There have been few developments in the technical aspects of thyroid surgery since the surgical approach described by Kocher greater than a century ago [
The Harmonic Scalpel (Ethicon Endosurgery, Cincinnati, Ohio) was introduced into the surgeon’s armamentarium almost two decades ago. Using mechanical vibrations at 55.5 kHz, this device is able to cut and coagulate tissue simultaneously. The proposed advantages of using this device over traditional electrocautery include less lateral thermal tissue injury, a lack of neuromuscular stimulation, and the avoidance of electrical energy transmission either to or through the patient [
Over the last decade, many reports have evaluated the utility of the HS for thyroid surgery and the majority of these studies have been carried out at European centers. The investigators have shown similar results regarding reduced operative times with its utilization, but conflicting results regarding other postoperative outcomes such as transient postoperative hypocalcemia and recurrent laryngeal nerve dysfunction (RLND). These complications are relatively uncommon and the number of cases reported in individual studies is limited. Consolidating the data may allow for elucidation of significant associations between HS utilization and postoperative complications. To date, no meta-analysis evaluating the utilization of HS in thyroid surgery has been reported. The purpose of this study was to determine whether conventional hemostasis (CH) or the HS results in shorter operative times for thyroidectomy and to evaluate the incidence of postoperative complications with each approach.
We sought to identify prospective, randomized clinical trials comparing HS to CH methods (i.e., ties, clips, and/or electrocautery) for thyroidectomy utilizing a computerized literature search. We searched the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE (January 1, 1995 to September 30, 2008), using the following index terms: thyroidectomy, thyroid surgery, harmonic scalpel, harmonic shears, ultrasonic shears, ultrasonic scalpel, ultrasonic coagulator, ultrasonic dissector, ultrasonic dissection, ultrasonically activated scalpel, ultrasonic scissors, and coagulating shears. In addition, we reviewed the reference lists of retrieved articles, contacted experts in the field, and contacted the major manufacturer of the HS (Ethicon Endosurgery) to determine if they were funding or aware of any trials being conducted using their product. We also searched the proceedings of major endocrine surgery conferences for any reported trials that may not have been published. All studies were considered relevant irrespective of publication status or the language of publication.
We restricted our study to adults older than 18 years of age. Only studies comparing traditional open thyroidectomy utilizing CH techniques to thyroidectomy using the HS were considered. Any studies evaluating video-assisted or endoscopic thyroidectomy were excluded. Studies where additional procedures were carried out at the time of thyroidectomy (e.g., lateral neck lymph node dissection) were also excluded, unless these additional procedures were accounted for by subtracting the time for the added procedure from the overall operative time. Thyroid surgery for either benign or malignant histology was included.
The principal outcome evaluated was the mean operative time, measured in minutes, for total or subtotal thyroidectomies carried out utilizing the two surgical techniques. Although studies could include a combination of total and subtotal thyroidectomies and thyroid lobectomies, they were excluded if they did not report a mean operative time specifically for the total and subtotal thyroidectomies. The secondary outcomes we evaluated were the incidence of transient postoperative RLND and hypocalcemia. Transient RLND was not well defined in most studies. One study defined RLND as transient if vocal cord function recovered within twelve months of the operation [
To be included, studies had to be prospective, randomized clinical trials and observational studies were not included in the analysis. Clearly blinding is not feasible in studies evaluating two different surgical techniques, though it was noted if assessors of the postoperative outcomes were blinded to the intervention.
Regarding data collection and analysis, the two authors (AM and SMW) independently assessed the titles and abstracts of studies retrieved from the literature search and obtained full articles for all those that appeared to satisfy inclusion criteria, ultimately including those that met inclusion criteria after in depth review. The data from those studies were extracted independently by the authors, and any differences were resolved by discussion. The following information was abstracted for each study: year of publication, language of publication, country of origin, study design (including details on randomization, blinding, allocation concealment, intention-to-treat analysis, and losses to follow-up), provision of industrial support for the study, reason for ineligibility if the study was ultimately excluded, number of patients enrolled in each study arm, indication for thyroidectomy, type of thyroidectomy carried out (e.g., partial versus total versus subtotal), details regarding type of HS and CH utilized (ties versus clips versus electrocautery), mean operative time for total and subtotal thyroidectomies in each group, number of cases of transient and permanent postoperative hypocalcemia (either symptomatic or biochemical), number of cases of postoperative transient or permanent RLND, and number of cases of postoperative hematoma formation. Study validity is presented qualitatively though no formal validity score was assigned.
