ABSTRACT
Objective
Assess associations between non‐tobacco nicotine usage and free flap repair complications in head and neck cancer (HNC) patients.
Study Design
Propensity‐matched retrospective cohort study.
Methods
The TriNetX database was queried for HNC patients who underwent free flap procedures from 2010 to 2024. Among these patients, the NIC cohort was defined as those with dependence on nicotine prior to surgery, but without the use of cigarettes, chewing tobacco, or other tobacco products. The non‐NIC cohort was defined as patients with no nicotine dependence, cigarettes, chewing tobacco, or other tobacco product use prior to surgery. Cohorts were propensity‐matched based on demographics and comorbidities. Primary outcomes included free flap failure, blood vessel repair, and other revisionary procedures (associated with wound disruption or repair) within 30 days of the primary reconstruction. Secondary outcomes included infection, pneumonia, cardiopulmonary complications, and hematoma within 30 days.
Results
Following propensity matching, 1324 patients were included in each cohort. Across all free flaps, non‐tobacco nicotine use was associated with a significantly increased risk of other revision procedures (RR: 1.230 [95% CI: 1.013, 1.493], p = 0.036), sepsis (RR: 1.563 [95% CI: 1.009, 2.419], p = 0.045), fistula (RR: 1.588 [95% CI: 1.041, 2.423], p = 0.032), cardiovascular complications (RR: 1.420 [95% CI: 1.054, 1.914], p = 0.021), pneumonia (RR: 2.055 [95% CI: 1.570, 2.689], p < 0.001), and pulmonary embolism (RR: 2.220 [95% CI: 1.217, 3.933], p = 0.008).
Conclusions
Non‐tobacco nicotine use is associated with an increased risk of postoperative complications in HNC patients following free flap reconstruction. Screening for non‐tobacco nicotine use in surgical candidates may better inform clinical management and counseling.
Level of Evidence
III
Keywords: free flap repair, head and neck oncology, head and neck surgery, nicotine
Non‐tobacco nicotine use is associated with an increased risk of postoperative complications in HNC patients following free flap reconstruction.
1. Introduction
Recent advances in microsurgery have made free flap repair the preferred treatment for head and neck reconstruction, offering excellent functional and cosmetic results with success rates reaching 95%–98% [1]. While largely successful, this procedure is not without the risk of complications. Postoperative complications include flap failures or the necessity for revision surgery, which have been associated with cardiovascular disease and venous congestion [2]. Associated modifiable risk factors such as diabetes and smoking have also been well‐characterized [3, 4].
Smoking has been associated with an increased risk of postoperative wound disruption, incidence of hematoma, and need for revisionary procedures following HNC free flap reconstruction [5]. Garip et al. reported a 19.12% increase in hematoma incidence in smokers compared to nonsmokers [5]. Additionally, Crippen et al. demonstrated higher rates of unplanned reoperation and increased length of stay in smokers among a cohort of 2193 patients that underwent free flap repair for HNC [4]. While the risks of tobacco‐based products have been widely examined, there is a paucity of literature assessing the impact of non‐tobacco nicotine usage on the risk of postoperative complications in HNC free flap repairs.
Although tobacco smoking prevalence has continued to decrease, unit sales of e‐cigarettes have grown by nearly 300% between 2017 and 2022 [6, 7]. With major tobacco companies such as British American Tobacco aiming to derive 50% of their revenue from “reduced‐risk products” including vapor and tobacco‐free oral products, by 2035, the prevalence of non‐tobacco nicotine usage has grown drastically. In 2021, the CDC reported the prevalence of e‐cigarette usage as 4.5%, accounting for 11.1 million US adults [8]. Alongside the growing popularity of e‐cigarettes, sales of nicotine pouches increased 641% from 126 to 808 million units between 2019 and 2022 [9]. Among middle and high school students in 2024, the CDC reports that 1.63 million (5.9%) students currently use e‐cigarettes, while approximately 497,000 (1.8%) students currently use nicotine pouches [10]. This increased prevalence of non‐tobacco nicotine usage, especially among younger populations, could be attributed to the overall perception of these products as a safer and more convenient alternative to tobacco products and conventional cigarettes [9, 11, 12]. These statistics highlight a growing public health concern that warrants further investigation to better understand the effects and implications of these products. Despite public perception, there is a growing body of evidence suggesting increased risk associated with non‐tobacco nicotine dependence and increased postoperative complications in other surgical specialties [13, 14, 15].
