- Email: [email protected]
Left lower limb may be a forbidden region for indwelling needle during operation
Thrombosis Research 144 (2016) 165–168
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Full Length Article
Left lower limb may be a forbidden region for indwelling needle during operation Kun Wang a, Zhihua Li a, Deguang Kong a, Qiuxia Cui a, Yu Liu b, Wenbo Zhou c, Shenghua Cao d, Kongming Wu e, Gaosong Wu a,⁎ a
Department of Thyroid and Breast Surgery, Tongji Hospital, HuazhongUniversity of Science and Technology, 1095 Jiefang Avenue, Wuhan, PR China Department of Geriatrics, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, PR China Department of General Surgery, Dongfeng Hospital, Yunyang Medical College, 10 Daling Road, Shiyan, PR China d Department of General Surgery, Yichang People's Hospital Affiliated to Three Gorges University, 10 Jiefang Road, Yichang, PR China e Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, PR China b c
a r t i c l e
i n f o
Article history: Received 12 March 2016 Received in revised form 12 May 2016 Accepted 18 June 2016 Available online 20 June 2016 Keywords: Incidence Venous thromboembolism Thyroid surgery Thyroidectomy Prophylaxis
a b s t r a c t Introduction: Information about the incidence and risk factors of venous thromboembolism (VTE) after thyroid operation is limited. This study aimed to analyze the incidence and risk factors of postoperative VTE in patients who had undergone thyroid surgery. Materials and methods: A prospective, multi-center cohort study was performed from June 2013 to June 2015 in 3 hospitals throughout South Central China. We analyzed 5029 patients who had undergone thyroid operation and received no VTE prophylaxis postoperatively. For the diagnosis of deep vein thrombosis (DVT), bilateral wholeleg ultrasound was conducted in patients with a high pretest probability of DVT. Lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography was implemented in patients suspected to have pulmonary embolism (PE). Results: DVT was diagnosed in 18 patients (0.36%). No patient was diagnosed with PE. Binomial logistic regression analysis revealed that age and left lower limb intraoperative venous access (IVA) were significant risk factors for DVT. The incidence of DVT increased as the number of risk factors increased. Conclusions: VTE is uncommon in patients who have undergone thyroid surgery. The left lower limb was not an appropriate insertion site IVA. Pharmacologic thromboprophylaxis was not mandatory, particularly in those patients without risk factors. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common cause of preventable death among patients who have undergone surgery [1]. About onethird of VTE-related deaths per year in the USA occur after surgery [2]. The incidence of VTE is reported to be lower in Asian countries than that in Western countries [3,4]. However, recent studies indicate the incidence of VTE among Asians is increasing rapidly [5,6]. VTE is becoming an increasingly crucial public health problem in Asia. To our knowledge, the precise incidence and risk factors of VTE among patients who have undergone thyroid surgery in China have not been fully studied using
⁎ Corresponding author at: Department of Thyroid and Breast Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Building 8, 1095 Jiefang Avenue, Wuhan 430030, PR China. E-mail address: [email protected] (G. Wu).
http://dx.doi.org/10.1016/j.thromres.2016.06.021 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
prospective epidemiological studies. Thus, we aimed to investigate the rate and risk factors of VTE after thyroid surgery. 2. Materials and methods This is a prospective, multi-center cohort study of consecutive patients who had undergone thyroid surgery from June 2013 to June 2015 in 3 hospitals throughout south Central China. 2.1. Patients Consecutive patients aged ≥ 18 years who had undergone thyroid surgery were recruited from 3 hospitals in South Central China. The thyroid surgery included total thyroidectomy, residual thyroidectomy, lymph nodes dissection (thyroid surgery plus any compartment lymph nodes dissection), lobectomy and partial thyroidectomy. Exclusion criteria were pregnancy, puerperium, previous inclusion in this study, and inability for the predetermined follow-up. There were no
166
K. Wang et al. / Thrombosis Research 144 (2016) 165–168
prophylactic recommendations given to researchers in order to reflect the actual clinical practice in China. The study protocol was approved by the Ethical Committee at all participating hospitals. Written informed consent was acquired from all patients before inclusion. 