Association between blood transfusion and infections after spinal surgery: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-2192841/v1

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Association between blood transfusion and infections after spinal surgery: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-2192841/v1

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Background

Blood transfusion is a crucial replacement therapy in surgery as its side effects on the human immune system may cause postoperative infections. Infections after spinal surgery include surgical site infection (SSI), urinary tract infection (UTI), pneumonia, and sepsis, which have a significant impact on mortality. Whether blood transfusion is a risk factor for postoperative infections in spinal surgery remains unclear. Hence, this meta-analysis aimed to reveal the association between infection after spinal surgery and blood transfusion in clinical trials.

Methods

PubMed, Embase, Cochrane Library, and Web of Science were explored up to January 31, 2020, for studies related to postoperative infection and spinal surgery. Stata 14.0 was used to pool the estimates with a random-effects model and relative risk (RR) with 95% confidence interval (95% CI) in each study and I-square test to evaluate the heterogeneity.

Results

Eight cohort studies met the inclusion criteria, comprising a total of 100,989 patients. We found that blood transfusion was significantly associated with postoperative infection (RR = 3.01; 95% CI, 2.74–3.31; p < 0.001) and played a critical role in different types of infections such as SSI, pneumonia, UTI, and sepsis.

Conclusion

Blood transfusion was a risk factor for postoperative infection in spinal surgery. Hence, efforts should be made to reduce bleeding during the operation, and more restrictive transfusion policies should be followed in the perioperative period.

Trial registration

This systematic review has been registered in PROSPERO. The registration number is CRD42020193853.

Transfusion

Spinal surgery

Infection

Meta-analysis

Blood transfusion was one of the three major factors that furthered the development of surgery in history. As a replacement treatment, blood transfusion can supplement blood volume and plasma protein and improve the oxygen carrying capacity of the blood and coagulation function. Blood transfusion is widely used in surgery, and it has been estimated that 85 million units of red blood cells are transfused annually worldwide and about 36.1% of patients who underwent spine operations received blood transfusion [1, 2]. Although blood transfusion is a significant therapy in surgery, side effects of the procedure have been cited in many reports, especially its effect on the human immune system that may cause postoperative infection [3].

Infections after spinal surgery including surgical site infection (SSI), urinary tract infection (UTI), pneumonia, and sepsis, among others, are related to the prognosis of spinal surgery and indicate a strong influence on postoperative mortality [4]. Surgical site infection is the most common type of nosocomial infection in the early postoperative period, and about 77% of acute mortality in SSI patients is directly related to infection [5, 6]. In addition, the medical costs of patients with SSI after lumbar spine surgery increased by more than 300% [7]. Therefore, preventing postoperative spinal infections from occurring is particularly important.

Patient characteristics and surgery are the main risk factors that increase the incidence of infection. Patient characteristics including advanced age, corticosteroid use, smoking, alcohol abuse, and diabetes have been identified as independent risk factors [4, 8–12]. Surgical factors involve surgical approach, surgical procedures, and operation time [8, 9]. However, whether blood transfusion, especially allogeneic blood transfusion, is a risk factor for infection remains controversial and debated among surgeons and clinical researchers.

This study aimed to conduct a meta-analysis on the relationship between perioperative blood transfusion and postoperative infection in spinal surgery. Its results may provide evidence and help surgeons in perioperative management decisions to decrease the incidence of infections in the future in spinal surgery.

Search strategy

PubMed, Embase, Cochrane, and Web of Science were explored from up to January 31, 2020. The subject terms we used included “spine,” “cervical vertebrae,” “thoracic vertebrae,” “lumbar vertebrae,” “sacrum,” “surgical procedures,” “operative,” “blood transfusion,” and “infection.” Additionally, to find as many relevant records as possible, we used free-text terms, which are synonyms of the subject terms, and the reference lists of qualified articles and relevant systematic reviews were also searched until there were no other potential articles found.

Inclusion and exclusion criteria

The inclusion criteria included ① all patients having undergone spinal surgery, ② the study type was a randomized controlled trial or a cohort study, ③ the intervention method was intraoperative or postoperative transfusion, and ④ the main outcome measure was the number of patients who had infections.

Contrarily, the exclusion criteria comprised ① nonclinical studies including reviews, conference presentations, expert consensus, comments, guidelines, letters and responses, basic medical research, etc.; ② case-control or cross-sectional studies; ③ interventions were not blood transfusions; and ④ main outcome measures were not provided.

