Association between intraoperative end-tidal carbon dioxide and postoperative nausea and vomiting in gynecologic laparoscopic surgery

Gynecologic laparoscopic surgery has a high incidence of postoperative nausea and vomiting (PONV). Studies suggest that low intraoperative end-tidal carbon dioxide (EtCO2) is associated with an increased incidence of PONV, but the results have not been consistent among studies. This study investigated the association between intraoperative EtCO2 and PONV in patients undergoing gynecologic laparoscopic surgeries under general anesthesia. This retrospective cohort study involved patients who underwent gynecologic laparoscopic surgeries under general anesthesia at Kyoto University Hospital. We defined low EtCO2 as a mean EtCO2 of < 35 mmHg. Multivariable modified Poisson regression analysis examined the association between low EtCO2 and PONV during postoperative two days and the postoperative length of hospital stay (PLOS). Of the 739 patients, 120 (16%) had low EtCO2, and 430 (58%) developed PONV during postoperative two days. There was no substantial association between low EtCO2 and increased incidence of PONV (adjusted risk ratio: 0.96; 95% confidence interval [CI] 0.80–1.14; p = 0.658). Furthermore, there was no substantial association between low EtCO2 and prolonged PLOS (adjusted difference in PLOS: 0.13; 95% CI − 1.00 to 1.28; p = 0.816). Intraoperative low EtCO2, specifically a mean intraoperative EtCO2 below 35 mmHg, was not substantially associated with either increased incidence of PONV or prolonged PLOS.

The incidence of postoperative nausea and vomiting (PONV) remains high despite considerable improvements in treatment over the past few decades. PONV is nausea or vomiting in the first 24-48 h after surgery 1 . Wellestablished risk factors for PONV include female gender, history of PONV or motion sickness, nonsmoking, and postoperative opioid use 2 . The risk of PONV is up to 80% in high-risk patients with all four risk factors 3 . The incidence of PONV is particularly high among patients undergoing gynecologic laparoscopic surgery 4 . PONV is associated with decreased patient satisfaction 5 , increased postoperative complications 6 , and longer postoperative length of hospital stay (PLOS) 7 .
Hypocapnia may be associated with decreased systemic vasodilation 8 and may cause tissue ischemia 9 , intestinal ischemia 10 , and cerebral ischemia 11,12 . Animal studies have reported that serotonin levels in the brain, a highly emetogenic substance, increase with intestinal 13,14 and cerebral ischemia 15 . Based on the hypothesis associating hypocapnia with increased serotonin levels due to intestinal and cerebral ischemia, studies associate intraoperative hypocapnia with increased incidence of PONV 16,17 . However, the relationship between hypocapnia and PONV remains unclear because some studies had conflicting results 18,19 .
Therefore, we examined the association between intraoperative end-tidal carbon dioxide (EtCO 2 ) and the incidence of PONV in patients undergoing gynecologic laparoscopic surgery. We adjusted for important confounding factors and assessed the effects of the duration and severity of low EtCO 2 exposure. Data collection. We collected data from the anesthesia information management and electronic medical record systems and constructed the Kyoto-IMPACT database. EtCO 2 was continuously measured using a sidestream gas analyzer (GF-220R Multigas/Flow Unit, Nihon Kohden ® , Japan) that was automatically uploaded to the anesthesia information management system every 1960s. Intraoperative EtCO 2 was the mean EtCO 2 level from skin incision to skin closure. We removed EtCO 2 levels lower than 20 mmHg as artifacts (EtCO 2 during aspiration or position change). The definitions of variables, including the minimum and maximum EtCO 2 levels, can be found in Supplementary Data Table S1. We collected data on PONV by reviewing all clinical data contained in the electronic medical records. Ward nurses assessed the presence of nausea and vomiting at least twice daily. We defined PONV as one or more episodes of nausea or vomiting during the first 2 days after surgery and vomiting as one or more episodes of vomiting during the same period.

