Professional Documents
Culture Documents
Falch2018 PDF
Falch2018 PDF
Claudius Falch, Jan Hornig, Moritz Senne, Manuel Braun, Alfred Konigsrainer,
Andreas Kirschniak, Sven Muller
PII: S1743-9191(18)30761-1
DOI: 10.1016/j.ijsu.2018.05.014
Reference: IJSU 4646
Please cite this article as: Falch C, Hornig J, Senne M, Braun M, Konigsrainer A, Kirschniak A, Muller S,
Factors predicting hypocalcemia after total thyroidectomy – A retrospective cohort analysis, International
Journal of Surgery (2018), doi: 10.1016/j.ijsu.2018.05.014.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Hypocalcemia after total thyroidectomy, prolonged surgery
Claudius Falch MD; Jan Hornig, Moritz Senne; Manuel Braun, MD; Alfred
PT
RI
Working Group for Surgical Technique and Training,
Clinic for Visceral, General and Transplant Surgery, Tuebingen University
SC
Hospital, Germany
U
All authors declare that they have no conflict of interest
AN
M
Correspondence:
Sven Muller, MD
D
Working Group for Surgical Technique and Training; Clinic for General,
TE
Waldhörnlestrasse 22
EP
72076 Tübingen
C
Germany
AC
Email: sven.mueller@med.uni-tuebingen.de
PT
RI
U SC
AN
M
D
TE
C EP
AC
1
ACCEPTED MANUSCRIPT
Abstract
Background:
PT
predictive for hypocalcemia and its long term persistence after total thyroidectomy.
RI
2005 until 2013. Outcome measures were initial postoperative hypocalcemia defined
SC
as serum calcium below 2.0 mmol/l after total thyroidectomy within 48h and
persistent hypocalcemia defined as serum calcium below 2.0 mmol/l above six
U
months and/or the need for additional calcium and vitamin D supplementation.
AN
Results: Initial postoperative hypocalcemia was present in 160 of 702 patients
(38 patients (41.8%) vs. 10 patients (14.5%), p < 0,001). In the binary logistic
EP
regression analysis, female gender (OR 2.4; CI95% 1.5 – 3.8), prolonged surgery
time >189 minutes (OR 1.8; CI95% 1.2 – 2.6) and parathyroid reimplantation (OR
C
2.4; CI95% 1.2 – 4.7) were associated with initial hypocalcemia while only initial
AC
2
ACCEPTED MANUSCRIPT
hypocalcemia after total thyroidectomy is associated with a high rate of persistent
hypocalcemia.
PT
RI
U SC
AN
M
D
TE
C EP
AC
3
ACCEPTED MANUSCRIPT
Introduction
procedure for benign thyroid disease has steadily increased over subtotal
thyroid resections in the last few decades [1]. However with this more radical
PT
approach, an increasing rate of postoperative hypocalcemia is described as well [2].
RI
around 15-30%, resulting in patient discomfort, longer hospital stay and higher
SC
treatment costs [3]. In the long term, persisting hypocalcaemia above 6 to 12 months
U
most cases [4, 5]. Factors associated with the development of postoperative
AN
hypocalcemia after total thyroidectomy are female gender, pathology and extent of
the underlying thyroid disease, failure to preserve the parathyroid glands and a pre-
M
existing low vitamin D level [6, 7]. Further a potential impact of prolonged surgery
D
4
ACCEPTED MANUSCRIPT
Methods
A series of 1209 consecutive patients undergoing thyroid surgery from January 2005
patient database. All patients with total thyroidectomy were included in the final
PT
analysis. Total thyroidectomy was performed according to the in house standards
RI
nerve was routinely applied. Identification and preservation of all parathyroid glands
was aspired. Reimplantation of a parathyroid gland was only performed if the gland
SC
was accidentally resected or judged to be devascularized. Excluded were patients
U
undergoing thyroid resection other than total thyroidectomy, patients with concurrent
AN
lymphadenectomy and patients where no follow up above 6 months was available.