Literature selection and data extraction

Records were selected by two independent researchers (CZ and YL). We scanned the title and abstract of these records to exclude unrelated researches and read the full text of the remaining articles to determine the studies meeting the inclusion criteria. Furthermore, the following data from the studies were extracted independently: the first author, year of publication, the total number of patients, study demographics (age, gender), and the number of patients in every case and control group.

The results were cross-checked, and discrepancies were resolved through discussion and determined by the third researcher (XT).

Methodological quality assessment

The methodological quality of the selected studies was evaluated using the Newcastle-Ottawa Scale (NOS) Quality Assessment, which ranged from 0 to 9 points [13]. Studies with more than 6 points were considered as high-quality studies. Analyses were independently conducted by two researchers (CZ and HJ), and discrepancies were resolved through discussion and determined by the third researcher (JD).

Statistical analysis

The outcome was infection occurrence including SSI, UTI, pneumonia, and sepsis. We treated incidences of infection as dichotomous variables and used relative risk (RR) with 95% confidence interval (95% CI) to express them in each study. The random effects model was used to collect all the data in every group to give a more conservative estimate of the association between blood transfusion and infections after spinal surgery. The I² and chi-square tests were used to assess heterogeneity between the studies, and I² ≥ 50% or chi-square test with P value < 0.10 indicated a high heterogeneity. Subgroup analyses were used to investigate the possible explanations of heterogeneity. The Egger and Begg tests were performed to estimate the publication bias of the studies. All analyses were conducted using Stata 14.0 (StataCorp LP, 4905 Lakeway Drive, College Station, TX, USA).

Selection and characteristics of studies

The search initially identified 1611 studies, but after removing 372 duplicates, we were left with 1239 studies for title and abstract screening. Among the remaining studies, 1184 records were excluded because of obvious irrelevant subjects and as they were nonclinical studies. Thus, the full text of only 55 articles was reviewed, and 47 of them were excluded from the study (7 were case-control studies and 40 did not report the number of patients who received a transfusion or had an infection). Finally, eight cohort studies were selected for analysis [5, 14–20]. The selection process is shown in Fig. 1.

The studies from the qualified articles included a total of 100,989 patients, of which 6522 received transfusion and 94467 did not. All patients underwent spinal surgery between 1988 and 2015 and had been followed up until the study endpoint. The endpoint of the studies was infection including SSI, pneumonia, UTI, sepsis, and other types of infection. The number of infected patients who received transfusion was 518 and those who did not receive transfusion was 2250. Table 1 presents the patient characteristics, including patient demographic data, research methods used, characteristics of operation, the number of patients who had or did not have transfusion, the number of different types of infection in each group, and the NOS for all the studies.

Correlation analysis between blood transfusion and postoperative infection

To investigate the relationship between blood transfusions and the total number of all kinds of postoperative infections, we pooled the relative risk of all the eight eligible studies. The result is shown in Fig. 2. The heterogeneity test suggested that there was no significant difference between the studies (I² = 0%, P = 0.468), with pooled RR of 3.01 and 95% CI ranging from 2.74 to 3.31. Moreover, findings suggested that blood transfusion was significantly related to postoperative infection (P < 0.001), with the risk of infection in the blood transfusion group about three times more than that of the group without blood transfusion. The Egger test (P = 0.606) and Begg test (P = 0.266) suggested that there was no publication bias.

The test showed no significant heterogeneity between each study; however, it was considered that the different regions may have different population proportions, health conditions, and antimicrobial drug and blood transfusion policies that may further lead to differing results. Hence, a subgroup analysis sorted by region was further conducted in our study, and the results are shown in Fig. 3. A total of 5 studies in the Americas showed a pooled RR of 3.27 with 95% CI ranging from 2.37 to 4.50, and heterogeneity test showed no significant difference (I² = 19.6%, P = 0.290). Conversely, the pooled RR of two European studies was 2.86 with 95% CI ranging from 1.52 to 5.39, and no significant heterogeneity was reported in each study (I² = 0%, P = 0.703). In addition, a study by Kato et al. revealed an RR of 2.93 with 95% CI ranging from 2.64 to 3.26. The conclusion of each subgroup analysis was consistent, and no significant heterogeneity was noted in these subgroups.

