Recommendations for perioperative management of lung cancer patients with comorbidities

Several types of drugs (e.g., steroids, erythromycin, and neutrophil elastase inhibitors) have been proposed to prevent AE-IPF onset after surgery. However, no consensus exists regarding definitive prophylaxis for AE-IPF after pulmonary resection. Oral pirfenidone, a pyridone compound with pleiotropic effects, exhibited antioxidant, anti-inflammatory, and antifibrotic effects in experimental models of pulmonary fibrosis. Pirfenidone might lower levels of factors associated with proliferation, such as transforming growth factor-beta [8]. A phase II study found that pirfenidone limited IPF disease progression and lowered AE-IPF incidence after lung cancer surgery [9]. However, these findings require confirmation in a larger, prospective phase III study.

Even though a minimally invasive approach is recommended in order to hasten recovery from surgical stress, the benefit in reducing AE-IPF incidence is unclear [5]. One-lung ventilation is usually used for minimally invasive surgery, but could increase the risk of acute lung injury [11].

Excessive fluid infusion can cause pulmonary edema under normal hydrostatic pressure, a reported risk factor for acute lung injury after thoracic surgery. A previous study reported that 7–8 mL/kg/h is the proper intraoperative fluid infusion rate for patients undergoing pulmonary resection [12].

A Japanese cohort survey found that the incidence rate of AE was 25.2% for the contralateral lung and 60.6% for both lungs among patients developing AE-IPF after lung cancer surgery [5]. These findings suggest that exposure to hyperoxia, barotrauma, and volutrauma associated with selective mechanical ventilation has a critical role in AE-IPF onset [12]. The synergy between lung-damaging noxious agents is mediated by oxygen radicals. Oxygenation may weaken the hypoxia-driven anti-inflammatory mechanism in local tissue, thereby exacerbating lung injury [13]. The minimum required oxygen concentration should be adjusted during surgery by using intermittent bilateral ventilation. High airway pressures or tidal volumes during one-lung ventilation can lead to barotrauma and volutrauma in the contralateral lung. Low-pressure controlled one-lung ventilation can relieve such stress [14]. These management decisions should be made in consultation with an anesthesiologist.

Pulmonary resection more extensive than partial resection is a risk factor for AE-IPF [5, 6]. However, it is unclear if the prognosis is better for limited resection than for standard resection. Underlying diseases associated with lung cancer, such as IPF, may be more advanced than clinical assessments indicate [15]. Thus, the extent of pulmonary resection should be carefully considered.

Nodal dissection increases tissue damage by reducing lymphatic drainage and bronchial circulation and denervating the vagal nerve, thus increasing the morbidity rate after lung cancer surgery [16]. The extent of nodal dissection was significantly related to AE-IPF incidence after lung cancer surgery [5]. Systematic nodal dissection should be indicated by preoperative PET assessment and nodal assessment by transbronchial biopsy through endobronchial ultrasonography. If mediastinal nodal involvement is diagnosed, surgical indications should be carefully reviewed. In particular, the prognoses of IPF and lung cancer with nodal involvement must be compared.

Oxygen therapy is often required for postoperative hypoxia. However, there is no evidence of benefit for oxygen treatment in patients with chronic hypoxia caused by IPF. Oxygen therapy should be limited unless it is necessary for recovery from limitations in postoperative activity.

The role of respiratory infection in AE-IPF is not well understood. Empiric use of antibiotics is largely attributable to the fact that AE-IPF cannot always be distinguished from bacterial infection. Procalcitonin, a peptide more frequently observed in the setting of microbial toxins and bacterial proinflammatory molecules, is useful in detecting whether the cause of inflammation is bacterial in origin and in guiding the initiation and discontinuation of antibiotics in acute respiratory infections. Antibiotic therapy guided by procalcitonin at a threshold of 0.25 ng/mL reduced antibiotic treatment duration [17]. Azithromycin, an antibiotic with anti-inflammatory properties, was evaluated as an IPF treatment and significantly reduced fibrosis and restrictive lung function pattern in a mouse model of bleomycin-induced pulmonary fibrosis [18]. To date, no formal clinical trial has examined azithromycin for patients with AE-IPF.

Liberal fluid treatment increases the incidence of acute lung injury. The volume of fluid administration should be adjusted at 1–2 mL/kg/h to maintain blood pressure and urine volume at > 0.5 mL/kg/h [19]. A positive daily fluid balance of 1.5 L should not be exceeded. Blood transfusion was reported to induce transfusion-related acute lung injury, which is distinguishable from AE-IPF but nevertheless a concern.

