Impact of autofluorescence-based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study

ARTICLE IN PRESS Surgery ■■ (2017) ■■–■■

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Surgery j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y m s y

American Association of Endocrine Surgeons

Impact of autofluorescence-based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study Fares Benmiloud, MD a,*, Stanislas Rebaudet, MD, PhD b, Arthur Varoquaux, MD, PhD c, Guillaume Penaranda, MSc d, Marie Bannier, MD e, and Anne Denizot, MD a a

Endocrine Surgery Unit, Hôpital Européen de Marseille, Marseilles, France Internal Medicine Unit, Hôpital Européen de Marseille, Marseilles, France c Radiology Unit, Hôpital La Timone, Hospital-APHM, Marseilles, France d Biostatistics Unit, Laboratoire Alphabio, Marseilles, France e Oncologic Surgery Unit, Institut Paoli-Calmettes, Marseilles, France b

A R T I C L E

I N F O

Article history: Accepted 26 June 2017

Background. The clinical impact of intraoperative autofluorescence-based identification of parathyroids using a near-infrared camera remains unknown. Methods. In a before and after controlled study, we compared all patients who underwent total thyroidectomy by the same surgeon during Period 1 (January 2015 to January 2016) without near-infrared (near-infrared− group) and those operated on during Period 2 (February 2016 to September 2016) using a near-infrared camera (near-infrared+ group). In parallel, we also compared all patients who underwent surgery without near-infrared during those same periods by another surgeon in the same unit (control groups). Main outcomes included postoperative hypocalcemia, parathyroid identification, autotransplantation, and inadvertent resection. Results. The near-infrared+ group displayed significantly lower postoperative hypocalcemia rates (5.2%) than the near-infrared− group (20.9%; P < .001). Compared with the near-infrared− patients, the nearinfrared+ group exhibited an increased mean number of identified parathyroids and reduced parathyroid autotransplantation rates, although no difference was observed in inadvertent resection rates. Parathyroids were identified via near-infrared before they were visualized by the surgeon in 68% patients. In the control groups, parathyroid identification improved significantly from Period 1 to Period 2, although autotransplantation, inadvertent resection and postoperative hypocalcemia rates did not differ. Conclusion. Near-infrared use during total thyroidectomy significantly reduced postoperative hypocalcemia, improved parathyroid identification and reduced their autotransplantation rate. (Surgery 2017;160:XXX-XXX.) © 2017 Elsevier Inc. All rights reserved.

Total thyroidectomy (TT) is responsible for postoperative hypocalcemia (PH) in 20 − 30% of patients, which remains permanent in 1 − 4% of patients who undergo an operation.1,2 This complication results primarily from surgery-induced parathyroid dysfunction, due to vascular impairment,3 autotransplantation,4 or inadvertent resection.5 Parathyroid damage and unintentional parathyroid resection could be largely avoided by improved intraoperative identification of the parathyroids,6 which, until recently, relied mainly on the surgeon’s opinion and level of experience. Intraoperative parathyroid autofluorescence visualization using near-infrared (NIR) light

Presented at the Annual Meeting of the American Association of Endocrine Surgeons on April 2–4, 2017, Orlando, FL. * Reprint requests: Fares Benmiloud, MD, Hopital Europeen, 6 rue Désirée Clary, 13003 Marseilles, France. E-mail: [email protected].

is an emerging technique initially described at Vanderbilt University.7 Endogenous fluorophores in the parathyroid tissue, which have yet to be clearly characterized,8 emit a fluorescent signal when exposed to NIR light.7 Without any dye injection, this spontaneous signal allows for accurate identification of normal parathyroids in almost all cases.7 Systems providing NIR light derived from this technique have since been commercialized, such as the Fluobeam (Fluoptics, Grenoble, France). At any point during surgery, such systems can provide realtime images of the surgical field. Recently, the technical aspects of the Fluobeam camera, concerning its application in intraoperative parathyroid detection based on autofluorescence, were described by 2 feasibility studies.9,10 However, the clinical impact of NIR light use during thyroid surgery remains unknown. Thus, the main objective of this study was to assess the impact of NIR camera use during surgery on PH. The secondary objectives were to assess the impact of NIR light on parathyroid identification, autotransplantation, and inadvertent resection rates during TT.

https://doi.org/10.1016/j.surg.2017.06.022 0039-6060/© 2017 Elsevier Inc. All rights reserved.

Please cite this article in press as: Fares Benmiloud, et al., Impact of autofluorescence-based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study, Surgery (2017), doi: 10.1016/j.surg.2017.06.022

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Fig 1. Flow diagram of patients.

