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Hemodynamic and inflammatory responses following transumbilical and transthoracic lung wedge resection in a live canine model
International Journal of Surgery 16 (2015) 116e122
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Original research
Hemodynamic and inflammatory responses following transumbilical and transthoracic lung wedge resection in a live canine model Hung-Yi Lu a, Yen Chu c, Yi-Cheng Wu c, Chien-Ying Liu b, Ming-Ju Hsieh c, Yin-Kai Chao c, Ching-Yang Wu c, Hsu-Chia Yuan c, Po-Jen Ko c, Yun-Hen Liu c, *, Hui-Ping Liu c a b c
Department of Thoracic Surgery, Chang Gung Memorial Hospital, Kaohsiung, Chang Gung University, Taiwan Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan Laboratory Animal Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
h i g h l i g h t s Transthoracic lung surgery is associated with severe post-operative pain. The potential benefits of transumbilical surgery is minimizes postoperative pain. We evaluate the outcome between transumbilical and transthoracic lung surgery in a canine model. Transumbilical lung resection is comparable to transthoracic approach in safety and efficacy.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 January 2014 Received in revised form 14 February 2015 Accepted 28 February 2015 Available online 11 March 2015
Background: Single-port transumbilical surgery is a well-established platform for minimally invasive abdominal surgery. The aim of this study was to compare the hemodynamics and inflammatory response of a novel transumbilical technique with that of a conventional transthoracic technique in thoracic exploration and lung resection in a canine model. Methods: Sixteen dogs were randomly assigned to undergo transumbilical thoracoscopy (n ¼ 8) or standard thoracoscopy (n ¼ 8). Animals in the umbilical group received lung resection via a 3-cm transumbilical incision in combination with a 2.5-cm transdiaphragmatic incision. Animals in the standard thoracoscopy group underwent lung resection via a 3-cm thoracic incision. Hemodynamic parameters (e.g., mean arterial pressure, heart rate, cardiac index, systemic vascular resistance, and global end-diastolic volume index) and inflammatory parameters (e.g., neutrophil count, neutrophil 20 ,70 -dichlorohydrofluorescein [DCFH] expression, monocyte count, monocyte inducible nitric oxide synthase expression, total lymphocyte count, CD4þ and CD8þ lymphocyte counts, the CD4þ/CD8þratio, plasma Creactive protein level, interleukin-6 level) were evaluated before surgery, during the operation, and on postoperative days 1, 3, 7, and 14. Results: Lung resections were successfully performed in all 16 animals. There were 2 surgery-related mortality complications (1 animal in each group). In the transumbilical group, 1 death was caused by early extubation before the animal fully recovered from the anesthesia. In the thoracoscopic group, 1 death was caused by respiratory distress and the complication of sepsis at 5 days after surgery. There was no significant difference between the two techniques with regard to the hemodynamic and immunologic impact of the surgeries. Conclusion: This study suggests that the hemodynamic and inflammatory changes with endoscopic lung resection performed by the transumbilical approach are comparable to those after using the conventional transthoracic approach. This information is novel and relevant for surgeons interested in developing new surgical techniques in minimally invasive surgery. © 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Lung resection Transumbilical thoracoscopy Hemodynamics Inflammation
* Corresponding author. Department of Thoracic Surgery, Chang Gung Memorial Hospital and Chang Gung University, 5 Fushing Street, Gueishan Shiang, Taoyuan, 333, Taiwan. E-mail address: [email protected] (Y.-H. Liu). http://dx.doi.org/10.1016/j.ijsu.2015.02.027 1743-9191/© 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
H.-Y. Lu et al. / International Journal of Surgery 16 (2015) 116e122
1. Introduction Transumbilical single-port laparoscopy has attracted attention in the field of minimally invasive surgery and is widely used in many types of surgeries, including tubal ligation, hysterectomy, appendectomy, cholecystectomy, colectomy, and nephrectomy. The procedure results in reduced pain after surgery and improves cosmetic results [1e7]. Several studies have reported the efficacy and utility of using the transumbilical incision as a novel platform for a variable surgical procedure. For example, Brennan et al. report successful experience in 245 patients who underwent transumbilical breast augmentation. The authors found that transumbilical breast augmentation is a safe and effective method for breast implant placement in select patients [8]. Clark et al. demonstrated the feasibility of transumbilical axillary lymph node dissection in 4 human cadaveric models. These authors report that the transumbilical approach is a potential platform for axillary dissection in breast cancer surgery and propose that this approach may be acceptably used if it were clinically approved for the general public [9]. The potential benefits of transumbilical surgery have more recently been supported by a randomized trial of single-port transumbilical versus transthoracic sympathectomy by Chen et al. He reports that single-port transumbilical surgery is safe, minimizes postoperative pain, and maximizes postoperative cosmetic results by hiding the wound in the umbilicus [10]. The expression of c-reactive protein (CRP), IL-6 have been found to correlate with the surgical stress and the magnitude of the surgery. Increased oxidative activity of neutrophils (DCFH) and monocytes (inducible nitric oxide synthase) have been utilized to provide an objective, quantitative measure of systemic inflammatory response. The lymphocyte count has been considered to be an important indication of postoperative immune function. The clinical relevance of these cellular and humoral inflammatory parameter in surgical patients have been accepted as a useful marker of tissue trauma after surgery [11e19]. We previously reported the efficacy and safety of transumbilical thoracoscopy in performing a pericardial window and surgical lung biopsy [20]. On the basis of the success in previous studies, we aim to evaluate the impact of transumbilical lung resection on the intraoperative hemodynamics, peri-and postoperative inflammatory response versus single-port video-assisted thoracic surgery lung resection. The main goal of the study was to collect evidence that might facilitate the utility of transumbilical thoracoscopy in clinical practice. 2. Methods 2.1. Ethics statement This study was conducted in the Animal Laboratory Center of the Chang Gung Memorial Hospital (Taiwan, China) and approved by the Institutional Animal Care and Use Committee (IACUC) of the Chang Gung Memorial Hospital (No. 2009121003). Sixteen dogs (8 in the transumbilical group and 8 in the transthoracic group) with a mean body weight of 7.5 kg (6.1e9.0 kg) were used to evaluate the hemodynamic and inflammatory impact of transumbilical wedge lung resection and transthoracic wedge lung resection. Induction of anesthesia was obtained with an intramuscular injection of ketamine (5 mg/kg) and xylazine HCL (10 mg/kg). For single lung ventilation, the animals were orally intubated with a 5.0-mm endotracheal tube (with the endotracheal cuff placed in the lung contralateral to surgery). General anesthesia was maintained with isoflurane (3%) and oxygen (3.0 L/min) under volume-controlled mechanical ventilation (tidal volume, 15 cc/kg; respiratory rate, 12 breaths/min). After wound closure, 0.6 mL of 2% xylocaine was
