Infectious morbi-mortality in thoracic surgery after major resections

Introduction

Background

Approximately 8,000 major resections are performed annually in France for bronchopulmonary cancer (1). This surgery is associated with an estimated mortality rate of 3% within 30 days (2). Infectious pulmonary complications are responsible for most of these deaths (2-5). Early mortality reaches 12.6% in cases of postoperative pneumonia (POP) (3). These complications lead to prolonged hospital stays, more frequent use of intensive care services, and more frequent readmissions, despite advances in anesthesia, surgery, and rehabilitation (2,5-7). Additionally, these complications impact early mortality at 30 and 90 days, as well as 5-year survival rates (4,8-10).

Rationale and knowledge gap

Major pulmonary resection surgeries, including segmentectomy, lobectomy, bilobectomy, and pneumonectomy, are classified as Altemeier II due to bronchial section, equating to a 5% to 10% risk of surgical site infection (SSI), and manifesting as wound infections, pleuritis, and empyemas. In France, this risk is covered by prophylactic cefazolin in accordance with the recommendations of the Société Française d’Anesthésie Réanimation (SFAR), Société de Pathologie Infectieuse de Langue Française (SPILF), and Société Française de Chirurgie Thoracique et Cardio-Vasculaire (SFCTCV) (11). Specifically, it consists of the intravenous administration of 2 g of cefazolin, with an additional 1 g every four hours until the end of the procedure. Cefuroxime (1.5 g) or amoxicillin-clavulanic acid (2 g) are alternatives if needed. In case of a beta-lactam allergy, 900 mg of clindamycin combined with 6 mg/kg of gentamicin is recommended.

However, this definition of SSI does not include POP, whose impact has been highlighted above. POP fall under the category of early nosocomial pneumonias, occurring within the first five days of hospitalization. They are linked to commensal pathogens colonizing the airways [S. pneumoniae, H. influenzae, Enterobacteriaceae, and methicillin-sensitive S. aureus (MSSA)]. POP should also be distinguished from ventilator-associated pneumonias (VAP), which are late nosocomial pneumonias occurring after five days of mechanical ventilation and involving resistant pathogens, such as P. aeruginosa, methicillin-resistant S. aureus (MRSA), or beta-lactamase-producing resistant Enterobacteriaceae (12,13). Therefore, management and prevention of POP must differ from those of SSI and VAP.

Objective

The following study aims to describe the incidence of POP, as well as the associated mortality, in the Department of Thoracic, Cardiac, and Vascular Surgery, Tours University Hospital, France. This work also seeks to identify the risk factors, pathogens and associated therapeutic management of these infectious complications. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2219/rc).

Methods

Design and data collection

The following cohort is derived from the extraction of the French EPITHOR database as of March 30, 2023 (14). All patients who underwent a major resection at the Tours University Hospital between January 1, 2019, and December 31, 2021, were included. For procedures recorded in the EPITHOR database as having a complication, additional data collection (radiological, bacteriological, and treatments administered) was carried out from their patient records. This additional data collection was conducted to distinguish procedures that required antibiotic therapy during hospital stay or upon discharge (“Antibiotic therapy” group) from those that did not require it (control group). These two groups were compared based on their characteristics and perioperative data to identify risk factors for post-operative use of antibiotic therapy. The design of the groups is detailed in Figure 1. The use of these data was approved by the Ethics Committee for Clinical Research in Thoracic and Cardiovascular Surgery (IRB00012919), and the Institutional Ethics Committee in Human Research of the Regional University Hospital Center of Tours and François Rabelais University of Tours (No. 2022_091). Informed consent was taken from all the patients. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Figure 1 Flowchart. Antibiotic group is identified by a green square. Control group is identified by a grey square. PPC, pulmonary postoperative complications.

In a second phase, the additional data collected for the “Antibiotic therapy” group were used to describe the bacteriological documentation performed, the type of antibiotic therapy used, and their relevance in relation to a clinical score, the Melbourne Group Scale (MGS). The MGS identifies postoperative pulmonary complications (PPCs), a composite criterion encompassing clinically significant atelectasis, pneumonia, and acute respiratory distress syndrome. The use of this PPC criterion and this standardized prognostic score was preferred over POP, whose definition varies according to the studies (10,15-17).

Surgeries and perioperative managements

In our department, we have standardized our surgeries and perioperative management. Video-assisted thoracic surgeries (VATS) are performed using three or four ports, with a utility incision in the 5th intercostal space along the axillary line. Thoracotomies are performed in the 5th intercostal space below the scapula, and we try to spare the latissimus dorsi whenever possible.

Loco-regional anesthesia is achieved through a paravertebral block and a paravertebral catheter for VATS procedures, whereas an epidural catheter is used when a thoracotomy approach is necessary. Drainage is managed with a single chest tube, with suction removed on day 1. If well tolerated when suction is off—without air leakage and with a chest tube output of less than 300 cc—it can be removed on day 1. In hemorrhagic procedures, two drains are inserted, and drain removal begins on day 2.

