Surgical access trauma following minimally invasive thoracic surgery

Summary

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Surgical access trauma has important detrimental implications for immunological status, organ function and clinical recovery. Thoracic surgery has rapidly evolved through the decades, with the advantages of minimally invasive surgery becoming more and more apparent. The clinical benefits of enhanced recovery after video-assisted thoracoscopic surgery (VATS) may be, at least in part, the result of better-preserved cellular immunity and cytokine profile, attenuated stress hormone release and improved preservation of pulmonary and shoulder function. Parameters of postoperative pain, chest drain duration, hospital stay and even long-term survival are also indirect reflections of the advantages of reduced access trauma. With innovations of surgical instruments, optical devices and operative platform, uniportal VATS, robotic thoracic surgery and non-intubated anaesthesia represent the latest frontiers in minimizing trauma from surgical access.

INTRODUCTION

In the past decade, video-assisted thoracoscopic surgery (VATS) has undergone significant evolution and refinement and has become the gold standard in multiple areas of thoracic surgery, including those of major lung resection [1]. Although its safety, oncological clearance and cost effectiveness have overcome initial scepticism and proven to be at least equivocal in comparison to open thoracic operations, there is increasing evidence that the reduction in surgical trauma has led to better immune function, improved stress marker profile and superior clinical outcomes. In the first section, we review both the cytokine and cellular immune response following VATS and open thoracotomy because these markers are surrogates for the degree of surgical access trauma (Table 1). In the second section, we discuss the indirect comparison of access trauma in terms of improved clinical outcomes, including early postoperative recovery, pulmonary and shoulder function and long-term prognosis (Table 2). In the final section, we examine the latest updates regarding novel minimally invasive techniques, comprising uniportal VATS, robotic thoracic surgery and non-intubated anaesthesia and their potential roles in improving clinical outcomes and immunological recovery.

IMMUNOLOGICAL FUNCTION

Cytokines and immune chemokines

Surgical trauma stimulates the systemic inflammatory cytokine response, increasing the levels of interleukin (IL)-1, IL-6 and tumour necrosis factor-α [2]. Early studies of laparoscopic abdominal surgery versus open surgery have shown that the former is associated with an attenuated rise in serum IL-6 and C-reactive protein [3]. In a similar fashion, major lung resection using VATS has been subsequently shown to have reduced postoperative C-reactive protein, IL-6 and IL-8 levels compared to open thoracotomy [4–6], and the variance is more likely related to the difference in access trauma than to the extensiveness of the intrathoracic procedure [7].

IL-6 is one of the major markers of surgical trauma. It modulates the other inflammatory cytokines IL-1β and tumour necrosis factor-α, which are necessary for effective cellular immunity and immunosurveillance, and thus may have a role in postoperative immunosuppression. In addition, IL-6 stimulates proliferation of certain subtypes of non-small-cell lung cancer (NSCLC), promotes activation of insulin growth factor (IGF) and leads to the inhibition of the IGF binding protein (IGFBP)-3 [8]. The immunomodulatory cytokine IGF-1 is well known to favour numerous lines of cancer proliferation and reduce cancer cell apoptosis [9]. Being a natural antagonist of IGF-1, IGFBP-3 can independently induce apoptosis in many colonic, prostatic and certain NSCLC cell lines [10], as well as impair deoxyribonucleic acid (DNA) synthesis in poorly differentiated tumour cells [11]. Major lung resection with VATS is associated with a significantly higher level of IGFBP-3 on postoperative day (POD) 3 compared with the open counterpart in a prospective study, although clinical benefits have not been shown in the small-scale study or during the short follow-up period [12].

The immune chemokine matrix metalloproteinase-9, released from mononuclear cells following surgical trauma, can cleave and deactivate IGFBP-3, thus facilitating tumour invasion and metastasis via its proteolytic activity against type IV collagen of the basement membrane [13, 14]. Studies have also shown that matrix metalloproteinase-9 levels are reciprocally lower in patients who underwent VATS lung resection as opposed to thoracotomy [13]. Our institute has demonstrated that the anti-inflammatory IL-10 has reduced release in the early postoperative period after VATS [5], which may be important because it is a T-helper type 2 cytokine that generally suppresses cell-mediated immunity. It also helps tumour cells evade the host immune system by direct inhibition of natural killer (NK) cell-mediated cytotoxicity and enhances the resistance of certain tumour cell lines to destruction by NK cells [15].

