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Review ArticleGastrectomy and D2 Lymphadenectomy forGastric Cancer: A Meta-Analysis Comparing the HarmonicScalpel to Conventional Techniques
Hang Cheng,1 Chia-Wen Hsiao,1 Jeffrey W. Clymer,1 Michael L. Schwiers,1
Bryanna N. Tibensky,2 Leena Patel,2 Nicole C. Ferko,2 and Edward Chekan1
1Ethicon Inc., 4545 Creek Road, Cincinnati, OH 45242, USA2Cornerstone Research Group, 204-3228 South Service Road., Burlington, ON, Canada L7N 3H8
Correspondence should be addressed to Jeffrey W. Clymer; jclymer@its.jnj.com
Received 18 February 2015; Revised 26 March 2015; Accepted 1 April 2015
Academic Editor: Kazuhiro Yoshida
Copyright © 2015 Hang Cheng et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The ultrasonic Harmonic scalpel has demonstrated clinical and surgical benefits in dissection and coagulation. To evaluate its use ingastrectomy, we conducted a systematic review andmeta-analysis of randomized controlled trials comparing the Harmonic scalpelto conventional techniques in gastrectomy for patients with gastric cancer. International databases were searched without languagerestrictions for comparisons in open or laparoscopic gastrectomy and lymphadenectomy.Themeta-analysis used a random-effectsmodel for all outcomes; continuous variables were analyzed for mean differences and dichotomous variables were analyzed forrisk ratios. Sensitivity analyses were conducted for study quality, type of conventional technique, and imputation of study results.Ten studies (𝑁 = 935) met the inclusion criteria. Compared with conventional hemostatic techniques, the Harmonic scalpeldemonstrated significant reductions in operating time (−27.5min; 𝑃 < 0.001), intraoperative blood loss (−93.2mL; 𝑃 < 0.001),and drainage volume (−138.8mL; 𝑃 < 0.001). Results were numerically higher for conventional techniques for hospital length ofstay, complication risk, and transfusions but did not reach statistical significance. Results remained robust to sensitivity analyses.This meta-analysis demonstrates the clear advantages of using the Harmonic scalpel compared to conventional techniques, withimprovements demonstrated across several outcome measures for patients undergoing gastrectomy and lymphadenectomy.
1. Introduction
Gastric cancer (GC) is the fourth most frequently occurringcancer in the world, with 989,600 new cases (8% of total) and738,000 deaths (10% of total) estimated worldwide in 2008[1, 2]. GC has a significant global burden, with a particularlyhigh incidence in Eastern Europe, South America, andEastern Asia [2, 3]. Several factors are associated with anincreased risk for GC, the most common including Heli-cobacter pylori infection and smoking [4, 5]. Until recently,the most common forms of GC were fundus and distalgastric cancers; however, there has recently been a shift to agreater prevalence of adenocarcinoma [3]. Current treatmentguidelines recommend the use of surgical gastric resection forthemanagement of resectable GC; however, there is variationbetween countries regarding the extent of lymphadenectomythat is performed alongside gastrectomy [1, 3, 6, 7].
Traditionally, hemostasis during gastrectomy has beenachieved using a variety of techniques, including suture liga-tion andmonopolar electrosurgery. However, the use of theseconventional techniques has been associated with severalchallenges. For instance, suture ligation not only is a time-consuming process, but is also associatedwith the risk of knotslipping [8]. Further, in monopolar electrosurgery, the hightemperatures (150∘C–400∘C) that result from using electricalenergy to cauterize the tissue can spread into neighboringstructures, increasing the risk of injuring surrounding tissue[8, 9].
Ultrasonic devices have been developed to address thechallenges associated with conventional hemostasis tech-niques. Through its design, the Harmonic scalpel simultane-ously cuts and coagulates tissue.Thedevice converts electricalenergy into mechanical energy, causing the blade to vibrate
Hindawi Publishing CorporationInternational Journal of Surgical OncologyVolume 2015, Article ID 397260, 11 pageshttp://dx.doi.org/10.1155/2015/397260
2 International Journal of Surgical Oncology
at a frequency of 55.5 kHz [9]. Simultaneous cutting andcoagulation of tissue are achieved by the high frequencyvibration of the blade, which generates stress and friction inthe tissue molecules. In turn, this disrupts hydrogen bondsand generates heat, causing protein molecules in the tissueto denature and adhere to one another, thereby forming ahemostatic seal. Importantly, no electrical current is passedthrough the patient, which reduces the risk of burns andinjury. Additionally, unlike monopolar electrosurgery, theHarmonic scalpel operates at lower temperatures, therebydispersing less energy to surrounding tissues and reducingthe risk of thermal damage [9, 10].
Several studies have demonstrated the clinical and sur-gical advantage of the Harmonic scalpel over conventionaltechniques in different surgical areas, including thyroidec-tomy [10–13], cholecystectomy [14, 15], and colectomy [16–19]. Furthermore, this device has been widely used in bothlaparoscopic and open surgeries [10]. More recently, a num-ber of randomized controlled trials (RCTs) have investigatedthe use of this device compared to conventional techniquesin gastrectomy [20, 21]. In this procedure, the Harmonicdevice is typically used for tissue dissection and sealing ofsmaller to moderately sized blood and lymphatic vessels,while hemoclips or surgical ties are used for major bloodvessels, such as the gastric or gastroepiploic vessels. Resultsfrom these studies demonstrate that the Harmonic scalpelcan significantly improve outcomes such as operating timein gastrectomy procedures. Further, comparison of ultrasonicdevices to conventional methods in a meta-analysis of RCTsand observational studies performed by Chen and colleagues[22] associated beneficial outcomes with ultrasonic scalpelsin open gastrectomy procedures.
