Prospective, randomized clinical trial comparing the useof a single-port device with that of a flexible endoscopewith no other device for transumbilical cholecystectomy:LLATZER-FSIS pilot study

Jose Noguera • Silvia Tejada • Carmen Tortajada •

Anna Sanchez • Jose Munoz

Received: 20 February 2013 / Accepted: 28 May 2013

� Springer Science+Business Media New York 2013

Abstract

Background Natural orifice transumbilical endoscopic

surgery (NOTES) is a technique still in experimental

development that requires clinical trials to assess its safety

and efficacy. We present a pilot prospective, randomized,

three-arm clinical trial of 1-year duration that was con-

ducted as a noninferiority trial comparing single-incision

laparoscopic surgery (SILS) and flexible single-incision

surgery (FSIS) with conventional laparoscopy for elective

cholecystectomy (NCT01558414).

Methods Sixty patients between aged 18 and 65 years

who were eligible for elective cholecystectomy were ran-

domly assigned in a 1:1:1 ratio (n = 20 per group): group

A (SILS), single-incision endoscopic surgery using a

transumbilical SILSTM device; group B (FSIS), single-

incision transumbilical surgery using a flexible endoscope;

and group C (CL), conventional laparoscopy. The main

outcome variable of the study was ‘‘parietal complica-

tions’’ (wound infection, bleeding, and ventral hernia). The

analysis was by intention to treat and attritions were not

replaced.

Results Cholecystectomy was performed in 100 % of the

cases; perioperative complications occurred in only 1.6 %

of the cases, and umbilical surgical wound infection in

3.33 %, with no differences between groups. After a min-

imum follow-up of 1 year, no differences were noted in the

frequency of parietal complications and no ventral hernias

occurred. Postoperative pain, hospital length of stay, and

downtime from work were similar in all three groups.

Surgical time was longer in cases in which a single-incision

transumbilical approach was used (58.95 min for SILS and

54.15 for FSIS vs. 49.21 for laparoscopy).

Conclusions Single-incision transumbilical approaches

are not inferior for safety or effectiveness compared with

conventional laparoscopy. The transumbilical approach

using a flexible endoscope is just as effective and safe as

the other two procedures and is a promising single-incision

approach.

Keywords FSIS � NOTES � SILS � Cholecystectomy �Laparoscopy � Minimally invasive surgery

During the past decade, advances in minimally invasive

surgery (MIS) have centered around two goals: increasing

the number of surgical conditions resolvable through lap-

aroscopy and minimizing surgical trauma. This second goal

led to the development of ‘‘minilaparoscopy,’’ natural

orifice transluminal endoscopic surgery (NOTES), and

single-incision endoscopic surgery.

NOTES comprises a variety of new endoscopic and

surgical entry points for accessing the abdominal cavity.

The technique may be considered a paradigm shift, but

although its feasibility and safety have been amply dem-

onstrated in clinical practice, it has been used infrequently

to date because questions remain regarding its safety and

certain technological limitations have not been overcome.

Nonetheless, the innovations that have resulted from

J. Noguera (&)

Unidad Terapias Mınimamente Invasivas, Servicio de Cirugıa

General, Consorcio Hospital General Universitario de Valencia,

C/ Tres Cruces, 2, Valencia 46014, Spain

e-mail: drjfnoguera@hotmail.com

S. Tejada � A. Sanchez � J. Munoz

Servicio de Cirugıa, Hospital Son Llatzer, Palma, Spain

C. Tortajada

Consorcio Hospital General Universitario de Valencia, Valencia,

Spain

123

Surg Endosc

DOI 10.1007/s00464-013-3044-y

and Other Interventional Techniques

research on NOTES have paved the way for the introduc-

tion of various ‘‘transitional technologies’’ whose purpose

has been to achieve MIS with the necessary effectiveness

and safety. At present, single-incision surgery is the most

attractive of these methods.

The most recent advances in endoscopic surgery have

laid the foundation for the development of a type of sur-

gical ‘‘fusion’’ based on previous experience with the use

of the flexible endoscope for NOTES [1–3] and on the new

umbilical approaches used for single-incision surgery [4].