For the primary outcome, the meta-analysis evaluated the weighted mean difference in operative times between thyroidectomy groups (HS versus CH) and the standard deviation of the difference from individual studies using the METAN command in STATA 9.2 (StataCorp, College Station, Texas). In one study, the data regarding operative times was not reported as a mean with standard deviation, but after correspondence with the authors, the data was provided in such a format as to allow inclusion in the analysis [
For the secondary outcomes of postoperative RLND and hypocalcemia, results are presented as risk ratios (RRs). The fixed effects model was utilized to obtain the summary estimates of the logRR from the group of studies. We did not proceed to a random effects model once the fixed effects analysis did not reveal any significant heterogeneity (Q statistic).
Publication bias was assessed with Begg’s and Egger tests and Begg’s funnel plot [
Thirty-four studies that potentially met inclusion criteria were identified from the literature search. After abstract screening, 19 were excluded for variety of reasons. Of the 15 that were reviewed in depth, 6 were excluded, leaving 9 studies that were incorporated into the meta-analysis. Figure
Characteristics of included studies.
Mean OR | |||||||||||
Author | Year | Country | Industry | CH | # | Time (min) for | Transient | Permanent | Transient | Permanent | Postoperative |
funding | techniques | patients | TT/ST (SD) | RLND | RLND | hypocalcemia | hypocalcemia | hematoma | |||
Hallgrimsson [ | 2008 | Sweden | No | Electrocautery | CH = 24 | CH = 168.8 (4.8) | CH = 1 | CH = 0 | CH = 7 | CH = 1 | CH = 0 |
ligatures clips | HS = 27 | HS = 134.7 (5.6) | HS = 4 | HS = 0 | HS = 5 | HS = 0 | HS = 0 | ||||
Lombardi [ | 2008 | Italy | No | Electrocautery | CH = 100 | CH = 75.2 (23.5) | CH = 1 | CH = 0 | CH = 29 | CH = 0 | CH = 1 |
ligatures | HS = 100 | HS = 53.1 (20.7) | HS = 2 | HS = 0 | HS = 28 | HS = 0 | HS = 1 | ||||
Yildirim [ | 2008 | Turkey | No | Electrocautery | CH = 54 | CH = 105 (16) | CH = 5 | CH = 1 | CH = 7 | CH = 1 | CH = 0 |
ligatures | HS = 50 | HS = 77.9 (12.5) | HS = 1 | HS = 0 | HS = 6 | HS = 1 | HS = 0 | ||||
Kilic [ | 2007 | Turkey | No | Electrocautery | CH = 40 | CH = 57.8 (12) | CH = 0 | CH = 0 | CH = 5 | CH = 0 | CH = 0 |
ligatures | HS = 40 | HS = 47.1 (8.2) | HS = 1 | HS = 0 | HS = 2 | HS = 0 | HS = 0 | ||||
Miccoli [ | 2006 | Italy | Yes | Electrocautery | CH = 50 | CH = 46.7 (10.8) | CH = 0 | CH = 0 | CH = 16 | CH = 0 | CH = 0 |
ligatures | HS = 50 | HS = 40 (6.8) | HS = 0 | HS = 0 | HS = 5 | HS = 0 | HS = 0 | ||||
Frazzetta [ | 2005 | Italy | No | Electrocautery | CH = 60 | CH = 96 (17) | CH = 2 | CH = 0 | CH = 6 | CH = 0 | CH = 0 |
ligatures | HS = 60 | HS = 56 (18) | HS = 1 | HS = 0 | HS = 4 | HS = 0 | HS = 0 | ||||
Cordon [ | 2005 | Mexico | Yes | Electrocautery | CH = 12 | CH = 136 (37) | CH = 0 | CH=0 | CH=9 | CH=0 | CH = 0 |
ligatures clips | HS = 7 | HS = 104 (29) | HS = 1 | HS = 0 | HS = 3 | HS = 0 | HS = 0 | ||||
Ortega [ | 2004 | Spain | No | Ligatures | CH = 57 | CH = 101 (16) | CH = 1 | CH = 0 | CH = 6 | CH = 0 | CH = 2 |