Methods

Intervention

Study model

For all patients who underwent conventional thyroidectomy (without the use of the NIR camera), we carefully tried to identify the parathyroids in order to dissect and preserve them in situ with an apparently intact vascular supply. However, we did not search for parathyroids if they were not apparent during thyroid capsular dissection. Autotransplantation was performed when parathyroids were impossible to preserve in situ (they were sliced into small pieces and inserted into the ipsilateral sternocleidomastoid muscle11). Hemostasis was achieved using the clamp-and-tie technique (no energy device was used). In the NIR+ group, during exposure of the thyroid lobe, a visual inspection was performed before any dissection was initiated. Next, the operating room lights were switched off, as the NIR system requires maximum darkness. The surgical field then was examined using a NIR camera for <5 minutes (Fig 2), a video was recorded, the lights were switched back on and conventional surgery was resumed. The images evocative of fluorescent parathyroids were visually verified (Fig 3, A, B, and C). This procedure was performed for each lobe of the thyroid, each one exposed at a time. For each

We conducted a before and after controlled study. We assessed a single component intervention: the use of a NIR light camera to identify parathyroids during TT. We compared patient outcome after TT before versus after the use of this intervention by one surgeon (Surgeon 1). We also compared these patients with 2 control groups of patients who were unexposed to the intervention; these individuals were operated on during the same periods by another surgeon in the same unit (Surgeon 2).

Setting All patients were selected by 2 surgeons (F.B., A.D.) at the Hôpital Européen Marseille, an endocrine surgery referral center. Surgeon 1 had 5 years of experience, while Surgeon 2 had 25 years of experience in thyroid surgery. The NIR light technique was introduced in our unit on January 28, 2016. The patient recruitment phase was divided into 2 periods: Period 1 (January 1, 2015 to January 27, 2016) and Period 2 (January 28, 2016 to September 13, 2016). During Period 2, NIR light was used during all thyroidectomies performed by Surgeon 1, but not by Surgeon 2. Patients with PH were followed up for at least 6 months, if they had not recovered by the end of that period.

Participants All consecutive patients who underwent one-stage TT in our unit were eligible and included in the study. Patients who had combined parathyroid disease (including patients with enlarged parathyroids that were incidentally identified during surgery and resected), who underwent TT + lymph node dissection, or who underwent two-stage (completion) thyroidectomy were excluded from the study. Patients operated on by Surgeon 1 during Period 1 constituted the NIR− group. Patients operated on by Surgeon 1 during Period 2 (with NIR) constituted the NIR+ group. The Control 1 and Control 2 groups (for Periods 1 and 2, respectively) included all consecutive patients who underwent surgery without NIR light by Surgeon 2 (see flow diagram, Fig 1).

Fig 2. Surgical field examined via NIR camera.

Please cite this article in press as: Fares Benmiloud, et al., Impact of autofluorescence-based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study, Surgery (2017), doi: 10.1016/j.surg.2017.06.022

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Fig 3. a-View of the exposed thyroid lobe before dissection. b-NIR light image of the same thyroid lobe. c-View of the same thyroid lobe after dissection.

parathyroid identified by the NIR system, we assessed whether this identification occurred before or after visualization by the naked eye. No biopsy was performed on apparently normal parathyroids. NIR light was generated by the Fluobeam system, which has been granted Food and Drug Administration 510(k) authorization for intraoperative use and European Community certification (Class 2A device). This system, which provides real-time images, consists of a camera connected by a wire to an integration box and a computer. The camera was inserted into a sterile cover and held by the surgeon at a distance of 15 − 20 cm from the patient tissue (as recommended in the instruction manual). The Fluobeam camera provides a NIR (750 nm) class 1 laser excitation (with a power <20 mW/cm2, which is 5 times less than the limit (100 mw/cm2) fixed by the international norm IEC 60601-241), and a visible white LED light (class RG1). Filters select wavelengths between 800 nm and 850 nm, corresponding to parathyroid fluorescence emission. Data collection The surgeons prospectively collected the following data using predefined forms: age, sex, body mass index (BMI), initial diagnosis, preoperative calcium level, total number of parathyroids observed by the surgeon, number of autotransplanted parathyroids, duration of the operation, corrected calcium nadir at postoperative days (POD) 1 and 2, treatment for hypocalcemia (treated with oral calcium only or with oral calcium + vitamin D ± intravenous calcium gluconate), duration of hypocalcemia (<1 month, 1 − 6 months, >6 months), occurrence of other complications, number of inadvertently resected parathyroids, thyroid weight, size of the largest nodule and definitive diagnosis. Outcome measures Corrected calcium level, calculated using the following formula12: corrected calcium (mg/dL) = measured calcium (mg/dL) – 0.8 * (albumin [g/dL] − 40), was assessed on POD 1 and 2. We defined a “hypocalcemic event,” or “PH,” as a corrected calcium level <8 mg/ dL (with or without symptoms) at POD 1 or 2.13 This biologic cutoff was used to consider starting treatment by oral calcium. Calcitriol (Rocaltrol) was added to oral calcium, depending on the level of hypocalcemia and/or if mild hypocalcemia symptoms occurred, and calcium gluconate was injected (repeatedly if needed) if intense paresthesia and/or cramps occurred. However, the initiation and modalities of treatment were based on each surgeon’s preference. PH was considered “transient” when it lasted <6 months and “permanent” when it was lasted >6 months. Parathyroid identification and autotransplantation were assessed by the surgeon and reported on surgical forms at the end

