PEEP Combined with Antibiotics for the Reduction of Pulmonary Infection Post-Thoracoscopic Segmentectomy in Stage IA Lung Cancer

Summary

This study evaluates the efficacy of positive end-expiratory pressure (PEEP) combined with antibiotics in reducing postoperative pulmonary infections in stage IA lung cancer patients undergoing thoracoscopic segmentectomy. Results show significant improvements in oxygenation, reduced infection rates, and faster recovery, highlighting its potential as an effective perioperative strategy.

Abstract

This study aimed to evaluate the efficacy of positive end-expiratory pressure (PEEP) combined with drug therapy in preventing postoperative pulmonary infections, providing a basis for optimizing perioperative management in clinical practice. This was a retrospective clinical controlled trial that enrolled 140 patients with stage IA non-small cell lung cancer (NSCLC) admitted between January 2023 and January 2025, all of whom underwent thoracoscopic pulmonary segmentectomy. Patients were divided into a control group (one-lung ventilation [OLV], n = 70) and a study group (PEEP + antibiotics, n = 70) based on the treatment method. The primary outcome measures were the rate of pulmonary infection within 7 days postoperatively and oxygenation function. Secondary outcome measures included hemodynamic indicators, pulmonary ventilation status, postoperative inflammatory markers, clinical prognosis indicators, and incidence of complications. The study demonstrated that PEEP combined with antibiotic intervention significantly reduced the incidence of postoperative pulmonary infection (7.14% in the study group vs. 21.43% in the control group, χ² = 5.833, P = 0.016). Dynamic monitoring revealed that the study group exhibited superior SpO₂ decline and oxygenation index (OI) improvement at the end of one-lung ventilation (OLV) and after extubation compared to the control group (P < 0.05), with lower lung ultrasound (LUS) scores in the early postoperative period (0 h, 24 h) (P < 0.05). The study group also showed lower increases in postoperative inflammatory markers (IL-1β, IL-6, CRP) (P < 0.05), shorter extubation time, awakening time, and hospital stay (P < 0.05), and a lower overall incidence of respiratory complications (χ² = 6.295, P = 0.012). PEEP combined with antibiotic pharmacological intervention can effectively reduce the risk of postoperative pulmonary infection in patients with stage IA lung cancer undergoing thoracoscopic pulmonary segmentectomy, alleviate inflammatory responses, promote pulmonary function recovery, and shorten hospital stay, making it a safe and effective perioperative management strategy.

Introduction

Lung cancer poses a significant global health burden, exhibiting high incidence, with the IARC reporting 2.2 million new cases and 1.8 million deaths in 2020¹. Low-dose spiral computed tomography (LDCT) screening and improved imaging technology have markedly enhanced early-stage lung cancer detection rates². Research has demonstrated that implementing LDCT screening among high-risk populations reduces lung cancer-related deaths by 20 % to 40 %³. Early diagnosis of lung cancer has become more achievable. According to the TNM staging system, stage IA non-small cell lung cancer (NSCLC) is characterized by a primary tumor no larger than 3 cm, absence of regional lymph node metastasis, and no distant metastasis, representing an early-stage lesion⁴. Such tumors are usually in a relatively indolent stage of development, with a longer tumor doubling time, and malignant characteristics such as angiogenesis and stromal remodeling have not yet fully manifested. The 5-year survival rate of stage IA patients receiving standardized treatment can reach 80%-90%, with the 5-year survival rate of sub-centimeter lung cancers (≤1 cm) exceeding 90%^5,6,7. Therefore, exploring optimized treatment strategies for stage IA NSCLC is of great significance for improving the overall prognosis of lung cancer.