Tumour angiogenesis has important implications for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is one of the most potent inducers of angiogenesis: It directly induces endothelial cell proliferation, migration and tube formation and acts as a potent tumour promotor. Researchers at the authors’ institution have found significantly higher levels of circulating VEGF on POD 3 in the open thoracotomy group versus the VATS group in a prospective study [16]. VEGF plays a key role in wound healing; thus, it is logical to infer that the difference in VEGF levels postoperatively is due to the extent of surgical access. Similar findings have also been reported by studies comparing open and laparoscopic colectomy [17]. Angiopoietin (Ang)-1 and Ang-2 are plasma proteins that compete to bind to endothelial cell-bound Tie-2 receptors, regulating endothelial cell proliferation and migration. In particular, Ang-2 destabilizes capillary integrity, disrupts connections between the endothelium and perivascular cells and enhances the effects of VEGF [18]. Ang-2 is known to increase following major thoracic and abdominal surgery [19]. Researchers at the author’s institute have also demonstrated that postoperative Ang-2 levels were significantly higher in patients undergoing open thoracotomy compared with those having the minimally invasive approach [16]. Such attenuated inflammatory markers or cytokine responses are found not only in lung operations but also in oesophagectomy [20]. Early postoperative differences in the levels of these inflammatory cytokines, immune chemokines and angiogenesis proteins between the surgical approaches may have important implications for tumour cell behaviour.

Cellular immunity

Cellular immunity plays an important role in postoperative infection and tumour immunosurveillance. Typically, one sees decreased lymphocyte proliferation, changes in the circulating blood lymphocyte subsets, downregulation of the T-helper type 1 (Th-1) cytokine response and decreased delayed-type hypersensitivity responses after major surgery [2, 21, 22]. Less immunosuppression of lymphocyte activities and less suppression of total T-cell and CD4 T-cell counts are found following VATS lobectomy for early stage NSCLC compared to the open approach [23]. We demonstrated in a prospective study that NK cell counts are significantly higher on POD 7 in the VATS group compared to the open group [24], suggesting that VATS is associated with a quicker recovery of NK cells [25]. NK cells are important for tumour immunosurveillance because they recognize and directly destroy tumour cells without prior sensitization. More recent studies have shown that the number of CD3+, CD4+ and CD8+ T lymphocytes and the CD4+/CD8+ ratio were significantly lower in patients undergoing open thoracotomy compared to those having VATS [23, 26]. T cells have long been known to be in a delicate balance, and any imbalance may be related to immunodeficiency or autoimmunity. In particular, a low CD4+/CD8+ ratio is implicated in reduced resistance to infection, as in the case of tuberculosis and human immunodeficiency virus infection [27]. Such a difference in cellular immunity is also observed in studies comparing VATS thymectomy versus trans-sternal thymectomy for non-thymomatous myasthenia gravis, with CD4+ and CD8+ T-cell counts being less disturbed postoperatively in the VATS group [28].

An 11-year follow-up study demonstrated the inverse relationship between the level of cytotoxic activity of peripheral blood lymphocytes and long-term cancer risk [29]. It was also noted that the neutrophil phagocytic activity in terms of reactive oxygen species production was also less affected after VATS major lung resection than after thoracotomy. Surgical stress caused a decrease in the function of the innate arm of the immune system: Studies have shown that the cytotoxic function of peripheral blood mononuclear cell nadirs on POD 2 and the effect thereof are significantly more deleterious in the thoracotomy group than in the VATS group [30]. However, the cytotoxic function returned to preoperative levels at the first follow-up. Lymphocyte oxidation was less suppressed on POD 2 in the VATS group in another prospective randomized study [23]. In general, the surgical changes in key cells of cellular immunity are smaller in the VATS group, and recovery to baseline is more rapid. A less suppressed cellular immunity postoperatively may confer a theoretical advantage of lower predisposition to tumour growth and recurrence, although these early changes occur on the order of a few days to weeks, and the effect on long-term tumour recurrence can only be speculated.

Although VATS has been shown to attenuate numerous undesirable immunological responses to trauma, there is still a paucity of evidence directly linking the blood markers to clinical outcomes. The preceding studies are also limited by their relatively small sample size and for the potential for selection bias and the possibility of confounding factors. Future work should aim to translate the findings from bench to bedside and eliminate bias by randomized, controlled studies.

