Effects of Intraoperative Insufflation With Warmed, Humidified CO<sub>2</sub> during Abdominal Surgery: A Review

Ju Yong Cheong; Anil Keshava; Paul Witting; Christopher John Young

doi:10.3393/ac.2017.09.26

Cheong, Keshava, Witting, and Young: Effects of Intraoperative Insufflation With Warmed, Humidified CO2 during Abdominal Surgery: A Review

Original Article

Annals of Coloproctology 2018;34(3):125-137.

Published online: June 30, 2018

DOI: https://doi.org/10.3393/ac.2017.09.26

Effects of Intraoperative Insufflation With Warmed, Humidified CO₂ during Abdominal Surgery: A Review

Ju Yong Cheong^1,²

, Anil Keshava¹, Paul Witting², Christopher John Young¹

¹Colorectal Surgical Department, Concord Repatriation General Hospital, Sydney Medical School, The University of Sydney, Sydney, Australia

²Discipline of Pathology, Charles Perkins Centre, Sydney Medical School, The University of Sydney, Sydney, Australia

Correspondence to: Ju Yong Cheong, MBBS, MS, FRACS Concord Institute of Academic Surgery, Colorectal Surgical Department, Concord Repatriation General Hospital, Teaching Hospital of University of Sydney, The University of Sydney, Sydney Medical School, Hospital Road, Concord, NSW 2139, Australia
Tel: +61-2-409-110-219 E-mail: Juyong.cheong@gmail.com

Received January 31, 2017 Accepted September 26, 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

During a laparotomy, the peritoneum is exposed to the cold, dry ambient air of the operating room (20℃, 0%–5% relative humidity). The aim of this review is to determine whether the use of humidified and/or warmed CO₂ in the intraperitoneal environment during open or laparoscopic operations influences postoperative outcomes.

Methods

A review was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, OVID MEDLINE, Cochrane Central Register of Controlled Trials and Embase databases were searched for articles published between 1980 and 2016 (October). Comparative studies on humans or nonhuman animals that involved randomized controlled trials (RCTs) or prospective cohort studies were included. Both laparotomy and laparoscopic studies were included. The primary outcomes identified were peritoneal inflammation, core body temperature, and postoperative pain.

Results

The literature search identified 37 articles for analysis, including 30 RCTs, 7 prospective cohort studies, 23 human studies, and 14 animal studies. Four studies found that compared with warmed/humidified CO₂, cold, dry CO₂ resulted in significant peritoneal injury, with greater lymphocytic infiltration, higher proinflammatory cytokine levels and peritoneal adhesion formation. Seven of 15 human RCTs reported a significantly higher core body temperature in the warmed, humidified CO₂ group than in the cold, dry CO₂ group. Seven human RCTs found lower postoperative pain with the use of humidified, warmed CO₂.

Conclusion

While evidence supporting the benefits of using humidified and warmed CO₂ can be found in the literature, a large human RCT is required to validate these findings.

Keywords: Humidified; Carbon dioxide; Pneumoperitoneum; Surgical adhesions; Intraperitoneal inflammation

INTRODUCTION

In recent years, minimally invasive abdominal operations have become prevalent. However, based on pathology and patient factors, open abdominal operations continue to be routinely performed. After open abdominal surgery, commonly encountered complications include postoperative ileus, postoperative infection, wound infection and anastomotic breakdown. Intraoperatively, the bowel is exposed to the ambient air, which is cold and dry relative to the unexposed abdominal environment. The average room temperature in the operating room (OR) is typically 20℃, and the average relative humidity is 0%–5%. The OR has negative air ventilation; i.e., clean air is blown in from the ceiling and then out of the OR. The dry and cold air convection causes serosal and peritoneal desiccation [1]. Desiccation results from superficial water loss through diffusion and convective gas movements. When the ambient gas is fully saturated, water loss cannot occur, regardless of the gas movements above the surface. By contrast, if the gas is not fully saturated with water, then convection will be a decisive factor for desiccation. Diffusion alone is a rather slow transfer process, but convection maximizes the evaporation rate by constantly exchanging the ‘humidified’ gas close to the surface of the intestine with ‘dry’ ambient gas (the diffusion gradient is maintained at a maximum) [1]. Surgeons who perform a prolonged laparotomy frequently cover the bowel with a warm, wet sponge to moisten the bowel.

Peritoneal desiccation leads to peritoneal inflammation, loss of barrier function and increased risk of infection [1-4], and peritoneal inflammation can lead to postoperative adhesion formation and long-term bowel obstruction [1, 2]. Cooling of the bowel due to exposure can lead to vasoconstriction of splanchnic blood flow to the intestine, which may increase the risk of bowel anastomosis breakdown. Bowel desiccation may also be a factor in delaying the return of bowel function. Previous studies [2-4] have also suggested that desiccation and cooling of the peritoneum from open surgical wounds or the use of cold, nonhumidified CO₂ insufflation gas may cause oxidative stress on peritoneal mesothelial cells. Thus, desiccation of the peritoneum has the potential to cause peritoneal inflammation and reduced splanchnic blood flow, with associated long-term consequences. One way of mitigating desiccation is the use of humidified, warmed CO₂ gas. CO₂ gas is heavier than other components of room air (nitrogen, oxygen) and therefore tends to sink into the abdominal wound rather than drift away. CO₂ also maintains heat, thus creating a localized greenhouse effect within the abdominal cavity. Animal studies have also suggested that CO₂ pneumoperitoneum has anti-inflammatory properties compared with a standard laparotomy, with a significantly greater increase in anti-inflammatory cytokines (interleukin [IL]-6) [5] and earlier expression of anti-inflammatory cytokines (IL-6) [6]. CO₂ pneumoperitoneum allows better regulation of the immune response to local infection (Escherichia coli peritonitis) and has been associated with lower levels of proinflammatory cytokines (IL-1, tumor necrosis factor-α [TNF-α]), a lower rate of positive blood culture, and lower bacterial counts in peritoneal fluid [6]. These observations may reflect a combination of improved regulation of the immune response, better splanchnic blood flow and less desiccation as a result of CO₂ pneumoperitoneum [7]. The aim of this review was to determine whether evidence supporting the benefits associated with the use of humidified, warmed CO₂ during abdominal surgery can be found in the literature.