The need for chest CT is usually based on patient clinical conditions, such as dyspnea, decreased oxygen saturation (SpO₂), abnormal shadows on chest radiography, and abnormal findings on blood tests. Scheduled chest CT examinations on postoperative days 4, 7, and 14 could hasten detection of AE-IPF [20]. Earlier treatment could decrease AE-IPF mortality. Scheduled chest CT should be considered for lung cancer patients at high risk, as determined by a scoring system for predicting AE-IPF after pulmonary resection.

N-Acetylcysteine (NAC) is a mucolytic antioxidant drug and has been studied as a potential treatment for IPF. It is hoped that NAC can prevent oxidative injury preceding fibroproliferation by restoring the natural oxidant/antioxidant balance. NAC inhalation monotherapy has not been studied as a prophylactic drug for AE-IPF, although favorable effects on lung function have been reported for patients with mild IPF, especially when NAC is combined with antifibrotic agents [21].

The Revised Cardiac Risk Index is widely used to predict the risk of cardiovascular complications and death (Table 2). Patients with high cardiovascular risk require appropriate interventions before surgery. However, the benefit of coronary artery revascularization before elective non-cardiac surgery for patients with IHD is unclear. Mcfalls et al. reported that coronary artery revascularization before elective major vascular surgery did not improve long-term survival or reduce incidences of early postoperative outcomes—including death, myocardial infarction, and duration of hospital stay—among patients with stable coronary disease [24]. Another study found that preoperative coronary revascularization was not associated with improved outcomes, even for high-risk patients with disease affecting two or three vessels or left main disease [25]. In contrast, the guidelines of the Japanese Circulation Society recommend coronary revascularization before non-cardiac surgery for patients with unstable angina and those with stable angina with left main coronary artery disease, severe triple-vessel disease, or double-vessel disease affecting the proximal left anterior descending artery and low left ventricular ejection fraction [23]. The need for coronary revascularization should be individually assessed. To determine the most appropriate treatment strategy, an anesthesiologist and cardiologist should be consulted.

Elective surgery that has a high risk of intra- or postoperative surgery bleeding should be avoided for 12 months after implantation of drug-eluting stents (DES) and for at least 1 month after implantation of bare-metal stents (BMS). However, for malignant disease such delays should be minimized to prevent disease progression. Therefore, indications for DES implantation should be carefully considered in patients who have or are suspected to have malignant disease. BMS and balloon angioplasty are preferable to DES implantation for patients who require surgery within 12 months of PCI [23].

A Japanese follow-up survey of 2,398 of 12,207 patients who had undergone PCI and underwent surgical treatment within 3 years found that 110 patients underwent respiratory surgery [26]. Stent thrombosis is a major concern, but the rate of restenosis is significantly lower for DES than for BMS. Dual antiplatelet therapy with aspirin and thienopyridine is the most beneficial regimen to prevent stent thrombosis and should continue for 12 months after DES implantation. Continuation of aspirin therapy during the perioperative period of non-cardiac surgery is recommended for patients already receiving aspirin [23].

Empirical perioperative use of heparin in patients with coronary stents is standard practice in many institutions in Japan, although there is no evidence that heparin prevents stent thrombosis. Guidelines vary regarding bridging with an anticoagulant agent. The Japanese Circulation Society maintains that heparinization is preferable when all antiplatelet agents must be discontinued [23]. In contrast, the American College of Chest Physicians does not recommend routine heparinization for patients who are receiving dual antiplatelet therapy and require surgery. Heparinization can be an obstacle in pain control by epidural anesthesia and may cause heparin-induced thrombocytopenia. Thus, perioperative antithrombotic therapy remains controversial, and future studies should assess the advantages and disadvantages of perioperative heparinization.

The frequency of stent thrombosis is lower for Japanese than for American and European populations. A Japanese study reported a cumulative incidence of definitive stent thrombosis of 0.6% at 1 year after sirolimus-eluting stent implantation [27]. The increase in the incidence of stent thrombosis during the 5 years after implantation was 0.2–0.3% per year. In European populations, the cumulative incidence of stent thrombosis for sirolimus-eluting stents and paclitaxel-eluting stents was 1.7% at 1 year and incidence continued to increase by 0.6% per year [28]. A recent report from Japan found that the incidence of stent thrombosis after lung resection was only 0.2% among patients with coronary stents, even though antiplatelet therapy had been discontinued in most patients [29]. Perioperative management of patients with coronary stents may differ for Japanese and American/European populations.

