Anesthesiology Clin 26 (2008) 293–304

Perioperative Anesthetic Management for Esophagectomy Ju-Mei Ng, FANZCAa,b,* a

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA b Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide, and its incidence is increasing rapidly in the United States [1]. The changing epidemiology from squamous cell to adenocarcinoma may reflect the increasing incidence of morbid obesity and gastroesophageal reflux (GER) disease, coupled with reduced fiber intake, in the West [2]. Although perioperative mortality and morbidity from esophagectomy have declined during the past 30 years, it still carries a high overall mortality rate of 8.8% [3]. In contrast to most other major surgery, improvements in anesthetic care, surgical technique, and intensive care management have not markedly lowered the incidence of mortality and morbidity. An understanding of the factors that influence outcome may help anesthesiologists adjust and improve perioperative anesthetic management. Although it is accepted that outcomes are closely related to the number of esophageal resections performed by individual surgeons and medical centers [4,5], some analyses have found other factors, such as advanced patient age, performance status, pulmonary complications, and need for transfusion, to be predictive of mortality [6–8]. Minimally invasive surgical (MIS) techniques have emerged for esophagectomy, including various combinations of thoracoscopy, laparoscopy, or laparoscopic-assisted methods, mediastinoscopy, and open thoracotomy and laparotomy [9]. There is a lack of consensus on which technique is superior, and randomized, controlled trials comparing MIS techniques with open esophagectomy, and especially addressing the impact on postoperative respiratory complications and survival, are needed.

* Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail address: [email protected] 1932-2275/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anclin.2008.01.004 anesthesiology.theclinics.com

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The most frequently seen surgical complication after esophagectomy is anastomotic leakage, and the most common medical complication is arrhythmia [6,7]. The reduction of pulmonary complications, the most common serious morbidity and a predictor of mortality [6,8,10], deserves more discussion, as do the benefits of epidural analgesia and the controversial topic of optimal fluid management. It is unlikely that a single intraoperative intervention alone will show benefit in outcome. An approach addressing several factors that either are shown to affect outcome or have promising benefits may demonstrate significant impact, however. The multimodal approach and/or standardized perioperative clinical care pathways may help improve the infrastructure for the management of these patients in high-volume centers and improve outcome [11,12].

Cardiovascular morbidity Perioperative arrhythmias have been reported in 20% to 60% of esophagectomies [6,7,10,13–15]. Although most are benign and may occur commonly during mediastinal manipulation in transhiatal esophagectomy [13], symptomatic arrhythmias may be associated with worse outcome [14,16]. Atrial fibrillation has been linked with pulmonary complications, anastomotic leakage, surgical sepsis [14], and supraventricular tachydysrhythmias with a higher rate of ICU admission and longer hospital stay [16]. In a recent meta-analysis, calcium-channel blockers and beta-blockers were effective in reducing atrial tachyarrhythmias in patients undergoing general thoracic surgery [17]. For esophagectomy, prophylactic digitalization has not been shown to reduce the incidence of cardiac dysrhythmias [15], but a diltiazem infusion has been used successfully to suppress supraventricular tachydysrhythmias [18]. Thoracic epidural analgesia (TEA) attenuated supraventricular tachydysrhythmias after pulmonary resection [19], and the presence or absence of TEA showed a temporal relationship with the incidence of atrial arrhythmias [20]. TEA, however, did not reduce the incidence of arrhythmias in patients undergoing transthoracic esophagectomy [21]. The reported incidence of myocardial infarction after esophagectomy ranges from 1% to 2% [6,7,10]. Although it would seem beneficial for high-risk patients to receive perioperative beta-blocker therapy [22], its role will be more clearly defined when results of the Perioperative Ischemic Evaluation) trial [23] are revealed. Interestingly, statin use has been associated with a decreased incidence of atrial fibrillation after noncardiac thoracic surgery [24] and with decreased mortality after major vascular surgery [25].

