Colorectal cancer (CRC) is one of the most common cancers in the world, with an estimated 1.8 million new cases and 861,000 deaths each year (1). The incidence of CRC is decreasing in western countries including the United States, Canada, and Australia. However, an upward trend has been existing in China; moreover, China is a country with the largest number of new cases and deaths of CRC every year in the world (2). At present, radical surgical treatment of CRC is still the most important and decisive treatment (3–5).

Due to the popularity of laparoscopic surgery and the development of surgical equipment such as electrothermal bipolar activation devices and ultrasound systems, the average intraoperative blood loss (IBL) has decreased (6, 7). However, IBL is still a matter of concern during the operation. Studies have found that larger IBL might affect complications and prognosis in gastrointestinal tumors (8–10).

Perioperative blood transfusion is another concern for surgeons. However, the influence of perioperative blood transfusion on short-term outcomes and prognosis was inconsistent. Some studies reported that perioperative blood transfusion could increase post-operative complications, prolong hospital stay, and affect prognosis (11–13). However, other studies suggested that perioperative blood transfusion did not affect prognosis (14, 15).

The effect of IBL in patients with CRC is still controversial. Some studies reported that larger IBL could increase complications and reduce prognosis (16–18). However, other studies reported that IBL had no effect on complications and prognosis (19, 20). Furthermore, no previous studies reported the intraoperative blood transfusion (IBT) on the outcomes and prognosis of patients with CRC. Thus, the purpose of the current study was to analyze the effect of IBL and IBT on the short-term outcomes and prognosis of patients who underwent primary CRC surgery.

We retrospectively collected the patients' information from database of a teaching hospital. The database included patients who underwent primary CRC surgery from Jan 2011 to Jan 2020. This study was conducted in accordance with the World Medical Association Declaration of Helsinki. Ethical approval from the institutional review board of the First Affiliated Hospital of Chongqing Medical University was obtained (2021-540). All patients signed the informed consent.

In this study, there were 1,911 patients in the larger IBL group and 2,339 patients in the smaller IBL group. As for IBT, after 1:1 ratio PSM, there were 82 patients in the IBT group and 82 patients in the non-IBT group. The larger IBL group had longer operation time, longer post-operative hospital stay, smaller retrieved lymph nodes, and higher overall complication than the smaller IBL group. The IBT group had longer operation time, longer hospital stays, and higher overall complications compared with the non-IBT group in terms of short-term outcomes. Larger IBL and IBT were independent predictive factors of OS.

The amount of IBL could reflect the difficulty of surgery. There was a controversy of prognosis regarding IBL for patients with CRC (16–20, 25–27). Egenvall et al. reported that larger IBL increases the risk of later surgery for small bowel obstruction caused by tumor recurrence and surgical complications, but OS was not affected (20). Another study also reported IBL was not associated with increased median length of hospital stay nor did it increase the 30-day readmission rate (19). However, other studies reported that larger IBL was associated with increased complications or poor prognosis (16–18). Therefore, it was necessary to analyze the effect of IBL on the short-term outcomes and prognosis of patients who underwent primary CRC surgery.

However, the cut-off value of IBL was inconsistent in previous studies. We concluded the baseline information, cut-off value of IBL, and outcomes of previous studies in Table 9. The cut-off value of IBL was 50 ml, 100 ml, 200 ml, 250 ml, 450 ml, 800 ml, and 1,400 ml (16–20, 25–27). In this study, the cut-off value of IBL was the 75th percentile of IBL (100 ml), which was according to a previous study (16).

Perioperative blood transfusion might affect the complications, hospital stay, short-term death, and prognosis (11–15). However, no previous studies analyzed the effect of IBT on the short-term outcomes or prognosis. In this study, we analyzed IBT on the outcomes of CRC surgery; furthermore, PSM was conducted to minimize the bias of baseline information and the results would be more robust after PSM.

In terms of short-term outcomes, we found that larger IBL and IBT prolonged operation time and hospital stay, and increased complications. The prolonged hospital stay might be due to post-operative complications, and the recovery of intestinal peristalsis might be affected by larger IBL and IBT, which resulted in prolonged hospital stay. Therefore, surgeons should try to ensure the accuracy of the operation to avoid larger IBL or IBT.

In this study, larger IBL was an independent predictive factor of OS and DFS. The mechanism might be as follows: the animal experiments show that the activity or cytotoxicity of natural killer cells was reduced after blood loss, and the degree of reduction was related to the amount of blood loss (28, 29). IBL might increase the risk of tumor spread through blood during CRC surgery, which might lead to early recurrence and poor prognosis (30). In addition, larger IBL could lead to insufficient tissue perfusion and insufficient oxygenation (18). These events inhibited mitogen-induced lymphocyte proliferation and the production of interleukin-2 (31, 32), thus hindering anti-tumor immunity and upregulating vascular endothelial growth factor, which accelerated tumor angiogenesis (33, 34). Moreover, hypoxia could promote genome instability and lead to various genetic changes, which resulted in more aggressive phenotypes of residual tumor cells (35).

Intraoperative blood transfusion was also an independent predictive factor of OS. The potential hypothesis was that IBT might cause immune disturbances through transfused leukocytes, including changes in circulating lymphocytes, B cell function, suppressor T cell ratios, and helper T cells (12, 36). Another possible interpretation was that the need for IBT was a marker for sicker patients who were more likely to have worse prognosis than non-IBT patients (37).

There were some limitations in this study. First, this was a single-center retrospective study, which might cause selection bias; second, the follow-up time was relatively short and long-term follow-up is needed in the future; third, the information of classification and differentiation of tumors was lacking; fourth, the preoperative hemoglobin, the kind and volume of transfusion were lacking as well. Therefore, larger sample size with detailed information and long-term follow-up should be conducted in the following experiments.

In conclusion, larger IBL and IBT were associated with longer operation time, longer hospital stay, higher overall complications, and poorer OS. Based on the short-term outcomes and prognosis of IBL and IBT, surgeons should be cautious and more careful during the operation, and they require proficient surgical skills.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. The patients/participants provided their written informed consent to participate in this study.

DP and BK contributed to the conception and design of the study and wrote the first draft of the manuscript. BK organized the database. DP performed the statistical analysis. X-YL, Z-WL, CY, BZ, and Z-QW wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

This study was supported by Chongqing Key Diseases Research and Application Demonstration Program (Colorectal Cancer Prevention and Treatment Technology Research and Application Demonstration [No. 2019ZX003]).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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