Introduction
Gastrointestinal tract cancer represents the leading cause of cancer death worldwide,
with an estimated mortality over 1.75 million [1]. Early endoscopic detection and treatment of potentially curable cancers or precancerous
lesions could potentially lead to a reduction of gastrointestinal cancer incidence
and cancer related mortality [2]
[3]
[4]
[5]. In the past decades, endoscopic resection therapies have gradually improved and
gained more importance for premalignant lesions and noninvasive early cancers with
a low risk of lymph node metastasis. The survival after endoscopic removal of an early
cancer may be similar to that after surgical resection, providing the rationale for
this approach [6]
[7].
Resection-based modalities consist of endoscopic mucosal resection (EMR) and endoscopic
submucosal dissection (ESD). Injection-assisted EMR was first introduced in 1955 for
rigid sigmoidoscopy [8] and then in 1973 for flexible colonoscopy [9]. In the following years, improvements in the EMR techniques, such as cap-assisted
EMR and ligation method, have been introduced [10]
[11], and nowadays, EMR is a widely used and useful method to resect minimally invasive
benign and early malignant lesions of the gastrointestinal tract [12]. However, despite its efficacy, this method is sometimes associated with local recurrence,
especially when lesions larger than 40 mm are resected in a piecemeal fashion [13]. To overcome this limitation, ESD has been developed, allowing en bloc resection
of superficial neoplasms and providing better histopathological diagnosis and decreased
local recurrence rates [14]
[15]
[16].
Endoscopic resection techniques are aided by mucosal elevation through the injection
of a solution into the submucosal space. This technique may reduce complications,
such as perforation or bleeding and improve the technical feasibility of the procedure.
The volume of injected fluid is highly variable and depends on the size and location
of the lesion, and repeated injections may be needed for complete removal.
Several solutions have been used to lift the mucosal lesion, but the optimal solution
is still a matter of debate. It is accepted that the “ideal” solution for submucosal
injection should provide a thick submucosal fluid cushion, remain in the submucosal
space long enough to safely allow EMR or ESD, and preserve tissue specimens and allow
for precise pathologic staging.
In this setting, normal saline (NS) has been the most widely used solution as it is
simple to use and available at a low cost. However, the mucosal protrusion created
by the submucosal injection of normal saline solution is only maintained for a short
period of time. This may not have a significant impact on the removal of small lesions
but, when performing longer procedures or resecting larger lesions, the need for repeated
injections in order to maintain the cushion may become problematic and the risk of
perforation may be higher. In order to overcome these limitations and to improve the
technical feasibility of EMR and ESD, several solutions have been studied. Submucosal
injection of glucose solution, glycerol, sodium hyaluronate (SH), colloids, hydroxypropyl
methylcellulose, fibrinogen solution, autologous blood, and other alternatives have
been investigated in different contexts. Nevertheless, these solutions are also associated
with some caveats: they can be difficult to prepare or administer, available at a
high cost or not readily available, or may be associated with toxicity.
In the past few years, several substances with different properties have been studied
in ex vivo and in vivo studies. Among these, only a few have been evaluated in clinical
trials. At the present time, no definitive proof of the superiority of any solution
has been provided and there is no systematic review or meta-analysis on this topic.
Material and methods
We performed a systematic review and a meta-analysis to evaluate the effectiveness
and safety of existing solutions for submucosal injection in endoscopic mucosal resection
or dissection. This review was registered on the International prospective register
of systematic reviews, PROSPERO: CRD42014009577.
We considered all published randomized controlled trials for the quantitative synthesis.
We performed a separate analysis for ESD and EMR. For the overall qualitative synthesis,
we included non-randomized trials, and observational studies (cohort, case-control,
case series and case reports) evaluating the safety and effectiveness of submucosal
injection solutions, regardless of blinding and language.
For the primary outcome, we included studies with humans submitted to upper or lower
gastrointestinal endoscopy. For the secondary outcomes, we also included animal studies
(including ex vivo).
We included procedures where polypectomy, EMR or ESD were performed after the injection
of submucosal solutions had taken place, either in the esophagus, stomach, colon or
rectum.
