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Accepted Manuscript

Factors predicting hypocalcemia after total thyroidectomy – A retrospective cohort


analysis

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

To appear in: International Journal of Surgery

Received Date: 21 February 2018


Revised Date: 20 March 2018
Accepted Date: 10 May 2018

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.

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ACCEPTED MANUSCRIPT
Hypocalcemia after total thyroidectomy, prolonged surgery

time matters – a retrospective cohort analysis

Claudius Falch MD; Jan Hornig, Moritz Senne; Manuel Braun, MD; Alfred

Konigsrainer, MD; Andreas Kirschniak, MD; Sven Muller, MD

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Working Group for Surgical Technique and Training,
Clinic for Visceral, General and Transplant Surgery, Tuebingen University

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Hospital, Germany

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All authors declare that they have no conflict of interest
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Correspondence:

Sven Muller, MD
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Working Group for Surgical Technique and Training; Clinic for General,
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Visceral and Transplant Surgery; Tübingen University Hospital, Germany

Waldhörnlestrasse 22
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72076 Tübingen
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Germany
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Email: sven.mueller@med.uni-tuebingen.de

Phone: +49 – 7071 2983379

Word count abstract: 244

Word count manuscript: 1974

Key words: total thyroidectomy, hypocalcemia, prolonged surgery time


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Factors predicting hypocalcemia after total thyroidectomy – a

retrospective cohort analysis

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Abstract

Background:

Hypocalcemia after total thyroidectomy is the most frequent complication resulting in

prolongation of hospitalisation. Therefore we aimed to analyse clinical risk factors

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predictive for hypocalcemia and its long term persistence after total thyroidectomy.

Methods: Retrospective analysis of patients undergoing total thyroidectomy from

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2005 until 2013. Outcome measures were initial postoperative hypocalcemia defined

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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

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months and/or the need for additional calcium and vitamin D supplementation.
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Results: Initial postoperative hypocalcemia was present in 160 of 702 patients

(22.8%) with 91 patients (13%) developing symptoms. 48 patients (6.8%) had a


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persistent hypocalcemia above six months. Patients with an initial symptomatic


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postoperative hypocalcemia showed significantly more often a persistent


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hypocalcemia compared to asymptomatic patients with biochemical hypocalcemia

(38 patients (41.8%) vs. 10 patients (14.5%), p < 0,001). In the binary logistic
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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
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2.4; CI95% 1.2 – 4.7) were associated with initial hypocalcemia while only initial
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symptomatic hypocalcaemia was shown to be independently associated with

persistent hypocalcemia (OR 40.9; CI95% 18.5 – 90.4).

Conclusion: Prolonged surgery time seems to correlate with initial postoperative

hypocalcemia independently of the underlying disease and surgical expertise but

does not affect the persistence of hypocalcemia. Initial symptomatic postoperative

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hypocalcemia after total thyroidectomy is associated with a high rate of persistent

hypocalcemia.

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Introduction

In order to avoid disease recurrence, total thyroidectomy as a standard

procedure for benign thyroid disease has steadily increased over subtotal

thyroid resections in the last few decades [1]. However with this more radical

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approach, an increasing rate of postoperative hypocalcemia is described as well [2].

The rate of temporary hypocalcemia after total thyroidectomy is described to be

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around 15-30%, resulting in patient discomfort, longer hospital stay and higher

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treatment costs [3]. In the long term, persisting hypocalcaemia above 6 to 12 months

presents in up to 5% requiring life long supplementation of calcium and vitamin D in

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most cases [4, 5]. Factors associated with the development of postoperative
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hypocalcemia after total thyroidectomy are female gender, pathology and extent of

the underlying thyroid disease, failure to preserve the parathyroid glands and a pre-
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existing low vitamin D level [6, 7]. Further a potential impact of prolonged surgery
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time on postoperative hypocalcemia is controversially reported [3, 8]. Therefore we


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analysed a consecutive cohort of total thyroidectomies in order to identify further

potential risk factors for the development and persistence of postoperative


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hypocalcemia after total thyroidectomy.