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administered topically. Acetaminophen (30 mg/kg) was administered daily for the first 3 days after surgery to reduce postoperative pain. 2.2. Dogs and surgical procedures In the transumbilical group, a 3-cm incision was created over the umbilicus and used as the entry port for transumbilical lung resection. A 1-cm diaphragmatic incision was performed with a needle knife inserted via the working channel of a flexible bronchoscope, which is inserted through the umbilical incision. The diaphragmatic incision was then sequentially dilated to 2.5 cm with a metallic tube and used as a working port for the lung resection. For the transthoracic approach, the working port (3-cm incision) was created over the seventh intercostal space near the midclavicular line. After thoracic exploration, the predetermined lung lobe was resected by an endostapler with the help of grasping forceps. The lobes included the right upper lobe (2 animals in the transumbilical group and 2 animals in the transthoracic group); right middle lobe (2 animals, transumbilical group; 2 animals, transthoracic group); right lower lobe (1 animal, transumbilical group; 1 animal, transthoracic group); left upper lobe (2 animals, transumbilical group; 2 animals, transthoracic group); and left lower lobe (1 animal, transumbilical group; 1 animal; transthoracic group). After completing the lung resection, the umbilical incision or thoracotomy incision was closed with interrupted 3-0 absorbable sutures. To prevent postoperative visceral herniation, the diaphragmatic wound of the transumbilical group was routinely repaired with a V-Loc suturing device (Covidien, Manfield, MA, USA) after the wedge lung resection. 2.3. Care after surgery The animals were allowed to resume a regular diet after they recovered from anesthesia. They were closely monitored for clinical performance and postoperative complications. To evaluate the surgical outcome, a necropsy was performed 14 days postoperatively, after the animals were humanely euthanized with xylocaine (200 mg). 2.4. Hemodynamic study During lung surgery, the mean arterial pressure (MAP; mmHg), heart rate (HR; beats per min [bpm]), cardiac index (CI; L/ [min$m2]), systemic vascular resistance index (SVRI; [dyn$s]/ [cm5$m2]), and global end-diastolic volume index (GEDVI; mL/ m2) were recorded at 5-min intervals beginning 20 min before the start of surgery until 20 min after the surgery. The transpulmonary thermodilution technique operated by the pulse contour cardiac output (PiCCOR) system (Pulsion Medical Systems, Munich, Germany) was used to measure all hemodynamic variables in the current study. 2.5. Leukocyte subset analysis and isolation of neutrophils and mononuclear cells The total leukocyte count was measured preoperatively and postoperatively on days 1, 3, 7, and 14. By using flow cytometry (Becton Dickinson, Mountain View, CA, USA), anti-canine CD3, CD4, CD8, CD14, or CD45 monoclonal antibodies (BD PharMingen, BD Biosciences, Franklin Lakes, NJ, USA) were used to measure subpopulations of leukocytes (e.g., CD4þ and CD8þ lymphocytes, monocytes, and neutrophils). After lysing erythrocytes with buffered ammonium chloride, neutrophils and mononuclear cells were separated from the leukocyte fraction over a discontinuous
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gradient with the FicollePaque Plus medium (Amersham Pharmacia Biotech, Piscataway, NJ, USA) (D ¼ 1.077 g/cm3, 450 g, 25 C, 30 min) for further study. 2.6. Intracellular oxidative activity of neutrophils The neutrophils (2 105 cells in 200 mL of supplemented Roswell Park Memorial Institute medium) were supplemented with cell-permeable, fluorogenic 20 ,70 - dichlorohydrofluoresceindiacetate (DCFH-DA, 5 mM; Sigma, St. Louis, MO, USA) for 30 min. On intracellular hydrolysis and subsequent oxidization, fluorescent DCFH was generated and rapidly analyzed via flow cytometry. 2.7. Inducible nitric oxide synthase expression inmonocytes After the cytosin preparation of peripheral blood mononuclear cells and fixation in methanol, the slides were incubated in 3% hydrogen peroxide in methanol for 30 min to quench endogenous peroxidase activity. They were then microwaved in citric acid buffer with 0.1% (v/v) Triton 100 for 5 min to enhance the antigen exposure and incubated in 0.2% (v/v) normal swine serum (Dako, Carpenteria, CA, USA) for 30 min to block the positive and negative charges of the cells. A rabbit polyclonal antibody to canine inducible nitric oxide synthase (iNOS) (Abcam Biochemicals, Cambridge, UK) was used for immunological staining. Antibody labeling was visualized by an avidin-biotin complex method (LSAB 2 kit, Dako, Carpenteria and Vector Laboratories, Burlingame, CA, USA). An image analyzer was used to determine the intensity of iNOS expression in the monocytes. 2.8. Enzyme-linked immunosorbent assay for interleukin-6 and Creactive protein The serum for interleukin-6 (IL-6) and C-reactive protein (CRP) analysis was stored at 80 C. The levels of IL-6 and CRP were determined by using in accordance with the manufacturers' instructions commercially available enzyme-linked immunosorbent assay (ELISA) kit containing monoclonal antibodies specific for IL-6 (Quantikine; R & D Systems Inc., Minneapolis, Minnesota, USA) and CRP (PharMingen; BD Biosciences, San Diego, California, USA). Cellfree serum was tested in triplicate. The IL-6 and CRP ELISA kits have sensitivity thresholds of 6.1 pg/mL and 1.3 pg/mL, respectively, and have an intra-assay coefficient of variation of less than 5% and an interassay coefficient of variation of less than 10%, based on the information provided by the manufacturers.
3. Results The wedge lung resection by each approach was successfully performed in all 16 dogs. The mean operation time for the transumbilical lung resection and for the transthoracic lung resection was 60.75 min (95% C.I., 46.47e75.03) and 51.88 min (32.15e71.60), respectively (p ¼ 0.2463). There were 2 mortalities because of lifethreatening complications related to operative procedures: 1 animal in the transumbilical group died in the perioperative period because of early removal of the endotracheal tube before the animal had completely recovered from general anesthesia and 1 animal in the transthoracic group had an intraoperative bleeding complication resulting from accidental injury to the lung parenchyma by the tip of the endostapler during the lung resection on account of the small working space in the current animal model. This animal had further complications of respiratory distress and sepsis, and died 5 days after surgery. The other 14 animals exhibited uneventful recoveries. At 14 days after surgery, the animals had a weight gain of 0.0286 kg (95% C.I., 0.3896e0.3325) in the transumbilical group and 0.3286 kg (0.3248e0.9819) in the transthoracic group (p ¼ 0.4413). 3.1. Hemodynamic study There was a minor increase in the MAP from its baseline level immediately before recovery from anesthesia. However, the change in all hemodynamic parameters (MAP, HR, CI, SVRI, GEDVI) between the groups was not statistically significant before or after surgery (Fig. 1). 3.2. Neutrophils and oxidative activity There was a significant increase in the neutrophil count on postoperative days 1, 3, and 7. However, there was no significant difference in neutrophil count between the groups over the 2-week study period. A significant decrease in DCFH activity was observed on postoperative day 7. However, there was no statistical significance in the difference in DCFH expression between the two groups during the study (Fig. 2A and B). 3.3. Monocytes and the intensity of iNOS expression There was a significant increase in the monocyte count on postoperative days 1 and 3. However, there was no statistical significance in the difference in the monocyte count between the 2 groups before or after surgery. There was similarly a significant increase in iNOS expression on postoperative days 1 and 3. However, the intergroup difference was not significant at any time during the study period (Fig. 2C and D).