Presently, there are no meta-analyses examining theexclusive impact of the Harmonic scalpel in gastrectomy.Consequently, this systematic review and meta-analysispaper was conducted to evaluate the performance of theHarmonic scalpel versus conventional techniques in bothopen and laparoscopic gastric surgery for patients withgastric cancer.
2. Methods
A systematic search of 21 databases was conducted, includingMEDLINE via PubMed, the Cochrane Central Registerof Controlled Trials (CENTRAL), EMBASE, and 18 othernational databases (Table 1). Comprehensive searches wereadditionally conducted using Google Scholar and Research-Gate. Reference lists of retrieved articles were hand-searched.No language restrictions were applied.
Specific inclusion criteria were defined according toPICOS (i.e., population, intervention, comparator, outcomes,and study design). Studies were considered eligible for inclu-sion if they were RCTs comparing the use of Harmonicsurgical devices to conventional methods, such asmonopolarelectrosurgery and suture, clips, or knot-tying (Table 2), inhuman subjects, for all types of surgery. Full-text studieswere then excluded firstly if they did not focus on eitheropen or laparoscopic gastrectomy for gastric cancer, secondly
Table 1: List of databases and search periods included in systematicsearch.
Databases Search datesEMBASEMEDLINE (via PubMed)CENTRAL
Until 30 September2013
LILACS and IBECSAfrican Index Medicus, Index Medicus forEastern and MediterraneanRegion, and Index Medicus for South-East AsiaRegion andTheWestern PacificRegion Index MedicusAfrican Journals OnlineIndMed (India)PakMediNet (Pakistan)Turk Tip Veri Tabani (Turkey)Krack (Croatia)SID and IrMedex (Iran)KoreaMed (Korea)
Conductedbetween 26 and 30September 2013
ICHUSHI-Web (Japan) Until 22 April 2013Wanfang, Cqvip, and CNKI (China) Until 16 April 2013
if they used advanced energy devices other than Harmonicdevices, and thirdly if they used the Harmonic device outsideof the cleared indication. In the Harmonic studies thatwere included, the Methods section had to identify thatthe Harmonic device was the principal device used for theprocedures. Records were evaluated for eligibility by twoindependent reviewers. Disagreements between reviewersregarding study inclusion were resolved through consensusor by consultation with a third reviewer.
For included studies, details (i.e., baseline characteristicsand outcomes) were extracted using a comprehensive dataextraction form. Data extraction was conducted by two inde-pendent reviewers with discrepancies resolved by consensusor a third party. The data from non-English articles weretranslated, extracted, and included in the form. One reviewerconducted the data extraction, which was cross-checked by asecond reviewer.
Clinical outcome measures included the following: (1)operating time, (2) intraoperative blood loss, (3) drainagevolume, (4) length of hospitalization, (5) transfusion risk,and (6) complication rate. When necessary, study authorswere contacted for additional methodological details regard-ing whether open or laparoscopic surgery was performed;however, study authors were not contacted for missing data.Missing variance data were calculated from other effectestimates and dispersion measures where feasible and appro-priate. Variance measures (i.e., standard deviation (SD))were not reported in one study [23] for operating timeor in another study [24] for drainage volume. Therefore,the missing variance measures were imputed according tothe standard methods outlined by Cochrane [25]. Anotherstudy reported all continuous outcomes as medians with 95%confidence intervals (CI) [26]; therefore, assuming a normaldistribution, the data were imputed using methods outlinedby Cochrane [25] and Hozo et al. [27].
International Journal of Surgical Oncology 3
Table2:Stud
yandbaselin
echaracteristicsfor
studies
meetin
ginclu
sioncriteria
.
Reference
Cou
ntry
Interventio
n𝑛
Age
(mean±SD
)%male
Surgery
Stud
ylength
(mon
ths)
Inclu
dedendp
oints
Choietal.,2014
[21]
Korea
Harmon
icscalpel
Mon
opolar
electriccoagulator
andclips
128 125
52.8±10.7
53.9±10.5
60.9%
64.8%
Gastre
ctom
ywith
D2
lymph
node
dissectio
n16
(i)Operatin
gtim
e(ii)Intraop
erativeb
lood
loss
(iii)Po
stoperativ
elym
phaticdrainage
(iv)P
ostoperativ
ecom
plication
Chen,2012[20]
China
Harmon
icscalpel(GEN
300)
Con
ventionaltechn
iques(kn
ot-ty
ing)
60 6058.9±19.3
65.0%
Distalradicalresectio
nof
gastr
iccarcinom
aand
lymph
adenectomy
25(i)
Operatio
ntim
e(ii)Intraop
erativeb
lood
loss
(iii)Drainagev
olum
e
Cuietal.,2012
[31]
China
Harmon
icscalpel(GEN
300)
Electro
surgery
31 3156.4±9.9
58.9±9.2
67.7%
58.1%
Gastre
ctom
ywith
D2
lymph
node
dissectio
n48
(i)Operatio
ntim
e(ii)B
lood
lossvolume