2.2. Study design Patients' demographic, surgical, and clinical laboratory data were collected during hospitalization. Patients stratified as being likely to have DVT by using the modified Wells clinical score [7] were to be examined by bilateral whole-leg ultrasound during hospitalization. Clinically suspected PE was to be identified by lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography. After entering the study, patients were taught the symptoms and signs of VTE (leg pain, heaviness, edema, redness, dyspnea and chest pain) throughout the study period. To remind them of these symptoms and signs, the patients were regularly contacted by telephone 15 days, 1 month, and 3 months after the operation and asked whether any signs or symptoms of VTE arising. A simple questionnaire comprising name, gender, age and the symptoms and signs of VTE was designed and completed during the telephone call. In the case of onset of any signs or symptoms of VTE during the follow-up, the patients were requested to go to the nearest research unit and objective diagnosis by means of whole-leg ultrasound, lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography was demanded. 2.3. Study outcomes The primary outcome was the incidence of confirmed DVT or PE, or both during the study period. The other study outcomes were the evaluation of risk factors for VTE and the overall mortality at the 3-month follow-up. DVT was defined as DVT which was suspected clinically by using the modified Wells clinical score and subsequently confirmed by bilateral whole-leg ultrasound. PE was defined as PE which was suspected clinically and finally confirmed by lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography. Each episode of VTE was reviewed by an independent event committee using patients' records, ultrasonography reports, venograms, scintigrams, angiograms, and any other accessible materials. 2.4. Statistical analysis The incidence of VTE was calculated and a subgroup analysis was performed by using chi-square test or Fisher's exact test. Risk factors for the development of VTE were evaluated by the backward binomial logistic regression model. The odds ratio (OR) and the associated 95% CI were calculated. P-values b 0.05 were considered statistically significant. All analyses were conducted using SPSS software (SPSS, Inc.). 3. Results 3.1. Study population Between June 2013 and June 2015, 5077 consecutive patients were screened at 3 hospitals. We excluded 48 patients owing to absence during the follow-up (40 patients) and refusal to offer informed consent (8 patients). Finally, 5029 patients were enrolled in the analysis. The study population consisted of 1242 (24.7%) men and 3787 (75.3%) women aged 46.0 ± 12.8 years (mean ± SD). The obese patients whose body mass index (BMI) were greater than or equal to 30 kg/m2 accounted for only 5.6% (283 patients). All patients were treated surgically under general anesthesia. The surgical procedures
included total thyroidectomy (47.9%), residual thyroidectomy (4.7%), lymph node dissection (7.1%), lobectomy (25.3%), and partial thyroidectomy (15.0%). The mean interval from admission to operation was 3.1 ± 2.2 (mean ± SD) days, and the mean duration of hospitalization was 8.4 ± 3.2 (mean ± SD) days. The postoperative pathological diagnosis consisted of 3692 (73.4%) carcinomas and 1337 (26.6%) benign diseases. No patient received pharmacologic or mechanical prophylaxis. The 3-month follow-up was completed for 99.1% of the cohort. The detail baseline characteristics of the enrolled patients are showed in Table 1. 3.2. Incidence of VTE The incidence of confirmed VTE was 0.36% (18 events, 95% CI = 0.19% to 0.52%) via bilateral whole-leg ultrasound during the 3-month study period. All 18 cases of confirmed VTEs were DVTs. Furthermore, 83.3% (15/18) of VTE cases occurred during the hospitalization. During the hospitalization, 45 patients were stratified as being likely to have DVT by the modified Wells clinical score, 15 DVTs of whom were confirmed by bilateral whole-leg ultrasound; no PE was suspected clinically. During the follow-up, 57, 23 and 12 patients reported the symptoms or signs of DVT 15 days, 1 month, and 3 months after the operation respectively, 3 DVTs of whom were confirmed by bilateral whole-leg ultrasound 15 days after the operation in the nearest research unit, no patient reported a PE event during follow-up. One (0.03%) patient committed suicide and died. There were no deaths related to VTE. 3.3. Risk factors for VTE According to the presence or absence of the predefined set of variables on the basis of previous knowledge and scientific interest, we first conducted the univariate analysis and summarized the results in Table 2. Age, BMI, diabetes mellitus, hypertension and site of IVA were identified as significant risk factors; however, sex, smoking, oral contraceptives, surgery duration and malignant disease were not statistically significant risk factors. When the patients were divided into 5 groups Table 1 Patient characteristics (n = 5029). Characteristics
Number of patients (%)
Age (years) Sex Male Female BMI (kg/m2) b 25 ≥ 25, b30 ≥ 30 Diabetes mellitus Hypertension Smoking Oral contraceptives Surgery type Total thyroidectomy Residual thyroidectomy Lymph node dissection Lobectomy Partial thyroidectomy Surgery duration (h) b1 ≥1,b2 ≥2,b3 ≥3 Site of IVA Left lower limb Right lower limb Upper limbs Malignant disease Yes No
46.0 ± 12.8 1242 (24.7) 3787 (75.3) 3534 (70.3) 1212 (24.1) 283 (5.6) 598 (11.9) 1313 (26.1) 553 (11.0) 147 (2.9) 2409 (47.9) 236 (4.7) 358 (7.1) 1272 (25.3) 754 (15.0) 31 (0.6) 3193 (63.5) 1767 (35.1) 38 (0.8) 3250 (64.6) 1748 (34.8) 31 (0.6) 3692 (73.4) 1337 (26.6)