2.9. Statistical analysis 3.4. Lymphocytes and CD4/CD8 T lymphocyte subset analysis Data are presented as the mean and the 95% confidence interval (C.I.), unless otherwise stated. Nonparametric statistical analyses were used since the data did not approximate a Gaussian distribution (for example, the mean value did not approximate the median value). For univariate analyses, the Wilcoxon signed-rank test was performed to assess the significance of the differences between measurements at different time intervals in either transumbilical or transthoracic thoracoscopic group, and the ManneWhitney U test was performed to assess the significance of the differences in values between the groups. The frequency distributions between the 2 groups were tested by using the Fisher exact probability test. GraphPad Prism software (version 5.0, GraphPad Software, San Diego, CA, USA) was used for all statistical analyses. Statistical significance was defined as p < 0.05.
There were no significant changes in the total lymphocyte count, CD4þ T-cell count, CD8þ T-cell count between the period before surgery, immediately post-surgery, and at days 1, 3 and 7 after surgery. We observed an interesting significant elevation in the CD4:CD8 ratio on postoperative day 3, when compared to the preoperative level. However, there was no significant difference in the total lymphocyte count, CD4þ Tcell counts, CD8þ T-cell counts, or CD4/CD8 ratio between the two groups at any time during the study (Fig. 3). 3.5. Interleukin-6 and C-reactive protein levels There was a significant increase in the plasma CRP level from the
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Fig. 1. Hemodynamic analyses that include (A) mean arterial pressure, (B) heart rate, (C) cardiac index, (D) systemic vascular resistance index, and (E) global enddiastolic index. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 8) for the same time interval, based on the ManneWhitney U test.
Fig. 2. (A) Neutrophil cell count and (B) dichlorodihydrofluorescein (DCFH) activity, and (C) monocyte cell counts and (D) inducible nitric oxide synthase (iNOS) activity. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 7e8) for the same time interval, based on the ManneWhitney U test.
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Fig. 3. (A) Lymphocyte cell count,(B) the CD4 subset and (C) CD8 subset, and (D) the CD4/CD8 lymphocyte ratio. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 8) for the same time interval, based on the ManneWhitney U test.
preoperative baseline level on postoperative days 1 and 3. However, there was no group difference in the plasma levels of CRP at any of the timepoints throughout the study. Significantly increased IL-6 levels were observed in the immediate postoperative period up to 1 day after surgery. However, there were no significant intergroup differences in the IL-6 levels at any of the study timepoints (Fig. 4). 3.6. Necropsy Necropsy revealed no signs of infectious complications or visceral injury in the abdominal cavity or the thoracic cavity in the 14 animals that survived 2 weeks after the surgery. The wedge lung resection was performed correctly (N ¼ 7 per group). The diaphragmatic wound of the transumbilical group healed well in all animals. Thirteen animals had adhesions on the pleural cavity or on the abdominal cavity (n ¼ 7 in the transumbilical group; n ¼ 6 in the transthoracic group) (p ¼ 1.0).
4. Discussion We recently published a study demonstrating the feasibility of performing a surgical lung biopsy via a transumbilical transdiaphragmatic approach in a canine model. The result of the current study further revealed the safety and effectiveness of transumbilical lung wedge resection with regard to hemodynamic and inflammatory conditions, incomparison with conventional thoracoscopy. Previous studies have reported clinical experiences of approaching the thoracic cavity and performing thoracic surgical procedures by using three-port laparoscopic surgical techniques. Chen et al. recently described the successful use of the single transumbilical incision for thoracic sympathectomy in humans and suggested that transumbilical surgery reduces postoperative pain and improves cosmetic outcomes [10,21]. However, the evidence for transumbilical thoracic surgery remains rare. Based on our
Fig. 4. (A) The serum levels of C-reactive protein and (B) interleukin-6. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 8) for the same time interval, based on the ManneWhitney U test.
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previous experience of evaluating the surgical stress associated with transoral surgical lung biopsy in a live canine model, the present study further investigated the inflammatory changes and the hemodynamic impact of transumbilical lung wedge resection. The intraoperative hemodynamics remains a major concern in the development of new surgical techniques. For example, Von Delius et al. reported the hemodynamic impact of transesophageal mediastinostomy in 8 pigs. They observed the complication of hemodynamic instability induced by tension pneumothorax in 3 animals, and suggested the importance of monitoring hemodynamic changes during surgery [22]. In 2003, Von Delius et al. reported that low-pressure pneumoperitoneum during transgastric peritoneoscopy decreases the surgical risk by reducing the hemodynamic impact, compared to standard-pressure pneumoperitoneum [23]. In 2008, Navarro-Ripoll et al. reported that on-demand endoscopic insufflation with feedback intra-abdominal pressure regulation can minimize the risk of hemodynamic compromise during natural orifice transluminal endoscopic surgery peritoneoscopy [24]. On the basis of these findings, we believe that developing a safe approach that precludes hemodynamic instability during surgery is the armamentarium to achieve wide spread clinical utility. In the present study, we observed a similar hemodynamic impact in the transumbilical and standard transthoracic groups. We believe that wedge lung resection by the transumbilical approach is a practical platform, compared to the standard transthoracic approach. Many researchers have investigated inflammatory responses after an operation [11e14]. The inflammatory and immunomodulatory mechanisms after surgery remain unclear; however, substantial scientific evidence suggests that minimal invasive surgery is associated with decreased inflammatory reaction and better preservation of immune function [11e19,25,26]. In the present study, we observed a similar inflammatory and immune response between the transumbilical approach and the standard transthoracic approach. We believe that the transumbilical approach is a potential alternative to the current transthoracic approach for thoracic exploration and lung wedge resection. The current transumbilical approach may encounter some technical challenges during surgery. First, diaphragmatic entrance to the thoracic cavity with a metallic tube can lead to iatrogenic lung contusions and lacerations. However, we believe that these complications can be avoided through dilating the diaphragmatic wound with the balloon dilation technique. Second, the normal triangulation of standard multiport thoracoscopic surgery is not possible with the current transumbilical approach and results in a greater workload, compared to the transthoracic approach. However, these challenges can be overcome by operators skilled in endoscopy or overcome as they gain more surgical experience. Third, the exploration and repair of the diaphragmatic wound under the gasless abdomen of the present study is somewhat more difficult than under conventional laparoscopy using CO2 pneumoperitoneum. However, we believe that the diaphragmatic incision could be effectively sealed with Bioglue (Cryolife, Kennesaw, GA) and facilitate the use of the transumbilical approach in clinical practice. Fourth, there are anatomical and physiological differences between humans and animals. Tall humans in particular may require the development of longer endoscopic instruments and staplers to perform transumbilical lung resection because of the long distance between the umbilicus and the upper lung region. There are many potential advantages of the transumbilical approach, compared to the conventional transthoracic thoracoscopic approach. First, the immediate postoperative pulmonary function may be better preserved after transumbilical lung resection because the creation of a thoracic incision is avoided. Second, after performing transumbilical lung resection without a thoracic incision, a surgeon may attempt to omit chest tube drainage to
