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Is it possible to limit the risks of thyroid surgery?
Annales d’Endocrinologie 76 (2015) 1S16-1S26
Is it possible to limit the risks of thyroid surgery? Est-il possible de réduire le risque de complications en chirurgie thyroïdienne ? R. Dahera, J.-C. Lifante a,*, N. Voiring, J.-L. Peix a, C. Colin b, J.-L. Kraimpsc, F. Menegauxd, F. Pattoue, F. Sebagf, S. Touzetb, S. Bourdyb, A. Duclosb,h, On behalf of the CATHY Study Group** Hospices civils de Lyon, Centre hospitalier Lyon-Sud, Service de chirurgie générale et endocrinienne, Pierre-Bénite, F-69495, France Hospices civils de Lyon, Pôle information médicale évaluation recherche, Lyon, F-69003 ; Université de Lyon, EA Santé-Individu-Société 4129, Lyon, F-69002, France c Department of Endocrine Surgery, Poitiers University, Jean-Bernard Hospital, 86021-Poitiers, France d Assistance publique-Hôpitaux de Paris, Hôpital la Pitié-Salpêtrière, Service de chirurgie générale, viscérale et endocrinienne, Paris, France e CHRU de Lille, Chirurgie générale et endocrinienne ; Université Lille-Nord de France, INSERM, UMR 859, Lille, 59000, France f Assistance publique-Hôpitaux de Marseille, CHU la Timone-Adulte, France g Hospices civils de Lyon, Hôpital Édouard-Herriot, Service d’hygiène, épidémiologie et prévention, Lyon, F-6943 ; Université de Lyon 1 ; CNRS, UMR 5558, Laboratoire de biométrie et biologie évolutive, Lyon, F-69373, France h Center for Surgery and Public Health, Brigham and Women’s Hospital – Harvard Medical School, Boston, MA, USA a
b
Abstract Objective: Inferior laryngeal nerve (ILN) palsy and hypocalcemia remain the two most frequent major complications after thyroid surgery. Their occurrences may be explained by the influence of factors related to the patient, the surgical procedure, thyroid pathology, or the surgeon’s technique. This study aims To assess whether systematically following a rigorous surgical technique during thyroidectomy affects postoperative complications and long-term patient recovery. Methods: We conducted a multicenter, cross-sectional study of prospectively collected data in five high-volume referral centers enrolling all patients who underwent thyroid surgery between April 2008 and December 2009. Inferior laryngeal nerve (ILN) palsy and hypocalcemia were systematically assessed during hospitalization based on objective criteria. A six-month follow-up was conducted in cases of early complications. Multivariate regression models were computed to quantify their relationship with potential risk factors. Results: A total of 3574 thyroid procedures were completed. Non-visualization of the ILN during dissection and a large thyroid mass were major risk factors for permanent ILN palsy (OR, 4.17 and 2.61, p<0.01) and persistent complications after initial injury (OR, 4.17 and 2.42, p<0.05). The presence of thyroiditis on the surgical specimen was an independent risk factor for permanent hypoparathyroidism and poor recovery after initial dysfunction (OR, 1.76 and 1.88, p<0.05). Conclusions: Thorough meticulous technique in thyroid surgery is a determinant of ILN function but fails to prevent persistent hypoparathyroidism. © 2015 Published by Elsevier Masson SAS. All rights reserved. Keywords: Thyroid; Surgery; Recurrent laryngeal nerve palsy; Hypoparathyroidism; Outcome Resumé Objectif : La paralysie du nerf laryngé inférieur (ILN) et l’hypocalcémie restent les deux complications les plus fréquentes de la chirurgie thyroïdienne. Leur survenue peut être expliquée par des facteurs liés au patient, à la procédure chirurgicale, à la pathologie thyroïdienne sous-jacente ou à la maitrise technique du chirurgien. Cette étude a pour but de rechercher si une technique chirurgicale rigoureuse affecte les complications post-opératoires et la récupération du patient à long-terme. Méthodes : Nous avons conduit une étude multicentrique, transversale à partir des données collectées prospectivement dans 5 centres de référence à haut volume chirurgical. Tous les patients opérés de la thyroïde entre avril 2008 et décembre 2009 ont été inclus. L’ILN et l’hypocalcémie ont été systématiquement recherchées sur des critères objectifs. Un suivi de 6 mois a été réalisé en cas de complication précoce.
** Members of the CATHY Study Group with corresponding affiliations are listed in the acknowledgements section of this article. * Corresponding author. E-mail address: [email protected] (J.C. Lifante). © 2015 Elsevier Masson SAS. All rights reserved.
R. Daher et al. / Annales d’Endocrinologie 76 (2015) 1S16-1S26
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Des modèles de régression multivariées ont été utilisés pour étudier leur relation avec les facteurs de risque potentiels Résultats : Un total de 3574 chirurgies thyroïdiennes ont été analysées. L’absence de visualisation de l’ILN pendant la dissection, un volume thyroïdien important, étaient les principaux facteurs de paralysie récurrentielle (OR, 4.17 and 2.61, p<0.01) et de leur persistance après lésion initiale (OR, 4.17 and 2.42, p<0.05). La présence de lésions de thyroïdite sur la pièce opératoire était un facteur de risque indépendant d’hypoparathyroïdie définitive et de mauvaise récupération après dysfonction initiale (OR, 1.76 and 1.88, p<0.05). Conclusions : La méticulosité chirurgicale est un déterminant de l’ILN mais ne permet pas de prévenir la survenue d’une hypoparathyroïdie © 2015 Publié par Elsevier Masson SAS. Tous droits réservés. Mots-clés : à venir
1. Introduction Thyroid surgery is currently a safe standardized procedure that is routinely performed for benign and malignant diseases [1-5]. Hypocalcemia and inferior laryngeal nerve (ILN) palsy remain the two most frequent major complications following thyroidectomy. Although they resolve spontaneously in most cases, early complications represent a negative outcome for the surgeon, and persistent complications hold the most concern regarding patient quality of life and economical issues that can potentially lead to medicolegal litigation. Complication rates are frequently employed as surgical outcome criteria [6], and the influence of a surgeon’s experience at reducing complications has been questioned [7,8]. The estimated rates for postoperative nerve palsy and hypocalcaemia vary widely throughout the literature depending on how complications are assessed, patient selection, procedure types, and assessment tools. Most risk factors of complications have been investigated in single center series [9-11], retrospective analyses [9,11-13], or administrative databases [7,14]. The few prospective multicenter studies examined specific pathology types or procedures [15,16]. We present a real-life example of a thyroid surgery practice in a prospective high-volume multicentric study, enrolling consecutive patients independent of pathology or surgical procedure. Transient and permanent complications were systematically screened through objective clinical and biological exams. The study purpose was to explore the influence of patients’ preoperative risk, surgical procedure, thyroid pathologies, or the surgeon’s technique on the occurrence of postoperative complications. In particular, we aimed to assess whether systematically following a rigorous surgical technique during thyroidectomy affects postoperative complications and long-term patient recovery.
2. Methods 2.1. Study design and population We conducted a prospective, cross-sectional study between April 1, 2008, and December 31, 2009, in five high-volume referral centers in France. All 28 endocrine surgeons performing thyroid surgery at these centers participated in the study.
All patients who underwent a thyroid procedure performed by one of these surgeons were eligible for inclusion during the recruitment period. The ethics committee waived the requirement for patient consent. Before surgery, patients received written information about personal data use and gave verbal consent for sharing their data. 2.2. Outcome measures Two major complications of thyroid surgery were considered: inferior laryngeal nerve palsy and hypoparathyroidism. An active follow-up protocol was implemented at the participating centers. Postoperative outcomes were systematically assessed during hospitalization within 48 hours after each thyroid procedure. In cases involving transient postoperative complications, a second assessment was planned at least six months following the thyroid surgery procedure to diagnose permanent complications. Systematic screening for postoperative inferior laryngeal nerve palsy was based on the objective evaluation of vocal cord mobility using laryngoscopy. Exclusion criteria for nerve palsy analysis included pre-existing nerve palsy before the intervention, previous thyroid surgery with unknown preexisting nerve palsy status, and voluntary resection of nerves during the intervention due to invasive carcinoma. Additionally, none of the procedures performed in one of the participating hospitals was included in the nerve palsy analysis because at this institution, vocal cord mobility was evaluated by laryngoscopy only in cases of postoperative voice alterations. Postoperative hypoparathyroidism was measured in patients who underwent a bilateral thyroidectomy and was defined as a serum calcium level lower than 2 mmol/L (8.0 mg/dL) or a requirement for vitamin D or calcium supplementation (or both) to maintain normocalcemia. Exclusion criteria for the hypoparathyroidism analysis included unilateral lobectomy; pre-existing hypocalcaemia or substitutive therapy with calcium and/or vitamin D before intervention; and previous thyroid surgery with unknown pre-existing parathyroid status. 2.3. Data collection After each thyroid surgery, a patient report form was completed by the attending surgeon, including items about the surgical intervention such as thyroid disease, type of procedure,
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and his/her perception of the procedure complexity (i.e., difficult parathyroid identification, large or intra-thoracic goiter, hypervascularization, intense fibrosis or thyroiditis, thyroid friability, and invasive extra-thyroid cancer). Large thyroid mass was designated in cases in which the gland volume represented a difficulty feature that interfered with the regular course of the procedure. This was a subjective criterion based on the surgeon’s perception depending on his/her experience. Research assistants completed the data collection using medical records. These data included patient demographics and information on previous thyroid surgeries, thyroid specimen characteristics (weight and presence of cancer or thyroiditis), postoperative supplementation with calcium and/or vitamin D, calcium assay values, and assessments of vocal cord mobility. The completeness of inclusions was 97% in relation to the number of eligible procedures recorded in the hospital administrative databases. 2.4. Statistical analysis We described the patient, disease, and surgical procedure characteristics using absolute frequencies with percentages for categorical variables or mean values with 95% confidence intervals (CI) for continuous variables. To identify the factors associated with postoperative complications, we compared thyroid procedures with and without postoperative complications. To identify the factors associated with permanent complications we compared 1) thyroid procedures with and without
permanent complications and 2) thyroid procedures with and without permanent complications among patients with postoperative complications. We used χ 2 and Mann-Whitney tests to compare categorical and continuous variables, respectively. We identified factors associated with the probability of each complication by calculating adjusted odds ratios (OR) with their 95% CI, using logistic regression. The following variables were entered into the multivariate models: patient (sex, age, BMI) and thyroid specimen characteristics (weight, presence of thyroiditis) and procedure complexity (extended thyroidectomy, lymph node dissection). To assess the goodness of fit of the multivariate models, we calculated Hosmer-Lemeshow statistics and the areas under the curve (AUC) based on a receiving operating characteristic (ROC) approach (C-statistic). All statistics converged toward an appropriate fit of the models allowing an accurate interpretation of the results. All analyses were carried out using IBM SPSS Statistics, version 19; all tests were two tailed; and p<0.05 was considered significant.
