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

Abstract

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.

Introduction

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 surgery1. Well-established risk factors for PONV include female gender, history of PONV or motion sickness, nonsmoking, and postoperative opioid use2. The risk of PONV is up to 80% in high-risk patients with all four risk factors3. The incidence of PONV is particularly high among patients undergoing gynecologic laparoscopic surgery4. PONV is associated with decreased patient satisfaction5, increased postoperative complications6, and longer postoperative length of hospital stay (PLOS) 7.

Hypocapnia may be associated with decreased systemic vasodilation8 and may cause tissue ischemia9, intestinal ischemia10, and cerebral ischemia11,12. Animal studies have reported that serotonin levels in the brain, a highly emetogenic substance, increase with intestinal 13,14 and cerebral ischemia15. Based on the hypothesis associating hypocapnia with increased serotonin levels due to intestinal and cerebral ischemia, studies associate intraoperative hypocapnia with increased incidence of PONV16,17. However, the relationship between hypocapnia and PONV remains unclear because some studies had conflicting results18,19.

Therefore, we examined the association between intraoperative end-tidal carbon dioxide (EtCO2) 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 EtCO2 exposure.

Methods

Ethics

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.

Study design, setting, and population

In this single-center retrospective cohort study, we used data from the Kyoto University Hospital IMProve Anaesthesia Care and ouTcomes (Kyoto-IMPACT) database. The Kyoto-IMPACT database aims to clarify the relationship between intraoperative respiratory and cardiovascular parameters and postoperative outcomes. We consecutively selected patients who underwent surgery under the care of anesthesiologists at Kyoto University Hospital (1121 beds). We have published several studies using the Kyoto-IMPACT database20,21. We included adult female patients aged 18 years or older who underwent gynecologic laparoscopic surgery (i.e., adnexal surgery and/or hysterectomy) at Kyoto University Hospital between January 2012 and December 2017. The gynecologic laparoscopic surgery population was selected because the predicted incidence rate of PONV in this population is 30–40%, assumed to be a medium risk of PONV4. The exclusion criteria were as follows: (1) patients with postoperative intensive care unit admission; (2) those who underwent multiple surgeries within one week during the study period; (3) those who received epidural anesthesia; (4) those with missing smoking data, and (5) those with missing intraoperative EtCO2 data.

Data collection

We collected data from the anesthesia information management and electronic medical record systems and constructed the Kyoto-IMPACT database. EtCO2 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 EtCO2 was the mean EtCO2 level from skin incision to skin closure. We removed EtCO2 levels lower than 20 mmHg as artifacts (EtCO2 during aspiration or position change). The definitions of variables, including the minimum and maximum EtCO2 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 EtCO2 affects PONV, we defined exposure by calculating the dose, time, and cumulative effects of EtCO2. First, we evaluated the dose effects of EtCO2 using the mean EtCO2. Next, we divided the patients into two groups based on the cutoff EtCO2 level of 35 mmHg proposed by Way and Hill22. We defined low EtCO2 as a mean EtCO2 lower than 35 mmHg and normal EtCO2 as a mean EtCO2 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 EtCO2 levels into quartiles (i.e., < 35, 35–37, 37–40, and ≥ 40 mmHg) because the relationship between EtCO2 and PONV might not be linear. To assess the effects of the duration and severity of low EtCO2 exposure, we determined the time effect based on the minutes when the EtCO2 level was below 35 mmHg and measured the cumulative effect as the area with EtCO2 levels below the threshold of 35 mmHg for each patient. Furthermore, we categorized the minutes and area under the threshold of an EtCO2 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 EtCO2 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 EtCO2 (mean EtCO2 of less than 35 mmHg) and PONV, with the reference category of normal EtCO2 (mean EtCO2 ≥ 35 mmHg)23. Additionally, we calculated the risk ratios of the mean EtCO2 level in the first quartile (mean EtCO2 of less than 35 mmHg), third quartile (mean EtCO2 of 37–40 mmHg), and fourth quartile (mean EtCO2 of more than or equal to 40 mmHg). The second quartile (mean EtCO2 of 35–37 mmHg) was the reference category because it was considered normocapnia. Furthermore, we examined the time and cumulative effects of EtCO2 by evaluating how each quartile affected PONV, with the first quartile (with minutes under an EtCO2 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 EtCO2 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 EtCO2 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 EtCO2 and PLOS, we performed a linear regression analysis adjusting for the possible covariates in the aforementioned models.

