Impact of Smoking On Surgical Outcomes For Patients Undergoing Cervical Surgery: A Systematic Review And Meta-Analysis

Objective: To determine whether smoking has adverse effects on outcomes following cervical surgery. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science through 13 July 2021 for cohort and case-control studies that investigated the effect of smoking on outcomes after cervical surgery. Two researchers independently screened the studies and extracted data according to the selection criteria. Results: The meta-analysis included 43 studies, including 27 case-control studies and 16 cohort studies, with 10020 patients. Pooled estimates showed that smoking was associated with higher rates of overall complications (odds ratio [OR]=2.00, 95% condence interval [CI]: 1.63-2.44, p<0.00001), respiratory complications (OR=3.14, 95% CI: 1.94-5.08, p<0.00001), reoperation (OR=2.22, 95% CI: 1.41-3.49, p=0.005), dysphagia (OR=1.49, 95% CI: 1.07-2.07, p=0.02), wound infection (OR=3.19, 95% CI: 1.64-6.21, p=0.0006), axial neck pain (OR=1.97, 95% CI: 1.25-3.10, p=0.003), and a lower rate of fusion (OR=0.63, 95% CI: 0.49-0.81, p=0.0003). There were no signicant differences between smoking and non-smoking groups in terms of operation time (mean difference [MD]=0.08, 95% CI: - 5.54 to 5.71, p=0.98), estimated blood loss (MD=-5.31, 95% CI: -148.83 to 139.22, p=0.94), length of hospital stay (MD=1.01, 95% CI: -2.17 to 4.20, p=0.53), Visual Analog Scale-neck pain (MD=-0.19, 95% CI: -1.19 to 0.81, p=0.71), Visual Analog Scale-arm pain (MD=-0.50, 95% CI: -1.53 to 0.53, p=0.34), Neck Disability Index (MD=11.46, 95% CI: -3.83 to 26.76, p=0.14), and Japanese Orthopaedic Association Scores (MD=-1.75, 95% CI: -5.27 to 1.78, p=0.33). Conclusions: Smokers appear to be more likely than non-smokers to suffer higher rates of overall complications, respiratory complications, reoperation, longer hospital stay, dysphagia, wound infection, axial neck pain, and a lower fusion rate following cervical surgery. It is essential to provide timely smoking cessation advice and explanation to patients before selective cervical surgery. advice and explanation to patients before selective cervical surgery.


Introduction
Cigarette smoking is a signi cant public health concern worldwide. Approximately 20% of adults in the US currently smoke cigarettes, responsible for up to 20% of all deaths each year 1 . In some cervical surgeries, more than half of the patients are smokers [2][3][4] . Smoking is highly detrimental to health and associated with cancer, respiratory disease, and cardiovascular disease 5 . A growing body of evidence shows that smoking is a signi cant risk factor for adverse surgical outcomes after spine surgery [5][6][7][8] .
The relationship between smoking and outcomes of cervical surgery has not been well evaluated. Some studies suggest that smoking may be associated with poorer outcomes after cervical surgery, including lower fusion rates 9,10 . Smoking has been independently linked to higher blood loss 11 , longer lengths of stay 2,11 , and higher reoperation rates 12,13 . There is also an increased risk of perioperative complications, including dysphagia, airway obstruction, nerve palsy, reintubation, axial neck pain, wound infection, deep venous thrombosis, pneumonia, and pseudarthrosis 7,11,12,14−17 . Pain control and functional outcomes have also been shown to be less favorable in smoking patients 18,19 .
Nevertheless, some studies disputed these ndings and suggest no relationship between smoking and adverse surgical outcomes after cervical surgery 18,20,21 . Some researchers even found that the incidence of complications in smokers was lower than that of non-smokers after posterior cervical fusion 22 . We performed the present study to resolve these discrepancies. To the best of our knowledge, there have been no previous systematic reviews and meta-analyses assessing the association between smoking and outcomes of cervical surgery.

Literature Search Strategy
This meta-analysis was performed following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) statement 23 . PubMed, Embase, Cochrane Library, and Web of Science electronic databases were searched from inception to 13 July 2021 using the MeSH terms "smoking," "cervical vertebrae," "surgical procedures, operative," and their corresponding free terms (Appendix S1). The search was restricted to human subjects. In addition, we also review the list of references for retrieved papers and recent reviews.