of each operation. Parathyroid glands were considered as “identified” when the surgeon had no doubts about their nature upon visual assessment. If the surgeon had a doubt or if no parathyroid was visualized, the parathyroids were considered as “nonidentified.” Autotransplantation was performed only when parathyroids were disconnected from any vascularization at the end of surgery, instead of relying on their color. Confirmatory biopsies of the structures before autotransplantation were done only when the surgeon had doubts about their nature (except in the NIR+ group, in which they were done systematically). The presence of inadvertently resected parathyroid tissue was documented in the pathology report. Statistical methods Continuous data was recorded as mean and standard deviation (SD), while categorical data was recorded as frequency (%). The χ2 test was used to assess percentage comparisons (after verification of the use assumptions), and the Kruskal-Wallis test was used for mean comparisons. The post-hoc Tukey-type multiple comparison test for unpaired multiple groups was used to compare proportions in each pair of groups. Similarly, the Dunn’s nonparametric comparison test was used for post hoc testing after the KruskalWallis test for continuous data. The Kappa index was used to assess agreement between parathyroids visualized with the naked eye and parathyroids visualized using NIR light. Factors associated with hypocalcemia were assessed using multiple logistic regression. Univariate analysis for hypocalcemia was performed prior to multivariate analysis. Among the following variables (age, sex, BMI, initial diagnosis, preoperative calcium level, number of parathyroids seen by the naked eye, number of autotransplanted parathyroids, duration of the operation, hypocalcemia event, other complications, number of inadvertently resected parathyroids, thyroid weight, size of the largest nodule, and definitive diagnosis), those with P value of <0.20 in univariate analysis were selected as potential covariates for multiple logistic regression analysis. There was no selection method applied in the multivariate model, all covariates had a P value assessed. Correlation analysis was performed in order to detect significant collinearity between covariates. Odds ratios (95% confidence interval [CI]) for hypocalcemia were reported. All tests were assessed using a significant criterion of α = 0.05. All analyses were conducted using SAS (version 9.1, SAS Institute Inc., Cary, NC). Ethical statement This study was approved by the ethics committee (equivalent to local Institutional Review Board) of the Hôpital Européen Marseille. Due to the routine healthcare nature of the intervention and the retrospective nature of the data, no specific informed consent was required.

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Results Patient characteristics Overall, 513 patients were involved in this study (Table I): NIR+ group (93 patients), NIR− group (153 patients), Control 1 group (180 patients) and Control 2 group (87 patients). Follow-up was completed on all patients included in the study. The preoperative characteristics did not vary between the groups. Although age and BMI seemed to vary between the groups upon global analysis, this was not statistically significant based on the results of a multiple comparison pairwise test. No difference concerning the other preoperative data was noted between the groups. Overall, the mean duration of surgery was significantly different between the various groups (P < .0001); surgery duration was shorter in the Control 1 group compared with the NIR+ and NIR− groups (Dunn’s test <.05). However, there was no significant difference between the NIR+ and NIR− groups (multiple post hoc comparison pairwise test). The overall mean weight of the resected specimens did not significantly differ between the groups (P = .0550). A post hoc multiple comparison pairwise test showed no difference in the weight of the specimens between the NIR+ and NIR− groups, although the specimens isolated from the NIR− group were heavier than those from the Control 1 group (Dunn’s test <0.05). No differences were observed for the other postoperative data. All patient characteristics are displayed in Table I. Postoperative hypocalcemia Postoperative transient hypocalcemia occurred significantly less frequently in the NIR+ group than in the other 3 groups: 5.3% in the NIR+ group vs 20.9% in the NIR− group, 16.1% in the Control 1 group and 19.5% in the Control 2 group (Tukey type test <0.05; Fig 4, Table II). Permanent hypocalcemia affected 2/153 patients in the NIR− group (1.3%, Table II). Parathyroid identification, autotransplantation, and inadvertent resection Overall, the number of identified parathyroids varied significantly between the different groups (P < .0001). Parathyroid identification rates were higher in the NIR+ group compared with