Hormonal response

Excessive quantities of stress hormones released after major trauma or surgery have detrimental effects on metabolic and physiological processes, leading to hypermetabolism and hypercatabolism, muscle wasting and impaired immune function and wound healing [31]. Cortisol secretion promotes protein breakdown and gluconeogenesis in the liver and has immunosuppressive effects. VATS is associated with a reduced rise in the early postoperative cortisol level [32]. The degree of sympathetic activation, in terms of blood epinephrine levels, is also found to be lower in minimally invasive thoracic surgery than in its open counterpart [33, 34].

INDIRECT MEASUREMENTS OF SURGICAL ACCESS TRAUMA

Less postoperative pain for the patient was undoubtedly one of the main goals of minimally invasive surgery, and this goal has been proven in lung resection, thymectomy, oesophagectomy and others. Surprisingly, despite the common belief that a longer wound entails more pain, there is a relative lack of data in support of this idea [35]. On the contrary, the mechanism of the notorious chronic post-thoracotomy pain syndrome suggests that multifactorial causes, including the site of surgical access, density of pain sensors and presence of nerve or bone injuries, are in play when considering postoperative pain [36]. Nociceptive somatic afferents are conveyed by intercostal nerves after skin incision, rib retraction, muscle splitting and injury to the parietal pleura, whereas nociceptive visceral afferents are conveyed by phrenic and vagus nerves after injury to the bronchus, visceral pleura and pericardium. Neuropathic pain after intercostal nerve injury results in reduced sensory output with hypersensitivity, whereas referred pain to the ipsilateral shoulder is relayed by the phrenic nerve. In standard posterolateral thoracotomy, the latissimus dorsi and sometimes the serratus anterior and trapezius muscles are divided. Although some surgeons use alternative muscle-sparing approaches to limit muscle damage, the reduced field of view may lead to excessive rib retraction, fracture, dislocation or even costovertebral disruption, and the modified incisions may span multiple dermatomes [36]. In contrast, most VATS procedures involve limited muscle splitting and rib retraction. Knowledge about the mechanism of pain production also provides a logical explanation as to why uniportal VATS is in general less painful than multiportal VATS [33] and why subxiphoid access is less painful than intercostal access [37]. However, one should bear in mind that excessive instrument manipulation during VATS or the use of rib retractors while attempting to extract a large piece of lung from a small wound can also cause collateral damage to surrounding ribs and intercostal nerves [38].

Lung function is more deleteriously affected after thoracotomy than after VATS procedures. In a retrospective analysis, the standard posterolateral thoracotomy or the anteroaxillary approach is associated with significantly more impairment of vital capacity and of the 6-min walk distance 1 week after surgery [39]. The difference in pulmonary function within 1 week of surgery has been well reported [40] but was also reported to last up to 3 months postoperatively [41]. Nevertheless, some studies reported no lasting effects of lung function impairment between the 2 approaches after 6–12 months [42], suggesting that short-term impairment of pulmonary function probably results from a difference in postoperative pain [6]. This finding has significant implications because VATS is associated with significantly fewer pulmonary morbidities including pneumonia, atelectasis requiring bronchoscopy and requirement of ventilator support [43]. Less shoulder dysfunction in terms of range of motion and shoulder strength is also found with VATS major lung resection as opposed to posterolateral thoracotomy [40, 41, 44].

Clinical recovery and return to baseline are generally faster after minimally invasive procedures than after their open counterparts. Numerous studies have demonstrated shortened hospital stay [45–47] and chest drain duration [46] after VATS major lung resection. Multiple quality of life assessments have also suggested a superior edge of VATS over thoracotomy access [48, 49].

Prognosis and survival

Initial concerns regarding the oncological clearance of cancers using the VATS approach have been unfounded. A majority of studies have confirmed the non-inferiority of VATS versus open techniques in terms of recurrence rates, disease-free survival and overall survival [50, 51]. Interestingly, an increasing body of evidence now even points to possible improved survival of patients with lung cancer after VATS in contrast to the traditional thoracotomy approach. In a recent nationwide propensity matched study conducted by a group from Finland, the 90-day mortality rate was significantly better after VATS when adjusted for patient-, tumour- and operation-specific features, and the 1-year survival rate showed a favourable trend towards VATS [52]. Another recent propensity score matched study by a group from China revealed that VATS lobectomy for stage 1 and stage 2 NSCLC has improved the 5-year overall survival rate compared with the open approach [53]. A group from Japan also reported significantly better 5-year overall survival and 5-year disease-free rates for patients with stage 1 lung cancers [46]. Another retrospective study by a group from the USA who analysed data between 2002 and 2013 from the Society of Thoracic Surgeons General Thoracic Surgery Database demonstrated a modest survival advantage at 4 years postoperatively for patients with stage 1 lung cancers undergoing VATS lobectomy [54]. A Swedish nationwide cohort study also showed a significant edge in 1- and 5-year survival rates after the VATS procedure for early stage NSCLC [55]. Although these results are encouraging, one should be cautious regarding the results, because most studies are retrospective and propensity matched, leaving room for bias and heterogeneity.