The relationship between intraoperative EtCO2 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 EtCO2.

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 EtCO2 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.

Results

Baseline patient characteristics

Of the 790 patients who underwent laparoscopic gynecologic surgery between 2008 and 2017, 774 met our inclusion criteria, and we included 739 in the complete case analysis (Fig. 1). Low EtCO2 (defined as the mean EtCO2 level of less than 35 mmHg) occurred in 120 patients (16%), whereas PONV occurred in 430 patients (58%). Table 1 shows the overall baseline characteristics of the study participants. The median EtCO2 values were 37 mmHg (IQR, 35–40 mmHg) overall, 33 mmHg (IQR, 32–34 mmHg) in patients with low EtCO2, and 38 mmHg (IQR, 36–40 mmHg) in patients with normal EtCO2.

Figure 1
figure 1

Flowchart of this study. We consecutively included patients aged 18 years or older who underwent laparoscopic gynecologic surgery under general anesthesia at Kyoto University Hospital from 2012 to 2017. Subsequently, cases that met the eligibility criteria were selected and analyzed as complete cases.

Table 1 Patient characteristics (n = 739).

Association between low EtCO2and PONV

Table 2 shows the study’s main results. PONV occurred in 67 (55.83%) of the 120 patients in the low EtCO2 group, whereas 363 (58.64%) of the 619 patients were in the normal EtCO2 group. We could not find a substantial association between low EtCO2 and PONV (crude risk ratio, 0.95; 95% confidence interval [CI] 0.80–1.13; p = 0.577) (adjusted risk ratio, 0.96; 95% CI 0.80–1.14; p = 0.658). For further analysis, we divided EtCO2 into quartiles. The second quartile (mean EtCO2 35–37 mmHg) was the reference, and the definition of low EtCO2 was the lowest quartile of mean EtCO2 (mean EtCO2 of less than 35 mmHg). The second (mean EtCO2 of 35–37 mmHg), third (mean EtCO2 37–40 mmHg), and fourth (mean EtCO2 ≥ 40 mmHg) quartiles of mean EtCO2 values were not substantially associated with increased incidence of PONV, with low EtCO2 (first quartile [mean EtCO2 of less than 35 mmHg]) as the reference category.

Table 2 Multivariable analysis of the relationship between EtCO2 and POD2-PONV.

For the time effects of EtCO2, compared with short-term exposure (first quartile of exposure time to EtCO2 of less than 35 mmHg, 0–11 min), long-term exposure to EtCO2 levels of less than 35 mmHg (fourth quartile of exposure time to EtCO2 of less than 35 mmHg, 67–613 min) was not substantially associated with increased incidence of PONV (crude risk ratio, 1.09; 95% CI 0.91–1.30; p = 0.323) (adjusted risk ratio, 1.03; 95% CI 0.87–1.22; p = 0.700).

Finally, for the cumulative effects of EtCO2, the fourth quartile of the area under the EtCO2 threshold of 35 mmHg (108–2213) was not substantially associated with increased incidence of PONV compared with the first quartile (0–7) (crude risk ratio, 1.08; 95% CI 0.91–1.29; p = 0.346) (adjusted risk ratio, 1.03; 95% CI 0.87–1.23; p = 0.654).

Association between low EtCO2 and nausea and vomiting 2 days postoperatively and PONV 3–7 day postoperatively

The adjusted risk ratio for the low EtCO2 group (mean EtCO2 of less than 35 mmHg) did not indicate an association between low EtCO2 and nausea and vomiting two days postoperatively or PONV 3–7 days postoperatively (Table 3), with normal EtCO2 being the reference category.

Table 3 Multivariable analysis of the relationship between EtCO2 and secondary outcomes.

Association between low EtCO2 and PLOS

The median PLOS was 6 days (IQR, 5–8 days) (Table 4). The median PLOS in patients with low EtCO2 was not different from that in patients with normal EtCO2 (6 days [IQR, 5–8 days] vs. 6 days (IQR, 5–7 days); p = 0.782). Linear regression analysis showed that low EtCO2 was not likely to be associated with PLOS (crude adjusted difference in PLOS, − 0.15; 95% CI − 1.29 to 0.97; p = 0.783) (adjusted difference in PLOS, − 0.13; 95% CI − 1.00 to 1.28; p = 0.816).

Table 4 Multivariable analysis of the relationship between EtCO2 and PLOS.