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Methods

A series of 1209 consecutive patients undergoing thyroid surgery from January 2005

to December 2013 at a Hospital was retrospectively analysed using an electronic

patient database. All patients with total thyroidectomy were included in the final

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analysis. Total thyroidectomy was performed according to the in house standards

with conventional knot tying technique. Neuromonitoring of the recurrent laryngeal

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nerve was routinely applied. Identification and preservation of all parathyroid glands

was aspired. Reimplantation of a parathyroid gland was only performed if the gland

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was accidentally resected or judged to be devascularized. Excluded were patients

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undergoing thyroid resection other than total thyroidectomy, patients with concurrent
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lymphadenectomy and patients where no follow up above 6 months was available.

The in-house standard for the treatment of postoperative hypocalcemia during the
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study period was as following: oral calcium was routinely administered when a

postoperative biochemical hypocalcemia below 2.0 mmol/l was proven. If clinical


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symptoms of hypocalcemia were present or did not improve over time, oral 1,25 OH
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vitamin D and if not sufficient intravenous calcium were added.


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Definitions
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Postoperative biochemical hypocalcemia was defined as an uncorrected serum


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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].

Further symptoms of tetany or cramps, treatment with oral or intravenous calcium,

treatment with 1,25 OH vitamin D, gender, age (years), thyroid disease pathology

(multinodular goitre, autoimmune thyroiditis, thyroid cancer), recurrent thyroid surgery

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(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

surgeon), anticoagulation, postoperative bleeding requiring surgery, preoperative

thyreostatic drug therapy, number of parathyroid glands identified, number of

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parathyroid glands preserved in situ and parathyroid replantation were assessed.

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Data were analysed with SPSS Statistics 22 for Windows (IBM Corporation, NY,

USA). Summary data are presented as a raw percentage, median (IQR). Proportions

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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).

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Continuous variables of interest were dichotomized using cut-off values. Cut-off
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values for surgery time correlating with initial postoperative biochemical
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hypocalcemia were determined by ROC (receiver operating characteristic) analysis

and determination of the Youden index. A p value < 0.05 was deemed to denote
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statistical significance. The above mentioned factors were all analyzed in an


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univariate logistic regression analysis if they were associated with initial

postoperative biochemical hypocalcemia and persistent hypocalcemia. Factors


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identified as significant in a univariate logistic regression analysis were selected to

perform a multiple logistic regression analysis. The study was conducted in


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accordance with the ethical requirements regarding the protection of the rights and
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welfare of human subjects participating in medical research and has been reported in

line with the STROCSS criteria [12].

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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

patients with lymphadenectomy and 9 patients with incomplete follow up were

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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

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biochemical hypocalcemia, initial postoperative biochemical hypocalcemia only and

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persistent biochemical hypocalcemia are shown in figure 1. Preoperative serum

calcium levels did not differ between patients with and without postoperative

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biochemical hypocalcemia.
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Initial postoperative biochemical hypocalcemia
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Initial postoperative biochemical hypocalcemia was present in 160 patients (22.8%)

with 91 patients (13.0%) showing symptoms of hypocalcemia. Treatment with oral


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calcium was necessary in 92 patients (14.6%), intravenous calcium in 36 patients


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(5%) and vitamin D in 29 patients (4%). Seven patients received oral calcium despite

normal biochemical calcium levels and no signs of symptoms. Receiver operating


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(ROC) analysis with Youden Index showed a cut off value 189 minutes for surgery
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time correlating with postoperative biochemical hypocalcemia (Youden-Index 0.138;


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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

reimplantation also had a significant higher rate of initial postoperative biochemical

hypocalcemia (45% vs. 21.5%, p= 0.001). In a multivariate logistic regression

analysis, only surgery time, a female gender and parathyroid gland reimplantation

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were the significant independent predictors for initial postoperative biochemical

hypocalcemia (table 3).