3. Results At total of 2473 patients were screened for inferior laryngeal nerve palsy analysis (figure 1). The overall rates of transient and permanent nerve palsy were 7.51% (178/2369, 95% CI, 6.46% to 8.61%) and 2.08% (49/2357, 95% CI 1.53% to 2.67%), respectively. In cases of transient nerve palsy, the
3574 Thyroid procedures
1101 Excluded procedures 1022 Procedures performed in center E 40 Pre-existing nerve palsies 29 Unknown pre-existing nerve palsy statuses 8 Voluntary resections of nerve 2 Patient deaths during follow-up
2473 Included unilateral or bilateral procedures
178 With postoperative complication
104 Lost to follow-up
12 Lost to follow-up
49 With permanent complication
117 With transient complication
Fig. 1a. Flow diagram of procedures in the analysis of inferior laryngeal nerve palsy.
2191 Without complication
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risk of permanent complication was 29.52% (49/166, 95% CI 22.89% to 36.75%). Bivariate analysis (table 3) revealed that patients had transient nerve palsy more frequently in cases of difficult nerve identification during surgery, large or intrathoracic goiter, and intraoperative features related to intense thyroiditis, thyroid friability, and invasive extra-thyroid cancer. Variables associated with permanent complications were an unidentified nerve, large goiter, and intense thyroiditis. Female sex and lack of nerve identification were also associated with permanent nerve palsy among The factors that were independently associated with complications after adjustment for patient, thyroid and procedure variables are shown in Table 4. Difficult identification of the inferior laryngeal nerve was associated with transient (OR 1.80, p<0.001) and permanent palsy (4.17, p<0.001). Large goiter was also linked with transient (1.75, p<0.01) and permanent palsy (2.61, p<0.01), whereas female sex was predictive of permanent nerve palsy (2.89, p<0.05). Factors associated with ILN recovery in cases of transient nerve palsy following thyroidectomy included male gender (4.29, p<0.05), the absence of a large goiter (2.42, p<0.05), and easy identification of the inferior laryngeal nerve during the procedure (4.17, p<0.001). At total of 2937 patients were screened for hypoparathyroidism analysis (figure 1). The rate of transient complications was 25.20% (737/2925, 95% CI 23.62% to 26.77%), whereas the permanent hypoparathyroidism rate was 2.69%
(78/2904, 95% CI 2.10% to 3.31%). Among patients who were followed after transient complication, 10.89% presented with permanent hypoparathyroidism at 6 months (78/716, 95% CI 8.66% to 13.27%). According to the bivariate statistics (table 1), the variables that were significantly associated with transient hypoparathyroidism were patient age, sex, and body mass index; the type of thyroid disease and procedure; a lymph node dissection; and the presence of cancer in the thyroid specimen. Permanent hypocalcemia was also associated with patient age and sex; the type of thyroid disease and procedure; lymph node dissection and the weight of the thyroid specimen or the presence of thyroiditis. Among patients with transient hypoparathyroidism, the only variable associated with permanent complications was the presence of thyroiditis in the surgical specimen. Multivariate modeling in table 2 shows that the occurrence of transient hypoparathyroidism was independently linked with female sex (p<0.001), young age (p<0.001), reduced BMI (p<0.001), extended thyroidectomy (p<0.05) or lymph node dissection (p<0.001), and weight of the thyroid specimen (p<0.001). Permanent complications were associated with female sex (OR 2.47, p<0.05), young age (1.02, p<0.05), extended thyroidectomy (4.77, p<0.05), or the presence of thyroiditis in the removed specimen (1.76, p<0.05). The absence of thyroiditis on the thyroid specimen also predicted the recovery of the parathyroid gland following transient hypocalcaemia (OR 1.88, p<0.05).
3574 Thyroid procedures
637 Excluded procedures 602 Procedures performed in center E 11 Pre-existing hypocalcemia or vitamin/calcium supplements 29 Unknown preexisting hypoparathyroidism statuses 8 Voluntary resections of nerve
2937 Included unilateral or bilateral procedures
737 With postoperative complication
12 Lost to follow-up
21 Lost to follow-up
78 With permanent complication
638 With transient complication
Fig. 1b. Flow diagram of procedures in the analysis of hypoparathyroidism.
2188 Without complication
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Table 1 Distribution of patient characteristics regarding inferior laryngeal nerve palsy. Transient nerve palsy
Permanent nerve palsy
All patients
All patients
Patients with transient nerve palsy
Yes (n=178)
No (n=2191)
P-value
Yes (n=49)
No (n=2308)
Male
41 (7.7)
490 (92.3)
0.837
6 (1.1)
524 (98.9)
Female
137 (7.5) 1701 (92.5)
43 (2.4)
Patient age. years
Mean
51.8
51.5
(95% CI)
(49.6-54) (50.6-51.9)
(47.2-55.8) (50.7-51.9)
(47.2-55.8) (49.2-54.3)
Patient body mass indexb
<25 kg/m² (%)
87 (7.3)
1099 (92.7) 0.673
26 (2.2)
1154 (97.8) 0.172
26 (32.1)
55 (67.9)
25-<30 kg/m² (%)
50 (7.1)
655 (92.9)
10 (1.4)
692 (98.6)
10 (21.3)
37 (78.7)
≥30 kg/m² (%)
36 (8.5)
389 (91.5)
13 (3.1)
410 (96.9)
13 (38.2)
21 (61.8)
Non-toxic solitary nodule (%)
20 (5.8)
326 (94.2)
3 (0.9)
340 (99.1)
3 (17.6)
14 (82.4)
Patient sex
Thyroid disease
Thyroid procedure
Lymph node dissection
51.2
0.465
No (n=117)
P-value
6 (15)
34 (85)
0.028
1784 (97.6) 0.083
43 (34.1)
83 (65.9)
51.3
51.5
51.7
0.953
0.243
Non-toxic multinodular goiter (%) 99 (7.6)
1210 (92.4)
27 (2.1)
1275 (97.9)
27 (29.3)
65 (70.7)
Hyperthyroidism (%)
22 (8.6)
233 (91.4)
7 (2.8)
246 (97.2)
7 (35)
13 (65)
Graves’disease (%)
15 (6.6)
213 (93.4)
8 (3.5)
220 (96.5)
8 (53.3)
7 (46.7)
Malignant neoplasm (%)
22 (9.5)
209 (90.5)
4 (1.7)
227 (98.3)
4 (18.2)
18 (81.8)
Unilateral lobectomy (%)
18 (5.2)
325 (94.8)
4 (1.2)
336 (98.8)
4 (26.7)
11 (73.3)
Subtotal thyroidectomy (%)
2 (10.5)
17 (89.5)
1 (5.6)
17 (94.4)
1 (100)
0 (0)
Total thyroidectomy (%)
152 (8)
1744 (92)
41 (2.2)
1847 (97.8)
41 (28.5)
103 (71.5)
Extended thyroidectomy (%)
3 (14.3)
18 (85.7)
1 (4.8)
20 (95.2)
1 (33.3)
2 (66.7)
Completion thyroidectomy (%)
3 (3.3)
87 (96.7)
2 (2.2)
88 (97.8)
2 (66.7)
1 (33.3)
Yes (%)
21 (10.9) 171 (89.1)
2 (1)
189 (99)
2 (10)
18 (90)
No (%)
157 (7.3) 2005 (92.7)
47 (2.2)
2104 (97.8)
47 (32.2)
99 (67.8)
28 (5.0)
530 (95.0)
28 (45.2)
34 (54.8)
21 (1.2)
1778 (98.8)
21 (20.2)
83 (79.8)
16 (4.4)
345 (95.6)
16 (42.1)
22 (57.9)
33 (1.7)
1963 (98.3)
33 (25.8)
95 (74.2)
9 (3.8)
228 (96.2)
9 (36)
16 (64)
40 (1.9)
2080 (98.1)
40 (28.4)
101 (71.6)
7 (3.0)
226 (97.0)
7 (30.4)
16 (69.6)
42 (2.0)
2082 (98.0)
42 (29.4)
101 (70.6)
3 (3.5)
83 (96.5)
3 (42.9)
4 (57.1)
46 (2.0)
2225 (98.0)
46 (28.9)
113 (71.1)
7 (3.3)
203 (963.7) 0.182
7 (36.8)
12 (63.2)
42 (2.0)
2105 (98.8)
42 (28.6)
105 (71.4)
6 (5.0)
113 (95.0)
6 (40)
9 (60)
43 (1.9)
2195 (98.1)
43 (28.5)
108 (71.5)
Difficult nerve Yes (%) identification No (%)
65 (11.6) 496 (88.4)
Large goiter
Yes (%)
41 (11.3) 323 (88.7)
No (%)
137 (6.8) 1868 (93.2)
Yes (%)
26 (10.9) 212 (89.1)
No (%)
152 (7.1) 1979 (92.9)
Intrathoracic goiter
0.688
P-value Yes (n=49)
0.130
0.065
0.000
113 (6.3) 1695 (93.8)
Hemorrhagic Yes (%) goiter No (%)
23 (9.9)
210 (90.1)
Bleeding difficult to control
Yes (%)
7 (8.1)
No (%)
171 (7.5) 2112 (92.5)
Intense fibrosis
Yes (%)
20 (9.5)
No (%)
158 (7.3) 2000 (92.7)
Intense thyroiditis
Yes (%)
15 (12.6) 104 (87.4)
No (%)
163 (7.2) 2087 (92.8)
0.003
0.035
0.151
155 (7.3) 1981 (92.7) 79 (91.1)
191 (90.5)
0.823
0.257
0.031
0.515
0.292
0.000
0.001
0.051
0.297
0.351
0.020
0.804
0.228
0.142
0.339
0.064
0.001
0.068
0.479
1
0.422
0.437
0.38
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Table 1 Distribution of patient characteristics regarding inferior laryngeal nerve palsy. Transient nerve palsy
Permanent nerve palsy
All patients
All patients
Yes (n=178) Thyroid friability
No (n=2191)
Yes (%)
16 (11.9) 118 (88.1)
No (%)
162 (7.2) 2073 (92.8)
Invasive Yes (%) extra-thyroid No (%) cancer
4 (23.5)
13 (73.5)
Weight of thyroid specimen, grams
Mean
51
(95% CI)
(42.9-59) (43.3-47.4)
Cancer in thyroid specimen
Yes (%)
49 (8.8)
No (%)
127 (7.1) 1654 (92.9)
Thyroiditis in thyroid specimen
Yes (%)
32 (7.3)
No (%)
144 (7.5) 1778 (92.5)
P-value
Yes (n=49)
No (n=2308)
P-value Yes (n=49)
0.045
3 (2.3)
129 (97.7)
0.872
46 (2.1)
2179 (97.9)
1 (5.9)
16 (94.1)
48 (2.1)
2292 (97.9)
49.3
45.8
0.012
174 (7.4) 2178 (92.6) 45.4
0.176
511 (91.3)
408 (92.7)
Patients with transient nerve palsy
0.270
0.561
(31.8-66.8) (43.8-47.7) 0.205
0.874
10 (1.8)
547 (98.2)
39 (2.2)
1733 (97.8)
8 (1.8)
431 (98.2)
41 (2.1)
1870 (97.9)
No (n=117)
P-value
3 (21.4)
11 (78.6)
0.76
46 (30.3)
106 (69.7)
1 (25)
3 (75)
48 (29.6)
114 (70.4)
49.3
53.2
1
0.714
(31.8-66.8) (43.3-63.1) 0.561
