Efficacy and Safety of a Novel Handheld Robotic Needle Holder Versus Conventional Instrument in Laparoscopic Ureterolithotomy: A Multicenter,Randomized,Single-Blind,Positive Parallel Controlled,and Noninferiority Clinical Trial

Abstract

Purpose:

This study aimed to validate the efficacy and safety of the HTH-1 handheld robotic needle holder versus conventional instrument in laparoscopic ureterolithotomy.

Methods:

This is a noninferiority clinical trial conducted in three hospitals. Patients were enrolled and randomly allocated into the experimental or control group on whom laparoscopic ureterolithotomy was performed with the ureteral incision sutured using the HTH-1 and conventional needle holder, respectively. The average suture time per stitch (STPS) of ureter was calculated as the primary efficacy indicator. Postoperative drainage volumes were recorded, and the instruments’ operating performance was subjectively evaluated and compared between groups. Adverse events occurred during the trial and interference of the instruments to the monitor were assessed as the safety indicators.

Results:

From April to September 2018, 50 patients were enrolled with 25 ones in each group. For the efficacy indicators, the noninferiority of the STPS was determined when the noninferiority margin was 40 seconds. The postoperative drainage volumes were not significantly different between groups. The instruments’ operating performance was rated as smooth in all cases of both groups. For the safety indicators, no adverse events or interference of the instruments to the monitor occurred during surgery in any case. Clavien 1 complications occurred in 7 (4 in the experimental group versus 3 in the control group, P = 1.000) patients after surgery.

Conclusions:

The HTH-1 is effective and safe and noninferior to conventional needle holder in laparoscopic ureterolithotomy. Adequate training and skills assessment are needed before application on patients.

Clinical trial registration:

The clinical trial registration was completed in Jiangsu Provincial Drug Administration (record number: Suxielinbei 20180018).

Introduction

Technological development brought about changes in surgical approach. In recent decades, minimally invasive surgery has been increasingly performed worldwide and actually benefited patients.^1,2 However, the laparoscopic or robotic techniques are associated with some inherent limitations. The limited degrees of freedom, fulcrum effect, and ergonomics issues of laparoscopy pose challenges to surgeons, especially intracorporeal suturing is technically difficult.^3,4 Surgical robot was developed to overcome these shortcomings, whereas the significant cost makes it unaffordable for some patients.⁵ The cumbersome system and lack of tactile feedback also partially limit its application.⁶ Handheld robotic or articulated instruments were developed to solve the problem combining some advantages of surgical robots and traditional laparoscopy.^7–10 They are typically featured with multi-degree-of-freedom (MDoF) movement, bedside setup, and cost economy. Wuhan University and Harbin Institute of Technology in China have cooperated to develop a handheld robotic needle holder and initially validated its efficacy in two previous studies.^11,12 This study represents, to our knowledge, the first clinical trial aiming to further determine the efficacy and safety of the system compared with conventional instruments in laparoscopic ureterolithotomy.

Materials and Methods

Study design

This is a randomized, single-blind, positive parallel controlled, and noninferiority clinical trial conducted in three university-affiliated teaching hospitals of Hubei province (protocol number: KD-B-001). This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the institutional review board of Zhongnan Hospital (approval number: Qilun 2017014) and also passed the ethics review in the other two centers. The clinical trial registration was completed in Jiangsu Provincial Drug Administration (record number: Suxielinbei 20180018). Written informed consent was obtained from all patients. They were randomly assigned into the experimental or control group in a 1:1 ratio, on whom laparoscopic ureterolithotomy was performed with the ureteral incision sutured using the handheld robotic needle holder and conventional needle holder, respectively.

Participants

Inclusion criteria

Each of the following criteria should be met for a patient to be considered for enrollment:

Adult patient aged ≥18 years;

At least one of the following four conditions is met:

–The patient with ureteral calculi who failed extracorporeal shockwave lithotripsy (ESWL), ureteroscopic lithotripsy (URL), or percutaneous nephrolithotomy (PNL);

–Ureteral calculi combined with other lesions of the ureter or adjacent tissues that need to be treated simultaneously;

–The stone is greater than 1.5 cm in diameter and the main investigators consider that multiple sessions of ESWL or URL may be required;

–The main investigators estimate that treatment through ESWL or URL will be difficult due to ureter twist and that laparoscopic surgery is suitable.