Persistent hypocalcemia

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Persistent biochemical hypocalcemia and/or supplementation with calcium and/or

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vitamin D was present in 48 of 702 patients (6.8%). Of these, 19 patients had a

biochemical normocalcemia under supplementation with calcium and/or vitamin D

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and 29 patients displayed a persistent biochemical hypocalcemia, despite

supplementation with calcium and/or vitamin D in 13 patients. An initial postoperative

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biochemical hypocalcemia accompanied by symptoms and/or the necessity for
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intravenous calcium was significantly more often associated with a persistent
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hypocalcemia than inital postoperative biochemical hypocalcemia without symptoms

(38/91 patients (41.8%) vs. 10/69 patients (14.5%); p <0.001). In the binary logistic
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regression analysis just the initial symptomatic postoperative biochemical


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hypocalcaemia was shown to be an independent factor associated with developing

persistent hypocalcemia (table 4).


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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

this more radical approach, the risk of postoperative hypocalcemia seems to be

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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,

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14, 15]. The present work analysing 702 patients after total thyroidectomy shows that

initial symptomatic postoperative hypocalcemia was the only factor independently

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associated with persistent hypocalcemia. Besides the known risk factors, female

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gender, parathyroid gland reimplantation and prolonged surgery time were also
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associated with initial postoperative hypocalcemia.

Problematic in reporting postoperative hypocalcemia is the lack of a uniform


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definition of initial postoperative hypocalcemia and persistent hypocalcemia [16]. The


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definitions of postoperative hypocalcaemia following thyroid surgery used in most


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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
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parathormone serum levels at various time points. Mahenna et al. showed that

depending on the definition of postoperative hypocalcaemia, the postoperative rate


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varied from 0-46% in the same cohort [17]. Lorente-Poch et al. proposed to classify
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postoperative persistent parathyroid dysregulation based on parathormone serum

levels into aparathyroidism (PTH undetectable) and hypoparathyroidism (subnormal

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

laboratory parameters irrespective of patient’s symptoms and its usefulness in clinical

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routine is doubtful [18]. As parathyroid insufficiency results in subnormal serum

calcium, serum calcium levels can be used as a surrogate parameter for

postoperative hypoparathyroidism [10]. A definition by parathormone serum levels

alone seems to underrate the problem of persisting hypocalcemia, as clinically

symptomatic patients can display subnormal to normal parathormone levels [19].

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This is also underlined by a recent systematic review by Mathur et al. concluding that

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single PTH thresholds are not a reliable measure of hypocalcemia and PTH

measurements to predict postthyroidectomy hypocalcemia are extremely

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heterogeneous [20, 21]. Postoperative parathormone levels were therefore not

assessed in this work to further differentiate the diagnosis of postoperative

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hypocalcemia as a valid conclusion was not possible due inconsistent determinations
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at varying time points.
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Applying our definition, persisting hypocalcemia proved to be the most relevant

problem after total thyroidectomy in our series. A systematic review by Edafe et al.
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showed that only low postoperative serum calcium was constantly reported with
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permanent hypoparathyroidism after thyroidectomy while clinical (e.g. disease entity)


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and surgical factors (e.g. parathyroid reimplantation, surgical expertise, procedure

time) were only reported inconsistently in some single series. The rather high rate of
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persistent hypocalcemia in our series matches with a report from an UK registry,


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stating that approximately 7% of patients needed calcium or vitamin D

supplementation six months after total thyroidectomy [22].

