce
postoperative fatigue.
We have investigated the effect of peritoneal inflammation and the local production of
cytokines on fatigue. Our data indicate that there is an association between the development
of postoperative fatigue and the concentration of peritoneal cytokines following colorectal
surgery. (Paddison, Hill - manuscript in submission). It is known that following surgery,
there are two possible modes of communication between the cytokines and the brain. One is a
hormonal routine by which the cytokines produced at the site of surgery enter the blood and
proceed through cell surface receptors to act directly on the brain. The second method is a
neural route represented by paracrine action of cytokines on primary afferent neurons that
innervate the body site where the injury has taken place. In the abdominal cavity, the vagus
nerve plays an important role in the latter form of communication. Vagal sensory neurons
express large numbers of receptors for immune derived mediators, including a number of
cytokines involved in inflammation and it has been shown that a major function of vagus may
involve signaling immune and inflammatory situations. The vagus is unique as it has
termination at the nucleus tractus solitarius (NTS) in the brain. The NTS is intensely
activated following peripheral immune challenges and is also by far the most sensitive area
in the brain following immune stimulation. The NTS projects monosynaptically to many regions
of the brain which mediate sickness responses. Pro-inflammatory cytokines have been found in
the blood, the skin, and the central nervous system after surgery and injury, however
following major abdominal surgery such as colectomy these cytokines are found in very high
concentrations in the peritoneal cavity. This local production of cytokines is far in excess
of the amounts found in the serum suggesting an important local role and potentially a
significant role in metabolic changes associated with colonic surgery. Therefore,
inflammation and the consequent production of large concentrations of cytokines at the site
of the surgery may activate the rich neurosensory vagal afferents to stimulate regions of
the brain which mediate "sickness" responses. Therefore, it is feasible to hypothesize that
strategies which lead to a reduction of the concentration of pro-inflammatory cytokines will
lead to a reduction in post-operative fatigue.
In laparoscopic surgery, insufflated CO2 is delivered as defined by the United States
Pharmacopoeia and National Formulary, which requires impurity of less than 200 parts per
million, including water vapor. It is delivered at room temperature (21°C) with a relative
humidity approaching 0%. Heat is lost by the body in warming and humidifying the cold, dry
gas 1, and animal models have demonstrated that this can induce hypothermia. Initial human
investigations showed that by simply heating the insufflating gas, core temperature was
maintained and pain scores were improved. Additional findings showed heating and
humidification helped to maintain core temperature in a porcine model 4. There is clinical
evidence suggesting that heating and humidification can increase intraoperative core body
temperature and reduce post-operative use of analgesia and pain scores for up to 14 days
postoperatively. This intervention has also been linked significantly to an earlier return
to normal activity in patients undergoing cholecystectomy.
Experimental studies have also shown that humidified gas is associated with less peritoneal
and systemic inflammation compared to unhumidified gas. Furthermore, it has been
demonstrated that use of warm, humidified gas is associated with a reduction in the
concentration of peritoneal IL-6. The magnitude of this change is even larger than the
effect seen after administration of anti-inflammatory agents in a similar setting.
Significant reduction in other inflammatory peritoneal cytokines (TNF, IL-1) have also been
observed in patients undergoing laparoscopic cholecystectomy with warmed CO2 insufflation
gas.
Currently, there are no studies which have examined the effect of humidification in patients
undergoing laparoscopic colonic surgery. We hypothesize that use of warm, humidified
insufflation gas will lead to a reduction in hypothermia and concentration of peritoneal
cytokines, with consequently decreased post-operative pain and fatigue, and earlier return
to normal bowel function and activity. Our aim is to design and execute a double-blinded
randomised controlled trial to test this hypothesis.
Research Design and Methods
Patients will be recruited from out-patient clinics across all three Auckland public
hospitals. On the day of the operation, using opaque envelopes and computer generated random
numbers; patients will be allocated into 2 groups. The intervention group will receive warm,
humidified insufflation gas and control group will receive standard dry gas. Other
intraoperative variables will be standardized and controlled. The patients, operating
surgeons and other members of the clinical team will be blinded to the treatment given.
Using the data from a previous study measuring post-operative pain following colonic
surgery; 37 patients are required in each group in to provide a 20% reduction in
post-operative in hospital opiate use with alpha of 0.05 and power of 0.8. In order to
achieve the required numbers we aim to enroll all patients undergoing laparoscopic colectomy
from North Shore, Auckland and Middlemore Hospitals. Exclusion criteria:Patients under 15
years, acute cases, stoma formation (preop or intraop decision, decision to change to open
surgery preoperatively (intraop conversions will be included as intention to treat), rectal
lesions defined as less than 15cm from anal verge on imaging and/or sigmoidoscopy /
colonoscopy, steroid dependence, inability to consent or answer SRS questions due to
cognitive impairment or language barrier, ASA >= 4.
A reduction in postoperative morphine use forms the primary outcome of this study. Secondary
outcomes include postoperative pain, fatigue, intraoperative heat loss and postoperative
inflammatory response as measured by plasma and peritoneal pro-inflammatory cytokine
concentration. Other outcomes that will be measured include nausea and vomiting, antiemetic
use, and return of bowel function; with a reduction in these variables contributing to an
endpoint of earlier return to normal activity.
Morphine equivalent analgesia usage will be documented in PACU, day of operation, day 1, day
2, and day 3. Visual analog scale measures of pain at rest will be obtained preoperatively,
then at 2, 4, 8 and 12 hours, and days 1, 2, 3, 7, 14, 30, and 60 postoperatively.
Intraoperative temperature will be measured at 15min intervals using an naso-pharyngeal
probe. A drain will be placed in the peritoneal cavity at the conclusion of surgery. On the
morning following the operation, fluid from this drain as well as a simultaneous sample of
blood will be collected, centrifuged and stored. Antioxidant levels will measures, and
cytokine assays will be carried out by multiplexed cytometric bead immunoassays using the
LINCOplex system (LINCO Research, St Charles, MO, USA). Drain fluid will be assayed for
pro-inflammatory cytokines, IL-1a, TNF-a, IL-6, IL-8, IL-10 concentrations. Data will be
acquired using a Luminex cytofluorimeter and analyzed using Luminex 100 IS software version
2.3 running a 4-parameter curve fit.
The SRS score will be used to measure surgical recovery, and will be administered
preoperatively and also at days 1, 3, 7, 30, and 60. Anti-emetic use as well as time of
return of normal bowel function (ability to eat and drink one complete hospital meal,
passages of flatus or bowel motion and absence of nausea and vomiting) will also be
recorded. Patients will be contacted on discharge to ascertain time to return of normal
preoperative function.
