Perioperative benefit and outcome of thoracic epidural in esophageal surgery: a clinical review

Perioperative benefit and outcome of thoracic epidural in esophageal surgery: a clinical review Summary Surgery for esophageal cancer is a highly stressful and painful procedure, and a significant amount of analgesics may be required to eliminate perioperative pain and blunt the stress response to surgery. Proper management of postoperative pain has invariably been shown to reduce the incidence of postoperative complications and accelerate recovery. Neuraxial analgesic techniques after major thoracic and upper abdominal surgery have long been established to reduce respiratory, cardiovascular, metabolic, inflammatory, and neurohormonal complications. The aim of this review is to evaluate and discuss the relevant clinical benefits and outcome, as well as the possibilities and limits of thoracic epidural anesthesia/analgesia (TEA) in the setting of esophageal resections. A comprehensive search of original articles was conducted investigating relevant literature on MEDLINE, Cochrane reviews, Google Scholar, PubMed, and EMBASE from 1985 to July2017. The relationship between TEA and important endpoints such as the quality of postoperative pain control, postoperative respiratory complications, surgical stress-induced immunosuppression, the overall postoperative morbidity, length of hospital stay, and major outcomes has been explored and reported. TEA has proven to enable patients to mobilize faster, cooperate comfortably with respiratory physiotherapists and achieve satisfactory postoperative lung functions more rapidly. The superior analgesia provided by thoracic epidurals compared to that from parenteral opioids may decrease the incidence of ineffective cough, atelectasis and pulmonary infections, while the associated sympathetic block has been shown to enhance bowel blood flow, prevent reductions in gastric conduit perfusion, and reduce the duration of ileus. Epidural anesthesia/analgesia is still commonly used for major ‘open’ esophageal surgery, and the recognized advantages in this setting are soundly established, in particular as regards the early recovery from anesthesia, the quality of postoperative pain control, and the significantly shorter duration of postoperative mechanical ventilation. However, this technique requires specific technical skills for an optimal conduction and is not devoid of risks, complications, and failures. INTRODUCTION Esophagectomy for cancer is recognized to be a highly aggressive surgical procedure, usually with a favorable outcome when conducted by experienced teams in high-volume centers but with potential significant postoperative morbidity and mortality in cases of complications. Although chemotherapy can achieve satisfactory rates of 5-year survival in selected patients, surgical management still remains the standard of treatment today. Radical two-three field open esophagectomy for cancer is a major invasive surgical procedure; it requires thoracic and abdominal incisions and is associated with significant perioperative pain, substantial fluid shift, potential abnormalities of distal gastric tube perfusion, and increased risk of postoperative respiratory and cardiovascular complications. Effective pain relief after thoracoabdominal surgery has been considered a key element in ensuring early recovery, low surgical morbidity, and short hospitalization. Epidural anesthesia/analgesia is still commonly used for major ‘open’ surgery: its superior effect compared with that of systemic opioid analgesia, the relatively low incidence of side-effects, and some favorable results as regards important endpoints have led physicians to consider it a preferential analgesic technique, to promote faster recovery compared with opioid-based standard analgesia. However, despite the widespread use of epidurals, increasing doubts about its benefits with respect to perioperative pathophysiology, outcome, and organ protection have emerged in recent literature, and a decline in its popularity and application have been recorded in some institutions.1,2 The increasing number of esophageal cancer patients under anticoagulants and/or platelet aggregation inhibitors is another problem supporting refusal for epidural puncture and catheterization. In addition, some of the favorable effects suggested by many authors, such as a decreased risk of postoperative mortality, myocardial infarction, pneumonia, venous thromboembolism and respiratory impairment, seem to be described primarily in older trials in which outdated systemic analgesia techniques might have been used.3-5 In this paper, the recognized advantages and benefits on the outcome of thoracic epidural anesthesia/analgesia (TEA), as well as its weaknesses, are briefly evaluated within the setting of thoracoabdominal or transhiatal open esophagectomy. METHODS The review includes relative literature identified during searches in MEDLINE, Cochrane reviews, Google Scholar, PubMed, and EMBASE from 1985 to July 2017. Search items were esophagectomy, postoperative thoracoabdominal pain, perioperative thoracic epidural analgesia, infusion of epidural local anesthetic combined with opioid, epidural analgesia for upper abdominal surgery, thoracic catheter placement, preventive respiratory effects of thoracic epidurals, thoracic epidural catheter-related complications, postesophagectomy morbidity, and mortality. This clinical review did not use systematic review standards, in view of the paucity of good evidence studies and the heterogeneity of data as regards the important endpoints considered, particularly methods of evaluating postoperative analgesia, pain management modalities apart from epidural, use of supplementary analgesics, how overall morbidity rates were reported, and evaluation of minor and major outcomes and complications. Many confounding factors were found during analysis of published trials on open esophagectomy, such as the relatively low number of individuals, the often retrospective nature and poor quality of trials, noncomparable modes of epidural management (i.e., different types and concentrations of anesthetic used, different association of opioid plus local anesthetics, different levels of locoregional blockade achieved, intra- and postoperative versus only postoperative use of epidurals, different duration of epidural catheterization), the frequent lack of acute pain practitioners or facilities to care for patients with epidurals, and many other nonreported problems regarding efficacy and safety. Thoracic epidural anesthesia/analgesia for thoracoabdominal and transhiatal open esophagectomy Intense pain in open esophagectomy is generated by large thoracic and/or abdominal surgical incisions, the transection of ribs and intercostal nerves, pleural incisions, and placement of pleural drainage tubing. Uncontrolled perioperative pain and the pathophysiological response to surgery have been demonstrated to cause potentially significant complications in many organ systems, increased sympathoadrenal and other neuroendocrine activity, and to increase cytokine production. Conducting thoracoabdominal or transhiatalesophagectomy under epidural anesthesia in combination with general anesthesia has been suggested to reduce perioperative morbidity and mortality compared with surgery associated with general anesthesia alone.6,7 This approach provides optimal acute pain relief, and its benefits on several perioperative variables, such as the respiratory, immunologic, hemodynamic and neuroendocrine responses to surgery, have been demonstrated in many studies.2,8,9 However, other modes of perioperative pain management (continuous infusion of short-acting analgesics, intercostal nerve blocks, paravertebral or transverse abdominis plane blockade, patient-controlled analgesia, continuous wound catheter infusion of local anesthetic) and the increasing use of multimodal approaches to postoperative analgesia, have been encouraged and performed. Alternative modalities to standard epidural analgesia have been considered attractive and applicable, due to the incidence of failed or contraindicated epidurals and the lower risk of adverse effects or complications. In a recent systematic review10 and meta-analysis which evaluated optimal pain management and the incidence of adverse effects after both open and minimally invasive esophagectomy, no differences in postoperative pain scores or respiratory complications between systemic and epidural analgesia were reported. In addition, some new evidence indicates that the protective effects of TEA and its substantial benefits are fewer than previously thought. There is also uncertainty as to whether the effects of neuraxial analgesia methods can be transformed into improvements in short- and long-term clinical outcomes in these patient populations—to the extent that considerable debate has arisen about its widespread use.10–13 Considering the limited evidence in favor of substantial therapeutic benefit, some authors question the routine use of epidurals in the majority of patients undergoing laparotomy only.14 It is known that the increased number of minimally invasive esophagectomies and the refinement of modern systemic multimodal analgesia have decreased anesthesiologists’ propensity toward epidurals. However, pain after thoracoabdominal incisions is usually severe and difficult to manage. Both abdominal and thoracic components of the surgical procedure cause protracted wound and visceral pain. The advantageous effects of a well-conducted and prolonged postoperative epidural analgesia cannot be replaced solely by current methods of systemic analgesia. Current strategies of early and aggressive postesophagectomy pain therapy certainly include systemic multimodal techniques. However, they also comprise effective blocking of nociceptive inputs from the wound, and thorough treatment of dynamic pain with regional analgesia. It has been demonstrated that the intensity of acute postoperative pain correlates with the risk of developing a state of persistent pain.15 Intraoperative use of TEA The use of thoracic epidural catheters is considered by many anesthesiologists as routine practice for both intra- and postoperative pain relief. The recommended sites for epidural puncture during two-three hole esophagectomy are at T6–8 levels; both puncture and catheterization are usually performed under light sedation before anesthesia is induced, and the epidural space is identified by the loss-of-resistance technique. Catheter-incision-congruent epidural analgesia is highly recommended, to provide effective analgesia and avoid major adverse effects. Depending on the surgical approach and the attending anesthesiologist's judgment of the patient's status, epidural segmental blockade is established during the course of general anesthesia, either with a bolus dose of local anesthetic or local anesthetic plus opioid, followed by repeated boluses or, alternatively, continuous infusion of anesthetic/opioid solutions. A combination of local anesthetic and opioid is often chosen in order to provide good anesthesia/analgesia with less hypotension than that observed with the local anesthetic alone. The concentration and volume of the local anesthetic may determine the intensity and limitations of the sympathetic block; a thoracic segmental sympathetic block for a thoracoabdominal or transhiatal esophagectomy should not include the legs and should avoid systemic hypotension, with its possible associated impaired intestinal perfusion.16 The benefit derived from cautious conduction of intraoperative thoracic epidural anesthesia is assumed to be related to a segmental sympathetic block. TEA is an effective technique for providing temporary selective thoracoabdominal sympathetic deafferentation, which has been proven to be associated with beneficial physiological effects on the cardiovascular, respiratory, and gastrointestinal systems.17,18 The sympathetic blockade may reduce the metabolic, endocrine, and immunologic responses to surgical trauma, and also prevent lipolysis and loss of protein.16,18–20 Protective effects on neurohormonal and inflammatory responses have been demonstrated by Fares et al.,21 who measured the concentrations of interleukin (IL)-6 and IL-8 at various stages of transthoracic esophagectomy and demonstrated that TEA with general anesthesia was associated with a significant reduction in IL-6 and IL-8 (when compared with that associated with general anesthesia alone). The levels of immune compounds associated with the development of the stress response and neuropathic pain (cortisol, IL-6, interferon (IFN)-γ, IL-4 and IL-17) were also recently evaluated in a patient population undergoing thoracoabdominal esophageal surgery.22 Patients who received intraoperative TEA displayed a perioperative decrease in the plasma levels of cortisol and IL-6 compared with that observed with general anesthesia alone. A combination of local metameric delivery of analgesic drugs with ‘light’ general anesthesia is reported to reduce the intraoperative requirement for opioids and anesthetic agents. Besides providing optimal perioperative conditions, it may also allow faster recovery, early ‘in theatre’ extubation, and an analgesic depth of a higher quality than that offered by systemic opioids.23 Minimal sensitive and motor postoperative block allows for minimal compromise of postoperative movements. TEA and gastric conduit perfusion Esophageal anastomotic leak is a serious and potentially life-threatening complication of esophagectomy; not infrequently, severe leaks may lead to mediastinitis, adult respiratory distress syndrome (ARDS), septic shock, and death. Maintenance of adequate perfusion to the anastomosis is therefore of paramount importance to prevent a reduction in gastric conduit oxygen tension. In patients undergoing major abdominal surgery, the sympathectomy of thoracic epidural anesthesia has been shown to enhance bowel blood flow and prevent reductions in gastric intramucosal pH. In humans, various reports have attested to the beneficial effects of TEA on intestinal perfusion during esophagectomy. The advantageous influence of an epidural block on splanchnic perfusion is of particular importance with regard to the microcirculatory changes observed in the gastric tube after esophagectomy. As the T6–T10 sympathetic nerves distribute to the stomach, a sympathetic block induced by TEA may increase gastric tube blood flow. Michelet et al.24 retrospectively analyzed the perioperative factors associated with the development of anastomotic leakage in 207 patients undergoing one-stage esophagectomy. They showed that TEA used during the postoperative course of esophagectomy was associated with decreased occurrence of anastomotic leakage. In 2007, the same authors25 measured gastric mucosal blood flow at the end of the surgical procedure by laser Doppler flowmetry, demonstrating that TEA improves the microcirculatory perfusion of the gastric tube, despite a slight decrease in mean arterial pressure but with no influence on the cardiac index; patients who refused TEA were affected by a higher incidence of anastomotic leaks. However, conflicting results regarding the effects of TEA on splanchnic blood flow and anastomotic perfusion have also been reported, and some studies do not put forward any substantial evidence for decreased anastomotic leakage.25-27 In fact, an epidural-mediated decrease in blood pressure may have highly deleterious hemodynamic consequences, as the splanchnic veins contribute substantially to the control of overall venous capacitance.28 Excessive mesenteric venodilatation may be associated with impairment of splanchnic blood flow, a reduction in gastric tube blood flow, and deterioration of tissue perfusion.29 TEA appears to protect from gut injury after major surgery and exerts beneficial effects on intestinal perfusion as long as systemic hemodynamics are adequately maintained. Marked vasodilation and hypotension induced by extensive thoracolumbar sympatholysis (e.g., after aggressive doses of anesthetic