Pulmonary morbidity Pulmonary complications are the most common cause of postoperative death in patients who have esophageal cancer [7,8]. Factors found predictive

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of pulmonary morbidity and/or acute lung injury (ALI) include age, performance status, lung function, duration of surgery and one-lung ventilation (OLV), perioperative cardiorespiratory instability (measured by perioperative hypoxemia, hypotension, and fluid and blood requirements) and the occurrence of a postoperative anastomotic leak [7,8,26]. Although the benefits of a short period of cardiopulmonary rehabilitation in preparation for esophagectomy to lower the risk of postoperative pulmonary complications has yet to be investigated, there are some perioperative strategies that may address some of the risk factors mentioned previously. Ventilation strategies Esophagectomy is marked by a significant inflammatory response [27], with a proinflammatory cytokine release that has been linked to the development of postoperative pulmonary morbidity [27–29]. The intraoperative use of prostaglandin E1 was associated with reduced interleukin-6 production and improved postoperative oxygenation in patients undergoing esophagectomy [30]. Although there is no clear cause-and-effect relationship between inflammatory cytokine release and the development of lung injury, the balance between proinflammatory and anti-inflammatory cytokines may be key. In patients who have ALI, ‘‘lung-protective’’ mechanical ventilation with a lower tidal volume resulted in decreased mortality, number of ventilated days, and plasma interleukin-6 levels than seen with conventional ventilation [31]. Both volutrauma and atelectrauma (low-volume injury) should be avoided. Guidelines for treating acute respiratory distress syndrome emphasize maintaining inspiratory plateau pressure below 35 cm H2O by reducing tidal volume to as low as 5 mL/kg [32]. Lung damage also may be caused by ventilation at low lung volume. Shear forces generated during repetitive opening and closing of atelectatic lung units exacerbates, or even initiates, significant lung injury and inflammation [33]. Positive end-expiratory pressure (PEEP) splints open the distal airways, maintaining recruitment throughout the ventilatory cycle. In thoracotomy patients undergoing OLV, pressure-controlled ventilation (PCV) with PEEP resulted in lower peak and plateau airway pressures compared with volume-controlled ventilation (VCV) with no PEEP, and improved oxygenation compared with PCV and no PEEP [34]. For patients who had good preoperative pulmonary function, however, the use of PCV during OLV did not lead to better oxygenation than seen with VCV [35]. Therefore the settings, rather than the mode of ventilation, are important. Lung-protective ventilation strategies during OLV should include a 5- to 6-mL/kg tidal volume, optimizing PEEP (setting the PEEP above the lower inflection point) [36], and limiting plateau and peak inspiratory pressures to less than 25 cm H2O and less than 35 cm H2O, respectively. The use of smaller tidal volumes and PEEP during OLV after esophagectomy was

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associated with a decrease in the proinflammatory response, improved lung function, and earlier extubation [37]. OLV has become standard practice during thoracic surgery and esophagectomy. OLV is used commonly to achieve good surgical exposure for aggressive lymphadenectomy during thoracotomy and during thoracoscopic mobilization in MIS esophagectomy. The proficiency of thoracic anesthesiologists in the positioning of double-lumen endobronchial tubes and bronchial blockers and the routine use of fiberoptic bronchoscopy have helped reduce the incidence of hypoxemia during OLV to less than 1% [38]. The clinical implications of the oxidative stress and ischemia/reperfusion injury generated by OLV are unclear. The high inspired oxygen concentration administered to the contralateral lung during OLV may promote the release of oxygen free radicals and reactive nitrogen species, which can lead to cellular damage and, ultimately, lung injury [39]. The reventilation of atelectatic lung after a period of OLV provoked severe oxidative stress, supporting the concept of reperfusion injury [40]. The degree of oxidative stress was related to the duration of OLV [40], which is one of the features associated with ALI after elective esophagectomy [26]. Earlier studies used two-lung ventilation rather than OLV during transthoracic esophagectomy [41,42]. Greater pulmonary shunting was evident in patients having OLV [41], and patients who received high-frequency positive-pressure ventilation experienced fewer sever hypoxic episodes and lower peak and mean airway pressures than seen in patients having OLV [42]. Whether newer ventilation strategies during esophagectomy can decrease the effect on ALI and improve pulmonary outcome remains to be investigated. Prevention of tracheal aspiration Patients undergoing thoracotomy are at risk of acid GER, which may lead to tracheal acid aspiration in an appreciable proportion of patients [43]. This effect may be enhanced in esophageal cancer, because variable degrees of obstruction may be present together with abnormal esophageal sphincter function. Some postoperative pulmonary complications are thought to be the result of GER and tracheal contamination [44,45]. Aside from prophylactic pharmacologic management of GER, rapid-sequence induction, securing the airway with a cuffed endotracheal tube, and using gel lubrication on the tracheal cuff of the single- or double-lumen tube has been shown to reduce pulmonary aspiration in anesthetized patients [46,47]. Intraoperative tube substitution is common during esophagectomy and may subject the patient to additional risks of aspiration. Moreover, GER and pharyngeal reflux commonly occur during emergence from anesthesia and during bucking on the endotracheal tube [48]. It therefore is important to perform proper and repeated suction of the nasogastric tube and oropharynx before and after extubation. Application of continuous low-grade