This new approach represents a fusion between NOTES

and single-incision surgery, because the procedure is per-

formed through a single umbilical incision using a flexible

endoscope. The technique, known as flexible single-inci-

sion surgery (FSIS) [5], has several advantages compared

to single-incision laparoscopy and NOTES. Compared to

the NOTES-techniques, FSIS uses the navel so we have a

wide port to extract the specimen and the umbilical closure

is quick and easy. Compared to the SILS-techniques, FSIS

does not need to use a device for the entry ports and allows

us to continue the development of the use of the flexible

endoscope through and easy and short route to the gall-

bladder: the navel.

The objective of the present study was to assess whether

transumbilical single-port approaches and single-incision

approaches using a flexible endoscope are as safe and

effective as conventional laparoscopy (CL) for endoscopic

cholecystectomy, because few prospective studies have

compared these approaches and assessed whether the

umbilicus is an appropriate entry point for NOTES with the

use of a flexible endoscope (FSIS).

Materials and methods

This was a pilot, 1-year, prospective, randomized, clinical

trial with three study arms conducted to assess the effec-

tiveness and safety of different entry points for minimally

invasive cholecystectomy. The study included 60 patients

of both sexes randomized in a 1:1:1 ratio (n = 20 patients

per group). Each group underwent surgery using a different

endoscopic entry point: (A) transumbilical, single-incision

surgery with a single-port SILSTM device; (B) single-

incision transumbilical surgery using a flexible endoscope

(FSIS) and accessory parallel trocars; and (C) multiport

CL.

The trial was designed as a pilot study (20 patients were

considered enough to investigate the safety and effective-

ness for the new approaches, being aware that a prospective

clinical trial with 5 % complications in laparoscopy and

2.5 % in the other approaches may need more than 200

patients per arm) whose purpose was primarily to assess

whether both endoscopic approaches are equally safe and

effective, compared with CL, for performing cholecystec-

tomy. Hence, the main outcome variable was an effec-

tiveness variable. The conversion rate, captured by a

secondary outcome variable—surgical time—reflects the

difficulty of using one or the other technique. The safety

variable, ‘‘parietal complications,’’ was a composite vari-

able comprising surgical wound infection, bleeding, and

ventral hernia at entry points. Although 1 year follow-up is

enough to detect the early postoperative ventral hernia, the

patients would be followed for 2 years more to detect the

late parietal complications.

Randomization was conducted by the coordinating

center following the ‘‘complete cohort’’ method or com-

prehensive cohort design, with attention to age and per-

formance status (ASA). Recruitment began in April 2011

and ended in October of the same year, and all patients

were followed up for a minimum of 1 year.

The study was approved by the local research ethics

committee and is registered in the European clinical trial

registry offices (EUDRACT-2011-002672-16 and Clinical

trials.gov as no. NCT011558414).

Cholelithiasis patients at the outpatient clinic who

were on the waiting list for conventional cholecystectomy

and who met all the inclusion criteria and none of the

exclusion criteria were informed about the study and the

different types of surgery. Patients were randomized

following the Johns Hopkins Oncology Center’s Block

Stratified Randomization program. Data collected for

randomization included sex, age, ASA, and body mass

index (BMI).

The inclusion criteria were patients with symptomatic

cholelithiasis between the ages of 18 and 65 years who

were eligible for elective surgery, signed general informed

consent for surgical cholecystectomy and specific consent

for participation in the trial, and an anesthetic risk of ASA

I–II. The exclusion criteria were acute cholecystitis and/or

suspected involvement of the main biliary duct, presence of

pelvic inflammatory disease or endometriosis, and ASA III

or above.

The surgical procedures were performed under general

anesthesia. Antibiotic prophylaxis was administered using

amoxicillin?clavulanic acid (2 g intravenously), along

with prophylactic antiemetics. After surgery postoperative

analgesia was the same for all patients (paracetamol 1 g

intravenously every 8 h).

Surgical treatments were given below.