Since the successful performance of the first pneumonectomy for lung cancer in 1933, the central role of surgical intervention in the treatment of early-stage NSCLC has been clinically validated over a long period. Modern oncology holds that radical surgical resection of localized solid tumors can maximize the reduction of tumor burden and create conditions for cure⁸. For stage IA NSCLC patients, anatomical lobectomy with systematic lymph node dissection achieves a local recurrence rate of less than 5%⁹. With the popularization of the minimally invasive concept and the innovation of technical equipment, video-assisted thoracoscopic surgery (VATS) has become the standard surgical approach for early-stage lung cancer, replacing conventional thoracotomy¹⁰. Among numerous VATS procedures, anatomical segmentectomy has evolved into an important surgical option for the treatment of stage IA NSCLC¹¹. Segmentectomy preserves more healthy lung tissue than lobectomy while maintaining adequate resection margins, benefiting patients with limited pulmonary function¹². Saji et al. compared segmentectomy and lobectomy in peripheral small NSCLC. Results demonstrated non-inferiority of segmentectomy, with superior 5-year overall survival (94.3% vs. 91.1%) and 33.7% lower mortality risk (HR = 0.663), while recurrence-free survival showed no significant difference¹³. Although thoracoscopic segmentectomy is less invasive and associated with faster recovery compared to traditional thoracotomy, the incidence of postoperative complications remains relatively high, especially pulmonary infection^14,15. Research indicates that postoperative pulmonary infection occurs in 5%-30% of thoracoscopic segmentectomy cases, making it a frequent complication^16,17,18. Infection not only prolongs hospital stay and increases medical costs but may also have a significant impact on patients' long-term quality of life¹⁹. Therefore, taking effective measures to prevent postoperative pulmonary infection is of great clinical significance for improving patient prognosis.

Postoperative pulmonary infection following thoracoscopic pulmonary segmentectomy is associated with multiple factors. Among these, one-lung ventilation (OLV), a critical surgical technique, increases postoperative pulmonary complication risks^20,21. To mitigate lung injury induced by OLV, positive end-expiratory pressure (PEEP) ventilation, as a mechanical lung-protective strategy, has garnered considerable attention²². By maintaining a certain level of positive airway pressure at the end of expiration, PEEP effectively prevents alveolar collapse, improves the ventilation/perfusion ratio, and reduces intrapulmonary shunt²³. Studies have demonstrated that moderate PEEP can alleviate ventilator-induced lung injury, diminish inflammatory responses, and aid in the prevention of postoperative pulmonary infection^24,25. However, high-quality evidence-based medicine regarding the optimal timing of application, parameter settings, and duration of PEEP following thoracoscopic pulmonary segmentectomy remains lacking. Additionally, given the multifactorial pathogenesis of postoperative pulmonary infection, single-intervention measures often fail to achieve ideal preventive outcomes. This has spurred researchers to explore comprehensive combined intervention strategies. By building upon the improved pulmonary mechanical environment afforded by PEEP, the concomitant use of prophylactic antibiotics can target potential bacterial infections.

Based on the aforementioned background, this study aims to investigate, through a controlled trial, the preventive effect of PEEP combined with prophylactic antibiotic intervention on postoperative pulmonary infection in patients with stage IA NSCLC undergoing thoracoscopic pulmonary segmentectomy. This study will offer high-quality evidence to inform clinical practice, aid in establishing standardized postoperative pulmonary infection prevention protocols, thereby improving patient prognosis and reducing healthcare resource consumption.

Protocol

The protocol was conducted in accordance with the Declaration of Helsinki, and it was approved by the Ethics Committee of the Second Hospital of Jiaxing (IRB approval number: 2023-066). The study secured a signed informed consent form from every participant. The study employs de-identified data processing, establishing an independent and encrypted database, and implementing a double-blind back-to-back data entry verification system to ensure data quality. In reference to the Strengthening the Reporting of Observational studies in Epidemiology. (STROBE) statement, a multidisciplinary data monitoring committee has been established to conduct blinded assessments of primary outcome indicators. The clinical data management process adheres to the ALCOAC principles to ensure the traceability and integrity of research data, thereby guaranteeing the reliable internal and external validity of the study results.