METHODS

A comprehensive literature search and review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [8]. Two authors (JYC, AK) performed the literature search using the databases PubMed, OVID MEDLINE, Cochrane Central Register of Controlled Trials and Embase (1980–2016 October). The key search terms included the following: “carbon dioxide,” “humidified,” “laparotomy,” “surgical procedures, minimally invasive,” “pneumoperitoneum,” “laparoscopy,” “temperature,” “helium,” “outcomes,” “inflammation,” and “postoperative pain.”

Comparative studies, including randomized controlled trials (RCTs) and prospective cohort studies, were included. Both laparotomy and laparoscopic studies were reviewed; laparoscopic studies that compared the effects of humidified, warmed CO₂ pneumoperitoneum with those of cold, dry CO₂ pneumoperitoneum were included because cold, dry CO₂ pneumoperitoneum is analogous to and mimics the environment in the operating theatre. Studies of humans and nonhuman animals were included. For human subject studies, a sample size of at least 20 patients was a prerequisite for inclusion. For work conducted with non-human animals, a minimum of 10 animals per treatment group was considered necessary for inclusion. A lower minimum sample size was acceptable for nonhuman animal studies because such studies tend to be more homogenous and better controlled than human studies.

Potentially eligible studies were selected based on their titles and abstracts. The full texts of these publications were obtained and reviewed to confirm the eligibility of each study for inclusion in the review. The reference lists of included and excluded articles were searched to identify any additional relevant articles. All publications related to each individual RCT were obtained along with the trial protocol, if available, in electronic format. The primary outcomes identified were peritoneal inflammation, core body temperature, postoperative pain, wound infection and tumor growth. An assessment of the quality of the evidence provided in the various studies was determined for each study by using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence system [9]. Given the significant heterogeneity in the outcome measures, no formal meta-analysis was applied, and the study results are presented individually in tabular format.

RESULTS

The literature search identified 37 articles that met the inclusion criteria for analysis (Fig. 1), including 30 RCTs, 7 nonrandomized cohort studies, 23 human studies, and 14 animal studies. The animal model studies examined the effects of pneumoperitoneum under various conditions (warmed/humidified CO₂ vs. cold/dry CO₂ vs. ambient air vs. helium). In human studies, the effects of various pneumoperitoneum conditions (warmed/humidified CO₂ vs. cold/dry CO₂ vs. air) in different operative settings were examined (bariatric surgery, colorectal surgery, gynecological surgery, and hepatobiliary surgery).

Effects on peritoneal inflammation

Eight studies compared the effects of warmed, humidified CO₂ insufflation vs. cold, dry CO₂ insufflation on peritoneal morphology, inflammation and adhesion formation (Table 1). Six studies were animal-based, and 2 were human studies. The 2 human studies examined the effects in patients undergoing a laparoscopic cholecystectomy or a laparoscopic colectomy [10, 11]. Brokelman et al. [10] found that the peritoneal plasminogen activator inhibitor-1 (PAI-1) level was ten times higher in peritoneal biopsies of patients who received cold gas insufflation than it was in patients who received warmed, humidified CO₂. Elevated PAI-1 levels can lead to lower levels of fibrinolysis and increased fibrin deposition, resulting in increased peritoneal adhesion formation [12]. An analysis of abdominal drain fluid 20 hours postoperatively found no difference in the levels of inflammatory cytokines (IL1, 6, 8, 10, and TNF-α) between the 2 groups [11].

The largest animal study employed 150 rats. The group that received cold, dry gas pneumoperitoneum had more intense peritoneal injury, with intra-abdominal adhesions, than the group that received warmed, humidified gas pneumoperitoneum [13]. Three smaller animal studies [14-16] found no difference in peritoneal inflammation between the 2 pneumoperitoneum groups; however, one found that cold, dry gas insufflation resulted in greater infiltration of the peritoneum by lymphocytes and desquamation of the mesothelial cells, with exposure of the underlying basement membranes [17]. One animal study [18] compared the effects of CO₂ pneumoperitoneum with those of air pneumoperitoneum and found that the air pneumoperitoneum group had higher levels of infiltration of the peritoneum by inflammatory cells than the CO₂ pneumoperitoneum group, with a threefold increase in the number of polymorphoneutrophils (PMNs) and lower PMN apoptosis rates. Collectively, these studies suggest that insufflation with cold, dry gas to create the pneumoperitoneum is associated with greater peritoneal injury, increased adhesion formation and greater recruitment of inflammatory cells; however, no difference in peritoneal cytokine levels was observed between treatment groups.

Effects on core body temperature

The surface area of the peritoneal cavity is equivalent to that of the external body, 1–2 m² [2]. Approximately 10% of cardiac output is routed through the splanchnic system. The peritoneal cavity has the potential for extensive heat exchange and resultant morbidity due to hypothermia [19-21]. Twenty studies examined the effects of humidified, warmed CO₂ on core body temperature (Table 2). Three studies were animal-based, and 17 studies were human-based. Among the 17 available human studies, 15 were RCTs, and 2 were nonrandomized prospective studies. The total number of patients in the RCTs was 1,014. The studies all involved laparoscopic operations. Many of the studies had small sample sizes, and only 7 studies had more than 30 patients in each arm [22-28]. Seven studies [19, 23, 27, 29-32] found significantly higher core body temperatures in the treatment group (humidified, warmed CO₂ group) than in the control group (cold, dry CO₂) whereas nine studies did not find any significant difference [22, 24-26, 28, 33-36].

The largest human-based RCT involved 195 patients who had undergone a laparoscopic appendectomy [26]. The study found no difference in core body temperature between the treatment group and the control group. However, the next-largest human RCT, based on 148 patients who had undergone a laparoscopic cholecystectomy, found higher core temperatures in the warmed, humidified CO₂ group (37.07℃ vs. 36.85℃, P = 0.01) [27]. Another study found that the core temperature decreased in both the treatment and the control groups; however, the decrease was greater in the treatment group (0.7℃ to 0.3℃ and 0.3℃ to 0.1℃, respectively) [37].