A) SILSTM (single-incision laparoscopic surgery):

patient in the modified lithotomy position, transumbilical,

craniocaudal skin incision measuring 2 cm in length, with

aperture under direct fascial observation and introduction

of specific multi-port device (SILSTM Port, Autosuture,

Covidien, USA). Next, insufflation to 14 mmHg to create

pneumoperitoneum and positioning of the instruments: an

Surg Endosc

123

assistant holding an 11-mm camera as the caudal port and

the main surgeon holding the articulated, flexible grasping

forceps in the left hand (SILSTM Clinch36, Autosuture,

Covidien) and, in the right hand, a straight, nonarticulating

forceps for dissection, electrocoagulation, clip placement,

and tissue cutting. Standard cholecystectomy was per-

formed with hilar exposure of the gallbladder; identifica-

tion of the main biliary duct; identification, ligation, and

section of the cystic duct and cystic artery between clips;

subserous cholecystectomy, from the cystic duct to the

fundus, with hemostasis of the vascular bed and lavage of

the cavity; extraction of the multiport device and of the

surgical specimen, protected within a plastic bag and

through the same incision; and closure of the fascia with

reabsorbable braided sutures and of the skin with reab-

sorbable intradermal sutures.

B) FSIS (flexible single-incision surgery): with the

patient in the same position and using the same type of skin

incision, a parietal aperture measuring \1 cm was created

at the umbilical disinsertion zone. The aponeurotic incision

was adjusted to allow entry of the double-channel gastro-

scope (videogastroscope 13806 PKS, Karl Storz, Tuttlin-

gen, Germany) and pneumoperitoneum was created

through one of the endoscope’s working channels. Subse-

quently two 5-mm trocars were introduced parallel to the

endoscope through the same skin incision, breaking

through the fascia at a different level from the main access

point. The main surgeon held the endoscope in the left

hand and the dissecting and electrocoagulation forceps in

the other hand while the assistant put traction on the gall-

bladder. Cholecystectomy was performed following the

same steps as in the previous group. The gallbladder also

was removed inside a protective bag, after joining the three

parietal incisions, when necessary, to facilitate extraction

and subsequent closure of the aponeurosis. Parietal closure

was conducted as in the previous group.

C) CL procedure (conventional laparoscopy): Minimally

invasive cholecystectomy through the conventional lapa-

roscopic approach using three ports (one 11-mm umbilical

port and two accessory 5-mm ports). Cholecystectomy and

extraction were conducted as in the previous groups, with

extension of the umbilical port of entry when required for

retrieval.

The main study outcome variable, ‘‘parietal complica-

tions,’’ was a composite variable comprising surgical

wound infection, bleeding, and ventral hernia at entry

points. The rest of the variables included in the analysis are

shown in Table 1. The analysis was by intention to treat

without replacement for attrition. The statistical analysis

was conducted with SPSS� software (v. 17.0 for Win-

dows�), using chi-squared and analysis of variance with

ANOVA and post-hoc tests.

Results

Table 2 shows the differences between the SILS, FSIS, and

CL groups.

Homogeneity between study groups

The mean age of patients in the different groups showed

homogeneity (SILS: 49; FSIS: 52; CL: 61 years; Table 2).

The sex distribution was similar, with 80–85 % women.

Mean BMI was 27.5, 26.4 and 32.3 in the SILS, FSIS and

CL groups, respectively. Although the age and BMI were

Table 1 Study variables

Abdominal wall complications

Surgical site infection

Bleeding

Postoperative ventral hernia

Postoperative pain: at 24 h, 7 days and 1, 6, and 12 months

Technical problems

Maneuvering the flexible endoscope

Performing hilar dissection or cholecystectomy

Intraoperative bleeding

Intraoperative bile leakage

Damage to the bile duct

Need to extend the entry port to remove the gallbladder

Need to convert to conventional laparoscopic or open surgery

Surgical time, hospital length of stay, downtime from work

Hospital readmission

General complications

Postoperative pneumonia

Urinary tract infection

Deep vein thrombosis, pulmonary embolism

Mortality

Table 2 Values of the generic variables studied

Variable Groups

CL SILS FSIS

Age (year) 60 ± 5 49 ± 4 52 ± 3

Sex (female %) 16 (80 %) 17 (85 %) 16 (80 %)