Primary outcome
Complete resection of the lesion – histological determination of en bloc lesion free
margins or endoscopic determination of no residual lesion. Endoscopic determination
included the lack of residual lesion as reported by the endoscopist (with or without
chromoendoscopy) or the inclusion of resection marks in the resected specimen or negative
follow-up with tissue forceps biopsies from the resection site.
Secondary outcomes
Number of injections given; volume injected; duration of submucosal cushion; procedure
time; endoscopic complications; residual lesion at follow-up; tissue injury.
Search strategy
We individually searched MEDLINE and included all studies published until March 2014. The
electronic search was performed using the following key words: submucosal injection
AND (endoscopic AND resection OR EMR OR ER OR mucosectomy OR endoscopic submucosal
dissection OR ESD OR polypectom*) AND (solution* OR saline OR hyaluron* OR glycerol
OR hypertonic OR fibrinogen OR epinephrine OR adrenaline OR dextrose OR blood OR gelatin
OR jelly OR mannitol OR sodium alginate OR carboxymethylcellulose OR albumin OR succiny*
OR indigo OR methylene) AND (complete resection OR R0 OR adverse event* OR complication*
OR injection* OR volume OR duration).
Study selection
Two authors (AF, JM) independently scanned all titles and abstracts for relevance
by electronic search. A third author (JT) intervened in case of disagreement.
Data extraction
Data extraction was performed independently by two authors (AF, JM) using a data extraction
form to evaluate risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. Studies were classified as high risk, low risk or unclear risk of bias.
The end points were rate of complete resection (primary end point), number of submucosal
injections, total volume (mL) used, duration of submucosal cushion (min), procedural
time (min), rate of en bloc resection, incidence of endoscopic complications (perforation
and bleeding), recurrence rate at follow-up and incidence of tissue injury or fibrosis.
Data synthesis
We provide a description of the findings including a summary of the study’s results
by intervention.
We performed the analysis in STATA 13 (Stata Corp., Texas, United States) and the
flow diagram using Review Manager 5. We meta-analyzed the complete resection rate
and the incidence of adverse events (bleeding and perforation), using both random-effects
and fixed-effect meta-analyses but we only report the random-effects meta-analyses,
since the two methods concurred. We present odds ratios with a 95 % confidence interval.
Heterogeneity was assessed using the I
2 statistic. We produced a summary of findings table, rating the quality of evidence
of the primary outcome.
Results
The electronic search resulted in a total of 159 published manuscripts that were scanned
based on the title and abstract; 105 did not meet the inclusion criteria. The remaining
54 were assessed for eligibility using the full text articles and 11 were initially
included for quantitative analysis. The flow diagram is shown in [Fig. 1], and the details of the studies are shown in [Table 1].
Fig. 1 Flow diagram with the selected studies for the meta-analysis.
Table 1
Characteristics of the randomized controlled trials included in the meta-analysis.
|
Study (reference)
|
Country
|
n
|
Lesion size, mm
|
Intervention
|
Control
|
R0 A, %
|
R0 B, %
|
P value
|
|
Stomach (ESD)
|
|
Sumiyama et al. (2014) [17]
|
Japan
|
100
|
18.29
|
Mesna
|
NS
|
100
|
98.8
|
NS
|
|
Kim et al. (2013) [18]
|
South Korea
|
63
|
13.84
|
SH
|
NS
|
90.9[*]
|
61.1[*]
|
0.004
|
|
Stomach (EMR)
|
|
Yamamoto et al. (2008) [22]
|
Japan
|
140
|
5 – 20
|
SH
|
NS
|
92.8
|
94.3
|
0.745
|
|
Stomach and colon (EMR)
|
|
Varadarajulu et al. (2006) [24]
|
USA
|
60
|
22.5
|
D50
|
NS
|
96.3
|
80.0
|
0.09
|
|
Lee et al. (2006) [25]
|
South Korea
|
72
|
17.98
|
Fibrinogen
|
NS
|
86.1
|
80.6
|
0.53
|
|
Colorectal (EMR)
|
|
Kishihara et al. (2012) [21]
|
Japan
|
94
|
–
|
SH
|
NS
|
97.8
|
93.8
|
0.06
|
|
Yoshida et al. (2012) [20]
|
Japan
|
189
|
8.54
|
SH
|
NS
|
79.5
|
65.6
|
0.03
|
|
Fasoulas et al. (2012) [26]
|
Greece
|
49
|
46
|
HES
|
NS
|
96.0
|
95.8
|
0.94
|
|
Moss et al. (2010) [27]
|
Australia
|
80
|
37.5
|
SG
|
NS
|
90.0
|
90.0
|
1.0
|
|
Katsinelos et al. (2008) [23]
|
Greece
|
92
|
23
|
D50
|
NS
|
93.3
|
87.2
|
0.13
|
|
Hurlstone et al. (2008) [19]
|
UK
|
163
|
19.1
|
D50
|
SH
|
72.0
|
69.1
|
> 0.01
|
R0 A, complete resection rate in active group; R0 B, complete resection rate in control
group; ESD, endoscopic submucosal dissection; EMR, endoscopic mucosal resection; SH,
sodium hyaluronate; NS, normal saline; D50, 50 % dextrose; SG, succinylated gelatin.