0.669
10 (21.7)
36 (78.3)
39 (33.1)
79 (66.9)
8 (25.8)
23 (74.2)
41 (30.8)
92 (69.2)
0.186
0.667
Table 2 Factors independently associated with inferior laryngeal nerve palsy. Variable
Transient nerve palsy (n=) Adjusted OR 95% CI
Permanent nerve palsy (n=) P-value Adjusted OR 95% CI
Permanent following transient nerve palsy (n=) P-value Adjusted OR 95% CI
P-value
Patient sex
Female vs. Male 1.14
0.79-1.66 0.488
2.89
1.20-6.94 0.018
4.29
1.50-12.27
Extended thyroidectomy
Yes vs. No
1.29
0.34-4.96 0.706
3.30
0.29-36.78 0.332
26.34
0.67-1040.86 0.081
Lymph node dissection
Yes vs. No
1.55
0.93-2.61 0.095
0.45
0.10-2.07 0.303
0.14
0.02-1.24
0.078
Difficult nerve identification Yes vs. No
1.80
1.29-2.49 0.000
4.17
2.31-7.51 0.000
4.17
1.94-8.98
0.000
Large goiter
Yes vs. No
1.75
1.19-2.56 0.004
2.61
1.39-4.93 0.003
2.42
1.02-5.73
0.045
Intense thyroiditis
Yes vs. No
1.73
0.98-3.07 0.060
2.25
0.92-5.53 0.077
1.86
0.54-6.37
0.324
Invasive extra-thyroid cancer Yes vs. No
2.72
0.81-9.13 0.105
2.40
0.23-25.53 0.468
0.41
0.02-10.06
0.589
Hosmer-Lemeshow test
Chi² = 5.104
0.277
Chi² = 2.030
0.845
Chi² = 2.071
0.913
C-statistic
AUC = 0.622
0.000
AUC = 0.753
0.000
AUC = 0.753
0.000
0.007
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Table 3 Distribution of patient characteristics regarding hypoparathyroidism. Transient hypoparathyroidism
Permanent hypoparathyroidism
All patients
All patients
Yes (n=737) Patient sex
No (n=2188)
P-value
Yes (n=78)
Patients with transient hypoparathyroidism No (n=2826)
Female
633 (27.6) 1663 (72.4)
Patient age, years
Mean
48.6
(95% CI)
(47.5-49.7) (52.1-53.3)
(44.4-51.8) (51.3-52.3)
(44.4-51.8) (47.5-49.9)
Patient body mass indexb
<25 kg/m² (%)
430 (29.9) 1006 (70.1) 0.000
39 (2.7)
1383 (97.3) 0.632
39 (9.4)
376 (90.6)
25-<30 kg/m² (%)
193 (21.7) 698 (78.3)
25 (2.8)
860 (97.2)
25 (13.4)
162 (86.6)
≥30 kg/m² (%)
104 (19.3) 434 (80.7)
11 (2.0)
527 (98.0)
11 (10.6)
93 (89.4)
Non-toxic solitary nodule (%)
31 (25.4)
0 (0)
121 (100)
0 (0)
30 (100)
Non-toxic multinodular goiter (%)
414 (22.9) 1395 (77.1)
44 (2.4)
1755 (97.6)
44 (10.9)
360 (89.1)
Hyperthyroidism (%)
67 (22.8)
6 (2.1)
286 (97.9)
6 (9.2)
59 (90.8)
Graves’disease (%)
101 (30.7) 228 (69.3)
11 (3.4)
313 (96.6)
11 (11.5)
85 (88.5)
Malignant neoplasm (%)
124 (33.4) 247 (66.6)
17 (4.6)
351 (95.4)
17 (14)
104 (86)
0 (0)
24 (100)
0 (0)
3 (100)
Thyroid disease
Thyroid procedure
Subtotal thyroidectomy (%) 3 (12.5)
227 (77.2)
21 (87.5)
0.022
0.039
0.025
69 (11.2)
545 (88.8)
48.1
48.7
2600 (97.4)
69 (10.4)
592 (89.6)
Extended thyroidectomy (%)
17 (43.6)
22 (56.4)
4 (10.3)
35 (89.7)
4 (23.5)
13 (76.5)
137 (79.7)
5 (2.9)
167 (97.1)
5 (14.3)
30 (85.7)
15 (4.5)
318 (95.5)
15 (13)
100 (87)
60 (2.4)
2414 (97.6)
60 (10.5)
513 (89.5)
17 (2.9)
562 (97.1)
17 (11.7)
128 (88.3)
61 (2.6)
2264 (97.4)
61 (10.7)
510 (89.3)
13 (2.4)
538 (97.6)
13 (10.7)
108 (89.3)
65 (2.8)
2288 (97.2)
65 (10.9)
530 (89.1)
8 (2.6)
299 (97.4)
8 (10.7)
67 (89.3)
70 (2.7)
2527 (97.3)
70 (10.9)
571 (89.1)
14 (4.2)
321 (95.8)
14 (14.9)
80 (85.1)
64 (2.5)
2505 (97.5)
64 (10.3)
558 (89.7)
4 (4.3)
88 (95.7)
4 (15.4)
22 (84.6)
74 (2.6)
2738 (97.4)
74 (10.7)
616 (89.3)
7 (2.8)
247 (97.2)
7 (12.5)
49 (87.5)
71 (2.7)
2579 (97.3)
71 (10.8)
589 (89.2)
Yes (%)
117 (34.9) 218 (65.1)
No (%)
592 (23.7) 1901 (76.3)
Large goiter
Yes (%)
128 (22.9) 430 (77.1)
No (%)
609 (25.7) 1758 (74.3)
Yes (%)
77 (24.9)
No (%)
660 (25.2) 1956 (74.8)
Hemorrhagic Yes (%) goiter No (%)
Intense fibrosis
51.8
92 (91.1)
69 (2.6)
584 (25.0) 1754 (75.0)
Bleeding difficult to control
0.011
48.1
9 (8.9)
682 (25.4) 2008 (74.6)
Difficult Yes (%) parathyroid identification No (%)
Intrathoracic goiter
0.000
2208 (97)
0.029
Total thyroidectomy (%)
Completion thyroidectomy 35 (20.3) (%) Lymph node dissection
91 (74.6)
0.000
69 (3)
No (n=638)
103 (16.4) 525 (83.6)
52.7
617 (98.6)
Yes (n=78)
Male
0.000
9 (1.4)
P-value
153 (26.1) 434 (73.9)
96 (28.5)
232 (75.1)
241 (71.5)
0.000
0.588
0.172
0.905
0.139
641 (24.8) 1947 (75.2)
Yes (%)
28 (29.8)
66 (70.2)
No (%)
709 (25.0) 2122 (75.0)
Yes (%)
58 (22.7)
198 (77.3)
No (%)
679 (25.4) 1990 (74.6)
0.297
0.327
0.027
0.677
0.598
0.927
0.072
0.316
0.942
P-value 0.606
0.695
0.343
0.275
0.293
0.414
0.719
1
1
0.212
0.514
0.656
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R. Daher et al. / Annales d’Endocrinologie 76 (2015) 1S16-1S26
Table 3 Distribution of patient characteristics regarding hypoparathyroidism. Transient hypoparathyroidism
Permanent hypoparathyroidism
All patients
All patients
Yes (n=737)
No (n=2188) 125 (74.0)
Intense thyroiditis
Yes (%)
44 (26.0)
No (%)
693 (25.1) 2063 (74.9)
Thyroid friability
Yes (%)
37 (20.8)
No (%)
700 (25.5) 2047 (74.5)
141 (79.2)
Invasive Yes (%) extra-thyroid No (%) cancer
12 (37.5)
20 (62.5)
Weight of thyroid specimen, grams
Mean
50.5
(95% CI)
(46.6-54.3) (45.6-49.6)
Cancer in thyroid specimen
Yes (%)
219 (28.7) 545 (71.3)
No (%)
514 (24.1) 1620 (75.9)
Thyroiditis in thyroid specimen
Yes (%)
128 (28.6) 363 (73.9)
No (%)
583 (25.2) 1729 (74.8)
P-value 0.796
0.162
0.107
725 (25.1) 2168 (74.9) 47.6
0.357
Yes (n=78)
Patients with transient hypoparathyroidism No (n=2826)
6 (3.6)
161 (96.4)
72 (2.6)
2665 (97.4)
8 (4.5)
170 (95.5)
70 (2.6)
2656 (97.4)
1 (3.1)
31 (96.9)
77 (2.7)
2795 (97.3)
51.1
48.2
P-value 0.455
0.123
0.877
0.046
(41.8-60.3) (46.4-50) 0.012
0.693
23 (3.0)
734 (97.0)
54 (2.5)
2066 (97.5)
20 (4.1)
463 (95.9)
53 (2.3)
2246 (97.7)
Yes (n=78)
No (n=638)
6 (14.3)
36 (85.7)
72 (10.7)
602 (89.3)
8 (21.6)
29 (78.4)
70 (10.3)
609 (89.7)
1 (8.3)
11 (91.7)
77 (10.9)
627 (89.1)
51.1
50.3
P-value 0.444
0.051
1
0.056
(41.8-54.6) (46.1-54.6) 0.472
0.022
23 (10.8)
189 (89.2)
54 (10.8)
446 (89.2)
20 (16.7)
100 (83.3)
53 (9.3)
517 (90.7)
1
0.022
Table 4 Factors independently associated with hypoparathyroidism Variable
Transient hypoparathyroidism (N=)
Permanent hypoparathyroidism (N=)
Adjusted OR
95% CI
P-value Adjusted OR
Permanent following transient hypoparathyroidism (N=)
95% CI
P-value Adjusted OR
95% CI
P-value
Patient sex
Female vs. Male
2.21
1.70-2.86
0.000
2.47
1.11-5.54
0.027
1.40
0.59-3.35
0.447
Patient age, years
By 1 year increase
0.98
0.98-0.99
0.000
0.98
0.97-1.00
0.035
0.99
0.97-1.01
0.411
Patient body mass index
By 1 point IMC increase
0.96
0.95-0.98
0.000
1.01
0.96-1.05
0.766
1.03
0.98-1.09
0.168
Extended thyroidectomy
Yes vs. No
2.67
1.26-5.71
0.010
4.77
1.45-15.71 0.010
3.25
0.94-11.26 0.063
Lymph node dissection Yes vs. No
1.88
1.42-2.48
0.000
1.83
0.94-3.59
0.077
1.15
0.57-2.31
0.694
Weight of thyroid specimen
By 1 gram increase
1.00
1.00-1.01
0.000
1.00
1.00-1.01
0.236
1.00
0.99-1.01
0.923
Thyroiditis in thyroid specimen
Yes vs. No
1.02
0.81-1.30
0.839
1.76
1.01-3.09
0.048
1.88
1.03-3.42
0.039
Hosmer-Lemeshow test
Chi² = 14.282
0.075
Chi² = 6.367
0.606
Chi² = 5.775
0.672
C-statistic
AUC = 0.647
0.000
AUC = 0.656
0.000
AUC = 0.607
0.004
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4. Discussion In this study, we sought to estimate the transient and permanent complication rates following thyroidectomy and then to quantify their association with perioperative risk factors related to the patient, the surgical procedure, thyroid pathology, or the surgeon’s technique. Although the risks of longterm hypoparathyroidism and nerve palsy complications are similar, the risk of transient complication is much higher for hypoparathyroidism than for recurrent nerve palsy. Risk factors associated with permanent ILN palsy are primarily related to intra-operative technical elements, whereas those associated with hypoparathyroidism are mainly controlled by preoperative pathology features. Meticulous dissection and thorough technique are mandatory for reducing ILN palsy but fail to prevent hypoparathyroidism occurrence. Transient nerve palsy is encountered in 7.51% of patients, one of the highest percentages reported in the literature, ranging from 0.2% to 9.8% [7,11,13,15,17-20]. In accordance with previous works insisting on the absolute need for nerve identification, the non-visualization of the ILN during dissection harbors the highest risk for nerve palsy occurrence [15,16]. Jointly, the presence of a large thyroid mass represents the difficulty perceived by the surgeon during the procedure and appears as the second independent risk factor of transient ILN palsy. In this particular setting, dissection of the ILN is found to be more difficult, especially when the Zuckerkandl tubercle is enlarged. This enlargement lead to excessive traction, which is recognized as a major mechanism for nerve dysfunction [8,11,21]. The 2.08% rate of permanent ILN palsy fits within the range of previous works: 0.7% to 5.65% [11,13,15-17,19,20]. Again, non-visualization of the ILN during dissection appears as the major risk factor for permanent nerve dysfunction. This fact provides additional proof that gentle dissection with ILN identification is the gold standard in thyroid surgery for reducing permanent nerve palsy, as mentioned in previous multivariate analyses [15,16]. After initial palsy, the recovery of nerve function at one year is expected to be as high as 95% when the anatomic integrity is confirmed during surgery [20,22]. This is the first report involving a multivariate analysis to identify the relevant predictive factors of the transition from transient to permanent palsy. The non-visualization of the ILN nerve during dissection represents a striking risk factor for irreversible damage. Injuries seem to be more severe (axonotmesis and neurotmesis) than when they occur under nerve identification (neurapraxia). The presence of a large thyroid mass additionally predicts a negative outcome regarding nerve function recovery. The intra-operative difficulty as perceived by the surgeon according to his/her experience presumes that failure to perform a thorough standardized technique ultimately negatively affects nerve function recovery when an early injury occurs. Neither extended thyroidectomy nor lymph node dissection nor the presence of cancer or thyroiditis is related to the occurrence of ILN palsy after thyroid surgery. The only consis-