1. Data and methods

1. Study population
   1. Include patients aged over 18 years, with ASA physical status classification of grades I-III, who underwent thoracoscopic pulmonary segmentectomy and were admitted between January 2023 and January 2025.
   2. Exclusion criteria:
      1. Exclude patients with poor cardiopulmonary function, NYHA classification > grade III, or who are unable to tolerate surgery.
      2. Exclude patients with a preoperative history of radiotherapy or severe pleural adhesion, making thoracoscopic surgery unfeasible.
      3. Exclude patients who had intraoperative conversion to thoracotomy or change to lobectomy.
      4. Exclude patients with a history of previous lung cancer surgery.
      5. Exclude patients with active pulmonary infection.
      6. Exclude patients with hepatorenal insufficiency, Child-Pugh grade C, or estimated glomerular filtration rate (eGFR) < 30 mL/min.
      7. Exclude patients with the presence of pneumothorax or pulmonary bullae. The specific flowchart of this study is shown in Figure 1.
2. Study protocol
   NOTE: The study implemented a uniform perioperative protocol, including 8-h fasting and 4-h fluid abstinence preoperatively. A single senior anesthesiologist conducted all anesthesia procedures following standardized protocols.
   1. Firstly, select a double-lumen endotracheal tube of appropriate size based on the patient's height and weight. After entering the operating room, establish continuous vital sign monitoring and open an upper limb intravenous access.
   2. During surgery, infuse a compound sodium acetate at a rate of 5-7 mL/(kg·h), and guide the blood transfusion therapy based on blood gas analysis results when necessary.
   3. Anesthesia management was divided into two stages: induction and maintenance.
      1. Induce anesthesia in the patient by administering 40 mg of methylprednisolone in combination with 2-4 µg/kg of fentanyl, 0.4 mg/kg of ciprofol, and 0.2 mg/kg of cisatracurium. After insertion of the double-lumen tube, confirm its position via fiberoptic bronchoscopy.
      2. Set the ventilation parameters as follows: During two-lung ventilation, set the tidal volume to 6-8 mL/kg, the respiratory rate to 12-20 breaths/min, the inspiration-to-expiration ratio to 1:2, and FiO₂ to 60%.
      3. During OLV, adjust parameters to a tidal volume of 5 mL/kg and FiO₂ of 100%.
      4. Maintain anesthesia through 1.5%-2.0% sevoflurane inhalation combined with a continuous infusion of remifentanil at 0.02-0.20 µg/(kg·min) and cisatracurium at 3 µg/(kg·min) to maintain muscle relaxation.
      5. Control the mean arterial pressure within ±20% of the baseline value using vasoactive drugs, maintain heart rate at 50-100 beats/min, adjust the respiratory rate to keep PetCO₂ between 35-45 mmHg, and maintain the core body temperature at 36-37 °C.
      6. Before administering any anesthetic drugs, confirm that the patient has no history of allergies and that emergency medications (such as epinephrine and antihistamines) are readily available.
      7. During the anesthesia induction phase, closely monitor blood pressure, heart rate, and oxygen saturation to prevent hypotension, arrhythmia, or respiratory depression. If allergic reactions, bronchospasm, or circulatory instability occur during the surgery, discontinue the the administration of anesthetic drugs immediately, and initiate the emergency rescue protocol.
      8. In addition, during OLV, conduct continuous monitoring of SpO, PaCO₂, and airway pressure to prevent hypoxemia or barotrauma. If SpO₂ remains persistently below 90%, assess the position of the endotracheal tube immediately, perform lung recruitment maneuvers, or resume double-lung ventilation temporarily.
   4. Administer postoperative analgesia using a multimodal approach.
      1. Perform intraoperative ultrasound-guided intercostal nerve block [0.3% ropivacaine], followed by postoperative patient-controlled intravenous analgesia (PCIA) with a formulation consisting of 0.2 mg/kg of butorphanol, 8 mg of azasetron, and normal saline to make up to 100 mL.
      2. Set the background infusion rate at 2 mL/h, with a bolus dose of 2 mL and a lockout interval of 15 min. Provide rescue analgesia if the NRS score is >3.
      3. Before performing a nerve block, confirm that the patient has normal blood coagulation function and that the puncture site is free from infection. Strictly control the use of local anesthetics within the maximum safe dosage range to prevent toxic reactions caused by local anesthetics.
      4. Postoperatively, monitor for complications related to nerve block, such as local anesthetic toxicity, nerve injury, or pneumothorax.
   5. In the control group, provide the patients with standard perioperative management without individualized PEEP titration or enhanced antibiotic prophylaxis.
   6. In the study group, provide the patients with intraoperative special treatments on the basis of the conventional protocol, including: (i) Individualized PEEP titration guided by electrical impedance tomography (EIT) technology and (ii) Enhanced prophylactic antibiotic protocol.
   7. Perform individualized PEEP titration guided by EIT technology.
      1. Use an electrical impedance tomography scanner. After anesthesia induction and before lateral decubitus positioning, paste 16 electrodes evenly between the 4th and 8th intercostal spaces on the chest wall to cover both lung fields.
      2. Collect EIT images every 10 min during OLV to calculate the percentage of ventilation in the gravity-dependent region (GDRV%) and the ventilation inhomogeneity index (VI).
      3. Starting from 6 cmH₂O, increase PEEP in 2 cmH₂O increments, with each adjustment maintained for 5 min until the following criteria are met: GDRV% ≥ 80%, indicating sufficient recruitment of the dorsal collapsed lung; VI ≤ 15%, avoiding overdistension of the ventral alveoli; while monitoring hemodynamic indicators (MAP, CVP, HR) to ensure that PEEP adjustments did not lead to circulatory depression.