(iii)Po
stoperativ
edrainagev
olum
eofthe
first72
hours
(iv)L
engthof
posto
perativ
ehospitalstay
(v)C
omplicationrate
Inou
eetal.,2012
[26]
Japan
Harmon
icFo
cus
Electro
surgeryandkn
ot-ty
ing
30 3064
(41–79)∗
67(45–92)∗
70.0%
73.3%
Gastre
ctom
ywith
lymph
node
dissectio
ns(∗combinedresection
perfo
rmed
in6patie
ntsin
each
grou
p)
11
(i)Operativ
etim
e(ii)B
lood
loss
(iii)Po
stoperativ
edrainagev
olum
e(iv
)Postoperativ
ehospitalstay
(v)S
urgery-related
complications
(vi)Num
bero
ftransfusedpatie
nts
Liuetal.,2
010[29]
China
Harmon
icscalpel(GEN
300)
Electro
surgery
19 2162 64
63.2%
57.1%
Radicald
istalresectionof
gastr
iccarcinom
awith
D2
dissectio
n29
(i)Operatio
ntim
e(ii)B
lood
loss
(iii)Periton
eald
rainagev
olum
eofthe
first3days
Luetal.,2008
[24]
China
Harmon
icscalpel(GEN
300)
Mon
opolar
electrosurgery
26 2366
∗
62
∗
61.5%
56.5%
Distalradicalgastre
ctom
ywith
D2dissectio
n†11
(i)Leng
thof
operatingtim
efor
lymph
adenectomy
(ii)B
lood
lossin
lymph
adenectomy
(iii)Drainagev
olum
e
Tsim
oyiann
iset
al.,2002
[28]
Greece
Harmon
icscalpel
Mon
opolar
electrosurgery
20 2059±10
62±9
80%
75%
Gastre
ctom
ywith
D2
dissectio
n24
(i)Operativ
etim
e(ii)O
perativ
eblood
loss
(iii)Po
stoperativ
eabd
ominaldrainage
(iv)N
umbero
fpatientstransfused
(v)P
ostoperativ
ehospitalstay
(vi)Frequencyof
major
complication
Wangetal.,2010
[30]
China
Harmon
icscalpel(GEN
300)
Mon
opolar
electrosurgery
38 3061.8±21.5
60.30%
Laparoscop
icradicald
istal
D2gastr
ectomy
23(i)
Operatio
ntim
e(ii)Intraop
erativeb
leedingvolume
(iii)Po
stsurgery
3-daydrainage
volume
Wilh
elmetal.,
2011[23]
Germany
Harmon
icWaveU
ltrasou
ndDiss
ector
Electro
cautery,sutures,andligatures
100 101
66±12
64±12
60%
61.40%
Lefthemicolectomy‡
and
gastr
ectomywith
D2
lymph
adenectomy
24(i)
Durationof
operation
(ii)P
erioperativ
eblood
loss
(iii)Intraoperativ
ecom
plications
(iv)D
urationof
hospita
lstay
Xuetal.,2010
[32]
China
Harmon
icscalpel
Electro
surgeryandkn
ot-ty
ing
23 1961 64
60.90%
63.20%
Distalradicalgastre
ctom
ywith
D2dissectio
n18
(i)Operatio
ntim
e(ii)Intraop
erativeb
lood
loss
(iii)Po
stoperativ
edrainagev
olum
e∗
Age
repo
rted
asmedian(range).
†
Repo
rted
outcom
esthatinclu
dedon
lylymph
adenectomypatie
ntsw
eree
xcludedfro
mthea
nalysis
.‡
Repo
rted
outcom
esthatinclu
dedpatientsw
horeceived
hemicolectomyweree
xcludedfro
mthea
nalysis
.
4 International Journal of Surgical Oncology
Records identified through database searches:21 international databases and Google Scholar and ResearchGate:4,541 records identified
4,541 titles and abstracts reviewed
388 full-text articles reviewed
213 studies identified for all surgery types
10 studies included in meta-analysis
Reasons for exclusion:(i) Not a Harmonic device (n = 2,682)(ii) Not an RCT (n = 332)(iii) Not human subjects (n = 978)(iv) Outcomes reported not associated with device
performance (n = 21)(v) Duplicates (n = 528)
Reasons for full-text article exclusion:(i) Not an RCT (n = 59)(ii) Undefined manufacturer (n = 32)(iii) Not a Harmonic device (n = 26)(iv) Abstract only (n = 20)(v) Outcomes reported not associated with device
performance (n = 14)(vi) Not human subjects (n = 6)(vii) Publication unavailable (n = 8)
Reasons for further article exclusion (n = 203):(i) Surgical procedure not gastrectomy(ii) Harmonic device used outside of the
cleared indication
Figure 1: PRISMA diagram for the systematic literature review.
The quality of the included studies was assessed using therisk of bias algorithm outlined by the Cochrane guidelines[25]. Studieswere scored as having low, unclear, or high risk ofbias for the seven domains (sequence generation, allocationconcealment, blinding of participants and personnel, blind-ing of outcome assessment, incomplete outcome data, selec-tive outcome reporting, and other issues) in the assessmenttool. Final decisions were dependent on the combinationof these factors and the individual characteristics of eachstudy. Study qualitywas assessed by two independent authors,where disagreements were resolved through consensus or byconsultation with a third author.
The meta-analysis was performed using ReviewManager(Version 5.3, The Nordic Cochrane Centre, The CochraneCollaboration, Copenhagen, Denmark, 2014). Continuousvariables (operating time, intraoperative blood loss, drainagevolume, and length of hospitalization) were analyzed formean differences (MD) using the inverse-variance method.Dichotomous variables (transfusion risk and complicationrate) were analyzed for risk ratios (RR) using the Mantel-Haenszel method. A random-effects model was used for themeta-analysis and forest plotswere generated for all outcomeswithin Review Manager. Heterogeneity of the included stud-ies was assessed using the 𝜒2 test and 𝐼2 measure.