This study seeks to examine the effects of non‐tobacco nicotine products in the context of free flap reconstruction among HNC patients. Utilizing a de‐identified national health database, we performed a 1:1 propensity‐score matching retrospective cohort study to quantitatively examine associations of non‐tobacco nicotine use and postoperative complications in free flap repair for HNC.
2. Methods
2.1. Study Design
This retrospective cohort study was conducted utilizing the TriNetX Research Network, a global health collaborative research platform, which provides access to deidentified retrospective electronic medical records. We queried the US Collaborative Network of 66 health care organizations (HCOs). TriNetX is compliant with the Health Insurance Portability and Accountability Act (HIPAA) and contains only deidentified data. Therefore, this study was exempt from the Northwestern University Institutional Review Board (IRB) review.
2.2. Data Collection
The TriNetX database was queried to identify patients diagnosed with HNC (ICD‐10 codes: C00‐14, C30, C31, C32) who were treated with a free flap reconstruction (CPT codes: 20956, 20970, 20955, 20969, 20962, 15758, 15756, 15757, 15842), from January 1, 2010, to December 14, 2024. The NIC cohort was defined as adult patients ≥ 18 years of age who had a dependence on nicotine (F17) but did not have existing or prior nicotine dependence on cigarettes (F17.21), chewing tobacco (F17.22), or other tobacco products (F17.29). The non‐NIC cohort was defined as adult patients who did not have a dependence on nicotine (F17) and had no personal history of prior use of cigarettes (F17.21), chewing tobacco (F17.22), or other tobacco products (F17.29) before surgery. These cohorts were based on previously published studies on surgical outcomes with non‐tobacco nicotine use [13, 14, 16, 17, 18]. Following patient identification, both cohorts were propensity matched according to age, sex, race, ethnicity, and specific co‐morbidities including hypertensive diseases (I10‐I15), chronic ischemic heart disease (I25), ischemic heart disease (I20‐I25), other forms of heart disease (I30‐I5A), diabetes mellitus (E08‐E13), glomerular disease (N00‐N08), acute kidney failure and chronic kidney disease (N17‐N19), obesity (E65‐E68), other nutritional deficiencies (E50‐E64), and factors influencing health status and contact with health services (Z00‐Z99). These codes were selected based on existing literature studying outcomes in free flap repair for HNC [19].
The primary outcomes measured in this study include free flap failure, blood vessel repair, and other flap revision procedures within 30 days postoperatively. Free flap failure refers to a secondary reconstruction following initial free flap repair, which includes a secondary free flap procedure or a pedicled flap with a named vascular pedicle. Blood vessel repair included procedural codes for blood vessel repair following primary reconstruction, while other flap revision procedures included procedural codes associated with wound repair or breakdown. Secondary outcomes consisted of DVT, sepsis, surgical site infections, fistula, cardiovascular complications, pneumonia, PE, and hematoma presenting within 30 days postoperatively. Diagnosis and procedural codes are available in Table S1. In cases where the incidental outcomes ranged from 1 to 9 patients, TriNetX rounds these values up to 10 for the purposes of patient confidentiality. Patient primary and secondary outcomes were analyzed across all free flaps and then were subdivided by the type of free flap: Bony flaps and soft‐tissue flaps. Patients that underwent both bony and soft‐tissue flaps were excluded from the bony flap and soft‐tissue flap subanalyses.