The largest animal study was conducted with 150 rats [13]; a decrease in core body temperature of between 2.3℃ and 3.1℃ was observed in the control group treated with cold/dry CO₂ pneumoperitoneum whereas the core body temperature of the humidified/warmed CO₂ group increased by 1.3℃. Another animal study examined the effects of 4 different combinations of pneumoperitoneum conditions: cold/dry, cold/humidified, warm/dry, and warm/humidified [15]. Conditions that were either cold or dry resulted in a significant decrease in core body temperature. By contrast, warmed/humidified pneumoperitoneum resulted in an increase in core body temperature of 2.4℃ (P = 0.031) [15]. Bessell et al. [38] suggested that the humidity of the insufflated CO₂ gas was more important than its temperature in maintaining core body temperature. Their study compared the use of dry-warm CO₂ with that of dry-cold CO₂ and found that both resulted in a significant drop in core body temperature. The provision of warmed, rather than cold, insufflated gas conferred no protection against changes in core temperature during laparoscopic surgery due to the small amount of heat required to warm the gas to body temperature. The study suggested that a greater amount of body heat is required to saturate the insufflated gas. Most of the hypothermic effect they observed was due to this saturation and could be minimized by humidifying the gas.

While some evidence exists that warmed, humidified CO₂ results in better control of core body temperature than cold, dry CO₂, this outcome has not been shown universally. Overall, the effect on core temperature appears to be more pronounced in larger studies than in smaller studies, suggesting that the smaller-scale studies were underpowered.

Effect on postoperative pain

Sixteen studies compared the effects of humidified, warmed CO₂ with those of cold, dry CO₂ on postoperative pain (Table 3). All of these studies were human RCTs, with a total of 1,223 patients. Pain was measured using a combination of the visual analogue score (VAS), verbal rating scale (VRS), morphine equivalent daily dose (MEDD), analogue pain score, Likert Scale and total analgesia requirement. Nine studies (with a total of 602 patients) found no difference in postoperative pain [11, 22, 23, 25, 26, 30, 32, 34, 36] whereas seven studies (with a combined total of 621 patients) found that pain was significantly lower with the use of humidified, warmed CO₂ [27-29, 33, 39-41].

The largest RCT, which was conducted by Yu et al. [26], revealed no difference in MEDD and VAS scores between the warmed, humidified CO₂ pneumoperitoneum group and the cold, dry CO₂ pneumoperitoneum group among patients who had undergone a laparoscopic appendectomy. However, a laparoscopic appendectomy is a minor operation, and whether the results of such a study can be justifiably compared with those of other studies involving major surgeries is questionable. The next-largest human RCT, which included 148 patients who had undergone a laparoscopic cholecystectomy, found that postoperative pain measured by using the VAS at day 0 was significantly lower in the warmed, humidified CO₂ group than it was in the cold, dry CO₂ group [27].

Similarly, Mouton et al. [33] determined that warmed, humidified CO₂ resulted in less perioperative pain, with improved pain noted for up to 10 days postoperatively, and Farley et al. [23] observed a similar benefit at postoperative day 14. Thus, while some evidence showing that the use of warmed, humidified CO₂ reduces postoperative pain exists, the overall evidence is inconclusive.

Effect on respiratory function

The CO₂ in the peritoneal cavity may be absorbed systemically, with conversion to carbonic acid (H₂CO₃) (Table 4). This buffering effect may decrease pH both locally (within the peritoneum) and systemically depending on the intrinsic carbonic acid levels. Consistent with this possibility, an animal study by Bergström et al. [42] found that CO₂ pneumoperitoneum resulted in a locoregional decrease in pH (6.4 vs. 7.5, P = 0.001) and a decrease in systemic arterial pH (7.43 vs. 7.49, P = 0.004) compared with insufflation with another gas (helium). Another independent animal study found that increasing the CO₂ temperature resulted in a greater systemic arterial concentration of CO₂ and a corresponding decrease in pH [43]. A locoregional decrease in pH and an increase in PaCO₂ will lead to local vasodilatation, which would be especially beneficial during bowel anastomosis.

A human study by Ozgonul et al. [24] found no difference in arterial pH, PaCO₂ level, or HCO₃- level between subjects receiving cold CO₂ and those receiving warmed CO₂. Another human study [44] found that the results of a pulmonary function test at 12 hours were significantly better in the warmed CO₂ group than in the cold CO₂ group.

Other suggested effects of humidified, warmed CO₂ on the peritoneum

Although not included in the review, other interesting effects of humidified, warmed CO₂ have been discussed in the literature. These effects were not included in this review because they were either observed in noncomparative studies or in vitro. However, the results of these studies are fascinating and should be mentioned.

First is the effect of humidified, warmed CO₂ on tumor migration. Nduka et al. [45] compared the effects of warmed CO₂ vs. cold CO₂ insufflation on peritoneal tumor growth. Twenty WAG rats were subjected to either cold CO₂ or warm CO₂ peritoneal insufflation. The rats then received injections of 1×10⁵/mL of CC531 colon cancer cells into the peritoneal cavity. After three weeks, the extent of tumor spread and cancer weight were measured, as determined by using the peritoneal cancer index (PCI). Cold CO₂ insufflation was associated with a significantly higher PCI score (266) compared with warm CO₂ insufflation (151), indicating a greater rate of peritoneal tumor growth and spread in the cold CO₂ group (P = 0.025). This study suggested a potential pathophysiological mechanism: peritoneal trauma resulting from cold gas insufflation may be responsible for the greater rate of tumor spread.

Furthermore, Texler et al. [46] examined the spread of tumor cells in warmed, humidified CO₂ and cold, dry CO₂ environments in vitro. A total of 24 tumor cell cultures were insufflated with CO₂ in an airtight environment, and laparoscopic instruments were used to agitate the contents of the bottle. The study found that the use of heated and humidified CO₂ with airtight seals around the trocars in vitro (thus mimicking the in vivo laparoscopic intra-abdominal environment) reduced cell deposition on the trocars compared with cold, dry CO₂ (P = 0.015). Although not a RCT, a study by Tan [47] found that CO₂ pneumoperitoneum inhibited tumor cell growth (TCC) for the first 48 hours in rat models. At high CO₂ concentrations (10%–15%), the TCC apoptosis and necrosis rates were 2.8–5.6 times higher than those in the controls without CO₂ pneumoperitoneum (P < 0.01).

Second is the effect of warmed, humidified CO₂ on local tissue oxygen tension. A 2015 study [48] using 15 Wistar rats found that compared with ambient air, local instillation of humidified, warmed CO₂ during a laparotomy significantly increased the local tissue oxygen tension by 96.6% (29.8 mmHg) and the local tissue temperature by 3.0℃.