* These proportions refer to clinical usefulness rate (complete resection within one
additional submucosal injection).
Since there were only two studies on ESD and with different solutions (Mesna and SH)
[17]
[18], a meta-analysis was not performed. In these studies, 53 lesions were randomized
to Mesna (vs NS) and 33 to SH (vs NS). There were 88 lesions randomized as controls.
In the Mesna RCT [17], Sumiyama and colleagues aimed to evaluate the procedural time with Mesna compared
to NS for gastric epithelial lesions. There was no statistically significant difference
in this outcome. There were no differences in other outcomes such as R0 resection
rate and adverse events (bleeding and perforation). Kim et al. [18] designed an RCT to compare SH to NS with “clinical usefulness” (a combination of
en bloc resection and the need for additional injection) as the primary outcome. They
randomized 76 gastric lesions and demonstrated a significant effect of SH in increasing
the usefulness rate (90.9 % vs 61.1 %; P = 0.004).
The nine EMR studies were all two-arm RCTs; eight of them used NS as the control group
and only one used SH as the control [19]. Three trials evaluated SH solutions [20]
[21]
[22], three trials evaluated D50 [19]
[23]
[24], and the others evaluated fibrinogen [25], hydroxyethyl starch (HES) [26], and succinylated gelatin (SG) [27].
The three studies that were excluded from the meta-analysis did not report the outcome
of interest [28]
[29]
[30].
Quality assessment of the nine RCT determined that six had a low risk of bias on the
generation of the randomization sequence and allocation concealment; six had kept
double blinding, while two studies failed to report adequate blinding of the subjects
and personnel, and one reported no blinding.
In the EMR studies, a total of 792 subjects and 793 lesions were included for analysis.
The majority were male patients (56.7 %) and their mean age was 63.6 ± 3.9 years.
Mean lesion size was 20.9 mm (range 8.5 – 46 mm).
After pooling, 209 lesions were randomized to SH (vs NS), 72 to D50 (vs NS), 82 to
D50 (vs SH), 43 to SG, 25 to HES and 36 to fibrinogen. In total, 385 were randomized
to NS as controls.
Six studies were performed on colorectal lesions, one on gastric, and two using both
gastric and colorectal lesions.
Meta-analysis results
Complete resection rate
All the nine studies included in the meta-analysis reported the resection efficacy
and explicitly provided the complete resection rate (either by endoscopic evaluation
or histological confirmation). The analysis results are shown as a forest plot in
[Fig. 2], with the studies having a low heterogeneity. The results indicate that the solution
used does not have a significant impact on the resection efficacy. However, most solutions
were only tried in one RCT which may limit the sensitivity to detect small effects.
SH is the best studied solution and was compared to NS in three RCTs (423 patients)
and the pooled results fail to suggest a difference between SH and NS with OR (95 %CI)
1.09 (0.82, 1.45). The overall plot indicates that the pooled results of the interventions
(SH, HES, SG, D50, and fibrinogen) were not superior to the comparator, which was
always NS with the exception of Hurlstone’s trial which compared D50 to SH with OR
(95 %CI) 1.07 (0.88, 1.29).