As soon as patients return to our department after surgery, physiotherapy begins with incentive spirometry and bronchial drainage supervised by a physiotherapist. When needed, beta-2 agonist aerosols and humidification with physiological saline are administered.

Statistical analyses

Results are expressed as percentages, means, and standard deviations. For missing data of continuous variables, we used the mean value of the variable for the entire cohort to replace the missing data. The values are as follows: for forced expiratory volume in one second (FEV₁) 87.4% (11 missing values), for diffusing capacity of the lungs for carbon monoxide (DLCO) 76.3% (31 missing values), and for operative time (OT) 184 minutes (3 missing values). Due to limited numbers, we grouped bilobectomies and pneumonectomies under the term “supralobar resections”. Surgeries performed for resection of primary lung lesions, as well as resections performed for pulmonary metastasis from any primary, pulmonary and extra-pulmonary, are considered “Oncological”. Univariate and multivariate analyses were performed using Student’s t-test, χ² test, Fisher’s test, and logistic regression on EasyMedStat. Data were checked for multicollinearity with the Belsley-Kuh-Welsch technique. Heteroskedasticity and normality of residuals were assessed, respectively, by the White test and the Shapiro-Wilk test. Intercept value was 0.0199 [95% confidence interval (CI): 0.00757–0.0521, P<0.001]. A P value less than 0.05 was considered significant.

Results

The EPITHOR extraction listed 413 major resection procedures, including 9 duplicate records, comprising 261 lobectomies, 128 segmentectomies, 9 bilobectomies, and 6 pneumonectomies. Among these, 107 were recorded as having at least one postoperative complication, and 60 received postoperative antibiotic therapy. Thus, as detailed in Figure 1, the “Antibiotic therapy” group consists of these 60 procedures, while the control group includes the remaining 344 procedures. The demographic characteristics of these two groups are compared in Table 1.

Postoperative antibiotic therapy was introduced for 60 procedures, representing 14.8% of cases. Considering that these antibiotic therapies were initiated for a postoperative infectious complication, the incidence of these complications was estimated at 14.8%. The “Antibiotic therapy” and control groups were comparable for most of the analyzed variables, except for male sex (87% vs. 67%; P=0.004), history of chronic obstructive pulmonary disease (COPD) (23% vs. 12%; P=0.03), and impairment of DLCO (mean DLCO 71%±21.6% vs. 77%±19.2%; P=0.03, 95% CI: −11.2485 to −0.4639).

Perioperative data are summarized in Table 2. Extended OT (209±75 vs. 180±56 min; P<0.001, 95% CI: 12.7236–45.4655), thoracotomy approach (63% vs. 40%; P=0.001) and right upper lobectomy (RUL) (58% vs. 29%, P=0.005) were overrepresented in the “Antibiotic therapy” group. Type of resections, redo surgeries and oncological surgeries were similarly distributed between the two groups.

Main complications other than infections are all overrepresented in the “Antibiotic therapy” group. We decided to include only prolonged air leaks in the univariate and multivariate analyses, as they could contribute to POP. Since arrhythmia, pleural effusion, and pulmonary embolism are more likely consequences rather than causes of POP, we decided not to include them in the multivariate analysis. Similarly, as hemorrhage is not directly linked to POP, it was also excluded from the multivariate analysis. For variables that differed significantly between the two groups, we calculated odds ratios (OR), and pursued a multivariate analysis, reported in Table 3. Extension of OT over 180 minutes (OR 1.95, 95% CI: 1.01–3.75, P=0.046), RUL (OR 2.53, 95% CI: 1.31–4.86, P=0.005), thoracotomy approach (OR 2.68, 95% CI: 1.44–4.97, P=0.002), impairment of DLCO below 50% (OR 3.68, 95% CI: 1.58–8.53, P=0.002), and prolonged air leaks (PAL) (OR 7.98, 95% CI: 2.87–22.2, P<0.001) were associated with higher rates of post-operative use of antibiotic therapy.

Although this is biased by the design of the study itself, we wanted to see how much the “Antibiotic therapy” group differed from the control group in terms of length of stay, surgical revision, and 30-day mortality. These three variables were all more pronounced in the “Antibiotic therapy” group (length of stay 16.1±11.6 vs. 5.7±4.6 days, P<0.001; surgical revision 17% vs. 0%, P<0.001; mortality 12% vs. 0%, P<0.001).

Focusing on the microbiological data collected in the “Antibiotic therapy” group, we were only able to document microorganisms (bacteria, viruses, or fungi) in 43 procedures (72%). This number dropped to 36 procedures (60%) when excluding infections documented solely by urine cytobacteriological examination (UCBE) (5 isolated documentations) and blood cultures (BC) (2 isolated documentations).