      4. For patients with concurrent cardiac dysfunction, pulmonary arterial hypertension, or hypovolemia, adjust PEEP cautiously, and consider advanced hemodynamic monitoring methods such as ultrasound or PiCCO.
      5. If hypotension (a decrease in MAP > 20%), tachycardia, or a significant increase in CVP occurs, reduce PEEP promptly or temporarily suspend the titration.
   8. Perform enhanced prophylactic antibiotic protocol.
      1. Have all patients in the study group receive a complete surgical-site infection prophylaxis.
      2. Choose the drug as follows: First-line: cefazolin sodium (CSPC, China) 2 g (30 mg·kg^-1 if body-weight ≤ 60 kg) i.v. β-lactam allergy: clindamycin phosphate (Xinyi, China) 900 mg i.v.
      3. Concentration /preparation: Reconstitute 2 g of cefazolin in 20 mL of water for injection (WFI). Dilute this further to 100 mL in 0.9% saline (final 20 mg·mL^-1). Clindamycin: Dilute 900 mg in 100 mL of 0.9% saline (9 mg·mL^-1).
      4. Maintain the infusion rate at 100 mL over 15 min (≈ 7 mL·min^-1) to guarantee peak tissue levels at incision. Start the infusion 30 min before pre-skin incision and complete it before tourniquet/draping.
      5. For intra-operative re-dosing, use Cefazolin: 1 g (15 mg·kg^-1) every 3 h from first infusion OR when estimated blood loss ≥ 1,500 mL, whichever occurs first. For clindamycin, use 450 mg every 6 h under the same trigger conditions. No postoperative continuation is necessary. Discontinue all prophylactic courses ≤ 48 h.
   9. In terms of surgical procedures, perform contralateral decubitus VATS segmentectomy in both groups.
      1. Perform anatomical management of pulmonary vessels after VATS exploration, starting with the pulmonary artery, followed by the pulmonary vein.
      2. Divide the bronchus using a stapler, identify the intersegmental plane via the oxygen inflation-deflation approach, and finally, resect the lesion. Achieve hemostasis, perform thoracic cavity irrigation, and place drainage tubes.
3. Outcomes
   1. Main outcome measures
      1. Diagnostic criteria for the incidence of postoperative pulmonary infection: With reference to the "Guidelines for the Diagnosis and Treatment of Hospital-acquired Pneumonia and Ventilator-associated Pneumonia in Chinese Adults"²⁶, ensure the following conditions are met: Imaging manifestations: newly developed or progressive pulmonary infiltrates within 1 week after surgery.
      2. Clinical criteria (at least 2 of the following must be met): Check if the body temperature is>38.0 °C or < 36.0 °C; white blood cell count is >10 × 10⁹/L or <4 × 10⁹/L; purulent sputum or airway secretions; oxygenation index (PaO₂/FiO₂) < 300 mmHg; positive sputum culture or bronchoalveolar lavage fluid culture.
      3. Postoperative oxygenation function: Record oxygen saturation (SpO₂) at the following time points: immediately before anesthesia induction (T₀), 10 min after the application of optimal PEEP (T₁), at the end of OLV (T₂), and after extubation (T₃). Meanwhile, at T₀, T₂, and T₃ time points, collect 1 mL of arterial blood sample, use a blood gas analyzer to measure PaO₂, pH, and PaCO₂, and calculate the oxygenation index (OI).
   2. Secondary outcomes
      1. Hemodynamic indicators: Compare the MAP, CVP, and HR between the two groups. Take measurements upon entry into the recovery room, at 30 min of mechanical ventilation, and after awakening.
      2. At 24 h and 48 h postoperatively, assess the ventilation status of the ventilated lung in patients using the lung ultrasound score (LUS).
         NOTE: LUS is an important tool for evaluating the air-water ratio within the lungs. During the assessment, the lungs are divided into 12 regions, and each region is scored based on its ultrasound findings: well-ventilated regions exhibit A-lines and are scored as 0; discrete B-lines are scored as 1; confluent B-lines are scored as 2; and atelectasis or consolidation regions are scored as 3. A higher score indicates a greater number of alveoli with impaired ventilation and poorer lung ventilation status.
      3. Inflammatory indicators: Collect 5 mL of fasting venous blood from patients preoperatively and on the 3rd day postoperatively, centrifuge at 1000 × g (radius = 10 cm) for 10 min at 4 °C, and then take the supernatant. Use a fully automated biochemical analyzer to detect the levels of IL-1β, IL-6, and CRP.
      4. Clinical prognosis indicators: Record the extubation time, awakening time, and hospitalization duration for both groups.
         NOTE: All biological specimens (arterial blood, venous blood, broncho-alveolar lavage fluid, sputum, swabs, disposable blood-gas syringes, gauze contaminated with blood, and personal protective equipment (PPE) that came into contact with body fluids) were handled and discarded in accordance with China's Regulations on the Management of Medical Waste and the hospital's Biosafety Level-2 guidelines.
   3. Safety outcomes
      ​To calculate/statistically analyze the occurrence rates of hypoxemia, ventilator-associated lung injury, and postoperative pulmonary complications (PPCs) within 1 week after surgery.
4. Sample size calculation
   1. Determine the sample size according to postoperative OI. Preliminary experimental data from 16 patients indicated that, at the T₃ time point, the OI was 391.18 ± 35.27 mmHg in the study group (PEEP + antibiotics) and 365.29 ± 32.33 mmHg in the control group (OLV). Apply a two-sample independent mean comparison hypothesis test, with a two-sided α level set at 0.01 and a power of 90%, to determine the minimum number of participants. Here, each group requires at least 54 participants.
      NOTE: Ultimately, this study decided to enroll 70 patients per group. This sample size design ensures sufficient statistical power to detect differences in oxygenation index between the two groups while meeting the feasibility requirements for clinical research. The sample size calculation was based on preliminary experimental data and employed conservative estimates to account for potential variability, thereby ensuring the reliability of the study results.

