An easy-to-use anesthetic strategy for mitigating postoperative complications following laparoscopic colorectal surgery

To the Editor: The abdominal surgical procedures are linked to a high incidence of postoperative pulmonary complications (PPCs) and may be mitigated by administration of lung-protective mechanical ventilation during anesthesia.[1,2] To date, no relevant studies have focused on protective lung ventilation strategies specifically for laparoscopic colorectal cancer (CRC). Herein, we propose an innovative easy-to-use lung-protective strategy with lower tidal volume (VT), pneumoperitoneum pressure (PnP) and deep neuromuscular blockade (NMB) and assess whether it is superior to conventional lung protection strategies in reducing PPCs. A single-center, randomized trial was conducted in patients who underwent laparoscopic colorectal surgery and followed up until 30 postoperative days (PODs). A total of 120 patients were enrolled and randomly assigned at a ratio of 1:1 to either the test group (protective lung ventilation with lower VT (6 mL/kg of predicted body weight [PBW] + low PnP [10 mmHg] + deep NMB) or the control group (conventional pulmonary ventilation [8 mL/kg of PBW for VT] + standard PnP [15 mmHg] + moderate NMB). The institutional Ethics Committee approved the study protocol (Approval No. NCC2018W-006) and the registry was completed at ClinicalTrials.gov (ChiCTR1900021989). The written informed consent were signed by each patient before enrollment. The patient follow-ups were performed throughout the hospital stay once daily or by telephone and outpatient records when patients were discharged at Day 30 after operation [Supplementary Figure 1, https://links.lww.com/CM9/C26]. In all the groups, mechanical ventilation during anesthesia consisted of volume-controlled modes of VT according to the group and PBW,[1,2] positive end expiratory pressure (PEEP) of 5 cm H2O, and alveolar recruitment maneuvers (ARMs) at 30-minute intervals. The respiratory rate was adjusted as necessary to maintain an end-tidal carbon dioxide (EtCO2) between 35 mmHg and 45 mmHg, with an inspiratory-to-expiratory ratio (I:E) of 1:2. The fraction of inspired oxygen (FiO2) was maintained at 40–60% throughout the anesthesia treatment. A portable neuromuscular monitor was applied to the ulnar nerve to confirm the depth of the NMB. The indications of NMB depth were defined as train-of-four count (TOFC) = 0 and posttetanic count (PTC) ≥1 for deep NMB and TOFC = 1–3 for moderate NMB.[3] The primary endpoint of the PPCs was systematically assessed via the operational definition of Kroenke et al[4] with the grades ranging from 1 to 4 [Supplementary Table 1, https://links.lww.com/CM9/C26]. For those suspected to have PPCs, low-dose chest computed tomography (CT) was routinely performed for confirmation. The secondary endpoints comprise postoperative analgesia and serological inflammatory factor expression. All the statistical analyses were performed by using SPSS 25.0 (IBM SPSS, Inc., NY, USA). The Kaplan–Meier (K–M) method combined with log-rank analysis was used to compare the incidence of PPCs between the two groups. Quantitative data are presented as the medians (interquartile ranges) and were compared using Student's t-test or the Mann–Whitney rank test. Categorical variables were analyzed using the chi-square or the Fisher exact test. The two-tailed P values <0.05 were considered as statistically significant. The sample size was calculated according to the results of our preliminary experiment. With a significance level of 0.05 and a power of 80%, a minimum of 55 patients were included in each group. Considering a 10% drop-out rate during the follow-up, 60 patients were enrolled in each group. In this study, 152 patients who underwent laparoscopic colorectal surgery were initially included, and a total of 120 patients were ultimately enrolled. The patients in the two groups had comparable baseline characteristics [Supplementary Table 2, https://links.lww.com/CM9/C26]. The K–M analysis revealed a significant difference in the incidence of PPCs within 30 days after surgery between the test group (9 of 60, 15.0%) and the control group (19 of 60, 31.7%) (P = 0.031; Table 1, Supplementary Figure 2, https://links.lww.com/CM9/C26). Of these, patients of grade 1 (primarily microatelectasis) account for the largest proportion of PPCs (test group vs. control group; 77.8% [7 of 9] vs. 68.4% [13 of 19]). For subgroup analysis, the test group exhibited superior analgesic outcomes and fewer related postoperative inflammatory responses than did the control group for individuals with a standard or overweight body mass index (BMI) <27.9 kg/m2, who were younger than 62 years, or who had an anesthesia duration of 3 hours or less [Supplementary Figure 3, https://links.lww.com/CM9/C26]. Atelectasis formation, a shift in the ventilation-to-perfusion ratio by reduced pulmonary compliance and increased chest pressure facilitates PPCs even in patients with healthy lungs. This pathophysiological alteration will be exacerbated during laparoscopic colorectal surgery. Pulmonary atelectasis is the main cause of PPCs progression and is mainly attributed to compression of the lung parenchyma, absorption of alveolar gases, and impaired extra-alveolar function. The use of higher FiO2 (>80%) can also lead to absorptive lung atelectasis and exacerbate inflammatory lung injury.