BMI (kg/m2) 30 ± 1 28 ± 4 26 ± 5

ASA I

ASA II

40 %

60 %

42 %

58 %

38 %

62 %

Values are expressed as mean ± standard error for quantitative

variables and as frequency (percentage within the group) for quali-

tative variables

CL conventional laparoscopy, SILS single-incision laparoscopic sur-

gery, FSIS flexible single-incision surgery using a flexible endoscope

Surg Endosc

123

higher in the CL group, there were no significant differ-

ences in age, sex, ASA anesthetic risk, or BMI.

Effectiveness of cholecystectomy

Cholecystectomy was equally effective in all three groups.

There was no conversion to CL in any of the cases.

Safety

There were no differences in patient safety (mortality,

intraoperative complications, and parietal complications)

across the three groups of patients who underwent chole-

cystectomy (Table 3). No differences in mortality, which

was zero, were noted. The main outcome variable, parietal

complications, was similar in the three groups (SILS: 0/20,

FSIS: 1/20, CL: 1/20). Superficial umbilical wound infec-

tion developed in two cases, one in a patient who under-

went FSIS and the other in a patient who underwent CL (2/

60, 3.33 %). During the minimum follow-up period of

1 year, no incisional hernias developed. One patient in the

CL group had an intraoperative complication consisting of

bleeding of the cystic artery. This was resolved through the

same laparoscopic approach.

Need to extend the port of entry

No statistically significant differences were found in the

final length of the aponeurotic incision; the average length

was 1.7 cm in the CL group, 1.9 cm in the FSIS group, and

2.0 cm in the SILS group (Table 4). There was no need to

extend the aponeurotic incision to remove the gallbladder

in the SILS group, the incision having measured 2 cm in

length from the start. The incision in the CL and FSIS

groups, originally 1.1 cm in length, did have to be extended

by 0.6 and 0.8 cm, respectively.

Surgical time

Surgery lasted a mean of 58.95 min in the SILS group,

54.15 min in the FSIS group, and 49.12 min in the CL

group (Table 4). There were no significant differences,

although it should be noted that both procedures require

4–8 min for correct umbilical entry and aponeurotic

closure.

Hospital length of stay

Some differences between groups reached statistical sig-

nificance. The study protocol called for a hospital length of

stay of at least 24 h for all patients, and 52 patients

(86.7 %) had a 1-day length of stay. Five required a 2-day

length of stay (n = 3 in the CL group; n = 2 in the SILS

group), and three required a 3-day length of stay (n = 3 in

the CL group). The patients included in the FSIS group

needed only a 1-day hospital stay. This proved to be sig-

nificantly different from the length of stay of the CL group

(Table 4).

Postoperative pain

Preoperative pain was assessed to eliminate patients who

scored 4 points or higher on the Visual Analog Scale

(AVS; Table 5). Postoperative pain was assessed at 24 h

postsurgery, at 7 and 30 days postsurgery, and at 6 and

12 months postsurgery. No significant differences in

postoperative pain were noted at any of the assessment

points.

Downtime from work

In all groups, patients were able to return to work 2 weeks

or more after the intervention, with the actual time it took

them to resume normal activity depending on their social

and occupational situation, as many of them did not have

continuous paid employment.