Third is the effect of warmed, humidified CO₂ on wound infection. Suggestions have been made that warmed, humidified carbon dioxide on open laparotomy may lead to reductions in both wound infection and intra-abdominal infections because CO₂ is bacteriostatic. For many years, CO₂ at high concentrations has been used in modified atmosphere packaging to prolong the shelf life of fresh food. The effect of CO₂ is especially marked in fresh meat [49]. High concentrations of CO₂ have a growth-inhibiting effect on most bacteria, including both aerobes and anaerobes [50, 51]. The inhibitory effect of CO₂ is associated with two main mechanisms: suffocation and a CO₂-specific effect that acts directly on the bacterial cell [1]. A study by Persson et al. [52] found that at body temperature, the bacterial growth after 4 hours of CO₂ exposure was 1/100 that after exposure to air.

Moreover, the use of laminar ultraclean airflow from the ceiling downward to the operating table may actually help convey airborne particles from the surgeons into the operating field. A study [53] found that when a surgeon leans over a wound with such an airflow (which is common), the surgeon increases the risk of airborne wound contamination by 27 fold. Additionally, more than 90% of contaminating bacteria in clean surgical wounds have been found to originate from ambient air [54], and a substantial proportion of these bacteria contaminate the wound directly. CO₂ is heavier than air and will therefore sink to the bottom of the laparotomy wound. Surplus CO₂ from ongoing insufflation will overflow, and this convective current may help block airborne contamination, as theoretically supported by Stokes’ law, which describes the settling velocity of particles in a gas/liquid. A study [6] in which 10 L/min of CO₂ was insufflated into open cardiothoracic wounds found that the rate of direct airborne contamination was reduced by 80%.

Furthermore, the use of CO₂ has been found to be beneficial in septicemia. A study by Hanly et al. [55] examined the effect of CO₂ pneumoperitoneum on lipopolysaccharide (LPS) septicemia. Two experiments were performed. The first involved randomizing 143 rats to receive either CO₂, helium, or air pneumoperitoneum while the control group did not receive pneumoperitoneum. The rats then received an IV injection of endotoxins (LPS). Survival was dramatically higher in the group receiving CO₂ insufflation (survival rate, 78%) compared with the groups receiving helium (52%) and air (55%) and compared with the control group (42%), P < 0.05. In the second experiment, 65 rats were administered CO₂, helium, or air pneumoperitoneum, and the control group did not receive pneumoperitoneum. All rats underwent a laparotomy, and endotoxins (LPS) were injected intraperitoneally. The survival rate was significantly higher in the CO₂ pneumoperitoneum group (85%) than that in the controls (25%), P < 0.05. Cytokine measurements revealed that the IL-10 level was 35% higher in the CO₂ pneumoperitoneum group than in the other groups (P < 0.05), and that the TNF-α level was 1 of 3 that of the other groups (P < 0.05). This study suggested the presence of direct humoral mediation by CO₂, in which the suppression of TNF-α release from macrophages by IL-10 may have been responsible for the increased survival. The results of this study are astounding. The possibility that CO₂ pneumoperitoneum has a positive impact on survival in septic patients implies that CO₂ pneumoperitoneum may actually be beneficial in acutely ill patients with septicemia (e.g., acute abdomen or trauma). In acute settings where laparotomies are performed more frequently, CO₂ pneumoperitoneum may still be established and may improve patient survival. This will be discussed further in the sections below.

DISCUSSION

In this literature review, human and nonhuman animal studies, as well as laparoscopic and laparotomy studies, were examined. Equivocal evidence exists concerning the benefits of warmed, humidified CO₂ on the postoperative outcomes of abdominal surgery. Four of eight studies showed that peritoneal inflammation and peritoneal damage were lower in the warmed, humidified CO₂ group than in the cold, dry CO₂ group. Some evidence also exists that warmed, humidified CO₂ results in a more desirable core body temperature (7 of 15 human RCTs) and less postoperative pain (7 of 16 human RCTs). Warmed, humidified CO₂ may lead to better postoperative lung function. Studies have found that CO₂ pneumoperitoneum leads to a decrease in local peritoneal pH. This decrease, in combination with local warming and the effects of CO₂, may lead to vasodilation in splanchnic blood flow. The locally increased splanchnic blood flow will be of benefit for the integrity of colorectal anastomosis.

This study does have several limitations. First, the studies in this review are very heterogeneous. A Cochrane review in 2011 [56] based on 16 human studies found no evidence to support the use of warmed, humidified CO₂ gas, with no observed difference in core body temperature, postoperative pain or perioperative outcomes. In 2016, a meta-analysis based on 17 laparoscopic human studies found that the only benefit of warmed, humidified CO₂ was a reduction in immediate postoperative pain [57]. In our review, we expanded our scope to include both open/laparoscopic and human/animal studies, as we believe that many of the potential benefits of warmed, humidified CO₂ would not otherwise be mentioned; one of these key benefits may be the effect on peritoneal inflammation. Second, potentially eligible studies were identified based on their title and abstracts. During the process, the two authors performing the search were blinded to neither the names of the authors nor the titles of the journals, which could contribute to selection bias.

In conclusion, the ultimate benefit of using warmed, humidified carbon dioxide during abdominal surgery remains to be determined. A need clearly exists for RCTs involving human subjects to examine the potential impacts of the use of warmed, humidified carbon dioxide during abdominal surgery on peritoneal inflammation and adhesion formation.

Notes

CONFLICT OF INTEREST

No conflicts of interest are reported.

Fig. 1.

Study flow chart.

Table 1.