bolus) was found to decrease flux at the anastomotic end of the gastric tube and compromise mucosal integrity.30 An important factor often associated with the occurrence of anastomotic breakdown and leak is the development of perioperative gut edema, which may occur after excessive perioperative crystalloid administration. For this reason, in cases of epidural-related hypotension, unnecessary fluid load beyond that required for ‘satisfactory’ intravascular filling should not be administered. Restricting the metameric diffusion of sympathetic block by congruent incisional epidural catheterization, intermittent intraoperative low volume boluses of local anesthetics instead of continuous infusion, and maintaining a light plan of general anesthesia (preferably under electrophysiological brain monitoring) may prevent significant hemodynamic impairment. Due to the risk of reducted blood flow at the anastomotic level, activation of an extensive sympathetic block in high-risk patients should be evaluated case by case, particularly in the elderly or in patients with myocardial dysfunction. However, if moderate systemic hemodynamic deterioration develops as a consequence of deliberate fluid restriction and perioperative epidural use of local anesthetics, correction of the mean perfusion pressure may reverse the adverse perfusion effects of TEA.31,32 Judicious short-term use of vasoactive agents may also reverse the adverse perfusion effects of TEA and re-establish adequate gastrointestinal blood flow.33 Phenylephrine or norepinephrine infusion, titrated to restore hypotension, has been shown to improve blood flow to the stomach during substantial vasodilation associated with extensive sympathectomy.30,31 Laser speckle imaging has shown that norepinephrine does not impair anastomotic blood flow as long as normovolemia and cardiac output are maintained.32 Currently, it is reasonable to believe that significant factors such as patient characteristics, operation-related factors, perioperative hemodynamic management on the whole, and the ‘intensity’ of postoperative patient care are much more important than the postoperative analgesic technique in itself, when anastomotic leakage occurs.34 Postoperative analgesia The complexity and morbidity of open esophagectomy and the ‘fragility’ of patients suffering from esophageal cancer, mean that adequate pain relief must continue for an indeterminate length of time postoperatively, at least until the intensity of the pain is greatly reduced. Sufficient freedom from pain allows for early mobilization, deep breathing, and effective coughing, and prevents hypoxemia and tachypnea. In patients undergoing thoracic and upper abdominal surgery for interventions on the gastrointestinal tract, TEA provides superior postoperative analgesia compared with that provided by parenteral opioids and can contribute to enhanced acute postoperative outcomes such as improved respiratory function, and reduction in protein loss and in the duration of ileus.35 Various reports have demonstrated that effective postoperative epidural analgesia is also successful in shortening the duration of mechanical ventilation, endotracheal intubation and stays in the intensive care unit (ICU).36 Early extubation has been advocated to reduce morbidity and costs after esophagectomy, as prolonged invasive ventilation has been associated with sedation-related side-effects, aspiration, pneumonia and barotrauma.7 An optimal mix of local anesthetic and opioids in a continuous epidural infusion would improve pain control at rest and during activity and minimize the side-effects associated with both drugs. In particular, epidural techniques with local anesthetic and opioid solutions are particularly effective at providing dynamic analgesia, an advantage not easily achievable with parenteral analgesics, and one which may result in improved lung volumes and decreased incidence of atelectasis and pulmonary infections.37 Assessment of pain during mobilization represents the best way to reveal differences between the various pain-relieving methods; effective TEA in the dermatomal distribution of thoracotomy and laparotomy been invariably been associated with improvements in dynamic pain scores when compared with less effective epidurals or systemic opioid analgesia.38,39 Properly conducted TEA has been proven to be substantial in aiding recovery and preventing complications.40 However, whether the benefits of continuous epidural infusion, patient-controlled epidural analgesia (PCEA) or a combination of the two effectively translate into better long-term outcomes in this setting is still not clear. The advantages and risks of TEA have mainly been described in the early period after surgery or, at most and less frequently, during the in-hospital stay.39,41 Cense et al.42 studied the in-hospital morbidity/mortality in two groups of patients undergoing transthoracic esophageal resection: one group was given epidural analgesia for at least 2 days postoperatively, and the other was not. The above authors found a marked difference in the rate of pneumonia, need for reintubation, ICU stay, and in-hospital stay between the groups. ICU and in-hospital stays were substantially longer in patients who did not receive TEA, and none of the eight patients who died during the hospitalization period had benefited from an epidural for at least two postoperative days. Epidural is conventionally favored as first-line analgesia method in open esophagectomy, and was recommended in a systematic review of enhanced recovery after surgery (ERAS) trials.43 However, two recent reviews and meta-analyses10,39,44 examined the published literature critically and did not confirm the suggested postoperative benefits: in fact, from the randomized controlled trials analyzed, significant differences in postoperative pain scores (pain at rest), overall postoperative morbidity, and adverse events between systemic and epidural analgesia after open esophagectomy were not demonstrated. The superiority of TEA over systemic methods as the most effective patient pathway following open esophagectomy was not proven. Besides the paucity of evidence for epidural use in this particular type of surgery, the main problems which emerged from these two meta-analyses included the sample sizes and quality of available studies (i.e. patient demographics and baseline clinical parameters were not well balanced), variability in clinical protocols between trials, prevalently retrospective analysis, and the difficulty of comparing postoperative pain evaluation (i.e. data on postoperative total opioid consumption and use of supplementary analgesics were not reported or incompletely reported; pain scores at rest, at deep breath and at mobilization were not described, inaccuracies regarding duration of epidural analgesic administration, procedure-specific analyses were not performed, and outcomes other than pain scores were not reported consistently). The need for adequately powered randomized controlled trials to define the optimal strategies of pain management after esophagectomy was advocated in both reviews. Regardless of the results of the above meta-analysis on epidural analgesia for transthoracic or transhiatal esophagectomy, this analgesia method is still widely encouraged, as many of its benefits are soundly established in clinical practice. However, it is not devoid of risks, complications and failures. Table 1 lists the main medication-related, epidural catheter-related and technical-related complications or side-effects associated with continuous TEA. Treatment of commonly occurring vasodilation and hypotension was mentioned previously: the possibility of lower limb motor block and hypoesthesia are prevented with reduced concentrations of local anesthetic, so that spontaneous ambulation is guaranteed. Reducing epidural opioids whenever feasible, reducing or discontinuing the doses of other sedative agents and/or rotating opioids may be useful in avoiding excessive sedation. As regards opioid-induced nausea, vomiting and itching, low-dose haloperidol, prokinetic medications, and serotonin receptor antagonists such as ondansetron, granisetron, and dolasetron, in single on-demand cases or at constant intervals, are usually efficacious in minimizing these symptoms; 4 mg of prophylactic ondansetron has also been shown to be effective in preventing nausea, vomiting, and pruritus after postoperative epidural morphine.44 Table 1 Side-effects and complications, with reported incidence, associated with thoracic epidural anesthesia/analgesia [from refs. 114–117] Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  View Large Table 1 Side-effects and complications, with reported incidence, associated with thoracic epidural anesthesia/analgesia [from refs. 114–117] Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  View Large Epidural naloxone is also administered to reduce postoperative nausea and vomiting induced by epidural sufentanil.45 Measures to prevent hypotension are also effective in preventing nausea and vomiting. Pruritus may also be managed with antihistamine drugs or opioid rotation to an agent with low histamine release (e.g. fentanyl). Constipation is usually minimal when low epidural opioid doses are administered and for a limited period of time. Apart from adopting a gastrointestinal regimen compatible with recent resective and reconstructive surgery, early out-of-bed mobilization seems to be the best strategy to prevent this adverse effect. Oral naloxone was once proposed; however, its use has been associated with the need to increase the opioid dose.46 The risk of respiratory depression associated with epidural analgesia is influenced by many factors, such as age, gender, comorbidities, prior opioid administration, intraoperative amount of fentanyl, time from last neuraxial opioid administration and epidural refilling, intensity of postoperative pain, amount of associated sedatives, and other factors. Morphine-induced respiratory depression, although rare, is generally dose-related and may occur at any time during the postoperative course: early and late onset of reduced levels of consciousness and respiratory rate have also been reported with fentanyl, sufentanil and pethidine. Careful titration and proper identification of the amount administered, together with strict patient surveillance at early onset of the first symptoms may prevent the deleterious effects of severe hypoxia and CO2 retention from epidural opioids. Epidural or small i.v. doses of the opioid antagonist naloxone are effective in reversing respiratory depression from neuraxial opioids, although naloxone has a shorter duration of action and often requires repeated administrations. In addition, the possible ‘individual’ recurrence of pain after reversing may require extra rescue doses of opioids.47 The possibility that epidural analgesia, by accelerating and improving recovery, could save healthcare costs in high-risk surgery patients has been hypothesized but not yet demonstrated. In other words, whether the superior analgesic regimen may be followed by positive changes in the length of ICU and hospital stays and overall intra-hospital costs has not been clearly elucidated. Bartha et al.48 evaluated the impact of an improved pain treatment on the entire clinical pathway and on both the intensive care and hospital resource utilization following major esophagectomy. The costs of treatment with PCEA and patient-controlled intravenous analgesia (PCIA) were analyzed for a six-day period, as well as the costs for every adverse event, staff hours and ICU stays. Unlike the results of Brodner et al.,49 who reported substantial ICU savings after the introduction of epidurals (as a consequence of shorter ICU stays), the above authors observed that postoperative epidural analgesia had higher overall costs than IV analgesia. Despite the better analgesic effects, using TEA did not reduce the costs for postoperative care and total healthcare costs in high-risk. Patients undergoing esophagectomy may have a high risk of progression from acute postoperative to chronic pain; chronic postsurgical pain (CPSP) is a relatively frequent complication of thoracic and abdominal procedures, with a high impact on quality of life. Although the relationship between the modality of acute pain management in these patients and the incidence/severity of CPSP requires further investigation, neither preemptive TEA (initiated before surgical incision) nor TEA initiated after completion of surgery have been associated with a significant reduction in the incidence of chronic postthoracotomy pain in large studies (although there are a few isolated reports with positive results).50,51 An issue still widely unexplored is the appropriate duration of epidural analgesic administration in the postoperative course of esophagectomy. Although TEA has been used for decades in perioperative care, no standard of practice has emerged from either recent or earlier literature, and large variability is still seen among hospital centers. The need to maintain epidural catheterization for more than 3 days is seen as a substantial extra cost by many institutions, although early removal (<3 days) undoubtedly increases the need for systemic opioid analgesia.52 As in other types of surgery, the timing of withdrawing epidural local anesthetics/opioids and substituting them with systemic analgesics after thoracoabdominal esophagectomy are still not well defined. Flisberg et al.53 found that continuing TEA (bupivacaine, 2.5 mg/mL mixed with morphine, 0.125 mg/mL, at a rate of 4 mL/h) for five postoperative days provided better pain relief at mobilization and fewer side-effects than those observed with an earlier switch to patient-controlled intravenous morphine. Patients receiving intravenous analgesics also needed more supplemental pain relievers. Niwa et al.54 have recently evaluated the effect of a continuous paravertebral block (PVB) for thoracotomy, combined with epidural anesthesia for laparotomy after esophagectomy. The control group received two epidural catheters for thoracotomy and laparotomy. In all patients, the anesthetic solution was continuously infused until postoperative day 7. The combined use of PVB and epidural anesthesia did not reveal any inferior efficacy for post-thoracoabdominal pain relief. Patients in the epidural group had a higher incidence of hypotension and took longer to ambulate, compared with those in the paravertebral group. The authors considered PVB plus epidural to be a simple, safe, and effective technique for postsurgical pain alleviation. TEA and intestinal motility Postoperative bowel function may benefit from both optimal pain control and the sympathectomy induced by local anesthetics in the thoracic epidural space. Unrelieved pain is associated with sympathetic hyperactivity, which leads to reflex inhibition of gastrointestinal secretion and motor activity and contraction of gastrointestinal sphincters. In addition, the sympathetic nerves control both precapillary and postcapillary resistance vessels in the digestive tract, with vasoconstriction and reduction in regional blood flow. Enhanced sympathetic activity due to surgical manipulation may lead to mesenteric hypoperfusion and intestinal paralysis. Postoperative ileus, by causing distension of the esophageal substitute and limiting regional perfusion, may adversely affect esophagogastric/esophagocolonic anastomosis. TEA after esophagectomy, by maintaining the activity of craniosacral parasympathetic efferent fibers and inhibiting thoracolumbar sympathetic efferent fibers, can shorten the duration of postoperative ileus.55 The activation of perioperative sympathectomy with TEA and the consequent unopposed parasympathetic activity are associated with increased bowel motility, but no evidence of any significant increase in anastomotic dehiscence has been reported.56–58 The position of the epidural catheter and the type of solution infused into the epidural space may make a difference in the recovery of bowel function. Mid-low thoracic catheter insertion and infusion