Cost of the procedure

Barring the depreciation cost of the flexible endoscope and

single-port devices, the cost of the procedure was very

similar across all groups. The mean cost of the procedure

was *1,600 ± 22 €, including surgical time, replaceable

materials, and complications. The differences between

groups are explained by the cost of each single-port device

(and whether or not there was any need to use additional

Table 3 Complications with the three approaches studied

SSI Bleeding Hernia Global

CL 1 (5 %) 1 (5 %) 0 2 (10 %)

SILS 0 0 0 0

FSIS 1 (5 %) 0 0 1 (5 %)

SSI surgical site infection

Table 4 Extension of entry ports and final incisional length

Variable Group

CL SILS FSIS

Port extension 0.6 ± 0.2 0.0 0.8 ± 0.2

Incision length 1.7 ± 0.2 2.0 ± 0.0 1.9 ± 0.2

Surgical time 49.2 ± 2 58 ± 3 54.3 ± 2

Hospital stay 1.5 ± 0.2 1.1 ± 0.7 1.0 ± 0.2*

Surgical time and hospital length of stay

Values are expressed as ‘‘frequency (percentage within the group)

* p \ 0.05 versus CL

Surg Endosc

123

replaceable articulated materials in each group) and by the

depreciation cost of the flexible endoscope.

Readmissions

No patient had to be readmitted to the hospital, and no

visits were paid to the emergency room for surgical wound

infection or other complications.

Discussion

The first description of NOTES was published by Kallo in

2004 [6]. He reported satisfactory outcomes after per-

forming peritoneoscopy and transgastric liver biopsy in a

pig model. Around the same time Rao and Reddy per-

formed peritoneoscopies and genital organ surgery using

flexible endoscopes inserted orally and were the first to

report transgastric appendectomy in humans. This gener-

ated widespread interest in the clinical application of

NOTES. The following year, several teams described

various techniques in animal models that stirred further

interest in the feasibility and reproducibility of NOTES.

Kaloo’s team [7, 8] reported satisfactory results with

transgastric tubal ligation and gastrojejunostomies, and

Thompson’s group [9] did the same after its experiences

with transgastric abdominal exploration and genital organ

resection. As for transgastric cholecystectomy, it was also

in 2005 that Swanstrom’s et al. [10] and Park’s et al. teams

[11] satisfactorily performed transgastric cholecystectomy

and cholecystogastrostomy using flexible endoscopes. In

early March 2007, the first transvaginal cholecystectomy

series was performed in four patients, on the foundations

laid down by previous experimental studies [12, 13].

Shortly after, Bessler et al. [14] successfully performed

hybrid transvaginal cholecystectomy through three lapa-

roscopic abdominal ports. In April 2007, Marescaux et al.

[15] performed the purest NOTES cholecystectomy in a

female patient through a single abdominal port. Subse-

quently, several teams contributed to the development of

transvaginal cholecystectomy, and cases and short series

began to accumulate [16–19].

The cholecystectomy technique described in the current

paper, which is known as FSIS, was designed on the

foundations of previous experience with transvaginal

NOTES and single-incision, single-port surgery. In previ-

ous experiences with this technique [5], cholecystectomy

has been achieved without the need to convert to CL and

with a very low rate of post-surgical complications. These

results are in line with the findings of this study.

The surgical time required to apply the FSIS technique

is longer than the time required for CL. It takes a mean of

*2 min to position the endoscope correctly and *3 min

to perform surgical maneuvers, such as freeing the gall-

bladder or the biliary pedicle from the peritoneum, with the

flexible endoscope. The SILS technique took longer than

CL and FSIS, because it required proper umbilical prepa-

ration at the aponeurotic aperture and because of the dif-

ficulty in obtaining correct exposure with traction

maneuvers. Correct closure of the incision used in SILS

also takes *5 min.

The three approaches proved equally effective for per-

forming cholecystectomy, and converting to another

approach was not necessary in any case. In terms of the

safety of the procedures, it is worth highlighting that no

differences were noted in mortality, general complications

or local complications at the entry ports. The most frequent

complication was superficial surgical wound infection at

the umbilical access site (3.33 %), but this was resolved

with local measures and no sequelae. Worth noting is the

fact that these local complications did not influence the

subsequent rate of ventral hernia, which was zero in the

entire series during the 1-year minimum follow-up period

observed for all patients. These results are in line with

those reported previously for other series [20, 21], although

there are some new papers reporting an alert about the

increase in trocar site hernia in single-port surgery [22, 23].

An international multicenter study [24] showed that when

different approaches (transgastric and transvaginal) are

combined and different surgical teams work together,

morbidity is somewhat higher, as high as 8.8 %, although

5.8 % were minor complications similar to those found in

the present study.