The primary analysis compared the Harmonic scalpel toconventional techniques. Sensitivity analyses were completedfor study quality, where studies with unclear or high risk
of bias across several measures were excluded [20, 26, 28],and for the type of conventional technique used, wherestudies using only monopolar electrosurgery (i.e., excludingsuture ligation) were included [24, 29–31]. Further, sensitivityanalyses were conducted by excluding any study outcomes forwhich imputed data were required.
3. Results
A total of 4,541 records were identified from database search-ing, of which 4,153 were excluded during the title and abstractreview (Figure 1). Of the 388 full-text articles retrieved forreview, 378 were further excluded if studies were non-RCTs,had an undefined manufacturer, and did not use a Harmonicdevice within the cleared indication, the publication wasunavailable and had nonhuman subjects, or the surgicalprocedure was not gastrectomy. Ten studies, consisting of atotal of 935 patients that reported on the use of Harmonicdevices in gastrectomy, were included in the meta-analysis[20, 21, 23, 24, 26, 28–32].
Study characteristics are presented in Table 2. Samplesizes of the included studies ranged from 40 to 253 patientsand study length ranged from 11 to 48 months. In all studies,Harmonic surgical devices (i.e., Harmonic scalpel, HarmonicWave, and Harmonic Focus) were compared to conventionaltechniques in gastrectomy. In five studies, the conventional
International Journal of Surgical Oncology 5
Table 3: Qualitative risk of bias assessment summary.
Study Sequencegeneration
Allocationconcealment
Blinding ofpersonnel andparticipants
Blinding ofoutcomes
Incompleteoutcome dataaddressed
Free of selectivereporting
Free of otherbiases
Choi et al., 2014 [21] Yes Unclear Yes Yes Yes Yes YesChen, 2012 [20] No Unclear Yes Yes Yes Unclear YesCui et al., 2012 [31] Yes Unclear Unclear Unclear Yes Yes YesInoue et al., 2012 [26] Unclear Unclear Unclear Unclear Yes Yes UnclearLiu et al., 2010 [29] Yes Unclear Yes Yes Unclear Yes YesLu et al., 2008 [24] Unclear Unclear Yes Yes Unclear Yes YesTsimoyiannis et al., 2002[28] Unclear Unclear Unclear Unclear Yes Yes Yes
Wang et al., 2010 [30] Unclear Unclear Yes Yes Unclear Yes YesWilhelm et al., 2011 [23] Yes Yes Yes Yes Yes Yes YesXu et al., 2010 [32] Unclear Unclear Yes Yes Yes Yes YesYes: low risk of bias; No: high risk of bias.
Low risk of biasUnclear risk of bias
High risk of bias
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other biases
0 25 50 75 100
(%)
Figure 2: Risk of bias assessment for studies meeting inclusion criteria.
method used was monopolar electrosurgery alone [24, 28–31]; four studies reported using monopolar electrosurgeryin combination with suture ligation or clips [21, 23, 26,32]; one study did not report the specific conventionalmethods used [20]. All studies performed lymphadenectomyalongside gastrectomy. Of the ten included studies, five wereChinese; however, patient characteristics were comparableacross all included studies. Operating time was reported innine studies [20, 21, 23, 26, 28–32] and eight studies reportedintraoperative blood loss [20, 21, 26, 28–32]. One study [24]reported operating time for lymphadenectomy patients onlyand was therefore excluded from this outcome. Nine studies[20, 21, 24, 26, 28–32] reported on drainage volume and threestudies reported the postoperative length of hospital stay[26, 28, 31]. Five included studies described the complicationrate for both treatment groups [21, 24, 26, 28, 31] and the ratefor blood transfusionswas reported in two studies [26, 28]. Ofthe 10 included studies, nine reported on open gastrectomyand one on laparoscopic gastrectomy.
Overall, the risk of bias varied across studies. The overallresults of the risk of bias assessments are presented in Figure 2and the results of the individual study quality assessments are
summarized in Table 3. Randomizationmethodwas reportedin four studies: two studies used a random permuted blockdesign [21, 23], one reported the use of a random numbertable [31], and one described the use of a lottery system[29]. Only one study [23] described concealment of therandomization sequence. One study [23] reported blinding ofpatients to the surgical technique. Of the nine studies that didnot report blinding, risk of performance bias was deemed lowin six studies [20, 21, 24, 29, 30, 32], where nonblinding wasassumed to have no impact on the outcomes assessed. Ninestudies reported all prespecified study outcomes; however,selective reporting remained unclear in one study [20].Attritions or exclusions were reported in two studies [21,23] but were assumed to have no clinical impact on theobserved effect size. In three studies, reporting of attritions orexclusions was insufficient [24, 29, 30].There were no patientwithdrawals in five studies [20, 26, 28, 31, 32]. Additional biaswas unclear in one study, as there was a reported difference insurgeon status between treatment groups (Harmonic group:40% residents versus conventional group: 56.7% residents)[26]. Studies generally reported positive results which could
6 International Journal of Surgical Oncology
Harmonic scalpel Study or subgroup
Mean SD Total8.1.1 Open
Chen, 2012 182.5 47.3 60Choi et al., 2014 89.3 15.6 128Cui et al., 2012 279.4 47.7 31Inoue et al., 2012 238.5 60.1 30Liu et al., 2010 110 15 19Tsimoyiannis et al., 2002 184 15 20Wang et al., 2010 137.8 31.5 38Wilhelm et al., 2011 199 51.2 50Xu et al., 2010 171.2 52.5 23
399Subtotal (95% CI)
399Total (95% CI)
Test for subgroup differences: not applicable
Conventional technique Mean SD Total
Weight
201.4 51.2 60 11.3%97.8 17.2 125 13.4%
322.6 45.5 31 10.1%300.5 60.7 30 8.5%165 20 21 12.6%190 18 20 12.7%
173.1 23.6 30 12.2%198 51.2 46 10.7%
202.8 47.9 19 8.6%382 100.0%
382 100.0%
Mean difference IV, random, 95% CI
Mean difference IV, random, 95% CI
0 100Favours Harmonic scalpel Favours conv. technique
200−200 −100
Heterogeneity: 𝜏2 = 416.24; 𝜒2 = 92.11, df = 8 (P < 0.00001); I2 = 91%
Test for overall effect: Z = 3.67 (P = 0.0002)
Heterogeneity: 𝜏2 = 416.24; 𝜒2 = 92.11, df = 8 (P < 0.00001); I2 = 91%
Test for overall effect: Z = 3.67 (P = 0.0002)
−18.90 [−36.54, −1.26]
−8.50 −12.55, −4.45][
−43.20 [−66.41, −19.99]
−62.00 [−92.57, −31.43]
−55.00 [−65.89, −44.11]
−6.00 [−16.27, 4.27]
−35.30 [−48.40, −22.20]
1.00 [−19.50, 21.50]
−31.60 [−62.00, −1.20]
−27.50 [−42.20, −12.81]
−27.50 [−42.20, −12.81]
Figure 3: Forest plot of meta-analysis results for operating time (minutes), stratified by open versus laparoscopic surgery.