of local anesthetic alone have been associated with greater postoperative intestinal motility than lumbar insertion and infusion of epidural narcotics.55,59 Better results are achieved when the epidural is used before surgical stress and nociceptive afferent stimulation are initiated (intraoperatively), and when local anesthetic solutions are postoperatively administered until bowel function returns (usually 2–3 days).56 High-dose systemic opioids, together with aggressive surgical handling of the gut and excessive i.v. fluids causing bowel edema, can all contribute to prolonged postoperative ileus. Delayed recovery of gastrointestinal function dramatically increases morbidity and the length of hospital stay after major surgery. Neuraxial analgesic techniques invariably reduce intra- and postoperative parenteral opioid consumption, and this condition promotes faster recovery of intestinal motility. A higher risk of nausea and vomiting in patients receiving systemic compared with epidural analgesia has been reported in several trials.10 Despite the paucity of published data in the field of thoracoabdominal or transhiatal open esophagectomy, the intraoperative administration of local anesthetics at thoracic level and continued in the postoperative period very probably also accelerates the resolution of postoperative ileus and allows for early enteral feeding. According to the results of the 2016 Cochrane review on abdominal surgery,60 local anesthetics epidurally administered reduced the time required for the return of gut function compared with that associated with an opioid-based systemic regimen. Local anesthetics, alone or in combination with opioids, were equally effective in accelerating intestinal recovery and superior to systemic and epidural opioids alone; there was no evidence that an epidural with a local anesthetic would affect the incidence of vomiting. The quality of the evidence for a better return of gastrointestinal function was rated as high. TEA and postoperative respiratory complications after esophagectomy Respiratory complications may affect up to 30% of patients after esophagectomy and they remain the major cause of postoperative morbidity and mortality.61 The most important postoperative respiratory complications (PPCs) include severe forms of interstitial acute lung injury, massive pleural effusions, bilateral atelectasis, pneumonia, and ARDS. Additional complications affecting the respiratory system may arise from anastomotic leakage, a trachea-esophageal fistula or recurrent laryngeal nerve palsy. Pulmonary complications and anastomotic leakage are the most serious and common complications even in experienced centers and contribute to substantial perioperative mortality. The pathogenesis of respiratory complications is multifactorial, but the prolonged systemic inflammatory response associated with a highly aggressive procedure seems to be the fundamental mechanism. Due to the possible higher risk of PPCs, the transthoracic approach has been abandoned by some surgeons in favor of a transhiatal approach. Avoiding a thoracotomy may reduce compromised respiratory function, especially in patients with coexisting lung disease. In various studies, perioperative respiratory morbidity, incidence of pneumonia, wound infection, duration of mechanical ventilation and hospital stay were all significantly lower in transhiatal techniques.62,63 On the contrary, case series with large numbers of patients demonstrated almost identical postoperative respiratory and cardiovascular complications in the two techniques.64–66 Considerable debate on which approach is superior as regards the short- and long-term outcomes is ongoing, especially in large-volume centers. Analysis of both the few randomized controlled studies (although with small numbers of patients) and some meta-analyses points toward a slightly higher risk of pulmonary complications with the transthoracic approach, but survival rates at five years are equivalent between the procedures.63,67 Anesthetic management may positively influence the incidence of pulmonary complications by promoting minimal risk of respiratory depression, avoiding excessive fluid administration, containing inflammatory activation, and promoting early recovery. Adequate postoperative analgesia is an essential component of multiple perioperative strategies to prevent pulmonary complications after esophagectomy, together with preoperative improvement of nutrition status, minimally invasive surgery, protective ventilation, goal-directed fluid therapy, nasogastric decompression, and rapid weaning from mechanical ventilation.61 Upper laparotomy and thoracotomy result in significant postoperative pain and are known to impair respiratory mechanics and coughing, to decrease lung volume, promote thoracic restriction, decrease diaphragm function and impair ventilation. It has been speculated that TEA, by inhibiting the efferent and afferent pathways of the intercostal nerve roots, may reduce inspiratory capacity, vital capacity, forced expiratory volume and expiratory minute ventilation. However, proper postoperative thoracic analgesia (i.e. with relatively low concentrations of local anesthetic and small amounts of opioids) does not alter respiratory mechanics, lung volume or pulmonary gas exchange. Epidural analgesia does not impair airway flow, even in patients with end-stage chronic obstructive pulmonary disease.68,69 Intercostal and abdominal muscle tone is not affected, and no decrease in the volume of the thoracic cavity or decreased thoracic and abdominal compliance usually occur. An improvement in vital capacity, forced vital capacity at 24 hours, forced expiratory volume in 1 second at 24 hours, and peak expiratory flow rate at 24 hours have been well documented.1,5 Optimal pain control is vital in ensuring aggressive pulmonary toilet, deep breathing exercises, use of an incentive spirometer, and promoting coughing without restriction. Prevention of sputum retention is essential, to prevent atelectasis (a potential precursor to pneumonia), deterioration of gas exchange and the risk of re-intubation. The excellent analgesia provided by TEA results in a lower incidence of respiratory morbidity after thoracic surgery, and no study has reported a deterioration in pulmonary function by this method.70–72 The potential benefit of TEA on reducing PPCs and improving the respiratory outcome of patients undergoing noncardiac procedures was emphasized in the large meta-analysis of the CORTRA study.73 TEA has been demonstrated to have the potential to prevent diaphragmatic dysfunction after thoracic and abdominal surgery by reducing the inhibitory effect of surgical trauma on phrenic motor neuron activity.74 A recent retrospective report on 543 patients undergoing elective McKeown-type esophagectomy (183 receiving TEA and 360 intravenous analgesia) demonstrated a 19.7% incidence of pneumonia in the TEA group compared with 32% in the intravenous group (significant reduction).75 The incidence of ARDS was also reduced in the TEA group, although it did not reach statistical significance. The importance of epidural analgesia to prevent pulmonary complications and pneumonia during the early postoperative period after a transthoracic esophageal cancer resection was also highlighted by Cense et al;42 authors reported increased needs for reintubation and longer ICU stays, mainly due to higher incidences of postoperative pneumonia, in patients who did not benefit from epidural analgesia for more than two days after the procedure. No application of epidural analgesia was an independent risk factor for pneumonia. Pöpping et al.5 evaluated the impact of epidural analgesia on the risk of pneumonia in a high-risk population undergoing thoracic or abdominal surgery. In their meta-analysis, the use of an epidural (compared with systemic analgesia) was associated with a statistically significant and clinically important decrease in the risk of postoperative pneumonia. In addition, patients who benefited from epidural analgesia also had a significantly decreased risk of prolonged ventilation (>24 h) or reintubation. However, some data from the same meta-analysis showed that the incidence of pneumonia with patient-controlled intravenous analgesia has decreased, from 34% to 12% over the past several decades. As the incidence of pneumonia with TEA is about 8% after thoracic or abdominal surgery,5 the authors concluded that the suggested benefit of TEA may currently be less than previously thought. A reduction in PPCs with epidural analgesia after esophagectomy was not found in the recent meta-analyses by Visser et al. and Hughes et al.10,39 In the six studies considered, no significant differences in the rates of pulmonary complications were found between systemic and epidural analgesia. Epidural seems to be associated with reduced pulmonary complications after gastrectomy, but no benefit is reported after open esophagectomy. However, many authors stress that effective postoperative analgesia is always required to achieve successful early extubation, satisfactory mobilization of bronchial secretions, and improvement of postoperative lung function and hypoxemia.69,76,77 Very early extubation with the aid of an effective TEA has also been advocated to manage two-stage oesophagectomy postoperative patients in a high-dependency unit, thus avoiding the need for admission to intensive care.78 In the work by Heinrich et al.,79 patients without epidural analgesia required more frequent and longer postoperative antibiotic therapy, and also prolonged mechanical ventilation and ICU stay. There was a clear trend to more frequent reintubations in the nonepidural group. Prolonged artificial ventilation and ICU stay are well-known risk factors for ventilator-associated and nosocomial infections. Lung dysfunction requiring mechanical ventilation may also be associated with anastomosis disruption.80 There is good evidence from older studies that thoracic epidural, in particular when only local anesthetics (not opioids) are used, is associated with a reduced risk of PPCs.71,81 The protection against pneumonia is seen mainly in high-risk patients undergoing high-risk surgery. Over the last 10–15 years, this benefit has probably lessened, due to a general decrease in baseline risk for postoperative pneumonia and other respiratory complications (minivasive surgery, improvement of anesthesiological and surgical management, accelerated postoperative clinical pathways, etc.). Epidural anesthesia and analgesia and surgical stress-induced immunosuppression Extensive surgical trauma inevitably evokes an acute stress response, which is associated with impaired perioperative immunity. Depressive immunological changes, if prolonged and severe, may be particularly harmful in the perioperative setting of major surgery or in patients undergoing tumor resection. The innate immune system (macrophages, monocytes, neutrophils, and dendritic cells) is activated by surgical stress and is associated with danger-associated molecular patterns and danger signals, which mediate both the early posttraumatic inflammatory response and the consequent postoperative immune dysfunction. The impaired ability of monocytes to respond to challenge with endotoxins (dysfunction of monocytes) and reduced proliferation of T lymphocytes are the recognized features of postoperative immunosuppression.82,83 Severe postoperative immunosuppression contributes to delayed wound healing, infectious complications and sepsis, and increases the risk of multiorgan failure.84 In general, the stress response to surgery is evaluated by the amount of liberation of catecholamines, adrenocorticotropic hormone and cortisol, and on the intensity of depression of the cell-mediated immune response, which includes the function of natural killer cells and cytotoxic T cells.85,86 Adequate anesthesia, good clinical perioperative care, a restrictive transfusion policy, and effective pain control are among the various strategies which may significantly influence the immune response in the postoperative period. Surgery for esophageal cancer is a highly stressful and painful procedure, and significant amounts of opioids may be required to blunt the stress response and eliminate perioperative pain. However, several studies have indicated that both the innate and adaptive immune responses may be depressed by intraoperative and postoperative opioids, with consequent host defense impairment.87,88 TEA has been shown to reduce the amount of intraoperative general anesthetics required: it has undoubted opioid sparing effects and preserves Th1 cell activity better than general anesthesia. The activation of a segmental thoracic sympathetic block, which includes a widespread sympathetic blockade of the adrenal medulla, may be associated with decreased release of epinephrine, norepinephrine, and cortisol. A reduced level of stress hormone catecholamines may positively modulate neuroendocrine responses and attenuate surgery-induced immune alterations.89,90 Beilin et al.91 demonstrated that intraoperative epidural anesthesia and continued postoperative analgesia were associated with reduced postoperative turn-down of total lymphocytes and T4 cells. However, in recent years, controversial data regarding the beneficial effects on the preservation of the immune function have also been published. In addition, the suggested improvement of postoperative immune function and tissue oxygen tension does not appear to affect the risk of postoperative infections positively, especially wound infections (little evidence of increased resistance to infectious complications conferred by TEA).2 Various older studies have emphasized that satisfactory prevention of the surgical stress response in procedures above the umbilicus by neuraxial techniques is frequently a very difficult task.92,93 Kawasaki et al.94 suggested that epidural anesthesia to the T4 dermatome as well as general anesthesia may not protect the innate immune system from being suppressed in the early period of upper abdominal surgery. They demonstrated no significant differences in the suppression of the phagocytic ability of neutrophils between the general anesthesia group and that undergoing general anesthesia with epidural anesthesia. Epidural anesthesia failed to prevent the suppression of monocyte mCD14 and the hyporesponsiveness of monocytes to endotoxins. The suppression of activation of the sympathetic and somatic nervous systems during surgery via thoracic epidural catheters seems feasible and effective, however, other unknown mechanisms, complex interactions between stress hormones and the immune system, activation of anomalous biochemical pathways, and unsuppressed neural reflexes may cause epidural anesthesia to be incompletely protective against immunosuppression and upregulation of immunoactiveproinflammatory cytokines.95 TEA and ‘major’ outcomes after esophagectomy Whether the use of perioperative TEA reduces perioperative surgery-specific complications and definitively improves important patient outcomes such as major morbidity and mortality still remains uncertain. Like its recognized positive effects on pulmonary morbidity, thoracic sympathetic block has been shown to preserve coronary perfusion and to decrease adverse perioperative cardiac events.96 A combination of epidural and general anesthesia attenuates the hypercoagulable response to surgery and improves fibrinolytic function. It may also directly prevent deep venous thrombosis and pulmonary embolism through sympathetic blockade, resulting in increased blood flow to the lower extremities. Continuous extradural analgesia does not impede mobilization of the patient.97 However, the meta-analysis of Liu and Wu1 gives minimal evidence on this topic, when postoperative epidural analgesia is compared with the appropriate use of current methods of effective thromboprophylaxis. If effective pain control and prevention of lung function impairment are consolidated findings of all reported experiences with TEA, improvement in clinical postoperative outcomes by epidural