Correlation analysis of blood transfusion and different types of infection

Furthermore, we analyzed different types of infections separately; the results are shown in Fig. 4.

Seven studies [5, 15–20] reported the relationship between blood transfusion and SSI (see results in Fig. 4-a). The heterogeneity test indicated that there is no significant heterogeneity in each study (I² = 0%, P = 0.998), with pooled RR of 2.80 and 95% CI ranging from 2.46 to 3.20. It was suggested that blood transfusion is significantly related to postoperative SSI (P < 0.001). The risk of SSI in the blood transfusion group was about 2.80 times more than that of the non-transfusion group.

Four studies [5, 16, 18, 19] revealed a relationship between blood transfusion and postoperative lung infection. The analysis results are presented in Fig. 4-b. Findings from the heterogeneity test showed a significant degree of heterogeneity (I² = 68.1%, P = 0.024). The pooled RR was 2.97, with 95% CI ranging from 1.45 to 6.11, indicating that the risk of pulmonary infection in the blood transfusion group was about 2.97 times more than that of the non-transfusion group (P = 0.003).

Furthermore, four studies [5, 16, 18, 19] have reported a relationship between blood transfusion and UTI. The results are displayed in Fig. 4-c. Heterogeneity test showed no significant heterogeneity between the studies (I² = 0%, P = 0.46). The pooled RR was 3.45, with 95% CI ranging from 2.80 to 4.25, suggesting that blood transfusion was significantly related to UTI after spinal surgery (P < 0.001) and that transfusion patients have a higher risk of UTI than non-transfusion patients.

Only three studies reported sepsis [16, 19, 20], and the analysis results are shown in Fig. 4-d. Using the heterogeneity test, there was no significant heterogeneity between researches (I² = 0%, P = 0.52). The pooled RR was 7.40, with 95% CI ranging from 4.84 to 11.32, denoting that transfused patients are 7.40 times more likely to acquire sepsis than non-transfused patients (P < 0.001).

This study found that blood transfusion is a risk factor for infection after spinal surgery. The subgroup analysis found that the research conclusions were consistent in the Americas, Europe, and Asia and the RR was similar, suggesting that the relationship between blood transfusion and postoperative infection is independent of population, health conditions, or policy.

A previous systematic review failed to find a consistent relationship between allogeneic transfusion and SSI in spine surgery patients [21]. It may be considered that the study included more retrospective studies with moderate or high risk of bias. To find a more accurate and persuasive result, we conducted an independent systematic review using a stricter search strategy which included higher-quality cohort studies and excluded case-control studies. In the eligible studies, although the results of most researches showed that blood transfusion has a significant impact on postoperative infections, the results of studies by Aoude et al. [17] seemed to reveal otherwise. In this study, information was collected from patients who had undergone cervical spine fusion surgery at multi-centers in the United States and Canada from 2010 to 2013 to evaluate the relationship between blood transfusion and SSI during cervical fusion surgery. Statistics found that neither superficial surgical site infection (P = 0.952) nor deep surgical site infection (P = 0.487) was related to blood transfusion. Another interesting result was in a report by Johnson et al. [20]. Their study collected data of patients who underwent posterior spinal surgery at their institution from 2009 to 2015. The number of patients with all types of infections was compared between the transfusion group and the non-transfusion group, and the results showed a significant difference (P = 0.04). However, when comparison between the two groups was made on a specific type of infection, any of the types mentioned in this study, it registered an opposite result. The number of patients with SSI, sepsis, drug-resistant infections, or Clostridium difficile in the two groups were not significantly different, with P values of 0.23, 0.53, 0.99, and 0.99, respectively.

It is worth noting that in the analysis of the SSI, UTI, and sepsis, the homogeneity of each study was not significant, while the studies investigating pneumonia displayed significant heterogeneity (I² = 68.1%, P = 0.024). Additionally, it was considered that differing sample sizes affected heterogeneity. The study conducted by Kato et al. [16] enrolled 84,650 patients, whereas the other three studies had less than 300.