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suction to the nasogastric tube may be the best way to prevent the significant and persistent tracheal acid aspiration present in all patients following esophagectomy [49]. Timing of extubation The potential complications associated with mechanical ventilation (including barotrauma and nosocomial pneumonia) and the side effects of sedation have led to studies looking at immediate or early extubation of patients after esophagectomy. This procedure was shown to be safe, was not associated with increased respiratory morbidity, and also reduced the length of ICU stay, potentially reducing costs [50–53]. A randomized, controlled trial evaluating early and late extubation after esophagectomy found that the early extubation group after transthoracic esophagectomy had a higher hospital mortality than the prolonged ventilation group (9.8% versus 1.9%), although this difference did not reach statistical significance [54]. Although early extubation does not reduce morbidity independently, as part of a multipronged management plan it assists in decreasing the number of ventilator days and the duration of ICU stay and contributes to improved outcome, as demonstrated in several series [11,12,55]. Other strategies for reducing pulmonary morbidity In a meta-analysis, the use of TEA with local anesthetic, compared with systemic opioids, was found to decrease the incidence of atelectasis, pulmonary infections, and pulmonary complications overall in upper abdominal and thoracic surgery [56]. The role of TEA is discussed later. The role of excessive fluid administration in adverse respiratory function is controversial. Although perioperative fluid overload is not the primary cause of pulmonary complications after esophagectomy, excessive infusion of fluids after the development of ALI may exacerbate or prolong the clinical condition.

Thoracic epidural analgesia TEA has a number of potential benefits after major surgery. Although evidence is lacking with regards to its effects on stress response and immune function in radical esophagectomy [57], there are clear benefits in other important areas including pain relief [58,59], reduction in respiratory complications [56,60–62], facilitating immediate or early postoperative tracheal extubation, reducing the length of intensive care stay, and possibly reducing cost [50–52]. TEA also plays a central role in a multimodal approach or standardized perioperative clinical pathway, which has shown improved outcomes [11,12,55]. The superior dynamic pain relief after esophagectomy with TEA is important for effective cough, vigorous physiotherapy, and mobilization in the early postoperative period. This control of acute

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postoperative pain also is vital for the reduction in the incidence of chronic postthoracotomy pain syndrome [63,64]. Earlier studies demonstrated a reduced incidence of respiratory complications and mortality with TEA after esophagectomy [60,61]. More recently, TEA for more than 48 hours reduced morbidity (pneumonia, reintubation), ICU stay, hospital stay, and in-hospital mortality when compared with either no epidural or TEA for less than 48 hours. The absence of epidural analgesia was an independent risk factor for pneumonia, and TEA was the key factor that facilitated immediate or early postoperative tracheal extubation [62]. These findings further substantiate the role of TEA for esophagectomy. It also has been suggested that TEA is associated with a decreased incidence of anastomotic leakage [65]. Ischemia of the gastric conduit and impairment of oxygen delivery have been postulated to be the main culprits in anastomotic leaks [66]. TEA may improve microcirculation of the distal part of the gastric tube in an experimental model [67] and also facilitates intensive physiotherapy, thereby preventing hypoxemia. TEA improved microvascular perfusion of the gastric conduit in the anastomotic area after esophagectomy [68], although larger clinical studies are required to evaluate the clinical relevance of this finding. In a recent meta-analysis, paravertebral block provided pain relief comparable to that achieved with epidural analgesia, had a better side-effect profile, and reduced pulmonary complications after thoracic surgery [69]. The successful use of paravertebral analgesia for esophagectomy has been described [70] and may be useful when epidural analgesia is contraindicated, but its role has not been clearly established. Fluid management There is a delicate balance between the maintenance of perfusion pressure and delivery of oxygen to vital organs and the gut mucosa and the prevention of pulmonary and peripheral edema [71]. Covert hypovolemia and inadequate tissue perfusion may lead to gut hypoperfusion with increased morbidity and duration of hospital stay [72], whereas excessive perioperative fluid administration may delay recovery of gastrointestinal function, impair wound/anastomotic healing and coagulation, and impair cardiac and respiratory function [71,73–75]. Recent evidence suggests that crystalloid restriction may improve outcome after major elective gastrointestinal surgery [76]. In elective intraabdominal surgery, a more restrictive fluid management reduced the total number of patients who had complications and shortened the time to recovery of gastrointestinal function and to hospital discharge [74,75]. A similar restrictive fluid regimen, however, demonstrated improvements in pulmonary function and oxygen saturation but no difference in overall functional recovery, with a tendency for increased morbidity [77]. Specific