2.3. Statistical Analysis
Statistical analyses were performed through TriNetX and R Statistical Software 4.1.2 (R foundation, Vienna, Austria). Demographics, co‐morbidities, and primary and secondary outcomes between NIC and non‐NIC cohorts were analyzed through the TriNetX database, which is based on the R, JAVA, and Python platforms [20]. Cohorts were propensity score‐matched (1:1) for demographics and co‐morbidities to maximize the generalizability of this study and minimize confounding bias by controlling for variables that may influence free flap outcomes in HNC patients. Furthermore, demographics and co‐morbidities were matched 1 month before surgery, extending past the procedure date. To reduce order bias, TriNetX creates randomized covariate datasets with patient characteristics when determining propensity scores. Once the propensity scores were calculated, both cohorts were considered balanced if the mean standardized differences were less than 0.1 for each characteristic.
Chi‐squared and Fisher's exact testing were utilized to compare categorical variable frequencies in primary and secondary outcomes between NIC and non‐NIC cohorts. Relative risk (RR) and 95% confidence intervals (CI) were also included to evaluate the outcomes between non‐tobacco nicotine use and free flap outcomes in HNC patients. Statistical significance was defined at an α of 0.05.
3. Results
A total of 11,370 HNC patients who underwent a free flap procedure from 2010 to 2024 were included in the study. Before propensity score matching, the majority of patients were based in the non‐NIC cohort (n = 10,045, 88.4%) compared to the NIC cohort (n = 1325, 11.6%) (Table 1). After 1:1 propensity score matching for age, sex, race, ethnicity, and co‐morbidities, NIC and non‐NIC groups contained 1324 HNC patients each. The mean age was 60.1 ± 10.0 and 60.3 ± 12.4 in the NIC and non‐NIC groups, respectively. In the NIC cohort, there was a predominance of males (n = 983, 74.2%) compared to females (n = 331, 25.0%). In the non‐NIC cohort, there was a similar predominance of males (n = 979, 73.9%) compared to females (n = 338, 25.5%). Patients of non‐Hispanic or Latino ethnicities made up the majority of both the NIC (n = 1036, 78.2%) and non‐NIC cohorts (n = 1062, 80.2%) and both cohorts were predominantly White ([n = 1017, 76.8%], [n = 1048, 79.2%], respectively). Cohorts were balanced as it relates to demographic data and co‐morbid incidence with standardized mean differences < 0.1. Detailed characteristics and comorbidities before and after propensity matching are represented in Tables 1 and 2.
TABLE 1.
Cohort demographics with propensity matching.
| Demographics | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Patients, no. (%) (N = 11,370) | Patients, no. (%) (N = 2648) | |||||
| NIC (N = 1325) | Non‐NIC (N = 10,045) | Std diff. | NIC (N = 1324) | Non‐NIC (N = 1324) | Std diff. | |
| Age, mean ± SD | 60.0 ± 10.1 | 64.3 ± 12.8 | 0.370 | 60.1 ± 10.0 | 60.3 ± 12.4 | 0.025 |
| Sex | ||||||
| Female | 331 (25.0) | 3637 (36.2) | 0.245 | 331 (25.0) | 338 (25.5) | 0.012 |
| Male | 984 (74.3) | 6341 (63.1) | 0.242 | 983 (74.2) | 979 (73.9) | 0.007 |
| Ethnicity | ||||||
| Hispanic or Latino | 48 (3.6) | 469 (4.7) | 0.053 | 48 (3.6) | 44 (3.3) | 0.016 |
| Not Hispanic or Latino | 1037 (78.3) | 7154 (71.2) | 0.163 | 1036 (78.2) | 1062 (80.2) | 0.048 |
| Unknown | 240 (18.1) | 2422 (24.1) | 0.147 | 240 (18.1) | 218 (16.5) | 0.044 |
| Race | ||||||
| White | 1017 (76.8) | 7503 (74.7) | 0.048 | 1017 (76.8) | 1048 (79.2) | 0.057 |
| Black or African American | 127 (9.6) | 599 (6.0) | 0.136 | 126 (9.5) | 115 (8.7) | 0.029 |
| Asian | 21 (1.6) | 442 (4.4) | 0.166 | 21 (1.6) | 18 (1.4) | 0.019 |
| American Indian or Alaskan Indian | 10 (0.8) | 27 (0.3) | 0.068 | 10 (0.8) | 10 (0.8) | < 0.001 |
| Native Hawaiian or other Pacific Islander | 10 (0.8) | 105 (1.0) | 0.031 | 10 (0.8) | 10 (0.8) | < 0.001 |
| Unknown Race | 134 (10.1) | 1154 (11.5) | 0.044 | 134 (10.1) | 120 (9.1) | 0.036 |
| Other | 13 (1.0) | 215 (2.1) | 0.094 | 13 (1.0) | 11 (0.8) | 0.016 |
Abbreviations: NIC, nicotine; Std diff., standardized mean difference.
