Abstract
Background/Aim: We evaluated the usefulness of prophylactic mini-tracheostomy (PMT) and perioperative administration of tazobactam/piperacillin (TAZ/PIPC) in high-risk patients after esophagectomy. Patients and Methods: We retrospectively studied 89 consecutive high-risk patients who underwent esophagectomy for esophageal cancer between January 2013 and December 2021. We defined patients with two or more of the following factors as high risk: age ≥70 years, performance status ≥1, respiratory dysfunction, liver dysfunction, cardiac dysfunction, renal dysfunction, diabetes mellitus, albumin <3.5 g/dl, and Brinkman index >600. Standard management was administered to the first 50 patients (standard group). PMT and TAZ/PIPC were administered to the next 39 patients (combination group). Patient characteristics and short-term outcomes were compared before and after propensity-score matching. Results: Before propensity-score matching, 24-hour urine creatinine clearance, retrosternal route, 3-field lymph node dissection, and open abdominal approach were more common, postoperative pneumonia (13% vs. 36%, p=0.045) and complications of grade ≥3b (2.6% vs. 22%, p=0.01) were less frequent, and the postoperative hospital stay was shorter (median: 23 vs. 28 days, p=0.022) in the combination group than in the standard group. In propensity-score matching, patient characteristics, except for 24-h creatinine clearance and reconstructive route, were matched for 23 paired patients. Postoperative pneumonia (8.7% vs. 39%, p=0.035) and complications of grade ≥3b (0% vs. 26%, p=0.022) were less frequent and postoperative hospital stay was shorter (median: 22 vs. 25 days, p=0.021) in the combination group than in the standard group. Conclusion: PMT with TAZ/PIPC can potentially prevent postoperative pneumonia in high-risk patients after esophagectomy.
Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide (1). It requires multidisciplinary curative treatments, including definitive chemoradiotherapy and esophagectomy with adequate lymphadenectomy plus neoadjuvant chemotherapy (2). However, esophagectomy is a highly invasive procedure with high morbidity and mortality rates (3). Moreover, prevention of respiratory complications is important since postoperative pneumonia worsens prognosis.
Risk factors for respiratory complications after surgery include old age, poor performance status (PS), a smoking history, low lung function, organ dysfunction, preoperative chemoradiotherapy, and recurrent laryngeal nerve palsy (4). Therefore, caution is needed for patients who meet these criteria. Perioperative oral care, respiratory rehabilitation, improvement of nutritional status, and minimally invasive surgery are effective in preventing postoperative respiratory complications (5, 6). However, there are few reports on postoperative procedures or antibiotic choices that have helped reduce the risk of pneumonia.
Postoperative respiratory complications are often caused by atelectasis due to sputum retention or aspiration due to impaired swallowing function. Mini-tracheostomy is a useful procedure that allows nurses to easily suction sputum from the trachea. Moreover, the insertion of a suction tube into the trachea through the mini-tracheostomy can trigger a cough to expel sputum. Prophylactic mini-tracheostomy (PMT) can help prevent postoperative respiratory complications in patients undergoing pulmonary resection for lung cancer (7, 8). However, the clinical value of PMT in patients undergoing esophagectomy is unclear. Sakatoku et al. reported that PMT in high-risk patients who underwent esophagectomy reduced atelectasis and reintubation (9) and may be useful in preventing pulmonary complications.
Cefazolin is generally administered during the perioperative period of esophagectomy to prevent surgical site infections. The guidelines of the Japanese Society of Surgical Infectious Diseases, as well as guidelines from other countries, recommend cefazolin administration (10-14). However, cefazolin is not effective against pneumonia-causing bacteria, including anaerobes and those that are indigenous to the oral cavity. Therefore, instead of cefazolin, early use of antibiotics that target pneumonia-causing bacteria may contribute to prevention of postoperative pulmonary complications.
From these ideas, we have used PMT and broad-spectrum antibiotics in high-risk patients for postoperative pneumonia since January 2018. We evaluated the usefulness of PMT and broad-spectrum antibiotics in high-risk patients undergoing esophagectomy for esophageal cancer.
