Effect of patient end-tidal carbon dioxide levels on cerebral regional oxygen saturation and inflammatory cytokine concentrations in elderly patients undergoing laparoscopic radical gastrectomy: a randomized controlled trial

1. Background

Laparoscopic radical gastrectomy is being increasingly performed on elderly adults (aged ≥60 years). Although it is reported that all adult patients are at risk for some level of postoperative cognitive dysfunction (POCD) after major surgery, this risk is significant mainly among elderly adults [1], in whom intraoperative cerebral oxygen desaturation has been associated with early POCD [2, 3].

Frequent changes in intracranial pressure and cerebral blood flow (CBF) may occur during laparoscopic surgery and can affect the cerebral perfusion pressure and cerebral oxygenation [4]. Therefore, intraoperative monitoring of cerebral regional oxygen saturation (rScO₂) is a significant determining factor for maintaining postoperative cognitive function.

Cerebral rScO₂ may be affected by various factors, including the arterial partial pressure of carbon dioxide (PaCO₂), the body’s position and intraoperative blood pressure [5]. Although we can control the factors affecting cerebral oxygen supply/demand, such as the PaCO₂, cardiac output, perfusion pressure, arterial oxygen content and cerebral metabolic rate, increasing the patient’s end-tidal carbon dioxide (P${}_{ET}$CO₂) level was shown to be the most powerful and convenient method in managing cerebral desaturation [6]. Therefore, intraoperative CO₂ regulation can improve cerebral rScO₂.

A lung-protective ventilation strategy resulting in permissive hypercapnia (PHC) can be used to enhance cerebral perfusion and induce a rightward shift in the oxygen dissociation curve; thus, maintaining a relatively stable P${}_{ET}$CO₂ level and improving tissue oxygenation. Further, a previous study reported a strong correlation between PaCO₂ and P${}_{ET}$CO₂ [7]. Intuitively and conveniently, an increase in P${}_{ET}$CO₂can improve CBF. A previous study observed a strong correlation between postoperative cognitive function and intraoperative cerebral rScO₂ [8], a parameter that can predict POCD occurrence with a sensitivity and accuracy of 90% and 86.5%, respectively [9].

This current study investigated whether appropriate elevation of P${}_{ET}$CO₂ could prevent the incidence of cerebral desaturation in elderly patients undergoing scheduled laparoscopic radical gastrectomy. The primary outcomes were changes in cerebral rScO₂ and the incidence of POCD following changes in P${}_{ET}$CO₂. The secondary outcomes were changes in the serum concentrations of interleukin (IL)-6, S100$\beta$ and neuron-specific enolase (NSE), which are associated with the occurrence of POCD.

2. Materials and methods

3. Results

4. Discussion

This study showed that a higher level of P${}_{ET}$CO₂ was associated with increased cerebral rScO$$ in elderly patients undergoing laparoscopic radical gastrectomy. In addition, maintaining an appropriate P${}_{ET}$CO₂ level reduced the serum concentrations of inflammatory cytokines IL-6 and S100$\beta$ in this population.

POCD is a well-known clinical phenomenon of multifactorial origin [11, 12]. Unlike other potential causes of POCD, intraoperative cerebral hypoxia can be modified [13]. Several studies have reported a positive correlation between POCD and lower intraoperative rScO₂ values in elderly patients [14, 15]. Several other studies investigating the effects of PaCO₂ on CBF also focused on rScO₂. Nakao et al. [11] found that cerebral inflammation due to anesthesia or surgery and perioperative vital sign changes that reduced CBF, such as persistent hypotension and/or hypocapnia, could contribute to the development of POCD, especially in patients whose CBF was already reduced. As CO₂ is the most effective regulator of CBF, cerebral rScO₂ should be improved in response to an increase in PaCO₂. Zhu et al. [12] showed that PHC could enhance CBF, improve the cerebral rScO₂ of patients undergoing cardiac surgery and adjust the cerebral oxygen supply balance. Based on these findings, we presumed that an increase in P${}_{ET}$CO₂ would improve intraoperative cerebral rScO₂ and reduce the incidence of POCD. However, no such conclusion could be deduced from our results, which showed that the increase in rScO₂ was observed only when P${}_{ET}$CO₂ was increased, while the MoCA scores were unaffected. These indicate that the correlation between rScO₂ and POCD remains to be further clarified.