Inclusion And Exclusion Criteria
The inclusion criteria were as follows: (1) The study design was cohort or case-control; (2) the study population consisted of smokers and non-smokers who underwent cervical surgery; (3) the study compared outcomes, including operating time, pain score, functional score, reoperation rate, length of hospital stay, estimated blood loss, fusion rate, and postoperative complications. Exclusion criteria were as follows: (1) reviews, letters, case reports, systematic reviews, animal studies, non-comparative studies, and studies that were unrelated to our topics; (2) the study did not involve any of the outcomes listed in the inclusion criteria; (3) duplicated publications from the same hospital or research center. For accepted articles covering the same population or subpopulation, the most informative articles or complete studies were used to avoid duplication of information. Disagreements between investigators were resolved by discussion and consensus.

Data Extraction
Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and data were extracted independently by two reviewers and examined by the other authors. Any disagreements were resolved by consensus or discussion with a third reviewer. The following information was extracted from the studies: (1) the general study information (name of the rst author, publishing date, country, study design, sample size, age, gender, surgical procedure, follow-up time, and de nition of smoking); (2) perioperative parameters, including operative time, estimated blood loss, and length of hospital stay; (3) clinical outcomes, including visual analog scale (VAS) of both neck pain and arm pain, Neck Disability Index (NDI), and Japanese Orthopaedic Association Scores (JOA); (4) complications, fusion rate and reoperation rate; the complications included dysphagia, airway obstruction, nerve palsy, reintubation, axial neck pain, wound infection, deep venous thrombosis, pneumonia, and pseudarthrosis. For continuous outcomes, we extracted the mean and standard deviation, and participant numbers were extracted. For dichotomous outcomes, we extracted the total numbers and the numbers of events of both groups. The data in other forms was recalculated when possible to enable pooled analysis.

Methodological Quality
Two reviewers independently applied the Newcastle-Ottawa Scale (NOS) to evaluate the methodological quality of the included studies 24 . The NOS is a scoring checklist for solving design and implementation issues of a cohort or case-control study, consisting of participant selection, comparability of cases and controls, exposure, and outcomes. If the study is awarded six or more stars, it was considered a high-quality study and was analyzed.

Statistical Analysis
We used Review Manager version 5.4 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) 25 to generate forest plots and the funnel plot to determine whether there was a statistical association between the case and control groups and to assess heterogeneity of the included studies.
Dichotomous outcomes were expressed as odds ratios (ORs) with 95% con dence intervals (CIs); continuous outcomes are expressed as the mean differences (MDs). Heterogeneity was quanti ed evaluated using the chi-square based Cochran's Q statistic 26 and the I² statistic, which yields results ranged from 0 to 100% (I² = 0-25%, no heterogeneity; I² = 25-50%, moderate heterogeneity; I² = 50-75%, large heterogeneity; and I² = 75-100%, extreme heterogeneity) 27 . In cases of substantial heterogeneity, the random-effects model was applied. Otherwise, the xed-effects model was used. When heterogeneity was present, a 'leave-one-out sensitivity analysis was performed by iteratively removing one study at a time to con rm the source of the heterogeneity. Analysis was then performed without the study to determine if heterogeneity was still present and if so, random-effects modeling was used. For the primary outcomes, subgroup analyses were carried out according to surgical approach (anterior or posterior cervical surgery). Publication bias was assessed using visual inspection of the funnel plot with the Begg 28 and Egger tests 29 . STATA version 12.0 (StataCorp, College Station, TX) was used for Begg and Egger tests. All statistical tests were two-sided, and p-values of <0.05 were considered statistically signi cant.

Identi cation of Eligible Studies
A owchart of the search and study selection process is shown in Fig. 1. The electronic search identi ed a total of 352 citations (69 from PubMed, 212 from EMBASE, 20 from the Cochrane Library, and 51 from the Web of Science). After screening titles and abstracts and removal of duplicates, 122 were considered of interest; the full text of these 122 studies was retrieved for detailed evaluation; 79 studies were excluded, and 43 studies were ultimately included in the meta-analysis 2-4,7,9-

Characteristics Of Included Studies
Characteristics of the studies are summarized in Table 1. The 43 independent observational studies included in this meta-analysis were published from 1995 to 2021. These forty-three studies included 10,020 patients, including 3,107 smokers and 6,913 non-smokers. Twenty-seven studies were conducted in the United States and seven in China. The other nine were conducted in India, Japan, Czech Republic, Italy, Korea, Singapore, and Taiwan. Of these, 16 were cohort studies, and 27 were case-controls. Patients in twenty-eight studies underwent anterior cervical surgery 57 , eight underwent posterior cervical surgery 4,12,14,15,36,40,41,48 , and the remaining seven underwent anterior and posterior cervical surgery 2,7,13,21,35,42,50 .