Fig. 2 Forest plot for complete resection (right side favors intervention).
Bleeding rate
All the studies reported the post-polypectomy bleeding rate. Even though the bleeding
definition was different across studies, the heterogeneity of the results was low.
The pooled results are shown in [Fig. 3]. No single solution was shown to be more effective in decreasing the post-polypectomy
bleeding rate but HES, SG, and fibrinogen have shown a non-significant favorable trend
against NS with a pooled OR (95 %CI) 0.59 (0.34, 1.01). Pooled results for SH suggest
that there is no beneficial effect on the bleeding risk when using this agent.
Fig. 3 Forest plot for post-polypectomy bleeding (left side favors intervention).
Post-polypectomy coagulation syndrome/perforation rate
Only four studies reported the occurrence of perforations or coagulation syndrome.
The results are shown in [Fig. 4]. There is only one RCT for each solution and none for SH. These studies were underpowered
to detect significant differences in this specific outcome but the pooled analyses
seem to suggest that NS may be effective in preventing perforations and coagulation
syndrome ([Fig. 5]) with an OR (95 %CI) 0.27 (0.06, 1.19), especially when compared to HES (OR 0.15;
95 %CI 0.007, 3.03) and D50 (OR 0.16; 95 %CI 0.02, 1.38).
Fig. 4 Forest plot for post-polypectomy coagulation syndrome/perforation (left side favors
intervention).
Fig. 5 Forest plot for post-polypectomy coagulation syndrome/perforation with specific solutions
compared with normal saline (left side favors intervention).
Other secondary end points
Due to the lack of data and heterogeneity of definitions, it was not possible to analyze
the other proposed end points, such as number of submucosal injections, total volume
(mL) used, duration of submucosal cushion (min), procedural time (min), rate of en
bloc resection, recurrence rate at follow-up, and incidence of tissue injury or fibrosis.
Descriptive analysis
This section will evaluate the 54 studies included in the systematic review in order
to assess the proposed outcomes. A summary of these studies is available in the Appendix.
Sodium hyaluronate (SH) solution is widely used as an endoscopic submucosal injection
material. It was first reported in animal models that the submucosal fluid cushion
created by SH persists for longer periods of time than other available submucosal
solutions [31]
[32]
[33]
[34]. Its efficacy in EMR and ESD was also reported in clinical practice. Using 0.4 %
SH as a submucosal injection solution in endoscopic resection enabled an effective
lifting of a colorectal intramucosal lesion, reducing the need for additional injections
[22]. Fujishiro et al. [35] reported that a mixture of a high concentration of SH and glycerine had good results
in ESD. SH was compared with NS in two randomized controlled trials that included
patients with colorectal lesion < 20 mm managed with EMR. Yoshida et al. [20] concluded that EMR using 0.13 % SH applied to colon lesions of less than 20 mm diameter
is more effective than NS for complete resection and maintenance of mucosal elevation,
since complete resection was achieved in 74 of 93 lesions (79.5 %) in the SH group
and 63 of 96 lesions (65.6 %) in the NS group (P < 0.05) and high mucosal elevation was maintained in 83.9 % of procedures in the
SH group and 54.1 % in the NS group (P < 0.01). Kishihara et al. [21] also reported the superiority of NS solution for the ease of submucosal injection
and snaring with less variability (P < 0.05). Finally, SH was compared to NS in a randomized controlled trial with gastric
lesions proposed for ESD and it was shown that the usefulness rate and the volume
of solution injected were significantly better in the 0.4 % SH group [18]. However, SH still faces some problems, namely its higher cost, requirement of an
air-sealed container for storage, and the conflicting data concerning stimulation
of tumor growth [36]
[37].
Sodium alginate is an inexpensive high viscosity solution. Eun et al. demonstrated
that mucosa-elevating capacity was comparable between 1 % sodium alginate solution
and 0.5 % SH solution [38]. It also showed greater elevation when compared to that created by NS solution [39]. In a clinical study, 0.4 % SH solution exhibited no significant difference in catheter
injectability but significant superiority in mucosa-elevating capacity over 0.6 %
sodium alginate solution, with no findings indicative of tissue injury. En bloc resection
was achieved in all cases, no adverse events were observed, and no case showed recurrence
[40]. Further investigation is needed on the usefulness of this material as a submucosal
injection solution for endoscopic procedures.