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reduce acute postoperative discomfort. Third, omitting chest tube drainage may reduce the duration of the hospital stay and accelerate postoperative physiological rehabilitation. Forth, the postthoracotomy pain syndrome complications can be avoided because there is no thoracic incision. Fifth, there are better cosmetic results because the lung resection is completed through an umbilical incision that is partially obscured or hidden in the umbilicus. However, potential shortcoming of omitting chest tube drainage is the missing diagnosis of postoperative complications such as bleeding or pneumothorax. It is essential to make sure of the sealing of vessel, lung parenchyma, and airway margin is completed in this approach. Complications overall were high in this study and the mortality rate was the same in both groups (1 death each in the transumbilical group and the transthoracic group). Incomplete recovery from general anesthesia before extubation of the endotracheal tube in 1 animal in the transumbilical group is the probable reason for its acute postoperative respiratory failure. However, we believe that such complications may be avoided through good anesthesia management. The short distance between chest wall and the lung in the current animal model can lead to difficulty in performing lung resection with an endostapler and bleeding complications. However, we also feel that the complications can be minimized by performing lung resection in larger animal models or in humans. The present study has some limitations. First, the sample size in our study is small. Comparative studies using a large number of animals may be needed before introducing the transumbilical technique for clinical use. Second, the anatomy of dogs and humans is different; a longer distance to the pulmonary hilum from the umbilicus in tall humans may require longer endoscopic instruments and staplers to complete the lung resection. Third, we only performed the lung wedge resection over a predetermined lung lobe. Thus, we could not determine whether performing the anatomic pulmonary lobectomy and mediastinal lymph node dissection via the umbilical incision would be successful. Fourth, the 2-week follow-up period was based on our previous animal study; it is possible that a 2-week follow-up period is too short to evaluate chronic visceral herniation of a diaphragmatic incision. However, we believe that this chronic complication can be effectively prevented by meticulously repairing the wounds. In summary, our study demonstrates in a live canine model that the transumbilical lung wedge resection is comparable to conventional transthoracoscopic surgery in safety and efficacy. We also found that both approaches have similar inflammatory and hemodynamic responses after lung wedge resection. Studies comparing the safety and efficacy of transumbilical anatomic lobectomy and conventional video-assisted transthoracic surgery are underway in our laboratory. Ethical approval The animal studies were approved by the Chang Gung Memorial Hospital Animal Care Institutional Review Board. Sources of funding This work was supported by the Chang-Gung Memorial Hospital, Taiwan (Contract No. CMRPG 391913). Conflicts of interest Hung-Yi Lu, Yen Chu, Yi-Cheng Wu, Chien-Ying Liu, Ming-Ju Hsieh, Ying-Kai Chao, Ching-Yang Wu, Hsu-Chia Yuan, Po-Jen Ko, Yun-Hen Liu, Hui-Ping Liu have no conflicts of interest or financial ties to disclose.
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Author contribution Conceived and designed the experiments: Hung-Yi Lu, Yi-Cheng Wu, Po-Jen Ko, Hui-Ping Liu. Performed the experiments: Hung-Yi Lu, Ching-Yang Wu, HsuChia Yuan, Ming-Ju Hsieh. Analyzed the data: Yen-Chu, Chien-Ying Liu, Ying-Kai Chao. Analysis tools: Yen-Chu, Chien-Ying Liu, Ying-Kai Chao. Wrote the paper: Hung-Yi Lu, Yun-Hen Liu, Hui-Ping Liu. Supervision and coordination of project: Yen-Chu, Yun-Hen Liu, Hui-Ping Liu. Guarantor Yun-Hen Liu. Acknowledgments This work was supported by the Chang-Gung Memorial Hospital, Taiwan (Contract No. CMRPG 391913) and by the National Science Council of Taiwan (NMRPG3B0171). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ijsu.2015.02.027. References [1] F. Froghi, M.H. Sodergren, A. Darzi, P. Paraskeva, Single-incision Laparoscopic Surgery (SILS) in general surgery: a review of current practice, Surg. Laparosc. Endosc. Percutaneous Tech. 20 (2010) 191. [2] S. Shekherdimian, D. DeUgarte, Transumbilical laparoscopic-assisted appendectomy: an extracorporeal single-incision alternative to conventional laparoscopic techniques, Am. Surg. 77 (2011) 557e560. [3] T. Abdel Azeez, K.M. Mahran, Transumbilical laparoscopic cholecystectomy: towards a scarless abdominal surgery, Hepatogastroenterology 58 (2011) 298e300. [4] J.C. Siegle, L.J. Bishop, W.F. Rayburn, Randomized comparison between two microlaparoscopic techniques for partial salpingectomy, JSLS 9 (2005) 30e34. [5] J.U. Stolzenburg, G. Hellawell, P. Kallidonis, M. Do, T. Haefner, et al., Laparoendoscopic single-site surgery: early experience with tumor nephrectomy, J. Endourol. 23 (2009) 1287e1292. [6] Y.W. Jung, Y.T. Kim, D.W. Lee, Y.I. Hwang, E.J. Nam, et al., The feasibility of scarless single-port transumbilical total laparoscopic hysterectomy: initial clinical experience, Surg. Endosc. 24 (2010) 1686e1692. [7] P. Bucher, F. Pugin, N.C. Buchs, S. Ostermann, P. Morel, Randomized clinical trial of laparoendoscopic single-site versus conventional laparoscopic cholecystectomy, Br. J. Surg. 98 (2011) 1695e1702. [8] W.A. Brennan, J. Haiavy, Transumbilical breast augmentation: a practical
review of a technique, Ann. Plast. Surg. 59 (2007) 243e249. [9] J. Clark, D.R. Leff, M. Sodergren, R. Newton, D. Noonan, et al., Single-incision transumbilical levels 1 and 2 axillary lymph node dissection using a flexible endoscope in human cadaveric models, Surg. Endosc. 27 (2013) 478e486. [10] L.H. Zhu, W. Wang, S. Yang, D. Li, Z. Zhang, et al., Transumbilical thoracic sympathectomy with an ultrathin flexible endoscope in a series of 38 patients, Surg. Endosc. 27 (2013) 2149e2155. [11] P.S. Martins, E.G. Kallas, M.C. Neto, M.A. Dalboni, S. Blecher, et al., Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock, Shock 20 (2003) 208e212. €hler, T. Lyberg, Production of oxidants in [12] T.S. Haugen, O.H. Skjønsberg, H. Ka alveolar macrophages and blood leukocytes, Eur. Respir. J. 14 (5) (1999 Nov) 1100e1113. , et al., Peritoneal [13] C. Romeo, P. Impellizzeri, P. Antonuccio, N. Turiaco, S. Cifala macrophage activity after laparoscopy or laparotomy, J. Pediatr. Surg. 38 (2003) 97e101. [14] N. Ni Choileain, H.P. Redmond, Cell response to surgery, Arch. Surg. 141 (2006) 1132e1140. € sslein, J.M. Müller, Cellular and [15] J. Ordemann, C.A. Jacobi, W. Schwenk, R. Sto humoral inflammatory response after laparoscopic and conventional colorectal resections, Surg. Endosc. 