Considering the retrospective identification of these 5 urinary tract infections and 2 isolated bacteremias, we reanalyzed the demographic and operative characteristics to see if their exclusion would alter the identified risk factors. The results being similar, we therefore maintained our initial methodology. For informational purposes, the adjusted variables after excluding these non-pulmonary infections for the “Antibiotic therapy” group are as follows: male sex, 86% (n=46); age, 66±11.9 years; body mass index (BMI), 25±5.0 kg/m²; history of COPD, 24% (n=13); FEV₁, 84%±18%; DLCO, 71%±21.7%; DLCO below 50%, 22% (n=12); OT, 207±5 min; OT over 180 mins: 70% (n=37). These non-pulmonary infections were excluded from subsequent analyses, as their etiology and management differ from those of pulmonary origin.

To explore only postoperative infections of pulmonary origin, we focused on the 36 procedures for which documentation was obtained, excluding UCBE and BC. This represents 43 positive samples (17 sputum cultures, 8 bronchial aspirations, 10 bronchoalveolar lavages, 8 pleural fluids) with 55 documented microorganisms; 51 after excluding the 4 fungal documentations (2 A. fumigatus, 1 T. fissilis, 1 P. variotii). Table 4 and Figure 2 summarize the direct examinations, main strains, and primary antibiotic resistances. Direct examinations were obtained after Gram staining. Oropharyngeal flora (OPF) (16 documentations, 29%) were distinguished from other, more classic identifications. Gram-negative bacilli (GNB) represented 47% of the documentations (26 identifications). Gram-positive cocci (GPC) were the third most frequent documentation after GNB and OPF, with 11% of cases (6 identifications). Gram-negative cocci (GNC: 2%, 1 identification) and gram-positive bacilli (GPB: 4%, 2 identifications) were anecdotal. H. influenzae was the most represented strain (7 identifications, 14%), followed by E. coli (4 identifications, 8%). Strains of K. pneumoniae, P. aeruginosa, and S. pneumoniae were found in similar proportions (3 identifications, 6%). Only one MSSA was identified among the positive bronchopulmonary samples. It is important to note that 38 of the 51 identified bacterial strains (75%) were sensitive to amoxicillin-clavulanic acid.

Figure 2 Direct examinations of bacteriological samples excluding urine cytobacteriological examination and blood cultures. GNB, gram-negative bacillus; GNC, gram-negative cocci; GPB, gram-positive bacillus; GPC, gram-positive cocci; OPF, oropharyngeal flora.

The probabilistic antibiotic therapies used, excluding urinary infection and isolated bacteremia, are summarized in Table 5. Most patients were treated with amoxicillin-clavulanic acid (29 cases: 55%) or piperacillin-tazobactam (18 cases: 34%). These antibiotic therapies were initiated, on average, 3.49±3.91 days after surgery, with a mean total duration of 5.58±4.43 days. They were administered according to the standard of care (i.e., 1 gram every 8 hours for amoxicillin-clavulanic acid and 4 grams every 8 hours for piperacillin-tazobactam). Almost half of these therapies were adjusted after reception of the antibiogram (25 adjustments: 47%), with the aim of providing targeted antibiotic therapy.

Finally, to assess the relevance of postoperative antibiotic therapy, we calculated the MGS for each of these 53 uses, taking the most unfavorable score value for the entire stay of each patient. MGS values and details are summarized in Table 6. Overall, 41 patients (77%) presented a PPC (defined by a MGS ≥4). Among these 41 patients, 36 have microbiological documentation, excluding isolated UCBE and BC. Thus, the incidence of confirmed POP (PPC with bacteriological documentation) was 8.9% in this series. The mortality rate related to these POP was 11.3% (6 deaths).

Discussion

Key findings

The incidence of confirmed POP in our series was 8.9% and was associated with a mortality rate of 11.3%. The main risk factors identified were prolonged OT over 180 minutes, thoracotomy approach, RUL, preoperative impairment of DLCO below 50% and PAL. Most of the identified pathogens responsible for POP were commensal (e.g., H. influenzae, E. coli, K. pneumoniae, and S. pneumoniae), and thus sensitive to amoxicillin-clavulanic acid.

Strengths and limitations

Our main limitation is the retrospective nature of our work, subject to missing data, as demonstrated by our inability to analyze VO₂max, despite its prognostic value and its implication in recommendations in case of FEV₁ and DLCO impairments (18,19).