techniques seems to be procedure specific.98 The short- and long-term advantages which go beyond optimal perioperative pain relief and the way in which individuals benefit from TEA without being affected by adverse (usually minor) effects are still incompletely identified. One of the most controversial issues is the relationship between the adoption of TEA with general anesthesia and the potential reduction in mortality in different types of surgeries. In the specific setting of esophagectomy, the first article with a relatively large number of patients reporting on mortality was published in 1997 by Tsui et al.36 In that study, after transthoracic esophagectomy patients underwent either epidural morphine administration or standardized IV or PCA morphine infusion. The group receiving an epidural showed better analgesia with cough, less incidence of both respiratory and cardiovascular complications, and an overall lower hospital mortality. In the work of Whooley et al.99 the increased postoperative use of epidural analgesia was considered among the most important perioperative factors, which correlated with the decreased death rate over time. Markedly higher in hospital mortality and complications in patients without epidural with respect to those observed in the group with epidural were also reported in the previous quoted study by Cense et al.42 Similar conclusions emerged from the recent meta-analysis by Pöpping et al.,3 in which epidurals in major surgery were associated with a lower risk of cardiorespiratory and other systemic complications and death.4 However, the heterogeneity of the procedures do not allow the reported observations to be translated to the specific field of thoracoabdominal esophagectomy. In the relatively recent retrospective analysis by Heinrich et al.,79 no significant difference in one-year mortality between the epidural and nonepidural groups was reported in cases of abdomino-right thoracic esophagus resections. Sufficient evidence to confirm or deny the ability of epidural techniques to affect significantly postoperative mortality after open esophagectomy do not appear in the available literature. The relatively low number of individuals included in published trials, the often-retrospective nature of the studies, the quality of the trials, and in particular the very low mortality rates of the recent years even in high-risk patients undergoing esophagectomy, make it extremely difficult to demonstrate any significant effect on mortality. Another debated topic that has attracted attention is the potential of TEA to influence positively the long-term outcome after tumor resection. The postulated protective effects of TEA have been attributed to the opioid-sparing effect and attenuation of the neurohumoral stress response; in experimental animal models of inducing cancer, exogenous opioids have repeatedly been shown to reduce natural killer cell activity and to promote malignant cell growth.100,101 Almost all general anesthetic agents have been shown to have a negative impact on various components of the immune system and to promote cancer spread and metastasis; instead, local anesthetics seem to be protective against tumor growth and metastasis.102 In the specific setting of gastrectomy and esophagectomy, a study by Hiller et al.103 reported that intraoperative use of TEA followed by postoperative epidural infusion for >36 hours from surgery commencement was not associated (for the combined gastroesophageal surgical group) with any statistically significant effect in preventing cancer recurrence. However, in the subgroup of patients with esophageal cancer, effective epidural analgesia provided epidural-related medium-term cancer recurrence benefits (reduced risk of cancer recurrence within two years and significant survival advantage within two years). Heinrich et al.79 did not find any significant influence of postoperative epidural analgesia on long-term mortality and oncological advantage. Current evidence from systematic reviews is insufficient to draw any solid conclusions regarding the benefit of regional anesthesia combined with general anesthesia in preventing cancer spread and recurrence. TEA and enhanced recovery after surgery clinical pathways In recent years, the ERAS programs have shown to be associated with benefits in perioperative outcomes in a wide range of surgical procedures. In a major abdominal surgery, adequate preoperative assessment and preparation, fast-track anesthesia techniques, preventive measures aiming at reducing intra- and postoperative stress response, excellent postoperative pain relief, early mobilization, and early enteral feeding have all been proven to achieve optimal recovery rates, reduce major complications, and accelerate the discharge of patients.104 Evidence that using ERAS pathways in open esophagectomy may improve postoperative morbidity and length of hospital stay is still poor and sparse; the positive impact on various patient outcomes has been reported mainly in small case series, single-center experiences, and in studies with often limited quality, combined with difficulty in comparing protocols.105–108 However, ERAS protocols are now increasingly applied, as they are considered to be feasible and safe even in this setting.108–111 Complete control of postoperative static and dynamic pain is fundamental in ERAS pathways and, as previously noted, perioperative analgesia with TEA remains the gold standard in open esophagectomy. Especially in at-risk patients, the initiation of perimedullary blockade before incision and its maintenance throughout surgery is associated with reduced need for anesthetic agents and opioids: this implies faster recovery of consciousness after surgery, valid respiratory function, and potentially early out-of-bed mobilization. Properly personalized epidural mixtures of local anesthetic and fentanyl or morphine, ‘judicious’ use of vasopressors, and institutional guidelines on how to treat epidural side-effects may all limit excessive sedation, orthostatic hypotension at ambulation, nausea and vomiting, pruritus, and urinary retention. Avoiding the side-effects of large doses of systemic opioids is not only beneficial for spontaneous ventilation and gastrointestinal recovery, but may also contribute toward preventing the frequent cognitive dysfunction of elderly patients. Standardized perioperative clinical pathways that include patients controlled postoperative epidural analgesia or continuous epidural infusion and supervised by an acute pain service have all led to reductions in overall morbidity, lower incidence of pulmonary complications, no occurrences of respiratory failure, and faster convalescence.112,113 Single-center or multicenter shared protocols with instructions and recommendations on how to recognize rapidly an insufficient or absent metameric block (failing epidural), how and when to decrease doses of epidural opioid in favor of local anesthetics, how to refill epidurals, how to identify real harm from complications, and how to manage it according to more contemporary views, when to terminate epidural infusion and catheterization, and how to guarantee adequate transitional analgesia—all of these may turn out to be extremely useful in implementing successful ERAS programs. TEA has been considered the cornerstone of modern pain control in many enhanced recovery programs. As open esophagogastrectomy is one of the highest-risk routinely performed surgical procedures, clinicians should routinely consider using epidurals as core components of multimodal, procedure-specific, opioid-sparing analgesic regimens.109,104 CONCLUSIONS TEA offers a number of proven benefits in open thoracoabdominal esophagectomy. It provides high-quality postoperative pain control for several days; when carefully personalized and supervised, it carry a lower risk of respiratory depression and other adverse effects, and may reduce the incidence of both fatal and nonfatal pulmonary complications. Opioid systemic analgesia may also be very effective, but the balance of analgesia versus side effects is not favorable in high-risk patients with significant cardiorespiratory co-morbidity or extreme age. When comparing analgesic modalities, other outcomes beyond pain scores are crucial, in that their impact on recovery must be assessed. The benefits of a properly conducted neuraxial blockade in this type of surgery tend to extend beyond sufficient freedom from pain and include several advantages in many perioperative physiological functions. Although epidural analgesia has not been convincingly shown to alter postoperative mortality in various types of general surgery, in the field of esophagectomy its influence on overall outcomes has not yet been sufficiently investigated on a large scale. However, previous and recent experiences indicate that optimum benefits result if TEA is combined with active management of other aspects of multimodal recovery pathways.112,43 Although the risks and complications of TEA are well known, experienced anesthesiologists can provide it safely in these patients, with a minimal incidence of serious side effects. 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Google Scholar CrossRef Search ADS PubMed  86 Ben-Eliyahu S, Page G G, Yirmiya R et al.   Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer  1999; 80: 880– 8. Google Scholar CrossRef Search ADS PubMed  87 Sacerdote P. Opioid-induced immunosuppression. Curr Opin Support Palliat Care  2008; 2: 14– 18. Google Scholar CrossRef Search ADS PubMed  88 Stefano G B, Fricchione G, Goumon Y et al.   Pain, immunity, opiate, and opioid compounds and health. Med Sci Monit  2005; 11: MS47– s53. Google Scholar PubMed  89 Ahlers O, Nachtigall I, Lenze J et al.   Intraoperative thoracic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal surgery. Br J Anaesth  2008; 101: 781– 7. Google Scholar CrossRef Search ADS PubMed  90 Freise H, Van Aken H K. Risks and benefits of thoracic epidural anaesthesia. Br J Anaesth  2011; 107: 859– 68. Google Scholar CrossRef Search ADS PubMed  91 Beilin B, Shavit Y, Trabekin E et al.   The effects of postoperative pain management on immune response to surgery. Anesth Analg  2003; 97: 822– 7. Google Scholar CrossRef Search ADS PubMed  92 Tsuji H, Asoh T, Takeuchi Y, Shirasaka C. Attenuation of adrenocortical response to upper abdominal surgery with epidural blockade. Br J Surg  1983; 70: 122– 4. Google Scholar CrossRef Search ADS PubMed  93 Norman J G, Fink G W. The effects of epidural anesthesia on the neuroendocrine response to major surgical stress: a randomized prospective trial. Am Surg  1997; 63: 75– 80. Google Scholar PubMed  94 Kawasaki T, Ogata M, Kawasaki C, Okamoto K, Sata T. Effects of epidural anaesthesia on surgical stress-induced immunosuppression during upper abdominal surgery. Br J Anaesth  2007; 98: 196– 203. Google Scholar CrossRef Search ADS PubMed  95 Liu S, Carpenter R L, Neal J M. Epidural anesthesia and analgesia. Their role in postoperative outcome. Anesthesiology  1995; 82: 1474– 506. Google Scholar CrossRef Search ADS PubMed  96 Rigg J R, Jamrozik K, Myles P S et al.   MASTER Anaethesia Trial Study Group. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet  2002; 359: 1276– 82. Google Scholar CrossRef Search ADS PubMed  97 Shouhed D, Amersi F, Sibert T, Sibert K, Hemaya E, Silberman A W. Thromboprophylaxis and major oncologic surgery performed with epidural analgesia. JAMA Surg  2013; 148: 81– 84. Google Scholar CrossRef Search ADS PubMed  98 Kehlet H, Holte K. Effect of postoperative analgesia on surgical outcome. Br J Anaesth  2001; 87: 62– 72. Google Scholar CrossRef Search ADS PubMed  99 Whooley B P, Law S, Murthy S C, Alexandrou A, Wong J. Analysis of reduced death and complication rates after esophageal resection. Ann Surg  2001; 233: 338– 44. Google Scholar CrossRef Search ADS PubMed  100 Gupta K, Kshirsagar S, Chang L et al.   Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res  2002; 62: 4491– 8. Google Scholar PubMed  101 Yeager M P, Colacchio T A, Yu C T et al.   Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology  1995; 83: 500– 8. Google Scholar CrossRef Search ADS PubMed  102 Tedore T. Regional anaesthesia and analgesia: relationship to cancer recurrence and survival. Br J Anaesth  2015; 115: ii34– 45. Google Scholar CrossRef Search ADS PubMed  103 Hiller J G, Hacking M B, Link E K, Wessels K L, Riedel B J. Perioperative epidural analgesia reduces cancer recurrence after gastro-oesophageal surgery. Acta Anaesthesiol Scand  2014; 58: 281– 90. Google Scholar CrossRef Search ADS PubMed  104 Feldheiser A, Aziz O, Baldini G et al.   Enhanced recovery after surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice. Acta Anaesthesiol Scand  2016; 60: 289– 334. Google Scholar CrossRef Search ADS PubMed  105 Preston S R, Markar S R, Baker C R et al.   Impact of a multidisciplinary standardized clinical pathway on perioperative outcomes in patients with oesophageal cancer. Br J Surg  2013; 100: 105– 12. Google Scholar CrossRef Search ADS PubMed  106 Munitiz V, Martinez-de-Haro L F, Ortiz A et al.   Effectiveness of a written clinical pathway for enhanced recovery after transthoracic (Ivor Lewis) oesophagectomy. Br J Surg  2010; 97: 714– 8. Google Scholar CrossRef Search ADS PubMed  107 Li C, Ferri L E, Mulder D S et al.   An enhanced recovery pathway decreases duration of stay after esophagectomy. Surgery  2012; 152: 606– 14. Google Scholar CrossRef Search ADS PubMed  108 Pisarska M, Małczak P, Major P et al.   Enhanced recovery after surgery protocol in oesophageal cancer surgery: systematic review and meta-analysis. PLoS One  2017; 12: e0174382. Google Scholar CrossRef Search ADS PubMed  109 Findlay J M, Tustian E, Millo J et al.   The effect of formalizing enhanced recovery after esophagectomy with a protocol. Dis Esophagus  2015; 28: 567– 73. Google Scholar CrossRef Search ADS PubMed  110 Underwood T J, Noble F, Madhusudan N et al.   South coast cancer collaboration-oesophago-gastric (SC-OG). The development, application and analysis of an enhanced recovery programme for major oesophagogastric resection. J Gastrointest Surg  2017; 21: 614– 21. Google Scholar CrossRef Search ADS PubMed  111 Markar S R, Karthikesalingam A, Low D E. Enhanced recovery pathways lead to an improvement in postoperative outcomes following esophagectomy: systematic review and pooled analysis. Dis Esophagus  2015; 28: 468– 75. Google Scholar CrossRef Search ADS PubMed  112 Low D E, Kunz S, Schembre D et al.   Esophagectomy-it's not just about mortality anymore: standardized perioperative clinical pathways improve outcomes in patients with esophageal cancer. J Gastrointest Surg  2007; 11: 1395– 402. Google Scholar CrossRef Search ADS PubMed  113 Cerfolio R J, Bryant A S, Bass C S et al.   Fast tracking after Ivor Lewis esophagogastrectomy. Chest  2004; 126: 1187– 94. Google Scholar CrossRef Search ADS PubMed  114 Nimmo S M. Benefit and outcome after epidural analgesia. Continuing Education in Anaesthesia, Critical Care & Pain  2004; 4: 44– 7. Google Scholar CrossRef Search ADS   115 Gedney J A, Liu E H. Side-effects of epidural infusions of opioid bupivacaine mixtures. Anaesthesia  1998; 53: 1148– 55. Google Scholar CrossRef Search ADS PubMed  116 Bujedo B M, Santos S G, Azpiazu A U. A review of epidural and intrathecal opioids used in the management of postoperative pain. J Opioid Manag  2012; 8: 177– 92. Google Scholar CrossRef Search ADS PubMed  117 Christie I W, McCabe S. Major complications of epidural analgesia after surgery: results of a six-year survey. Anaesthesia  2007; 62: 335– 41. Google Scholar CrossRef Search ADS PubMed  © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Perioperative benefit and outcome of thoracic epidural in esophageal surgery: a clinical review

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The International Society for Diseases of the Esophagus
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© The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
ISSN
1120-8694
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1442-2050
D.O.I.