tent factors affecting early and late dysfunction, as well as the ability for the nerve to recover, appear to be dependent on the intra-operative technique. Nerves are at increased risk whenever the surgeon fails to scrupulously apply established principles for safe intervention. Patients with transient ILN palsy in the context of an unidentified nerve or large thyroid mass must be warned of the potential persistence of this complication and be closely followed-up and managed accordingly. In this study, transient hypocalcemia occurred in 25.1% of total patients, which is in accordance with the range reported in the literature: 0.2% to 50.2% [7,9,10,13,15,19,23,24]. Lymph node dissection and female gender are associated with this complication, as previously suggested in case series [9,10,14,15,19,25]. Nevertheless, this effect vanishes with time because parathyroid function recovery and permanent hypocalcemia are not affected. Hypocalcemia after lymph node dissection seems to be mainly caused by extensive dissection of parathyroid glands rather than irreversible injury. Although advocated in other series, Graves’disease [15,2] and total thyroidectomy [14,15,26,27] did not appear as independent parameters here. Thorough follow-up of patients reveals a permanent hypoparathyroidism rate of 2.69%, fitting within the range of previously published studies: 0.5% to 4.4% [9,10,13,15,19,23,27]. Thyroiditis on pathology specimens is identified as a major predictive factor for this complication, especially when early hypocalcemia occurs after thyroid surgery. This observation represents a novel insight because thyroiditis is vaguely reported in the literature as a risk factor for early postoperative hypocalcemia [24]. Often, thyroiditis indicates Hashimoto’s and de Quervain diseases, which are both rare and usually excluded from studies [15]. Hypervascularization associated with thyroiditis may jeopardize small parathyroid vessels, whereas excessive fibrosis renders gland identification and dissection more difficult. Although these findings do not seem to alter transient hypocalcemia rates, increased permanent hypoparathyroidism indicates that in the context of thyroiditis, parathyroid gland dysfunction is subsequent to irreversible devascularization, inadvertent resection or profound trauma rather than transient sideration. To the best of our knowledge, no specific practical tips are available in the current literature to better address this particular situation involving a high risk for the parathyroid glands. The number of identified parathyroid glands left in situ has been reported as an objective factor associated with hypocalcemia [9,23,26]. We could not establish such an association because the difficulty of parathyroid identification did not appear as an independent factor in our multivariate analysis. If the initial pathology and patient characteristics play a slight role in transient hypocalcemia, they represent major uncontrollable factors for parathyroid recovery and permanent hypoparathyroidism. Assuming that the risk of hypoparathyroidism after thyroid surgery may be reduced when the procedure is conducted by an experienced surgeon, this study shows that the long-term outcome is unpredictable
R. Daher et al. / Annales d’Endocrinologie 76 (2015) 1S16-1S26
based solely on the surgical technique [7,8,12]. This information may push the surgeon toward a limited surgery (such as subtotal lobectomy) or even surveillance whenever possible if the diagnosis of thyroiditis is made pre-operatively. Additionally, patients must be promptly treated and regularly followed-up regarding these considerations. Because all patients undergoing a thyroidectomy were prospectively enrolled, irrespective of pathology and procedure type, and were systematically assessed for postoperative complications through objective screening, this multicenter study is assumed to provide a valid picture of thyroid surgery practices and expected outcomes. However, there are several limitations to this work. Our study sample was extracted from a population of French academic surgeons at high-volume referral centers, which may alter the representativeness in relation to regular patient recruitment and outcomes and may also transform surgeons’perceptions about procedure complexity. Furthermore, surgical outcomes depend on interactions between many factors that are still poorly understood and are difficult to characterize. We cannot exclude the possibility that other unknown or unmeasured risk factors may have further explained the reasons for the complications. Despite attempts to consider the characteristics of the patients, thyroid specimens and procedures, as well as the surgeons’perception during thyroidectomy, the singularity of thyroid diseases sometimes requires procedures of a complexity that might not have been sufficiently captured in statistical models. This large-volume multicenter prospective study highlights that even among experienced teams, complications after thyroid surgery are not uncommon. The surgeon’s ability to apply the gold-standard technique of inferior laryngeal nerve visualization is the principal determinant of short- and long-term nerve function as well as the patient’s ability to recover from initial injury. Conversely, meticulous dissection and thorough technique are not the sole predictors of parathyroid function outcome. The initial pathology represents a major technically uncontrollable factor in permanent hypoparathyroidism and parathyroid function recovery. The presence of thyroiditis perfectly illustrates this high-risk situation.
Acknowledgments The following are members of the CATHY Study Group: Matthew Carty and Stuart Lipsitz (Boston); Laurent Arnalsteen, Robert Caizzo, Bruno Carnaille, Guelareh Dezfoulian, Carole Eberle, Ziad El Khatib, Emmanuel Fernandez, Antoine Lamblin, François Pattou, and Marie-France Six (Lille); Stéphanie Bourdy, Laetitia Bouveret, Cyrille Colin, Antoine Duclos, Benoît Guibert, Marie-Annick Le Pogam, Jean-Christophe Lifante, Jean-Louis Peix, Gaétan Singier, Pietro Soardo, Sandrine Touzet, and Nicolas Voirin (Lyon); Pascal Auquier, JeanFrançois Henry, Claire Morando, Frédéric Sebag, and Sam Van Slycke (Marseille); Inès Akrout, Fares Benmiloud, JeanPaul Chigot, Isabelle Colombet, Gaëlle Godiris-Petit, Pierre Leyre, Fabrice Ménégaux, Séverine Noullet, Benoît Royer,
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and Christophe Tresallet (Paris); Thibault Desurmont, Claudia Dominguez, Jean-Louis Kraimps, Chiara Odasso, and Laetitia Rouleau (Poitiers); and Yves-Louis Chapuis, Pierre Durieux, Alain Lepape, and Frédéric Triponez (Scientific Committee).
Conflicts of interest Authors declare no conflict of interest.
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[19] Bergenfelz A, Jansson S, Kristoffersson A, et al. Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg 2008;393:667-673. [20] Dionigi G, Boni L, Rovera F, Rausei S, et al. Postoperative laryngoscopy in thyroid surgery: proper timing to detect recurrent laryngeal nerve injury. Langenbecks Arch Surg 2010;395:327331. [21] Snyder SK, Lairmore TC, Hendricks JC, et al. Elucidating mechanisms of recurrent laryngeal nerve injury during thyroidectomy and parathyroidectomy. J Am Coll Surg 2008;206:123130. [22] Mohil RS, Desai P, Narayan N, et al. Recurrent laryngeal nerve and voice preservation: routine identification and appropriate assessment – two important steps in thyroid surgery. Ann R Coll Surg Engl 2011;93:49–53.