With regard to dextrose solution, in a prospective, uncontrolled clinical study, Katsinelos
et al. [41] first investigated the effectiveness of EMR using a hypertonic dextrose plus epinephrine
solution as a submucosal cushion agent for the resection of 59 large sessile colorectal
polyps, showing that 23/59 (39 %) were resected en bloc and 36/59 (61 %) in a piecemeal
fashion. Also, Varadarajulu et al. [24] compared D50 and NS for injection assisted resection of 52 sessile gastrointestinal
lesions. Compared with NS, lower volumes (median 2 vs 1 mL; P = 0.03) were required. Even after completion of resection, submucosal elevation persisted
in 36 % of the patients randomly assigned to D50 compared with 20 % of those randomized
to NS (P < 0.001). There were no significant differences in the rates of complete resection.
Later, Katsinelos et al. [23] performed a prospective, double-blind, randomized study that compared EMR of 92
sessile rectosigmoid lesions ( > 10 mm) using D50 plus epinephrine or NS plus epinephrine.
Injected solution volumes and number of injections were lower in the D50 group (P = 0.033 and P = 0.028, respectively). Submucosal elevation had a longer duration in the D50 group
(P = 0.043). This difference mainly included large (≥ 20 mm) and giant (> 40 mm) lesions.
There were 6 cases versus 1 case of post-polypectomy syndrome in the D50 and NS groups
(P = 0.01). Dextrose solution was also compared with SH [19] in a RCT including 174 patients. R0 resection was achieved in 59 of the 82 lesions
(72 %) in the dextrose group and in 56 of the 81 lesions (69 %) in the SH group (P > 0.1). Nevertheless, Fujishiro et al. [33] showed that injection of 20 % submucosal dextrose in an animal model was associated
with mucosal and muscle damage on the day of injection, with ulceration extending
to the submucosal layer within a week after injection.
Glycerol was first evaluated for mucosal elevation in porcine esophagus, showing a
longer disappearance time when compared with NS [34], and later in EMR of colorectal laterally spreading tumors (LSTs) [42]. In this clinical study, particularly for non-granular, laterally spreading tumors
(LST-NGs) < 20 mm, the glycerol group had a higher en bloc resection rate than the
NS group (P < 0.01), however a similar recurrence rate and complications were achieved and there
was no difference between en bloc resection for LST ≥ 20 mm.
Sodium carboxymethylcellulose is a water-soluble polymer derived from cellulose. In
vitro, the submucosal injection of sodium carboxymethylcellulose solution was able
to dissect by itself most of the mucosal layer from the muscular layer at a concentration
above 2.0 %. In vivo, three specimens were resected with 2.5 % sodium carboxymethylcellulose
without difficulty. There were no procedure-related complications and histologic examination
revealed no tissue damage [43].
Hydroxypropyl methylcellulose is a high viscosity agent that has been considered to
be a good and low cost option readily available in the United States. Its superiority
over NS solution in height and duration of mucosal elevation has been shown in animal
studies [31]
[32]. Further studies are needed to clarify the real benefits of this synthetic agent.
Photocrosslinkable chitosan in DMEM/F12 medium is a viscous solution that crosslinks
UV irradiation, resulting in an insoluble hydrogel. Photocrosslinkable chitosan hydrogel
injection led to a longer lasting elevation with clearer margins compared with NS
or SH solutions [44], and was useful when used in ESD [44]. Furthermore, photocrosslinkable chitosan hydrogel may contribute to the healing
of artificial ulcers after EMR and ESD [45], which makes it a promising agent for endoscopic procedures and it should be evaluated
in clinical trials after biocompatibility has been established.