TABLE 2.
Co‐morbidity demographics with propensity score matching.
| Diagnosis (code) | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Patients, no. (%) (N = 11,370) | Patients, no. (%) (N = 2648) | |||||
| NIC (N = 1325) | Non‐NIC (N = 10,045) | Std diff. | NIC (N = 1324) | Non‐NIC (N = 1324) | Std diff | |
| Hypertensive diseases (I10‐I15) | 679 (51.2) | 4717 (47.0) | 0.086 | 679 (51.3) | 651 (49.2) | 0.042 |
| Acute kidney failure and chronic kidney disease (N17‐N19) | 118 (8.9) | 948 (9.4) | 0.018 | 118 (8.9) | 105 (7.9) | 0.035 |
| Chronic ischemic heart disease (I25) | 238 (18.0) | 1479 (14.7) | 0.088 | 238 (18.0) | 230 (17.4) | 0.016 |
| Ischemic heart disease (I20‐I25) | 249 (18.8) | 1551 (15.4) | 0.089 | 249 (18.8) | 240 (18.1) | 0.018 |
| Other forms of heart disease (I30‐I15A) | 337 (25.4) | 2333 (23.2) | 0.051 | 336 (25.4) | 300 (22.7) | 0.064 |
| Diabetes mellitus (E08‐E13) | 187 (14.1) | 1704 (17.0) | 0.079 | 187 (14.1) | 161 (12.2) | 0.058 |
| Glomerular disease (N00‐N08) | 10 (0.8) | 59 (0.6) | 0.021 | 10 (0.8) | 11 (0.8) | 0.009 |
| Overweight, obesity and other hyperalimentation (E65‐E68) | 115 (8.7) | 1130 (11.2) | 0.086 | 115 (8.7) | 84 (6.3) | 0.089 |
| Other nutritional deficiencies (E50‐E64) | 78 (5.9) | 610 (6.1) | 0.008 | 78 (5.9) | 50 (3.8) | 0.099 |
| Factors influencing health status and contact with health services (Z00‐Z99) | 1110 (83.8) | 7789 (77.5) | 0.158 | 1109 (83.8) | 1107 (83.6) | 0.004 |
Abbreviations: NIC, nicotine; Std diff., standardized mean difference.
3.1. Risk Analysis of Primary Outcomes
Primary outcomes included free flap failure (requiring secondary free flap procedure or pedicled flap with named vascular pedicle), blood vessel repair, and other flap revision procedures (including procedures related to wound repair or breakdown) within 30 days of primary reconstruction. When examining primary outcomes across all flaps, there was a significantly increased risk of other flap revision procedures among the NIC cohort (RR: 1.230 [95% CI: 1.013, 1.493], p = 0.036) compared to the non‐NIC cohort (Table 3). There was no significant difference in the risk of free flap failure or blood vessel repair across the all‐flap analysis. In the bony and soft‐tissue flap subanalyses, there were no significant differences seen in primary outcomes between the NIC and non‐NIC cohorts.
TABLE 3.