[23] Pattou F, Combemale F, Fabre S, et al. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg 1998;22:718-724. [24] de Andrade Sousa A, Salles JM, Soares JM, et al. Course of ionized calcium after thyroidectomy. World J Surg 2010;34:987-992. [25] Henry JF, Gramatica L, Denizot A, et al. Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma. Langenbecks Arch Surg 1998;383:167-169. [26] Thomusch O, Machens A, Sekulla C, et al. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: A multivariate analysis of 5846 consecutive patients. Surgery 2003;133:180-185. [27] Mehanna HM, Jain A, Randeva H, et al. Postoperative hypocalcemia – the difference a definition makes. Head Neck 2010;32:279-283.
Is it possible to limit the risks of thyroid surgery? Est-il possible de réduire le risque de complications en chirurgie thyroïdienne ? R. Dahera, J.-C. Lifante a,*, N. Voiring, J.-L. Peix a, C. Colin b, J.-L. Kraimpsc, F. Menegauxd, F. Pattoue, F. Sebagf, S. Touzetb, S. Bourdyb, A. Duclosb,h, On behalf of the CATHY Study Group** Hospices civils de Lyon, Centre hospitalier Lyon-Sud, Service de chirurgie générale et endocrinienne, Pierre-Bénite, F-69495, France Hospices civils de Lyon, Pôle information médicale évaluation recherche, Lyon, F-69003 ; Université de Lyon, EA Santé-Individu-Société 4129, Lyon, F-69002, France c Department of Endocrine Surgery, Poitiers University, Jean-Bernard Hospital, 86021-Poitiers, France d Assistance publique-Hôpitaux de Paris, Hôpital la Pitié-Salpêtrière, Service de chirurgie générale, viscérale et endocrinienne, Paris, France e CHRU de Lille, Chirurgie générale et endocrinienne ; Université Lille-Nord de France, INSERM, UMR 859, Lille, 59000, France f Assistance publique-Hôpitaux de Marseille, CHU la Timone-Adulte, France g Hospices civils de Lyon, Hôpital Édouard-Herriot, Service d’hygiène, épidémiologie et prévention, Lyon, F-6943 ; Université de Lyon 1 ; CNRS, UMR 5558, Laboratoire de biométrie et biologie évolutive, Lyon, F-69373, France h Center for Surgery and Public Health, Brigham and Women’s Hospital – Harvard Medical School, Boston, MA, USA a
b
Abstract Objective: Inferior laryngeal nerve (ILN) palsy and hypocalcemia remain the two most frequent major complications after thyroid surgery. Their occurrences may be explained by the influence of factors related to the patient, the surgical procedure, thyroid pathology, or the surgeon’s technique. This study aims To assess whether systematically following a rigorous surgical technique during thyroidectomy affects postoperative complications and long-term patient recovery. Methods: We conducted a multicenter, cross-sectional study of prospectively collected data in five high-volume referral centers enrolling all patients who underwent thyroid surgery between April 2008 and December 2009. Inferior laryngeal nerve (ILN) palsy and hypocalcemia were systematically assessed during hospitalization based on objective criteria. A six-month follow-up was conducted in cases of early complications. Multivariate regression models were computed to quantify their relationship with potential risk factors. Results: A total of 3574 thyroid procedures were completed. Non-visualization of the ILN during dissection and a large thyroid mass were major risk factors for permanent ILN palsy (OR, 4.17 and 2.61, p<0.01) and persistent complications after initial injury (OR, 4.17 and 2.42, p<0.05). The presence of thyroiditis on the surgical specimen was an independent risk factor for permanent hypoparathyroidism and poor recovery after initial dysfunction (OR, 1.76 and 1.88, p<0.05). Conclusions: Thorough meticulous technique in thyroid surgery is a determinant of ILN function but fails to prevent persistent hypoparathyroidism. © 2015 Published by Elsevier Masson SAS. All rights reserved. Keywords: Thyroid; Surgery; Recurrent laryngeal nerve palsy; Hypoparathyroidism; Outcome Resumé Objectif : La paralysie du nerf laryngé inférieur (ILN) et l’hypocalcémie restent les deux complications les plus fréquentes de la chirurgie thyroïdienne. Leur survenue peut être expliquée par des facteurs liés au patient, à la procédure chirurgicale, à la pathologie thyroïdienne sous-jacente ou à la maitrise technique du chirurgien. Cette étude a pour but de rechercher si une technique chirurgicale rigoureuse affecte les complications post-opératoires et la récupération du patient à long-terme. Méthodes : Nous avons conduit une étude multicentrique, transversale à partir des données collectées prospectivement dans 5 centres de référence à haut volume chirurgical. Tous les patients opérés de la thyroïde entre avril 2008 et décembre 2009 ont été inclus. L’ILN et l’hypocalcémie ont été systématiquement recherchées sur des critères objectifs. Un suivi de 6 mois a été réalisé en cas de complication précoce.
** Members of the CATHY Study Group with corresponding affiliations are listed in the acknowledgements section of this article. * Corresponding author. E-mail address: [email protected] (J.C. Lifante). © 2015 Elsevier Masson SAS. All rights reserved.
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Des modèles de régression multivariées ont été utilisés pour étudier leur relation avec les facteurs de risque potentiels Résultats : Un total de 3574 chirurgies thyroïdiennes ont été analysées. L’absence de visualisation de l’ILN pendant la dissection, un volume thyroïdien important, étaient les principaux facteurs de paralysie récurrentielle (OR, 4.17 and 2.61, p<0.01) et de leur persistance après lésion initiale (OR, 4.17 and 2.42, p<0.05). La présence de lésions de thyroïdite sur la pièce opératoire était un facteur de risque indépendant d’hypoparathyroïdie définitive et de mauvaise récupération après dysfonction initiale (OR, 1.76 and 1.88, p<0.05). Conclusions : La méticulosité chirurgicale est un déterminant de l’ILN mais ne permet pas de prévenir la survenue d’une hypoparathyroïdie © 2015 Publié par Elsevier Masson SAS. Tous droits réservés. Mots-clés : à venir
1. Introduction Thyroid surgery is currently a safe standardized procedure that is routinely performed for benign and malignant diseases [1-5]. Hypocalcemia and inferior laryngeal nerve (ILN) palsy remain the two most frequent major complications following thyroidectomy. Although they resolve spontaneously in most cases, early complications represent a negative outcome for the surgeon, and persistent complications hold the most concern regarding patient quality of life and economical issues that can potentially lead to medicolegal litigation. Complication rates are frequently employed as surgical outcome criteria [6], and the influence of a surgeon’s experience at reducing complications has been questioned [7,8]. The estimated rates for postoperative nerve palsy and hypocalcaemia vary widely throughout the literature depending on how complications are assessed, patient selection, procedure types, and assessment tools. Most risk factors of complications have been investigated in single center series [9-11], retrospective analyses [9,11-13], or administrative databases [7,14]. The few prospective multicenter studies examined specific pathology types or procedures [15,16]. We present a real-life example of a thyroid surgery practice in a prospective high-volume multicentric study, enrolling consecutive patients independent of pathology or surgical procedure. Transient and permanent complications were systematically screened through objective clinical and biological exams. The study purpose was to explore the influence of patients’ preoperative risk, surgical procedure, thyroid pathologies, or the surgeon’s technique on the occurrence of postoperative complications. In particular, we aimed to assess whether systematically following a rigorous surgical technique during thyroidectomy affects postoperative complications and long-term patient recovery.
2. Methods 2.1. Study design and population We conducted a prospective, cross-sectional study between April 1, 2008, and December 31, 2009, in five high-volume referral centers in France. All 28 endocrine surgeons performing thyroid surgery at these centers participated in the study.
All patients who underwent a thyroid procedure performed by one of these surgeons were eligible for inclusion during the recruitment period. The ethics committee waived the requirement for patient consent. Before surgery, patients received written information about personal data use and gave verbal consent for sharing their data. 2.2. Outcome measures Two major complications of thyroid surgery were considered: inferior laryngeal nerve palsy and hypoparathyroidism. An active follow-up protocol was implemented at the participating centers. Postoperative outcomes were systematically assessed during hospitalization within 48 hours after each thyroid procedure. In cases involving transient postoperative complications, a second assessment was planned at least six months following the thyroid surgery procedure to diagnose permanent complications. Systematic screening for postoperative inferior laryngeal nerve palsy was based on the objective evaluation of vocal cord mobility using laryngoscopy. Exclusion criteria for nerve palsy analysis included pre-existing nerve palsy before the intervention, previous thyroid surgery with unknown preexisting nerve palsy status, and voluntary resection of nerves during the intervention due to invasive carcinoma. Additionally, none of the procedures performed in one of the participating hospitals was included in the nerve palsy analysis because at this institution, vocal cord mobility was evaluated by laryngoscopy only in cases of postoperative voice alterations. Postoperative hypoparathyroidism was measured in patients who underwent a bilateral thyroidectomy and was defined as a serum calcium level lower than 2 mmol/L (8.0 mg/dL) or a requirement for vitamin D or calcium supplementation (or both) to maintain normocalcemia. Exclusion criteria for the hypoparathyroidism analysis included unilateral lobectomy; pre-existing hypocalcaemia or substitutive therapy with calcium and/or vitamin D before intervention; and previous thyroid surgery with unknown pre-existing parathyroid status. 2.3. Data collection After each thyroid surgery, a patient report form was completed by the attending surgeon, including items about the surgical intervention such as thyroid disease, type of procedure,
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and his/her perception of the procedure complexity (i.e., difficult parathyroid identification, large or intra-thoracic goiter, hypervascularization, intense fibrosis or thyroiditis, thyroid friability, and invasive extra-thyroid cancer). Large thyroid mass was designated in cases in which the gland volume represented a difficulty feature that interfered with the regular course of the procedure. This was a subjective criterion based on the surgeon’s perception depending on his/her experience. Research assistants completed the data collection using medical records. These data included patient demographics and information on previous thyroid surgeries, thyroid specimen characteristics (weight and presence of cancer or thyroiditis), postoperative supplementation with calcium and/or vitamin D, calcium assay values, and assessments of vocal cord mobility. The completeness of inclusions was 97% in relation to the number of eligible procedures recorded in the hospital administrative databases. 2.4. Statistical analysis We described the patient, disease, and surgical procedure characteristics using absolute frequencies with percentages for categorical variables or mean values with 95% confidence intervals (CI) for continuous variables. To identify the factors associated with postoperative complications, we compared thyroid procedures with and without postoperative complications. To identify the factors associated with permanent complications we compared 1) thyroid procedures with and without
permanent complications and 2) thyroid procedures with and without permanent complications among patients with postoperative complications. We used χ 2 and Mann-Whitney tests to compare categorical and continuous variables, respectively. We identified factors associated with the probability of each complication by calculating adjusted odds ratios (OR) with their 95% CI, using logistic regression. The following variables were entered into the multivariate models: patient (sex, age, BMI) and thyroid specimen characteristics (weight, presence of thyroiditis) and procedure complexity (extended thyroidectomy, lymph node dissection). To assess the goodness of fit of the multivariate models, we calculated Hosmer-Lemeshow statistics and the areas under the curve (AUC) based on a receiving operating characteristic (ROC) approach (C-statistic). All statistics converged toward an appropriate fit of the models allowing an accurate interpretation of the results. All analyses were carried out using IBM SPSS Statistics, version 19; all tests were two tailed; and p<0.05 was considered significant.