Effects of humidified, warmed carbon dioxide on peritoneal inflammation

Study	Study type	Humans/animals	Operation/samples taken	Device used	Study group		Control group		Results
Study	Study type	Humans/animals	Operation/samples taken	Device used	Treatment	No.	Treatment	No.	Results
Peng et al. 2009 [13]	RCT	Animals (rats)	Pneumoperitoneum creation (peritoneum/muscle of anterior/upper abdomen harvested)	Self-developed system	Warmed (37°C) + humidified (95% RH) CO₂ gas	75	Cold (21°C) + dry (<1% RH) CO₂ gas	75	Cold, dry group: intense peritoneal injury + intraabdominal adhesions
Peng et al. 2009 [13]	RCT	Animals (rats)		Self-developed system	Warmed (37°C) + humidified (95% RH) CO₂ gas	75	Cold (21°C) + dry (<1% RH) CO₂ gas	75	Warmed, humidified group: less peritoneal injury, no adhesion
Brokelman et al. 2008 [10]	RCT	Humans	Laparoscopic cholecystectomy (parietal peritoneal biopsy)	Thermoflator (Karl Storz GmbH & Co., Tuttlingen, Germany)	Warmed (37°C) CO₂ gas	15	Cold (21°C) CO₂	15	Significantly higher PAI (10x) level in the peritoneum of the control group with cold CO₂ insufflation
Sammour et al. 2010 [11]	RCT	Humans	Elective laparoscopic colectomy (4-mL peritoneal drain fluid)	Insuflow (MR 860, Fisher & Paykel Healthcare, Auckland, New Zealand)	Warmed (37°C) + humidified (98% RH) CO₂	41	Standard CO₂ (19°C, 0% RH)	41	No difference in peritoneal cytokine levels (IL1, 6, 8, 10, TNF-α)
Sammour et al. 2011 [14]	Prospective, non-RCT	Animals (rats)	Pneumoperitoneum creation (biopsies of liver, kidney, pancreas, jejunum)	Insufflator: CO₂-OP-Pneu insufflator, (Wisap, Munich, Germany)	Warmed (37°C), humidified (98% RH) CO₂	10	Standard (19°C, 0% RH)	10	No difference in oxidative stress measures (malondialdehyde-MDA, Protein Carbonl-PC)
Sammour et al. 2011 [14]	Prospective, non-RCT	Animals (rats)		Humidifier: Insuflow (MR 860, Fisher & Paykel Healthcare)	Warmed (37°C), humidified (98% RH) CO₂	10	Standard (19°C, 0% RH)	10
Moehrlen et al. 2006 [18]	RCT	Animals (NMRI mice)	Pneumoperitoneum creation (peritoneal lavage sample)	Olympus laparoscopic UHI-1 insufflator (Olympus Volketswil, Volketswil, Switzerland)	CO₂	9	Air	9	CO₂ pneumoperitoneum resulted in less peritoneal inflammation Air resulted in higher PMN recruitment (3×), and lower PMN apoptosis rates
Hazebroek et al. 2002 [15]	RCT	Animals (rats)	Pneumoperitoneum creation (peritoneal tissue samples from anterior abdominal wall)	MR600 anesthesia respiratory humidifier (Fisher & Paykel Healthcare)	Group 1- Cold (24.9°C), dry (4% RH) CO₂	12	No pneumoperitoneum	12	No significant morphological difference among the groups
					Group 2- Cold (24.8°C), humidified (87% RH) CO₂	12
					Group 3- Warm (36.9°C), dry (5% RH) CO₂	12
					Group 4- Warm (37.1°C), humidified (88% RH) CO₂	12
Erikoglu et al. 2005 [17]	RCT	Animals (rats)	Pneumoperitoneum creation (peritoneal tissue samples)	Datascope GmbH, Passport XG, Bensheim	Warmed (40°C), humidified (98% RH) CO₂	10	No pneumoperitoneum	10	Greater peritoneal alteration in the cold, dry CO₂ group
Erikoglu et al. 2005 [17]	RCT	Animals (rats)	Pneumoperitoneum creation (peritoneal tissue samples)	Datascope GmbH, Passport XG, Bensheim	Cold (21°C), dry (2% RH) CO₂	10	No pneumoperitoneum	10	Greater peritoneal alteration in the cold, dry CO₂ group
Margulis et al. 2005 [16]	RCT	Animals (pigs)	Laparoscopic nephrectomy (peritoneal fluid sample)	Insuflow (MR 860, Fisher & Paykel Healthcare)	Warmed, humidified CO₂	5	Cold, dry CO₂	5	No difference in serum and peritoneal levels of TNF-α, IL-1, IL-6, glucose, and cortisol

RCT, randomized controlled trial; RH, relative humidity; TNF, tumor necrosis factor; IL, interleukin.

Table 2.