15 (2001) 600e608. [16] S.R. Craig, H.A. Leaver, P.L. Yap, G.C. Pugh, W.S. Walker, Acute phase responses following minimal access and conventional thoracic surgery, Eur. J. Cardiothorac. Surg. 20 (2001) 455e463. [17] M.W. Wichmann, T.P. Hüttl, H. Winter, F. Spelsberg, M.K. Angele, et al., Immunological effects of laparoscopic vs open colorectal surgery: a prospective clinical study, Arch. Surg. 140 (2005) 692e697. [18] C.S. Ng, S. Wan, C.W. Hui, T.W. Lee, M.J. Underwood, et al., Video-assisted thoracic surgery for early stage lung cancer e can short-term immunological advantages improve long-term survival? Ann. Thorac. Cardiovasc Surg. 12 (2006) 308e312. [19] T. Natsume, H. Kawahira, H. Hayashi, Y. Nabeya, T. Akai, et al., Low peritoneal and systemic inflammatory response after laparoscopy-assisted gastrectomy compared to open gastrectomy, Hepatogastroenterology 58 (2011) 659e662. [20] Y.C. Wu, Yeh CJ. Yen-Chu, M.J. Hsieh, T.P. Chen, et al., Feasibility of transumbilical surgical lung biopsy and pericardial window creation, Surg. Innov. 21 (2014) 15e21. [21] Chen W, Zhu LH, Yang S, Li D, Wang W, et al., EMBRYONIC-NOTES Thoracic Sympathectomy for Palmar Hyperhidrosis: Results of a Novel Technique and Comparison with the Conventional VATS Procedure. SAGES 2013 2013 Annual Meeting. [22] S. von Delius, D. Wilhelm, H. Feussner, J. Sager, V. Becker, et al., Natural orifice transluminal endoscopic surgery: cardiopulmonary safety of transesophageal mediastinoscopy, Endoscopy 42 (2010) 405e412. [23] S. von Delius, A. Schorn, M. Grimm, A. Schneider, D. Wilhelm, et al., Naturalorifice transluminal endoscopic surgery: low-pressure pneumoperitoneum is sufficient and is associated with an improved cardiopulmonary response (PressurePig Study), Endoscopy 43 (2011) 808e815. rdova, [24] R. Navarro-Ripoll, G. Martínez-Pallí, C. Guarner-Argente, H. Co M.A. Martínez-Zamora, et al., On-demand endoscopic CO2 insufflation with feedback pressure regulation during natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy induces minimal hemodynamic and respiratory changes, Gastrointest. Endosc. 76 (2012) 388e395. [25] W.S. Walker, H.A. Leaver, Immunologic and stress responses following videoassisted thoracic surgery and open pulmonary lobectomy in early stage lung cancer, Thorac. Surg. Clin. 17 (2007) 241e249 (ix. Review). [26] G. Wang, Z. Jiang, K. Zhao, G. Li, F. Liu, et al., Immunologic response after laparoscopic colon cancer operation within an enhanced recovery program, J. Gastrointest. Surg. 16 (2012 Jul) 1379e1388.
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Original research
Hemodynamic and inflammatory responses following transumbilical and transthoracic lung wedge resection in a live canine model Hung-Yi Lu a, Yen Chu c, Yi-Cheng Wu c, Chien-Ying Liu b, Ming-Ju Hsieh c, Yin-Kai Chao c, Ching-Yang Wu c, Hsu-Chia Yuan c, Po-Jen Ko c, Yun-Hen Liu c, *, Hui-Ping Liu c a b c
Department of Thoracic Surgery, Chang Gung Memorial Hospital, Kaohsiung, Chang Gung University, Taiwan Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan Laboratory Animal Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
h i g h l i g h t s Transthoracic lung surgery is associated with severe post-operative pain. The potential benefits of transumbilical surgery is minimizes postoperative pain. We evaluate the outcome between transumbilical and transthoracic lung surgery in a canine model. Transumbilical lung resection is comparable to transthoracic approach in safety and efficacy.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 January 2014 Received in revised form 14 February 2015 Accepted 28 February 2015 Available online 11 March 2015
Background: Single-port transumbilical surgery is a well-established platform for minimally invasive abdominal surgery. The aim of this study was to compare the hemodynamics and inflammatory response of a novel transumbilical technique with that of a conventional transthoracic technique in thoracic exploration and lung resection in a canine model. Methods: Sixteen dogs were randomly assigned to undergo transumbilical thoracoscopy (n ¼ 8) or standard thoracoscopy (n ¼ 8). Animals in the umbilical group received lung resection via a 3-cm transumbilical incision in combination with a 2.5-cm transdiaphragmatic incision. Animals in the standard thoracoscopy group underwent lung resection via a 3-cm thoracic incision. Hemodynamic parameters (e.g., mean arterial pressure, heart rate, cardiac index, systemic vascular resistance, and global end-diastolic volume index) and inflammatory parameters (e.g., neutrophil count, neutrophil 20 ,70 -dichlorohydrofluorescein [DCFH] expression, monocyte count, monocyte inducible nitric oxide synthase expression, total lymphocyte count, CD4þ and CD8þ lymphocyte counts, the CD4þ/CD8þratio, plasma Creactive protein level, interleukin-6 level) were evaluated before surgery, during the operation, and on postoperative days 1, 3, 7, and 14. Results: Lung resections were successfully performed in all 16 animals. There were 2 surgery-related mortality complications (1 animal in each group). In the transumbilical group, 1 death was caused by early extubation before the animal fully recovered from the anesthesia. In the thoracoscopic group, 1 death was caused by respiratory distress and the complication of sepsis at 5 days after surgery. There was no significant difference between the two techniques with regard to the hemodynamic and immunologic impact of the surgeries. Conclusion: This study suggests that the hemodynamic and inflammatory changes with endoscopic lung resection performed by the transumbilical approach are comparable to those after using the conventional transthoracic approach. This information is novel and relevant for surgeons interested in developing new surgical techniques in minimally invasive surgery. © 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Lung resection Transumbilical thoracoscopy Hemodynamics Inflammation
* Corresponding author. Department of Thoracic Surgery, Chang Gung Memorial Hospital and Chang Gung University, 5 Fushing Street, Gueishan Shiang, Taoyuan, 333, Taiwan. E-mail address: [email protected] (Y.-H. Liu). http://dx.doi.org/10.1016/j.ijsu.2015.02.027 1743-9191/© 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
H.-Y. Lu et al. / International Journal of Surgery 16 (2015) 116e122
1. Introduction Transumbilical single-port laparoscopy has attracted attention in the field of minimally invasive surgery and is widely used in many types of surgeries, including tubal ligation, hysterectomy, appendectomy, cholecystectomy, colectomy, and nephrectomy. The procedure results in reduced pain after surgery and improves cosmetic results [1e7]. Several studies have reported the efficacy and utility of using the transumbilical incision as a novel platform for a variable surgical procedure. For example, Brennan et al. report successful experience in 245 patients who underwent transumbilical breast augmentation. The authors found that transumbilical breast augmentation is a safe and effective method for breast implant placement in select patients [8]. Clark et al. demonstrated the feasibility of transumbilical axillary lymph node dissection in 4 human cadaveric models. These authors report that the transumbilical approach is a potential platform for axillary dissection in breast cancer surgery and propose that this approach may be acceptably used if it were clinically approved for the general public [9]. The potential benefits of transumbilical surgery have more recently been supported by a randomized trial of single-port transumbilical versus transthoracic sympathectomy by Chen et al. He reports that single-port transumbilical surgery is safe, minimizes postoperative pain, and maximizes postoperative cosmetic results by hiding the wound in the umbilicus [10]. The expression of c-reactive protein (CRP), IL-6 have been found to correlate with the surgical stress and the magnitude of the surgery. Increased oxidative activity of neutrophils (DCFH) and monocytes (inducible nitric oxide synthase) have been utilized to provide an objective, quantitative measure of systemic inflammatory response. The lymphocyte count has been considered to be an important indication of postoperative immune function. The clinical relevance of these cellular and humoral inflammatory parameter in surgical patients have been accepted as a useful marker of tissue trauma after surgery [11e19]. We previously reported the efficacy and safety of transumbilical thoracoscopy in performing a pericardial window and surgical lung biopsy [20]. On the basis of the success in previous studies, we aim to evaluate the impact of transumbilical lung resection on the intraoperative hemodynamics, peri-and postoperative inflammatory response versus single-port video-assisted thoracic surgery lung resection. The main goal of the study was to collect evidence that might facilitate the utility of transumbilical thoracoscopy in clinical practice. 