3. Results At total of 2473 patients were screened for inferior laryngeal nerve palsy analysis (figure 1). The overall rates of transient and permanent nerve palsy were 7.51% (178/2369, 95% CI, 6.46% to 8.61%) and 2.08% (49/2357, 95% CI 1.53% to 2.67%), respectively. In cases of transient nerve palsy, the
3574 Thyroid procedures
1101 Excluded procedures 1022 Procedures performed in center E 40 Pre-existing nerve palsies 29 Unknown pre-existing nerve palsy statuses 8 Voluntary resections of nerve 2 Patient deaths during follow-up
2473 Included unilateral or bilateral procedures
178 With postoperative complication
104 Lost to follow-up
12 Lost to follow-up
49 With permanent complication
117 With transient complication
Fig. 1a. Flow diagram of procedures in the analysis of inferior laryngeal nerve palsy.
2191 Without complication
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risk of permanent complication was 29.52% (49/166, 95% CI 22.89% to 36.75%). Bivariate analysis (table 3) revealed that patients had transient nerve palsy more frequently in cases of difficult nerve identification during surgery, large or intrathoracic goiter, and intraoperative features related to intense thyroiditis, thyroid friability, and invasive extra-thyroid cancer. Variables associated with permanent complications were an unidentified nerve, large goiter, and intense thyroiditis. Female sex and lack of nerve identification were also associated with permanent nerve palsy among The factors that were independently associated with complications after adjustment for patient, thyroid and procedure variables are shown in Table 4. Difficult identification of the inferior laryngeal nerve was associated with transient (OR 1.80, p<0.001) and permanent palsy (4.17, p<0.001). Large goiter was also linked with transient (1.75, p<0.01) and permanent palsy (2.61, p<0.01), whereas female sex was predictive of permanent nerve palsy (2.89, p<0.05). Factors associated with ILN recovery in cases of transient nerve palsy following thyroidectomy included male gender (4.29, p<0.05), the absence of a large goiter (2.42, p<0.05), and easy identification of the inferior laryngeal nerve during the procedure (4.17, p<0.001). At total of 2937 patients were screened for hypoparathyroidism analysis (figure 1). The rate of transient complications was 25.20% (737/2925, 95% CI 23.62% to 26.77%), whereas the permanent hypoparathyroidism rate was 2.69%
(78/2904, 95% CI 2.10% to 3.31%). Among patients who were followed after transient complication, 10.89% presented with permanent hypoparathyroidism at 6 months (78/716, 95% CI 8.66% to 13.27%). According to the bivariate statistics (table 1), the variables that were significantly associated with transient hypoparathyroidism were patient age, sex, and body mass index; the type of thyroid disease and procedure; a lymph node dissection; and the presence of cancer in the thyroid specimen. Permanent hypocalcemia was also associated with patient age and sex; the type of thyroid disease and procedure; lymph node dissection and the weight of the thyroid specimen or the presence of thyroiditis. Among patients with transient hypoparathyroidism, the only variable associated with permanent complications was the presence of thyroiditis in the surgical specimen. Multivariate modeling in table 2 shows that the occurrence of transient hypoparathyroidism was independently linked with female sex (p<0.001), young age (p<0.001), reduced BMI (p<0.001), extended thyroidectomy (p<0.05) or lymph node dissection (p<0.001), and weight of the thyroid specimen (p<0.001). Permanent complications were associated with female sex (OR 2.47, p<0.05), young age (1.02, p<0.05), extended thyroidectomy (4.77, p<0.05), or the presence of thyroiditis in the removed specimen (1.76, p<0.05). The absence of thyroiditis on the thyroid specimen also predicted the recovery of the parathyroid gland following transient hypocalcaemia (OR 1.88, p<0.05).
3574 Thyroid procedures
637 Excluded procedures 602 Procedures performed in center E 11 Pre-existing hypocalcemia or vitamin/calcium supplements 29 Unknown preexisting hypoparathyroidism statuses 8 Voluntary resections of nerve
2937 Included unilateral or bilateral procedures
737 With postoperative complication
12 Lost to follow-up
21 Lost to follow-up
78 With permanent complication
638 With transient complication
Fig. 1b. Flow diagram of procedures in the analysis of hypoparathyroidism.
2188 Without complication
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Table 1 Distribution of patient characteristics regarding inferior laryngeal nerve palsy. Transient nerve palsy
Permanent nerve palsy
All patients
All patients
Patients with transient nerve palsy
Yes (n=178)
No (n=2191)
P-value
Yes (n=49)
No (n=2308)
Male
41 (7.7)
490 (92.3)
0.837
6 (1.1)
524 (98.9)
Female
137 (7.5) 1701 (92.5)
43 (2.4)
Patient age. years
Mean
51.8
51.5
(95% CI)
(49.6-54) (50.6-51.9)
(47.2-55.8) (50.7-51.9)
(47.2-55.8) (49.2-54.3)
Patient body mass indexb
<25 kg/m² (%)
87 (7.3)
1099 (92.7) 0.673
26 (2.2)
1154 (97.8) 0.172
26 (32.1)
55 (67.9)
25-<30 kg/m² (%)
50 (7.1)
655 (92.9)
10 (1.4)
692 (98.6)
10 (21.3)
37 (78.7)
≥30 kg/m² (%)
36 (8.5)
389 (91.5)
13 (3.1)
410 (96.9)
13 (38.2)
21 (61.8)
Non-toxic solitary nodule (%)
20 (5.8)
326 (94.2)
3 (0.9)
340 (99.1)
3 (17.6)
14 (82.4)
Patient sex
Thyroid disease
Thyroid procedure
Lymph node dissection
51.2
0.465
No (n=117)
P-value
6 (15)
34 (85)
0.028
1784 (97.6) 0.083
43 (34.1)
83 (65.9)
51.3
51.5
51.7
0.953
0.243
Non-toxic multinodular goiter (%) 99 (7.6)
1210 (92.4)
27 (2.1)
1275 (97.9)
27 (29.3)
65 (70.7)
Hyperthyroidism (%)
22 (8.6)
233 (91.4)
7 (2.8)
246 (97.2)
7 (35)
13 (65)
Graves’disease (%)
15 (6.6)
213 (93.4)
8 (3.5)
220 (96.5)
8 (53.3)
7 (46.7)
Malignant neoplasm (%)
22 (9.5)
209 (90.5)
4 (1.7)
227 (98.3)
4 (18.2)
18 (81.8)
Unilateral lobectomy (%)
18 (5.2)
325 (94.8)
4 (1.2)
336 (98.8)
4 (26.7)
11 (73.3)
Subtotal thyroidectomy (%)
2 (10.5)
17 (89.5)
1 (5.6)
17 (94.4)
1 (100)
0 (0)
Total thyroidectomy (%)
152 (8)
1744 (92)
41 (2.2)
1847 (97.8)
41 (28.5)
103 (71.5)
Extended thyroidectomy (%)
3 (14.3)
18 (85.7)
1 (4.8)
20 (95.2)
1 (33.3)
2 (66.7)
Completion thyroidectomy (%)
3 (3.3)
87 (96.7)
2 (2.2)
88 (97.8)
2 (66.7)
1 (33.3)
Yes (%)
21 (10.9) 171 (89.1)
2 (1)
189 (99)
2 (10)
18 (90)
No (%)
157 (7.3) 2005 (92.7)
47 (2.2)
2104 (97.8)
47 (32.2)
99 (67.8)
28 (5.0)
530 (95.0)
28 (45.2)
34 (54.8)
21 (1.2)
1778 (98.8)
21 (20.2)
83 (79.8)
16 (4.4)
345 (95.6)
16 (42.1)
22 (57.9)
33 (1.7)
1963 (98.3)
33 (25.8)
95 (74.2)
9 (3.8)
228 (96.2)
9 (36)
16 (64)
40 (1.9)
2080 (98.1)
40 (28.4)
101 (71.6)
7 (3.0)
226 (97.0)
7 (30.4)
16 (69.6)
42 (2.0)
2082 (98.0)
42 (29.4)
101 (70.6)
3 (3.5)
83 (96.5)
3 (42.9)
4 (57.1)
46 (2.0)
2225 (98.0)
46 (28.9)
113 (71.1)
7 (3.3)
203 (963.7) 0.182
7 (36.8)
12 (63.2)
42 (2.0)
2105 (98.8)
42 (28.6)
105 (71.4)
6 (5.0)
113 (95.0)
6 (40)
9 (60)
43 (1.9)
2195 (98.1)
43 (28.5)
108 (71.5)
Difficult nerve Yes (%) identification No (%)
65 (11.6) 496 (88.4)
Large goiter
Yes (%)
41 (11.3) 323 (88.7)
No (%)
137 (6.8) 1868 (93.2)
Yes (%)
26 (10.9) 212 (89.1)
No (%)
152 (7.1) 1979 (92.9)
Intrathoracic goiter
0.688
P-value Yes (n=49)
0.130
0.065
0.000
113 (6.3) 1695 (93.8)
Hemorrhagic Yes (%) goiter No (%)
23 (9.9)
210 (90.1)
Bleeding difficult to control
Yes (%)
7 (8.1)
No (%)
171 (7.5) 2112 (92.5)
Intense fibrosis
Yes (%)
20 (9.5)
No (%)
158 (7.3) 2000 (92.7)
Intense thyroiditis
Yes (%)
15 (12.6) 104 (87.4)
No (%)
163 (7.2) 2087 (92.8)
0.003
0.035
0.151
155 (7.3) 1981 (92.7) 79 (91.1)
191 (90.5)
0.823
0.257
0.031
0.515
0.292
0.000
0.001
0.051
0.297
0.351
0.020
0.804
0.228
0.142
0.339
0.064
0.001
0.068
0.479
1
0.422
0.437
0.38
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Table 1 Distribution of patient characteristics regarding inferior laryngeal nerve palsy. Transient nerve palsy
Permanent nerve palsy
All patients
All patients
Yes (n=178) Thyroid friability
No (n=2191)
Yes (%)
16 (11.9) 118 (88.1)
No (%)
162 (7.2) 2073 (92.8)
Invasive Yes (%) extra-thyroid No (%) cancer
4 (23.5)
13 (73.5)
Weight of thyroid specimen, grams
Mean
51
(95% CI)
(42.9-59) (43.3-47.4)
Cancer in thyroid specimen
Yes (%)
49 (8.8)
No (%)
127 (7.1) 1654 (92.9)
Thyroiditis in thyroid specimen
Yes (%)
32 (7.3)
No (%)
144 (7.5) 1778 (92.5)
P-value
Yes (n=49)
No (n=2308)
P-value Yes (n=49)
0.045
3 (2.3)
129 (97.7)
0.872
46 (2.1)
2179 (97.9)
1 (5.9)
16 (94.1)
48 (2.1)
2292 (97.9)
49.3
45.8
0.012
174 (7.4) 2178 (92.6) 45.4
0.176
511 (91.3)
408 (92.7)
Patients with transient nerve palsy
0.270