Effects of warmed, humidified carbon dioxide on core body temperature

Study	Study type	Humans/animals	Operation	Device used	Study group		Control group		Results
Study	Study type	Humans/animals	Operation	Device used	Treatment	No.	Treatment	No.	Results
Nguyen et al. 2002 [30]	RCT	Humans	Lap Nissen fundoplication	Insuflow (MR 860, Fisher & Paykel Healthcare, Auckland, New Zealand)	Warmed (37°C) + humidified (95% RH) CO₂ gas + warming blanket	10	Warming blanket	10	Intraabdominal T increased by 0.2°C in the study group, but decreased by 0.5°C in the control group after 1.5 hours
Nguyen et al. 2002 [30]	RCT	Humans	Lap Nissen fundoplication			10	Warming blanket	10	Difference not significant
Hamza et al. 2005 [29]	RCT	Humans	Lap Roux-en-Y gastric bypass	Insuflow (MR 860, Fisher & Paykel Healthcare, NZ)	Warmed (37°C) + humidified (95% RH) CO₂ gas	23	Room temperature (20°C) gas	21	Study group showed a significantly higher core body temperature intraoperatively (35.5°C vs. 35.0°C) and at the end of surgery, P = 0.01
Hamza et al. 2005 [29]	RCT	Humans	Lap Roux-en-Y gastric bypass	Insuflow (MR 860, Fisher & Paykel Healthcare, NZ)	Warmed (37°C) + humidified (95% RH) CO₂ gas	23	Room temperature (20°C) gas	21	Study group also had a significantly lower rate of postoperative shivering (0% vs. 19%)
Davis et al. 2006 [22]	RCT	Humans	Lap Roux-en-Y gastric bypass	Control- standard CO₂	Group 1- Warmed CO₂	33 (11 each group)	Standard CO₂	11	No difference in core body temperature or humidity
				Group 1- heated insufflator tube set (Stryker)	Group 2- Humidified CO₂
				Group 2,3- Insuflow (MR 860, Fisher & Paykel Healthcare)	Group 3- Warmed + Humidified CO₂
Peng et al. 2009 [13]	RCT	Animals (rats)	Laparoscopic insufflation only	Self-developed system	Warmed (37°C) + humidified (95% RH) CO₂ gas	75	Cold (21°C) + dry (<1% RH) CO₂ gas	75	Significant decrease in core body temperature in cold, dry CO₂ group (decrease of 2.3°C-3.11°C); warmed + humidified CO₂ group showed increased temperature by 1.3°C
Mouton et al. 1999 [33]	RCT	Humans	Elective laparoscopic cholecystectomy	Modified LINS-1000 Insufflator (Cook Medical Technology, Queensland, Australia)	Warmed (37°C) + humidified (90% RH) CO₂	20	Standard CO₂ (21°C, 0% RH)	20	No difference in core body temperature or humidity
Farley et al. 2004 [23]	RCT	Humans	Elective laparoscopic cholecystectomy	Insuflow Filter Heater Hydrator; (Lexion Medical, St Paul, MN, USA)	Warmed (35°C), humidified (95% RH) CO₂	49	Standard CO₂	52	Core body temperature increased by 0.29°C in humidified, warmed
Farley et al. 2004 [23]	RCT	Humans	Elective laparoscopic cholecystectomy		Warmed (35°C), humidified (95% RH) CO₂	49	Standard CO₂	52	CO₂ group and decreased by 0.03°C in standard group, P = 0.01
Saad et al. 2000 [34]	RCT	Humans	Elective laparoscopic cholecystectomy	Flow Therme (WISAP, Sauerlach, Germany)	Warmed (37°C) CO₂	10	Standard (21°C) CO₂	10	No difference in core body temperature
Bäcklund et al. 1998 [31]	RCT	Humans	Elective laparoscopic surgery (not specified)	Therme-Pneu Electronic Ltd., Wisap, Germany	Warmed (37°C) CO₂	13	Cold (21°C) CO₂	13	Warm CO₂ group had higher core body temperature (35.8°C vs. 35.4°C, P < 0.05)
Bäcklund et al. 1998 [31]	RCT	Humans	Elective laparoscopic surgery (not specified)	Therme-Pneu Electronic Ltd., Wisap, Germany	Warmed (37°C) CO₂	13	Cold (21°C) CO₂	13	Warm CO₂ group had higher cardiac index intraoperatively (P < 0.05). Warm CO₂ group had better urine output (P < 0.05) and lower requirement of mannitol intraoperatively for low urine output
Nelskylä et al. 1999 [37]	RCT	Humans	Laparoscopic hysterectomy	Thermoflator (Karl Storz, Tuttlingen, Germany)	Warmed (37°C) CO₂	18	Cold (24°C) CO₂	19	Greater decrease in temperature in the group with warmed CO₂ (0.7°C vs. 0.3°C, 0.3°C vs. 0.1°C)
Ozgonul et al. 2007 [24]	RCT	Humans	Elective laparoscopic cholecystectomy	H-500 Fluid warmer (Level 1 Technologies, Inc., Rockland, MA, USA)	Warmed (37°C) CO₂	31	Cold (21°C) CO₂	31	No difference in core body temperature, mean arterial pressure, or heart rate
Hazebroek et al. 2002 [15]	RCT	Animals (rats)	Pneumoperitoneum creation	MR600 anesthesia respiratory humidifier (Fisher & Paykel Healthcare)	Group 1- Cold (24.9°C) dry (4% RH) CO₂	12	No pneumoperitoneum	12	Cold, dry CO₂ group: decrease in core body temperature by 1.6°C (P < 0.001)
					Group 2- Cold (24.8°C), humidified (87% RH) CO₂	12			Cold, humidified CO₂ group: decrease in core body temperature by 0.3°C (P = 0.011)
					Group 3- Warm (36.9°C), dry (5% RH) CO₂	12			Warm, dry CO₂ group: decrease in core body temperature by 0.9°C (P = 0.031)
					Group 4- Warm (37.1°C), humidified (88% RH) CO₂	12			Warm, humidified CO₂ group: increase in core body temperature by 2.4°C (P = 0.031)
Ott 1991 [19]	Prospective, non-RCT	Humans	Diagnostic laparoscopy	R. Wolf/Weiss insufflator	Warmed (35°C) CO₂	20	Cold CO₂	20	In the cold CO₂ group, a decrease in core body temperature of 0.3°C per 50 L of CO₂ used was observed
Ott 1991 [19]	Prospective, non-RCT	Humans	Diagnostic laparoscopy	R. Wolf/Weiss insufflator	Warmed (35°C) CO₂	20	Cold CO₂	20	Warmed, humidified group had improved intraoperative nor-mothermia and postoperative pain, and reduced recovery room stay
Bessell et al. 1995 [38]	RCT	Animals (pigs)	Pneumoperitoneum creation	LINS-1000 insufflator (Cook Medical Technology, Queensland, Australia)	Warmed (30°C) CO₂	6	Cold (25°C) CO₂	6	No significant temperature difference was observed between animals receiving cold CO₂ and those receiving warm CO₂ over a 3-hour period
Yeh et al. 2007 [35]	Prospective, non-RCT	Humans	Laparoscopic colectomies	Insuflow (MR 860, Fisher & Paykel Healthcare)	Warmed (36°C), humidified (95% RH) CO₂	20	Cold (30.2°C), dry (0% RH)	20	No significant difference in change in core body temperature
Manwaring et al. 2008 [25]	RCT	Humans	Laparoscopic gynecologic procedures	Insuflow (MR 860, Fisher & Paykel Health care)	Warmed (37°C), humidified (100% RH) CO₂	30	Cold, dry CO₂	30	No difference in core body temperature or recovery room time
Champion and Williams 2006 [36]	RCT	Humans	Laparoscopic Roux-en-Y gastric bypass	Insuflow device (Lexion Medical, St Paul, MN, USA)	Warmed (35°C), humidified (95% RH) CO₂	25	Cold, dry CO₂	25	No difference in core body temperature, operative time, or recovery room time
Yu et al. 2013 [26]	RCT	Humans	Laparoscopic appendectomy	Insuflow (MR 860, Fisher & Paykel Healthcare)	Warmed (37°C), humidified (98% RH) CO₂	97	Cold (20°C–21°C), dry (0% RH) CO₂	98	No difference in core body temperature
Savel et al. 2005 [32]	RCT	Humans	Laparoscopic Roux-en-Y gastric bypass	Insuflow device (Lexion Medical, St. Paul, MN, USA)	Warmed (35°C), humidified (95% RH) CO₂	15	Cold, dry CO₂	15	No change in core body temperature in the cold, dry CO₂ group
Savel et al. 2005 [32]	RCT	Humans	Laparoscopic Roux-en-Y gastric bypass	Insuflow device (Lexion Medical, St. Paul, MN, USA)	Warmed (35°C), humidified (95% RH) CO₂	15	Cold, dry CO₂	15	In the humidified, warmed CO₂ group, core body temperature increased from 35.8°C to 36.2°C (P = 0.004)
Klugsberger et al. 2014 [27]	RCT	Humans	Laparoscopic cholecystectomy	Optitherm device (Storz, Tuttlingen, Germany)	Warmed, humidified CO₂	81	Cold, dry CO₂	67	Higher core body temperature in the warmed, humidified CO₂ group (37.07°C vs. 36.85°C, P = 0.01)
Herrmann and De Wilde 2015 [28]	RCT	Humans	Laparoscopic assisted vaginal hysterectomy	Insuflow (MR 860, Fisher & Paykel Healthcare)	Warmed (37°C), humidified (98% RH) CO₂	48	Cold (20°C–21°C), dry (0% RH) CO₂	49	No difference in core body temperature