K. Wang et al. / Thrombosis Research 144 (2016) 165–168 Table 2 Subgroup analysis through univariate analyses. Variables Age (years) b65 ≥65 Sex Male Female BMI (kg/m2) b30 ≥30 Diabetes mellitus Yes No Hypertension Yes No Smoking Yes No Oral contraceptives Yes No Surgery duration (h) b2 ≥2 Site of IVA Left lower limb Other site Malignant disease Yes No
VTE (+)
VTE (−)
167
Table 4 Multivariable analysis of risk factors of VTE. OR (95% CI)
P value
Variables
Direction
OR (95% CI)
P value
Age BMI Diabetes mellitus Hypertension Site of IVA
≥65 years vs. b65 years ≥30 kg/m2 vs. b30 kg/m2 Yes vs. No Yes vs. No Left lower limb vs. Other sites
4.32 (1.55–12.06) 3.03 (0.82–11.11) 3.39 (0.98–11.77) 0.97 (0.29–3.29) 4.80 (1.10–21.03)
0.01 0.10 0.06 0.96 0.04
12 6
4636 375
6.18 (2.31–16.56)
0.00
3 15
1239 3772
1.64 (0.48–5.68)
0.43
12 6
4734 277
8.55 (3.18–22.94)
0.00
9 9
589 4422
7.51 (2.97–18.99)
0.00
9 9
1304 3707
2.84 (1.13–7.18)
0.03
3 15
550 4461
1.62 (0.47–5.62)
0.44
1 17
146 4865
1.96 (0.26–14.83)
0.41
8 10
3216 1795
2.24 (0.88–5.69)
0.08
16 2
3234 1777
4.40 (1.01–19.14)
0.03
14 4
3678 1333
1.27 (0.42–3.86)
0.68
based on the types of surgery, no significant difference in the incidence was noted between the groups (Table 3). Considering the small number of VTEs, we continued directly with a backward binomial logistic regression model with all the variables mentioned above to reach the most important predictors of VTE. Age and site of IVA were independent risk factors when examined by the logistic regression model (Table 4). Patients older than 65 years were more likely to develop VTE (OR = 4.32, p = 0.01). The risk of developing VTE was significantly higher among patients with left lower limb IVA as compared to others site IVA (OR = 4.80, p = 0.04). The association between VTE and risk factors became more obvious when patients were classified according to the number of risk factors (Table 5). The incidence of VTE increased markedly as the number of risk factors increased. The incidence of VTE was 2.07% in patients with all the two risk factors. However, patients with no risk factors hardly developed VTE. 4. Discussion The study investigated the incidence and risk factors of VTE in patients who had undergone thyroid surgery. Ultrasound was applied to
identify patients for DVT because it is a safe and easy diagnostic method. Lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography were planned to confirm the PE. However, no patient was suspected clinically during the study. The incidence of VTE at 3 months was low (0.36%), and PE did not occur in the cohort of 5029 patients. The comparable studies about VTE after thyroid surgery are extremely limited. Roy et al. reviewed 16,022 patients who underwent thyroid or parathyroid operation and found a VTE rate of 0.16% (26/16022) within the first 30 days after surgery [8]. Sezeret al. reported a VTE incidence of 0.9% among patients who had undergone thyroidectomy, but their study was limited by the small size (n = 116) [9]. In addition, Reinke et al. [10] retrospectively analyzed 19,640 patients, who had undergone thyroidectomy, using the ACS NSQIP database and reported a VTE rate of 0.08%. However, the ACS NSQIP database can only identify patients with known VTE; thus, the true incidence of VTE may have been underestimated. Age and left lower limb IVA were identified as significant independent risk factors of VTE in patients after thyroid surgery. Age, obesity and presence of malignancy have been reported to be risk factors for VTE [6,7,11]. However, in our study, malignancy was not identified as a significant risk factor. Trousseau described the syndrome of migratory superficial thrombophlebitis for the first time in 1865, and he linked this hypercoagulable state with malignancy, especially mucin-producing adenocarcinomas, such as those of the stomach, lung, breast, and ovary [12]. With respect to thyroid malignancies, only few studies of a hypercoagulable state associated with thyroid malignancy have been reported [12–15]. A large cohort study performed by Reinke et al. showed that the risk of VTE after thyroidectomy was not different between patients with thyroid cancer and without a diagnosis of thyroid malignancy, both before and after adjustment for patient characteristics; moreover, the rate of VTE was significantly lower than that predicted using the guidelines [10]. The findings for thyroid malignancies are different from those for some aggressive malignancies owing to the shorter surgery duration and hospitalization time and the absence of chemotherapy. In china, obese patients and patients who take oral contraceptives are uncommon in the clinical practice. Thus, obesity and oral contraceptives could not be excluded from risk factors completely on the basis of our study. Left lower limb IVA was identified as a significant risk factor of VTE. One possible explanation is as follows: first, narrowing of the lumen of the vein by the needle and reduced blood flow rate; second, the injury
Table 3 Development of VTE in different types of thyroid surgeries. All patients
A
B
C
D
E
N = 5029
N = 2409
N = 236
N = 358
N = 1272
N = 754
Outcome
n
Rate (%)
n
Rate (%)
n
Rate (%)
n
Rate (%)
n
Rate (%)
n
Rate (%)