2. Methods 2.1. Ethics statement This study was conducted in the Animal Laboratory Center of the Chang Gung Memorial Hospital (Taiwan, China) and approved by the Institutional Animal Care and Use Committee (IACUC) of the Chang Gung Memorial Hospital (No. 2009121003). Sixteen dogs (8 in the transumbilical group and 8 in the transthoracic group) with a mean body weight of 7.5 kg (6.1e9.0 kg) were used to evaluate the hemodynamic and inflammatory impact of transumbilical wedge lung resection and transthoracic wedge lung resection. Induction of anesthesia was obtained with an intramuscular injection of ketamine (5 mg/kg) and xylazine HCL (10 mg/kg). For single lung ventilation, the animals were orally intubated with a 5.0-mm endotracheal tube (with the endotracheal cuff placed in the lung contralateral to surgery). General anesthesia was maintained with isoflurane (3%) and oxygen (3.0 L/min) under volume-controlled mechanical ventilation (tidal volume, 15 cc/kg; respiratory rate, 12 breaths/min). After wound closure, 0.6 mL of 2% xylocaine was
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administered topically. Acetaminophen (30 mg/kg) was administered daily for the first 3 days after surgery to reduce postoperative pain. 2.2. Dogs and surgical procedures In the transumbilical group, a 3-cm incision was created over the umbilicus and used as the entry port for transumbilical lung resection. A 1-cm diaphragmatic incision was performed with a needle knife inserted via the working channel of a flexible bronchoscope, which is inserted through the umbilical incision. The diaphragmatic incision was then sequentially dilated to 2.5 cm with a metallic tube and used as a working port for the lung resection. For the transthoracic approach, the working port (3-cm incision) was created over the seventh intercostal space near the midclavicular line. After thoracic exploration, the predetermined lung lobe was resected by an endostapler with the help of grasping forceps. The lobes included the right upper lobe (2 animals in the transumbilical group and 2 animals in the transthoracic group); right middle lobe (2 animals, transumbilical group; 2 animals, transthoracic group); right lower lobe (1 animal, transumbilical group; 1 animal, transthoracic group); left upper lobe (2 animals, transumbilical group; 2 animals, transthoracic group); and left lower lobe (1 animal, transumbilical group; 1 animal; transthoracic group). After completing the lung resection, the umbilical incision or thoracotomy incision was closed with interrupted 3-0 absorbable sutures. To prevent postoperative visceral herniation, the diaphragmatic wound of the transumbilical group was routinely repaired with a V-Loc suturing device (Covidien, Manfield, MA, USA) after the wedge lung resection. 2.3. Care after surgery The animals were allowed to resume a regular diet after they recovered from anesthesia. They were closely monitored for clinical performance and postoperative complications. To evaluate the surgical outcome, a necropsy was performed 14 days postoperatively, after the animals were humanely euthanized with xylocaine (200 mg). 2.4. Hemodynamic study During lung surgery, the mean arterial pressure (MAP; mmHg), heart rate (HR; beats per min [bpm]), cardiac index (CI; L/ [min$m2]), systemic vascular resistance index (SVRI; [dyn$s]/ [cm5$m2]), and global end-diastolic volume index (GEDVI; mL/ m2) were recorded at 5-min intervals beginning 20 min before the start of surgery until 20 min after the surgery. The transpulmonary thermodilution technique operated by the pulse contour cardiac output (PiCCOR) system (Pulsion Medical Systems, Munich, Germany) was used to measure all hemodynamic variables in the current study. 2.5. Leukocyte subset analysis and isolation of neutrophils and mononuclear cells The total leukocyte count was measured preoperatively and postoperatively on days 1, 3, 7, and 14. By using flow cytometry (Becton Dickinson, Mountain View, CA, USA), anti-canine CD3, CD4, CD8, CD14, or CD45 monoclonal antibodies (BD PharMingen, BD Biosciences, Franklin Lakes, NJ, USA) were used to measure subpopulations of leukocytes (e.g., CD4þ and CD8þ lymphocytes, monocytes, and neutrophils). After lysing erythrocytes with buffered ammonium chloride, neutrophils and mononuclear cells were separated from the leukocyte fraction over a discontinuous
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gradient with the FicollePaque Plus medium (Amersham Pharmacia Biotech, Piscataway, NJ, USA) (D ¼ 1.077 g/cm3, 450 g, 25 C, 30 min) for further study. 2.6. Intracellular oxidative activity of neutrophils The neutrophils (2 105 cells in 200 mL of supplemented Roswell Park Memorial Institute medium) were supplemented with cell-permeable, fluorogenic 20 ,70 - dichlorohydrofluoresceindiacetate (DCFH-DA, 5 mM; Sigma, St. Louis, MO, USA) for 30 min. On intracellular hydrolysis and subsequent oxidization, fluorescent DCFH was generated and rapidly analyzed via flow cytometry. 2.7. Inducible nitric oxide synthase expression inmonocytes After the cytosin preparation of peripheral blood mononuclear cells and fixation in methanol, the slides were incubated in 3% hydrogen peroxide in methanol for 30 min to quench endogenous peroxidase activity. They were then microwaved in citric acid buffer with 0.1% (v/v) Triton 100 for 5 min to enhance the antigen exposure and incubated in 0.2% (v/v) normal swine serum (Dako, Carpenteria, CA, USA) for 30 min to block the positive and negative charges of the cells. A rabbit polyclonal antibody to canine inducible nitric oxide synthase (iNOS) (Abcam Biochemicals, Cambridge, UK) was used for immunological staining. Antibody labeling was visualized by an avidin-biotin complex method (LSAB 2 kit, Dako, Carpenteria and Vector Laboratories, Burlingame, CA, USA). An image analyzer was used to determine the intensity of iNOS expression in the monocytes. 2.8. Enzyme-linked immunosorbent assay for interleukin-6 and Creactive protein The serum for interleukin-6 (IL-6) and C-reactive protein (CRP) analysis was stored at 80 C. The levels of IL-6 and CRP were determined by using in accordance with the manufacturers' instructions commercially available enzyme-linked immunosorbent assay (ELISA) kit containing monoclonal antibodies specific for IL-6 (Quantikine; R & D Systems Inc., Minneapolis, Minnesota, USA) and CRP (PharMingen; BD Biosciences, San Diego, California, USA). Cellfree serum was tested in triplicate. The IL-6 and CRP ELISA kits have sensitivity thresholds of 6.1 pg/mL and 1.3 pg/mL, respectively, and have an intra-assay coefficient of variation of less than 5% and an interassay coefficient of variation of less than 10%, based on the information provided by the manufacturers.