RCT, randomized controlled trial; RH, relative humidity.

Table 3.

Effects of warmed, humidified carbon dioxide on postoperative pain in humans

Study	Study type	Humans/animals	Operation	Device used	Study group		Control group		Results	Method of measuring pain
Study	Study type	Humans/animals	Operation	Device used	Treatment	No.	Treatment	No.	Results	Method of measuring pain
Nguyen et al. 2002 [30]	RCT	Humans	Lap Nissen fundo-plication	Insuflow device (Lexion Medical, St. Paul, MN, USA)	Heated + humidified CO₂ gas + warming blanket	10	Warming blanket	10	No significant difference	VAS
Hamza et al. 2005 [29]	RCT	Humans	Lap Roux-en-Y gastric bypass	Insuflow device (Lexion Medical)	Heated + humidified CO₂ gas	23	Room temperature gas	21	Maximum VRS and morphine consumption significantly lower in study group	11-point VRS
Davis et al. 2006 [22]	RCT	Humans	Lap Roux-en-Y gastric bypass	Control- standard CO₂	Group 1-heated CO₂	33 (11 each group)	Standard CO₂	11	No difference in postoperative pain	VAS
				Group 1- heated insufflator tube set (Stryker)	Group 2-humidified CO₂
				Group 2,3- Insuflow (MR 860, Fisher & Paykel Healthcare, Auckland, New Zealand)	Group 3-heated+ humidified CO₂
Sammour et al. 2010 [11]	RCT	Humans	Elective laparoscopic colonic resections	Insuflow (MR 860, Fisher & Paykel Healthcare)	Warmed (37°C) + humidified (98% RH) CO₂	41	Standard CO₂ (19°C, 0% RH)	41	No difference in postoperative pain	(1) VAS
Sammour et al. 2010 [11]	RCT	Humans	Elective laparoscopic colonic resections	Insuflow (MR 860, Fisher & Paykel Healthcare)	Warmed (37°C) + humidified (98% RH) CO₂	41	Standard CO₂ (19°C, 0% RH)	41	No difference in postoperative pain	(2) MEDD
Mouton et al. 1999 [33]	RCT	Humans	Elective laparoscopic cholecystectomy	Modified LINS-1000 Insufflator (Cook Medical Technology, Queensland, Australia)	Warmed (37°C) + humidified (90% RH) CO₂	20	Standard CO₂ (21°C, 0% RH)	20	Humidified + warmed CO₂ group had significantly less postoperative pain at 6 hours, at 1st, 2nd, 3rd day postoperatively and on follow-up on day 10	Analogue pain score
Mouton et al. 1999 [33]	RCT	Humans	Elective laparoscopic cholecystectomy		Warmed (37°C) + humidified (90% RH) CO₂	20	Standard CO₂ (21°C, 0% RH)	20	Mean time to return to normal activity was significantly lower in warmed, humidified group (5.9 days vs. 10.9 days)	Analogue pain score
Farley et al. 2004 [23]	RCT	Humans	Elective laparoscopic cholecystectomy	Insuflow device (Lexion Medical)	Warmed (35°C), humidified (95% RH) CO₂	49	Standard CO₂	52	No difference in postoperative pain during admission	(1) Likert Scale (010)
Farley et al. 2004 [23]	RCT	Humans	Elective laparoscopic cholecystectomy	Insuflow device (Lexion Medical)	Warmed (35°C), humidified (95% RH) CO₂	49	Standard CO₂	52	However, significant difference in pain on follow-up at week 2 (Likert Scale 1.0 vs. 0.3, P = 0.02)	(2) Morphine Equivalent Score (use of analgesia)
Saad et al. 2000 [34]	RCT	Humans	Elective laparoscopic cholecystectomy	Flow Therme, (WISAP, Sauer-lach, Germany)	Warmed (37°C) CO₂	10	Standard (21°C) CO₂	10	No difference in postop pain (visual analogue score + analgesia usage)	(1) VAS
Saad et al. 2000 [34]	RCT	Humans	Elective laparoscopic cholecystectomy	Flow Therme, (WISAP, Sauer-lach, Germany)	Warmed (37°C) CO₂	10	Standard (21°C) CO₂	10		(2) Postoperative ibuprofen usage
Beste et al. 2006 [39]	RCT	Humans	Laparoscopic gynecological procedures: tubal ligation, salpingo-oo-phorectomy, cystectomy, ablation of endometriosis, adhesiolysis, che-mopertubation	Insuflow device (Lexion Medical)	Warmed, humidified CO₂	47	Warmed, dry CO₂	42	Humidified CO₂ reduced postoperative pain and requirements for analgesia	Total morphine equivalent
Kissler et al. 2004 [40]	RCT	Humans	Laparoscopic gynecological procedures	Laparo-CO₂-pneu 2232 (Wolf, Knit-tlingen, Germany)	Warmed, humidified CO₂	30	Cold, dry CO₂	-	Significant differences in postoperative pain and analgesia requirements	(1) Total analgesia requirement
					Warmed, dry CO₂	30		30	Non-significant tendency towards less pain and higher patient satisfaction in patients who received cold, dry CO₂	(2) VAS
					Warmed, dry CO₂	30		30		(3) Patient satisfaction
Manwaring et al. 2008 [25]	RCT	Humans	Laparoscopic gynecological procedures	Insuflow (MR 860, Fisher & Paykel Healthcare)	Heated (37°C), humidified (100% RH) CO₂	30	Cold, dry CO₂	30	No difference in postoperative pain or analgesia requirements	VAS
Champion and Williams 2006 [36]	RCT	Humans	Laparoscopic Roux-en-Y gastric bypass	Insuflow device (Lexion Medical)	Heated (35°C), humidified (95% RH) CO₂	25	Cold, dry CO₂	25	No difference in analgesia requirement or abdominal pain; significant difference in shoulder pain at 18 hours (but not at 6, 12, 24, or 48 hours)	VAS
Yu et al. 2013 [26]	RCT	Humans	Laparoscopic appendectomy	Insuflow (MR 860, Fisher & Paykel Healthcare)	Heated (37°C), humidified (98% RH) CO₂	97	Cold (20-21°C), dry (0% RH) CO₂	98	No difference in quantity of analgesia required	(1) MEDD
Yu et al. 2013 [26]	RCT	Humans	Laparoscopic appendectomy	Insuflow (MR 860, Fisher & Paykel Healthcare)	Heated (37°C), humidified (98% RH) CO₂	97	Cold (20-21°C), dry (0% RH) CO₂	98	No difference in pain on visual analogue score	(2) VAS
Savel et al. 2005 [32]	RCT	Humans	Laparoscopic Roux-en-Y gastric bypass	Insuflow device (Lexion Medical)	Heated (35°C), humidified (95% RH) CO₂	15	Cold, dry CO₂	15	No difference in quantity of morphine required postoperatively	(1) Total morphine use
Savel et al. 2005 [32]	RCT	Humans	Laparoscopic Roux-en-Y gastric bypass	Insuflow device (Lexion Medical)	Heated (35°C), humidified (95% RH) CO₂	15	Cold, dry CO₂	15	No difference in visual analogue score	(2) VAS
Klugsberger et al. 2014 [27]	RCT	Humans	Laparoscopic cholecystectomy	Optitherm device ptorz, Tuttlingen, Germany)	Heated, humidified CO₂	81	Cold, dry CO₂	67	Lower visual analogue score in the heated, humidified CO₂ group at postoperative day 0	(1) Total analgesia requirement
Klugsberger et al. 2014 [27]	RCT	Humans	Laparoscopic cholecystectomy	Optitherm device ptorz, Tuttlingen, Germany)	Heated, humidified CO₂	81	Cold, dry CO₂	67	No difference in total analgesia required	(2) VAS
Herrmann and De Wilde 2015 [28]	RCT	Humans	Laparoscopic assisted vaginal hysterectomy	Insuflow (MR 860, Fisher & Paykel Healthcare)	Heated (37°C), humidified (98% RH) CO₂	48	Cold (20-21°C), dry (0% RH) CO₂	49	Lower total morphine consumption in warmed, humidified CO₂ group (P = 0.02)	(1) Total morphine consumption
Herrmann and De Wilde 2015 [28]	RCT	Humans	Laparoscopic assisted vaginal hysterectomy	Insuflow (MR 860, Fisher & Paykel Healthcare)	Heated (37°C), humidified (98% RH) CO₂	48	Cold (20-21°C), dry (0% RH) CO₂	49		(2) VAS
Benavides et al. 2009 [41]	RCT	Humans	Laparoscopic gastric banding	Insuflow device (Lexion Medical)	Heated (35°C), humidified (95% RH) CO₂	38	Cold, dry CO₂	35	Significantly less postoperative pain in warmed, humidified CO₂ group than in the cold, dry CO₂ and heated, dry CO₂ groups (P < 0.01, P < 0.05)	MEDD
Benavides et al. 2009 [41]	RCT	Humans	Laparoscopic gastric banding	Insuflow device (Lexion Medical)	Heated (35°C), humidified (95% RH) CO₂	38	Heated, dry CO₂	40		MEDD