The in-house standard for the treatment of postoperative hypocalcemia during the
M
study period was as following: oral calcium was routinely administered when a
symptoms of hypocalcemia were present or did not improve over time, oral 1,25 OH
TE
Definitions
C
calcium below 2.0 mmol/l within 48 hours [9]. Persistent hypocalcemia was defined
as a serum calcium below 2.0 mmol/l and/or the need for supplementation with
calcium and/or 1,25 OH vitamin D above 6 months after total thyroidectomy [10, 11].
treatment with 1,25 OH vitamin D, gender, age (years), thyroid disease pathology
5
ACCEPTED MANUSCRIPT
(any previous subtotal thyroid surgery), thyroid specimen weight (g), surgery time
(min), educational type of surgery (expert procedure (surgeon performing more than
50 procedures per year) vs. teaching procedure with the attendance of an expert
PT
parathyroid glands preserved in situ and parathyroid replantation were assessed.
RI
Data were analysed with SPSS Statistics 22 for Windows (IBM Corporation, NY,
USA). Summary data are presented as a raw percentage, median (IQR). Proportions
SC
were compared using the Chi2 test (Fisher's exact test, two-tailed analysis) and
medians were compared using the Mann-Whitney U test (Wilcoxon rank sum test).
U
Continuous variables of interest were dichotomized using cut-off values. Cut-off
AN
values for surgery time correlating with initial postoperative biochemical
M
and determination of the Youden index. A p value < 0.05 was deemed to denote
D
accordance with the ethical requirements regarding the protection of the rights and
AC
welfare of human subjects participating in medical research and has been reported in
6
ACCEPTED MANUSCRIPT
Results
Out of a total of 1209 patients who underwent thyroid surgery, 702 patients were
finally analysed. Some 474 patients with unilateral or subtotal thyroid resections, 24
PT
excluded. Patient characteristics and surgical details are displayed in table 1 and
table 2 respectively. Pre- and postoperative serum calcium levels for patients with no
RI
biochemical hypocalcemia, initial postoperative biochemical hypocalcemia only and
SC
persistent biochemical hypocalcemia are shown in figure 1. Preoperative serum
calcium levels did not differ between patients with and without postoperative
U
biochemical hypocalcemia.
AN
Initial postoperative biochemical hypocalcemia
M
(5%) and vitamin D in 29 patients (4%). Seven patients received oral calcium despite
(ROC) analysis with Youden Index showed a cut off value 189 minutes for surgery
C
AUC 0.565 (CI 95% CI: 0.515 – 0.615). Patients with a surgery time ≥189 minutes
had significantly more often a postoperative hypocalcemia than those with shorter
surgery time (18.3% vs. 28.3%, p= 0.002). Patients with parathyroid gland
analysis, only surgery time, a female gender and parathyroid gland reimplantation
7
ACCEPTED MANUSCRIPT
were the significant independent predictors for initial postoperative biochemical
Persistent hypocalcemia
PT
Persistent biochemical hypocalcemia and/or supplementation with calcium and/or
RI
vitamin D was present in 48 of 702 patients (6.8%). Of these, 19 patients had a
SC
and 29 patients displayed a persistent biochemical hypocalcemia, despite
U
biochemical hypocalcemia accompanied by symptoms and/or the necessity for
AN
intravenous calcium was significantly more often associated with a persistent
M
(38/91 patients (41.8%) vs. 10/69 patients (14.5%); p <0.001). In the binary logistic
D
8
ACCEPTED MANUSCRIPT
Discussion
Over the last decade total thyroidectomy is increasingly utilized for benign thyroid
disease in order to avoid disease recurrence and revision surgery [13]. However with
PT
increasing as well resulting in a higher patient discomfort, prolongation of hospital
stay, a higher consumption of health care resources and higher treatment costs [6,
RI
14, 15]. The present work analysing 702 patients after total thyroidectomy shows that
SC
associated with persistent hypocalcemia. Besides the known risk factors, female
U
gender, parathyroid gland reimplantation and prolonged surgery time were also
AN
associated with initial postoperative hypocalcemia.
reports are very inconsistent, ranging from a simple chemical lab reference range
values for serum calcium levels to the presence of clinical symptoms of tetany and
EP
parathormone serum levels at various time points. Mahenna et al. showed that
varied from 0-46% in the same cohort [17]. Lorente-Poch et al. proposed to classify
AC
PTH) and relative parathyroid insufficiency (normal PTH and subnormal serum
calcium) at different time points (protracted resolving after one month and permanent
after one year) [16]. However this differentiated classification is only based on
9
ACCEPTED MANUSCRIPT
routine is doubtful [18]. As parathyroid insufficiency results in subnormal serum
PT
This is also underlined by a recent systematic review by Mathur et al. concluding that
RI
single PTH thresholds are not a reliable measure of hypocalcemia and PTH
SC
heterogeneous [20, 21]. Postoperative parathormone levels were therefore not
U
hypocalcemia as a valid conclusion was not possible due inconsistent determinations
AN
at varying time points.