HS = 57 | HS = 86 (20) | HS = 2 | HS = 0 | HS = 5 | HS = 0 | HS = 0 | |||||
Defechereux [ | 2003 | Belgium | No | Electrocautery | CH = 17 | CH = 96.5 (28.9) | CH = 0 | CH = 0 | CH = 4 | CH = 0 | CH = 0 |
Ligatures clips | HS=17 | HS = 70.7 (18.3) | HS=0 | HS=0 | HS=1 | HS=0 | HS=0 | ||||
TOTAL | CH = 414 | CH = 10 | CH = 1 | CH = 89 | CH = 2 | CH = 3 | |||||
HS = 408 | HS = 12 | HS = 0 | HS = 59 | HS = 1 | HS = 1 |
CH: conventional hemostasis; OR: operative; HS: harmonic scalpel; TT: total thyroidectomy; ST: subtotal thyroidectomy; SD: standard deviation; RLND: recurrent laryngeal nerve dysfunction.
Flow diagram showing the number of studies initially identified and the reasons for study exclusion.
Regarding the primary outcome of mean operative time, the pooled estimate of the weighted mean difference (WMD) in operative time obtained from a random effects model was 23.1 minutes (95% CI = 13.8, 32.33). This was statistically significant, with a
Forest plot depicting individual and pooled weighted mean difference (WMD) in operative times with 95% confidence intervals.
Begg’s funnel plot with pseudo 95% confidence limits.
Regarding secondary outcomes, the pooled estimate and 95% confidence interval of the relative risk of postoperative transient RLND from a fixed effects model was 1.25 (
Forest plot depicting individual and pooled risk ratios (RRs) with 95% confidence intervals (CIs) for transient postoperative recurrent laryngeal nerve dysfunction.
The pooled estimate and 95% confidence interval of the relative risk of postoperative transient hypocalcemia from a fixed effects model was 0.69 (
Forest plot depicting individual and pooled risk ratios (RRs) with 95% confidence intervals (CIs) for transient postoperative hypocalcemia.
A sensitivity analysis excluding studies with industry support revealed an even greater reduction in operative time with use of the HS (25 minutes; 95% CI = 16.3, 33.62). Interestingly, there were a total of 3 cases of postoperative hematoma in the CH group and 1 in the HS group (Table
The quality of the studies was assessed based on the following criteria: appropriateness of randomization, allocation concealment, blinding of patients, blinding of outcome assessors, utilization of intention-to-treat analysis, and a description of any patients that were lost to follow-up. In most cases, these parameters were not specified and thus the methodological quality of the included studies could only be deemed as fair. These results are presented in Table
Study validity.
Author | Randomization | Concealed | Patients | Outcome assessors | Intention- to-treat | Patients LTFU? | |
Done Adequate | allocation | blinded | blinded | Analysis | |||
Hallgrimsson | Yes | UC | UC | UC | UC | Yes | UC |
Lombardi | Yes | UC | UC | Yes | UC | UC | UC |
Yildirim | Yes | UC | UC | UC | UC | UC | UC |
Kilic | Yes | UC | UC | UC | UC | UC | UC |
Miccoli | Yes | UC | UC | Yes | UC | UC | UC |
Frazzetta | Yes | UC | UC | UC | UC | UC | UC |
Cordon | Yes | Yes | UC | UC | Yes | UC | UC |
Ortega | Yes | UC | UC | UC | UC | UC | UC |
Defechereux | Yes | Yes | UC | UC | UC | UC | UC |
UC: unclear; LTFU: loss to follow-up.