RCT, randomized controlled trial; RH, relative humidity; VAS, visual analogue score; MEDD, morphine equivalent daily dose; VRS, verbal rating scale.

Table 4.

Effects of warmed, humidified carbon dioxide on respiratory function

Study	Study type	Humans/animals	Operation	Device used	Study group		Control group		Results
Study	Study type	Humans/animals	Operation	Device used	Treatment	No.	Treatment	No.	Results
Bashirov et al. 2007 [43]	Prospective, non-RCT	Animals (pigs)	Pneumoperitoneum creation	Model Ref L-70 NI Hotline (Sims-Smith Industries Medical Systems, Rockland, MA, USA)	Warmed CO₂ groups	6 (7°C), 6 (22°C), 6 (37°C)	No CO₂ pneumoperitoneum	6	Increase in temperature of CO₂ resulted in increased peritoneal CO₂ absorption, increased PaCO₂ and a greater decrease in pH (7.44 vs. 7.26)
Uzunkoy et al. 2006 [44]	RCT	Humans	Elective lap cholecystectomy	H-500 fluid warmer (Level 1 Technologies, Inc.,Rockland, MA, USA)	Warmed CO₂ (37°C)	15	Cold CO₂ (21°C)	15	Pulmonary function test performed 12 hours after the operation found lung function was significantly better in those receiving warmed CO₂ (FVC, FEV₁, PEF)
Bergström et al. 2008 [42]	Prospective, non-RCT	Animals (pigs)	Pneumoperitoneum creation	Laparoscopic insufflator (Storz, Tuttlingen, Germany)	CO₂	10	Helium	10	CO₂ pneumoperitoneum resulted in significantly lower peritoneal pH (6.4 vs. 7.5, P = 0.001)
Bergström et al. 2008 [42]	Prospective, non-RCT	Animals (pigs)	Pneumoperitoneum creation	Laparoscopic insufflator (Storz, Tuttlingen, Germany)	CO₂	10	Helium	10	However, very minimal changes in arterial pH (7.43 vs. 7.49, P = 0.004) were found, with no clinical significance
Ozgonul et al. 2007 [24]	RCT	Humans	Elective laparoscopic cholecystectomy	H-500 fluid warmer (Level 1 Technologies, Inc., MA, USA)	Warmed (37°C) CO₂	31	Cold (21°C) CO₂	31	No significant difference in arterial pH, pCO₂, or HCO₃^-

RCT, randomized controlled trial; RH, relative humidity; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; PEF, peak expiratory flow.

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