Patients and Methods
Patients. We retrospectively reviewed data for 176 consecutive patients who underwent esophagectomy for esophageal cancer at the Yamaguchi University Hospital between January 2013 and December 2021. Sixteen patients who underwent salvage esophagectomy, total pharyngo-laryngo-esophagectomy, two-stage esophagectomy, pedicled jejunum reconstruction, or R1/2 resection were excluded (Figure 1). We selected 89 patients by extracting cases at high-risk of respiratory complications, as defined below. Of these, 50 patients from January 2013 to December 2017 were included in the standard management group, and 39 patients from January 2018 to December 2021 were included in the PMT plus tazobactam/piperacillin (TAZ/PIPC) combination group. A 1:1 propensity-score matching analysis was performed, and 23 paired cases were matched (Figure 1). Short-term results, including postoperative complications, were retrospectively examined. This study was approved by the Ethics Committee of the Yamaguchi University Hospital (H2022-033). Informed consent was obtained from the patients.
Flowchart for patient selection. 24hCCr: 24-Hour urine creatinine clearance; Alb: albumin; EF: ejection fraction; FEV1.0%: percentage forced expiratory volume in 1 s; ICG15R: indocyanine green retention rate at 15 min; PMT: prophylactic mini-tracheostomy; PS: performance status; TAZ/PIPC: perioperative tazobactam/piperacillin; VC: vital capacity.
Definition of high-risk respiratory complications. The reported risk factors for morbidity or mortality after esophagectomy include advanced age, poor PS, a smoking history, low pulmonary function, low cardiac function, poor nutrition, poor liver function, poor renal function, and diabetes mellitus (15-19). We defined patients with two or more of the following factors as being at high-risk for postoperative pneumonia: age ≥70 years, PS ≥1, vital capacity <80% or a predicted forced expiratory volume in 1 s (FEV1.0%) <70%, albumin <3.5 g/dl, indocyanine green retention rate after 15 min (ICG15R) >10%, Brinkman index (BI) >600, 24-h urine creatinine clearance (24hCCr) <50 ml/min, ejection fraction (EF) <60%, and diabetes mellitus.
Perioperative management. In the combination group, PMT was performed on the patients using a Minitrach II® (SIMS Portex, Hythe, UK) with the percutaneous Seldinger technique immediately before extubation. TAZ/PIPC (Zosyn®, Taisho Toyama Pharmaceutical Co., Ltd., Tokyo, Japan) (4.5 g) was administered intravenously and repeated at 3 h during surgery and every 8 h after surgery until the inflammatory response was sufficiently reduced. The mini-tracheal tube was extubated after oral intake was initiated.
In the standard management group, patients received intravenous injections of cefazolin (1.0 g) repeated at 3 h during surgery and every 8 h for 2 days after surgery. No PMT was performed. Other perioperative management procedures were the same for both groups. Perioperative physical and respiratory rehabilitation and oral care were provided to all patients. Enteral nutrition was initiated 6 h after admission to the Intensive Care Unit. The tracheal tube was routinely extubated on the first postoperative day, and rehabilitation was resumed after extubation. Oral intake was usually started on the seventh postoperative day.
Surgical procedures. All patients underwent right transthoracic esophagectomy or prone-position thoracoscopic esophagectomy with mediastinal lymphadenectomy, including bilateral recurrent laryngeal nerve lymph node dissection and laparotomy for abdominal lymph node dissection. Cervical lymph node dissection was not performed for lower esophageal cancer without upper mediastinal lymph node metastasis on computed tomography or positron-emission tomography-computed tomography. The gastric tube was selected as the reconstructive conduit in all cases. The mediastinal route was our first choice. However, since patients experienced gastric tube necrosis and severe anastomotic leakage, we switched to the retrosternal route in January 2018. Hence, the post-mediastinal route was more frequently chosen in the standard group, and the retrosternal route was more commonly selected in the combination group.
Definition of postoperative pneumonia. Postoperative pneumonia was defined as the presence of new infiltrates on a chest X-ray or computed tomography, with high fever and/or pathogenic bacteria identified by a sputum culture.
Statistical analyses. Clinicopathological factors were noted as per the Union for International Cancer Control Tumor Node Metastasis Classification of Malignant Tumors, eighth edition (20). Postoperative complications were categorized using the Clavien-Dindo classification, and patients with grade II or higher were defined as having postoperative complications (21). The chi-square test, Fisher’s exact test, Student’s t-test, and Mann-Whitney U-test were used for analysis, as appropriate. A propensity-score matching analysis was performed to compensate for differences in baseline characteristics between the two groups. The logistic regression model included age >70 years, sex, PS >0, EF <60%, vital capacity <80%, FEV1.0% <70%, ICG15R >10%, diabetes mellitus, albumin <3.5 g/dI, BI >600, 24hCCr <50 ml/min, extent of lymph node dissection, thoracic approach, and abdominal approach. Finally, a matched cohort of 23 pairs of cases was obtained from the two groups. All statistical analyses were performed using JMP software (JMP Pro 15 for Windows, SAS Institute, Cary, NC, USA). Statistical significance was set at p<0.05.