0.561
(31.8-66.8) (43.8-47.7) 0.205
0.874
10 (1.8)
547 (98.2)
39 (2.2)
1733 (97.8)
8 (1.8)
431 (98.2)
41 (2.1)
1870 (97.9)
No (n=117)
P-value
3 (21.4)
11 (78.6)
0.76
46 (30.3)
106 (69.7)
1 (25)
3 (75)
48 (29.6)
114 (70.4)
49.3
53.2
1
0.714
(31.8-66.8) (43.3-63.1) 0.561
0.669
10 (21.7)
36 (78.3)
39 (33.1)
79 (66.9)
8 (25.8)
23 (74.2)
41 (30.8)
92 (69.2)
0.186
0.667
Table 2 Factors independently associated with inferior laryngeal nerve palsy. Variable
Transient nerve palsy (n=) Adjusted OR 95% CI
Permanent nerve palsy (n=) P-value Adjusted OR 95% CI
Permanent following transient nerve palsy (n=) P-value Adjusted OR 95% CI
P-value
Patient sex
Female vs. Male 1.14
0.79-1.66 0.488
2.89
1.20-6.94 0.018
4.29
1.50-12.27
Extended thyroidectomy
Yes vs. No
1.29
0.34-4.96 0.706
3.30
0.29-36.78 0.332
26.34
0.67-1040.86 0.081
Lymph node dissection
Yes vs. No
1.55
0.93-2.61 0.095
0.45
0.10-2.07 0.303
0.14
0.02-1.24
0.078
Difficult nerve identification Yes vs. No
1.80
1.29-2.49 0.000
4.17
2.31-7.51 0.000
4.17
1.94-8.98
0.000
Large goiter
Yes vs. No
1.75
1.19-2.56 0.004
2.61
1.39-4.93 0.003
2.42
1.02-5.73
0.045
Intense thyroiditis
Yes vs. No
1.73
0.98-3.07 0.060
2.25
0.92-5.53 0.077
1.86
0.54-6.37
0.324
Invasive extra-thyroid cancer Yes vs. No
2.72
0.81-9.13 0.105
2.40
0.23-25.53 0.468
0.41
0.02-10.06
0.589
Hosmer-Lemeshow test
Chi² = 5.104
0.277
Chi² = 2.030
0.845
Chi² = 2.071
0.913
C-statistic
AUC = 0.622
0.000
AUC = 0.753
0.000
AUC = 0.753
0.000
0.007
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Table 3 Distribution of patient characteristics regarding hypoparathyroidism. Transient hypoparathyroidism
Permanent hypoparathyroidism
All patients
All patients
Yes (n=737) Patient sex
No (n=2188)
P-value
Yes (n=78)
Patients with transient hypoparathyroidism No (n=2826)
Female
633 (27.6) 1663 (72.4)
Patient age, years
Mean
48.6
(95% CI)
(47.5-49.7) (52.1-53.3)
(44.4-51.8) (51.3-52.3)
(44.4-51.8) (47.5-49.9)
Patient body mass indexb
<25 kg/m² (%)
430 (29.9) 1006 (70.1) 0.000
39 (2.7)
1383 (97.3) 0.632
39 (9.4)
376 (90.6)
25-<30 kg/m² (%)
193 (21.7) 698 (78.3)
25 (2.8)
860 (97.2)
25 (13.4)
162 (86.6)
≥30 kg/m² (%)
104 (19.3) 434 (80.7)
11 (2.0)
527 (98.0)
11 (10.6)
93 (89.4)
Non-toxic solitary nodule (%)
31 (25.4)
0 (0)
121 (100)
0 (0)
30 (100)
Non-toxic multinodular goiter (%)
414 (22.9) 1395 (77.1)
44 (2.4)
1755 (97.6)
44 (10.9)
360 (89.1)
Hyperthyroidism (%)
67 (22.8)
6 (2.1)
286 (97.9)
6 (9.2)
59 (90.8)
Graves’disease (%)
101 (30.7) 228 (69.3)
11 (3.4)
313 (96.6)
11 (11.5)
85 (88.5)
Malignant neoplasm (%)
124 (33.4) 247 (66.6)
17 (4.6)
351 (95.4)
17 (14)
104 (86)
0 (0)
24 (100)
0 (0)
3 (100)
Thyroid disease
Thyroid procedure
Subtotal thyroidectomy (%) 3 (12.5)
227 (77.2)
21 (87.5)
0.022
0.039
0.025
69 (11.2)
545 (88.8)
48.1
48.7
2600 (97.4)
69 (10.4)
592 (89.6)
Extended thyroidectomy (%)
17 (43.6)
22 (56.4)
4 (10.3)
35 (89.7)
4 (23.5)
13 (76.5)
137 (79.7)
5 (2.9)
167 (97.1)
5 (14.3)
30 (85.7)
15 (4.5)
318 (95.5)
15 (13)
100 (87)
60 (2.4)
2414 (97.6)
60 (10.5)
513 (89.5)
17 (2.9)
562 (97.1)
17 (11.7)
128 (88.3)
61 (2.6)
2264 (97.4)
61 (10.7)
510 (89.3)
13 (2.4)
538 (97.6)
13 (10.7)
108 (89.3)
65 (2.8)
2288 (97.2)
65 (10.9)
530 (89.1)
8 (2.6)
299 (97.4)
8 (10.7)
67 (89.3)
70 (2.7)
2527 (97.3)
70 (10.9)
571 (89.1)
14 (4.2)
321 (95.8)
14 (14.9)
80 (85.1)
64 (2.5)
2505 (97.5)
64 (10.3)
558 (89.7)
4 (4.3)
88 (95.7)
4 (15.4)
22 (84.6)
74 (2.6)
2738 (97.4)
74 (10.7)
616 (89.3)
7 (2.8)
247 (97.2)
7 (12.5)
49 (87.5)
71 (2.7)
2579 (97.3)
71 (10.8)
589 (89.2)
Yes (%)
117 (34.9) 218 (65.1)
No (%)
592 (23.7) 1901 (76.3)
Large goiter
Yes (%)
128 (22.9) 430 (77.1)
No (%)
609 (25.7) 1758 (74.3)
Yes (%)
77 (24.9)
No (%)
660 (25.2) 1956 (74.8)
Hemorrhagic Yes (%) goiter No (%)
Intense fibrosis
51.8
92 (91.1)
69 (2.6)
584 (25.0) 1754 (75.0)
Bleeding difficult to control
0.011
48.1
9 (8.9)
682 (25.4) 2008 (74.6)
Difficult Yes (%) parathyroid identification No (%)
Intrathoracic goiter
0.000
2208 (97)
0.029
Total thyroidectomy (%)
Completion thyroidectomy 35 (20.3) (%) Lymph node dissection
91 (74.6)
0.000
69 (3)
No (n=638)
103 (16.4) 525 (83.6)
52.7
617 (98.6)
Yes (n=78)
Male
0.000
9 (1.4)
P-value
153 (26.1) 434 (73.9)
96 (28.5)
232 (75.1)
241 (71.5)
0.000
0.588
0.172
0.905
0.139
641 (24.8) 1947 (75.2)
Yes (%)
28 (29.8)
66 (70.2)
No (%)
709 (25.0) 2122 (75.0)
Yes (%)
58 (22.7)
198 (77.3)
No (%)
679 (25.4) 1990 (74.6)
0.297
0.327
0.027
0.677
0.598
0.927
0.072
0.316
0.942
P-value 0.606
0.695
0.343
0.275
0.293
0.414
0.719
1
1
0.212
0.514
0.656
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Table 3 Distribution of patient characteristics regarding hypoparathyroidism. Transient hypoparathyroidism
Permanent hypoparathyroidism
All patients
All patients
Yes (n=737)
No (n=2188) 125 (74.0)
Intense thyroiditis
Yes (%)
44 (26.0)
No (%)
693 (25.1) 2063 (74.9)
Thyroid friability
Yes (%)
37 (20.8)
No (%)
700 (25.5) 2047 (74.5)
141 (79.2)
Invasive Yes (%) extra-thyroid No (%) cancer
12 (37.5)
20 (62.5)
Weight of thyroid specimen, grams
Mean
50.5
(95% CI)
(46.6-54.3) (45.6-49.6)
Cancer in thyroid specimen
Yes (%)
219 (28.7) 545 (71.3)
No (%)
514 (24.1) 1620 (75.9)
Thyroiditis in thyroid specimen
Yes (%)
128 (28.6) 363 (73.9)
No (%)
583 (25.2) 1729 (74.8)
P-value 0.796
0.162
0.107
725 (25.1) 2168 (74.9) 47.6
0.357
Yes (n=78)
Patients with transient hypoparathyroidism No (n=2826)
6 (3.6)
161 (96.4)
72 (2.6)
2665 (97.4)
8 (4.5)
170 (95.5)
70 (2.6)
2656 (97.4)
1 (3.1)
31 (96.9)
77 (2.7)
2795 (97.3)
51.1
48.2
P-value 0.455
0.123
0.877
0.046
(41.8-60.3) (46.4-50) 0.012
0.693
23 (3.0)
734 (97.0)
54 (2.5)
2066 (97.5)
20 (4.1)
463 (95.9)
53 (2.3)
2246 (97.7)
Yes (n=78)
No (n=638)
6 (14.3)
36 (85.7)
72 (10.7)
602 (89.3)
8 (21.6)
29 (78.4)
70 (10.3)
609 (89.7)
1 (8.3)
11 (91.7)
77 (10.9)
627 (89.1)
51.1
50.3
P-value 0.444
0.051
1
0.056
(41.8-54.6) (46.1-54.6) 0.472
0.022
23 (10.8)
189 (89.2)
54 (10.8)
446 (89.2)
20 (16.7)
100 (83.3)
53 (9.3)
517 (90.7)
1
0.022
Table 4 Factors independently associated with hypoparathyroidism Variable
Transient hypoparathyroidism (N=)
Permanent hypoparathyroidism (N=)
Adjusted OR
95% CI
P-value Adjusted OR
Permanent following transient hypoparathyroidism (N=)
95% CI
P-value Adjusted OR
95% CI
P-value
Patient sex
Female vs. Male
2.21
1.70-2.86
0.000
2.47
1.11-5.54
0.027
1.40
0.59-3.35
0.447
Patient age, years
By 1 year increase
0.98
0.98-0.99
0.000
0.98
0.97-1.00
0.035
0.99
0.97-1.01
0.411
Patient body mass index
By 1 point IMC increase
0.96
0.95-0.98
0.000
1.01
0.96-1.05
0.766
1.03
0.98-1.09
0.168
Extended thyroidectomy
Yes vs. No
2.67
1.26-5.71
0.010
4.77
1.45-15.71 0.010
3.25
0.94-11.26 0.063
Lymph node dissection Yes vs. No
1.88
1.42-2.48
0.000
1.83
0.94-3.59
0.077
1.15
0.57-2.31
0.694
Weight of thyroid specimen
By 1 gram increase
1.00
1.00-1.01
0.000
1.00
1.00-1.01
0.236
1.00
0.99-1.01
0.923
Thyroiditis in thyroid specimen
Yes vs. No
1.02
0.81-1.30
0.839
1.76
1.01-3.09
0.048
1.88
1.03-3.42
0.039
Hosmer-Lemeshow test
Chi² = 14.282
0.075
Chi² = 6.367
0.606
Chi² = 5.775
0.672
C-statistic
AUC = 0.647
0.000
AUC = 0.656
0.000
AUC = 0.607
0.004
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4. Discussion In this study, we sought to estimate the transient and permanent complication rates following thyroidectomy and then to quantify their association with perioperative risk factors related to the patient, the surgical procedure, thyroid pathology, or the surgeon’s technique. Although the risks of longterm hypoparathyroidism and nerve palsy complications are similar, the risk of transient complication is much higher for hypoparathyroidism than for recurrent nerve palsy. Risk factors associated with permanent ILN palsy are primarily related to intra-operative technical elements, whereas those associated with hypoparathyroidism are mainly controlled by preoperative pathology features. Meticulous dissection and thorough technique are mandatory for reducing ILN palsy but fail to prevent hypoparathyroidism occurrence. Transient nerve palsy is encountered in 7.51% of patients, one of the highest percentages reported in the literature, ranging from 0.2% to 9.8% [7,11,13,15,17-20]. In accordance with previous works insisting on the absolute need for nerve identification, the non-visualization of the ILN during dissection harbors the highest risk for nerve palsy occurrence [15,16]. Jointly, the presence of a large thyroid mass represents the difficulty perceived by the surgeon during the procedure and appears as the second independent risk factor of transient ILN palsy. In this particular setting, dissection of the ILN is found