Relative risk of primary outcomes between propensity‐matched NIC and non‐NIC cohorts.
| All flaps | After matching patients, no. (%) (N = 2648) | |||
|---|---|---|---|---|
| NIC (N = 1324) | Non‐NIC (N = 1324) | RR (95% Cl) | p | |
| Free flap failure | 58 (4.38) | 56 (4.23) | 1.036 (0.723, 1.484) | 0.847 |
| Blood vessel repair | 131 (9.89) | 106 (8.01) | 1.236 (0.968, 1.578) | 0.089 |
| Other flap revision procedures | 198 (14.95) | 161 (12.16) | 1.230 (1.013, 1.493) | 0.036 |
| Bony flaps | After matching patients, no. (%) (N = 652) | |||
|---|---|---|---|---|
| NIC (N = 326) | Non‐NIC (N = 326) | RR (95% Cl) | p | |
| Free flap failure | 16 (4.91) | 14 (4.29) | 1.143 (0.567, 2.304) | 0.709 |
| Blood vessel repair | 36 (11.04) | 30 (9.20) | 1.200 (0.758, 1.901) | 0.437 |
| Other flap revision procedures | 61 (18.71) | 43 (13.19) | 1.419 (0.990 2.032) | 0.056 |
| Soft‐tissue flaps | After matching patients, no. (%) (N = 1828) | |||
|---|---|---|---|---|
| NIC (N = 914) | Non‐NIC (N = 914) | RR (95% Cl) | p | |
| Free flap failure | 29 (3.17) | 34 (3.72) | 0.853 (0.524, 1.388) | 0.522 |
| Blood vessel repair | 82 (8.97) | 78 (8.53) | 1.051 (0.782, 1.414) | 0.742 |
| Other flap revision procedures | 109 (11.93) | 123 (13.46) | 0.886 (0.696, 1.128) | 0.326 |
Abbreviations: CI, confidence interval; NIC, nicotine; RR, risk ratio.
3.2. Risk Analysis of Secondary Outcomes
Secondary outcomes assessed included DVT, sepsis, surgical site infection, fistula, cardiovascular complications, pneumonia, PE, and hematoma (Table 4). Among all flaps, there was a significantly increased risk of sepsis (RR: 1.563 [95% CI: 1.009, 2.419], p = 0.045), fistula (RR: 1.588 [95% CI: 1.041, 2.423], p = 0.032), cardiovascular complications (RR: 1.420 [95% CI: 1.054, 1.914], p = 0.021), pneumonia (RR: 2.055 [95% CI: 1.570, 2.689], p < 0.001), and PE (RR: 2.188 [95% CI: 1.217, 3.933], p = 0.012) among the NIC cohort compared to the non‐NIC cohort.
TABLE 4.
Relative risk of secondary outcomes between propensity‐matched NIC and Non‐NIC cohorts.
| All flaps | After matching | |||
|---|---|---|---|---|
| Patients, no. (%) (N = 2648) | ||||
| NIC (N = 1324) | Non‐NIC (N = 1324) | RR (95% Cl) | p | |
| Deep vein thrombosis | 62 (4.68) | 59 (4.46) | 1.051 (0.742, 1.489) | 0.780 |
| Sepsis | 50 (3.78) | 32 (2.42) | 1.563 (1.009, 2.419) | 0.045 |
| Surgical site infection | 44 (3.32) | 49 (3.70) | 0.898 (0.602, 1.339) | 0.598 |
| Fistula | 54 (4.08) | 34 (2.57) | 1.588 (1.041, 2.423) | 0.032 |
| Cardiovascular complications | 98 (7.40) | 69 (5.21) | 1.420 (1.054, 1.914) | 0.021 |
| Pneumonia | 150 (11.33) | 73 (5.51) | 2.055 (1.570, 2.689) | < 0.001 |
| Pulmonary embolism | 35 (2.64) | 16 (1.21) | 2.188 (1.217, 3.933) | 0.012 |
| Hematoma | 100 (7.55) | 81 (6.12) | 1.235 (0.930, 1.638) | 0.144 |
| Bony flaps | After matching | |||
|---|---|---|---|---|
| Patients, no. (%) (N = 652) | ||||
| NIC (N = 326) | Non‐NIC (N = 326) | RR (95% Cl) | p | |
