Introduction

Robot-assisted laparoscopic prostatectomy (RALP) has a number of advantages, such as lower perioperative blood loss and transfusion rate and a shorter hospital stay, compared to open prostatectomy in patients with prostate cancer [1, 2]. RALP requires carbon dioxide pneumoperitoneum and steep Trendelenburg positioning. Carbon dioxide pneumoperitoneum can cause hypercarbia and respiratory acidosis. In addition, a steep Trendelenburg position can result in decreased lung volume, lung compliance, functional residual capacity, and vital capacity and increased ventilation–perfusion mismatch and peak airway pressure [3]. Furthermore, most patients undergoing RALP are elderly patients, who have lower lung compliance and pulmonary function [4]. These particular surgical conditions and patient characteristics may compromise the respiratory system and may cause a relatively high incidence of postoperative pulmonary complications (PPCs). Previous studies demonstrated that PPCs occurred in 30.9%–43.3% of patients who underwent RALP [5, 6].

Neostigmine can accelerate neuromuscular function recovery [7]. However, a previous study demonstrated that neostigmine was associated with increased PPCs, such as atelectasis, particularly when used without neuromuscular monitoring [8]. Conversely, sugammadex reportedly induces rapid and complete reversal of even deep neuromuscular blockade by selectively binding with rocuronium [9, 10]. Unlike neostigmine, sugammadex can reverse the effect of neuromuscular blockade regardless of the depth of the neuromuscular block and reduce the postoperative residual neuromuscular blockade [11,12,13]. In addition, sugammadex rarely has muscarinic side effects [14]. Despite these advantages of sugammadex, its effect on postoperative outcomes, particularly PPCs, is controversial [15,16,17,18]. Moreover, little is known about the difference in the incidence of PPCs according to the type of neuromuscular blockade reversal agents in RALP, which can adversely affect the respiratory system.

Therefore, we compared the incidence of PPCs between patients receiving neostigmine (neostigmine group) and those receiving sugammadex (sugammadex group) as a neuromuscular blockade reversal agent in prostate cancer patients who underwent RALP requiring carbon dioxide pneumoperitoneum and steep Trendelenburg positioning.

Materials and methods

Patients

This was a large, retrospective, observational single-center study of patients who underwent RALP at the Asan Medical Center between January 2019 and March 2020. Patients with incomplete medical records were excluded. This study was approved by the institutional review board at the Asan Medical Center (approval no. 2020–0607), which waived the requirement for written informed consent.

Intraoperative and postoperative protocols

Before the induction of anesthesia, routine monitoring, which included pulse oximetry, electrocardiography, non-invasive blood pressure, end-tidal carbon dioxide concentration, bispectral index (BIS), and train-of-four (TOF) count and ratio, was performed. General anesthesia was induced with 4–5 mg/kg thiopental sodium or 1.5–2 mg/kg propofol. For muscle relaxation, 0.5–0.8 mg/kg rocuronium was used. Radial arterial catheterization was performed to continuously monitor arterial blood pressure. General anesthesia was maintained with 1–3 vol% sevoflurane or 4–6 vol% desflurane with 1–5 ng/mL remifentanil under continuous infusion. Medical air with 50% oxygen was supplied. Tidal volume was adjusted at 6–8 mL per ideal body weight, and the respiratory rate was adjusted to maintain an end-tidal carbon dioxide concentration of 30–40 mmHg while not surpassing a maximum peak airway pressure of 30 cmH2O. Positive end-expiratory pressure was not applied, and recruitment maneuvers were not performed. The BIS was maintained at 40–60. Rocuronium was administered intermittently to maintain a TOF count of  ≤ 2 throughout the surgery. Mean arterial blood pressure was maintained at  > 65 mmHg, and heart rate was maintained at 60–100 bpm by administering fluid or a vasopressor/inotropic. The administered fluid was either crystalloid, such as plasma solution A (CJ Pharmaceutical; Seoul, Korea) or Plasma-Lyte 148 (Baxter; Deerfield, IL, USA), or colloid, such as 6% hydroxyethyl starch. The administered vasopressor or inotropic was phenylephrine or ephedrine. Red blood cells were transfused when the hemoglobin level was < 8 g/dL. After skin closure, 40 µg/kg of neostigmine and 8 µg/kg of glycopyrrolate mixture were administered after the TOF count increased to 4; alternatively, 2 mg/kg of sugammadex was administered after TOF count was ≥ 2 to reverse the neuromuscular blockade, as per the anesthesiologist’s preference. In addition, extubation was performed when the BIS was > 90 and the TOF ratio was > 90%.

