Introduction and hypothesis

Kidney cancer is of increasing incidence in Europe and Worldwide. According to the Global Cancer Observatory, it is the 14th most common malignancy with 431,288 new cases in 2020 including 138,611 in Europe [1]. One explanation for this rising incidence is the increasing incidental diagnosis of small renal masses on imaging done for another cause [2, 3]. For these localized tumors (cT1-T2), conservative surgery (partial nephrectomy) is the standard of care [4], allowing good carcinological results while reducing morbidity. The minimally invasive approach with robotic assistance (robot-assisted partial nephrectomy (RAPN)) is now widely used in many hospitals. It combines a reduced perioperative morbidity and shorter hospital stays without altering the oncological results [5, 6]. This improvement in the procedure’s safety has allowed the development of Enhanced Recovery After Surgery protocols and ambulatory protocols [7,8,9]. Nevertheless, in general and in the context of outpatient care in particular, the control of postoperative pain is a crucial issue to allow convalescence and return to activity in the best possible conditions.

Laparoscopic procedures require the generation of a pneumoperitoneum by intra-abdominal insufflation of carbon dioxide (CO2) resulting in an impact on the cardiovascular and respiratory system (reduced venous flow and cardiac output, increased peripheral vascular resistance and blood pressure, increased pulmonary ventilatory resistance and hypercapnia) [10]. In order to limit these adverse effects, it is commonly recommended to limit the insufflation pressure to the minimum level necessary to allow sufficient exposure and working space. The commonly used insufflation pressure is 12–15 mmHg [10]. In addition to the side effects described above, this abdominal overpressure is also responsible for postoperative pain due to phrenic irritation and residual CO2 [11], which is, based on our expertise, mainly experienced during the first 48 h postoperatively and is difficult to control with the usual analgesics.

The AirSeal® system consists of an insufflator, a 3-channel tubing set, and a special trocar. It provides active, continuous, and self-regulated insufflation, suction and filtration of CO2. This allows the preservation of a stable pneumoperitoneum while ensuring continuous extraction and active filtration of electrocoagulation smoke [12].

This system has been shown to improve intra-operative ventilatory parameters during laparoscopic total cystectomy in a prospective randomized study [13]. Shahait et al. also reported a decrease in operative time and postoperative pain during robot-assisted total prostatectomy with the use of AirSeal at standard pressure in a non-randomized comparative study [14], while La Falce et al. demonstrated the feasibility of robot-assisted total prostatectomies at low insufflation pressure (8 mmHg) using the AirSeal® system [15]. Low-pressure insufflation is also being evaluated in other surgical areas. Therefore, Celarier et al. presented evidence of shorter hospital stay and decreased postoperative pain after laparoscopic colonic resection in a phase III randomized controlled trial evaluating the use of AirSeal at low pressure (7 mmHg) versus standard pressure (12 mmHg) [16]. Finally, specific data in the literature regarding the use of AirSeal® in RAPN is limited to the non-randomized prospective study of Annino et al. comparing standard insufflation with AirSeal® (at standard pressure of 12 mmHg) and reporting a benefit in terms of operating time, duration of renal ischemia, and rate of procedures without arterial clamping [17].

During the COVID-19 pandemic, the risk of contamination by surgical smoke, which may contain toxic gas but also viral pathogens, has been highlighted [18]. Their concentration within the abdominal cavity and the circulating insufflation gas result in a risk of aerosolization [19] and contamination of the operating theater and staff during laparoscopic procedures with or without robotic assistance [20]. This is especially significant in renal conservative surgery as SARS-COV-2 appears to have a capacity to bind to proximal convoluted tubules through its affinity for ACE2 receptors [20, 21]. This risk has led the EAU Robotic Urology Section (ERUS) committee to publish specific practice recommendations [22] advocating for the use of the lowest possible pneumoperitoneum pressure, active aspiration, and filtration of surgical smoke.

In this context, the P-NeLoP (partial nephrectomy in low pressure) trial aims to compare the effectiveness of AirSeal use at low pressure (7 mmHg), in terms of decreasing postoperative pain and therefore allowing fast re-autonomization of the patient, and its safety compared to its use at standard pressure (12 mmHg).

Design

Protocol overview

This is a two-arm, single blinded, prospective, multicenter randomized controlled trial that evaluates the impact of low insufflation pressure using AirSeal system (7 mmHg) during RAPN on post-operative pain, 24 h after surgery. We hypothesize that the use of AirSeal® at low pressure (7 mmHg) for RAPN would reduce post-operative pain, decrease the intake of analgesics, and thus facilitate patient re-autonomization. The study design is presented in Fig. 1.

Fig. 1
figure 1

Study flowchart. RAPN, robot-assisted partial nephrectomy; NRS, numeric rating scale. Medication Quantification Scale Version III [23]

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Study population and setting

This trial protocol is supported by the French research network on kidney cancer UroCCR (www.uroccr.fr; NCT03293563). Fifteen hospitals and clinics are involved in this multicentric study. The objective is to include 280 patients divided into two parallel groups: a control group undergoing surgery with a standard insufflation pressure (12 mmHg) and an experimental group undergoing surgery with a low insufflation pressure (7 mmHg), both using the AirSeal system. All adult patients managed for renal tumor and scheduled for transperitoneal RAPN are eligible for inclusion. The inclusion and exclusion criteria are summarized in Table 1.