| Deep vein thrombosis | 22 (6.75) | 17 (5.21) | 1.294 (0.700, 2.391) | 0.411 |
| Sepsis | 16 (4.91) | 10 (3.07) | 1.600 (0.737, 3.476) | 0.235 |
| Surgical site infection | 15 (4.60) | 20 (6.13) | 0.750 (0.391, 1.439) | 0.387 |
| Fistula | 12 (3.68) | 10 (3.07) | 1.200 (0.526, 2.738) | 0.665 |
| Cardiovascular complications | 31 (9.51) | 13 (3.99) | 2.385 (1.271, 4.474) | 0.007 |
| Pneumonia | 44 (13.50) | 16 (4.91) | 2.750 (1.585, 4.772) | < 0.001 |
| Pulmonary embolism | 10 (3.07) | 10 (3.07) | 1.000 (0.422, 2.370) | 1 |
| Hematoma | 25 (7.67) | 19 (5.83) | 1.316 (0.739, 2.342) | 0.351 |
| Soft‐tissue flaps | After matching | |||
|---|---|---|---|---|
| Patients, no. (%) (N = 1828) | ||||
| NIC (N = 914) | Non‐NIC (N = 914) | RR (95% Cl) | p | |
| Deep vein thrombosis | 35 (3.83) | 38 (4.16) | 0.921 (0.587, 1.444) | 0.720 |
| Sepsis | 30 (3.28) | 21 (2.30) | 1.563 (1.009, 2.419) | 0.045 |
| Surgical site infection | 26 (2.84) | 36 (3.94) | 0.722 (0.440, 1.186) | 0.198 |
| Fistula | 38 (4.16) | 23 (2.52) | 1.652 (0.993, 2.750) | 0.053 |
| Cardiovascular complications | 58 (6.35) | 50 (5.47) | 1.160 (0.804, 1.674) | 0.428 |
| Pneumonia | 92 (10.07) | 60 (6.56) | 1.533 (1.123, 2.094) | 0.007 |
| Pulmonary embolism | 25 (2.74) | 13 (1.42) | 1.923 (0.990, 3.735) | 0.054 |
| Hematoma | 67 (7.33) | 62 (6.78) | 1.081 (0.775, 1.507) | 0.646 |
Note: Bold values indicate statistical significance.
Abbreviations: CI, confidence interval; NIC, nicotine; RR, risk ratio.
Among bony flaps, there was a significantly increased risk of cardiovascular complications (RR: 2.385 [95% CI: 1.271, 4.474], p = 0.007) and pneumonia (RR: 2.750 [95% CI: 1.585, 4.772], p < 0.001) among the NIC cohort compared to that of the non‐NIC. When examining secondary outcomes among the soft‐tissue flaps, the NIC cohort demonstrated a significantly increased risk of sepsis (RR: 1.563 [95% CI: 1.009, 2.419], p = 0.045) and pneumonia (RR: 1.533 [95% CI: 1.123, 2.094], p = 0.007).
4. Discussion
The increasing prevalence of non‐tobacco nicotine products, including e‐cigarettes and nicotine pouches, raises significant concerns regarding their impact on reconstructive head and neck free flap outcomes. Despite their widespread use, the effects of these products on surgical complications remain poorly understood. In this propensity‐matched retrospective analysis of the TriNetX US Collaborative Network, non‐tobacco nicotine use was associated with a significantly increased risk of secondary flap revision procedures associated with wound repair and disruption, sepsis, fistula formation, cardiovascular complications, pneumonia, and PE across all flap types. Non‐tobacco nicotine use was also associated with a significantly increased risk of cardiovascular complications and pneumonia in patients undergoing bony free flap reconstruction. Among patients undergoing soft‐tissue free flap reconstruction, non‐tobacco nicotine use was associated with a significantly increased risk of sepsis and pneumonia.