Quality Of Included Studies
Because all included studies were cohort studies or case-control studies, the quality of each study was evaluated using the NOS (maximum of nine stars) in three categories: selection, comparability, and exposure or outcomes. According to the NOS scale, all included studies were considered to be of high-quality: 21 were awarded eight stars, 13 were awarded seven stars, and 9 were awarded six stars ( Table 2). The meta-analysis revealed that the incidence of postoperative complications in smokers was signi cantly higher than that of non-smokers (OR=1.88, 95% CI: 1.46-2.76, p<0.0001). Because of the heterogeneity (I²=52%), a sensitivity analysis was performed. The study of Reinard et al. 2 excluded patients with a recombinant human bone morphogenetic protein associated with dysphagia after cervical surgery 58 . It may affect the incidence of postoperative dysphagia. Excluding this paper reduced I² to 47% (Fig. 2). Re-analysis using a xed-effects model revealed that, compared with non-smokers, smokers had a higher incidence of complications (OR=2.00, 95% CI: 1.63-2.44, p<0.00001).

Respiratory Complications
Six studies reported the postoperative incidence of respiratory complications, including dyspnea, reintubation, airway obstruction, pneumonia, and tracheotomy 7,11,20,35,48,53 . There was signi cant heterogeneity (I²=54%, p=0.06); therefore, the random-effects model was used. Pooling of the results demonstrated that the incidence of respiratory complications in smokers was signi cantly higher than that of non-smokers (OR=2.34, 95% CI: 1.04-5.26, p=0.04). After performing sensitivity analysis and removing the study by Sagi et al. 53 a higher proportion of patients who had exposure of C4 or above compared with other studies, the heterogeneity was reduced to 37% (Fig. 3). Fixed-effects modeling showed that the incidence of respiratory complications in smokers was signi cantly higher than that of non-smokers (OR=3.14, 95% CI: 1.94-5.08, p<0.00001).

Reoperation
The number of patients who underwent reoperation was provided in eight studies 4,[11][12][13]20,42,47,50 . Signi cant heterogeneity was observed, and a randomeffects model was used (I²=58%, p=0.02). Pooling of the results demonstrated that the incidence of reoperation in the smoking group was signi cantly higher than that of the non-smoking group (OR=1.94, 95% CI: 1.0-3.80, p=0.05). When performing statistical analysis of Mangan et al. 47 , we de ned the sum of current and former smokers as the total number of smokers. We then removed Mangan et al., performed a sensitivity analysis, and found that heterogeneity was reduced to 39% (Fig. 4). Re-analysis using a xed-effects model revealed that the incidence of reoperation in the smoking group was signi cantly higher than that of the non-smoking group (OR=2.22, 95% CI: 1.41-3.49, p=0.005).

Axial Neck Pain
Three studies reported the postoperative incidence of axial neck pain 15,40,45 . Signi cant heterogeneity was observed, and a random-effects model was used (I²=64%, p=0.06). Pooling of the results shows no signi cant difference in the incidence of axial neck pain after cervical surgery between smokers and nonsmokers. (OR=1.54, 95% CI: 0.75-3.16, p=0.24). After performing sensitivity analysis and removing the study by Liu et al. 45 the only article on anterior cervical surgery, the heterogeneity was reduced to 39% (Fig. 8). Fixed-effects modeling revealed that the incidence of axial neck pain in the smoking group was signi cantly higher than that of the non-smoking group (OR=1.97, 95% CI: 1.25-3.10, p=0.003).

Operation Time
The operation time was provided in two studies 21,49 . No signi cant heterogeneity was observed, and a xed-effects model was used (I²=0, p=0.96). Pooling of the results revealed no signi cant difference in operation time after cervical surgery between smokers and non-smokers (MD=0.08, 95% CI: -5.54 to 5.71, p=0.98; Fig. 9).

Estimated Blood Loss
The estimated blood loss was provided in three studies 2,11,49 . Signi cant heterogeneity was observed, and a random-effects model was used (I²=66%, p=0.05). Pooling of the results revealed no signi cant difference in estimated blood loss after cervical surgery between smokers and non-smokers (MD=-5.31, 95% CI: -148.83 to 139.22, p=0.94; Fig. 10). After performing leave-one-out sensitivity analysis, the heterogeneity did not change substantially and remained signi cant.

Length Of Hospital Stay
The length of hospital stay was provided in four studies 2 Fig. 15). After performing leave-one-out sensitivity analysis, the heterogeneity did not change substantially and remained signi cant.

Subgroup Analysis
For primary outcomes, we conducted subgroup analysis based on the type of surgical approach. In patients who underwent anterior cervical surgery, smoking had adverse effects on overall complications (OR=1. 71 Fig. 17, Fig. 18), and funnel plots showed a symmetric distribution, indicating no publication bias. (Fig. 16).