Lower limb DVT Distal DVT Proximal DVT Both Upper limb DVT Pulmonary embolism
18 14 0 4 0 0
0.36 0.28
13 10 0 3 0 0
0.54 0.42
1 1 0 0 0 0
0.42 0.42
1 0 0 1 0 0
0.28
2 2 0 0 0 0
0.16 0.16
1 1 0 0 0 0
0.13 0.13
0.08
0.12
A. Total thyroidectomy; B. Residual thyroidectomy; C. Lymph node dissection; D. Lobectomy; E. Partial thyroidectomy.
0.28
168
K. Wang et al. / Thrombosis Research 144 (2016) 165–168
Addendum
Table 5 The incidence of VTE and the number of risk factors. Number of risk factors
VTE (+)
VTE (−)
Incidence (%)
Fisher's exact test
0 1 2
1 12 5
1638 3137 236
0.06 0.38 2.07
0.00
Gaosong Wu designed and coordinated the study. Kun Wang wrote the paper, performed the statistical analysis and interpreted the data. Zhihua Li, Deguang Kong, Wenbo Zhou and Shenghua Cao recruited subjects and collected the data. Qiuxia Cui and Yu Liu contacted participants, took responsibility for the follow-up and collected the data. Conflicts of interest
to the endothelium and phlebitis caused by needle and drug stimulation; third, voluntary immobilization of patients due to the needle and prolonged retention of the needle; finally, predisposition of MayThurner syndrome patients to thrombosis [16–18]. In many developing countries like China, nurses in the surgical department have to manage several patients per working day and some may have little time to place the intraoperative venous indwelling needle. The great saphenous vein is an easier and more common venipuncture site because it is thicker in diameter and shallower in position. In our study, the great saphenous vein was chosen as the insertion site in 99.3% of the patients. The left lower limb was more likely to be punctured than the right lower limb (64.6% versus 34.8%), which was a compelling finding but ignored by most nurses. In order to leave wider space to the surgeons, patients were always placed in the reverseTrendelenburg position on the operating table during thyroid operation. In this position, the upper limbs of patients were immobilized close to walls of the chest and wrapped in the operating sheet. Under the circumstances, the upper limb IVA was not accepted by anesthetists who needed to inject muscle relaxant or other drugs during the operation. After being transferred to the operating room, patients' right lower limbs were often blocked by the operating board of the scrub nurse, which made it difficult to be punctured, and intravenous injection by the anesthetist would also become uncomfortable if the needle indwelled in the right lower limb. Therefore, the nurse first considered the left lower limb as the insertion side. Only when the left lower limb was inappropriate would the right lower limb or upper limbs be considered. However, the left lower limb was not an appropriate insertion site in our study. This is a significant finding for clinical practice and requires further studies. The rate of VTE was found to be low in our study, although no patients received pharmacologic or mechanical prophylaxis. As reported by other studies [19], the incidence of VTE increased as the number of risk factors increased; the rate increased to 0.38% in patients with one risk factor and 2.07% in patients with two risk factors. The VTE rate was higher in patients underwent total thyroidectomy (0.54%) than other patients, but no significance was found. Considering the complications, we believed that the routine use of pharmacologic prophylaxis was not mandatory in patients who had undergone thyroid surgery and the use of anticoagulation therapy should be determined based on the patients' risk factors. This study has some potential limitations: the patients were not screened for VTE routinely so that asymptomatic DVTs were missed; the overall incidence of VTE after thyroid surgery was so low that we only encountered 18cases of DVTs. In conclusion, even without prophylaxis, the incidence of VTE after thyroid surgery is quite low in Chinese patients. The left lower limb was not an appropriate insertion site for the IVA. Routine use of pharmacologic prophylaxis was not mandatory. For patients with several risk factors, thromboprophylaxis should be administered based on a comprehensive evaluation of patient characteristics.