3. Results The wedge lung resection by each approach was successfully performed in all 16 dogs. The mean operation time for the transumbilical lung resection and for the transthoracic lung resection was 60.75 min (95% C.I., 46.47e75.03) and 51.88 min (32.15e71.60), respectively (p ¼ 0.2463). There were 2 mortalities because of lifethreatening complications related to operative procedures: 1 animal in the transumbilical group died in the perioperative period because of early removal of the endotracheal tube before the animal had completely recovered from general anesthesia and 1 animal in the transthoracic group had an intraoperative bleeding complication resulting from accidental injury to the lung parenchyma by the tip of the endostapler during the lung resection on account of the small working space in the current animal model. This animal had further complications of respiratory distress and sepsis, and died 5 days after surgery. The other 14 animals exhibited uneventful recoveries. At 14 days after surgery, the animals had a weight gain of 0.0286 kg (95% C.I., 0.3896e0.3325) in the transumbilical group and 0.3286 kg (0.3248e0.9819) in the transthoracic group (p ¼ 0.4413). 3.1. Hemodynamic study There was a minor increase in the MAP from its baseline level immediately before recovery from anesthesia. However, the change in all hemodynamic parameters (MAP, HR, CI, SVRI, GEDVI) between the groups was not statistically significant before or after surgery (Fig. 1). 3.2. Neutrophils and oxidative activity There was a significant increase in the neutrophil count on postoperative days 1, 3, and 7. However, there was no significant difference in neutrophil count between the groups over the 2-week study period. A significant decrease in DCFH activity was observed on postoperative day 7. However, there was no statistical significance in the difference in DCFH expression between the two groups during the study (Fig. 2A and B). 3.3. Monocytes and the intensity of iNOS expression There was a significant increase in the monocyte count on postoperative days 1 and 3. However, there was no statistical significance in the difference in the monocyte count between the 2 groups before or after surgery. There was similarly a significant increase in iNOS expression on postoperative days 1 and 3. However, the intergroup difference was not significant at any time during the study period (Fig. 2C and D).
2.9. Statistical analysis 3.4. Lymphocytes and CD4/CD8 T lymphocyte subset analysis Data are presented as the mean and the 95% confidence interval (C.I.), unless otherwise stated. Nonparametric statistical analyses were used since the data did not approximate a Gaussian distribution (for example, the mean value did not approximate the median value). For univariate analyses, the Wilcoxon signed-rank test was performed to assess the significance of the differences between measurements at different time intervals in either transumbilical or transthoracic thoracoscopic group, and the ManneWhitney U test was performed to assess the significance of the differences in values between the groups. The frequency distributions between the 2 groups were tested by using the Fisher exact probability test. GraphPad Prism software (version 5.0, GraphPad Software, San Diego, CA, USA) was used for all statistical analyses. Statistical significance was defined as p < 0.05.
There were no significant changes in the total lymphocyte count, CD4þ T-cell count, CD8þ T-cell count between the period before surgery, immediately post-surgery, and at days 1, 3 and 7 after surgery. We observed an interesting significant elevation in the CD4:CD8 ratio on postoperative day 3, when compared to the preoperative level. However, there was no significant difference in the total lymphocyte count, CD4þ Tcell counts, CD8þ T-cell counts, or CD4/CD8 ratio between the two groups at any time during the study (Fig. 3). 3.5. Interleukin-6 and C-reactive protein levels There was a significant increase in the plasma CRP level from the
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Fig. 1. Hemodynamic analyses that include (A) mean arterial pressure, (B) heart rate, (C) cardiac index, (D) systemic vascular resistance index, and (E) global enddiastolic index. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 8) for the same time interval, based on the ManneWhitney U test.
Fig. 2. (A) Neutrophil cell count and (B) dichlorodihydrofluorescein (DCFH) activity, and (C) monocyte cell counts and (D) inducible nitric oxide synthase (iNOS) activity. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 7e8) for the same time interval, based on the ManneWhitney U test.
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Fig. 3. (A) Lymphocyte cell count,(B) the CD4 subset and (C) CD8 subset, and (D) the CD4/CD8 lymphocyte ratio. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 8) for the same time interval, based on the ManneWhitney U test.
preoperative baseline level on postoperative days 1 and 3. However, there was no group difference in the plasma levels of CRP at any of the timepoints throughout the study. Significantly increased IL-6 levels were observed in the immediate postoperative period up to 1 day after surgery. However, there were no significant intergroup differences in the IL-6 levels at any of the study timepoints (Fig. 4). 3.6. Necropsy Necropsy revealed no signs of infectious complications or visceral injury in the abdominal cavity or the thoracic cavity in the 14 animals that survived 2 weeks after the surgery. The wedge lung resection was performed correctly (N ¼ 7 per group). The diaphragmatic wound of the transumbilical group healed well in all animals. Thirteen animals had adhesions on the pleural cavity or on the abdominal cavity (n ¼ 7 in the transumbilical group; n ¼ 6 in the transthoracic group) (p ¼ 1.0).
4. Discussion We recently published a study demonstrating the feasibility of performing a surgical lung biopsy via a transumbilical transdiaphragmatic approach in a canine model. The result of the current study further revealed the safety and effectiveness of transumbilical lung wedge resection with regard to hemodynamic and inflammatory conditions, incomparison with conventional thoracoscopy. Previous studies have reported clinical experiences of approaching the thoracic cavity and performing thoracic surgical procedures by using three-port laparoscopic surgical techniques. Chen et al. recently described the successful use of the single transumbilical incision for thoracic sympathectomy in humans and suggested that transumbilical surgery reduces postoperative pain and improves cosmetic outcomes [10,21]. However, the evidence for transumbilical thoracic surgery remains rare. Based on our
Fig. 4. (A) The serum levels of C-reactive protein and (B) interleukin-6. There is no significant difference between the transumbilical approach (n ¼ 7) and the transthoracic approach (n ¼ 8) for the same time interval, based on the ManneWhitney U test.