M
problem after total thyroidectomy in our series. A systematic review by Edafe et al.
D
showed that only low postoperative serum calcium was constantly reported with
TE
time) were only reported inconsistently in some single series. The rather high rate of
C
While a prolonged procedure time was associated with initial hypocalcemia in our
the association of surgery time and postoperative hypocalcemia after thyroid surgery
with contradictory results [8, 23-29]. An analysis of the Swedish thyroid registry by
10
ACCEPTED MANUSCRIPT
Hallgrimsen et al. found that in patients with underlying Graves disease and
hypocalcemia being considered as proxies for the extent of dissection [23]. On the
hypocalcemia did not include more than 200 patients in their analysis making a
PT
sound conclusion uncertain [25, 27-29]. As in most existing reports on the influence
RI
of surgery time on postoperative hypocalcemia, no clear standardization in the
SC
technique (knot tying and clips versus energy derived device resections) is
guaranteed, a valid analysis is very heterogeneous and difficult. In our analysis all
U
patients received a total thyroidectomy without further surgical extensions (e.g.
AN
lymphadenectomy) using a standardized knot tying technique. As surgeons
M
this series, the observed correlation of surgery time can not only be explained by
TE
complexity of the procedure itself. Further we checked that prolonged surgery time
did not have any correlation with other complications after total thyroidectomy as
EP
thyroid surgery observed consistently that not only surgery time was significantly
dissection device itself or the shorter surgery time remains unclear and might be
11
ACCEPTED MANUSCRIPT
procedure time resulting in less tissue trauma with a reduced tissue inflammation,
Also observed in this study was, that patients receiving thyreostatic drugs to achieve
PT
Hyperthyroidism itself is not described to be associated with increased postoperative
RI
control are lacking. Mehanna et al. described an increased postoperative
SC
syndrome [17]. This might explain why patients could experience a risk reduction of
U
postoperative hypocalcemia by a previous long-standing thyreostatic treatment.
AN
To reduce the incidence of postoperative hypocalcemia after total thyroidectomy,
underlying disease and surgical expertise but does not affect the persistence of
C
hypocalcemia.
AC
12
ACCEPTED MANUSCRIPT
Abbreviations
PT
RI
U SC
AN
M
D
TE
C EP
AC
13
ACCEPTED MANUSCRIPT
Gesellschaft fur Allgemein- und Viszeralchirurgie und fur die Deutsche Gesellschaft
PT
surgery]. Chirurg. 2009;80(4):352-63.
RI
on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate
SC
analysis of 5846 consecutive patients. Surgery. 2003;133(2):180-5.
U
predictors of post-thyroidectomy hypocalcaemia. Br J Surg. 2014;101(4):307-20.
AN
4. Seo GH, Chai YJ, Choi HJ, et al. Incidence of Permanent Hypocalcaemia after
Total Thyroidectomy with or without Central Neck Dissection for Thyroid Carcinoma:
M
5. Kim SM, Kim HK, Kim KJ, et al. Recovery from Permanent
D
2015;400(3):319-24.
C
during thyroid surgery: risk factors, incidence, and outcomes. Turk J Med Sci.
2014;44(1):84-8.
14
ACCEPTED MANUSCRIPT
9. Sitges-Serra A, Ruiz S, Girvent M, et al. Outcome of protracted
10. Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective
cohort study of 5583 cases of thyroid carcinoma treated in the united states during
1996. U.S. and German Thyroid Cancer Study Group. An American College of
PT
Surgeons Commission on Cancer Patient Care Evaluation study. Cancer.
RI
2000;89(1):202-17.
SC
surgery: results as reported in a database from a multicenter audit comprising 3,660
12.
U
Agha RA, Borrelli MR, Vella-Baldacchino M, et al. The STROCSS statement:
AN
Strengthening the Reporting of Cohort Studies in Surgery. Int J Surg. 2017;46:198-
M
202.
