A systematic review: comparative analysis of the effects of propofol and sevoflurane on postoperative cognitive function in elderly patients with lung cancer

Cognitive impairment is a neurological disorder that occurs in adults, which involves cognitive disorders with impairment in instrumental activities of daily living [1, 2]. Previous studies have shown that about 234 million patients worldwide undergo surgery each year, and about 41% of elderly patients have cognitive impairment after surgery or anesthesia. Thirteen percent of patients still have cognitive impairment 3 months after discharge [3, 4]. Cognitive impairment severely affects the prognosis of patients who have undergone general anesthesia surgeries, especially elderly patients, including decreased quality of life, loss of independence, and increased mortality [5]. Patients with lung cancer frequently encounter postoperative cognitive dysfunction. In elderly patients, severe cognitive impairment is more likely to occur after anesthesia. This may be due to a combination of multiple factors, such as inflammation caused by surgical trauma, infection, opioids, stress, and sleep disorders [6]. Because the incidence of cognitive impairment is positively correlated with the duration of anesthesia, general anesthetic drugs are thought to be one of the causes of cognitive impairment in elderly patients [7].

Worldwide, lung cancer occurred in approximately 1.8 million patients in 2012 and caused an estimated 1.6 million deaths [8]. This is increased from 1.6 million new diagnoses and 1.4 million lung cancer deaths in 2008 [9]. The treatment for early-stage lung cancer is mainly surgical treatment. Propofol and sevoflurane are the most commonly used general anesthetic drugs in clinical practice [10]. However, in terms of causing postoperative cognitive functions, there are still controversies regarding the use of propofol anesthesia or sevoflurane anesthesia in elderly patients with lung cancer. Current published studies on this topic were with relatively smaller sample sizes and were lack of consistency. Therefore, we conducted this systematic review and meta-analysis to derive a pooled estimate of the effects of propofol and sevoflurane on postoperative cognitive functions in patients with lung cancer, with an improved statistical power as compared to individual studies. The primary endpoints are postoperative mini-mental state examination (MMSE) scores at various time points; the secondary endpoints are serum S100beta concentration 24 h after surgery. S100β is glial-specific and is expressed primarily by astrocytes. It functions in the process of neurite extension, proliferation of melanoma cells, stimulation of Ca2+ fluxes, inhibition of PKC-mediated phosphorylation, astrocytosis, axonal proliferation, and inhibition of microtubule assembly. In the developing central nervous system (CNS), it acts as a neurotrophic factor and neuronal survival protein. In the adult organism, it is usually elevated due to nervous system damage, which makes it a potential clinical marker. S100β is involved in the regulation of cell shape, cell growth, energy metabolism, cell-to-cell communication, contraction, and intracellular signal transduction. The correlation between serum S100β protein levels and cognitive dysfunction.

At present, there is no uniform standard for the assessment of cognitive dysfunction in the world, and the most commonly used standard clinically is the MMSE score [26]. Studies found that the sensitivity and specificity of the MMSE method for assessing cognitive brain function were 87 and 82%, respectively [27]. The MMSE method is feasible and straightforward and is widely used for the screening of clinical cognitive dysfunction and cognitive decline [28]. The results of this meta-analysis showed that the MMSE scores at 6 h, 1d, 3d, and 7d after intravenous propofol anesthesia were significantly lower than those of sevoflurane. The reason may be that the sevoflurane has a shorter action time and is eliminated quickly. Laboratory data also showed that rats pretreated with high concentrations of sevoflurane could be effectively protected from focal cerebral ischemia, thus reducing neurological deficit scores, the volume of cerebral infarction, and cerebral edema areas. The incidence of post-cognitive disorders is adversely associated with higher concentrations of sevoflurane as a potential protective factor in non-cardiovascular procedures [29]. Experimental data have demonstrated that it may be because of the up-regulation of the expression levels of NR1 and NR2 subunits of hippocampal N-methyl-D-aspartate receptors that sevoflurane has a slighter effect on cognitive function in the elderly patients than propofol [30].

On a contour-enhanced funnel plot, contours of statistical significance are overlaid on the funnel plot. Adding contours of statistical significance facilitates the assessment of whether the areas where studies exist are areas of statistical significance and whether the areas where studies are potentially missing correspond to areas of low statistical significance. Generally, if studies appear to be missing in areas of low statistical significance, then it is possible that the asymmetry is due to publication bias. Conversely, studies perceived to be missing areas of high statistical significance likely do not suffer from publication bias as a source of funnel asymmetry. In the present meta-analysis, the funnel plot indicated no publication bias.

This meta-analysis has a few limitations. Firstly, we included only 14 articles. Although all these studies were conducted with propofol anesthesia and sevoflurane anesthesia as the experimental group and the control group, respectively, the doses of the drugs used for the elderly patients with lung cancer, the length of the operation time, and the use of adjuvant drugs were not the same. So, the problem of generalizability might exist. Secondly, most literature tends to report positive outcomes, while the studies with negative results are often not reported. Though not suggested via contour-enhanced funnel plots, the possibility of potential publication bias in included studies should not be overlooked. Thirdly, we did not perform a grey literature search, which might cause overestimations of effect sizes. Grey literature stands for manifold document types produced on all levels of government, academics, business and industry in print and electronic formats that are protected by intellectual property rights, of sufficient quality to be collected and preserved by libraries and institutional repositories, but not controlled by commercial publishers; i.e. where publishing is not the primary activity of the producing body. Fourthly, there are several tools more extensive tools available for assessment of recovery; however, in the present study, we only adopted MMSE as the outcome because of the data availability (MMSE is the most commonly used for screening). Although one may argue that merely presenting repeated MMSE scores is not sufficient for assessment of cognitive capacity and discriminating differences between groups, we believe that at this present time, due to the data availability mentioned above, the MMSE could say something. Fifthly, most of the included studies did not report enough the details of each patient, so it is not easy to separate between emergence reaction within hours from emergence, early cognitive changes - delirium and more protracted changes. Additionally, the many included studies had a relatively low methodology quality, so more rigorous large-scale randomized controlled trials are needed. Sixthly, the vast majority of the studies were conducted in China. The inter-racial variability of propofol anesthesia is well described. Therefore, it is not sure if the results are valid for other races. Seventhly, as is understood, co-administered drugs differed in included studies, but did any of the studies include regional anesthetic techniques? Could the greater peri-operative hypotension sometimes see with propofol have been a cause? Due to lacking these related data, the accuracy of the study’s conclusions will be questioned.

In summary, propofol has a more significant adverse effect on postoperative cognitive function in lung cancer patients than sevoflurane. In the included studies, some of the documents are of low quality and may affect the stability and reliability of the final results. Therefore, larger samples, more rigorous design, and higher quality tests are still needed for verification.