Possible explanations for this phenomenon include the increased number of lymph node dissections achieved by some groups using the VATS approach [53]. Some have postulated that the less impaired immunity during the early postoperative period after VATS contributed to enhanced tumour surveillance [56]. For disease recurrence, tumour cells need to possess the ability to grow and invade. This ability is related to angiogenesis factors like VEGF and Ang-2 as well as to being able to evade the host immune system, which is regulated by NK cells and neutrophils and pro-apoptotic factors like IGFBP-3. Surgery represents a window of immunosuppression and tumour cell dissemination through manipulation; thus, it is logical to hypothesize that any immune disturbance in the early postoperative period may have long-lasting effects on oncological outcome. With the recent advancements in detection assays, circulating tumour cells (CTC) in the bloodstream can be quantified and are found to increase in the first few PODs compared to preoperative levels. The postoperative rise in CTC count was significantly lower in the VATS group than in the conventional thoracotomy group [57]. A meta-analysis showed that the disease control rate in CTC-negative patients was significantly higher than that in CTC-positive patients at baseline and during chemotherapy [58]. A review of small-cell lung cancers has also demonstrated that CTC counts constitute a prognostic parameter and marker of response to therapy [59]. Conventionally, CTC enumeration is used mainly to predict survival in patients with advanced or metastatic lung cancers [60]. Whether it has implications for surgically resected early stage lung cancers presents an exciting area of research. Last but not least, a trend towards improved tolerance to chemotherapy [61, 62] and hence better long-term tumour control, has been suggested in favour of VATS surgery.

RECENT ADVANCEMENTS IN MINIMALLY INVASIVE THORACIC SURGERY

Uniportal VATS is the inevitable milestone in the history of thoracic surgery advancement, as surgeons reduce the number and length of incisions in an attempt to minimize surgical access trauma [63]. The increase in inflammatory mediators following skin-only surgical trauma is proportionally dependent on the length of the skin incision [35]; therefore a reduction of total wound length by means of uniportal VATS may reduce surgical stress. In general, a single incision of 2.5 cm is sufficient for diagnostic and minor therapeutic procedures like lung wedge resections, whereas wound length up to 5 cm is still accepted under the umbrella of uniportal VATS for major lung resections, mostly to retrieve the specimen from the pleural cavity [64]. Intercostal uniportal VATS has been proven to result in reduced pain [65], shorter drain duration or less drain output [51, 66] and earlier discharge [51] than traditional 3-port or 2-port VATS. Uniportal VATS opened a new era of minimally invasive thoracic surgery, stimulating pioneers to develop even less invasive access approaches, for example subxiphoid uniportal VATS, ‘scarless’ embryonic natural orifice transumbilical endoscopic thoracic surgery and robotic single-site thoracic incision. Intercostal preservation techniques such as subxiphoid or subcostal access make use of knowledge about post-thoracostomy pain to avoid intercostal nerve injury and thus are associated with less postoperative pain [37, 67] and are especially useful when both sides of the pleural cavity need to be accessed.

Robotic-assisted thoracoscopic surgery (RATS) using the Da Vinci System boasts several features superior to the traditional VATS procedure, namely 3-dimensional high-definition vision, 7 degrees of freedom of instruments and filtration of physiological hand tremor. During the conventional VATS approach, surgeons often unintentionally cause excessive friction between the instruments and the wound in order to perform specific actions or reach certain targets. In contrast, RATS possesses the theoretical advantage of reducing surgical access trauma because the EndoWrist system allows excellent manoeuvrability without instrument fencing. The ‘fulcrum-effect’ enables robotic arms to rotate around a fulcrum point at the level of the trocar, avoiding pressure on the ribs and torque on the chest wall, both of which are known culprits for postoperative pain [68]. Carbon dioxide insufflation is commonly used for certain procedures during RATS to facilitate lung collapse and enhance surgical exposure. On the one hand, this procedure increases the risk of a venous air embolism, elevated intrathoracic pressures leading to reduced venous return and cardiovascular collapse and increased ventilatory pressures that may introduce barotrauma to the contralateral lung [69]. On the other hand, interestingly, the use of carbon dioxide pneumoperitoneum in laparoscopic operations has been shown to attenuate IL-6 production in peritoneal macrophages [70]. With similar mesothelial cell lining, carbon dioxide insufflation during minimally invasive thoracic surgery may have similar anti-inflammatory immune effects.