Exclusion criteria

Patients cannot be enrolled if any of the following criteria is met:

Coagulation dysfunction;

Use of anticoagulants 7 days before surgery;

Diabetic patients with preoperative morning fasting blood glucose >10 mmol/L;

Hypertensive patients with preoperative systolic pressure > 160 mmHg or diastolic pressure >95 mmHg;

Severe hepatic or renal insufficiency;

History of severe heart disease or cardiac function New York Heart Association （NYHA） class III or IV;

History of severe chronic obstructive pulmonary disease or bronchial asthma;

Installation of artificial heart or lung;

Use of wearable medical electronic devices;

Combined ureteral stricture requiring ureteroplasty;

Stroke within 6 months before surgery and imaging diagnosis of cerebral infarction or cerebral hemorrhage;

Other contraindications to anesthesia;

Pregnant women;

Patients who are participating in other clinical trials or considered unsuitable for the trial by main investigators.

Equipment

The HTH-1 handheld robotic needle holder (Suzhou Kangduo Robot Co., Ltd., Suzhou, China) was used in the experimental group (Fig. 1a).¹¹ The E705R laparoscopic needle holder (Johnson & Johnson Medical [Shanghai] Co., Ltd. Shanghai, China) was used in the control group.

FIG. 1.

The major components of the HTH-1 handheld robotic needle holder: the control box, the operating handle, the end instrument, and the clutch pedal (a) and the surgical scenario of laparoscopic ureterolithotomy using the system (b).

Surgery

The surgeries were completed by a major surgeon in each center. Each surgeon accepted previous dry- and wet-lab training of the HTH-1 and passed the skill test. Laparoscopic ureterolithotomy was performed via retroperitoneal approach (Fig. 1b).

Evaluation indicators

Efficacy indicators

The primary indicator was the average suture time per stitch (STPS) calculated by dividing the total ureteral suture time by the number of stitches. The secondary indicators included postoperative drainage volumes and the operating performance of the needle holder subjectively evaluated by operators using a four-level Likert scale.

Safety indicators

The safety indicators included the adverse events that occurred during the trial and the needle holder’s interference with the monitor or the display screen during surgery, the latter was evaluated by operators using a four-level Likert scale. Results of postoperative blood routine tests were also compared.

Sample size estimation

Combined with the results of a preliminary trial and statistical expert opinions, it was decided that the margin of STPS between groups δ = −40 seconds and the standard deviation of STPS σ = 48 seconds. According to the sample size estimation formula for noninferiority trials, the number of patients required for each group n = 2(Z₁₋ _α + Z₁₋ _β )² × σ²/δ² = 20.7 ≈ 21. With an estimated rate of 20% of withdrawal or loss to follow-up, at least 25 patients should be enrolled in each group.

Randomization and blinding

Randomization was performed using a sealed, light–tight envelope with an allocation ratio of 1:1. The statistician was blinded to the patient grouping.

Statistical analysis

Data management was conducted using the EpiData3.0 with double independent input. The statistical analysis was performed by an independent statistician using the SAS9.1.3 after data verification.

Statistical significance was determined atp < 0.05. The statistical methods used are described as follows:

Balance analysis: The demographic and baseline characteristics of the two groups were compared using the t test or the Wilcoxon rank sum test for measurement data, the Mann–Whitney U test for rank data, and the X² test or the Fisher’s exact test for count data.

Efficacy evaluation: The noninferiority evaluation was performed on the STPS.¹³ The Wilcoxon rank sum test was used for the comparison of postoperative drainage volumes and the Mann–Whitney U test for the instruments’ operating performance.

Safety evaluation: Comparisons of adverse events between groups were performed using the X² test or Fisher’s exact test.

Results

From April to September 2018, a total of 50 (18, 18, and 14 in each center, respectively) patients were enrolled with 25 ones in each group. Three patients (6%) of the control group were removed because of the change in treatment plan. The remaining 47 patients completed the study as required. Comparisons of the demographic and baseline characteristics of the two groups are presented in Table 1. Except for urinary WBC, no statistical differences were determined in other indicators. The operation time was comparable between the experimental group and the control group (139.36 ± 50.09 minutes versus 144.91 ± 71.45 minutes, P = .757).

Table 1.