Results
Patients’ characteristics. The characteristics of the 89 enrolled patients are presented in Table I and Table II. The mean patient age was 69.6 years, and 72 patients (80.8%) were male. Of the patients, 51 (57.3%) had PS 0. The number of patients with clinical stages I, II, III, and IV was 42 (47%), 21 (24%), 19 (21%), and 7 (8%), respectively. Minimally invasive esophagectomy and hand-associated laparoscopic surgery were used in 96.6% of thoracic approaches and 93.2% of abdominal approaches, respectively. A total of 52 (58.4%) patients underwent 3-field lymph node dissection. The reconstructive route was subcutaneous, retrosternal, or post-mediastinal in 1.1%, 47.1%, and 51.7% of patients, respectively. The median (range) duration of TAZ/PIPC administration in the combination group was 5 (3-9) days, and the median time of mini-tracheal tube removal was postoperative day 9 (range=day 4-18). Before propensity-score matching, no significant differences in age, sex, pulmonary function, prevalence of diabetes, serum albumin level, liver function, and cancer characteristics (location of tumor and clinical stage) were noted between the two groups. On the contrary, 24hCCr was higher and cases with EF <60% were more frequent in the combination group than in the standard management group. Moreover, the standard management group had more cases with PS 1 and BI ≥600 than did the combination group.
Patient profiles and tumor characteristics before and after propensity-score matching of the standard therapy and combination therapy (prophylactic mini-tracheostomy with perioperative tazobactam/piperacillin) groups.
Surgical procedures before and after propensity-score matching of the standard therapy and combination therapy (prophylactic mini-tracheostomy with perioperative tazobactam/piperacillin) groups.
The proportion of surgeries which used the retrosternal reconstructive route, 3-field lymph node dissection, and open abdominal approach was higher in the combination group than in the standard management group. Minimally invasive esophagectomy was more common in the standard management group than in the combination group. No differences were found in operative time, blood loss, or blood transfusions.
After propensity-score matching, there were no significant differences in patient characteristics between the two groups, except for 24hCCr and reconstructive route.
Postoperative outcomes. The short-term outcomes are presented in Table III. Overall, postoperative pneumonia, acute respiratory distress syndrome, recurrent nerve palsy, and anastomotic leakage was present in 26%, 3.4%, 27%, and 17% of patients, respectively. Before propensity-score matching, the incidence of postoperative pneumonia (12.8% vs. 36%, p=0.045) and anastomotic leakage (5% vs. 26%, p=0.01) was significantly lower in the combination group than in the standard management group. There were no significant differences in the incidence of acute respiratory distress syndrome, recurrent laryngeal nerve palsy, paroxysmal tachycardia, chylothorax, or gastric necrosis. Complications of grade 3b or more (2.6% vs. 22%, p=0.01) were significantly fewer and the median postoperative hospital stay was shorter [23 (range=16-86) vs. 28 (range=15-139) days, p=0.007] in the combination group than in the standard management group.
Postoperative outcomes before and after propensity-score matching of the standard therapy and combination therapy (prophylactic mini-tracheostomy with perioperative tazobactam/piperacillin) groups.
After propensity-score matching, the trends remained the same. The incidence of postoperative pneumonia (8.7% vs. 39%, p=0.035) and anastomotic leakage (0% vs. 22%, p=0.049) was significantly lower, complications of grade 3b or more (0% vs. 26%, p=0.022) were significantly fewer, and postoperative hospital stay was significantly shorter [22 (16-86) vs. 25 (15-139) days, p=0.021] in the combination group compared to the standard management group. Other complications did not differ between the two groups.
Discussion
In this study, we demonstrated that PMT and TAZ/PIPC reduce postoperative pneumonia in high-risk patients after esophagectomy. Pneumonia after esophagectomy can be fatal, and its prevention is important for safe surgery. For this, preoperative guidance on smoking cessation, oral care, and respiratory rehabilitation is effective (5, 6). However, these require relatively long-term intervention and patient effort. In contrast, PMT and TAZ/PIPC procedures are reliable interventions, regardless of the patient’s motivation. Sakatoku et al. reported that PMT after esophagectomy reduced the incidence of pneumonia to the same level in both high-risk and low-risk patients (10). Even after lung surgery, PMT prevented fatal complications related to sputum retention and might prevent severe pneumonia that may lead to long-term hospitalization or postoperative hospital death (7).