the NIR− group (76.3% vs 65.7% of the theoretically present parathyroids, respectively, Dunn’s test P < .05) and the Control 1 group (76.3% vs 62.6%, respectively, Dunn’s test P < .05). Parathyroid identification rates were also higher in the Control 2 group compared with the Control 1 group (71.3% vs 62.6%, respectively, Dunn’s test P < .05; Table II). In the NIR+ group, NIR light facilitated parathyroid identification (before they became visible to the naked eye) in 245/320 (68%) of theoretically present parathyroids (3 patients with missing data). Furthermore, all 259 NIR images suspected to correspond to parathyroids were confirmed by naked eye assessment (Kappa concordance test [IC 95]: 1.00 [0.95 − 1.00]). Parathyroid autotransplantation rates (Table II) significantly differed between the groups (P = .0034). Significantly fewer patients underwent parathyroid autotransplantation in the NIR+ group (2.1%) compared with the other 3 groups (15.0% in the NIR− group, 16.7 % in the Control 1 group and 16.1% in the Control 2 group; Dunn’s multiple comparison pairwise test, P < .05). Inadvertent parathyroid resection occurred in only one patient in the NIR+ group (1.1%) vs 7.2% of patients in the NIR− group, 8% in the Control 1 group, and 6.9% in the Control 2 group. A multiple comparison pairwise test showed a statistical difference only between the NIR+ group and the Control 1 group (Dunn’s test, P < .05). Factors associated with PH We found that in the control patients for whom ≥3 parathyroids were identified during surgery, hypocalcemia rates were significantly increased compared with the patients with <3 identified parathyroids: 22% vs 10%, respectively, (P = .0452) in the Control 1 group and 28% vs 3%, respectively, (P = .0046) in the Control 2 group (Table III). Although we noted a trend in the NIR− group, this difference was not significant (26% vs 15%, respectively, P = .1079). No difference was observed in the NIR+ group: 6% of patients with ≥3 identified parathyroids experienced PH versus 4% of patients with <3 identified parathyroids (P = 1.000). Multivariate analysis showed a 5-fold decrease in the risk of hypocalcemia among patients in the NIR+ group compared with those in the NIR− group. Furthermore, the risk of hypocalcemia was higher among patients for whom 2 parathyroids were autotransplanted compared with nonautotransplanted patients (OR 15.12 [1.39 − 164.29], P = .03; Table IV).

Table I Patient characteristics.

Preoperative

Intraoperative Postoperative

Sex ratio: M/F Age mean ± SD BMI mean ± SD Preoperative calcium mean ± SD (mg/dL) Initial diagnosis, N (%): Cancer MNG Toxic MNG Graves’ disease Mean duration of surgery mean ± SD (min) Complications, N (%): RLNP (per nerve at risk) Infection (per patient) Hematoma (per patient) Weight of the specimen mean ± SD (g) Size of the largest nodule mean ± SD (mm) Final diagnosis, N (%): Benign Malignant

NIR− n = 153

NIR+ n = 93

Control 1 n = 180

Control 2 n = 87

0.24 50.1 ± 13.9 26.6 ± 4.9 9.35 ± 0.36

0.19 49.6 ± 14.5 27.2 ± 5.6 9.29 ± 0.31

0.29 53.8 ± 14.1 27.5 ± 4.6 9.34 ± 0.37

0.30 54.3 ± 13.2 27.2 ± 6.0 9.32 ± 0.36

5 (3.3%) 100 (65.4%) 18 (11.7%) 30 (19.6%) 96.8 ± 25.5 8 (5.2%) 7 (2.2%) 0 1 (0.7%) 50.3 ± 34.2 22.3 ± 16.2

6 (6.5%) 66 (71.0%) 5 (5.4%) 16 (17.2%) 96.5 ± 24.5 4 (4.3%) 3 (1.6%) 1 (1.1%) 0 47.5 ± 32.8 26.1 ± 17.2

5 (2.8%) 133 (73.9%) 9 (5.0%) 33 (18.3%) 85.7 ± 24.2 7 (3.9%) 5 (1.4%) 0 2 (1.1%) 40.8 ± 27.7 22.6 ± 15.3

2 (2.3%) 64 (73.6%) 9 (10.3%) 12 (13.8%) 89.5 ± 17.8 7 (8.0%) 6 (3.4%) 0 1 (1.1%) 46.4 ± 33.2 25.1 ± 28.4

119 (77.8%) 34 (22.2%)

74 (78.7%) 20 (21.3%)

146 (81.1%) 34 (19.9%)

73 (83.9%) 14 (16.1%)

P value .6095 .0084 .0327 .5850 .2629

<.0001 .3105

.0550 .3474 .6649

MNG, multinodular goiter; TT, total thyroidectomy; RLNP, recurrent laryngeal nerve palsy.