We also found the association between transfusion and intraoperative blood loss or operation time in eligible studies. The blood loss was larger and operation time was longer in transfusion group, which was determined by indications of blood transfusion. Along with transfusion, these factors were also related to infection [22–24]. In case-control studies conducted by Veeravagu et al. and Li et al., multivariate analysis of risk factors for infection revealed that blood transfusion and operation duration were both independent risk factors [23, 24], which was consistent with our results. Therefore, although there were factors related to blood transfusion that also affected the outcome of postoperative infection, blood transfusion was still a risk factor for postoperative infection. The effect of blood transfusion on the occurrence of infections is not limited to a certain type of infection, and other surgical subspecialty studies also found that blood transfusion is a risk factor for postoperative infection, which is not associated with anemia, bleeding, hypotension, or surgery time and other confounding factors [25]. The relationship between allogeneic blood transfusions and postoperative infections was also confirmed by an animal experiment. In a study on mice, Gianotti et al. [26] reported that allogeneic leukocytes mediate the effect more strongly than red blood cells or plasma. Early scholars have assumed that there is a relationship between allogeneic blood transfusion and systemic immunity. Moreover, some studies discovered that allogeneic blood transfusion can occur similar to drug-induced immunosuppression [27]. Refaai and Blumberg [3] systematically summarized the effect of allogeneic blood transfusion on the immune system, including ① reduced cytokine production of T helper type 1 in vitro, mixed lymphocyte culture response, proliferation response of mitogen or soluble antigen in vitro, the number and activity of natural killer cells in vitro, the number of CD4 helper T cells, monocyte/macrophage function in vitro and in vivo, and cell-mediated cytotoxicity against target cells in vitro; ② increased cytokine production of T helper type 2 in vitro, suppressor function or the number of CD8 T cells in vitro, the number and function of T regulatory cells, and enhanced production of anti-idiotypic antibodies that inhibit mixed lymphocyte responses in vitro; ③ damaged delayed-type hypersensitivity skin reaction; and ④ human alloimmunization leading to cell-related and soluble antigen. Most of the immune changes were related to white blood cells in blood products, and reducing whole blood transfusion and filtering white blood cells can effectively reduce the risk of infection after surgery[28, 29].

The advantages of this study were that it had a more accurate search strategy and it excluded case-control studies when reading the full text, including only cohort studies, which can effectively reduce heterogeneity between all eligible studies and make the pooled estimates more accurate and credible while not missing important information from case-control studies. However, this study still had limitations in terms of design and research. Firstly, we failed to include randomized controlled trials when searching and selecting studies; hence, the level of clinical evidence found was relatively low and the value of the results was limited. Secondly, there were only a few studies involved; hence, the efficiency of the Egger and Begg tests was low and the publication bias could not be estimated effectively. Thirdly, the sample size of each study differed, resulting in some research weights being too high, which may have affected all the final meta-analysis results.

There are few current studies investigating the relationship between blood transfusion and infections in patients following spinal surgery. Since most of the published studies are retrospective [21], prospective cohort studies with larger sample sizes are needed in the future to find more valuable evidence to explore the mechanism, and better alternative treatments are needed to reduce postoperative complications.

This meta-analysis revealed that blood transfusion was a risk factor for postoperative infection in patients undergoing spinal surgery. Efforts should be made to reduce intraoperative bleeding with more restrictive transfusion policies to decrease the transfusion rate.

SSI: surgical site infection; UTI: urinary tract infection; RR: relative risk; CI: confidence interval.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

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

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported in part by grants from Intec Research Foundation of Jiangsu Transfusion Association (ID: JS20190028).

Authors' contributions

JY and CZ carried out the study design and wrote the manuscript. CZ and YL searched the databases and selected the records. CZ and HJ assessed the methodological quality of the selected studies. XT and JD resolved the discrepancies in literature selection and quality assessment. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

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Table 1. Study characteristics