The use of broad-spectrum antibiotics in the perioperative period is not generally practiced, except for therapeutic administration in emergency surgery. However, since early pneumonia after esophagectomy tends to be severe, the use of antibiotics in the perioperative period may be effective. Pseudomonas aeruginosa had been reported to be the most frequent organism causing pneumonia after esophagectomy (22, 23). Therefore, we decided to administer TAZ/PIPC perioperatively which reduced the incidence of pneumonia. Recently, Higaki et al. reported that ampicillin/sulbactam prevents early onset pneumonia after esophagectomy (24). The key difference between cefazolin and ampicillin/sulbactam in pneumonia treatment is the coverage of obligate anaerobes, such as Bacteroides spp. Similar to ampicillin/sulbactam, TAZ/PIPC is a combination of broad-spectrum penicillin with a beta-lactamase inhibitor and is expected to be effective through a similar mechanism.
However, the risks associated with these two interventions must be considered. Complications of mini-tracheostomy include bleeding during the procedure, tracheal injury, and air way narrowing due to postoperative granulation (25, 26). In this study, only one case each of skin hemorrhage and subcutaneous emphysema occurred, but they were treated conservatively, and we believe that the mini-tracheostomy was performed safely (Table IV). On the other hand, aspiration through the mini-tracheostomy was clinically effective in only 12 out of the 39 cases in this study (data not shown). Mini-tracheostomy is an invasive procedure, and we feel it is necessary to further narrow down the indications.
Complications of mini-tracheostomy in patients treated with the combination therapy of prophylactic mini-tracheostomy with perioperative tazobactam/piperacillin.
Furthermore, the incidence of bacterial resistance due to the use of broad-spectrum antibiotics is a major problem (27, 28). Surveillance sputum cultures were performed on postoperative days 1, 3 and 7, but methicillin-resistant Staphylococcus aureus and other resistant bacteria did not increase in the combination group (Table V). So far, the use of broad-spectrum antibiotics does not seem to have led to the increase of resistant bacteria. Since pneumonia is not only a major cause of postoperative hospital deaths after esophagectomy but also affects the long-term prognosis (29-31), we consider this combination to be acceptable. This postoperative management may be worth implementing in institutions suffering from frequent postoperative pneumonia or in those where esophagectomy in high-risk patients is performed.
Bacteria detected in surveillance culture of sputum from patients treated with standard therapy or with the combination therapy of prophylactic mini-tracheostomy with perioperative tazobactam/piperacillin.
We showed that anastomotic leakage was significantly lower in the combination group than that in the standard management group. The PMT–TAZ/PIP combination is intended to prevent pneumonia and is unlikely to be associated with anastomotic leakage. The choice of reconstructive route differed significantly between the two groups, which may have influenced the difference in the rate of anastomotic leakage. Additionally, we also created gastric tubes with a greater awareness recently of preserving blood flow, and this change in the surgical technique may have contributed to the low incidence of anastomotic leakage.
Study limitations. Firstly, this study was retrospective with a small sample size. Secondly, the reconstruction routes were quite different in the two groups, which may have affected the results. Kikuchi et al. reported that the retrosternal route was associated with significantly less pneumonia than the post-mediasternal route (32). Therefore, the difference in route may have influenced the results. Thirdly, the presence of two interventions did not allow us to measure how effective each was in preventing pneumonia. It is also unclear whether each intervention was truly effective, given the lack of reports on the effects of PMT and antibiotics after esophagectomy. Fourthly, the treatment duration differed between the groups. Advances in perioperative management and proficiency in surgical techniques may have influenced these results. Therefore, a prospective validation with matched patient backgrounds is needed for accurate evaluations. We are planning a prospective comparative study on antibiotic interventions.
In conclusion, PMT and perioperative administration of TAZ/PIPC in high-risk patients are useful in preventing postoperative pneumonia after esophagectomy.
Acknowledgements
The Authors are grateful to Shinsuke Kanekiyo for their great help in planning this study. The Authors would like to thank the staff of the Department of Gastroenterological, Breast, and Endocrine Surgery, Yamaguchi University Graduate School of Medicine for their assistance.
Footnotes
Authors’ Contributions
Mitsuo Nishiyama, Shigeru Takeda and Yusaku Watanabe designed the study, the main conceptual ideas and collected the data. Mitsuo Nishiyama wrote the article with the other Authors’ support. All Authors read and approved the final article.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received February 20, 2024.
- Revision received March 25, 2024.
- Accepted March 26, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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