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to esophagectomy, Kita and colleagues [78] found that restricting intraoperative fluid administration reduced postoperative pulmonary complications and shortened the in-hospital recovery period. This report, however, was a small, retrospective and nonrandomized case series. Moreover, there was significantly more blood loss in the ‘‘early period’’ or ‘‘nonrestricted fluid’’ group, and the need for blood transfusion and blood loss has been shown to be an intraoperative risk factor for morbidity [6,7]. Neal and colleagues [55] reported a significant reduction in esophagectomy-related morbidity with standardized multimodal management and intraoperative fluid restriction. This report was an observational, nonrandomized small case series of 56 patients, and the mean intraoperative crystalloid infused was about 4 L, which is not necessarily ‘‘fluid restriction’’ but rather is an avoidance of excessive volume infusion. Naturally, the different fluid regimens and end points used in these studies make it difficult to derive guidelines regarding perioperative fluid therapy, including the amount and choice of fluid. Liberal fluid regimens have contributed to poor outcomes after lung surgery [79], and although the pathophysiology of postpneumonectomy pulmonary edema or ALI after lung resection probably is multifactorial, any excess fluid will exacerbate the problem. No pulmonary resection is performed in esophagectomy, but there is potential for ALI during OLV and a high incidence of pulmonary complications after esophagectomy [26–28,40]. With regards to anastomotic healing, the risk of decreased oxygen tension secondary to interstitial edema (excessive crystalloids) also should be weighed against the problems of dehydration and gut hypoperfusion. The optimum perioperative fluid administration is a matter of continuing discussion. Instead of either a ‘‘restricted’’ or ‘‘liberalized’’ approach, the amount of fluid should be titrated individually to dynamic changes in appropriate monitoring. A recent review of goal-directed therapy with individual maximization of flow-related hemodynamic parameters showed that this approach reduced hospital stay, reduced postoperative nausea and vomiting, and facilitated faster gastrointestinal functional recovery [80]. In eight of nine studies, patients undergoing major cardiac, intra-abdominal, or orthopedic surgery received more fluid and relatively more colloid than persons in control groups. The esophageal Doppler monitor was used as a guide to plasma volume expansion. Some of the observed benefits may be attributable to the use of colloids rather than to the total amount of fluids infused. The use of the esophageal Doppler monitor is impractical in esophagectomy, but the dynamic changes in central venous pressure in response to a fluid challenge can be monitored; in hip surgery this approach has been shown to produce equivalent results [81]. The FloTrach/Vigileo system (Edwards Lifesciences, Irving, California), which has been evaluated in cardiac surgery, may be a feasible alternative for use in esophagectomy [82]. Goaldirected therapy has not been investigated in thoracic noncardiac surgery or esophagectomy.

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Summary It is unlikely that a single intraoperative intervention will show a benefit in outcome. A multimodal management plan that includes the use of TEA seems to demonstrate improved results in high-volume centers. Anesthetic management may contribute to the containment of pulmonary morbidity and anastomotic leakage by the use of TEA, protective ventilation strategies during OLV, prevention of tracheal aspiration, and judicious fluid management.

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