Single-incision umbilical techniques have not shown

lower rates of postoperative pain than CL, but patients

experience less surgical trauma of the abdominal wall

when they see a single scar, largely concealed inside the

umbilicus. These results are in keeping with the results of

previous published studies [25–27] in which postoperative

pain levels have been similar after CL and single-port

Table 5 Postoperative pain, as measured with the VAS (Visual Analog Scale)

VAS group 24 PO h 7 PO days 30 PO days 6 PO months 12 PO months

CL 1.53 ± 0.18 0.11 ± 0.07 0.22 ± 0.13 0.23 ± 0.23 0.00 ± 0.00

SILS 1.47 ± 0.19 0.11 ± 0.07 0.2 ± 0.16 0.00 ± 0.00 0.00 ± 0.00

FSIS 1.08 ± 0.08 0.17 ± 0.11 0.08 ± 0.08 0.00 ± 0.00 0.00 ± 0.00

Values are expressed as ‘‘mean ± standard error’’

Surg Endosc

123

surgery. The rates of conversions and of general and local

surgical wound complications have also resembled those

observed after laparoscopy.

The grouping of entry ports in an umbilical incision

entails problems of space between the optical device and

the surgical instruments, loss of triangulation, and diffi-

culty achieving proper tissue traction and surgical field

exposure. With the FSIS technique several of these prob-

lems are reduced because the instruments never touch the

optical device and the mobility of the laparoscopic ports is

not restricted. These ports can be freely moved about.

Since the two entry ports remain completely separate from

each other (no single-port device is used) and from the

optical device (flexible endoscope), the use of conven-

tional, nonarticulating, non-preshaped laparoscopic instru-

ments poses no problems. The gallbladder can be removed

through the same orifice used to introduce the endoscope,

or, alternatively, the different incisions can be merged if

necessary. The use of the flexible endoscope provides two

additional working channels for single-incision surgery,

which thereby becomes surgery with four potential chan-

nels. We think the use of the flexible endoscope with no

other device for transumbilical cholecystectomy is a

promising technique because it improves the freedom in

the surgeon’s hands, allows performing the procedure

without cost increment and provides the opportunity to

develop the use of the flexible endoscope for surgical

procedures.

In the present paper, the cost of the procedures was

similar across groups because the rate of complications did

not differ and surgical time varied little. If all of the

materials employed were reusable, including the flexible

endoscope and the precurved grasping forceps, the only

additional cost would be that of the single-port device used

in the SILS group. Despite our data the operative time is

much longer for single site surgery and the technique is

considered more expensive (considering the device and the

surgical time) in some recent publications [28–32] so the

single-port surgery is not recommended.

Hospital length of stay was shorter in the FSIS group

than in the CL group, but we do not believe that single-

incision surgery is associated with a shorter postoperative

stay, because this was not observed in the SILS group.

Delayed oral tolerance and pain not controlled with regular

analgesics explain why length of stay was longer in the CL

group. All patients spent 24 h in the hospital, as per the

study protocol. No postoperative readmissions or emer-

gency visits occurred during the study on account of

intervening problems.

After globally assessing all outcomes, it is reasonable to

conclude that the surgical approaches studied are as

effective and safe as CL and that the single-incision tran-

sumbilical approach with a single-port device (SILSTM) or

with the use of a flexible endoscope (FSIS) are reproduc-

ible techniques whose use for cholecystectomy shows no

increase in the rate of postoperative umbilical wound

problems.

Acknowledgments This work was partially subsidized by a grant

for ‘‘Projectes d’investigacio clınica i epidemiologica’’ [Clinical

medicine and epidemiological research projects] in the call for papers

for 2012 issued by the Direccio General d’Avaluacio i Acreditacio

(DGAVAL), with reference DGAVAL_ PI_018/11.

Disclosures Jose Noguera, Silvia Tejada, Carmen Tortajada, Anna

Sanchez and Jose Munoz have no conflict of interest or financial ties

to disclose.

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