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Fig 4. Postoperative hypocalcemia in each group.

Discussion This study is the first suggesting that the intraoperative autofluorescence-based identification of the parathyroid glands using NIR light during TT could help reduce transient PH rate. Although this study did not show any effect of NIR-camera use on permanent PH rates, which is a serious issue, a reduction of transient PH is clinically relevant. As transient PH can be severely symptomatic, it needs to be monitored and, in general, treated by oral calcium ± calcitriol (±intravenous calcium) for an unpredictable duration of time. This can result in treatment-related complications, such as skin necrosis in case of calcium gluconate

extravasation14 or hypo/hypercalcemia after discharge,15 additional healthcare costs associated with extended hospitalization (or rehospitalization) fees,15 as well as costs linked to treatments and monitoring after discharge.16 In this study, postoperative hypocalcemia was defined as a calcium level below an 8 mg/dL cutoff (at POD 1 or 2). This is one of many existing definitions for PH,17 although it was considered, in a recent review of the literature, as the most widely admitted.13 All patients in the NIR+ and NIR− groups (Surgeon 1) were treated and discharged systematically with treatment when calcium dropped below that cutoff. Therefore, in order to make a comparison, we applied the same limit to the Control groups (Surgeon 2),

Table II Main outcomes.

Postoperative calcium

Parathyroid identification

Parathyroid autotransplantation Inadvertent parathyroid resection

Calcium nadir mean ± SD (mg/dL) No. of Hypocalcemia events, N (%) Degree of hypocalcemia, N (%; mg/dL): ≥7.8; <8 ≥7.6; <7.8 ≥7.2; <7.6 <7.2 Required treatment, N (%): No treatment Calcium alone Calcium and Vitamin D Calcium injection Duration of hypocalcemia, N (%) <1 m 1−6m >6 m No. of identified parathyroids (/theoretically present), N (%) Mean per patient ± SD % of theoretically present parathyroids % per patient % of theoretically present parathyroids % per patient

NIR− n = 153

NIR+ n = 93

Control 1 n = 180

Control 2 n = 87

8.48 ± 0.57 32 (20.9%)

8.66 ± 0.43 5 (5.3%)

8.43 ± 0.43 29 (16.1%)

8.46 ± 0.47 17 (19.5%)

14 (43.7%) 7 (21.9%) 8 (25%) 3 (9.4%)

2 (40%) 1 (20%) 1 (20%) 1 (20%)

13 (44.8%) 7 (24.1%) 8 (27.6%) 1 (3.4%)

7 (41.2%) 6 (35.3%) 4 (23.5%) 0

0 11 (34.3%) 20 (65.7%) 2

0 1 (20%) 4 (80%) 0

3 (10.3%) 9 (31%) 17 (58.7%) 0

3 (17.6%) 4 (23.5%) 10 (58.9%) 1

19 (59.4%) 11 (34.3%) 2 (6.3%) 401/612 (65.5%)

3(60%) 2(40%) 0 284/372 (76.3%)

20 (68.9%) 9 (31.1%) 0 451/720 (62.6%)

12 (70.6%) 5 (29.4%) 0 248/348 (71.3%)

2.6 ± 1.0 26/612 (4.2%) 23/153 (15.0%) 11/612 (1.8%) 11/153 (7.2%)

3.1 ± 0.9 2/372 (0.5%) 2/93 (2.1%) 2/372 (0.5%) 1/93 (1.1%)

2.5 ± 1.1 33/720 (4.6%) 30/180 (16.7%) 16/720 (2.2%) 15/180 (8.3%)

2.9 ± 1.0 17/348 (4.9%) 14/87 (16.1%) 6/348 (1.7%) 6/87 (6.9%)

P value .0006 .0104 .8648

.7839

— .7923

<.0001 .0001 .0034 .0050 .2333 .1276

Ca, corrected serum calcium level. Hypocalcemic events: corrected serum calcium level <8 mg/dL at postoperative day 1 or 2 (with or without symptoms).