While a prolonged procedure time was associated with initial hypocalcemia in our

series, it failed to be of relevance for persisting hypocalcemia. Few reports focus on

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

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Hallgrimsen et al. found that in patients with underlying Graves disease and

prolonged surgery time resulted in a higher incidence of symptomatic temporary

hypocalcemia being considered as proxies for the extent of dissection [23]. On the

other hand, studies reporting no influence of surgery time on postoperative

hypocalcemia did not include more than 200 patients in their analysis making a

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sound conclusion uncertain [25, 27-29]. As in most existing reports on the influence

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of surgery time on postoperative hypocalcemia, no clear standardization in the

procedure (inclusion of total thyroidectomies and subtotal resections) and resection

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technique (knot tying and clips versus energy derived device resections) is

guaranteed, a valid analysis is very heterogeneous and difficult. In our analysis all

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patients received a total thyroidectomy without further surgical extensions (e.g.
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lymphadenectomy) using a standardized knot tying technique. As surgeons
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experience, extent of surgery (all total thyroidectomies), disease pathology and

specimen weights had no impact on the occurrence of postoperative hypocalcemia in


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this series, the observed correlation of surgery time can not only be explained by
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complexity of the procedure itself. Further we checked that prolonged surgery time

did not have any correlation with other complications after total thyroidectomy as
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recurrent nerve palsy.


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Additionally, several randomized trials on the use of ultrasonic dissection devices in


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thyroid surgery observed consistently that not only surgery time was significantly

reduced in comparison to conventional dissection techniques but also rates of

postoperative hypocalcemia decreased [30]. If this effect is due to the ultrasonic

dissection device itself or the shorter surgery time remains unclear and might be

subject of further research. As a hypothetical explanation for the association of

postoperative hypocalcemia with surgery time observed in this study, a shorter

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procedure time resulting in less tissue trauma with a reduced tissue inflammation,

local edema and ischemia might be deployed.

Also observed in this study was, that patients receiving thyreostatic drugs to achieve

euthyreosis were less likely to develop initial postoperative hypocalcemia.

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Hyperthyroidism itself is not described to be associated with increased postoperative

hypocalcemia [3]. However reports on the impact on sufficient medical thyreostatic

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control are lacking. Mehanna et al. described an increased postoperative

hypocalcemia after prolonged hyperthyroidism due to a preexisting hungry bone

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syndrome [17]. This might explain why patients could experience a risk reduction of

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postoperative hypocalcemia by a previous long-standing thyreostatic treatment.
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To reduce the incidence of postoperative hypocalcemia after total thyroidectomy,

prophylactic administration of calcium and/or 25OH vitamin D has been described to


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be effective in several randomized controlled trials [31, 32].


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Altogether initial symptomatic postoperative hypocalcemia after total thyroidectomy is


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associated with a high rate of persistent hypocalcemia. Prolonged surgery time

seems to correlate with initial postoperative hypocalcemia independently of the


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underlying disease and surgical expertise but does not affect the persistence of
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hypocalcemia.
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Abbreviations

PTH – parathormone, OR – odds ratio, ROC – Receiver operating Characteristics,

AUC – Area under the curve, IQR – interquartile range

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Figure 1)

Pre- and postoperative serum calcium levels for patients with no biochemical

hypocalcemia, initial postoperative biochemical hypocalcemia only and persistent

biochemical hypocalcemia preoperative, 24h after surgery and 48h after surgery

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Postoperative biochemical Persistent biochemical

hypocalcaemia (48 h) hypocalcaemia (> 6 months)

Total No Yes p-value No Yes p-value

n= 702 542 (77.2%) 160 (22.8%) 654 (93.2%) 48 (6.8%)

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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

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Treatment with

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oral calcium 7 92 29
0
oral Vitamin D 0 29 9

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intravenous calcium 0 36 0

Diagnosis

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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%)

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malignant 55 (7.8%) 37 (6.8%) 18 (11.2%) 49 (7.5%) 6 (12.5%)

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Thyreostatic drug therapy

Yes 104 (14.8%) 88 (16.2%) 16 (10%) 0.057 102 (15.6%) 2 (4.2%) 0.017

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No 598 (85.2%) 454 (83.8%) 144 (90%) 552 (84.4%) 46 (95.8%)

Days of hospital stay [median (IQR)] 4 (4 – 5) 4 (4 – 5) 5 (4 – 5) 0.017 4 (4 – 5) 5 (4 – 6) 0.005


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Table 1 Patient characteristics