10.1093/dote/dox135
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Abstract

Summary Surgery for esophageal cancer is a highly stressful and painful procedure, and a significant amount of analgesics may be required to eliminate perioperative pain and blunt the stress response to surgery. Proper management of postoperative pain has invariably been shown to reduce the incidence of postoperative complications and accelerate recovery. Neuraxial analgesic techniques after major thoracic and upper abdominal surgery have long been established to reduce respiratory, cardiovascular, metabolic, inflammatory, and neurohormonal complications. The aim of this review is to evaluate and discuss the relevant clinical benefits and outcome, as well as the possibilities and limits of thoracic epidural anesthesia/analgesia (TEA) in the setting of esophageal resections. A comprehensive search of original articles was conducted investigating relevant literature on MEDLINE, Cochrane reviews, Google Scholar, PubMed, and EMBASE from 1985 to July2017. The relationship between TEA and important endpoints such as the quality of postoperative pain control, postoperative respiratory complications, surgical stress-induced immunosuppression, the overall postoperative morbidity, length of hospital stay, and major outcomes has been explored and reported. TEA has proven to enable patients to mobilize faster, cooperate comfortably with respiratory physiotherapists and achieve satisfactory postoperative lung functions more rapidly. The superior analgesia provided by thoracic epidurals compared to that from parenteral opioids may decrease the incidence of ineffective cough, atelectasis and pulmonary infections, while the associated sympathetic block has been shown to enhance bowel blood flow, prevent reductions in gastric conduit perfusion, and reduce the duration of ileus. Epidural anesthesia/analgesia is still commonly used for major ‘open’ esophageal surgery, and the recognized advantages in this setting are soundly established, in particular as regards the early recovery from anesthesia, the quality of postoperative pain control, and the significantly shorter duration of postoperative mechanical ventilation. However, this technique requires specific technical skills for an optimal conduction and is not devoid of risks, complications, and failures. INTRODUCTION Esophagectomy for cancer is recognized to be a highly aggressive surgical procedure, usually with a favorable outcome when conducted by experienced teams in high-volume centers but with potential significant postoperative morbidity and mortality in cases of complications. Although chemotherapy can achieve satisfactory rates of 5-year survival in selected patients, surgical management still remains the standard of treatment today. Radical two-three field open esophagectomy for cancer is a major invasive surgical procedure; it requires thoracic and abdominal incisions and is associated with significant perioperative pain, substantial fluid shift, potential abnormalities of distal gastric tube perfusion, and increased risk of postoperative respiratory and cardiovascular complications. Effective pain relief after thoracoabdominal surgery has been considered a key element in ensuring early recovery, low surgical morbidity, and short hospitalization. Epidural anesthesia/analgesia is still commonly used for major ‘open’ surgery: its superior effect compared with that of systemic opioid analgesia, the relatively low incidence of side-effects, and some favorable results as regards important endpoints have led physicians to consider it a preferential analgesic technique, to promote faster recovery compared with opioid-based standard analgesia. However, despite the widespread use of epidurals, increasing doubts about its benefits with respect to perioperative pathophysiology, outcome, and organ protection have emerged in recent literature, and a decline in its popularity and application have been recorded in some institutions.1,2 The increasing number of esophageal cancer patients under anticoagulants and/or platelet aggregation inhibitors is another problem supporting refusal for epidural puncture and catheterization. In addition, some of the favorable effects suggested by many authors, such as a decreased risk of postoperative mortality, myocardial infarction, pneumonia, venous thromboembolism and respiratory impairment, seem to be described primarily in older trials in which outdated systemic analgesia techniques might have been used.3-5 In this paper, the recognized advantages and benefits on the outcome of thoracic epidural anesthesia/analgesia (TEA), as well as its weaknesses, are briefly evaluated within the setting of thoracoabdominal or transhiatal open esophagectomy. METHODS The review includes relative literature identified during searches in MEDLINE, Cochrane reviews, Google Scholar, PubMed, and EMBASE from 1985 to July 2017. Search items were esophagectomy, postoperative thoracoabdominal pain, perioperative thoracic epidural analgesia, infusion of epidural local anesthetic combined with opioid, epidural analgesia for upper abdominal surgery, thoracic catheter placement, preventive respiratory effects of thoracic epidurals, thoracic epidural catheter-related complications, postesophagectomy morbidity, and mortality. This clinical review did not use systematic review standards, in view of the paucity of good evidence studies and the heterogeneity of data as regards the important endpoints considered, particularly methods of evaluating postoperative analgesia, pain management modalities apart from epidural, use of supplementary analgesics, how overall morbidity rates were reported, and evaluation of minor and major outcomes and complications. Many confounding factors were found during analysis of published trials on open esophagectomy, such as the relatively low number of individuals, the often retrospective nature and poor quality of trials, noncomparable modes of epidural management (i.e., different types and concentrations of anesthetic used, different association of opioid plus local anesthetics, different levels of locoregional blockade achieved, intra- and postoperative versus only postoperative use of epidurals, different duration of epidural catheterization), the frequent lack of acute pain practitioners or facilities to care for patients with epidurals, and many other nonreported problems regarding efficacy and safety. Thoracic epidural anesthesia/analgesia for thoracoabdominal and transhiatal open esophagectomy Intense pain in open esophagectomy is generated by large thoracic and/or abdominal surgical incisions, the transection of ribs and intercostal nerves, pleural incisions, and placement of pleural drainage tubing. Uncontrolled perioperative pain and the pathophysiological response to surgery have been demonstrated to cause potentially significant complications in many organ systems, increased sympathoadrenal and other neuroendocrine activity, and to increase cytokine production. Conducting thoracoabdominal or transhiatalesophagectomy under epidural anesthesia in combination with general anesthesia has been suggested to reduce perioperative morbidity and mortality compared with surgery associated with general anesthesia alone.6,7 This approach provides optimal acute pain relief, and its benefits on several perioperative variables, such as the respiratory, immunologic, hemodynamic and neuroendocrine responses to surgery, have been demonstrated in many studies.2,8,9 However, other modes of perioperative pain management (continuous infusion of short-acting analgesics, intercostal nerve blocks, paravertebral or transverse abdominis plane blockade, patient-controlled analgesia, continuous wound catheter infusion of local anesthetic) and the increasing use of multimodal approaches to postoperative analgesia, have been encouraged and performed. Alternative modalities to standard epidural analgesia have been considered attractive and applicable, due to the incidence of failed or contraindicated epidurals and the lower risk of adverse effects or complications. In a recent systematic review10 and meta-analysis which evaluated optimal pain management and the incidence of adverse effects after both open and minimally invasive esophagectomy, no differences in postoperative pain scores or respiratory complications between systemic and epidural analgesia were reported. In addition, some new evidence indicates that the protective effects of TEA and its substantial benefits are fewer than previously thought. There is also uncertainty as to whether the effects of neuraxial analgesia methods can be transformed into improvements in short- and long-term clinical outcomes in these patient populations—to the extent that considerable debate has arisen about its widespread use.10–13 Considering the limited evidence in favor of substantial therapeutic benefit, some authors question the routine use of epidurals in the majority of patients undergoing laparotomy only.14 It is known that the increased number of minimally invasive esophagectomies and the refinement of modern systemic multimodal analgesia have decreased anesthesiologists’ propensity toward epidurals. However, pain after thoracoabdominal incisions is usually severe and difficult to manage. Both abdominal and thoracic components of the surgical procedure cause protracted wound and visceral pain. The advantageous effects of a well-conducted and prolonged postoperative epidural analgesia cannot be replaced solely by current methods of systemic analgesia. Current strategies of early and aggressive postesophagectomy pain therapy certainly include systemic multimodal techniques. However, they also comprise effective blocking of nociceptive inputs from the wound, and thorough treatment of dynamic pain with regional analgesia. It has been demonstrated that the intensity of acute postoperative pain correlates with the risk of developing a state of persistent pain.15 Intraoperative use of TEA The use of thoracic epidural catheters is considered by many anesthesiologists as routine practice for both intra- and postoperative pain relief. The recommended sites for epidural puncture during two-three hole esophagectomy are at T6–8 levels; both puncture and catheterization are usually performed under light sedation before anesthesia is induced, and the epidural space is identified by the loss-of-resistance technique. Catheter-incision-congruent epidural analgesia is highly recommended, to provide effective analgesia and avoid major adverse effects. Depending on the surgical approach and the attending anesthesiologist's judgment of the patient's status, epidural segmental blockade is established during the course of general anesthesia, either with a bolus dose of local anesthetic or local anesthetic plus opioid, followed by repeated boluses or, alternatively, continuous infusion of anesthetic/opioid solutions. A combination of local anesthetic and opioid is often chosen in order to provide good anesthesia/analgesia with less hypotension than that observed with the local anesthetic alone. The concentration and volume of the local anesthetic may determine the intensity and limitations of the sympathetic block; a thoracic segmental sympathetic block for a thoracoabdominal or transhiatal esophagectomy should not include the legs and should avoid systemic hypotension, with its possible associated impaired intestinal perfusion.16 The benefit derived from cautious conduction of intraoperative thoracic epidural anesthesia is assumed to be related to a segmental sympathetic block. TEA is an effective technique for providing temporary selective thoracoabdominal sympathetic deafferentation, which has been proven to be associated with beneficial physiological effects on the cardiovascular, respiratory, and gastrointestinal systems.17,18 The sympathetic blockade may reduce the metabolic, endocrine, and immunologic responses to surgical trauma, and also prevent lipolysis and loss of protein.16,18–20 Protective effects on neurohormonal and inflammatory responses have been demonstrated by Fares et al.,21 who measured the concentrations of interleukin (IL)-6 and IL-8 at various stages of transthoracic esophagectomy and demonstrated that TEA with general anesthesia was associated with a significant reduction in IL-6 and IL-8 (when compared with that associated with general anesthesia alone). The levels of immune compounds associated with the development of the stress response and neuropathic pain (cortisol, IL-6, interferon (IFN)-γ, IL-4 and IL-17) were also recently evaluated in a patient population undergoing thoracoabdominal esophageal surgery.22 Patients who received intraoperative TEA displayed a perioperative decrease in the plasma levels of cortisol and IL-6 compared with that observed with general anesthesia alone. A combination of local metameric delivery of analgesic drugs with ‘light’ general anesthesia is reported to reduce the intraoperative requirement for opioids and anesthetic agents. Besides providing optimal perioperative conditions, it may also allow faster recovery, early ‘in theatre’ extubation, and an analgesic depth of a higher quality than that offered by systemic opioids.23 Minimal sensitive and motor postoperative block allows for minimal compromise of postoperative movements. TEA and gastric conduit perfusion Esophageal anastomotic leak is a serious and potentially life-threatening complication of esophagectomy; not infrequently, severe leaks may lead to mediastinitis, adult respiratory distress syndrome (ARDS), septic shock, and death. Maintenance of adequate perfusion to the anastomosis is therefore of paramount importance to prevent a reduction in gastric conduit oxygen tension. In patients undergoing major abdominal surgery, the sympathectomy of thoracic epidural anesthesia has been shown to enhance bowel blood flow and prevent reductions in gastric intramucosal pH. In humans, various reports have attested to the beneficial effects of TEA on intestinal perfusion during esophagectomy. The advantageous influence of an epidural block on splanchnic perfusion is of particular importance with regard to the microcirculatory changes observed in the gastric tube after esophagectomy. As the T6–T10 sympathetic nerves distribute to the stomach, a sympathetic block induced by TEA may increase gastric tube blood flow. Michelet et al.24 retrospectively analyzed the perioperative factors associated with the development of anastomotic leakage in 207 patients undergoing one-stage esophagectomy. They showed that TEA used during the postoperative course of esophagectomy was associated with decreased occurrence of anastomotic leakage. In 2007, the same authors25 measured gastric mucosal blood flow at the end of the surgical procedure by laser Doppler flowmetry, demonstrating that TEA improves the microcirculatory perfusion of