Exposure.
To determine how EtCO 2 affects PONV, we defined exposure by calculating the dose, time, and cumulative effects of EtCO 2 . First, we evaluated the dose effects of EtCO 2 using the mean EtCO 2 . Next, we divided the patients into two groups based on the cutoff EtCO 2 level of 35 mmHg proposed by Way and Hill 22 . We defined low EtCO 2 as a mean EtCO 2 lower than 35 mmHg and normal EtCO 2 as a mean EtCO 2 greater than or equal to 35 mmHg. We classified the patients in either of these groups and used them as the primary exposure for further analysis. Additionally, we categorized the mean EtCO 2 levels into quartiles (i.e., < 35, 35-37, 37-40, and ≥ 40 mmHg) because the relationship between EtCO 2 and PONV might not be linear. To assess the effects of the duration and severity of low EtCO 2 exposure, we determined the time effect based on the minutes when the EtCO 2 level was below 35 mmHg and measured the cumulative effect as the area with EtCO 2 levels below the threshold of 35 mmHg for each patient. Furthermore, we categorized the minutes and area under the threshold of an EtCO 2 level of 35 mmHg into quartiles; the lowest quartile was the reference category.
Outcomes. The primary outcome in this study was PONV, defined as PONV for two days postoperatively.
The secondary outcomes were nausea for two days postoperatively, vomiting for two days postoperatively, PONV for 3-7 days postoperatively, and PLOS. We defined PLOS as the duration of hospital stay after surgery for patients who survived until discharge.
Statistical analysis. We analyzed the relationship between intraoperative EtCO 2 and PONV before data collection. We used the Mann-Whitney test for group comparisons, and continuous variables were expressed as the median and interquartile range (IQR), and categorical variables were expressed as counts and percentages (%).
First, we performed modified Poisson regression analysis with robust variance to calculate the risk ratio for low EtCO 2 (mean EtCO 2 of less than 35 mmHg) and PONV, with the reference category of normal EtCO 2 (mean EtCO 2 ≥ 35 mmHg) 23 . Additionally, we calculated the risk ratios of the mean EtCO 2 level in the first quartile (mean EtCO 2 of less than 35 mmHg), third quartile (mean EtCO 2 of 37-40 mmHg), and fourth quartile (mean EtCO 2 of more than or equal to 40 mmHg). The second quartile (mean EtCO 2 of 35-37 mmHg) was the reference category because it was considered normocapnia. Furthermore, we examined the time and cumulative effects of EtCO 2 by evaluating how each quartile affected PONV, with the first quartile (with minutes under an EtCO 2 of 35 mmHg and the area below the threshold of 35 mmHg) being the reference category. We created a model using the covariates previously used to demonstrate the relationship between intraoperative EtCO 2 and PONV. The model included age, smoking history, surgery duration, body mass index (BMI), total intravenous anesthesia (TIVA), mean arterial pressure (MAP), intraoperative fentanyl use, postoperative fentanyl dose for intravenous patient-controlled analgesia (IVPCA), the use of prophylactic antiemetics, the addition of droperidol to postoperative IVPCA, American Society of Anesthesiologists Physical Status (ASAPS), malignancy, and emergency surgery. Additionally, a modified Poisson regression model investigated whether the dose, time, or cumulative effect of EtCO 2 affects postoperative nausea two days, vomiting two days, and PONV 3-7 days postoperatively, adjusting for the aforementioned models. To further evaluate the relationship between EtCO 2 and PLOS, we performed a linear regression analysis adjusting for the possible covariates in the aforementioned models. www.nature.com/scientificreports/ The relationship between intraoperative EtCO 2 and PONV may depend on patient and surgical characteristics. Therefore, we performed a subgroup analysis to assess this potential heterogeneity. We used the modified Poisson regression model for the following subgroups: (1) age (≥ 50/ < 50 years), (2) malignancy (yes/no), (3) smoking history (ever smoked/never smoked), (4) duration of surgery (≥ 4/ < 4 h), (5) TIVA (yes/no), (6) the use of intraoperative prophylactic antiemetics (yes/no), (7) postoperative fentanyl dose for IVPCA (≥ 20/ < 20 μg/h) and (8) addition of droperidol in IVPCA (yes/no). We calculated the crude risk ratio of PONV in each subgroup and examined the interaction between subgroups and the mean of intraoperative EtCO 2 .
To maximize statistical power, all eligible patients enrolled in the Kyoto-IMPACT database since 2012, when postoperative nausea and vomiting began to be recorded in their current form, were included in the analysis.
To determine the study power, we estimated that approximately 120 laparoscopic gynecologic surgeries were performed annually at Kyoto University Hospital, with 720 surgeries performed over six years. The risk ratio was 1.53, the incidence of PONV was 40% 4 , and the proportion of low EtCO 2 was 50% 24 , giving an estimated power of 80%. The rate of missing data was 0.04%, so we conducted a complete case analysis. All statistical tests were two-tailed. We used Stata/SE 15.1 (StataCorp LLC, College Station, Texas, USA) to conduct all statistical analyses.
Ethics approval. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Certified Review Board of Kyoto University, Kyoto, Japan (Chairperson Prof. Shinji Kosugi) approved the protocol for this study (approval no.: R1272-3, January 23, 2020). Additionally, the informed consent requirement was waived due to this study's retrospective nature.