Harmonic scalpel Study or subgroup Mean SD Total8.2.1 Open
Chen, 2012 Choi et al., 2014Cui et al., 2012 Inoue et al., 2012 Liu et al., 2010Tsimoyiannis et al., 2002 Wang et al., 2010 Xu et al., 2010
Subtotal (95% CI)
101.6 72.1 60267 146.4 128
231.9 59.1 31351 615 30220 20 19318 163 2091.3 33.4 3897.3 74.1 23
349
349Total (95% CI)
Test for subgroup differences: not applicable
Conventional technique Mean SD Total Weight
193.7 68.1 60 16.2%296.7 151.9 125 14.5%272.9 69.3 31 15.2%569.5 614.8 30 1.0%350 30 21 17.2%580 198 20 5.6%
189.5 54.7 30 16.5%186.1 67.4 19 13.6%
336 100.0%
336 100.0%
Mean differenceMean difference IV, random, 95% CIIV, random, 95% CI
0 250 500
Favours Harmonic scalpel Favours conv. technique
Test for overall effect: Z = 5.68 (P < 0.00001)Heterogeneity: 𝜏2 = 1497.31; 𝜒2 = 50.33, df = 7 (P < 0.00001); I2 = 86%
Test for overall effect: Z = 5.68 (P < 0.00001)Heterogeneity: 𝜏2 = 1497.31; 𝜒2 = 50.33, df = 7 (P < 0.00001); I2 = 86%
−93.15 [−125.29, −61.00]
−92.10 [−117.19, −67.01]
29.70 [−66.47, 7.07]−
−41.00 [−73.06, −8.94]
−218.50 [−529.68, 92.68]
−130.00 [−145.67, −114.33]
−262.00 [−374.40, −149.60]
−98.20 [−120.47, −75.93]
−88.80 [−131.64, −45.96]
−93.15 [−125.29, −61.00]
−250−500
Figure 4: Forest plot of meta-analysis results for intraoperative blood loss (mL), stratified by open versus laparoscopic surgery.
result from a publication selection bias; however, funnel plotsdid not indicate any clear omission of negative studies.
3.1. Operating Time. Mean operating time was statisticallysignificantly reduced by 27.50 minutes (95% CI: −42.20 to−12.81; 𝑃 = 0.0002; 9 studies; 𝐼2 = 91%) with theHarmonic scalpel in contrast to conventional methods inopen gastrectomy (Figure 3). All results were reported foropen gastrectomy.
3.2. Intraoperative Blood Loss. Results demonstrated that,with the Harmonic scalpel, mean intraoperative blood losswas statistically significantly reduced by 93.15mL (95% CI:−125.29 to −61.00; 𝑃 < 0.00001; 8 studies; 𝐼2 = 86%) in opengastric resection (Figure 4). All results were reported for opengastrectomy.
3.3. Drainage Volume. Compared to conventional tech-niques, mean drainage volume was statistically significantlyreduced (MD = −138.83mL; 95% CI: −177.57 to −100.10;𝑃 < 0.00001; 9 studies; 𝐼2 = 94%) with the Harmonic
scalpel (Figure 5). The study device also showed significantreductions in drainage volume in open surgery (MD =−134.36mL; 95% CI: −172.86 to −95.87; 𝑃 < 0.00001; 8studies; 𝐼2 = 94%). While a subgroup analysis for studiesusing laparoscopic surgery was not performed due to limiteddata, the results from the primary analysis and open surgerysubgroup analysis were in line with those from the singlestudy that conducted gastrectomy laparoscopically [24].
3.4. Length of Hospital Stay. On the basis of the three studiescomparing the Harmonic scalpel to conventional techniquesin open gastrectomy, no statistically significant differencesin the postoperative length of hospitalization were observed(MD = −0.63 days; 95% CI: −2.48 to 1.23; 𝑃 = 0.51; 3 studies;𝐼2
= 65%) (Figure 6). All results were reported for opengastrectomy.
3.5. Blood Transfusion. Results demonstrated a lower riskof blood transfusions with the Harmonic scalpel than withconventional methods, although not statistically significant(RR of 0.68; 95% CI: 0.38 to 1.19; 𝑃 = 0.18; 2 studies; 𝐼2 = 0%)(Figure 7). All results were reported for open gastrectomy.