the gastric tube, despite a slight decrease in mean arterial pressure but with no influence on the cardiac index; patients who refused TEA were affected by a higher incidence of anastomotic leaks. However, conflicting results regarding the effects of TEA on splanchnic blood flow and anastomotic perfusion have also been reported, and some studies do not put forward any substantial evidence for decreased anastomotic leakage.25-27 In fact, an epidural-mediated decrease in blood pressure may have highly deleterious hemodynamic consequences, as the splanchnic veins contribute substantially to the control of overall venous capacitance.28 Excessive mesenteric venodilatation may be associated with impairment of splanchnic blood flow, a reduction in gastric tube blood flow, and deterioration of tissue perfusion.29 TEA appears to protect from gut injury after major surgery and exerts beneficial effects on intestinal perfusion as long as systemic hemodynamics are adequately maintained. Marked vasodilation and hypotension induced by extensive thoracolumbar sympatholysis (e.g., after aggressive doses of anesthetic bolus) was found to decrease flux at the anastomotic end of the gastric tube and compromise mucosal integrity.30 An important factor often associated with the occurrence of anastomotic breakdown and leak is the development of perioperative gut edema, which may occur after excessive perioperative crystalloid administration. For this reason, in cases of epidural-related hypotension, unnecessary fluid load beyond that required for ‘satisfactory’ intravascular filling should not be administered. Restricting the metameric diffusion of sympathetic block by congruent incisional epidural catheterization, intermittent intraoperative low volume boluses of local anesthetics instead of continuous infusion, and maintaining a light plan of general anesthesia (preferably under electrophysiological brain monitoring) may prevent significant hemodynamic impairment. Due to the risk of reducted blood flow at the anastomotic level, activation of an extensive sympathetic block in high-risk patients should be evaluated case by case, particularly in the elderly or in patients with myocardial dysfunction. However, if moderate systemic hemodynamic deterioration develops as a consequence of deliberate fluid restriction and perioperative epidural use of local anesthetics, correction of the mean perfusion pressure may reverse the adverse perfusion effects of TEA.31,32 Judicious short-term use of vasoactive agents may also reverse the adverse perfusion effects of TEA and re-establish adequate gastrointestinal blood flow.33 Phenylephrine or norepinephrine infusion, titrated to restore hypotension, has been shown to improve blood flow to the stomach during substantial vasodilation associated with extensive sympathectomy.30,31 Laser speckle imaging has shown that norepinephrine does not impair anastomotic blood flow as long as normovolemia and cardiac output are maintained.32 Currently, it is reasonable to believe that significant factors such as patient characteristics, operation-related factors, perioperative hemodynamic management on the whole, and the ‘intensity’ of postoperative patient care are much more important than the postoperative analgesic technique in itself, when anastomotic leakage occurs.34 Postoperative analgesia The complexity and morbidity of open esophagectomy and the ‘fragility’ of patients suffering from esophageal cancer, mean that adequate pain relief must continue for an indeterminate length of time postoperatively, at least until the intensity of the pain is greatly reduced. Sufficient freedom from pain allows for early mobilization, deep breathing, and effective coughing, and prevents hypoxemia and tachypnea. In patients undergoing thoracic and upper abdominal surgery for interventions on the gastrointestinal tract, TEA provides superior postoperative analgesia compared with that provided by parenteral opioids and can contribute to enhanced acute postoperative outcomes such as improved respiratory function, and reduction in protein loss and in the duration of ileus.35 Various reports have demonstrated that effective postoperative epidural analgesia is also successful in shortening the duration of mechanical ventilation, endotracheal intubation and stays in the intensive care unit (ICU).36 Early extubation has been advocated to reduce morbidity and costs after esophagectomy, as prolonged invasive ventilation has been associated with sedation-related side-effects, aspiration, pneumonia and barotrauma.7 An optimal mix of local anesthetic and opioids in a continuous epidural infusion would improve pain control at rest and during activity and minimize the side-effects associated with both drugs. In particular, epidural techniques with local anesthetic and opioid solutions are particularly effective at providing dynamic analgesia, an advantage not easily achievable with parenteral analgesics, and one which may result in improved lung volumes and decreased incidence of atelectasis and pulmonary infections.37 Assessment of pain during mobilization represents the best way to reveal differences between the various pain-relieving methods; effective TEA in the dermatomal distribution of thoracotomy and laparotomy been invariably been associated with improvements in dynamic pain scores when compared with less effective epidurals or systemic opioid analgesia.38,39 Properly conducted TEA has been proven to be substantial in aiding recovery and preventing complications.40 However, whether the benefits of continuous epidural infusion, patient-controlled epidural analgesia (PCEA) or a combination of the two effectively translate into better long-term outcomes in this setting is still not clear. The advantages and risks of TEA have mainly been described in the early period after surgery or, at most and less frequently, during the in-hospital stay.39,41 Cense et al.42 studied the in-hospital morbidity/mortality in two groups of patients undergoing transthoracic esophageal resection: one group was given epidural analgesia for at least 2 days postoperatively, and the other was not. The above authors found a marked difference in the rate of pneumonia, need for reintubation, ICU stay, and in-hospital stay between the groups. ICU and in-hospital stays were substantially longer in patients who did not receive TEA, and none of the eight patients who died during the hospitalization period had benefited from an epidural for at least two postoperative days. Epidural is conventionally favored as first-line analgesia method in open esophagectomy, and was recommended in a systematic review of enhanced recovery after surgery (ERAS) trials.43 However, two recent reviews and meta-analyses10,39,44 examined the published literature critically and did not confirm the suggested postoperative benefits: in fact, from the randomized controlled trials analyzed, significant differences in postoperative pain scores (pain at rest), overall postoperative morbidity, and adverse events between systemic and epidural analgesia after open esophagectomy were not demonstrated. The superiority of TEA over systemic methods as the most effective patient pathway following open esophagectomy was not proven. Besides the paucity of evidence for epidural use in this particular type of surgery, the main problems which emerged from these two meta-analyses included the sample sizes and quality of available studies (i.e. patient demographics and baseline clinical parameters were not well balanced), variability in clinical protocols between trials, prevalently retrospective analysis, and the difficulty of comparing postoperative pain evaluation (i.e. data on postoperative total opioid consumption and use of supplementary analgesics were not reported or incompletely reported; pain scores at rest, at deep breath and at mobilization were not described, inaccuracies regarding duration of epidural analgesic administration, procedure-specific analyses were not performed, and outcomes other than pain scores were not reported consistently). The need for adequately powered randomized controlled trials to define the optimal strategies of pain management after esophagectomy was advocated in both reviews. Regardless of the results of the above meta-analysis on epidural analgesia for transthoracic or transhiatal esophagectomy, this analgesia method is still widely encouraged, as many of its benefits are soundly established in clinical practice. However, it is not devoid of risks, complications and failures. Table 1 lists the main medication-related, epidural catheter-related and technical-related complications or side-effects associated with continuous TEA. Treatment of commonly occurring vasodilation and hypotension was mentioned previously: the possibility of lower limb motor block and hypoesthesia are prevented with reduced concentrations of local anesthetic, so that spontaneous ambulation is guaranteed. Reducing epidural opioids whenever feasible, reducing or discontinuing the doses of other sedative agents and/or rotating opioids may be useful in avoiding excessive sedation. As regards opioid-induced nausea, vomiting and itching, low-dose haloperidol, prokinetic medications, and serotonin receptor antagonists such as ondansetron, granisetron, and dolasetron, in single on-demand cases or at constant intervals, are usually efficacious in minimizing these symptoms; 4 mg of prophylactic ondansetron has also been shown to be effective in preventing nausea, vomiting, and pruritus after postoperative epidural morphine.44 Table 1 Side-effects and complications, with reported incidence, associated with thoracic epidural anesthesia/analgesia [from refs. 114–117] Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  View Large Table 1 Side-effects and complications, with reported incidence, associated with thoracic epidural anesthesia/analgesia [from refs. 114–117] Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  Undesirable side-effects associated with epidural local anesthetics  Reported incidence (%)  Cardiovascular changes: mild hypotension, bradycardia, tachycardia  3–30  Loss of strength or control of muscles, motor block  0.5–3  Local anesthetic systemic toxicity  0.01–0.12  Imbalance in pain relief, uneven distribution, or insufficient analgesia  1–5  Undesirable side-effects associated with epidural opioids  Reported incidence (%)  Nausea and vomiting  10–50  Itchy skin  12–40  Urinary retention  5–20  Respiratory effects: clouding of consciousness, decrease in respiratory rates; oxygen desaturation; respiratory arrest  4; 1–30; 01–04  Sedation  7–20  Complications/side-effects associated with thoracic catheter placement and removal  Reported incidence(%)  Accidental dural puncture  0.3–1.2  Transient neurologic symptoms, nerve root irritation, paresthesia  0.01–3  Bleeding puncture; epidural hematoma  0.3–3; 0.0004–0.03  Unsuccessful catheter placement  Not known  Pain in injection side  Not known  Vasovagal syncope  Not known  Catheter-related infections, epidural abscess  0.01–0.05  View Large Epidural naloxone is also administered to reduce postoperative nausea and vomiting induced by epidural sufentanil.45 Measures to prevent hypotension are also effective in preventing nausea and vomiting. Pruritus may also be managed with antihistamine drugs or opioid rotation to an agent with low histamine release (e.g. fentanyl). Constipation is usually minimal when low epidural opioid doses are administered and for a limited period of time. Apart from adopting a gastrointestinal regimen compatible with recent resective and reconstructive surgery, early out-of-bed mobilization seems to be the best strategy to prevent this adverse effect. Oral naloxone was once proposed; however, its use has been associated with the need to increase the opioid dose.46 The risk of respiratory depression associated with epidural analgesia is influenced by many factors, such as age, gender, comorbidities, prior opioid administration, intraoperative amount of fentanyl, time from last neuraxial opioid administration and epidural refilling, intensity of postoperative pain, amount of associated sedatives, and other factors. Morphine-induced respiratory depression, although rare, is generally dose-related and may occur at any time during the postoperative course: early and late onset of reduced levels of consciousness and respiratory rate have also been reported with fentanyl, sufentanil and pethidine. Careful titration and proper identification of the amount administered, together with strict patient surveillance at early onset of the first symptoms may prevent the deleterious effects of severe hypoxia and CO2 retention from epidural opioids. Epidural or small i.v. doses of the opioid antagonist naloxone are effective in reversing respiratory depression from neuraxial opioids, although naloxone has a shorter duration of action and often requires repeated administrations. In addition, the possible ‘individual’ recurrence of pain after reversing may require extra rescue doses of opioids.47 The possibility that epidural analgesia, by accelerating and improving recovery, could save healthcare costs in high-risk surgery patients has been hypothesized but not yet demonstrated. In other words, whether the superior analgesic regimen may be followed by positive changes in the length of ICU and hospital stays and overall intra-hospital costs has not been clearly elucidated. Bartha et al.48 evaluated the impact of an improved pain treatment on the entire clinical pathway and on both the intensive care and hospital resource utilization following major esophagectomy. The costs of treatment with PCEA and patient-controlled intravenous analgesia (PCIA) were analyzed for a six-day period, as well as the costs for every adverse event, staff hours and ICU stays. Unlike the results of Brodner et al.,49 who reported substantial ICU savings after the introduction of epidurals (as a consequence of shorter ICU stays), the above authors observed that postoperative epidural analgesia had higher overall costs than IV analgesia. Despite the better analgesic effects, using TEA did not reduce the costs for postoperative care and total healthcare costs in high-risk. Patients undergoing esophagectomy may have a high risk of progression from acute postoperative to chronic pain; chronic postsurgical pain (CPSP) is a relatively frequent complication of thoracic and abdominal procedures, with a high impact on quality of life. Although the relationship between the modality of acute pain management in these patients and the incidence/severity of CPSP requires further investigation, neither preemptive TEA (initiated before surgical incision) nor TEA initiated after completion of surgery have been associated with a significant reduction in the incidence of chronic postthoracotomy pain in large studies (although there are a few