Prospective randomized clinical trial comparing nitrous oxide and carbon dioxide pneumoperitoneum for laparoscopic surgery. Metabolic and immunologic consequences of laparoscopy with helium or carbon dioxide insufflation: a randomized clinical study. Comparison of N2O and CO2 pneumoperitoneums during laparoscopic cholecystectomy with special reference to postoperative pain. Comparative stress hormone changes during helium versus carbon dioxide laparoscopic cholecystectomy.
Recent publications demonstrating the safety and advantages of N2O for pneumoperitoneum (PP) prompted us to reconsider N2O as an agent for PP in general surgical laparoscopy. The purpose of this prospective, double-blind, randomized clinical trial was to determine whether N2O PP has any benefits over CO2 PP.
                One hundred three patients received N2O (group I, n = 52) or CO2 (group II, n = 51) PP for elective laparoscopic surgery. Heart rate, mean arterial blood pressure, end-tidal CO2, minute ventilation, and O2 saturation were recorded before PP, during PP, and in the recovery room. Postoperative pain medication use was recorded. Pain was assessed by means of visual analog scale (VAS) at postoperative hours 2 and 4, and on day 1.
                There were no differences between groups I and II in patient age, gender, weight, anesthesia risk (American Society of Anesthesiologists Score > 2), operative time, duration of PP, or length of hospital stay. Mean end-tidal CO2 increase under anesthesia was greater in group II than group I (3.0 versus 0.5 mmHg, p < 0.001) despite a greater mean intraoperative increase in minute ventilation in group II than group I (0.7 versus -0.2 L/min p < 0.001). The patients who had N2O PP had less pain 2 hours postoperatively (VAS: 4.9 versus 5.7, p <0.05), 4 hours postoperatively (VAS: 3.3 versus 5.1, p < 0.01), and 1 day postoperatively (VAS: 1.7 versus 3.5, p < 0.01) than patients who had CO2 PP. Postoperative narcotic or ketorolac use was not statistically different between groups. There were no adverse events related to either N2O or CO2 pneumoperitoneum.
                These results suggest that the use of N2O PP has sufficient advantages over CO2 that it should be considered as the standard agent for therapeutic PP. Previous studies using animal models have demonstrated that carbon dioxide (CO2) pneumoperitoneum during laparoscopy is associated with adverse physiological, metabolic, immunological and oncological effects, and many of these problems can be avoided by the use of helium insufflation. The present study was performed in patients to compare the effect of helium and CO2 insufflation on intraperitoneal markers of immunological and metabolic function.
                Eighteen patients undergoing elective upper gastrointestinal laparoscopic surgery were randomized to have insufflation achieved by using either helium (n = 8) or CO2 (n = 10) gas. Intraperitoneal pH was monitored continuously during surgery, and peritoneal macrophage function was determined by harvesting peritoneal macrophages at 5 min and 30 min after commencing laparoscopy, and then assessing their ability to produce tumour necrosis factor-alpha (TNF-alpha), and their phagocytic function.
                Carbon dioxide laparoscopy was associated with a lower intraperitoneal pH at the commencement of laparoscopy, although this difference disappeared as surgery progressed. The production of TNF-alpha was better preserved by CO2 laparoscopy, but the insufflation gas used did not affect macrophage phagocytosis. Patients undergoing helium laparoscopy required less postoperative analgesia.
                The choice of insufflation gas can affect intraperitoneal macrophage function in the clinical setting, and possibly acid-base balance. The present study suggested no immunological advantages for the clinical use of helium as an insufflation gas. The outcomes of the present study, however, are different to those obtained from previous laboratory studies and further research is needed to confirm this outcome. To study the possible benefits of N2O pneumoperitoneum, 40 patients scheduled for laparoscopic cholecystectomy for symptomatic cholelithiasis were randomized into either CO2-induced (n = 20) or N2O-induced (n = 20) pneumoperitoneum groups. The intensity of postoperative pain was assessed by the patients themselves using an visual analogue pain score scale. CO2 insufflation caused respiratory acidosis. The total amount of anesthetic enflurane needed was lower in the N2O than in the CO2 group (p < 0.041). The N2O group experienced less pain 1 hour (p < 0.040) and 6 hours (p < 0.017) postoperatively and the next morning. Serum cortisol and plasma adrenaline concentrations in the N2O group did not differ from those in the CO2 group. Patients with N2O pneumoperitoneum seem to have less pain without the side effects caused by CO2. The N2O pneumoperitoneum is a good alternative to the CO2 pneumoperitoneum, especially for prolonged laparoscopic operations in patients with chronic cardiopulmonary diseases. Laparoscopic surgery has been termed minimally invasive surgery by advocates of this technology. It has been demonstrated previously that using carbon dioxide for insufflation produces a respiratory acidosis due to transperitoneal absorption of gas. Insufflation with helium does not create this acidosis. We questioned whether laparoscopic surgery would elicit a stress response and whether the absence of acidosis with helium might prevent or reduce the levels of stress hormones. Sixteen female patients undergoing laparoscopic cholecystectomy were randomly assigned to helium (n = 8) or CO2 (n = 8) insufflation. Serum cortisol, epinephrine, and norepinephrine were measured preoperatively, after induction of anesthesia but before insufflation, at 45 min of surgery, and after desufflation. There were increases in epinephrine, norepinephrine, plasma cortisol, and urine cortisol at 45 min and at the conclusion of the procedure over the preoperative value. With ANOVA, each variable showed significant increases from preoperative values, at 45 min, and at the end of the case. Except for the increased epinephrine when helium was used, there were no significant differences in the other variables between helium and CO2. Laparoscopic cholecystectomy produces significant increases in stress hormone levels. Prevention of acidosis with helium insufflation does not appear to protect against increases in stress hormones. Epinephrine levels with helium insufflation are higher than with CO2, and elevations in stress hormones suggest that laparoscopic cholecystectomy is not physiologically minimally invasive.
1. Nitrous oxide pneumoperitoneum during laparoscopic abdominal surgery appears to decrease post-operative pain in patients with low anaesthetic risk.
2. Helium pneumoperitoneum decreases the cardiopulmonary changes associated with laparoscopic abdominal surgery. However, this did not translate into any clinical benefit over carbon dioxide pneumoperitoneum in patients with low anaesthetic risk. 
3. The safety of nitrous oxide and helium pneumoperitoneum has yet to be established. More randomized controlled trials on this topic are needed. Future trials should include more patients with high anaesthetic risk. Furthermore, such trials need to use adequate methods to reduce the risk of bias.