A previous study showed that mild hypercapnia (PaCO₂ at 45–55 mmHg) could improve cerebral oxygenation, increase rScO₂ and reduce the incidence of POCD [12]. This approach is believed to activate neuronal nitric oxide synthase, thus promoting nitric oxide production and causing cerebrovascular dilatation. The expansion of cerebral blood vessels improves the cerebral oxygen supply, reduces the risk of cerebral ischemia and hypoxia, and effectively protects brain functions. Therefore, in this current study, a lung protective ventilation strategy was applied to explore the effects of different levels of P${}_{ET}$CO₂ on rScO₂ and postoperative cognitive function in elderly patients undergoing laparoscopic radical gastrectomy. The key finding of this study is that maintaining a high intraoperative P${}_{ET}$CO₂ (46–50 mmHg) improved elderly patients’ postoperative cognitive scores (MoCA scores). In addition, the results also showed that P${}_{ET}$CO₂ significantly improved rScO$$, but for P${}_{ET}$CO₂ values $$45 mmHg, which is similar to the results of previous studies. Further, the association between elevation in P${}_{ET}$CO₂ and improvement of cerebral rScO₂ suggests that P${}_{ET}$CO₂ might be an influential factor of rScO₂. However, the premise of this conclusion is that P${}_{ET}$CO₂ should be increased to a certain level, i.e., at least up to 45 mmHg. Although the exact reason remains to be clarified, we hypothesized that it might be related to the specific lung protective ventilation strategies used in this study.

At present, the pathogenesis of POCD is unclear. Studies have shown that the infiltration of inflammatory factors into the central nervous system and expansion of immune responses might promote nerve cell apoptosis, necrosis and degenerative changes [16, 17, 18]. A meta-analysis showed that peripheral markers of inflammation, especially IL-6 and S100$\beta$, were closely associated with POCD [19]. Therefore, in this study, we assessed the levels of these serological factors and found that they decreased with increasing P${}_{ET}$CO₂. Compared with groups L and C, the levels of most inflammatory markers were significantly reduced in group H. Therefore, the increase in P${}_{ET}$CO₂ might help reduce these inflammatory factors, including IL-6 and S100$\beta$, although it only occurred above a certain P${}_{ET}$CO₂ threshold.

Many studies have verified the ability of CO₂ to regulate cerebrovascular and improve CBF [20, 21] and have established the effects of oxygen supply on the brain’s cognitive functions. But always experiment is to stop more levels. In a previous experimental research, the effects of changes in P${}_{ET}$CO₂ were demonstrated by determining the changes in cognitive function after surgery, and the results not only indicated that cerebral rScO₂ could predict POCD but also suggested that it could be used to improve patients’ cognitive function after surgery. However, these observations are inconsistent with the results of this present study, possibly due to no direct link between rScO₂ and POCD. Here, we observed that the levels of inflammatory markers IL-6 and S100$\beta$ were significantly decreased with higher P${}_{ET}$CO₂ and rScO₂, while MoCA scores showed no significant change, indicating that IL-6 and S100$\beta$ may not be related factors of POCD, or at least not the main influencing factors.

A low BIS value and a prolonged period of deep anesthesia have emerged as risk factors for POCD [22]. In this study, the risk of POCD due to deep anesthesia was avoided by monitoring BIS intraoperatively to guide the depth of anesthesia. The enhanced recovery after surgery (ERAS) program can enhance postoperative recovery and reduce the length of hospital stay and morbidity by applying a series of optimization measures from evidence-based medicine during the perioperative period [23]. All patients in this study were treated with target-directed fluid therapy following the ERAS principle, which might be related to the observed faster recovery with this lung-protective ventilation strategy.

5. Conclusions

In conclusion, this study confirms that an increase in P${}_{ET}$CO₂ can increase rScO₂ and improve postoperative cognition, but not MoCA scores. However, an insufficient increase in CO₂ levels may increase cerebral rScO₂, and an excessive increase in CO₂ may lead to other complications, such as CO₂ accumulation, brain edema and pulmonary inflammation. The specific determination of a safe and effective CO₂ level requires further in-depth research. However, this study is limited by its single-center design, a relatively small sample size and a lack of long-term follow-up data. Additional studies using larger cohort and multicentre settings are needed to validate these findings [24].

Abbreviations

P${}_{ET}$CO₂: end-tidal carbon dioxide; POCD: postoperative cognitive dysfunction; rScO₂: mregional cerebral oxygen saturation; MoCA: Montreal Cognitive assessment; IL-6: cytokine interleukin-6; ASA: American Standards of Association; BMI: body mass index; BIS: bispectral index; CO: cardiac output; SV: stroke volume; MAP: mean arterial pressure; HR: heart rate; PCIA: patient-controlled intravenous analgesia.

Author contributions

KZ—Guarantor of integrity of the entire study & Manuscript review; YZL and ML—Study concepts; YLY and LRL—Study design & Clinical studies & Manuscript preparation; CZL and HDC—Definition of intellectual content; KZ and CZL—Literature research; YZL, ML and HDC—Data analysis; YLY, YZL and ML—Statistical analysis; YLY—Manuscript editing.

Ethics approval and consent to participate

This trial was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Ethical Review Committee for Clinical Trials of the First Affiliated Hospital of Fujian Medical University y (NO. [2018]080). Written Informed consent to participate in the study was obtained from participants.

Acknowledgment

Not applicable.

Funding

Grants covering the research: We gratefully acknowledge Fujian Provincial Health Technology Project (No. 2019-1-47 and 2019-2-19) and Startup Fund for Scientific Research of Fujian Medical University (No.2018QH1080 and 2021QH1305).

Conflict of interest

The authors declare no conflict of interest.