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Table III Parathyroid identificaton and hypocalcemia rates. No. of identified parathyroids

Hypocalcemia events

NIR− group (n = 153) NIR+ group (n = 93) Control 1 (n = 180) Control 2 (n = 87)

<3

≥3

10/67 (14.9%) 1/24 (4.2%) 9/87 (10.3%) 1/30 (3.3%)

22/86 (25.6%) 4/69 (5.8%) 20/93 (21.5%) 16/57 (28.1%)

P value

.1079 1.0000 .0452 .0046

although a few patients in these 2 groups, with “border line” calcium levels (between 7.8 and 8 mg/dL) at POD 1, were not treated. Our study also showed significant changes in the identification and the preservation of parathyroid glands in situ. During thyroidectomy, systematic identification of all four parathyroids, which can be dispersed, is not mandatory,18 and several studies have shown that increasing the number of visualized parathyroids could result in higher rates of PH.19 In this study, in all groups in which NIR light was not used, the greater the number of parathyroids identified, the higher the rate of hypocalcemia (the difference was statistically significant for both the Control 1 and Control 2 groups and nearly significant for the NIR− group). Meanwhile, in the NIR+ group, the rate of hypocalcemia remained low, even when more than three parathyroids were identified. Furthermore, we found that NIR light facilitated identification of the parathyroids (before any dissection was performed) in 68% of patients. Thus, in this study, anticipating parathyroid identification was likely more critical than the number of identified parathyroids. It is also noteworthy that the mean duration of surgery between the NIR− and the NIR+ was exactly the same. Although this can be explained by normal variation in operating duration, it is contradictory with what we had expected, since the NIR procedure is timeconsuming (3 − 5 minutes). One hypothesis is that the use of the NIR camera may have in fact enabled the surgeon to save time during the overall procedure. We observed a significant 15-fold increased risk of hypocalcemia in patients for whom ≥2 parathyroids were autotransplanted. This is concordant with large series that found autotransplantation as a risk factor of PH.20,21 Our study is the first to show that it is possible to correct parathyroid autotransplantation rates using NIR technology. We think that this was made possible because the NIR light technique enabled us to identify the parathyroids beforehand, search for their potential blood supply origin, and dissect more carefully in order to leave them in situ. This procedure thus resulted in a marked improvement in patient outcome compared with the NIR− group.

Table IV Multivariate Analysis.

Use of NIR Autotransplanted parathyroids 0 1 2 Initial diagnosis Cancer MNG Toxic MNG Graves’ disease Inadvertent parathyroid resection 0 1 2 Age, y BMI, kg/m2 Size of the largest nodule, mm Duration of surgery, min

OR [95 CI %]

P value

0.21 [0.07 − 0.64]

.0061

— 1.02 [0.29 − 3.60] 15.12 [1.39 − 164.29]

— .1181 .0289

— 1.11 [0.12 − 10.33] 2.65 [0.25 − 28.79] 1.54 [0.15 − 15.55]

— .5087 .2338 .9151

— 0.85 [0.17 − 4.33] >999.99 [ < .001 − >999.99] 0.98 [0.95 − 1.01] 0.97 [0.89 − 1.06] 0.98 [0.94 − 1.01] 1.00 [0.99 − 1.02]

— .9726 .9730 .2099 .4501 .2085 .6306

Inadvertent resection of the parathyroids, which occurs in 2.9% to 21.6% of patients, is a risk factor for hypocalcemia,5,21 although it has been reported that inadvertent removal of 1 or 2 parathyroids was not associated with PH.22 Although this rate dropped from 7.2% to 1.1% between the NIR− group and the NIR+ group, the difference was not significant between these two groups. However, a multiple comparison pairwise test showed there was a statistical difference between the NIR+ group (1.1% inadvertent resection rate) and the Control 1 group, which had a slightly higher inadvertent resection rate (8%) than the NIR− group (7.2%). Because parathyroid discoloration is not a reliable sign,3,23 and parathyroid autofluorescent signal emission is independent from parathyroid vascularization,7 in the present study it was not possible to assess whether NIR light was useful in improving parathyroid vascularization. Future studies assessing NIR light combined with dye injection, as was recently shown in feasibility studies using indocyanine green23 or methylene blue,24 would provide further insight.