RALP was carried out according to the standard technique of our institution using the da Vinci™ robot system (Intuitive Surgical; Sunnyvale, CA, USA) [19, 20]. Abdominal pressure was maintained at 15 mmHg by insufflating carbon dioxide gas into the intraperitoneal cavity. Patients were positioned in the steep Trendelenburg position (45°). Six trocars were placed, and the prostate was dissected with a transperitoneal antegrade approach. A nerve-sparing procedure was performed, and vesicourethral anastomosis was performed with continuous sutures. Low-risk patients underwent selective pelvic lymph node dissection, and high-risk patients underwent routine pelvic lymph node dissection as described [21]. All RALPs were performed by five highly experienced surgeons.

Not all patients received epidural anesthesia for postoperative pain management. Patients received meperidine 25 mg intravenously upon request from postoperative day 0 to discharge. In addition, all patients routinely received a non-steroidal anti-inflammatory drug (nimesulide) 100 mg orally twice a day from postoperative day 1 to discharge. All patients were encouraged to actively cough and practice deep breathing during postoperative days. From the first postoperative day to the day of discharge, patients were encouraged to ambulate the ward and exercise an inspirometer.

Definition of PPCs

PPCs were defined as the development of one or more of the following within postoperative 7 days [22, 23]: (1) atelectasis defined by computed tomography or chest radiograph; (2) pneumonia defined using US Centers for Disease Control criteria; (3) acute respiratory distress syndrome using the Berlin consensus definition; and (4) pulmonary aspiration with clear clinical history and radiological evidence.

Data collection

Patient demographics and preoperative data included age, body mass index, American Society of Anesthesiologists physical status, comorbidities (hypertension, diabetes mellitus, coronary artery disease, atrial fibrillation, cerebrovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and interstitial pneumonia), smoking history, Gleason score, anti-hormonal therapy application, preoperative laboratory parameters (white blood cell count, neutrophil percentage, lymphocyte percentage, hemoglobin concentration, platelets count, serum albumin level, aspartate aminotransferase, alanine aminotransferase, serum creatinine level, glomerular filtration rate (GFR), serum uric acid level, and serum C-reactive protein level), and pre-induction O2 saturation. Intraoperative data included inhalation agent type, rocuronium and remifentanil amounts, anesthesia and operation times, infused crystalloid amount, colloid administration rate, red blood cell transfusion rate, and pelvic lymph node dissection. Postoperative data included the meperidine amount. Postoperative outcomes included PPCs, duration of hospital stays (the days from RALP to discharge), major adverse cardiac events during hospital stays, and death during hospital stays. Major adverse cardiac events were defined as one or more of the following: acute myocardial infarction, congestive heart failure, arrhythmia, or nonfatal cardiac arrest [24].

Statistical analysis

Continuous variables were examined by Student’s t-test or the Mann–Whitney U test and are expressed as mean ± standard deviation. Categorical variables were examined by the chi-square test or the Fisher’s exact test and are expressed as number (percent). All variables including demographic and preoperative data were compared between the neostigmine and sugammadex groups before propensity score matching. The 1:1 propensity score-matched analysis was performed by the nearest neighbor method with a 0.2 caliper size to identify the impact of the neuromuscular blockade reversal agent on PPCs. The propensity score was examined by multiple logistic regression analysis using the following variables: age, body mass index, American Society of Anesthesiologists physical status, comorbidities (hypertension, diabetes mellitus, coronary artery disease, atrial fibrillation, cerebrovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and interstitial pneumonia), smoking history, Gleason score, anti-hormonal therapy application, preoperative laboratory parameters (white blood cell count, neutrophil percentage, lymphocyte percentage, hemoglobin concentration, platelets count, serum albumin level, aspartate aminotransferase, alanine aminotransferase, serum creatinine level, GFR, serum uric acid level, and serum C-reactive protein level), pre-induction O2 saturation, and inhalation agent. The standardized mean difference was examined to determine the balance between the two groups, and the standardized mean difference of  < 0.2 was considered to have a sufficient balance between groups. After 1:1 propensity score matching, intraoperative data and postoperative outcomes were compared by McNemar’s test for categorical variables and the paired t-test for continuous variables. A p value of  < 0.05 was considered statistically significant. All statistical analyses were conducted by SPSS® version 21.0 software (IBM; Armonk, NY, USA).