Discussion
The major purpose of the present meta-analysis was to determine whether smoking has adverse effects on surgical outcomes after cervical surgery. Our results suggest that smoking is associated with a higher risk of reoperation and postoperative complications, including dysphagia, axial neck pain, and wound infection. Smokers had a higher incidence of overall complications and respiratory complications and a lower fusion rate. There were no signi cant differences among smokers and non-smokers concerning outcomes, including operation time, estimated blood loss, length of hospital stays, VAS-neck pain, VAS-arm pain, NDI, or JOA. Our results suggest that smoking might have adverse effects on surgical outcomes in patients who undergo cervical surgery.
Complications were the primary outcome to evaluate the safety of cervical surgery among smoking patients. Siemionow et al. conducted a study of 35 patients undergoing anterior and posterior cervical decompression and fusion and reported that smoking appeared to be the most critical factor related to perioperative complications; the risks for at least one perioperative complication were 50% and 31.6% for smokers and non-smokers, respectively 7 . Lau et al.
studied 160 patients undergoing anterior cervical corpectomy and found that smoking patients had longer hospital stays, more bleeding, a higher rate of pseudarthrosis, and more complications at 30 days than non-smoking patients 11  We assessed perioperative outcomes, including operation time, estimated blood loss, and length of hospital stay in our meta-analysis and failed to nd any signi cant difference between the smoking and non-smoking groups. As measured by NDI, JOA, and VAS, functional recovery was similar between the two groups. This nding indicates that cervical surgery might offer similar functional outcomes in smoking patients. However, the relatively small sample size limited the generalizability of this conclusion.
After cervical surgery, smokers had a higher reoperation rate and a lower fusion rate. In this meta-analysis, given that functional improvement between the groups was similar, it is possible that higher reoperation rates were directly related to the higher incidence of complications in smoking patients, including wound infection, respiratory complications, and pseudarthrosis. Through subgroup analysis, we found that smoking did not in uence reoperation rates for patients undergoing anterior cervical surgery, while higher rates were found for smoking patients undergoing posterior cervical surgery. Due to limited data, we did not perform a subgroup analysis based on the type of surgical procedure.
There are several potential explanations for the observed association between smoking and adverse effects on the surgical outcomes for patients after cervical surgery. First, cigarette smoke products have been shown to inhibit prostacyclin production, a potent vasodilator, and an inhibitor of platelet aggregation. This effect can lead to impaired blood ow and increased blood viscosity, resulting in impaired blood supply 60-64 , leading to decreased angiogenesis and epithelialization 65 . Moreover, inhibition of revascularization by nicotine was observed in a rabbit study, and this mechanism may retard cellular metabolism and promote tissue degeneration 66 . Second, at the cellular level, nicotine has been shown to inhibit proliferation, differentiation, and collagen synthesis in osteoblasts 67 , which was the primary determinant of the tensile strength of a surgical wound 68 . Free radicals produced by burning cigarettes have been associated with cell membrane destabilization, impair osteoblasts' mitochondrial oxidative function and lead to local tissue hypoxia 60,69-73 .
Third, it is well-documented that smoking harms bone physiology, resulting in decreased bone mineral density, impaired bone metabolism, and accelerated osteoporosis, with resulting lower fusion rates 74 . Animal and in vitro studies found that nicotine impaired bone healing, retarded bone formation and growth, and decreased graft biomechanical properties 75,76 .
Finally, cigarette smoke contains many toxic ingredients. Nicotine, tar, and other components irritate mucous membranes of the respiratory tract and cause cilia of bronchial epithelial cells to become shorter and irregular, which can hinder the movement of ciliary bodies, reduce local resistance, weaken phagocytosis and sterilization functions of alveolar phagocytes, leading to bronchospasm and increased airway resistance 77 . For these reasons, smokers are susceptible to respiratory complications after cervical surgery. In addition, carbon monoxide combines with hemoglobin, reducing the oxygen-carrying capacity of the blood, and hydrogen cyanide inhibits cytochrome c, which leads to inhibition of aerobic metabolism 78 .
To the best of our knowledge, our meta-analysis, on the basis of 16 cohort studies and 27 case-control studies, is the rst, also the largest and most comprehensive assessment to investigate the association between smoking and outcomes of cervical surgery. The main strength of this systematic review and meta-analysis is the thorough literature search, careful study selection with strict inclusion criteria, and comprehensive assessment of methodological quality of included studies using the NOS, which is the accepted standard currently. In addition, we performed subgroup analysis according to the surgical approach for the primary outcomes. Although we found signi cant heterogeneity in several outcomes among the included studies, the sensitivity analysis showed no signi cant change, suggesting that the pooled estimate in our study was stable. Finally, publication bias was assessed by visually inspecting funnel plots and quantitatively evaluated using Begg and Egger linear regression tests.
This systematic review and meta-analysis has several limitations that are worthy of comment. First, studies included in our review span over two decades (1995 to 2021), during which advancements in cervical surgery techniques might have improved outcomes. Despite this, point estimates for earlier and more recent studies were similar. Second, all of the included studies were retrospective observational trials rather than randomized controlled trials. The inherent nature of observational trials may be associated with selective bias, which might have in uences on our results. Third, in most studies, the de nition of smoking was not standardized, and self-reporting introduces recall bias or response bias because non-smokers may be current or former smokers. Therefore, the true impact of smoking may be larger than we have reported here. Moreover, the de nition of complications was not uniform and might introduce an additional source of bias. Fourth, since most of the information collected was not used to answer speci c questions, all characteristics of smoker and nonsmoker cohorts such as age, sex, BMI, ethnic group, indications for surgery, and comorbidities were not necessarily consistently matched, leaving some possible residual confusion. What's more, due to the limited number of articles, we did not compare the various types of cervical surgeries in detail. Nevertheless, we attempted to perform a subgroup analysis for the primary outcomes via the surgical approach. Finally, we do not know how investigators con rmed that their patients did not smoke before or after surgery or even if they quitted smoking before surgery, which may have impacted the evaluated results.
One study analyzed the pack-year history and found that, after lumbar surgery, nicotine exposure was associated with an increased risk of disease, and there was a dose-response trend; but this trend was not signi cant 79 . On the contrary, another study did not support this view and found that after anterior cervical discectomy and fusion, pack-years were not signi cantly associated with greater odds of developing any one complication or any major complication 80 . This may be related to differences in the number, characteristics, surgical sites, and follow-up time of the population included in the study. Therefore, there is an urgent need for further high-quality studies that are su ciently prepared and designed with su cient detail to adjust for multiple confounders and allow exploration of dose-response relationships.
Some researchers reported that preoperative smoking cessation might improve surgery outcomes and could lower medical costs by decreasing postoperative complications and length of post-surgical hospital stay among smokers 11,81 . Sørensen et al. performed a meta-analysis and found that smoking cessation reduced the risk of surgical site infection in plastic and general surgery patients by more than half 82 . Andersen et al. found that quitting smoking signi cantly increased the rate of fusion after spinal surgery compared to those who continued to smoke, bringing it close to the level of non-smokers 83 . This may be related to the rapid recovery of tissue local oxygenation and metabolism after smoking cessation 84 . Therefore, it is theoretically necessary to quit smoking before elective surgery.
Nevertheless, the optimal timing to quit smoking remains a matter of considerable debate. A study showed that quitting smoking 1 to 2 months before surgery can signi cantly reduce the perioperative risk 79 . Another report indicated that smoking cessation must be at least 4 weeks before surgery to be effective 12 .
Thus, exploring the optimal timing to quit smoking before the operation should determine future efforts.