This study's findings of increased risk of postoperative complications in non‐tobacco nicotine users align with existing literature. Troiano et al. demonstrated that e‐cigarette vapor exposure in a rat model significantly increased rates of free flap necrosis compared to controls, with outcomes comparable to those observed in traditional tobacco smoke exposure [21]. A study by Li et al. found a significantly higher rate of fistula formation among smokers undergoing free flap reconstruction of the tongue and floor of mouth [22]. While this study did not specifically focus on non‐tobacco nicotine, comparable findings in our own study suggest that non‐tobacco nicotine use may similarly increase the risk of fistula development. Postoperative complications associated with non‐tobacco nicotine use are most extensively described in orthopedics. DeShazo et al. found that non‐tobacco nicotine use was associated with a significantly increased risk of infection, DVT, PE, sepsis, prosthetic joint infection, and higher 3‐year revision rate following total knee arthroplasty [14]. Other similar orthopedic studies demonstrate increased risk of sepsis, pneumonia, surgical site infections, and surgical reintervention with non‐tobacco nicotine use following surgery [13, 16]. These studies highlighting the postoperative complications associated with non‐tobacco nicotine in the orthopedic literature are compelling, with results similar to those of our own study, particularly pertaining to the risk of postoperative sepsis, pneumonia, PE, and need for revision procedures. Furthermore, the current study underscores a significant gap in the otolaryngology literature, emphasizing the need for future research to investigate the association of non‐tobacco nicotine use with post‐surgical outcomes across otolaryngology procedures.
Several studies have investigated the pathophysiology of nicotine and wound healing [23, 24, 25]. Nicotine has been shown to induce the release of epinephrine in animal models, resulting in peripheral vasoconstriction and reduced tissue perfusion while also stimulating the production of thromboxane A2, a potent vasoconstrictor [23]. As such, this vasoconstrictive property of nicotine is one hypothesized mechanism thought to contribute to tissue hypoxia and delayed wound healing. Additionally, a study by Lei et al. exposed lung fibroblasts to nicotine and e‐cigarette condensate and found that both substances led to inhibited mitochondrial oxidative phosphorylation that resulted in the inhibition of myofibroblast differentiation [24]. These effects were associated with inhibition of wound healing and gel contraction, suggesting that nicotine contributes to dysregulated wound repair. Another study in mouse models by Xanthoulea et al. found that nicotine led to a downregulation of growth factors such as VEGF, PDGF, TGF‐β1 and TGF‐β2, and the anti‐inflammatory cytokine IL‐10 [25]. This reduced growth factor expression by nicotine is hypothesized to contribute to the detrimental effects on wound healing seen with smoking and nicotine. Other studies have also shown that nicotine can induce vascular dysfunction and promote thrombosis through mechanisms such as endothelial damage, increased platelet activation, and inflammation [26, 27]. While non‐tobacco nicotine use is often perceived as a less dangerous form of nicotine consumption relative to tobacco, literature suggests that nicotine, even without tobacco‐associated additives, has detrimental effects on wound healing and vasculature at the cellular level. These mechanisms likely contribute to the increased risk of secondary procedures related to wound disruption, fistula, cardiovascular complications, and PE found in our study.
Of note, our study found a significantly increased risk of cardiovascular complication in the NIC cohort among all flaps as well as the bony flap subanalysis, while this was not seen in the soft‐tissue flap analysis. While there is limited literature looking at the risk of cardiovascular complications among bony‐ and soft‐tissue flaps, our finding may be a result of the impact of variables such as operative time and blood transfusion requirements which have been associated with cardiovascular complications in previous studies [28, 29, 30, 31, 32, 33]. A large retrospective database study by Cannady et al. showed that bony‐tissue flaps had a significantly greater operative time compared to soft‐tissue flaps [28]. Increased operative time has been found to be a predictor of complications (including cardiovascular complications) in a number of studies examining free flap reconstruction for HNC [28, 29, 30, 31]. Regarding blood transfusion receipt, a previous study of patients undergoing free flap reconstruction for HNC found that bony free tissue transfer was associated with significantly increased odds of blood transfusion receipt compared to soft‐tissue free flaps [32]. In turn, blood transfusion receipt has been associated with increased risk of cardiovascular complications such as myocardial infarction and congestive heart failure among patients undergoing free tissue transfer for HNC [33]. It is possible that through the previously proposed mechanisms, non‐tobacco nicotine use exacerbates the risk of cardiovascular dysfunction that bony‐tissue flap recipients may be particularly predisposed to due to prolonged operating times, increased blood loss, and transfusion requirements compared to soft‐tissue flap recipients.