None. Funding No external funding. References [1] M.K. Gould, D.A. Garcia, S.M. Wren, et al., Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (2012) e227S–e277S. [2] K.T. Horlander, D.M. Mannino, K.V. Leeper, Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data, Arch. Intern. Med. 163 (2003) 1711–1717. [3] S.C. Tso, V. Wong, V. Chan, et al., Deep vein thrombosis and changes in coagulation and fibrinolysis after gynaecological operations in Chinese: the effect of oral contraceptives and malignant disease, Br. J. Haematol. 46 (1980) 603–612. [4] M. Hirose, K. Inada, Postoperative deep vein thrombosis–early diagnosis and prophylaxis, Jpn. Circ. J. 48 (1984) 111–117. [5] C.H. Lee, L.J. Lin, C.L. Cheng, et al., Incidence and cumulative recurrence rates of venous thromboembolism in the Taiwanese population, J. Thromb. Haemost. 8 (2010) 1515–1523. [6] H.Y. Yhim, M.J. Jang, S.M. Bang, et al., Incidence of venous thromboembolism following major surgery in Korea: from the Health Insurance Review and Assessment Service database, J. Thromb. Haemost. 12 (2014) 1035–1043. [7] S. Goodacre, In the clinic. Deep venous thrombosis, Ann. Intern. Med. 149 (2008) (Itc3-1). [8] M. Roy, V. Rajamanickam, H. Chen, et al., Is DVT prophylaxis necessary for thyroidectomy and parathyroidectomy? Surgery 148 (2010) 1163–1168 (discussion 8-9). [9] A. Sezer, N. Tuncbilek, S. Gultiken, et al., The risk of venous thromboembolism with thyroid surgery, Endocrinologist 20 (2010) 236–239. [10] C.E. Reinke, R.A. Hadler, G.C. Karakousis, et al., Does the presence of thyroid cancer increase the risk of venous thromboembolism in patients undergoing thyroidectomy? Surgery 150 (2011) 1275–1285. [11] L. Parkin, S. Sweetland, A. Balkwill, et al., Body mass index, surgery, and risk of venous thromboembolism in middle-aged women: a cohort study, Circulation 125 (2012) 1897–1904. [12] M. Herskovitz, E. Kouperberg, M.M. Krausz, et al., Young patient with acute ischemic stroke due to papillary carcinoma of the thyroid, J. Clin. Neurosci. 19 (2012) 1593–1594. [13] D.J. Tiede, A. Tefferi, R. Kochhar, et al., Paraneoplastic cholestasis and hypercoagulability associated with medullary thyroid carcinoma. Resolution with tumor debulking, Cancer 73 (1994) 702–705. [14] E. Raveh, M. Cohen, T. Shpitzer, et al., Carcinoma of the thyroid: a cause of hypercoagulability? Ear Nose Throat J. 74 (1995) 110–112. [15] G. Lal, T.V. Brennan, J. Hambleton, et al., Coagulopathy, marantic endocarditis, and cerebrovascular accidents as paraneoplastic features in medullary thyroid cancer– case report and review of the literature, Thyroid 13 (2003) 601–605. [16] R. May, J. Thurner, The cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins, Angiology 8 (1957) 419–427. [17] K.D. Zander, B. Staat, H. Galan, May-Thurner syndrome resulting in acute iliofemoral deep vein thrombosis in the postpartum period, Obstet. Gynecol. 111 (2008) 565–569. [18] A. Narayan, J. Eng, L. Carmi, et al., Iliac vein compression as risk factor for left- versus right-sided deep venous thrombosis: case-control study, Radiology 265 (2012) 949–957. [19] M. Sakon, Y. Maehara, H. Yoshikawa, et al., Incidence of venous thromboembolism following major abdominal surgery: a multi-center, prospective epidemiological study in Japan, J. Thromb. Haemost. 4 (2006) 581–586.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Full Length Article
Left lower limb may be a forbidden region for indwelling needle during operation Kun Wang a, Zhihua Li a, Deguang Kong a, Qiuxia Cui a, Yu Liu b, Wenbo Zhou c, Shenghua Cao d, Kongming Wu e, Gaosong Wu a,⁎ a
Department of Thyroid and Breast Surgery, Tongji Hospital, HuazhongUniversity of Science and Technology, 1095 Jiefang Avenue, Wuhan, PR China Department of Geriatrics, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, PR China Department of General Surgery, Dongfeng Hospital, Yunyang Medical College, 10 Daling Road, Shiyan, PR China d Department of General Surgery, Yichang People's Hospital Affiliated to Three Gorges University, 10 Jiefang Road, Yichang, PR China e Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, PR China b c
a r t i c l e
i n f o
Article history: Received 12 March 2016 Received in revised form 12 May 2016 Accepted 18 June 2016 Available online 20 June 2016 Keywords: Incidence Venous thromboembolism Thyroid surgery Thyroidectomy Prophylaxis