Comparison with similar research

Our results are consistent with the literature. We found an overall 30-day mortality rate of 1.7%, compared to 2.9% nationally in 2020 (2). These data are comparable to the incidence of POP estimated between 3 and 30% in the literature, and the associated mortality rate of 12% (3-5,8-11,13,20,21). Among the risk factors we identified, open surgery and extended OT over 180 minutes have already been described (7,21,22). History of COPD or male gender, significant only in univariate analysis here, have also been described as risk factors for POP (5,10,21). Some factors previously reported in the literature, such as age, overweight, impaired FEV₁, or American Society of Anesthesiologists (ASA) status, were not identified, which could reflect a lack of power of our study (5,9,13,20,21,23). We found that RUL is more subject to post-operative pneumonia, which could be linked to its higher frequency of post-lobectomy atelectasis, as described by Korst et al. in 1997 (24). This is reflected in our MGS values, with 92% of radiological pulmonary consolidation or collapse.

Explanations of findings

This impairment of DLCO, less documented in the literature than FEV₁ impairments, is reported as an important predictive factor of morbidity and mortality (25,26). Lower DLCO values are associated with increased COPD symptoms, reduced exercise capacity, and a higher risk of severe exacerbations (27). Even if the relationship between DLCO impairment and POP cannot be fully explained, it must be seen as a marker of a more fragile state. DLCO impairment is not linearly correlated with FEV₁ impairment, and its reduction below 60% is a mortality factor for COPD patients even outside a surgical context, including those with FEV₁ above 80% (27). However, as with FEV₁ impairments, significant improvement in DLCO values is possible after rehabilitation (28,29).

Concerning the role of RUL in POP, we believe that the anatomic rearrangement due to the lobectomy results in kinking of the bronchi, as described by Chen et al. and Ueda et al. (30,31). This leads to less efficient bronchial drainage, resulting in increased bronchial encumbrance and potentially explaining the higher incidence of POP in this topography. Another possibility could be the loss of collateral ventilation due to the stapling of the small fissure, leading to reduced ventilation of the middle lobe and increased atelectasis, as described by Gudbjartsson for non-obstructive middle lobe syndrome (32).

Extension of OT and the thoracotomy approach, in the era of minimally invasive surgery, reflect a more extensive disease or a more complex surgery, including conversion due to perioperative complications (22). Thus, it seems logical that these patients are at higher risk of post-operative complications. Moreover, thoracotomy is more painful than a minimally invasive approach, leading to reduced ability to cough and, consequently, more atelectasis and POP. PAL might be linked to POP through alterations in lobar or sublobar ventilation. As some of the air flows outside the parenchyma, it might artificially create new dead space areas, leading to more atelectasis. It could also be due to reduced mobilization of the patient, as drainage must be prolonged until the air leaks resolve. These are only assumptions, and more research is needed on this topic.

Implications and actions needed

Proposing respiratory rehabilitation to patients not meeting the DLCO values required for resection surgery remains an option to discuss, even in the absence of FEV₁ impairment (18,27-29). We believe that patients could benefit from a comprehensive pulmonary prehabilitation program, including incentive spirometry, exercise, walking, postural training, and nutritional support if needed. To maximize its effectiveness, this program should be supervised by a physiotherapist or a pulmonologist. However, due to heterogeneity of rehabilitation programs in literature, establishing precise recommendations remains today unfeasible. More data are needed to identify the patients who would benefit the most from such a program.

The recommendations have evolved since, now advocating antibiotic prophylaxis with amoxicillin-clavulanic acid for patients with a history of COPD and for centers with a high incidence of POP. This antibiotic prophylaxis can be extended up to 48 hours postoperatively and could be more important than changing the antibiotic itself, as suggested by Deguchi et al. or Wu et al. (33,34). On the other hand, this change in prophylaxis is based on the difference between pathogens responsible for POP (H. influenzae, P. aeruginosa, and gram-negative bacteria) and those responsible for SSI (Staphylococcus spp.) (11). Our work supports this reasoning, with 75% of identified strains being sensitive to amoxicillin-clavulanic acid. More research is needed to determine which antibiotic prophylaxis is most effective in preventing surgical wound infections and POP.

Conclusions

Our study is consistent with the literature in terms of incidence of POP (8.9%), 30-day mortality (1.7%), and identified risk factors (DLCO impairment below 50%, thoracotomy approach, OT over 180 mins, RUL and PAL). The main identified pathogens are consistent with those responsible for POP (H. influenzae, E. coli, P. aeruginosa, K. pneumoniae, and S. pneumoniae), and are mostly sensitive to amoxicillin-clavulanic acid.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2219/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2219/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2219/prf

Funding: AstraZeneca partially funded data collection of this study (to Antoine Legras).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2219/coif). Antoine Legras reports that AstraZeneca partially funded data collection of this study. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The use of these data was approved by the Ethics Committee for Clinical Research in Thoracic and Cardiovascular Surgery (IRB00012919), and the Institutional Ethics Committee in Human Research of the Regional University Hospital Center of Tours and François Rabelais University of Tours (No. 2022_091). Informed consent was taken from all the patients. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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