First author (year) Methodology	Location	Population	Transfused	Not transfused	Surgical approach	Surgical site	Operation duration (min)	Timing	NOS
Aoude (2017) Cohort	America	N = 11588 Mean age: 36.5 Male: n = 5678 Female: n = 5910	N = 171 Infection: n = 3 SSI: n = 3	N = 11417 Infection: n = 69 SSI: n = 69	Anterior and posterior	Cervical vertebra	Transfused: 273.1 ± 139.0 Not transfused: 130.4 ± 73.1	Postoperative	8 Selection: **** Comparability: * Outcome: ***
Elsamadicy (2017) Cohort	America	N = 160 Mean age: 56.84 Male: n = 80 Female: n = 80	N = 60 Infection: n = 24 SSI: n = 1 Pneumonia: n = 3 UTI: n = 11 Other infection: n = 9	N = 100 Infection: n = 19 SSI: n = 0 Pneumonia: n = 5 UTI: n = 5 Other infection: n = 9	Posterior	Spine	Transfused: 289.5 ± 103.83 Not transfused: 201.15 ± 71.48	Intraoperative	9 Selection: ** Comparability: Outcome: ***
Fisahn (2017) Cohort	Europe	N = 56 Mean age: 65.3 Male: n = 20 Female: n = 36	N = 36 Infection: n = 13 SSI: n = 5 Pneumonia: n = 2 UTI: n = 5 Sepsis: n = 1 Clostridium difficile: n = 0	N = 20 Infection: n = 2 SSI: n = 0 Pneumonia: n = 0 UTI: n = 1 Sepsis: n = 0 Clostridium difficile: n = 1	Anterior and posterior	Cervical, thoracic, and lumbar vertebrae	Transfused: 473.8 ± 63.3 Not transfused: 414.6 ± 76.9	Intraoperative	8 Selection: * Comparability: Outcome: ***
Janssen (2015) Cohort	America	N = 3219 Mean age: 54 Male: NR Female: NR	N = 280 Infection: n = 62 SSI: n = 18 Pneumonia: n = 16 UTI: n = 36	N = 2939 Infection: n = 170 SSI: n = 65 Pneumonia: n = 27 UTI: n = 86	Anterior and posterior	Lumbar vertebra	NR	Perioperative	7 Selection: ** Comparability: Outcome: *
Johnson (2017) Cohort	America	N = 963 Mean age: 56 Male: n = 410 Female: n = 553	N = 603 Infection: n = 14 SSI: n = 10 Sepsis: n = 2 Drug-resistant infection: n = 1 Clostridium difficile: n = 1	N = 360 Infection: n = 2 SSI: n = 2 Sepsis: n = 0 Drug-resistant infection: n = 0 Clostridium difficile: n = 0	Posterior	Lumbar vertebra	Transfused: 390 [294, 480] Not transfused: 288 [234, 294]	Perioperative	6 Selection: ** Comparability: Outcome:
Kato (2016) Cohort	Asia	N = 84650 Mean age: 69.2 Male: n = 46247 Female: n = 38403	N = 5289 Infection: n = 385 SSI: n = 221 Pneumonia: n = 67 UTI: n = 66 Sepsis: n = 31	N = 79361 Infection: n = 1971 SSI: n = 1189 Pneumonia: n = 397 UTI: n = 325 Sepsis: n = 60	NR	Lumbar vertebra	Transfused: 379 ± 187 Not transfused: 238 ± 131	Intraoperative	7 Selection: ** Comparability: Outcome: *
Osterhoff (2015) Cohort	Europe	N = 244 Mean age: 53.85 Male: n = 147 Female: n = 97	N = 59 Infection: n = 12 SSI: n = 12	N = 185 Infection: n = 14 SSI: n = 14	Posterior	Thoracic vertebra	Transfused: 190 ± 112 Not transfused: 154 ± 84	Preoperative	8 Selection: **** Comparability: * Outcome: ***
Triulzi (1992) Cohort	America	N = 109 Mean age: 32.4 Male: n = 50 Female: n = 59	N = 24 Infection: n = 5	N = 85 Infection: n = 3	Anterior and posterior	Cervical vertebra; Thoracic vertebra; Lumbar vertebra	Transfused: 309 ± 87 Not transfused: 231 ± 64	Perioperative	9 Selection: ** Comparability: Outcome: ***
NOS: Newcastle-Ottawa Scale; SSI: surgical site infection; UTI: urinary tract infection; NR: not reported

No competing interests reported.

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Association between blood transfusion and infections after spinal surgery: a systematic review and meta-analysis

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Version 1

Abstract

Background

Methods

Results

Conclusion

Trial registration

Figures

Background

Methods

Search strategy

Inclusion and exclusion criteria

Literature selection and data extraction

Methodological quality assessment

Statistical analysis

Results

Selection and characteristics of studies

Correlation analysis between blood transfusion and postoperative infection

Correlation analysis of blood transfusion and different types of infection

Discussion

Conclusion

Abbreviations

Declarations

References

table

Additional Declarations

Supplementary Files

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