Conclusions
We found signi cant differences in overall complications, respiratory complications, reoperation rate, fusion rate, dysphagia, wound infection, and axial neck pain between smokers and non-smokers after cervical surgery. Our results suggest that smoking increases the rate of adverse outcomes after neck surgeries.
It is crucial to provide timely smoking cessation advice and explanation to patients before selective cervical surgery.

Abbreviations
CIs=con dence intervals; ORs=odds ratios; NR=not reported; NOS=Newcastle-Ottawa Scale; ACDF=Anterior cervical discectomy and fusion; SD=Standard         Forest plot showing the effect of smoking on operation time. CI, con dence interval; df, degree of freedom; SD, standard deviation.

Figure 10
Forest plot showing the effect of smoking on estimated blood loss. CI, con dence interval; df, degree of freedom; SD, standard deviation.

Figure 11
Forest plot showing the effect of smoking on length of hospital stay. CI, con dence interval; df, degree of freedom; SD, standard deviation.

Figure 12
Forest plot showing the effect of smoking on VAS-neck pain. CI, con dence interval; df, degree of freedom; SD, standard deviation.

Figure 13
Forest plot showing the effect of smoking on VAS-arm pain. CI, con dence interval; df, degree of freedom; SD, standard deviation.

Figure 14
Forest plot showing the effect of smoking on NDI. CI, con dence interval; df, degree of freedom; SD, standard deviation.  Begg's funnel plot to evaluate the publication bias of overall complications.

Figure 18
Egger's publication bias plot to evaluate the publication bias of overall complications.

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