Results

Of the 914 patients who underwent RALP between January 2019 and March 2020, 906 patients were included. Eight patients were excluded due to incomplete medical records. Among these 906 patients, 258 patients received neostigmine and 648 patients received sugammadex as the neuromuscular blockade reversal agent. After 1:1 propensity score matching, patients were divided into the neostigmine group (n = 237) and the sugammadex group (n = 237) (Fig. 1).

Fig. 1
figure 1

Flowchart of the study’s patients. In total, 914 patients who underwent robot-assisted laparoscopic prostatectomy were evaluated, and 906 patients were included in this study. Patients were divided into the neostigmine group and sugammadex group, and propensity score-matched analysis was performed. The neostigmine group included patients receiving neostigmine as a neuromuscular blockade reversal agent. The sugammadex group included patients receiving sugammadex as a neuromuscular blockade reversal agent

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Before 1:1 propensity score matching, the parameters of hypertension, diabetes mellitus, interstitial pneumonia, anti-hormonal therapy, pre-induction O2 saturation, and inhalation agent were significantly different between the two groups (Table 1). After 1:1 propensity score matching, none of the covariates were significantly different, and all were well-balanced with a standardized mean difference of < 0.2 between the two groups (Table 1). After 1:1 propensity score matching, the intraoperative and postoperative data including rocuronium and remifentanil amounts, anesthesia and operative times, crystalloid amount, colloid administration rate, red blood cell transfusion rate, pelvic lymph node dissection, and postoperative meperidine amount were not significantly different between the two groups (Table 2).

Table 1 Demographic and clinical data before and after propensity score matching
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Table 2 Intraoperative and postoperative data after propensity score matching
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The overall incidence of PPCs was 28.9% (137/474) in RALP. The incidence of PPCs was significantly lower in the sugammadex group than in the neostigmine group (18.6% vs. 39.2%, p < 0.001) (Fig. 2). The incidence of atelectasis was significantly lower in the sugammadex group than in the neostigmine group after RALP (18.6% vs. 39.2%, p < 0.001). Atelectasis occurred in 94.2% (129/137) of patients on the first postoperative day and in 5.8% (8/137) of patients on the second postoperative day. However, the incidence of pneumonia was not significantly different between the sugammadex and neostigmine groups after RALP (0.0% vs. 0.4%, p > 0.999).

Fig. 2
figure 2

Comparison of the incidence of PPCs between the neostigmine group and sugammadex group. The neostigmine group included patients receiving neostigmine as a neuromuscular blockade reversal agent. The sugammadex group included patients receiving sugammadex as a neuromuscular blockade reversal agent. PPC postoperative pulmonary complication

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In addition, duration of hospital stays, major adverse cardiac events during hospital stays, and death during hospital stays were not significantly different between the two groups before and after 1:1 propensity score matching (Table 3).

Table 3 Postoperative outcomes
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Discussion

In this propensity score-matched study, we found that the overall incidence of PPCs was 28.9% in RALP and that the incidence of PPCs was significantly lower in patients receiving sugammadex than in those receiving neostigmine as a neuromuscular blockade reversal agent during RALP requiring carbon dioxide pneumoperitoneum and a steep Trendelenburg position.