International Journal of Surgical Oncology 7
Harmonic scalpel Conventional techniqueStudy or subgroup
Mean SD Total Mean SD Total8.3.1 Open
Chen, 2012 293.7 121.6 60 533.2 134.5 60Choi et al., 2014 1,486.3 926.8 128 1,566.8 1,321.4 125Cui et al., 2012 195.2 73.2 31 273.5 56.9 31Inoue et al., 2012 48 92.7 30 40.5 79.3 30Liu et al., 2010 165 20 19 250 15 21Tsimoyiannis et al., 2002 480 242 20 985 602 20Wang et al., 2010 95.3 12.6 38 201.2 13.2 30Xu et al., 2010 282.7 102.6 23 741.8 214.3 19
336349Subtotal (95% CI)
8.3.2 LaparoscopicLu et al. 2008 226 632.3 26 712 632.3 23
2326Subtotal (95% CI)Heterogeneity: not applicable
359375 Total (95% CI)
Mean difference Weight
IV, random, 95% CI
Mean difference
IV, random, 95% CI
15.4% 1.7%
17.3% 15.7% 19.4% 1.7%
19.6% 8.0%
98.9%
1.1% 1.1%
100.0%
0 500Favours Harmonic scalpel Favours conv. technique
1000−1000 −500
−486.00 [−840.75, −131.25]−486.00 [−840.75, −131.25]
−138.83 [−177.57, −100.10]
−239.50 [−285.38, −193.62]
−80.50 [−362.35, 201.35]
−78.30 [−110.94, −45.66]
7.50 [−36.15, 51.15]
−85.00 [−96.05, −73.95]
−505.00 [−789.35, −220.65]
−105.90 [−112.09, −99.71]
−459.10 [−564.19, −354.01]
−134.36 [−172.86, −95.87]
Heterogeneity: 𝜏2 = 1984.25; 𝜒2 = 127.90, df = 8 (P < 0.00001); I2 = 94%
Test for overall effect: Z = 7.02 (P < 0.00001)Test for subgroup differences: 𝜒2 = 3.73, df = 1 (P = 0.05), I2 = 73.2%
Heterogeneity: 𝜏2 = 1927.69; 𝜒2 = 123.39, df = 7 (P < 0.00001); I2 = 94%
Test for overall effect: Z = 6.84 (P < 0.00001)
Test for overall effect: Z = 2.69 (P = 0.007)
Figure 5: Forest plot of meta-analysis results for drainage volume (mL), stratified by open versus laparoscopic surgery.
Harmonic scalpel Conventional technique Study or subgroup
Mean SD Total Mean SD Total Weight
8.4.1 OpenTsimoyiannis et al., 2002 9.3 4.3Inoue et al., 2012 12 4.7Cui et al., 2012 8.5 0.9
Subtotal (95% CI)
20 12.5 5.5 20 21.4%30 12.5 4.6 30 28.2%31 8.1 0.6 31 50.4%
100.0%8181
Total (95% CI) 100.0%81 81
Test for subgroup differences: not applicable
Mean difference
IV, random, 95% CI
Mean difference
IV, random, 95% CI
0 5Favours Harmonic scalpel Favours conv. technique
10
−3.20 [−6.26, −0.14]
−0.50 [−2.85, 1.85]
0.40 [0.02, 0.78]
−0.63 [−2.48, 1.23]
−0.63 [−2.48, 1.23]
Heterogeneity: 𝜏2 = 1.74; 𝜒2 = 5.72, df = 2 (P = 0.06); I2 = 65%
Test for overall effect: Z = 0.66 (P = 0.51)
Heterogeneity: 𝜏2 = 1.74; 𝜒2 = 5.72, df = 2 (P = 0.06); I2 = 65%
Test for overall effect: Z = 0.66 (P = 0.51) −5−10
Figure 6: Forest plot of meta-analysis results for length of hospital stay (days).
3.6. Postoperative Complications. Themain reported compli-cations for both study groups included postoperative bleed-ing, chylous leakage, gastrointestinal paralysis, and woundinfection. The Harmonic scalpel reduced the risk of postop-erative complications compared to conventional techniques,although not significantly so (RR = 0.58; 95% CI: 0.33 to 1.02;𝑃 = 0.06; 5 studies; 𝐼2 = 12%) (Figure 8). Similar results wereobserved between the open surgery subgroup and the singlestudy reporting on laparoscopic gastric resection.
Sensitivity Analyses. Results of sensitivity analyses on studyquality were similar to the primary analysis and wererelatively robust to variables tested with some exceptions.For operating time, intraoperative blood loss, and drainagevolume, results remained statistically significantly lower withthe Harmonic scalpel in all sensitivity analyses (Table 4).Also, when studies with a higher risk of bias were removed, itis interesting to note that the Harmonic scalpel significantlyreduced the risk of postoperative complications compared toconventional techniques (𝑃 = 0.03). For hospital length ofstay and transfusion risk, there were an inadequate numberof studies to conduct a full meta-analysis for some sensitivity
variables. Additionally, results of the primary analysis wereinsensitive to whether or not conventional methods focusedsolely on monopolar electrosurgery or when the imputedresults by Wilhelm et al. [23], Lu et al. [24], and Inoue et al.[26] were excluded for operating time, drainage volume, orall continuous variables, respectively.
4. Discussion
Given the challenges associatedwith conventional hemostatictechniques in gastric surgery, advanced devices that can over-come these drawbacks and improve surgical outcomes maybe preferred. This meta-analysis assessed the performance ofthe Harmonic scalpel compared to electrosurgery or sutureligation in gastrectomy. The breadth of the systematic searchwas quite extensive, with a large quantity of international,national, and regional databases searched.
