Cardiopulmonary adaption to one-lung ventilation and neoadjuvant therapy during treatment of esophageal cancer

Introduction: Esophagectomy is the main form of curative treatment for esophageal cancer and has a high morbidity rate. Neoadjuvant chemo- (CT) or chemoradiotherapy (CRT) is employed to increase long-term survival. To improve perioperative care the effects of measures taken to improve surgical exposure i.e. one-lung ventilation (OLV) and the effects of adding radio- to chemotherapy needs to be understood.

Aims: I. Compare inflammatory response and factors regulation pulmonary vascular tone after one- and two-lung ventilation during esophageal resection (paper I-II). II. Compare the effects of chemotherapy and chemoradiotherapy on cardiac function, perioperative hemodynamics and inflammatory response (paper III-V).

Methods: Study one (papers I-II) was a randomised controlled trial comparing one- (n=16) vs. two-lung ventilation (n=14) during esophagectomy. Cytokines, complement activation markers, nitrite and endothelin were measured in plasma during and after surgery. Lung biopsies acquired before and after the thoracic part of the operation were accesses for levels of iNOS and vascular congestion. Study two (papers III-V) was a single centre cohort from within a multi-centre randomised controlled trial comparing CT vs. CRT regarding complete histological response. In paper III cardiac function following neoadjuvant treatment was evaluated in 40 patients as intention to treat (CT n=23, CRT n=17) using echocardiography with strain and tissue doppler analysis as well as plasma NT-proBNP. In paper IV the perioperative hemodynamic profile was investigated in 31 patients as per protocol (CT n=17, CRT n=14) using LiDCOplus. Measurements were performed before, during and after surgery. In addition plasma NT-proBNP and Troponin T were measured repeatedly. In paper V, concerning the same group of patients as in paper IV cytokines and complement activation markers in plasma were measured before, during and after surgery. In perioperative lung biopsies cytokine mRNA was measured and the number of CD45 positive cells counted.

Results: In study one, inflammatory markers, factors regulating pulmonary vascular tone, iNOS levels and pulmonary congestion were similar between the groups apart from the terminal complement complex, C5b-9, which was increased in the OLV group on the 3rd and 10th postoperative day. In study two, a decrease of septal systolic function and global diastolic function was seen in the CRT group as well as a lower preoperative cardiac index. However, when challenged by surgery a similar hemodynamic profile was seen in both groups. IL-β mRNA was higher in lung biopsies from patients that had received CRT, but there were no differences regarding systemic inflammation. Respiratory complications and other types of morbidity were similar in the CRT and CT groups.

Conclusions: One-lung ventilation during esophagectomy increases activation of the complement system compared to two-lung ventilation but does not appear to induce factors related to pulmonary vascular tone. CRT induces a slight impairment of cardiac function compared to CT, an effect that did not persist when the cardiovascular system was challenged by surgery. Thus CRT as administered in this study appears safe from a cardiovascular perspective. However, CRT increases local inflammation in the lung, which might affect postoperative morbidity.

List of scientific papers

I. One-Lung Ventilation During Thoracoabdominal Esophagectomy Elicits Complement Activation. J. A. Tsai, M. Lund, L. Lundell, K. Nilsson-Ekdahl. Journal of Surgical Research. 2009 ,152, 331-7.
https://doi.org/10.1016/j.jss.2008.03.046

II. Nitric oxide and endothelin-1 release after one-lung ventilation during thoracoabdominal oesophagectomy. M. Lund, L. Ny, R. E. Malmström, J. O. Lundberg, Å. Öst, M. Björnstedt, L. Lundell, J. A. Tsai Diseases of the Esophagus 2013, 26, 853-8.
https://doi.org/10.1111/j.1442-2050.2012.01388.x

III. Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the oesophagus or gastroesophageal junction - a prospective cohort pilot study within a randomized clinical trial. M. Lund, G. Alexandersson von Döbeln, M. Nilsson, R. Winter, L. Lundell, J. A. Tsai, S. Kalman. Radiation Oncology. 2015, 10, 1-9.
https://doi.org/10.1186/s13014-014-0310-7

IV. Effects of neoadjuvant chemo- or chemoradiotherapy for oesophageal cancer on perioperative hemodynamics – a prospective cohort study within a randomized clinical trial. M. Lund, J. A. Tsai, M. Nilsson, R. Winter, L. Lundell, S. Kalman [Submitted]

V. Postoperative inflammatory response after neoadjuvant chemoradiotherapy or chemoradiotherapy for cancer of the oesophagus or gastroesophageal junction – a substudy within a randomized trial. M. Lund, H. Kozarcanin, T-E. Mollnes, K. Nilsson-Ekdahl, M. Rydén, M. Nilsson, L. Lundell, S. Kalman, J. A. Tsai. [Manuscript]