Limitations The major limits of this study include the monocenter setting, the observational nature of the study, and the fact that the NIR light technique was used by a single surgeon. It is indeed difficult to conclude if the results were due to the use of the NIR camera, or to the fact that the surgeon using the system changed his attitude, even subconsciously, due to the fact that he was taking part in a study, which is classically known as the “Hawthorne effect.”25 However, we aimed to compensate for this potential bias with the Control groups. The mean number of identified parathyroids significantly improved between the control 1 and the control 2 groups, although Surgeon 2 neither used the NIR camera, nor changed the surgical technique. This enhanced identification of the parathyroids by Surgeon 2 could then only be explained by a change in attitude, presumably a more attentive or more extensive dissection of the parathyroid glands, due to the Hawthorne effect. However, this behavioral change did not result in any change in parathyroid autotransplantation nor in transient postoperative hypocalcemia rates. One can thus assume that a more attentive attitude by Surgeon 1 would probably not be sufficient to explain the observed results. Nevertheless, these preliminary results must be confirmed by multicenter studies involving different surgeons with various levels of experience, as well as long-term longitudinal observational studies, to reduce the effect that new technologies may have on behavioral changes. Near-infrared light use during thyroid surgery improved parathyroid identification and autotransplantation rates. This resulted in a sharp reduction in the rate of transient postoperative hypocalcemia, although no reduction in permanent PH was observed. These encouraging results warrant further confirmation in multicenter studies. We thank Dr Jean Gaudart for his advice concerning the study design; Professor Jean François Henry for his advice concerning the correction of the manuscript; the operating room nurse team at the Hôpital Européen Marseille, particularly Julien Chaise; Sophie Hascouet, Isabelle Ramirez, Dominique Vinck; the pathologists from Massalia Pathologie: Muriel Civatte, Benedicte Crebassa, Marc de Fromont; the senior Clinical Research Associate at the Hôpital Européen Marseille: Wahiba Bidaut.

References 1. Duclos A, Peix J-L, Colin C, et al. Influence of experience on performance of individual surgeons in thyroid surgery: prospective cross sectional multicentre study. BMJ 2012;344:d8041.

Please cite this article in press as: Fares Benmiloud, et al., Impact of autofluorescence-based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study, Surgery (2017), doi: 10.1016/j.surg.2017.06.022

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2. Chadwick D, Kinsman R, Walton P. The British Association of Endocrine and Thyroid Surgeons: fourth national audit report. In: Dendrite Clin Syst Ltd Hub Stn Road Henley. Thames (UK): 2012. 3. Promberger R, Ott J, Kober F, et al. Intra-and postoperative parathyroid hormonekinetics do not advocate for autotransplantation of discolored parathyroid glands during thyroidectomy. Thyroid 2010;20:1371-5. 4. Olson JA Jr, DeBenedetti MK, Baumann DS, Wells SA Jr. Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up. Ann Surg 1996;223:472. 5. Lin DT, Patel SG, Shaha AR, Singh B, Shah JP. Incidence of inadvertent parathyroid removal during thyroidectomy. Laryngoscope 2002;112:608-11. 6. Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003;133:180-5. 7. McWade MA, Sanders ME, Broome JT, Solórzano CC, Mahadevan-Jansen A. Establishing the clinical utility of autofluorescence spectroscopy for parathyroid detection. Surgery 2016;159:193-203, 8. 8. Thomas G, McWade MA, Sanders ME, Solórzano CC, McDonald WH, Mahadevan-Jansen A. Identifying the novel endogenous near-infrared fluorophore within parathyroid and other endocrine tissues. In: Optical Tomography and Spectroscopy. Optical Society of America; 2016 p. PTu3A. 5. 9. Falco J, Dip F, Quadri P, de la Fuente M, Rosenthal R. Cutting edge in thyroid surgery: autofluorescence of parathyroid glands. J Am Coll Surg 2016;223:374-80. 10. Leeuw F, Breuskin I, Abbaci M, et al. Intraoperative near-infrared imaging for parathyroid gland identification by auto-fluorescence: a feasibility study. World J Surg 2016;40:2131-8. 11. Wells SA Jr, Gunnells JC, Shelburne JD, Schneider AB, Sherwood LM. Transplantation of the parathyroid glands in man: clinical indications and results. Surgery 1975;78:34-44. 12. Payne RB, Little AJ, Williams RB, Milner JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 1973;4:643-6. 13. Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surg 2015;4:82.