The findings of the meta-analysis support the benefit ofusing the Harmonic scalpel in surgery, with a significantreduction in operating time, drainage volume, and intraop-erative blood loss, in comparison to conventional methods.Although no significant differences between groups were
8 International Journal of Surgical Oncology
Table4:Summaryof
prim
aryandsensitivityanalyses.
Operatin
gtim
e(min)
(MD[95%
CI])
Intraoperativ
eblood
loss(m
L)(M
D[95%
CI])
Drainagev
olum
e(mL)
(MD[95%
CI])
LOS(days)
(MD[95%
CI])
Com
plications
(𝑛)
(RR[95%
CI])
Patie
nttransfu
sions
(𝑛)
(RR[95%
CI])
Prim
aryanalysis
−27.50(−42.20,−12.81)
−93.15
(−125.29,−
61.00)
−138.83
(−177.5
7,−100.10)−0.63
(−2.48,1.23)
0.58
(0.33
,1.02)
0.68
(0.38,1.19)
Sensitivityanalyses
Exclu
ding
“lower”q
uality
studies∗
(Tsim
oyiann
isetal.,
2002
[28],C
hen,
2012
[20],
andInou
eetal.,2012
[26])
−28.66(−49.47,−7.8
5)−79.20(−118
.09,−40
.32)−126.00
(−161.9
2,−90.08)
Toofewstu
dies
(<2)
toinform
0.41
(0.18
,0.92)
Toofewstu
dies
(<2)
toinform
Onlymon
opolar
electro
surgery(i.e.,
exclu
ding
suture
ligation)
−45.15
(−58.96,−31.33
)−91.59(−137.55,−45.62)
−93.55(−114
.08,−73.02)
Toofewstu
dies
(<2)
toinform
Toofewstu
dies
(<2)
toinform
Toofewstu
dies
(<2)
toinform
Exclu
ding
impu
teddata
(Inou
eetal.,2012
[26],
Wilh
elm,2011[23],andLu
etal.,2008
[24])
−27.62(−43.84,−11.41)
−91.92(−124.39,−
59.45)
−157.39(−196.50,−
118.27)−1.0
7(−4.53,2.40)
0.58
(0.33
,1.02)
0.68
(0.38,1.19)
CI:con
fidence
interval;LOS:leng
thof
stay;MD:m
eandifference;RR
:rela
tiver
isk.
∗
Lower
quality
study
defin
edas≥4“unclear”o
rone
“No”
listedin
anyris
kof
bias
assessmentcategory.
International Journal of Surgical Oncology 9
Harmonic scalpel Conventional technique Study or subgroup
Events Total Events Total Weight
8.6.1 Open6 30 8 30 37.3%7 20 11 20 62.7%
100.0%50 50 Subtotal (95% CI) 1913 Total events
100.0%50 50 Total (95% CI) 1913 Total events
Test for subgroup differences: not applicable
Risk ratio M-H, random, 95% CI
Risk ratio M-H, random, 95% CI
0.75 [0.30, 1.90]0.64 [0.31, 1.30] 0.68 [0.38, 1.19]
0.68 [0.38, 1.19]
0.01 0.1 1Favours Harmonic scalpel
10Favours conv. techniques
100
Heterogeneity: 𝜏2 = 0.00; 𝜒2 = 0.08, df = 1 (P = 0.78); I2 = 0%
Test for overall effect: Z = 1.35 (P = 0.18)
Heterogeneity: 𝜏2 = 0.00; 𝜒2 = 0.08, df = 1 (P = 0.78); I2 = 0%
Test for overall effect: Z = 1.35 (P = 0.18)
Inoue et al., 2012Tsimoyiannis et al., 2002
Figure 7: Forest plot of meta-analysis results for patient transfusion risk.
Harmonic scalpel Conventional techniqueStudy or subgroup
Events Total Events Total Weight
8.5.1 Open13.3%125101282Choi et al., 201427.0%318315Cui et al., 2012
Inoue et al., 2012 65
3020
59
3020
24.0%Tsimoyiannis et al., 2002 32.1%
206209Subtotal (95% CI) 96.4%3218Total events
8.5.2 LaparoscopicLu et al. 2008 0 26 2 23 3.6%
3.6%2326Subtotal (95% CI)20Total events
Heterogeneity: not applicable
100.0%229235Total (95% CI)3418 Total events
Risk ratio
M-H, random, 95% CI
Risk ratio
M-H, random, 95% CI
0.20 [0.04, 0.87]0.63 [0.23, 1.70]1.20 [0.41, 3.51]
0.56 [0.23, 1.37] 0.60 [0.32, 1.10]
0.18 [0.01, 3.52] 0.18 [0.01, 3.52]
0.58 [0.33, 1.02]
0.01 0.1 1 10 100Favours Harmonic scalpel Favours conv. technique
Heterogeneity: 𝜏2 = 0.09; 𝜒2 = 3.88, df = 3 (P = 0.27); I2 = 23%
Test for overall effect: Z = 1.64 (P = 0.10)
Test for overall effect: Z = 1.13 (P = 0.26)
Heterogeneity: 𝜏2 = 0.05; 𝜒2 = 4.56, df = 4 (P = 0.34); I2 = 12%
Test for overall effect: Z = 1.89 (P = 0.06)Test for subgroup differences: 𝜒2 = 0.61, df = 1 (P = 0.44), I2 = 0%
Figure 8: Forest plot of meta-analysis results for total complication rate.
observed for other outcome measures, results numericallyfavored the Harmonic scalpel for reducing length of hospitalstay, transfusions, and postoperative complications.Themainreported complications for both study groups included post-operative bleeding, chylous leakage, gastrointestinal paraly-sis, and wound infection. Results for all outcome measuresremained relatively consistent when subgroup and sensitivityanalyseswere conducted,which restricted included studies bytype of conventional device, type of surgery, and data impu-tation of results, highlighting the robustness of the findings.However, sensitivity analyses excluding lower quality studiesproduced a significant reduction in the risk of complicationswith the Harmonic scalpel. Methods outlined by Cochrane[25] were used to evaluate the quality and potential bias of theincluded studies. Results showed that the quality of includedstudies was acceptable overall, with fairly low risk of bias.