13. Dralle H, Stang A, Sekulla C, et al. [Surgery for benign goiter in Germany:
D
2014;85(3):236-45.
14. Tredici P, Grosso E, Gibelli B, et al. Identification of patients at high risk for
EP
15. Conzo G, Avenia N, Ansaldo GL, et al. Surgical treatment of thyroid follicular
C
2017;55(2):530-8.
16. Lorente-Poch L, Sancho JJ, Munoz-Nova JL, et al. Defining the syndromes of
15
ACCEPTED MANUSCRIPT
18. Raffaelli M, De Crea C, D'Amato G, et al. Post-thyroidectomy hypocalcemia is
PT
20. Mathur A, Nagarajan N, Kahan S, et al. Association of Parathyroid Hormone
RI
Level With Postthyroidectomy Hypocalcemia: A Systematic Review. JAMA Surg.
2018;153(1):69-76.
SC
21. Karefilakis CM, Mazokopakis EE. Re: Management of post-thyroidectomy
22.
U
Chadwick DR. Hypocalcaemia and permanent hypoparathyroidism after
AN
total/bilateral thyroidectomy in the BAETS Registry. Gland Surg. 2017;6(Suppl
M
1):S69-S74.
thyroidectomy for Graves' disease and for benign atoxic multinodular goitre.
TE
24. Lang BH, Yih PC, Ng KK. A prospective evaluation of quick intraoperative
EP
parathyroid hormone assay at the time of skin closure in predicting clinically relevant
2012;152(5):863-8.
16
ACCEPTED MANUSCRIPT
28. Moriyama T, Yamashita H, Noguchi S, et al. Intraoperative parathyroid
29. Lombardi CP, Raffaelli M, Princi P, et al. Parathyroid hormone levels 4 hours
PT
2006;140(6):1016-23; discussion 23-5.
RI
30. Cheng H, Soleas I, Ferko NC, et al. A systematic review and meta-analysis of
SC
Res. 2015;8:15.
31. Arer IM, Kus M, Akkapulu N, et al. Prophylactic oral calcium supplementation
U
therapy to prevent early post thyroidectomy hypocalcemia and evaluation of
AN
postoperative parathyroid hormone levels to detect hypocalcemia: A prospective
M
32. Jaan S, Sehgal A, Wani RA, et al. Usefulness of pre- and post-operative
D
2017;21(1):51-5.
C EP
AC
17
ACCEPTED MANUSCRIPT
Figure 1)
Pre- and postoperative serum calcium levels for patients with no biochemical
biochemical hypocalcemia preoperative, 24h after surgery and 48h after surgery
PT
RI
U SC
AN
M
D
TE
C EP
AC
18
ACCEPTED MANUSCRIPT
PT
Age, years at surgery [median (IQR)] 53 (43 – 63) 53 (43 – 63) 51 (40 – 63) 0.36 53 (43 – 63) 54.5 (43 – 67) 0.36
Gender (female) 501 (71.4%) 369 (68.1%) 132 (82.5%) < 0.001 461 (70.5%) 40 (83.3%) 0.07
RI
Treatment with
SC
oral calcium 7 92 29
0
oral Vitamin D 0 29 9
U
intravenous calcium 0 36 0
Diagnosis
AN
multinodular goiter 481 (68.5%) 378 (69.8%) 103 (64.4%) 449 (68.6%) 32 (66.7%)
0.17 0.43
autoimmune thyroiditis 166 (23.6%) 127 (23.4%) 39 (24.4%) 156 (23.9%) 10 (20.8%)
M
malignant 55 (7.8%) 37 (6.8%) 18 (11.2%) 49 (7.5%) 6 (12.5%)
D
Thyreostatic drug therapy
Yes 104 (14.8%) 88 (16.2%) 16 (10%) 0.057 102 (15.6%) 2 (4.2%) 0.017
TE
No 598 (85.2%) 454 (83.8%) 144 (90%) 552 (84.4%) 46 (95.8%)
1
ACCEPTED MANUSCRIPT
Recurrent surgery
PT
Yes 49 (7.0%) 41 (7.6%) 8 (5%) 0.3 45 (6.9%) 4 (8.3%) 0.77
RI
No 653 (93.0%) 501 (92.4%) 152 (95%) 609 (93.1%) 44 (91.7%)
Specimen weight [g; median (IQR)] 40 (23 – 74) 40 (23 – 75) 40.5 (20 – 71) 0.56 40 (23 – 75) 40 (20 – 72) 0.68
SC
Surgery time [min, median (IQR)] 181 (150 – 225) 178.5 (148 – 221) 193.5 (154 – 241) 0.011 181 (150 – 224) 196.5 (146 – 253) 0.36
Surgery time
U
≥189min 315 (44.9%) 226 (41.7%) 89 (55.6%) 0.002 289 (44.2%) 26 (54.2%) 0.23