The association between non‐tobacco nicotine use and increased risk of sepsis and pneumonia is also consistent with existing literature. While the pathophysiology remains incompletely understood, vaping is thought to impair local respiratory immune responses, increasing susceptibility to bacterial and viral infection [34]. Additionally, nicotine has been established as a coordinator of key inflammatory processes through upregulation of c‐reactive protein, soluble intercellular adhesion molecule, and the danger signal machinery high‐mobility group box 1 (HMGB1) [35, 36]. This enhanced inflammatory state may play a role in promoting the pathogenesis of postoperative sepsis and pneumonia. In our study, there was an increased risk of sepsis among all flaps as well as the soft‐tissue flap subanalysis. Furthermore, e‐cigarette use has also been implicated in conditions such as acute lipoid pneumonia, potentially due to the inhalation of aerosolized oils causing local inflammatory responses within distal airways and alveoli [37]. These mechanisms compounded with the already increased risk of pneumonia in free flap repair patients likely contribute to the higher risk of pneumonia found in our study among non‐tobacco nicotine users. Although our study did not differentiate between specific types of non‐tobacco nicotine use, this increased risk may be particularly associated with the use of e‐cigarettes. Future studies should investigate the impact on postoperative outcomes related to e‐cigarette use specifically.
Limitations of this study are consistent with those of retrospective studies utilizing large databases. Database studies such as TriNetX are restricted by the availability of potential variables of interest, such as operative length or amount of blood transfused, which limits the possibility of utilizing a multivariate regression to account for such factors in the analysis. This study relies on proper database coding, which could be influenced by inaccuracies in documenting nicotine dependence and differentiating between tobacco and non‐tobacco nicotine products. Additionally, the use of ICD codes for cohort identification may introduce variability due to subjectivity in physician coding practices. Lastly, the dataset's inability to delineate between specific nicotine product types, such as pouches and e‐cigarettes, or to capture duration and frequency of use, further limits the specificity of our analysis. Previous studies have highlighted challenges in accurately documenting the use of nicotine pouches and e‐cigarettes in electronic health records, underscoring the need for improved preoperative screening for patients using non‐tobacco nicotine products [38].
This study provides insights into the impact of non‐tobacco nicotine use on postoperative outcomes in free flap reconstruction for HNC patients, which has not previously been described. A strength of this study is the use of a large dataset that encompasses a diverse patient population nationwide across a number of healthcare organizations, enhancing the generalizability of our findings. Additionally, the use of propensity score matching allows for a robust comparison between our study cohorts, minimizing bias and enhancing the validity of these findings. By identifying increased risks associated with non‐tobacco nicotine use, this study underscores the need for clinical awareness and appropriate preoperative screening and counseling to mitigate adverse outcomes in free flap reconstruction.
5. Conclusion
This retrospective propensity‐matched cohort study demonstrated that non‐tobacco nicotine use is associated with an increased risk of postoperative complications in patients undergoing free flap repair for HNC. Future prospective studies should explore postoperative outcomes associated with specific types of non‐tobacco nicotine products, accounting for duration and dosage of use. The interplay of non‐tobacco nicotine usage and surgical complications warrants further investigation to inform clinical management as this modality of nicotine consumption continues to grow in popularity.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
TABLE S1. Codes utilized for cohort generation.
Park A. C., Wang L., Fehrenbach M. P., et al., “Non‐Tobacco Nicotine Use and Complications in Free Flap Repair in Head and Neck Cancer,” The Laryngoscope 135, no. 10 (2025): 3630–3638, 10.1002/lary.32178.
Funding: The authors received no specific funding for this work.
This study was submitted for presentation at the 2025 Combined Otolaryngology Spring Meetings—Triological Society Section in New Orleans from May 14–18, 2025.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
TABLE S1. Codes utilized for cohort generation.