a b s t r a c t Introduction: Information about the incidence and risk factors of venous thromboembolism (VTE) after thyroid operation is limited. This study aimed to analyze the incidence and risk factors of postoperative VTE in patients who had undergone thyroid surgery. Materials and methods: A prospective, multi-center cohort study was performed from June 2013 to June 2015 in 3 hospitals throughout South Central China. We analyzed 5029 patients who had undergone thyroid operation and received no VTE prophylaxis postoperatively. For the diagnosis of deep vein thrombosis (DVT), bilateral wholeleg ultrasound was conducted in patients with a high pretest probability of DVT. Lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography was implemented in patients suspected to have pulmonary embolism (PE). Results: DVT was diagnosed in 18 patients (0.36%). No patient was diagnosed with PE. Binomial logistic regression analysis revealed that age and left lower limb intraoperative venous access (IVA) were significant risk factors for DVT. The incidence of DVT increased as the number of risk factors increased. Conclusions: VTE is uncommon in patients who have undergone thyroid surgery. The left lower limb was not an appropriate insertion site IVA. Pharmacologic thromboprophylaxis was not mandatory, particularly in those patients without risk factors. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common cause of preventable death among patients who have undergone surgery [1]. About onethird of VTE-related deaths per year in the USA occur after surgery [2]. The incidence of VTE is reported to be lower in Asian countries than that in Western countries [3,4]. However, recent studies indicate the incidence of VTE among Asians is increasing rapidly [5,6]. VTE is becoming an increasingly crucial public health problem in Asia. To our knowledge, the precise incidence and risk factors of VTE among patients who have undergone thyroid surgery in China have not been fully studied using
⁎ Corresponding author at: Department of Thyroid and Breast Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Building 8, 1095 Jiefang Avenue, Wuhan 430030, PR China. E-mail address: [email protected] (G. Wu).
http://dx.doi.org/10.1016/j.thromres.2016.06.021 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
prospective epidemiological studies. Thus, we aimed to investigate the rate and risk factors of VTE after thyroid surgery. 2. Materials and methods This is a prospective, multi-center cohort study of consecutive patients who had undergone thyroid surgery from June 2013 to June 2015 in 3 hospitals throughout south Central China. 2.1. Patients Consecutive patients aged ≥ 18 years who had undergone thyroid surgery were recruited from 3 hospitals in South Central China. The thyroid surgery included total thyroidectomy, residual thyroidectomy, lymph nodes dissection (thyroid surgery plus any compartment lymph nodes dissection), lobectomy and partial thyroidectomy. Exclusion criteria were pregnancy, puerperium, previous inclusion in this study, and inability for the predetermined follow-up. There were no
166
K. Wang et al. / Thrombosis Research 144 (2016) 165–168
prophylactic recommendations given to researchers in order to reflect the actual clinical practice in China. The study protocol was approved by the Ethical Committee at all participating hospitals. Written informed consent was acquired from all patients before inclusion. 2.2. Study design Patients' demographic, surgical, and clinical laboratory data were collected during hospitalization. Patients stratified as being likely to have DVT by using the modified Wells clinical score [7] were to be examined by bilateral whole-leg ultrasound during hospitalization. Clinically suspected PE was to be identified by lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography. After entering the study, patients were taught the symptoms and signs of VTE (leg pain, heaviness, edema, redness, dyspnea and chest pain) throughout the study period. To remind them of these symptoms and signs, the patients were regularly contacted by telephone 15 days, 1 month, and 3 months after the operation and asked whether any signs or symptoms of VTE arising. A simple questionnaire comprising name, gender, age and the symptoms and signs of VTE was designed and completed during the telephone call. In the case of onset of any signs or symptoms of VTE during the follow-up, the patients were requested to go to the nearest research unit and objective diagnosis by means of whole-leg ultrasound, lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography was demanded. 2.3. Study outcomes The primary outcome was the incidence of confirmed DVT or PE, or both during the study period. The other study outcomes were the evaluation of risk factors for VTE and the overall mortality at the 3-month follow-up. DVT was defined as DVT which was suspected clinically by using the modified Wells clinical score and subsequently confirmed by bilateral whole-leg ultrasound. PE was defined as PE which was suspected clinically and finally confirmed by lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography. Each episode of VTE was reviewed by an independent event committee using patients' records, ultrasonography reports, venograms, scintigrams, angiograms, and any other accessible materials. 