to be more difficult, especially when the Zuckerkandl tubercle is enlarged. This enlargement lead to excessive traction, which is recognized as a major mechanism for nerve dysfunction [8,11,21]. The 2.08% rate of permanent ILN palsy fits within the range of previous works: 0.7% to 5.65% [11,13,15-17,19,20]. Again, non-visualization of the ILN during dissection appears as the major risk factor for permanent nerve dysfunction. This fact provides additional proof that gentle dissection with ILN identification is the gold standard in thyroid surgery for reducing permanent nerve palsy, as mentioned in previous multivariate analyses [15,16]. After initial palsy, the recovery of nerve function at one year is expected to be as high as 95% when the anatomic integrity is confirmed during surgery [20,22]. This is the first report involving a multivariate analysis to identify the relevant predictive factors of the transition from transient to permanent palsy. The non-visualization of the ILN nerve during dissection represents a striking risk factor for irreversible damage. Injuries seem to be more severe (axonotmesis and neurotmesis) than when they occur under nerve identification (neurapraxia). The presence of a large thyroid mass additionally predicts a negative outcome regarding nerve function recovery. The intra-operative difficulty as perceived by the surgeon according to his/her experience presumes that failure to perform a thorough standardized technique ultimately negatively affects nerve function recovery when an early injury occurs. Neither extended thyroidectomy nor lymph node dissection nor the presence of cancer or thyroiditis is related to the occurrence of ILN palsy after thyroid surgery. The only consis-
tent factors affecting early and late dysfunction, as well as the ability for the nerve to recover, appear to be dependent on the intra-operative technique. Nerves are at increased risk whenever the surgeon fails to scrupulously apply established principles for safe intervention. Patients with transient ILN palsy in the context of an unidentified nerve or large thyroid mass must be warned of the potential persistence of this complication and be closely followed-up and managed accordingly. In this study, transient hypocalcemia occurred in 25.1% of total patients, which is in accordance with the range reported in the literature: 0.2% to 50.2% [7,9,10,13,15,19,23,24]. Lymph node dissection and female gender are associated with this complication, as previously suggested in case series [9,10,14,15,19,25]. Nevertheless, this effect vanishes with time because parathyroid function recovery and permanent hypocalcemia are not affected. Hypocalcemia after lymph node dissection seems to be mainly caused by extensive dissection of parathyroid glands rather than irreversible injury. Although advocated in other series, Graves’disease [15,2] and total thyroidectomy [14,15,26,27] did not appear as independent parameters here. Thorough follow-up of patients reveals a permanent hypoparathyroidism rate of 2.69%, fitting within the range of previously published studies: 0.5% to 4.4% [9,10,13,15,19,23,27]. Thyroiditis on pathology specimens is identified as a major predictive factor for this complication, especially when early hypocalcemia occurs after thyroid surgery. This observation represents a novel insight because thyroiditis is vaguely reported in the literature as a risk factor for early postoperative hypocalcemia [24]. Often, thyroiditis indicates Hashimoto’s and de Quervain diseases, which are both rare and usually excluded from studies [15]. Hypervascularization associated with thyroiditis may jeopardize small parathyroid vessels, whereas excessive fibrosis renders gland identification and dissection more difficult. Although these findings do not seem to alter transient hypocalcemia rates, increased permanent hypoparathyroidism indicates that in the context of thyroiditis, parathyroid gland dysfunction is subsequent to irreversible devascularization, inadvertent resection or profound trauma rather than transient sideration. To the best of our knowledge, no specific practical tips are available in the current literature to better address this particular situation involving a high risk for the parathyroid glands. The number of identified parathyroid glands left in situ has been reported as an objective factor associated with hypocalcemia [9,23,26]. We could not establish such an association because the difficulty of parathyroid identification did not appear as an independent factor in our multivariate analysis. If the initial pathology and patient characteristics play a slight role in transient hypocalcemia, they represent major uncontrollable factors for parathyroid recovery and permanent hypoparathyroidism. Assuming that the risk of hypoparathyroidism after thyroid surgery may be reduced when the procedure is conducted by an experienced surgeon, this study shows that the long-term outcome is unpredictable
R. Daher et al. / Annales d’Endocrinologie 76 (2015) 1S16-1S26
based solely on the surgical technique [7,8,12]. This information may push the surgeon toward a limited surgery (such as subtotal lobectomy) or even surveillance whenever possible if the diagnosis of thyroiditis is made pre-operatively. Additionally, patients must be promptly treated and regularly followed-up regarding these considerations. Because all patients undergoing a thyroidectomy were prospectively enrolled, irrespective of pathology and procedure type, and were systematically assessed for postoperative complications through objective screening, this multicenter study is assumed to provide a valid picture of thyroid surgery practices and expected outcomes. However, there are several limitations to this work. Our study sample was extracted from a population of French academic surgeons at high-volume referral centers, which may alter the representativeness in relation to regular patient recruitment and outcomes and may also transform surgeons’perceptions about procedure complexity. Furthermore, surgical outcomes depend on interactions between many factors that are still poorly understood and are difficult to characterize. We cannot exclude the possibility that other unknown or unmeasured risk factors may have further explained the reasons for the complications. Despite attempts to consider the characteristics of the patients, thyroid specimens and procedures, as well as the surgeons’perception during thyroidectomy, the singularity of thyroid diseases sometimes requires procedures of a complexity that might not have been sufficiently captured in statistical models. This large-volume multicenter prospective study highlights that even among experienced teams, complications after thyroid surgery are not uncommon. The surgeon’s ability to apply the gold-standard technique of inferior laryngeal nerve visualization is the principal determinant of short- and long-term nerve function as well as the patient’s ability to recover from initial injury. Conversely, meticulous dissection and thorough technique are not the sole predictors of parathyroid function outcome. The initial pathology represents a major technically uncontrollable factor in permanent hypoparathyroidism and parathyroid function recovery. The presence of thyroiditis perfectly illustrates this high-risk situation.
Acknowledgments The following are members of the CATHY Study Group: Matthew Carty and Stuart Lipsitz (Boston); Laurent Arnalsteen, Robert Caizzo, Bruno Carnaille, Guelareh Dezfoulian, Carole Eberle, Ziad El Khatib, Emmanuel Fernandez, Antoine Lamblin, François Pattou, and Marie-France Six (Lille); Stéphanie Bourdy, Laetitia Bouveret, Cyrille Colin, Antoine Duclos, Benoît Guibert, Marie-Annick Le Pogam, Jean-Christophe Lifante, Jean-Louis Peix, Gaétan Singier, Pietro Soardo, Sandrine Touzet, and Nicolas Voirin (Lyon); Pascal Auquier, JeanFrançois Henry, Claire Morando, Frédéric Sebag, and Sam Van Slycke (Marseille); Inès Akrout, Fares Benmiloud, JeanPaul Chigot, Isabelle Colombet, Gaëlle Godiris-Petit, Pierre Leyre, Fabrice Ménégaux, Séverine Noullet, Benoît Royer,
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and Christophe Tresallet (Paris); Thibault Desurmont, Claudia Dominguez, Jean-Louis Kraimps, Chiara Odasso, and Laetitia Rouleau (Poitiers); and Yves-Louis Chapuis, Pierre Durieux, Alain Lepape, and Frédéric Triponez (Scientific Committee).
Conflicts of interest Authors declare no conflict of interest.
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