A systematic review and meta-analysis comparing multiport, uniportal and robotic VATS revealed that the different VATS approaches resulted in similar outcomes in most areas, including overall survival, recurrence, number of lymph nodes harvested and nodal upstaging and rate of adverse events. Nevertheless, the group did conclude that uniportal VATS may be associated with less pain and fewer analgesics requirements [level C- limited data (LD) evidence] than multiport VATS, whereas robotic VATS is associated with higher costs compared to multiport VATS (level B evidence) [71].

The recent popularity of non-intubated VATS stems from the belief that surgical stress comes not only from the procedure but also from the method of anaesthesia. Despite the overall effectiveness of the double lumen endotracheal tube and lung isolation for thoracic operations, they do have certain drawbacks, including a higher risk of pneumonia, barotrauma, postoperative ventilator dependency, residual neuromuscular blockade and injury to major airways and vocal cords [72]. Over the new millennium, non-intubated VATS gained momentum because studies have shown significant benefits over intubated VATS [72], namely, shortened global operative and anaesthesia time [73–75], shorter chest drain duration [73], lower use of sedatives and analgesics [74], earlier oral intake and discharge [73, 75–77]. The advantage of non-intubated VATS may be more exemplified in high-risk candidates with poor lung function or multiple comorbidities [75]. Although hypoxia may result during the procedure, better oxygenation postoperatively can be achieved by non-intubated VATS [75]. The overall surgical trauma inferred from postoperative pain and the use of postoperative opioid analgesics is also reduced in non-intubated VATS [73, 74]. Non-intubated VATS has also been found to better preserve immunological and hormonal function postoperatively in comparison with intubated controls. A randomized study showed significantly higher NK cell levels on PODs 1 and 2 following non-intubated VATS [78]. Another controlled study echoes the finding regarding NK cells, in addition to a lower IL-6 level up to 14 days after surgery [77]. Non-intubated VATS also leads to a better surgical stress hormone profile, with an attenuated rise in cortisol levels [79]. Increases in C-reactive protein and D-dimer levels are also less marked in the non-intubated VATS group [73, 79]. Combining the best of both worlds, non-intubated uniportal VATS for major lung resection may be the perfect match to push the frontier of minimally invasive thoracic surgery forward [80].

CONCLUSION

Pioneers in minimally invasive thoracic surgery have been pushing the limits since the early 1990s in order to minimize surgical access trauma and improve patient outcomes. To date, we have consolidated evidence that minimally invasive operations mitigate immunological and hormonal postoperative responses, which may be a crucial factor in prompt clinical recovery. Given the promising results from early and intermediate studies, the efficacy and the response to surgical trauma of novel minimally invasive techniques including non-intubated uniportal VATS and RATS will be an exciting area of research.

Conflict of interest: Calvin S.H. Ng is a consultant for Johnson and Johnson and for Medtronic, USA. All other authors declared no conflict of interest.

Author contributions

Joyce W.Y. Chan: Methodology; Writing—original draft. Peter S.Y. Yu: Resources; Writing—review & editing. Jack Hong Yang: Methodology; Writing—review & editing. Evan Qize Yuan: Conceptualization; Investigation; Methodology; Writing—review & editing. Hao Jia: Investigation; Project administration; Writing—review & editing. Jia Peng: Data curation; Resources; Writing—review & editing. Rainbow W.H. Lau: Data curation; Investigation; Resources; Writing—review & editing. Calvin S.H. Ng: Conceptualization; Data curation; Investigation; Methodology; Project administration; Supervision; Writing—original draft; Writing—review & editing.

Presented at the 7^th Asian Single Port VATS Symposium, Nagoya, Japan, 24–25 May 2019.

REFERENCES

ABBREVIATIONS

 
• Ang

  Angiopoietin

 
• CTC

  Circulating tumour cells

 
• IGF

  Insulin growth factor

 
• IGFBP

  Insulin growth factor binding protein

 
• IL

  Interleukin

 
• NK

  Natural killer

 
• NSCLC

  Non-small-cell lung cancer

 
• POD

  Postoperative day

 
• RATS

  Robotic-assisted thoracoscopic surgery

 
• VATS

  Video-assisted thoracoscopic surgery

 
• VEGF

  Vascular endothelial growth factor