[2] PPCs can also cause lung injury, lung infection, or barotrauma in turn. Tidal volumes in the range of 6–8 mL/kg of PBW are widely accepted for non-injured lungs.[2] Single low-tidal volume ventilation plays the most important role in protective ventilation,[1,2,5] which may lead to decreased compliance and atelectasis formation. Therefore, in comparison to the control group, which had a concentration of 8 mL/kg, 6 mL/kg was adopted for the test group. The ideal level of PEEP to resist atelectasis remains in dispute, with low-risk patients receiving PEEP of less than 5 cm H2O but high-risk patients requiring higher levels of PEEP.[5] Once atelectasis has occurred, ARMs are required to recruit alveoli. Additionally, it has been proven that a lower PnP involves reduced peak inspiratory pressure and facilitates respiratory compliance, especially in the Trendelenburg position. Some evidence has shown that postoperative lung function is equivalent in patients receiving the same PnP, regardless of whether deep or moderate NMB is used, thus demonstrating a close correlation between PnP and postoperative PPCs.[6] Postoperative pain is another critical factor in the formation of PPCs, pain-induced restriction of abdominal breathing initiates the microatelectasis and subsequent atelectasis formation. Despite using the same standardized analgesic protocol in both groups, our results indicate that the lung-protective strategy was associated with lower short-term postoperative VAS scores (P = 0.016 for postoperative 1 h, P = 0.071 for POD 1 [Table 1]) and decreased serum interleukin-6 (IL-6) expression on POD 3 (P = 0.017). Of note, the subgroup results reveal a superior advantage in analgesia and systemic inflammation suppression in the test group, especially in those with BMI <27.9 kg/m2, age <62 years, or anesthesia duration ≤3 hours [Supplementary Figure 3, https://links.lww.com/CM9/C26]. One potential mechanism through which analgesia is achieved could be the reduction in tension exerted on the abdominal wall facilitated by deep NMB, thereby reducing postoperative incisional pain.[7] Additionally, low PnP can relieve visceral and shoulder pain by lowering the partial pressure of carbon dioxide in the blood and reducing inflammatory cytokines/oxygen-free radicals arising from visceral ischemia–reperfusion injury. Given that inflammation is implicated in the progression of pain, lung injury, and PPCs,[1] the causal relationship remains undetermined. Table 1 - Clinical outcomes between the test and control groups. Indexes Control group (N = 60) Test group (N = 60) P value Incidence of PPCs within 30 days 19 (31.7) 9 (15.0) 0.031 Grade 1 13 (21.7) 7 (11.7) 0.143 Grade 2 5 (8.3) 2 (1.3) 0.213 Grade 3 1 (1.7) 0 0.608 Systemic inflammatory index IL-1β (pg/mL) Preoperation 3.0 (2.5–3.3) 2.7 (2.4–3.0) 0.583 POD 1 4.0 (3.2–6.0) 3.6 (2.9–4.5) 0.245 POD 3 3.3 (2.9–3.8) 2.9 (2.5–3.4) 0.673 IL-6 (pg/mL) Preoperation 2.2 (2.0–2.3) 2.1 (1.5–2.3) 0.125 POD 1 2.6 (2.2–3.7) 2.5 (2.2–3.3) 0.172 POD 3 2.3 (2.1–2.5) 2.1 (1.5–2.3) 0.017 Postoperative analgesia, VAS 1 h 2 (1–4) 1 (1–2) 0.016 POD 1 2 (2–3) 2 (1–2) 0.071 POD 2 2 (1–2) 2 (1–2) 0.283 POD 3 1 (1–2) 1 (1–2) 0.520 POD 5 1 (0–1) 1 (0–1) 0.735 The data are shown as n (%) or medians (Q1–Q3). P values were calculated by Kaplan–Meier analysis, or the Mann–Whitney rank test. IL-1β: Interleukin-1β; IL-6: Interleukin-6; POD: Postoperative day; PPCs: Postoperative pulmonary complications; VAS: Visual analog scale. As a single-center study, only one study site cannot be representative of the clinical practices in a larger patient population. Chronic postsurgical pain and more detailed pain categories should be further explored. Furthermore, mechanistic studies in the outcome after novel treatment strategies need to be investigated. In conclusion, the holistic anesthetic strategy of protective lung ventilation combined with deep NMB and low PnP can reduce the PPCs in patients undergoing laparoscopic colorectal surgery. Further studies are needed to test the efficacy and heterogeneity of the clinical application of this easy-to-use anesthetic strategy. Funding This work was supported by grants from the CAMS Innovation Fund for Medical Sciences (Nos. CIFMS, 2022-I2M-C&T-B-061, 2021-I2M-1-066), the Beijing Hope Run Special Fund of Cancer Foundation of China (Nos. LC2021A18, LC2022B06), and the National Natural Science Foundation of China (No. 82073327). Conflicts of interest None.