2. Statistical analysis

1. Use an appropriate statistical analysis software for all statistical analyses. For primary outcomes, compare the incidence of postoperative pulmonary infection between groups using either the χ2 or Fisher's exact test. Evaluate oxygenation parameters, including SpO₂, PaO₂, and OI, through repeated measures analysis of variance to assess time and group effects.
2. Compare secondary outcomes, i.e., hemodynamic indicators such as MAP, CVP, and HR, as well as LUS scores between groups using t-tests or the Mann-Whitney U test.
3. Analyse changes in inflammatory markers (IL-1β, IL-6, CRP) from preoperative to postoperative day 3 using paired t-tests, with intergroup differences assessed via independent samples t-tests.
4. Compare clinical prognosis measures, including extubation time, awakening time, and hospital stay, using independent samples t-tests. Evaluate safety outcomes with either the chi-square test or Fisher's exact test. Consider P < 0.05 as a statistically significant difference.

Results

The two groups showed comparable demographic and clinical characteristics, including age, gender, ASA classification, BMI, surgical site, operative time, and preoperative pulmonary function, with no statistically significant differences (P > 0.05). Specific data are presented in Table 1.

The incidence of postoperative pulmonary infection was 21.43% in the control group, whereas it was only 7.14% in the study group (χ² = 5.833, P = 0.016). This indicates that PEEP...

Discussion

Lung cancer, a highly prevalent and lethal malignancy, requires early detection and intervention to enhance outcomes. Advances in imaging have improved early-stage diagnosis, with VATS emerging as a preferred minimally invasive treatment for stage IA NSCLC due to its reduced invasiveness and faster recovery²⁷. However, postoperative pulmonary infection is one of the common complications of this surgery, significantly affecting patients' postoperative recovery and long-term prognosis. Therefore...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
0.3% ropivacaine	Guangdong Jiabo Company, China	H20133178	Used for postoperative analgesia
Compound sodium acetate solution	Kelun Pharmaceutical Limited Company, China	H20150049	Infused at a rate of 5-7 mL/(kg·h) during surgery to maintain hemodynamic stability.
Double-lumen endotracheal tube	Covidien, America	125035	Used for one-lung ventilation during thoracoscopic pulmonary segmentectomy.
Lung Ultrasound Score (LUS) assessment tool	Philips Healthcare, Netherlands	Philips CX50	Used to evaluate postoperative pulmonary ventilation status at 0 h, 24 h, and 48 h postoperatively.
Patient-controlled intravenous analgesia (PCIA) pump	Braun, America	8713080U	Contains butorphanol, azasetron, and normal saline for postoperative pain management.
PulmoVista500 Electrical Impedance Tomography Scanner	Dräger, Germany	8420000	Used for individualized PEEP titration during one-lung ventilation (OLV) to optimize recruitment and ventilation homogeneity.