RALP has gained increasing attention because it offers advantages of improved visualization of the surgical field, lower intraoperative blood loss, and shorter duration of hospital stays in comparison to open prostatectomy [1]. Therefore, RALP is more commonly performed in prostate cancer patients [1]. Previous studies have reported the incidence of PPCs as 30.9%–43.3% in patients who underwent RALP [5, 6]. Consistent with previous reports [5, 6], we found that the overall incidence of PPCs was 28.9% in our study. To optimize the surgical field, RALP requires carbon dioxide pneumoperitoneum of 15 mmHg and a steep Trendelenburg position of 45º. Therefore, the lungs and diaphragm are lifted by intraperitoneal organs, and consequently, lung compliance and functional residual capacity are reduced, and respiratory acidosis is induced [25, 26]. Furthermore, most older prostate cancer patients undergo RALP, and they typically have lower lung compliance and relatively compromised pulmonary function [4]. In the present study, the mean ages of patients were 66.0 years and 65.9 years in the sugammadex and neostigmine groups, respectively. In RALP, the relatively high incidence of PPCs could be due to surgical conditions and patient characteristics. Therefore, meticulous anesthetic and surgical management to reduce the incidence of PPCs are needed in patients undergoing RALP.

In the present study, we found that sugammadex administration was associated with a lower incidence of PPCs compared to neostigmine administration in patients who underwent RALP. Sugammadex rapidly reverses steroidal non-depolarizing neuromuscular blockers by selectively binding to these neuromuscular blockers [10, 27]. Sugammadex is neither involved with cholinergic mechanisms nor does it produce cholinergic side effects [27]. Postoperative residual neuromuscular block is associated with postoperative complications, such as upper airway obstruction, hypoxemia, atelectasis, and pneumonia [28,29,30,31,32]. Sugammadex is effective even in cases with profound blockades and can reduce residual neuromuscular block. However, there is still debate regarding the effect of neuromuscular blockade reversal agents on PPCs [15,16,17,18]. In line with the present study, a retrospective matched-cohort analysis revealed that sugammadex administration was associated with a significantly lower incidence of PPCs, such as pneumonia and respiratory failure, in non-cardiac surgical procedures [15]. In addition, a previous randomized study demonstrated that sugammadex administration was associated with faster reversal of moderate neuromuscular blockade and a decreased incidence of postoperative hypoxia compared with neostigmine administration in thoracic surgery with single-lung ventilation [16]. Conversely, a multicenter, prospective, observational study demonstrated no difference in the incidence of PPCs between neostigmine and sugammadex administration [17]. Another randomized controlled trial showed no differences in pulmonary functions evaluated by spirometry after major abdominal surgery between sugammadex and neostigmine administration [18]. These inconsistent results may, at least in part, be induced by different surgical conditions and patient characteristics. Our study population comprised older patients (mean ages: 66.0 years in the sugammadex group and 65.9 years in the neostigmine group), and specific surgical conditions, such as carbon dioxide pneumoperitoneum and steep Trendelenburg positioning, were needed during the intraoperative period. Therefore, in older patients undergoing RALP, sugammadex administration seems to have a beneficial effect on PPCs.

The most common pulmonary complication in the present study was atelectasis, and its incidence was significantly lower in the sugammadex group (18.6%) than in the neostigmine group (39.2%). Reduction in diaphragm activity is associated with the postoperative development of atelectasis [33]. The use of sugammadex can improve electromyographic activity of the diaphragm and intercostal muscles, enable higher tidal volumes, and improve the ability to remove secretions [34, 35]. Therefore, sugammadex administration may be protective against the development of atelectasis.

The present study has inevitable limitations due to its retrospective study design. There may have been a possible selection bias and confounders that could influence the incidence of PPCs. In particular, the pulmonary function test was not routinely performed in RALP, which may have influenced our results. However, we included almost all possible variables and performed a propensity score-matched analysis. Therefore, we minimized the selection bias in the present study. Second, because the present study was performed at a single large center, the results should be interpreted carefully. Third, the beneficial effect of sugammadex on the reduction of PPCs in this study was almost limited to the reduction of atelectasis. Our results need to be interpreted cautiously.

Conclusion

The overall incidence of PPCs was 28.9% in RALP. The incidence of PPCs was significantly lower in patients receiving sugammadex than in those receiving neostigmine while undergoing RALP. These results provide useful information on the appropriate selection of neuromuscular blockade reversal agents in prostate cancer patients undergoing RALP who are at a higher risk of developing PPCs because of specific surgical conditions, such as carbon dioxide pneumoperitoneum and steep Trendelenburg positioning, and generally being of advanced age.