Succinylated gelatin (SG) is a widely available, inexpensive, safe, colloidal solution
that exerts an oncotic pressure comparable with that of human albumin, with a favorable
safety profile. In an animal study [46], the mean EMR specimen dimension and surface area were significantly larger and
the duration of mucosal elevation was significantly longer for SG (P = 0.005). Three perforations were recorded, two with SG and one with NS (P = 1.0). However, these perforations occurred in the proximal porcine colon which
is thinner than distal porcine colon and human colon. The clinical efficacy of SG
was evaluated by Moss et al. in a randomized double-blind trial, conducted to compare
the performance of EMR with SG or NS for sessile lesions of the colon sized ≥ 20 mm
[27].
The “Sydney Resection Quotient” (defined as lesion size in millimeters divided by
the number of pieces to resect) was significantly different between groups, favoring
SG; fewer injections per lesion (P = 0.002), lower injection volume (P = 0.009), and shorter procedure duration (P = 0.006) were reported with the SG group. There was also a non-significant trend
towards higher en bloc resection rate with SG (30 % vs 15 %, P = 0.137). There were no perforations.
Mesna (sodium-2-mercaptoethanesulfonate [C2H5NaO3S2]) is a mucolytic agent that acts by cleaving disulfide bonds in proteins, thereby
breaking down the connective tissue between anatomical planes. A preliminary clinical
study that used submucosal mesna injection for ESD demonstrated the feasibility and
safety of the procedure [47]. In an animal study comparing it with NS, there were no differences between groups
related to ESD procedure time and en bloc resection, but mesna injection was associated
with a non-significant lower incidence of intraprocedural bleeding (P = 0.09) [48]. Recently, mesna solution was compared to NS in a randomized controlled trial and
it showed that ESD time was not significantly different between groups, but multivariate
analysis indicated that mesna reduced procedural challenges associated with submucosal
dissection [17].
Autologous blood is readily available at low cost. Previous human and animal studies
have demonstrated that autologous whole blood produced the longest durable cushion
compared with standard agents [49]. The feasibility of EMR with blood submucosal injection was also reported with no
complications [29]
[50]. Regarding tissue injury, a study has shown that blood produces less tissue injury
(measured as hydrops and tears) than NS [29]. However, some potential problems need to be clarified, namely the fact that autologous
blood could hamper the specialist’s view during the procedure and the possibility
for blood coagulation [51].
Other agents such as fibrinogen mixtures, poloxamers, and photocrosslinkable chitosan
have been reported for EMR with great enthusiasm. Compared with SH, fibrinogen mixtures
and poloxamer solutions are significantly less expensive but remain substantially
more expensive than NS [25]. A study that included EMR of 35 early gastric neoplasms showed that, after an initial
injection of fibrinogen mixture, additional submucosal injection was not required
for any lesion. The rates of en bloc resection and complete resection were, respectively,
82.9 % and 88.6 %. The en bloc resection rate was significantly lower for lesions
over 20 mm in diameter (60 % vs. 92 %; P < 0.05) and for lesions on the lesser curvature or posterior wall of the stomach
compared with those on the greater curvature or anterior wall (55.6 % vs. 92.3 %;
P < 0.05). During follow-up, recurrence was noted in only one patient in whom the lesion
had been resected piecemeal [52].
Later, the clinical efficacy of the fibrinogen mixture was evaluated in a RCT, comparing
it with NS in EMR of early gastric neoplasms [25]. This study did not show differences between the two groups in the rates of en bloc
resection and recurrence rate, but mean procedure time was significantly shorter in
the fibrinogen group and additional submucosal injection to maintain elevation of
the lesion was less frequently required in the fibrinogen group (P < 0.05). In addition, the use of fibrinogen mixtures for endoscopic resections still
needs to be critically considered with regard to their potential to transfer infections.
The poloxamer solution PS137 – 25 was studied in porcine models, comparing it with
NS and hydroxypropyl methylcellulose [53], showing greater height of the initial mucosal elevation and longer mucosal elevation.
Five EMRs were successfully performed after one injection of PS137 – 25, with no thermal
injury or perforations.