Comparisons of the Demographic and Baseline Characteristics of the Two Groups

	Experimental group	Control group	P
n	25	22
Age (years)	50.36 ± 10.19	54.36 ± 12.35	.230
Sex (n)	Male (20), female (5)	Male (21), female (1)	.194
Hypertension (n)	8	4	.278
Diabetes (n)	2	1	.625
Other concomitant diseases (n)	9	5	.321
Preoperative vital signs
Heart rate (BPM)	75.40 ± 6.13	73.73 ± 8.79	.449
Respiratory rate (BPM)	18.72 ± 1.24	18.90 ± 1.23	.604
Systolic pressure (mmHg)	134.56 ± 12.11	129.45 ± 11.32	.142
Diastolic pressure (mmHg)	83.56 ± 8.17	78.82 ± 9.85	.078
Preoperative abnormal ECG	0	1	.468
Preoperative abnormal blood tests (n)
WBC	3	0	.237
RBC	2	0	.419
HGB	1	0	1.000
NEUT %	2	0	.419
PLT	0	0	1.000
ALT	0	0	1.000
BUN	0	2	.213
Cr	4	4	1.000
UA	3	2	1.000
ALB	1	0	1.000
Preoperative abnormal urine tests (n)^a
WBC	14	3	.003
RBC	7	6	.956
GLU	1	0	1.000
Ureteral stones
Diameter (cm), median (interquartile range)	1.60 (1.50 ～ 1.80)	1.60 (1.50 ～ 1.80)	.880
Location in ureter (n)	Upper (22), middle (3)	Upper (18), middle (4)	.553
Adjacent tissue lesions (n)	Yes (11), no (14)	Yes (9), no (13)	.831

Clinically significant abnormality.

ALB, Albumin; ALT, Alanine Aminotransferase; BUN, Blood Urea Nitrogen; CR, Creatinine; GLU, Glucose; HGB, Hemoglobin; NEUT, Neutrophil; PLT, Platelet; RBC, Red Blood Cell; UA, Uric Acid; WBC, White Blood Cell.

Efficacy indicators

Primary indicator

The mean STPS of the experimental group was shorter than that of the control group (186.50 ± 40.67 seconds versus 202.80 ± 46.87 seconds). The mean difference was −16.22 seconds and the 95% confidence interval (CI) was −41.92 ～ 9.49 seconds. The one-sided 95% CI (experimental group − control group) was thus in the range of −∞ ∼ 40.00 seconds, indicating that the experimental group was noninferior to the control group when the noninferiority margin was 40 seconds. The statistical significance was achieved (Table 2).

Table 2.

Comparisons of the Efficacy Indicators of the Two Groups

	Experimental group	Control group	P
STPS (seconds)^a
Mean value	186.50 ± 40.67	202.80 ± 46.87	<.0001
Mean difference (95% CI) (experimental group − control group)	−16.22 (−41.92 ～ 9.49)
	−16.22 (−41.92 ～ 9.49)
Postoperative drainage volume (mL), median (interquartile range)
Total volume	69 (42 ～ 120)	61 (49 ～ 95)	.873
3 days after surgery	55 (31 ～ 95)	40 (30 ～ 65)	.316
5 days after surgery	59 (37 ～ 107)	55 (42 ～ 90)	.725
Operating performance of the needle holder (n)	Smooth (25), less smooth (0), not smooth (0), fault (0)	Smooth (22), less smooth (0), not smooth (0), fault (0)	1.000

Suture time per stitch of ureter.

STPS, average suture time per stitch.

Secondary indicators

The total postoperative drainage volume and the drainage volume 3 and 5 days after surgery were not significantly different between groups. The operating performance of the needle holder was rated as smooth in all cases of both groups (Table 2).

Safety indicators

No adverse events or interference of instruments to the monitor or the display screen occurred during surgery in any case. Mild (Clavien 1) complications occurred in 7 (15%) (4 in the experimental group versus 3 in the control group, P = 1.000) patients after surgery, including fever, dizziness, palpitation and chest tightness, and wound pain. They were mostly related to the patients’ constitution and postoperative response but not directly to the operating instruments. All patients recovered after symptomatic treatment. No serious adverse events occurred. No clinically significant abnormality of postoperative blood routine tests occurred in both groups (Table 3).

Table 3.

Comparisons of the Safety Indicators of the Two Groups

	Experimental group	Control group	P
Intraoperative adverse events
Complications (n)	0	0	1.000
Damage to the patient (n)	0	0	1.000
Device fault (n)	0	0	1.000
Interfere of instruments to the monitor or the display screen (n)	None (25), a little (0), general (0), serious (0)	None (22), a little (0), general (0), serious (0)	1.000
Postoperative adverse events
Total number	4	3	1.000
Details (n)	Palpitation and chest tightness (1), fever (2), wound pain (1)	Dizziness (1), wound pain (2)
Outcome (n)	Recovered (4), unrecovered (0)	Recovered (3), unrecovered (0)	1.000
Postoperative abnormal blood tests (n)^a
WBC	0	0	1.000
RBC	0	0	1.000
HGB	0	0	1.000
NEUT %	0	0	1.000
PLT	0	0	1.000

Clinically significant abnormality.