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14. Lee TG, Chung S, Chung YK. A retrospective review of iatrogenic skin and soft tissue injuries. Arch Plast Surg 2012;39:412-6. 15. Cayo AK, Yen TW, Misustin SM, et al. Predicting the need for calcium and calcitriol supplementation after total thyroidectomy: results of a prospective, randomized study. Surgery 2012;152:1059-67. 16. Wang TS1, Cheung K, Roman SA, So1sa JA. To supplement or not to supplement: a cost- utility analysis of calcium and vitamin D repletion in patients after thyroidectomy. Ann Surg Oncol 2011;18:1293-9. 17. Mehanna HM, Jain A, Randeva H, Watkinson J, Shaha A. Postoperative hypocalcemia—the difference a definition makes. Head Neck 2010;32:27983. 18. Sheahan P, Mehanna R, Basheeth N, Murphy MS. Is systematic identification of all four parathyroid glands necessary during total thyroidectomy?: a prospective study. Laryngoscope 2013;123:2324-8. 19. Edafe O, Antakia R, Laskar N, Uttley L, Balasubramanian SP. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg 2014;101:307-20. 20. Hallgrimsson P, Nordenström E, Almquist M, Bergenfelz A. Risk factors for medically treated hypocalcemia after surgery for Graves’ disease: a Swedish multicenter study of 1,157 patients. World J Surg 2012;36:1933-42. 21. Sitges-Serra A, Ruiz S, Girvent M, Manjón H, Dueñas JP, Sancho JJ. Outcome of protracted hypoparathyroidism after total thyroidectomy. Br J Surg 2010;97:1687-95. 22. Sasson AR, James F, Pingpank J, Wetherington RW, Hanlon AL, Ridge JA. Incidental parathyroidectomy during thyroid surgery does not cause transient symptomatic hypocalcemia. Arch Otolaryngol Neck Surg 2001;127:304-8. 23. Vidal Fortuny J, Belfontali V, Sadowski SM, Karenovics W, Guigard S, Triponez F. Parathyroid gland angiography with indocyanine green fluorescence to predict parathyroid function after thyroid surgery. Br J Surg 2016;103:537-43. 24. Tummers QR, Schepers A, Hamming JF, et al. Intraoperative guidance in parathyroid surgery using near-infrared fluorescence imaging and low-dose Methylene Blue. Surgery 2015;158:1323-30. 25. Grimshaw J, Campbell M, Eccles M, Steen N. Experimental and quasiexperimental designs for evaluating guideline implementation strategies. Fam Pract 2000;17:116.

Discussion Dr Bradford K. Mitchell (Lansing, Michigan): I will start with a couple questions. How often did you do repeated imaging during the course of the exposure? And can you tell us if that added significantly to the length of the operation, if you looked at that? Dr Fares Benmiloud: For each lobe of the thyroid, we used once or maybe twice the NIR light. As for the second question, the procedure takes about 3 to 5 minutes in total, but when you look at the global duration time of operation, there was no difference whether or not the autofluorescence technique was used. Dr Mira Milas (Phoenix, AZ): My question is whether this technique has a different result according to the type of thyroid pathology? So, for example, do the parathyroids autofluoresce less with severe Graves’ disease or severe thyroiditis? Do they have a different pattern in multigland disease or adenomas if you looked at abnormal parathyroids? Thank you. Dr Fares Benmiloud: Thank you for your question. We did not observe any difference in parathyroid gland intensity of signal according to thyroid pathology. However, the thyroid sometimes provides false positive images, in case of small nodules full of colloid. But with a little experience, it is easy to differentiate between the colloid nodules and the parathyroid glands. Dr Scott Wilhelm (Cleveland, OH): Very nice work. In regard to inadvertent resection of parathyroid glands, you mentioned that in the non-NIR group, I believe it was 7% and in the NIR group, it was 1%. I know it was not clinically significant in terms of P values, but I think that is an important point. And my question to you comes

up, as in the inadvertent resected parathyroid glands, did NIR see any of those? Or can you tell us how many glands of the 4 you did find on ones that you had that happen? And a second question would be, do you have a concept of how much power it would take, how many in order to actually reduce the inadvertent resection rate? Dr Fares Benmiloud: The first question is very interesting. In the only patient in which we resected inadvertently 2 inferior parathyroid glands, even when we looked back at the movie we captured during surgery, we did not see the parathyroid glands, so maybe it is because they were included in the thyroid. Nevertheless, we must consider it a true false negative. And the second question? Dr Scott Wilhelm (Cleveland, OH): The concept of power as to how many you might need to do in order to show a difference there, if you have any concept. Dr Fares Benmiloud: Actually, we did not calculate this. Thank you. Dr Carmen C. Solorzano (Nashville, TN): Vanderbilt. Excellent paper. We agree with you. This is great technology to identify parathyroid tissue reliably. It does not necessarily help you find it. If you see it glow, then you see it. You said that the rate of transplantation went down, and I just want to have you comment on the fact that this technology, you said that maybe it made you a more detailed surgeon. And I just want to make sure that folks know that this technology does not tell you that the parathyroid is devascularized. Can you comment on why you thought the autotransplantation rate went down, because this is not telling you that the gland

Please cite this article in press as: Discussion, Surgery (2017), doi: 10.1016/j.surg.2017.06.026

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is devascularized. It should not because it makes no difference. It does not show you that. Dr Fares Benmiloud: Absolutely, the technique does not give us any information on the vascularization of the parathyroid. In routine, we usually autotransplant parathyroid glands only if they are ob-

viously disconnected and devascularized, and we do not rely on their color to decide if we autotransplant or not. We think that we decreased the rate of autotransplantation because we anticipated the identification of the parathyroid glands, and therefore, we dissected them better.

Please cite this article in press as: Discussion, Surgery (2017), doi: 10.1016/j.surg.2017.06.026