Recently, other alternatives have been presented. A novel injectable drug eluting
elastomeric biodegradable polymer (iDEEP) was developed to overcome the limitations
of previous solutions, using both viscosity and gel formation through redox initiated
crosslinking [54], and showing more durable cushions than those formed with NS and SH. Carbon dioxide
(CO2) was also tested as an injection agent. Uraoka et al. [55] performed an animal study that showed the safety and efficacy of CO2 as a satisfactory submucosal injection agent during ESD, the submucosal elevation
created by CO2 being longer than with either NS or sodium hyaluronic acid (P < 0.001). Creating and maintaining a CO2 submucosal cushion of sufficient elevation was achieved combined with partial physical
dissection of the submucosal layer, followed by complete endoscopic dissection of
the CO2 submucosal layer with ESD, resulting in successful en bloc resection with no complications.
Cook Medical’s (Bloomington, IN, United States) submucosal lifting gel consists of
a proprietary combination of known biocompatible components that appears to be a promising
safe and effective substance for submucosal injection. In an animal study, every injection
resulted in adequate mucosal lifting, with no evidence of perforation, bleeding, gel
extravasation through the serosal surface, or damage to surrounding tissue or organs
[56].
Discussion
EMR and ESD are minimally invasive endoscopic procedures now accepted worldwide as
a treatment modality in the removal of dysplastic and early malignant lesions limited
to the superficial layers of the gastrointestinal tract [6]
[7]. Endoscopic resection techniques are aided by mucosal elevation through the injection
of a solution into the submucosal space in order to reduce complications. In this
study, we tried to identify the best solution to use to lift the mucosal lesion. Our
primary outcome was to evaluate complete resection of the lesion. All studies included
in the meta-analysis [19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27] provided the complete resection rate. SH is the best studied solution, being compared
with NS in three RCTs [20]
[21]
[22]. The remaining solutions, namely fibrinogen mixture [25], hydroxyethyl starch [26], and succinylated gelatin [27], were only studied in one RCT each. Our study shows that the available evidence
does not allow a robust conclusion to be drawn on the solution’s effect on resection
rate (OR 1.07; 95 %CI 0.88, 1.29) and, particularly, there is no difference between
SH and NS (OR 1.09; 95 %CI 0.82, 1.45) ([ Fig.3]).
Regarding the complications, bleeding rate was reported in all studies, but the definition
of bleeding was different across studies. We found that no single solution was shown
to be more effective in decreasing the post-polypectomy bleeding rate, but HES, SG,
and fibrinogen have shown a non-significant favorable trend against NS. The post-polypectomy
coagulation syndrome/perforation rate was evaluated in four studies [19]
[23]
[26]
[27]. From the analysis, we infer that NS may have a beneficial effect in preventing
perforations and coagulation syndrome ( [Fig.5]) with an OR (95 %CI) 0.27 (0.06, 1.19), especially when compared to HES (OR 0.15;
95 %CI 0.007, 3.03) and D50 (OR 0.16; 95 %CI 0.02, 1.38). However, these are rare
events and a much larger sample size would be needed to determine a more precise effect
estimate.
In the descriptive analysis section, we analyzed several solutions with different
properties. Many solutions have been tested in animal studies and most seem more effective
for mucosal elevation than NS, without significant differences in complication rates.
We highlight that the superiority of these solutions must be evaluated in RCTs.
According to our results, no solution was proven to be superior in complete resection
rate, post-polypectomy bleeding, or coagulation syndrome/perforation incidence. We
emphasize the need for continuing research in this topic.
Potential biases and limitations
Our conclusions are limited by the small number of published RCTs and because there
are several solutions being evaluated and different control groups.
There is a potential bias in the analysis as many studies were not clear as to whether
they report the intention-to-treat (ITT) or the per protocol analysis. Also two of
the RCTs were not adequately blinded. The studies include lesions in the stomach,
in the colon or rectum, and the effect of the submucosal injection may be different
according to the anatomical site. In addition, the size of the lesions was quite different
between studies, ranging from 8.5 mm to 46 mm lesions (EMR studies) and this represents
a heterogeneous sample to pool.
We chose to consider complete resection as either endoscopic or histologically assessed
in the original studies even though they may not be perfectly correlated. In the adverse
event reporting, there were also a wide range of definitions for post-polypectomy
bleeding and some of the studies reported immediate and/or delayed bleeding rates,
while we counted the totals.