isolated reports with positive results).50,51 An issue still widely unexplored is the appropriate duration of epidural analgesic administration in the postoperative course of esophagectomy. Although TEA has been used for decades in perioperative care, no standard of practice has emerged from either recent or earlier literature, and large variability is still seen among hospital centers. The need to maintain epidural catheterization for more than 3 days is seen as a substantial extra cost by many institutions, although early removal (<3 days) undoubtedly increases the need for systemic opioid analgesia.52 As in other types of surgery, the timing of withdrawing epidural local anesthetics/opioids and substituting them with systemic analgesics after thoracoabdominal esophagectomy are still not well defined. Flisberg et al.53 found that continuing TEA (bupivacaine, 2.5 mg/mL mixed with morphine, 0.125 mg/mL, at a rate of 4 mL/h) for five postoperative days provided better pain relief at mobilization and fewer side-effects than those observed with an earlier switch to patient-controlled intravenous morphine. Patients receiving intravenous analgesics also needed more supplemental pain relievers. Niwa et al.54 have recently evaluated the effect of a continuous paravertebral block (PVB) for thoracotomy, combined with epidural anesthesia for laparotomy after esophagectomy. The control group received two epidural catheters for thoracotomy and laparotomy. In all patients, the anesthetic solution was continuously infused until postoperative day 7. The combined use of PVB and epidural anesthesia did not reveal any inferior efficacy for post-thoracoabdominal pain relief. Patients in the epidural group had a higher incidence of hypotension and took longer to ambulate, compared with those in the paravertebral group. The authors considered PVB plus epidural to be a simple, safe, and effective technique for postsurgical pain alleviation. TEA and intestinal motility Postoperative bowel function may benefit from both optimal pain control and the sympathectomy induced by local anesthetics in the thoracic epidural space. Unrelieved pain is associated with sympathetic hyperactivity, which leads to reflex inhibition of gastrointestinal secretion and motor activity and contraction of gastrointestinal sphincters. In addition, the sympathetic nerves control both precapillary and postcapillary resistance vessels in the digestive tract, with vasoconstriction and reduction in regional blood flow. Enhanced sympathetic activity due to surgical manipulation may lead to mesenteric hypoperfusion and intestinal paralysis. Postoperative ileus, by causing distension of the esophageal substitute and limiting regional perfusion, may adversely affect esophagogastric/esophagocolonic anastomosis. TEA after esophagectomy, by maintaining the activity of craniosacral parasympathetic efferent fibers and inhibiting thoracolumbar sympathetic efferent fibers, can shorten the duration of postoperative ileus.55 The activation of perioperative sympathectomy with TEA and the consequent unopposed parasympathetic activity are associated with increased bowel motility, but no evidence of any significant increase in anastomotic dehiscence has been reported.56–58 The position of the epidural catheter and the type of solution infused into the epidural space may make a difference in the recovery of bowel function. Mid-low thoracic catheter insertion and infusion of local anesthetic alone have been associated with greater postoperative intestinal motility than lumbar insertion and infusion of epidural narcotics.55,59 Better results are achieved when the epidural is used before surgical stress and nociceptive afferent stimulation are initiated (intraoperatively), and when local anesthetic solutions are postoperatively administered until bowel function returns (usually 2–3 days).56 High-dose systemic opioids, together with aggressive surgical handling of the gut and excessive i.v. fluids causing bowel edema, can all contribute to prolonged postoperative ileus. Delayed recovery of gastrointestinal function dramatically increases morbidity and the length of hospital stay after major surgery. Neuraxial analgesic techniques invariably reduce intra- and postoperative parenteral opioid consumption, and this condition promotes faster recovery of intestinal motility. A higher risk of nausea and vomiting in patients receiving systemic compared with epidural analgesia has been reported in several trials.10 Despite the paucity of published data in the field of thoracoabdominal or transhiatal open esophagectomy, the intraoperative administration of local anesthetics at thoracic level and continued in the postoperative period very probably also accelerates the resolution of postoperative ileus and allows for early enteral feeding. According to the results of the 2016 Cochrane review on abdominal surgery,60 local anesthetics epidurally administered reduced the time required for the return of gut function compared with that associated with an opioid-based systemic regimen. Local anesthetics, alone or in combination with opioids, were equally effective in accelerating intestinal recovery and superior to systemic and epidural opioids alone; there was no evidence that an epidural with a local anesthetic would affect the incidence of vomiting. The quality of the evidence for a better return of gastrointestinal function was rated as high. TEA and postoperative respiratory complications after esophagectomy Respiratory complications may affect up to 30% of patients after esophagectomy and they remain the major cause of postoperative morbidity and mortality.61 The most important postoperative respiratory complications (PPCs) include severe forms of interstitial acute lung injury, massive pleural effusions, bilateral atelectasis, pneumonia, and ARDS. Additional complications affecting the respiratory system may arise from anastomotic leakage, a trachea-esophageal fistula or recurrent laryngeal nerve palsy. Pulmonary complications and anastomotic leakage are the most serious and common complications even in experienced centers and contribute to substantial perioperative mortality. The pathogenesis of respiratory complications is multifactorial, but the prolonged systemic inflammatory response associated with a highly aggressive procedure seems to be the fundamental mechanism. Due to the possible higher risk of PPCs, the transthoracic approach has been abandoned by some surgeons in favor of a transhiatal approach. Avoiding a thoracotomy may reduce compromised respiratory function, especially in patients with coexisting lung disease. In various studies, perioperative respiratory morbidity, incidence of pneumonia, wound infection, duration of mechanical ventilation and hospital stay were all significantly lower in transhiatal techniques.62,63 On the contrary, case series with large numbers of patients demonstrated almost identical postoperative respiratory and cardiovascular complications in the two techniques.64–66 Considerable debate on which approach is superior as regards the short- and long-term outcomes is ongoing, especially in large-volume centers. Analysis of both the few randomized controlled studies (although with small numbers of patients) and some meta-analyses points toward a slightly higher risk of pulmonary complications with the transthoracic approach, but survival rates at five years are equivalent between the procedures.63,67 Anesthetic management may positively influence the incidence of pulmonary complications by promoting minimal risk of respiratory depression, avoiding excessive fluid administration, containing inflammatory activation, and promoting early recovery. Adequate postoperative analgesia is an essential component of multiple perioperative strategies to prevent pulmonary complications after esophagectomy, together with preoperative improvement of nutrition status, minimally invasive surgery, protective ventilation, goal-directed fluid therapy, nasogastric decompression, and rapid weaning from mechanical ventilation.61 Upper laparotomy and thoracotomy result in significant postoperative pain and are known to impair respiratory mechanics and coughing, to decrease lung volume, promote thoracic restriction, decrease diaphragm function and impair ventilation. It has been speculated that TEA, by inhibiting the efferent and afferent pathways of the intercostal nerve roots, may reduce inspiratory capacity, vital capacity, forced expiratory volume and expiratory minute ventilation. However, proper postoperative thoracic analgesia (i.e. with relatively low concentrations of local anesthetic and small amounts of opioids) does not alter respiratory mechanics, lung volume or pulmonary gas exchange. Epidural analgesia does not impair airway flow, even in patients with end-stage chronic obstructive pulmonary disease.68,69 Intercostal and abdominal muscle tone is not affected, and no decrease in the volume of the thoracic cavity or decreased thoracic and abdominal compliance usually occur. An improvement in vital capacity, forced vital capacity at 24 hours, forced expiratory volume in 1 second at 24 hours, and peak expiratory flow rate at 24 hours have been well documented.1,5 Optimal pain control is vital in ensuring aggressive pulmonary toilet, deep breathing exercises, use of an incentive spirometer, and promoting coughing without restriction. Prevention of sputum retention is essential, to prevent atelectasis (a potential precursor to pneumonia), deterioration of gas exchange and the risk of re-intubation. The excellent analgesia provided by TEA results in a lower incidence of respiratory morbidity after thoracic surgery, and no study has reported a deterioration in pulmonary function by this method.70–72 The potential benefit of TEA on reducing PPCs and improving the respiratory outcome of patients undergoing noncardiac procedures was emphasized in the large meta-analysis of the CORTRA study.73 TEA has been demonstrated to have the potential to prevent diaphragmatic dysfunction after thoracic and abdominal surgery by reducing the inhibitory effect of surgical trauma on phrenic motor neuron activity.74 A recent retrospective report on 543 patients undergoing elective McKeown-type esophagectomy (183 receiving TEA and 360 intravenous analgesia) demonstrated a 19.7% incidence of pneumonia in the TEA group compared with 32% in the intravenous group (significant reduction).75 The incidence of ARDS was also reduced in the TEA group, although it did not reach statistical significance. The importance of epidural analgesia to prevent pulmonary complications and pneumonia during the early postoperative period after a transthoracic esophageal cancer resection was also highlighted by Cense et al;42 authors reported increased needs for reintubation and longer ICU stays, mainly due to higher incidences of postoperative pneumonia, in patients who did not benefit from epidural analgesia for more than two days after the procedure. No application of epidural analgesia was an independent risk factor for pneumonia. Pöpping et al.5 evaluated the impact of epidural analgesia on the risk of pneumonia in a high-risk population undergoing thoracic or abdominal surgery. In their meta-analysis, the use of an epidural (compared with systemic analgesia) was associated with a statistically significant and clinically important decrease in the risk of postoperative pneumonia. In addition, patients who benefited from epidural analgesia also had a significantly decreased risk of prolonged ventilation (>24 h) or reintubation. However, some data from the same meta-analysis showed that the incidence of pneumonia with patient-controlled intravenous analgesia has decreased, from 34% to 12% over the past several decades. As the incidence of pneumonia with TEA is about 8% after thoracic or abdominal surgery,5 the authors concluded that the suggested benefit of TEA may currently be less than previously thought. A reduction in PPCs with epidural analgesia after esophagectomy was not found in the recent meta-analyses by Visser et al. and Hughes et al.10,39 In the six studies considered, no significant differences in the rates of pulmonary complications were found between systemic and epidural analgesia. Epidural seems to be associated with reduced pulmonary complications after gastrectomy, but no benefit is reported after open esophagectomy. However, many authors stress that effective postoperative analgesia is always required to achieve successful early extubation, satisfactory mobilization of bronchial secretions, and improvement of postoperative lung function and hypoxemia.69,76,77 Very early extubation with the aid of an effective TEA has also been advocated to manage two-stage oesophagectomy postoperative patients in a high-dependency unit, thus avoiding the need for admission to intensive care.78 In the work by Heinrich et al.,79 patients without epidural analgesia required more frequent and longer postoperative antibiotic therapy, and also prolonged mechanical ventilation and ICU stay. There was a clear trend to more frequent reintubations in the nonepidural group. Prolonged artificial ventilation and ICU stay are well-known risk factors for ventilator-associated and nosocomial infections. Lung dysfunction requiring mechanical ventilation may also be associated with anastomosis disruption.80 There is good evidence from older studies that thoracic epidural, in particular when only local anesthetics (not opioids) are used, is associated with a reduced risk of PPCs.71,81 The protection against pneumonia is seen mainly in high-risk patients undergoing high-risk surgery. Over the last 10–15 years, this benefit has probably lessened, due to a general decrease in baseline risk for postoperative pneumonia and other respiratory complications (minivasive surgery, improvement of anesthesiological and surgical management, accelerated postoperative clinical pathways, etc.). Epidural anesthesia and analgesia and surgical stress-induced immunosuppression Extensive surgical trauma inevitably evokes an acute stress response, which is associated with impaired perioperative immunity. Depressive immunological changes, if prolonged and severe, may be particularly harmful in the perioperative setting of major surgery or in patients undergoing tumor resection. The innate immune system (macrophages, monocytes, neutrophils, and dendritic cells) is activated by surgical stress and is associated with danger-associated molecular patterns and danger signals, which mediate both the early posttraumatic inflammatory response and the consequent postoperative immune dysfunction. The impaired ability of monocytes to respond to challenge with endotoxins (dysfunction of monocytes) and reduced proliferation of T lymphocytes are the recognized features of postoperative immunosuppression.82,83 Severe postoperative immunosuppression