2.4. Statistical analysis The incidence of VTE was calculated and a subgroup analysis was performed by using chi-square test or Fisher's exact test. Risk factors for the development of VTE were evaluated by the backward binomial logistic regression model. The odds ratio (OR) and the associated 95% CI were calculated. P-values b 0.05 were considered statistically significant. All analyses were conducted using SPSS software (SPSS, Inc.). 3. Results 3.1. Study population Between June 2013 and June 2015, 5077 consecutive patients were screened at 3 hospitals. We excluded 48 patients owing to absence during the follow-up (40 patients) and refusal to offer informed consent (8 patients). Finally, 5029 patients were enrolled in the analysis. The study population consisted of 1242 (24.7%) men and 3787 (75.3%) women aged 46.0 ± 12.8 years (mean ± SD). The obese patients whose body mass index (BMI) were greater than or equal to 30 kg/m2 accounted for only 5.6% (283 patients). All patients were treated surgically under general anesthesia. The surgical procedures
included total thyroidectomy (47.9%), residual thyroidectomy (4.7%), lymph node dissection (7.1%), lobectomy (25.3%), and partial thyroidectomy (15.0%). The mean interval from admission to operation was 3.1 ± 2.2 (mean ± SD) days, and the mean duration of hospitalization was 8.4 ± 3.2 (mean ± SD) days. The postoperative pathological diagnosis consisted of 3692 (73.4%) carcinomas and 1337 (26.6%) benign diseases. No patient received pharmacologic or mechanical prophylaxis. The 3-month follow-up was completed for 99.1% of the cohort. The detail baseline characteristics of the enrolled patients are showed in Table 1. 3.2. Incidence of VTE The incidence of confirmed VTE was 0.36% (18 events, 95% CI = 0.19% to 0.52%) via bilateral whole-leg ultrasound during the 3-month study period. All 18 cases of confirmed VTEs were DVTs. Furthermore, 83.3% (15/18) of VTE cases occurred during the hospitalization. During the hospitalization, 45 patients were stratified as being likely to have DVT by the modified Wells clinical score, 15 DVTs of whom were confirmed by bilateral whole-leg ultrasound; no PE was suspected clinically. During the follow-up, 57, 23 and 12 patients reported the symptoms or signs of DVT 15 days, 1 month, and 3 months after the operation respectively, 3 DVTs of whom were confirmed by bilateral whole-leg ultrasound 15 days after the operation in the nearest research unit, no patient reported a PE event during follow-up. One (0.03%) patient committed suicide and died. There were no deaths related to VTE. 3.3. Risk factors for VTE According to the presence or absence of the predefined set of variables on the basis of previous knowledge and scientific interest, we first conducted the univariate analysis and summarized the results in Table 2. Age, BMI, diabetes mellitus, hypertension and site of IVA were identified as significant risk factors; however, sex, smoking, oral contraceptives, surgery duration and malignant disease were not statistically significant risk factors. When the patients were divided into 5 groups Table 1 Patient characteristics (n = 5029). Characteristics
Number of patients (%)
Age (years) Sex Male Female BMI (kg/m2) b 25 ≥ 25, b30 ≥ 30 Diabetes mellitus Hypertension Smoking Oral contraceptives Surgery type Total thyroidectomy Residual thyroidectomy Lymph node dissection Lobectomy Partial thyroidectomy Surgery duration (h) b1 ≥1,b2 ≥2,b3 ≥3 Site of IVA Left lower limb Right lower limb Upper limbs Malignant disease Yes No
46.0 ± 12.8 1242 (24.7) 3787 (75.3) 3534 (70.3) 1212 (24.1) 283 (5.6) 598 (11.9) 1313 (26.1) 553 (11.0) 147 (2.9) 2409 (47.9) 236 (4.7) 358 (7.1) 1272 (25.3) 754 (15.0) 31 (0.6) 3193 (63.5) 1767 (35.1) 38 (0.8) 3250 (64.6) 1748 (34.8) 31 (0.6) 3692 (73.4) 1337 (26.6)
K. Wang et al. / Thrombosis Research 144 (2016) 165–168 Table 2 Subgroup analysis through univariate analyses. Variables Age (years) b65 ≥65 Sex Male Female BMI (kg/m2) b30 ≥30 Diabetes mellitus Yes No Hypertension Yes No Smoking Yes No Oral contraceptives Yes No Surgery duration (h) b2 ≥2 Site of IVA Left lower limb Other site Malignant disease Yes No
VTE (+)
VTE (−)
167
Table 4 Multivariable analysis of risk factors of VTE. OR (95% CI)
P value
Variables
Direction
OR (95% CI)
P value
Age BMI Diabetes mellitus Hypertension Site of IVA
≥65 years vs. b65 years ≥30 kg/m2 vs. b30 kg/m2 Yes vs. No Yes vs. No Left lower limb vs. Other sites
4.32 (1.55–12.06) 3.03 (0.82–11.11) 3.39 (0.98–11.77) 0.97 (0.29–3.29) 4.80 (1.10–21.03)
0.01 0.10 0.06 0.96 0.04
12 6
4636 375
6.18 (2.31–16.56)
0.00
3 15
1239 3772
1.64 (0.48–5.68)
0.43
12 6
4734 277
8.55 (3.18–22.94)
0.00
9 9
589 4422
7.51 (2.97–18.99)
0.00
9 9
1304 3707
2.84 (1.13–7.18)
0.03
3 15
550 4461
1.62 (0.47–5.62)
0.44
1 17
146 4865
1.96 (0.26–14.83)
0.41
8 10
3216 1795