Table 1 Inclusion and exclusion criteria
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This study was authorized and approved ethically by the Ouest I Ethics Committee on April 27, 2022 (ID-RCB: 2021-A03136-35), and is prospectively registered in the US National Library of Medicine Trial Registry (NCT number: NCT05404685).

Assessment of baseline characteristics and inclusion

Patient characteristics, including medical history, blood work, imaging (including RENAL [24] and PADUA [25] nephrometry scores), and clinical data, will be collected by the investigating physician during diagnostic work-up and included in the web-based shared clinical and biological national database on kidney cancer UroCCR.

During the inclusion consultation, the patient will be fully informed by the investigating physician on the research protocol and given information notes on the P-NeLoP research trial and the UroCCR network. An informed consent form will be signed by each patient participating in the research protocol (Appendix).

Randomization and blinding

Randomization will be performed just before surgery, with the patient being already under anesthesia. It will be conducted directly on the UroCCR database. After validation of the patient’s eligibility, the participant’s research number and the randomization result from the database, as well as the degree of insufflation, will be immediately communicated to the surgeon. The randomization list will be generated by the statistician at the Methodology and Data Management Center of the promoting hospital. The two groups will be balanced with a 1:1 ratio, and the randomization will be stratified according to the investigating centers. A detailed description of the analgesia habits of each center will be made at the beginning of the study.

A single blind will be applied. Patients will therefore not be informed of the group they have been allocated to.

Procedure

All surgeries will be performed via transperitoneal robot-assisted approach with the use of an AirSeal device. The pressure level will be adjusted at the beginning of the surgery, after placement of the ports, according to the randomization result. In the event of technical difficulties experienced by the surgeon that may be induced by low pressure during a procedure performed at 7 mmHg, the pressure can be increased to the standard pressure of 12 mmHg. This information will then be collected as described in the secondary objectives.

Intra- and post-operative follow-up

The follow-up does not differ from the standard follow-up after RAPN. Four post-operative follow-up time points will be set to collect the data needed for evaluation (Fig. 2).

Fig. 2
figure 2

Timeline. NRS, numeric rating scale

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During surgery, complications, type of clamping, operative time, volume of blood loss, changes in insufflation pressure, and duration as well as the plateau pressure and PETCO2 60 min after incision will be collected.

Post-operatively, we will record adverse events (according to Clavien-Dindo classification), presence of pain (according to the numeric rating scale (NRS)), and the use of analgesics (according to the Medication Quantification Scale Version III [23]), at H+6, H+24, and H+48. The return to eating, walking, and transit should also be noted. Finally, a first follow-up consultation is planned at day 30 (± 15 days) with collection of adverse events during the postoperative period.

Statistics

Calculation of the study size

We hypothesize that the average pain level measured at 24 h post-operatively by NRS will be 4.8 in the AirSeal® standard pressure group of 12 mmHg [11]. We also believe that the use of the AirSeal® device at a low pressure of 7 mmHg will decrease the mean pain by at least 0.8 points to 4.0 or less. With a common standard deviation of 2 [11], a power of 90%, an alpha risk of 5%, and a proportion of 5% missing or uninterpretable data, a total of 280 patients (140 patients per group) should be included (SAS® version 9.4, “Proc power” with a two-sided t-test on the difference in mean).

Data analysis

The data will be analyzed by the biostatistician of the promoting hospital. The analyses will be performed with the SAS® software (version 9.4 or later). The main analysis will be performed on an intention-to-treat basis (any missing value of the primary endpoint will be replaced by the value corresponding to the failure of management, i.e., the maximum NRS value for all groups combined). Secondary objectives will be analyzed on available data.

A descriptive analysis will be performed overall and by group. The primary endpoint (NRS at H+24 postoperative) will be compared between the two randomization groups without adjustment and then after adjustment for the center and the level of analgesia prescribed (1, 2, or 3) using a linear regression model. Tests on the primary endpoint will be performed with an α risk of 5%.

Trial status

The protocol number is ID-RCB: 2021-A03136-35, version no. 1.0 from 04/04/2022 promotor code: CHUBX 2020/62. The first inclusion was on October 4, 2022; the trial was scheduled to end around April 2024. The inclusion period is 18 months with 1 month of participation for the patient. The trial registration dataset can be found at https://clinicaltrials.gov/ct2/show/record/NCT05404685?term=NCT05404685&draw=2&rank=1.

Conclusion

In recent years, we have witnessed an increase in cases of small renal tumors for which RAPN is now the standard of care. This surgery allows a shortening of hospital stay and is even performed on an outpatient basis for selected patients. Post-operative pain management is essential to the completion of these care paths and to the early rehabilitation of the patient. The AirSeal system allows the reduction of the insufflation pressure of the pneumoperitoneum during these surgeries which could lead to a significant decrease in postoperative pain. The P-NeLoP trial will evaluate the efficacy and safety of this low insufflation pressure device on a prospective basis.