Subgroup analysis

Subgroup analyses included age (≥ 50/< 50 years), malignancy, smoking history, duration of surgery (≥ 4 h/< 4 h), TIVA, the use of intraoperative prophylactic antiemetics, postoperative fentanyl dose for IVPCA (≥ 20 μg/h/< 20 μg/h) and addition of droperidol in IVPCA. There was no interaction between these variables and PONV (Table 5).

Table 5 Subgroup analyses stratified by patient and operative variable.

Discussion

In this retrospective cohort study, mean of intraoperative EtCO2 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 EtCO2 exposure using the time and cumulative effects of EtCO2 but found no clear association.

Two small studies have studied whether there is an association between low EtCO2 and PONV17,18, 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 PONV17. However, a prospective observational study involving 90 pediatric patients who underwent inguinal surgery has reported that elevated levels of EtCO2 were an independent predictor of PONV18. 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 PONV19. That study did not evaluate the effects of low EtCO2 (mean EtCO2 level of less than 35 mmHg). Alternatively, a retrospective cohort study involving 146 patients undergoing open gynecologic surgery has reported that the minimum EtCO2 level of ≤ 31 mmHg lasting longer than 10 min was associated with an increased incidence of PONV16. 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 EtCO2 level of 35 mmHg. Furthermore, an RCT involving 60 patients undergoing gynecologic laparoscopic surgery reported that low EtCO2 management reduced the incidence of nausea, PONV score, and the use of rescue antiemetics25; these results differed from the two aforementioned studies. Management to keep 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 ischemia-sensitive 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 EtCO2 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 EtCO2 (mean EtCO2 of less than 35 mmHg) and the effects of the duration and severity of low EtCO2 exposure, we could not demonstrate an association between low EtCO2 and PONV. Even extremely low EtCO2, defined as EtCO2 of less than 31 mmHg sustained for more than 10 min16, 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 EtCO2 and PONV and PLOS, the dose effects of EtCO2 (mean level of less than 35 mmHg) and the effects of the duration (time effects, long-term exposure to EtCO2 of less than 35 mmHg) and severity (cumulative effects, area under the threshold of EtCO2 of less than 35 mmHg). Among the three previous studies that examined the association between intraoperative low EtCO2 and PONV, which only evaluated the dose effects 17,18,19, only one study evaluated the association between the time effects of low EtCO2 and PONV16. 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 PaCO2–EtCO2 gap to calibrate EtCO2 levels using PaCO2 levels. Thus, we underestimated the effects of low EtCO2 and overestimated the effects of hypercapnia. However, since PaCO2 is usually 2–5 mmHg higher than EtCO2 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 EtCO2 level, missing data on intraoperative ventilation parameters, and PONV risk factors among patient factors is, history of PONV and motion sickness.

Conclusion

Intraoperative low EtCO2 (mean EtCO2 level less than 35 mmHg) was not substantially associated with either increased incidence of PONV or prolonged PLOS in patients undergoing gynecologic laparoscopic surgery.

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Acknowledgements

We are grateful to Mr. Yoshihiro Kinoshita, Ms. Tomoko Hosoya, and Mr. Yohei Taniguchi (Medical Information Systems Section, Management Division, Kyoto University Hospital, Kyoto, Japan) for their assistance in data collection for this study.

Funding

This work was supported in part by the Japan Society for the Promotion of Science KAKENHI program (Grant number: 20K09242, principal investigator: Toshiyuki Mizota) and the 2019 Kyoto University ISHIZUE Research Development Program (principal investigator: Toshiyuki Mizota).

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Conceptualization: L.D. Methodology: L.D., T.M., Y.Y., C.T., H.Y., M.H., A.H. Formal analysis and investigation: L.D., C.T., H.Y., M.H., A.H., Y.Y., T.M. Writing—original draft preparation: L.D. Writing—review and editing: L.D., C.T., H.Y., M.H., A.H., Y.Y., T.M. Editing and approval of the manuscript: L.D., C.T., H.Y., M.H., A.H., Y.Y., T.M. Funding acquisition: T.M. Resources: L.D., T.M. Supervision: T.M.

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Correspondence to Toshiyuki Mizota.

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Dong, L., Takeda, C., Yamazaki, H. et al. Association between intraoperative end-tidal carbon dioxide and postoperative nausea and vomiting in gynecologic laparoscopic surgery. Sci Rep 12, 6865 (2022). https://doi.org/10.1038/s41598-022-10727-6

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