Pharmacological treatment to reduce pulmonary morbidity after esophagectomy

Abstract Esophagectomy for esophageal cancer is one of the most invasive procedures in gastrointestinal surgery. An invasive surgical procedure causes postoperative lung injury through the surgical procedure and one‐lung ventilation during anesthesia. Lung injury developed by inflammatory response to surgical insults and oxidative stress is associated with pulmonary morbidity after esophagectomy. Postoperative pulmonary complications negatively affect the long‐term outcomes; therefore, an effort to reduce lung injury improves overall survival after esophagectomy. Although significant evidence has not been established, various pharmacological treatments for reducing lung injury, such as administration of a corticosteroid, neutrophil elastase inhibitor, and vitamins are considered to have efficacy for pulmonary morbidity. In this review we survey the following topics: mediators during the perioperative periods of esophagectomy and the efficacy of pharmacological therapies for patients with esophagectomy on pulmonary complications.


| INTRODUC TI ON
Esophageal cancer is one of the major causes of cancer mortality worldwide, with more than 473,000 new cases and 436,000 deaths annually. 1 Esophagectomy for esophageal cancer plays an important role in the strategy for curative treatment, but is associated with considerable morbidity and mortality. [2][3][4] Morbidity after esophagectomy is significantly correlated with poor prognosis and especially pulmonary and infectious morbidities affected for long-term outcomes. [5][6][7][8] Several studies revealed that postoperative pulmonary complications may be an independent predictor of poor long-term survival in patients undergoing resection of esophageal cancers. 5,6,8 Among recent advances in the perioperative multidisciplinary treatments for the prevention of pulmonary complication, 9,10 we focus on pharmacological treatment and discuss immunological mechanisms related to lung injury caused by esophagectomy in this narrative review.

| Lung injury during esophagectomy
As one of the most invasive procedures in gastrointestinal surgery, esophagectomy may occasionally cause lung injury postoperatively. Lung injury is associated with tissue injury by the surgical procedure and onelung ventilation during anesthesia ( Figure 1). 11 Surgical insults cause alterations in the hemodynamic, metabolic, and immune responses of patients in the perioperative period, resulting in postoperative complications such as pneumonia. 12 Furthermore, one-lung ventilation during the operation could damage bilateral lungs, that is, the collapsed lung and the other ventilated lung. In the ventilated lung, high lung volume and ventilating pressure, high fraction of inspired oxygen, and capillary shear stress are related to the development of lung injury. [13][14][15] On the other hand, in the collapsed lung, atelectasis and recruitment, ischemia-reperfusion injury, and manipulation on the lung during the operation are considered to be the main causes of lung injury. 16,17 Not only inflammatory response, but also oxidative stress plays a major role in the development of lung injury following esophagectomy. 11,[18][19][20][21] In the inflammatory and oxidative stress response, the endothelial glycocalyx is considered to represent a common pathway for the lung injury development during one-lung ventilation, because the endothelial glycocalyx is damaged by most of the recognized lung injurious mechanisms. 22 This response spreads from local to systemic reaction, which is also known as the systemic inflammatory response syndrome (SIRS).
SIRS is followed by a compensatory antiinflammatory response syndrome (CARS) as a sequential reaction, which potentially predisposes the host to septic complications. 23

| Cytokine cascades and pulmonary inflammation
Various cytokine cascades, which consist of a complex biochemical network, are activated in acute response to surgical insults and work with diverse effects after invasive surgery. The invasive procedures such as esophagectomy sometimes cause an exaggerated production of proinflammatory cytokines, which can lead to systemic hemodynamic instability or metabolic derangements. 12 In particular, tumor necrosis factorα (TNFα) and interleukin 1β (IL-1β) are promoted by macrophages and monocytes at the primary local operative site, and play a key role during the acute phase response to surgical insults. 24 Stimulated by TNFα and IL-1β, this acute phase response is followed by the production and release of interleukin (IL)-6. 25 Several previous studies reported that surgical insults produce inflammatory mediators such as IL-6, IL-8, high-mobility group box chromosomal protein-1 (HMGB-1), or neutrophil elastase in esophagectomy and the elevation of these mediators was associated with pulmonary inflammation. 26-28

| Microcirculatory dysfunction and local inflammation
Higher invasive surgery generally tends to have more intraoperative blood loss and microcirculatory disturbances due to hypoperfusion, which is thought to involve endogenous TNFα release. 12,29 These inflammatory responses are also associated with an increase in microvascular hyperpermeability, which can lead to postoperative complications such as lung injury and cardiovascular dysfunction. 29 Moreover, microcirculatory disturbances following high invasive surgery are also related to alterations in intestinal permeability, which F I G U R E 1 Schema of lung injury during esophagectomy. Colored lines indicate the presumed main action sites of each drug can lead to postoperative bacterial translocation and can exacerbate surgically induced SIRS and postoperative lung injury following esophagectomy. 11,30,31