A more general meta-analysis by Chen et al. [22]compared the use of ultrasonic scalpels to conventionaltechniques in gastrectomy, providing evidence that these
devices can reduce operating time and intraoperative bloodloss, without compromising patient safety. Chen et al. [22]conducted analyses using both randomized and observa-tional studies. The results of our meta-analysis confirm thefindings of this published study, addmore recent data, includeonly RCTs, and exclusively assess Harmonic scalpel usein gastrectomy. Our findings are also aligned with severalmeta-analyses that evaluated the efficacy and safety of thisultrasonic device in patients undergoing thyroid surgery [10,12]. In the recent analysis of thyroidectomy by Contin et al.[12], the Harmonic scalpel significantly reduced operatingtime, blood loss, and postoperative drainage compared toother hemostatic techniques, demonstrating the clear benefitsacross surgical areas [10]. Furthermore, evidence demon-strates that the favourable outcomes associated with theHarmonic scalpel can translate into cost-savings for hospitalinstitutions [33, 34].
Although all the studies included within this analysisperformed gastrectomy plus D2 lymphadenectomy, it is
10 International Journal of Surgical Oncology
important to note that the extent of lymphadenectomyperformed alongside gastric resection differs between coun-tries and institutions [7]. While some suggest that a lessextensive D1 lymphadenectomy is the minimum standardfor gastric cancer, this is not universally implemented inlower incidence countries (e.g., United States). Conversely, inEastern Asia, where nearly half of gastric cancer cases occur,D2 lymphadenectomy is typically the standard procedureperformed. Prospective studies in both the East and Westhave shown that less extensive lymphadenectomies likelyresult in understaging of patients and increased locoregionalrecurrence; yet the effect on overall survival is more chal-lenging to determine. Further randomized studies inWesternpatients are required in order to make conclusions regardingthe survival benefits of D2 lymphadenectomy.
This study does have limitations. First, not all data wereavailable to inform variance inputs for the meta-analysis. Inorder to overcome this, imputationmethods and assumptionsoutlined by Cochrane were utilized [25]. Sensitivity analysesexcluding outcomes with imputed data showed that resultsremained similar to the primary analysis. Second, since theheterogeneity between studieswas significant for themajorityof the meta-analyses, a random-effects model was used topool all outcome data. Third, data were not available from allstudies for each of the included outcomes to be statisticallycombined in this meta-analysis, and four of the studies hadless than 50 subjects. Therefore, some outcome results maynot be as rigorous due to small sample sizes. Additionally,not all studies reported the rate of total postoperative com-plications; therefore the total rates included in the meta-analysis represent an addition of individual complicationsreported in the studies. Last, because the authors did not haveaccess to the study protocols of the included publications,there is potential for some variation in the study quality.The exclusion of lower quality studies in sensitivity analysesproduced a significant reduction in the risk of postoperativecomplications; however, this exclusion did not impact allother outcomes. Furthermore, this study should be viewedas representative of outcomes for open gastrectomy, sinceonly one of the ten studies was performed laparoscopically.The single laparoscopic study did not evaluate operative time,blood loss, hospital stay, or patient transfusion risk. Exclusionof the laparoscopic study did not have a substantial impact onthe parameters that were measured therein, namely, drainagevolume and total complication rate.
In summary, the findings of this study hold practicalimportance. Reductions in blood loss may translate into alower clinical burden for patients. Relevant to physiciansand economic stakeholders, reductions in resource use havepotential cost implications for hospitals. For example, reduc-tions in intraoperative blood loss can decrease the need forblood loss management resources, such as expensive bloodproducts, and hemostatic agents. Further, several studies haverevealed the high costs associated with operating time [35–37]; hence the use of time-saving devices in surgery canlead to substantial savings. Essentially, products that requirefewer people and less steps aremore time-cost efficient.Thesesavings in operating time and other resources (e.g., reducedhospital stay) can help to offset the product acquisition cost.
However, there is still a need for further costing studies tofully elucidate this impact of resource aversion on potentialcost savings.
5. Conclusions
The Harmonic scalpel is an effective surgical techniquecompared to conventional methods in gastrectomy and lym-phadenectomy. It offers several clinical advantages, includingreduced operating time and blood loss, which can ultimatelybenefit the surgeon, patient, and hospital, without the addi-tion of safety concerns.
Conflict of Interests
Hang Cheng, Chia-Wen Hsiao, Jeffrey W. Clymer, MichaelL. Schwiers, and Edward Chekan are employees of Ethicon,Inc., manufacturer of the Harmonic Scalpel. Bryanna N.Tibensky, Leena Patel, and Nicole C. Ferko are employeesof Cornerstone Research Group, who were sponsored toperform this study by Ethicon, Inc.
Acknowledgment
This work was supported by Ethicon, Inc., manufacturer ofthe Harmonic scalpel, that provided funding to conduct theanalysis and prepare the paper.
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