contributes to delayed wound healing, infectious complications and sepsis, and increases the risk of multiorgan failure.84 In general, the stress response to surgery is evaluated by the amount of liberation of catecholamines, adrenocorticotropic hormone and cortisol, and on the intensity of depression of the cell-mediated immune response, which includes the function of natural killer cells and cytotoxic T cells.85,86 Adequate anesthesia, good clinical perioperative care, a restrictive transfusion policy, and effective pain control are among the various strategies which may significantly influence the immune response in the postoperative period. Surgery for esophageal cancer is a highly stressful and painful procedure, and significant amounts of opioids may be required to blunt the stress response and eliminate perioperative pain. However, several studies have indicated that both the innate and adaptive immune responses may be depressed by intraoperative and postoperative opioids, with consequent host defense impairment.87,88 TEA has been shown to reduce the amount of intraoperative general anesthetics required: it has undoubted opioid sparing effects and preserves Th1 cell activity better than general anesthesia. The activation of a segmental thoracic sympathetic block, which includes a widespread sympathetic blockade of the adrenal medulla, may be associated with decreased release of epinephrine, norepinephrine, and cortisol. A reduced level of stress hormone catecholamines may positively modulate neuroendocrine responses and attenuate surgery-induced immune alterations.89,90 Beilin et al.91 demonstrated that intraoperative epidural anesthesia and continued postoperative analgesia were associated with reduced postoperative turn-down of total lymphocytes and T4 cells. However, in recent years, controversial data regarding the beneficial effects on the preservation of the immune function have also been published. In addition, the suggested improvement of postoperative immune function and tissue oxygen tension does not appear to affect the risk of postoperative infections positively, especially wound infections (little evidence of increased resistance to infectious complications conferred by TEA).2 Various older studies have emphasized that satisfactory prevention of the surgical stress response in procedures above the umbilicus by neuraxial techniques is frequently a very difficult task.92,93 Kawasaki et al.94 suggested that epidural anesthesia to the T4 dermatome as well as general anesthesia may not protect the innate immune system from being suppressed in the early period of upper abdominal surgery. They demonstrated no significant differences in the suppression of the phagocytic ability of neutrophils between the general anesthesia group and that undergoing general anesthesia with epidural anesthesia. Epidural anesthesia failed to prevent the suppression of monocyte mCD14 and the hyporesponsiveness of monocytes to endotoxins. The suppression of activation of the sympathetic and somatic nervous systems during surgery via thoracic epidural catheters seems feasible and effective, however, other unknown mechanisms, complex interactions between stress hormones and the immune system, activation of anomalous biochemical pathways, and unsuppressed neural reflexes may cause epidural anesthesia to be incompletely protective against immunosuppression and upregulation of immunoactiveproinflammatory cytokines.95 TEA and ‘major’ outcomes after esophagectomy Whether the use of perioperative TEA reduces perioperative surgery-specific complications and definitively improves important patient outcomes such as major morbidity and mortality still remains uncertain. Like its recognized positive effects on pulmonary morbidity, thoracic sympathetic block has been shown to preserve coronary perfusion and to decrease adverse perioperative cardiac events.96 A combination of epidural and general anesthesia attenuates the hypercoagulable response to surgery and improves fibrinolytic function. It may also directly prevent deep venous thrombosis and pulmonary embolism through sympathetic blockade, resulting in increased blood flow to the lower extremities. Continuous extradural analgesia does not impede mobilization of the patient.97 However, the meta-analysis of Liu and Wu1 gives minimal evidence on this topic, when postoperative epidural analgesia is compared with the appropriate use of current methods of effective thromboprophylaxis. If effective pain control and prevention of lung function impairment are consolidated findings of all reported experiences with TEA, improvement in clinical postoperative outcomes by epidural techniques seems to be procedure specific.98 The short- and long-term advantages which go beyond optimal perioperative pain relief and the way in which individuals benefit from TEA without being affected by adverse (usually minor) effects are still incompletely identified. One of the most controversial issues is the relationship between the adoption of TEA with general anesthesia and the potential reduction in mortality in different types of surgeries. In the specific setting of esophagectomy, the first article with a relatively large number of patients reporting on mortality was published in 1997 by Tsui et al.36 In that study, after transthoracic esophagectomy patients underwent either epidural morphine administration or standardized IV or PCA morphine infusion. The group receiving an epidural showed better analgesia with cough, less incidence of both respiratory and cardiovascular complications, and an overall lower hospital mortality. In the work of Whooley et al.99 the increased postoperative use of epidural analgesia was considered among the most important perioperative factors, which correlated with the decreased death rate over time. Markedly higher in hospital mortality and complications in patients without epidural with respect to those observed in the group with epidural were also reported in the previous quoted study by Cense et al.42 Similar conclusions emerged from the recent meta-analysis by Pöpping et al.,3 in which epidurals in major surgery were associated with a lower risk of cardiorespiratory and other systemic complications and death.4 However, the heterogeneity of the procedures do not allow the reported observations to be translated to the specific field of thoracoabdominal esophagectomy. In the relatively recent retrospective analysis by Heinrich et al.,79 no significant difference in one-year mortality between the epidural and nonepidural groups was reported in cases of abdomino-right thoracic esophagus resections. Sufficient evidence to confirm or deny the ability of epidural techniques to affect significantly postoperative mortality after open esophagectomy do not appear in the available literature. The relatively low number of individuals included in published trials, the often-retrospective nature of the studies, the quality of the trials, and in particular the very low mortality rates of the recent years even in high-risk patients undergoing esophagectomy, make it extremely difficult to demonstrate any significant effect on mortality. Another debated topic that has attracted attention is the potential of TEA to influence positively the long-term outcome after tumor resection. The postulated protective effects of TEA have been attributed to the opioid-sparing effect and attenuation of the neurohumoral stress response; in experimental animal models of inducing cancer, exogenous opioids have repeatedly been shown to reduce natural killer cell activity and to promote malignant cell growth.100,101 Almost all general anesthetic agents have been shown to have a negative impact on various components of the immune system and to promote cancer spread and metastasis; instead, local anesthetics seem to be protective against tumor growth and metastasis.102 In the specific setting of gastrectomy and esophagectomy, a study by Hiller et al.103 reported that intraoperative use of TEA followed by postoperative epidural infusion for >36 hours from surgery commencement was not associated (for the combined gastroesophageal surgical group) with any statistically significant effect in preventing cancer recurrence. However, in the subgroup of patients with esophageal cancer, effective epidural analgesia provided epidural-related medium-term cancer recurrence benefits (reduced risk of cancer recurrence within two years and significant survival advantage within two years). Heinrich et al.79 did not find any significant influence of postoperative epidural analgesia on long-term mortality and oncological advantage. Current evidence from systematic reviews is insufficient to draw any solid conclusions regarding the benefit of regional anesthesia combined with general anesthesia in preventing cancer spread and recurrence. TEA and enhanced recovery after surgery clinical pathways In recent years, the ERAS programs have shown to be associated with benefits in perioperative outcomes in a wide range of surgical procedures. In a major abdominal surgery, adequate preoperative assessment and preparation, fast-track anesthesia techniques, preventive measures aiming at reducing intra- and postoperative stress response, excellent postoperative pain relief, early mobilization, and early enteral feeding have all been proven to achieve optimal recovery rates, reduce major complications, and accelerate the discharge of patients.104 Evidence that using ERAS pathways in open esophagectomy may improve postoperative morbidity and length of hospital stay is still poor and sparse; the positive impact on various patient outcomes has been reported mainly in small case series, single-center experiences, and in studies with often limited quality, combined with difficulty in comparing protocols.105–108 However, ERAS protocols are now increasingly applied, as they are considered to be feasible and safe even in this setting.108–111 Complete control of postoperative static and dynamic pain is fundamental in ERAS pathways and, as previously noted, perioperative analgesia with TEA remains the gold standard in open esophagectomy. Especially in at-risk patients, the initiation of perimedullary blockade before incision and its maintenance throughout surgery is associated with reduced need for anesthetic agents and opioids: this implies faster recovery of consciousness after surgery, valid respiratory function, and potentially early out-of-bed mobilization. Properly personalized epidural mixtures of local anesthetic and fentanyl or morphine, ‘judicious’ use of vasopressors, and institutional guidelines on how to treat epidural side-effects may all limit excessive sedation, orthostatic hypotension at ambulation, nausea and vomiting, pruritus, and urinary retention. Avoiding the side-effects of large doses of systemic opioids is not only beneficial for spontaneous ventilation and gastrointestinal recovery, but may also contribute toward preventing the frequent cognitive dysfunction of elderly patients. Standardized perioperative clinical pathways that include patients controlled postoperative epidural analgesia or continuous epidural infusion and supervised by an acute pain service have all led to reductions in overall morbidity, lower incidence of pulmonary complications, no occurrences of respiratory failure, and faster convalescence.112,113 Single-center or multicenter shared protocols with instructions and recommendations on how to recognize rapidly an insufficient or absent metameric block (failing epidural), how and when to decrease doses of epidural opioid in favor of local anesthetics, how to refill epidurals, how to identify real harm from complications, and how to manage it according to more contemporary views, when to terminate epidural infusion and catheterization, and how to guarantee adequate transitional analgesia—all of these may turn out to be extremely useful in implementing successful ERAS programs. TEA has been considered the cornerstone of modern pain control in many enhanced recovery programs. As open esophagogastrectomy is one of the highest-risk routinely performed surgical procedures, clinicians should routinely consider using epidurals as core components of multimodal, procedure-specific, opioid-sparing analgesic regimens.109,104 CONCLUSIONS TEA offers a number of proven benefits in open thoracoabdominal esophagectomy. It provides high-quality postoperative pain control for several days; when carefully personalized and supervised, it carry a lower risk of respiratory depression and other adverse effects, and may reduce the incidence of both fatal and nonfatal pulmonary complications. Opioid systemic analgesia may also be very effective, but the balance of analgesia versus side effects is not favorable in high-risk patients with significant cardiorespiratory co-morbidity or extreme age. When comparing analgesic modalities, other outcomes beyond pain scores are crucial, in that their impact on recovery must be assessed. The benefits of a properly conducted neuraxial blockade in this type of surgery tend to extend beyond sufficient freedom from pain and include several advantages in many perioperative physiological functions. Although epidural analgesia has not been convincingly shown to alter postoperative mortality in various types of general surgery, in the field of esophagectomy its influence on overall outcomes has not yet been sufficiently investigated on a large scale. However, previous and recent experiences indicate that optimum benefits result if TEA is combined with active management of other aspects of multimodal recovery pathways.112,43 Although the risks and complications of TEA are well known, experienced anesthesiologists can provide it safely in these patients, with a minimal incidence of serious side effects. Notes Specific author contributions: Eugenio Serra, Andrea Bortolato, and Stefania Barbieri made literature search; Paolo Feltracco and Stefania Barbieri acquired and analyzed the data, and drafted the article; Paolo Feltracco, Andrea Bortolato, Stefania Barbieri, Elisa Michieletto, Eugenio Serra, Alberto Ruol, Stefano Merigliano, and Carlo Ori contributed to the manuscript preparation, data interpretation, revision for important intellectual content, editing, and approved the final version. Conflicts-of-interest: None of the authors has any financial interest or connection, direct or indirect, or other situations, which might involve bias in the work reported here or in its conclusions. References 1 Liu S S, Wu C L. Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg  2007; 104: 689– 702. Google Scholar CrossRef Search ADS PubMed  2 Rawal N. Current issues in postoperative pain management. 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Diseases of the EsophagusOxford University Press

Published: Dec 2, 2017

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