| Metabolic alterations
Invasive surgery such as esophagectomy reduces metabolism for ~24 h postoperatively and subsequently causes a catabolic phase. 32 In the catabolic phase, an increase in endogenous steroid hormone as a counter-response, induced by TNFα and IL-1β, causes inhibition of protein synthesis, increased muscular protein degradation, and mobilization of fats by lipolysis. [33][34][35] In postoperative metabolic alterations, which occurs frequently in invasive surgery, it is vital to attenuate the catabolic response and support an anabolic phase effectively, which follows a catabolic phase and yields protein synthesis. 36 Early enteral nutrition reduces the catabolic response to surgical stress and supports an anabolic phase effectively, which can improve surgical outcomes, including pulmonary complications. 36,37

| Innate immune alterations
Although IL-6 functions as a proinflammatory cytokine in the early postoperative period, it can also exert antiinflammatory effects by attenuating TNFα and IL-1 activity 38

| Minimally invasive esophagectomy and inflammatory response
Recently, minimally invasive esophagectomy (MIE) such as thoracoscopic, mediastinoscopic, or robot-assisted esophagectomy is performed more frequently for esophageal cancer treatment. MIE reduces surgical insults, which are related to the reduction of mortality and morbidities. 52,53 In addition, it is reported that minimally

| PHARMACOLOG IC AL TRE ATMENTS
In order to attenuate these acute responses, various treatments based on the pharmacological effect were developed and performed. Here we discuss and review some of the pharmacological treatments to reduce pulmonary complications in esophagectomy for esophageal cancer.

| Corticosteroid
Corticosteroid suppresses the production of cytokines such as IL-6 and TNFα in monocytes and macrophages. In esophagectomy, these cytokines are associated with tissue injury from the surgical procedure and one-lung ventilation further develops postoperative lung injury. Therefore, the presence of a corticosteroid is considered to reduce lung injury by reducing these inflammatory and oxidative responses. 56 It was reported that corticosteroids had no effect on serum cytokines already released. 57 Therefore, a corticosteroid was mainly administrated preoperatively or at the induction of anesthesia, which was reported to reduce postoperative IL-6 levels and the incidence of peripheral leukocytopenia caused by surgical stress. 58 Based on these theoretical mechanisms, the perioperative corticosteroid for patients with transthoracic esophagectomy was conventionally administered to improve mortality and pulmonary complications in Asia, especially in Japan. To evaluate the efficacy of perioperative corticosteroid, several studies were performed (Table 1)   Acute lung injury was evaluated as a pulmonary complication.

| Vitamins
Some vitamins have cell-protective effects. Vitamin D, which is a regulator of nitric oxide synthesis in endothelial cells, enhances the activity of antioxidative enzymes attenuating reactive oxygen species (ROS), and inhibits production of proinflammatory mediators such as TNFα and IL-6 by suppressing nuclear factor kappa B (NF-κB) signaling. These protective effects of vitamin D are considered to protect the pulmonary endothelium 83 and are considered to reduce postoperative lung injury. Vitamin C also attenuates inflammatory cytokines such as TNFα and IL-6. Vitamin C also reduces oxidative stress by scavenging free radicals, preventing further damage to the alveolar capillaries. Vitamin C inhibits the activation of neutrophil, resulting in the increase of alveolar fluid clearance and preventing lung vascular endothelial injury. 84 Studies have shown that these effects are synergically enhanced by the presence of corticosteroids. 84,85 A couple of studies evaluated the efficacy of several vitamin therapies, including trials using vitamins D and C (

| Others
Drugs that suppress the production of inflammatory mediators, The specific therapeutic effects of nitric oxide inhalation for postoperative lung injury in esophagectomy remains unclear, as no study targeted the population of patients with esophagectomy. 91 These inhalation therapies need further investigation to be considered one of the mainstream treatment options.

| CON CLUS ION
Lung injury following esophagectomy is associated with an invasive surgical procedure and one-lung ventilation during anesthesia.
Surgical insults cause alterations in hemodynamic, metabolic, and immune responses, and one-lung ventilation damages bilateral lungs by inflammatory and oxidative stress responses. Local response to tissue insults spreads to a systemic response through inflammatory mediators resulting in lung injury. Some of the pharmacological treatments for preventing lung injury have the potential to improve pulmonary morbidity after esophagectomy. However, further prospective studies with large samples are needed to confirm the efficacy of those therapies to establish better perioperative management for esophagectomy.

ACK N OWLED G M ENTS
The authors thank Ms. Izu Inada (Department of Gastroenterological Surgery, Tokai University School of Medicine) for assisting us in preparing this article.

D I SCLOS U R E
Funding: There was no funding for this review.