AN
<189min 387 (55.1%) 316 (58.3%) 71 (44.4%) 365 (55.8%) 22 (45.8%)
Parathyroid reimplantation
M
Yes 40 (5 7%) 22 (4.1%) 18 (11.3%) 0.001 35 (5.4%) 5 (10.4%) 0.18
No 662 (94 3%) 520 (95.9%) 142 (88.7%) 619 (94.6%) 43 (89.6%)
D
No. of parathyroids reimplanted
TE
0 662 (94 3%) 520 (95.9%) 142 (88.8%) 619 (94.6%) 43 (89.6%)
0.002 0.03
1 35 (5 0%) 20 (3.7%) 15 (9.4%) 32 (4.9%) 3 (6.3%)
EP
2 5 (0 7%) 2 (0.4%) 3 (1.8%) 3 (0.5%) 2 (4.1%)
Expert procedure 265 (37 7%) 216 (39.9%) 49 (30.6%) 0.04 249 (38.1%) 16 (33.3%) 0.5
AC
Teaching procedure 437 (62 3%) 326 (60.1%) 111 (69.4%) 405 (61.9%) 32 (66.7%)
No 687 (97 9%) 533 (98.3%) 154 (96.2%) 642 (98.2%) 45 (93.7%)
Variable Regression Coefficient (ß) Standard Error Odds Ratio (95% CI) p-value
Surgery time (≥189 minutes) 0.586 0.185 1.797 (1.249 – 2.584) 0.002
PT
Table 3 Multivariate analysis of variables associated with initial post-thyreoidectomy
RI
hypocalcaemia
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
Variable Regression Coefficient (ß) Standard Error Odds Ratio (95% CI) p-value
PT
RI
Table 4 Multivariate analysis of variables associated with persistent post-thyroidectomy
hypocalcemia
U SC
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
3.0
no hypocalcaemia
PT
initial postoperative hypocalcaemia only
persistant hypocalcaemia
RI
2.5
SC
serum calcium level (mmol/l)
2.0
U
AN
M
1.5
D
2.292 2.271 2.285
TE
2.095 2.109
1.0
1.881 1.804 1.805 1.717
C EP
0.5
AC
0.0
preoperative 1st pod 2nd pod
ACCEPTED MANUSCRIPT
International Journal of Surgery Author Disclosure Form
The following additional information is required for submission. Please note that
failure to respond to these questions/statements will mean your submission will be
returned. If you have nothing to declare in any of these categories then this should be
stated.
PT
Nothing to declare
RI
SC
Please state any sources of funding for your research
Nothing to declare
U
AN
Please state whether Ethical Approval was given, by whom and the relevant
M
Please enter the name of the registry and the unique identifying number of the study.
You can register your research at http://www.researchregistry.com to obtain your UIN
AC
if you have not already registered your study. This is mandatory for human studies
only.
1
ACCEPTED MANUSCRIPT
Author contribution
Please specify the contribution of each author to the paper, e.g. study design, data
collections, data analysis, writing. Others, who have contributed in other ways should
be listed as contributors.
S.M. & C.F. contributed by designing, facilitating and planning the study,
collecting data, performing the statistical analyses and interpretation, writing and
revising the manuscript, and final approval of the submitted manuscript. J.H.,
M.Se., M.B., A.Ko & A.K. contributed by planning the study, interpretation of
statistical analysis and final approval of the submitted manuscript.
PT
RI
Guarantor
The Guarantor is the one or more people who accept full responsibility for the work
SC
and/or the conduct of the study, had access to the data, and controlled the decision to
publish.
U
AN
M
D
TE
C EP
AC
2
ACCEPTED MANUSCRIPT
Highlights
PT
expertise
RI
• Prolonged surgery does not affect the persistence of hypocalcemia
U SC
AN
M
D
TE
C EP
AC