The effectiveness and feasibility of concurrent coronary artery surgery and pulmonary resection has been investigated [30]. The disadvantages of cardiopulmonary bypass can be avoided by using off-pump coronary artery bypass (OPCAB) grafting, a standard procedure for concomitant lung resection. Although clear indications have not been established for this concurrent operation, it might be optimal for patients with refractory stenosis of coronary arteries who cannot be treated with PCI. Another concern is the duration of antiplatelet therapy required between PCI and lung resection, as a delay in pulmonary surgery could allow cancer progression. Concurrent coronary artery bypass and lung cancer resection is an alternative therapeutic strategy for patients with advanced lung cancer requiring immediate resection.

In addition to decreasing cholesterol synthesis, statins have pleiotropic effects, including vasodilation, anticoagulation, platelet inhibition, atherosclerotic plaque stabilization, and anti-inflammatory function. It has been reported that statins reduce mortality and cardiovascular outcomes in patients undergoing non-cardiac surgery. Moreover, statins were associated with reduced risks of respiratory, renal, and infection-related complications. A recent large-scale prospective cohort study indicated that preoperative statin therapy improved cardiovascular outcomes among patients undergoing non-cardiac surgery [31]. A retrospective observational cohort analysis of 180,478 veterans showed that early perioperative statin use significant reduced 30-day all-cause mortality and cardiovascular and non-cardiovascular complications, as compared with non-use [32]. These studies support the strong recommendation to continue perioperative statin use for non-cardiac surgery patients already receiving statins [22]. It remains to be determined whether statin treatment improves clinical outcomes for statin-naïve patients undergoing surgery. Although preoperative statin use might benefit statin-naïve patients undergoing cardiovascular surgery, there are insufficient data to support a definitive recommendation regarding perioperative statin therapy for patients undergoing non-cardiac surgery. The benefit of statins for statin-naïve patients is less clear, and ACC/AHA guideline includes less-than-strong recommendations to start perioperative statins for patients undergoing vascular surgery [22]. In contrast, the guidelines of the Japanese Circulation Society strongly recommend initiation of statin therapy for patients with high cardiovascular risk [23].

Beta-blockers can prevent myocardial infarction by prolonging coronary diastolic filling time, reducing myocardial oxygen consumption, and decreasing myocardial wall stress. Although some randomized controlled trials, a large-scale retrospective cohort study, and a meta-analysis showed a benefit for beta-blockers, several subsequent studies did not. The randomized trial over 8,000 patients undergoing non-cardiac surgery to extended-release metoprolol or placebo within 2–4 h before surgery; therapy was continued for 30 postoperative days [33]. Metoprolol reduced myocardial infarction risk, but increased risks of all-cause mortality and stroke. Thus, perioperative use of beta-blockers remains controversial. According to current ACC/AHA guideline, perioperative beta-blocker use is strongly recommended for patients receiving chronic treatment [22]. In the ACC/AHA guidelines, initiation of beta-blocker treatment before surgery receives a weak recommendation for patients with an intermediate or high risk of myocardial ischemia, as indicated by preoperative risk stratification. Current guidelines recommend against starting beta-blocker therapy on the day of surgery. Previous studies varied in the beta-blocker used, timing of initiation, and dose; thus, additional studies are necessary to determine the utility of perioperative beta-blockade.

Aspirin can prevent myocardial infarction in patients with coronary artery disease. Determining whether aspirin should be continued in patients undergoing non-cardiac surgery is a common clinical dilemma, as clinicians must balance the benefit of aspirin in preventing thromboembolic complications with the possibility of increased intra- and postoperative bleeding. The POISE-II trial randomly assigned over 10,000 patients undergoing non-cardiac surgery to receive aspirin or placebo [34]. Perioperative administration of low-dose aspirin did not reduce rates of mortality or myocardial infarction, although aspirin was associated with increases in major bleeding episodes. However, only 23% of patients in the POISE-II trial had coronary heart disease, and patients who received a BMS less than 6 weeks before surgery or a DES less than 1 year before surgery were excluded. Only 4.7% had a history of PCI and only 1.2% had a DES in this trial. Thus, this analysis cannot conclusively determine whether perioperative temporary aspirin cessation is optimal for patients in high-risk groups. A recent report from Japan suggested that discontinuation of antiplatelet therapy may not increase postoperative complications in patients with coronary artery disease who underwent pulmonary resection [29]. In that study of 902 patients who had received preoperative diagnoses of coronary artery stenosis, 532 patients (59%) had coronary stents and 204 patients (23%) were treated with DES. Nevertheless, stent thrombosis developed only in one patient in the study. Therefore, perioperative discontinuation of aspirin may be beneficial, even for patients with coronary stents. However, present Japanese guidelines recommend continuation of aspirin therapy during the perioperative period of non-cardiac surgery for patients already receiving aspirin and specify that perioperative aspirin use should be determined on an individual basis, after considering cardiovascular and perioperative hemorrhagic risks [23].