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Initial Postoperative biochemical Persistent biochemical

hypocalcaemia (48 h) hypocalcaemia (> 6 months)

Total No Yes p-value No Yes p-value

n= 702 542 (77.2%) 160 (22.8%) 654 (93.2%) 48 (6.8%)

Recurrent surgery

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Yes 49 (7.0%) 41 (7.6%) 8 (5%) 0.3 45 (6.9%) 4 (8.3%) 0.77

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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

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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

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≥189min 315 (44.9%) 226 (41.7%) 89 (55.6%) 0.002 289 (44.2%) 26 (54.2%) 0.23

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<189min 387 (55.1%) 316 (58.3%) 71 (44.4%) 365 (55.8%) 22 (45.8%)

Parathyroid reimplantation

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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%)

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No. of parathyroids reimplanted

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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%)

Educational type of surgery


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Expert procedure 265 (37 7%) 216 (39.9%) 49 (30.6%) 0.04 249 (38.1%) 16 (33.3%) 0.5
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Teaching procedure 437 (62 3%) 326 (60.1%) 111 (69.4%) 405 (61.9%) 32 (66.7%)

Postop. bleeding requiring surgery

Yes 15 (2 1%) 9 (1.7%) 6 (3.8%) 0.1 12 (1.8%) 3 (6.3%) 0.08

No 687 (97 9%) 533 (98.3%) 154 (96.2%) 642 (98.2%) 45 (93.7%)

Table 2 Surgical details


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Variable Regression Coefficient (ß) Standard Error Odds Ratio (95% CI) p-value

Female Gender 0.881 0.232 2.414 (1.533 – 3.803) < 0.001

Parathyroid Reimplantation 0.879 0.340 2.408 (1.237 – 4.687) 0.010

Surgery time (≥189 minutes) 0.586 0.185 1.797 (1.249 – 2.584) 0.002

Thyreostatic drug therapy - 0.625 0.295 0.535 (0.300 – 0.954) 0.034

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Table 3 Multivariate analysis of variables associated with initial post-thyreoidectomy

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hypocalcaemia

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Variable Regression Coefficient (ß) Standard Error Odds Ratio (95% CI) p-value

Symptomatic hypocalcaemia 3,712 0,404 40,931 (18.538-90,370) < 0.001

Female Gender -0.110 0.483 0.896 (0.348-2.308) 0.820

Parathyroid Reimplantation 0.222 0,635 1.248 (0.360-4,331) 0.727

Surgery time (≥189 minutes) 0.127 0.369 1.135 (0.551-2.338) 0.731

Thyreostatic drug therapy -0.629 0.796 0.533 (0.112-2.539) 0.430

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Table 4 Multivariate analysis of variables associated with persistent post-thyroidectomy
hypocalcemia

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3.0
no hypocalcaemia

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initial postoperative hypocalcaemia only
persistant hypocalcaemia

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2.5

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serum calcium level (mmol/l)

2.0

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AN
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1.5

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2.292 2.271 2.285

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2.095 2.109
1.0
1.881 1.804 1.805 1.717
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0.5
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0.0
preoperative 1st pod 2nd pod
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International Journal of Surgery Author Disclosure Form

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returned. If you have nothing to declare in any of these categories then this should be
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Nothing to declare

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Nothing to declare

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Please state whether Ethical Approval was given, by whom and the relevant
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Judgement’s reference number

Ethics Review Board of the University of Tübingen, Germany


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Research Registration Unique Identifying Number (UIN)


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Research Registry Unique Identifying Number - researchregistry3709

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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.

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Guarantor
The Guarantor is the one or more people who accept full responsibility for the work

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and/or the conduct of the study, had access to the data, and controlled the decision to
publish.

Dr. Sven Müller

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Highlights

• Persistence of hypocalcemia over six months after total thyroidectomy

was found in around 6.8%

• Prolonged surgery time is correlated with initial postoperative

hypocalcemia independently of the underlying disease and surgical

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expertise

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• Prolonged surgery does not affect the persistence of hypocalcemia

over six months

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