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previous experience of evaluating the surgical stress associated with transoral surgical lung biopsy in a live canine model, the present study further investigated the inflammatory changes and the hemodynamic impact of transumbilical lung wedge resection. The intraoperative hemodynamics remains a major concern in the development of new surgical techniques. For example, Von Delius et al. reported the hemodynamic impact of transesophageal mediastinostomy in 8 pigs. They observed the complication of hemodynamic instability induced by tension pneumothorax in 3 animals, and suggested the importance of monitoring hemodynamic changes during surgery [22]. In 2003, Von Delius et al. reported that low-pressure pneumoperitoneum during transgastric peritoneoscopy decreases the surgical risk by reducing the hemodynamic impact, compared to standard-pressure pneumoperitoneum [23]. In 2008, Navarro-Ripoll et al. reported that on-demand endoscopic insufflation with feedback intra-abdominal pressure regulation can minimize the risk of hemodynamic compromise during natural orifice transluminal endoscopic surgery peritoneoscopy [24]. On the basis of these findings, we believe that developing a safe approach that precludes hemodynamic instability during surgery is the armamentarium to achieve wide spread clinical utility. In the present study, we observed a similar hemodynamic impact in the transumbilical and standard transthoracic groups. We believe that wedge lung resection by the transumbilical approach is a practical platform, compared to the standard transthoracic approach. Many researchers have investigated inflammatory responses after an operation [11e14]. The inflammatory and immunomodulatory mechanisms after surgery remain unclear; however, substantial scientific evidence suggests that minimal invasive surgery is associated with decreased inflammatory reaction and better preservation of immune function [11e19,25,26]. In the present study, we observed a similar inflammatory and immune response between the transumbilical approach and the standard transthoracic approach. We believe that the transumbilical approach is a potential alternative to the current transthoracic approach for thoracic exploration and lung wedge resection. The current transumbilical approach may encounter some technical challenges during surgery. First, diaphragmatic entrance to the thoracic cavity with a metallic tube can lead to iatrogenic lung contusions and lacerations. However, we believe that these complications can be avoided through dilating the diaphragmatic wound with the balloon dilation technique. Second, the normal triangulation of standard multiport thoracoscopic surgery is not possible with the current transumbilical approach and results in a greater workload, compared to the transthoracic approach. However, these challenges can be overcome by operators skilled in endoscopy or overcome as they gain more surgical experience. Third, the exploration and repair of the diaphragmatic wound under the gasless abdomen of the present study is somewhat more difficult than under conventional laparoscopy using CO2 pneumoperitoneum. However, we believe that the diaphragmatic incision could be effectively sealed with Bioglue (Cryolife, Kennesaw, GA) and facilitate the use of the transumbilical approach in clinical practice. Fourth, there are anatomical and physiological differences between humans and animals. Tall humans in particular may require the development of longer endoscopic instruments and staplers to perform transumbilical lung resection because of the long distance between the umbilicus and the upper lung region. There are many potential advantages of the transumbilical approach, compared to the conventional transthoracic thoracoscopic approach. First, the immediate postoperative pulmonary function may be better preserved after transumbilical lung resection because the creation of a thoracic incision is avoided. Second, after performing transumbilical lung resection without a thoracic incision, a surgeon may attempt to omit chest tube drainage to
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reduce acute postoperative discomfort. Third, omitting chest tube drainage may reduce the duration of the hospital stay and accelerate postoperative physiological rehabilitation. Forth, the postthoracotomy pain syndrome complications can be avoided because there is no thoracic incision. Fifth, there are better cosmetic results because the lung resection is completed through an umbilical incision that is partially obscured or hidden in the umbilicus. However, potential shortcoming of omitting chest tube drainage is the missing diagnosis of postoperative complications such as bleeding or pneumothorax. It is essential to make sure of the sealing of vessel, lung parenchyma, and airway margin is completed in this approach. Complications overall were high in this study and the mortality rate was the same in both groups (1 death each in the transumbilical group and the transthoracic group). Incomplete recovery from general anesthesia before extubation of the endotracheal tube in 1 animal in the transumbilical group is the probable reason for its acute postoperative respiratory failure. However, we believe that such complications may be avoided through good anesthesia management. The short distance between chest wall and the lung in the current animal model can lead to difficulty in performing lung resection with an endostapler and bleeding complications. However, we also feel that the complications can be minimized by performing lung resection in larger animal models or in humans. The present study has some limitations. First, the sample size in our study is small. Comparative studies using a large number of animals may be needed before introducing the transumbilical technique for clinical use. Second, the anatomy of dogs and humans is different; a longer distance to the pulmonary hilum from the umbilicus in tall humans may require longer endoscopic instruments and staplers to complete the lung resection. Third, we only performed the lung wedge resection over a predetermined lung lobe. Thus, we could not determine whether performing the anatomic pulmonary lobectomy and mediastinal lymph node dissection via the umbilical incision would be successful. Fourth, the 2-week follow-up period was based on our previous animal study; it is possible that a 2-week follow-up period is too short to evaluate chronic visceral herniation of a diaphragmatic incision. However, we believe that this chronic complication can be effectively prevented by meticulously repairing the wounds. In summary, our study demonstrates in a live canine model that the transumbilical lung wedge resection is comparable to conventional transthoracoscopic surgery in safety and efficacy. We also found that both approaches have similar inflammatory and hemodynamic responses after lung wedge resection. Studies comparing the safety and efficacy of transumbilical anatomic lobectomy and conventional video-assisted transthoracic surgery are underway in our laboratory. Ethical approval The animal studies were approved by the Chang Gung Memorial Hospital Animal Care Institutional Review Board. Sources of funding This work was supported by the Chang-Gung Memorial Hospital, Taiwan (Contract No. CMRPG 391913). Conflicts of interest Hung-Yi Lu, Yen Chu, Yi-Cheng Wu, Chien-Ying Liu, Ming-Ju Hsieh, Ying-Kai Chao, Ching-Yang Wu, Hsu-Chia Yuan, Po-Jen Ko, Yun-Hen Liu, Hui-Ping Liu have no conflicts of interest or financial ties to disclose.
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Author contribution Conceived and designed the experiments: Hung-Yi Lu, Yi-Cheng Wu, Po-Jen Ko, Hui-Ping Liu. Performed the experiments: Hung-Yi Lu, Ching-Yang Wu, HsuChia Yuan, Ming-Ju Hsieh. Analyzed the data: Yen-Chu, Chien-Ying Liu, Ying-Kai Chao. Analysis tools: Yen-Chu, Chien-Ying Liu, Ying-Kai Chao. Wrote the paper: Hung-Yi Lu, Yun-Hen Liu, Hui-Ping Liu. Supervision and coordination of project: Yen-Chu, Yun-Hen Liu, Hui-Ping Liu. Guarantor Yun-Hen Liu. Acknowledgments This work was supported by the Chang-Gung Memorial Hospital, Taiwan (Contract No. CMRPG 391913) and by the National Science Council of Taiwan (NMRPG3B0171). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ijsu.2015.02.027. References [1] F. Froghi, M.H. Sodergren, A. Darzi, P. Paraskeva, Single-incision Laparoscopic Surgery (SILS) in general surgery: a review of current practice, Surg. Laparosc. Endosc. Percutaneous Tech. 20 (2010) 191. [2] S. Shekherdimian, D. DeUgarte, Transumbilical laparoscopic-assisted appendectomy: an extracorporeal single-incision alternative to conventional laparoscopic techniques, Am. Surg. 77 (2011) 557e560. [3] T. Abdel Azeez, K.M. Mahran, Transumbilical laparoscopic cholecystectomy: towards a scarless abdominal surgery, Hepatogastroenterology 58 (2011) 298e300. [4] J.C. Siegle, L.J. Bishop, W.F. Rayburn, Randomized comparison between two microlaparoscopic techniques for partial salpingectomy, JSLS 9 (2005) 30e34. [5] J.U. Stolzenburg, G. Hellawell, P. Kallidonis, M. Do, T. Haefner, et al., Laparoendoscopic single-site surgery: early experience with tumor nephrectomy, J. Endourol. 23 (2009) 1287e1292. [6] Y.W. Jung, Y.T. Kim, D.W. Lee, Y.I. Hwang, E.J. Nam, et al., The feasibility of scarless single-port transumbilical total laparoscopic hysterectomy: initial clinical experience, Surg. Endosc. 24 (2010) 1686e1692. [7] P. Bucher, F. Pugin, N.C. Buchs, S. Ostermann, P. Morel, Randomized clinical trial of laparoendoscopic single-site versus conventional laparoscopic cholecystectomy, Br. J. Surg. 98 (2011) 1695e1702. [8] W.A. Brennan, J. Haiavy, Transumbilical breast augmentation: a practical
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