Cardiovascular evaluation is important before surgery, as approximately 50% of dialysis patients undergoing surgery have cardiovascular disease [51]. The mortality rate for dialysis patients with diabetes is 44 times that of the non-ESRD population; thus, preoperative cardiovascular evaluation is essential [52]. When cardiovascular disease is suspected, further assessment is necessary, including cardiac catheter testing or myocardial perfusion scintigraphy. Pulmonary hypertension is a risk factor for pulmonary resection and an independent predictor of mortality in hemodialysis patients [53]. Screening of pulmonary hypertension by echocardiography is essential before lung cancer surgery.

Minimally invasive surgery might decrease postoperative complications for hemodialysis patients, because greater blood loss and longer surgical time worsen postoperative outcomes [54]. Although there is no evidence regarding surgical procedure, we avoid pneumonectomy when possible, to limit the possibility of hypostasis. The range of lymph node dissection is considered for each patient. Lymph node sampling may be appropriate for early cancer, but systematic lymph node dissection may be an option for advanced cancer, because sequential chemotherapy is limited for dialysis patients.

To prevent excessive acidosis, we routinely perform hemodialysis on the day before surgery at our institution. Chronic acidosis is common in ESRD patients, as the kidneys are unable to excrete the nonvolatile acid load [55]. However, major surgery often causes postoperative metabolic acidosis [56]. Particularly after pulmonary resection, respiratory compensation decreases and leads to severe postoperative metabolic acidosis, which is associated with the worst postoperative outcomes [57]. Therefore, strict acid–base control is crucial in ESRD patients.

Hemodialysis should be resumed within 24 h after surgery, to avoid the risk of bleeding and insufficient fluid shifts, unless there is severe progression of acidosis or volume overloads requiring emergent dialysis. Heparin-free hemodialysis is performed to avoid postoperative hemorrhage.

Routine evaluation of arterial blood gasses is necessary for ESRD patients to prevent unexpected acidosis and hyperkalemia. Fluid management is also important. However, perioperative use of a pulmonary artery catheter for fluid management in non-cardiac surgery is not recommended [58]. Ultrasonographic evaluation of the diameter of the inferior vena cava may be a convenient technique to estimate intravascular volume [59].

Acetaminophen and opioids are the usual drugs for postoperative pain control. Fentanyl is the best choice for dialysis patients, because of its short redistribution phase [60]. In contrast, meperidine, morphine, and propoxyphene should be avoided. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be considered if the patient has residual renal function.

The rate of surgical site infection associated with thoracic surgery was reported to be 0.7–2.0% [61], and the rate for ESRD patients is believed to be much higher. Antibiotic prevention of surgical site infection is administered within 1 h before the initial incision, and cefazolin is recommended for hemodialysis patients undergoing thoracic surgery. There is no consensus regarding postoperative surgical antibiotic prophylaxis prolongation for ESRD or non-ESRD patients [5, 62]. Because antibiotic dose is limited for hemodialysis patients, we administered only once before postoperative hemodialysis.

Long-term outcomes are not as good for hemodialysis patients undergoing lung cancer surgery as for patients not receiving hemodialysis. Some small studies reported a 5-year overall survival rate of 28–43% [45, 47, 50], while 5-year overall survival after induction of hemodialysis was approximately 41.5–60.8% [36, 37]. Survival is worse for patients with diabetes than for those without diabetes (20.7–34%) [63]. It is unclear whether surgical intervention is indicated for diabetic ESRD patients with advanced lung cancer. Thus, further study is necessary.

In conclusion, we reviewed and discussed recent trends in specialized perioperative care for comorbidities such as IPF, CVD, and ESRD in patients undergoing lung cancer surgery. To improve surgical outcomes for lung cancer patients, future studies should attempt to identify optimal perioperative management strategies for these comorbidities.