Discussion

This study aimed to validate the efficacy and safety of the HTH-1 compared with conventional needle holder in laparoscopic ureterolithotomy.

The HTH-1 is effective and noninferior to conventional laparoscopic needle holder in laparoscopic ureterolithotomy. The mean STPS of the experimental group was noninferior to the control group and the postoperative drainage volumes were comparable. It indicates that the HTH-1 is effective, with which both the speed and quality of suture could be guaranteed. The operating performance of the HTH-1 was rated as smooth in all cases, which further demonstrated its operability. There exist some other MDoF laparoscopic instruments that were tested and proved to be effective by other investigators. The performance of the HandX^TM needle driver was compared with da Vinci® robot and standard laparoscopic instrument in inguinal hernia repairs and proved to be comparable inefficiency. The HandX^TM cases also had a lower cost versus robotic surgery.^14,15 Takazawa et al. developed an MDoF needle driver for use in infants and compared its performance with conventional instruments in in vivo experiments. They found no significant difference in needle grasping or handling time between groups.¹⁶

The safety of HTH-1 is also validated. No adverse events or interference of instruments to the monitor or the display screen occurred during surgery. The postoperative complications were mild and comparable between groups and not directly related to the operating instruments. Although the application of HTH-1 on patients can be safe, adequate preclinical training is necessary for surgeons to master the operation. The learning curve associated with MDoF laparoscopic instruments could be longer than conventional instruments due to the relative complexity of operations. We found in a previous study that novice surgeons took a longer time to achieve proficiency of the HTH-1 but the suture tension was lower after the learning curve compared with standard laparoscopic needle holder.¹² Uysal et al. declared in their study that laparoscopic novices felt overwhelmed by motorized articulating laparoscopic instruments, although they valued their additional degrees of freedom.⁴ Sánchez-Margallo et al. demonstrated the feasibility and safety of handheld robotic instruments in single-site laparoscopic surgeries in a porcine model but also stated the need of previous training.¹⁷ European Association of Endoscopic Surgery Executive Office distributed an online survey to its active members from different countries and found that training and skills assessment for the safe use of steerable laparoscopic instruments is lacking. The respondents stressed the need for specific hands-on training during which feedback and assessment of skills should be guaranteed before operating on real patients.¹⁸

The HTH-1 permits MDoF movement in restricted space in laparoscopic surgery, which may improve the dexterity and accuracy of suture and lead to better suture outcomes. This potential superiority was not fully evaluated in this trial due to the nature of the study. Sieber et al. found that a handheld robotic system was superior to conventional laparoscopy for suturing at difficult angles.¹⁹ A study of Bensignor et al. suggested that the use of a robotized needle holder improved both posture and the quality of laparoscopic sutures.⁹

Combining some advantages of surgical robots (e.g., the MDoF movement and the clutch function) and conventional laparoscopic instruments (e.g., convenience and cost-effectiveness), the HTH-1 could be a new choice in laparoscopic surgeries especially those demanding complex suture operations, such as pyeloplasty and prostatectomy. As a noninferiority trial, the statistical results are limited in demonstrating the superiority of the HTH-1. The operating performance of the system and the ureteral suture quality may not be fully reflected by subjective evaluation indicators or postoperative drainage volumes either. In future studies, we would further explore the system’s performance in more complex surgeries using more intuitive evaluation metrics or tools (e.g., electromyography for ergonomic assessment). Currently, the system only offers a needle holder as the end instrument and the force feedback after motor conversion is relatively unsatisfactory. These shortcomings remain to be improved.

Conclusions

The HTH-1 is effective and noninferior to conventional laparoscopic needle holder in laparoscopic ureterolithotomy. The safety of the system is also validated. Adequate training and skills assessment are necessary before application to patients.

Footnotes

Acknowledgments

The authors would like to thank their colleagues from the Department of Urology of Wuhan Central Hospital and Yichang Central People’s Hospital for their support in this study.

Authors’ Contributions

Z.W., K.Y., and X.W.: Project development, data analysis, and article writing/editing; Y.G. and Z.D.: Data collection, data analysis, and article editing. All authors read and approved the final article.

Disclosure Statement

The authors declare that they have no conflicts of interest.

Funding Information

The authors did not receive support from any organization for the submitted work.

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