Utilization of the HS for total and subtotal thyroidectomy significantly reduced operative time compared to CH techniques by greater than 23 minutes (
All of the studies uniformly report decreased operating time with the use of an HS. This is not a surprising observation, given that the same outcome has been reported repeatedly for a variety of other surgical procedures [
All studies reported an increased risk of postoperative hypocalcemia with conventional hemostasis techniques, though only one report had a large enough cohort for the association to be statistically significant [
The complication of RLND after thyroidectomy is also an extremely uncommon occurrence. Included studies had conflicting results in terms of the risks of RLND with HS utilization compared to CH, and all reported either very few or no cases of this complication. In the current meta-analysis, there were only twenty-two incidents of transient RLND out of 822 total thyroidectomies (.03%) or 1,644 nerves at risk (.01%). Given that HS has been shown to cause less collateral thermal injury than conventional electrocautery, we would expect to see less RLND in the HS group. Unfortunately, the numbers in this analysis are too small to generate any meaningful conclusions. Only one case of permanent RLND occurred in a patient who underwent the CH technique. The time cutoff to differentiate between transient and permanent RLND was not well defined in the studies, but most investigators did use postoperative laryngoscopy in all patients to document vocal cord paralysis.
Regarding the internal validity of included studies, one must accept that for studies evaluating surgical techniques, blinding of the surgeon is not possible. However, patients can be blinded to the procedure they have undergone to minimize reporting bias when evaluating postoperative outcomes such as symptomatic hypocalcemia or pain. Furthermore, those individuals evaluating outcomes (operative time, RLND, hypocalcemia) can also be blinded to the intervention to reduce observation bias, and this was only explicitly carried out in a single study [
No tests of publication bias were statistically significant. Begg’s funnel plot for the pooled estimate of the WMD in operative time did exhibit some asymmetry, but this was not statistically significant. The asymmetry was likely a result of between-study heterogeneity (tau-squared = 175.88). When between-study heterogeneity is large and when the number of included studies is small, none of these tests to detect publication bias work well. Though all studies found that thyroidectomy was faster with the HS, they were quite heterogeneous in terms of the baseline length of time required to carry out a conventional thyroidectomy (range from 46.7 to 168.8 minutes). This observed difference in time required to carry out the same operation is quite striking. The heterogeneity may have been due to the size of the gland that was being resected, which was not clearly defined in all studies. In addition, all of the thyoidectomies in the Hallgrimsson study, which reported the longest mean operative time for conventional thyroidectomy, were carried out for Graves’ thyrotoxicosis, wherein the vascularization of the thyroid gland can be very extensive. In contrast, the majority of thyroidectomies in the study reporting the fastest mean operative time excluded patients with Graves’ disease or extensive goiters [
One must consider whether or not benign versus malignant thyroid pathology affected our results. All of the studies incorporated in the meta-analysis excluded patients requiring either a central or lateral compartment lymph node dissection; thus this could not have played a role in operative time or incidence of postoperative hypocalcemia. Of the 9 studies, 4 excluded malignant disease (7, 10, 11, 13), 3 had no significant difference in the proportion of malignant cases between the HS and CH groups (5, 6, 9), 1 only included low-risk T1N0M0 papillary thyroid cancers (12), and 1 did not clearly outline the pathologies. Given this, we do not feel that thyroid pathology is confounding our results for the primary or secondary outcomes.
Another consideration when interpreting the results of the current meta-analysis is that surgeons who conduct these trials may have significantly more experience with the HS than the average thyroid surgeon, and the timesaving effect of the HS might be exaggerated compared to what a less-familiar surgeon would experience when first adopting its use into their practice.
Future prospective, randomized trials of larger patient cohorts with more detailed and uniform definitions of postoperative complications, randomization procedures, intention-to-treat analyses, and blinding of outcome assessors are needed to draw more meaningful conclusions with regard to the influence of HS utilization on complications after total or subtotal thyroidectomy. In addition, cost-effectiveness analyses to determine whether the costs saved from the reduced time spent in the operating theater outweigh the added cost of the HS scalpel would also be important. Several of the studies did report reduced overall cost associated with the HS [
The authors would like to thank Dr. Andrea Petrucci and Mr. Antonio Canino for their help with translation of the French and Italian articles. In addition, they would like to thank Dr. Rob van Dam and Ms. Christie Jeon of the Harvard School of Public Health for their invaluable input. Dr. Wiseman is a Michael Smith Foundation for Health Research Scholar.