Discussion
In this retrospective cohort study, mean of intraoperative EtCO 2 was not substantially associated with increased incidence of PONV and prolonged PLOS in patients undergoing gynecologic laparoscopic surgery. Furthermore, we examined the effects of the duration and severity of low EtCO 2 exposure using the time and cumulative effects of EtCO 2 but found no clear association. Two small studies have studied whether there is an association between low EtCO 2 and PONV 17,18 , but the results have been inconsistent. A randomized controlled trial (RCT) involving 75 patients who underwent percutaneous nephrolithotripsy reported that the hypercapnia management group had less PONV 17 . However, a prospective observational study involving 90 pediatric patients who underwent inguinal surgery has reported that elevated levels of EtCO 2 were an independent predictor of PONV 18 . As the aforementioned studies have different types of surgery and patient backgrounds, their results might not be directly applicable to patients undergoing gynecologic laparoscopic surgery.
Furthermore, three studies on patients who had undergone gynecologic surgery have shown inconsistent results. An RCT involving 387 patients who underwent gynecologic laparoscopic surgery reported mild hypercapnia management did not reduce PONV 19 . That study did not evaluate the effects of low EtCO 2 (mean EtCO 2 level of less than 35 mmHg). Alternatively, a retrospective cohort study involving 146 patients undergoing open gynecologic surgery has reported that the minimum EtCO 2 level of ≤ 31 mmHg lasting longer than 10 min was associated with an increased incidence of PONV 16 . Still, that study only evaluated the effects of extremely low EtCO2 levels (mean EtCO2 of ≤ 31 mmHg). It did not evaluate the dose and time effects of low EtCO2 below the commonly defined EtCO 2 level of 35 mmHg. Furthermore, an RCT involving 60 patients undergoing gynecologic laparoscopic surgery reported that low EtCO 2 management reduced the incidence of nausea, PONV score, and the use of rescue antiemetics 25 ; these results differed from the two aforementioned studies. Management to keep Table 3. Multivariable analysis of the relationship between EtCO 2 and secondary outcomes. EtCO 2 end-tidal carbon dioxide, POD 2 postoperative day 2, POD 3-7 postoperative days 3 to 7, PONV postoperative nausea and vomiting, CI confidence interval.
Number of events (%) Crude risk ratio (95% CI) P-value Adjusted risk ratio (95% CI) P-value www.nature.com/scientificreports/ EtCO2 at a low level may avoid PONV by inhibiting cerebral vasodilation, preventing increased intracranial pressure caused by the pneumoperitoneum and Trendelenburg position, which would not affect the ischemiasensitive vestibular system. However, this study may have an internal validity problem in which it was not blinded. Furthermore, it had a generalizability problem because it excluded patients with severe systemic diseases, ASAPS-III patients, those with a history of PONV motion sickness, and smokers.
Considering that the results of previous studies are inconsistent, the evidence on the association between intraoperative low EtCO 2 and PONV remains limited. Therefore, we conducted this study, which involved the largest cohort from real-world data, which provided a sufficient sample size, resulting in a statistical power of 80% to detect a risk ratio of 1.53. Furthermore, adjusting for important confounders, such as blood pressure, age, and intraoperative fentanyl use, and assessing the dose-effect of low EtCO 2 (mean EtCO 2 of less than 35 mmHg) and the effects of the duration and severity of low EtCO 2 exposure, we could not demonstrate an association between low EtCO 2 and PONV. Even extremely low EtCO 2 , defined as EtCO 2 of less than 31 mmHg sustained for more than 10 min 16 , failed to show an association with PONV (Supplemental Data Table S2).
This study has several strengths. First, it investigated the association between the effects of EtCO 2 and PONV and PLOS, the dose effects of EtCO 2 (mean level of less than 35 mmHg) and the effects of the duration (time effects, long-term exposure to EtCO 2 of less than 35 mmHg) and severity (cumulative effects, area under the threshold of EtCO 2 of less than 35 mmHg). Among the three previous studies that examined the association between intraoperative low EtCO 2 and PONV, which only evaluated the dose effects [17][18][19] , only one study evaluated the association between the time effects of low EtCO 2 and PONV 16 . Second, this study adjusted for potential confounding factors that were not adjusted in previous studies, such as blood pressure, age, and intraoperative fentanyl use, using a modified Poisson regression model. Third, this was a large study with sufficient sample size. All previous studies had small sample sizes, so the number of confounding factors that can be adjusted is limited.
This study has several limitations. First, we extracted information on the presence of nausea and vomiting from the records of assessments performed by the ward nurses at least twice a day, so PONV occurring at other times may have been overlooked. However, we thought that moderate to severe PONV reported voluntarily by patients or required treatment was fully measured. Second, we did not consider the PaCO 2 -EtCO 2 gap to calibrate EtCO 2 levels using PaCO 2 levels. Thus, we underestimated the effects of low EtCO 2 and overestimated the effects of hypercapnia. However, since PaCO 2 is usually 2-5 mmHg higher than EtCO 2 in healthy populations, this was considered a limited effect. Last, there may be unknown and unmeasured confounding factors, such as potential reasons for anesthesiologists to target a specific EtCO 2 level, missing data on intraoperative ventilation parameters, and PONV risk factors among patient factors is, history of PONV and motion sickness. www.nature.com/scientificreports/

Conclusion
Intraoperative low EtCO 2 (mean EtCO 2 level less than 35 mmHg) was not substantially associated with either increased incidence of PONV or prolonged PLOS in patients undergoing gynecologic laparoscopic surgery.