2.24 (0.88–5.69)
0.08
16 2
3234 1777
4.40 (1.01–19.14)
0.03
14 4
3678 1333
1.27 (0.42–3.86)
0.68
based on the types of surgery, no significant difference in the incidence was noted between the groups (Table 3). Considering the small number of VTEs, we continued directly with a backward binomial logistic regression model with all the variables mentioned above to reach the most important predictors of VTE. Age and site of IVA were independent risk factors when examined by the logistic regression model (Table 4). Patients older than 65 years were more likely to develop VTE (OR = 4.32, p = 0.01). The risk of developing VTE was significantly higher among patients with left lower limb IVA as compared to others site IVA (OR = 4.80, p = 0.04). The association between VTE and risk factors became more obvious when patients were classified according to the number of risk factors (Table 5). The incidence of VTE increased markedly as the number of risk factors increased. The incidence of VTE was 2.07% in patients with all the two risk factors. However, patients with no risk factors hardly developed VTE. 4. Discussion The study investigated the incidence and risk factors of VTE in patients who had undergone thyroid surgery. Ultrasound was applied to
identify patients for DVT because it is a safe and easy diagnostic method. Lung ventilation/perfusion scintigraphy, pulmonary angiography, or helical computed tomography were planned to confirm the PE. However, no patient was suspected clinically during the study. The incidence of VTE at 3 months was low (0.36%), and PE did not occur in the cohort of 5029 patients. The comparable studies about VTE after thyroid surgery are extremely limited. Roy et al. reviewed 16,022 patients who underwent thyroid or parathyroid operation and found a VTE rate of 0.16% (26/16022) within the first 30 days after surgery [8]. Sezeret al. reported a VTE incidence of 0.9% among patients who had undergone thyroidectomy, but their study was limited by the small size (n = 116) [9]. In addition, Reinke et al. [10] retrospectively analyzed 19,640 patients, who had undergone thyroidectomy, using the ACS NSQIP database and reported a VTE rate of 0.08%. However, the ACS NSQIP database can only identify patients with known VTE; thus, the true incidence of VTE may have been underestimated. Age and left lower limb IVA were identified as significant independent risk factors of VTE in patients after thyroid surgery. Age, obesity and presence of malignancy have been reported to be risk factors for VTE [6,7,11]. However, in our study, malignancy was not identified as a significant risk factor. Trousseau described the syndrome of migratory superficial thrombophlebitis for the first time in 1865, and he linked this hypercoagulable state with malignancy, especially mucin-producing adenocarcinomas, such as those of the stomach, lung, breast, and ovary [12]. With respect to thyroid malignancies, only few studies of a hypercoagulable state associated with thyroid malignancy have been reported [12–15]. A large cohort study performed by Reinke et al. showed that the risk of VTE after thyroidectomy was not different between patients with thyroid cancer and without a diagnosis of thyroid malignancy, both before and after adjustment for patient characteristics; moreover, the rate of VTE was significantly lower than that predicted using the guidelines [10]. The findings for thyroid malignancies are different from those for some aggressive malignancies owing to the shorter surgery duration and hospitalization time and the absence of chemotherapy. In china, obese patients and patients who take oral contraceptives are uncommon in the clinical practice. Thus, obesity and oral contraceptives could not be excluded from risk factors completely on the basis of our study. Left lower limb IVA was identified as a significant risk factor of VTE. One possible explanation is as follows: first, narrowing of the lumen of the vein by the needle and reduced blood flow rate; second, the injury
Table 3 Development of VTE in different types of thyroid surgeries. All patients
A
B
C
D
E
N = 5029
N = 2409
N = 236
N = 358
N = 1272
N = 754
Outcome
n
Rate (%)
n
Rate (%)
n
Rate (%)
n
Rate (%)
n
Rate (%)
n
Rate (%)
Lower limb DVT Distal DVT Proximal DVT Both Upper limb DVT Pulmonary embolism
18 14 0 4 0 0
0.36 0.28
13 10 0 3 0 0
0.54 0.42
1 1 0 0 0 0
0.42 0.42
1 0 0 1 0 0
0.28
2 2 0 0 0 0
0.16 0.16
1 1 0 0 0 0
0.13 0.13
0.08
0.12
A. Total thyroidectomy; B. Residual thyroidectomy; C. Lymph node dissection; D. Lobectomy; E. Partial thyroidectomy.
0.28
168
K. Wang et al. / Thrombosis Research 144 (2016) 165–168
Addendum
Table 5 The incidence of VTE and the number of risk factors. Number of risk factors
VTE (+)
VTE (−)
Incidence (%)
Fisher's exact test
0 1 2
1 12 5
1638 3137 236
0.06 0.38 2.07
0.00
Gaosong Wu designed and coordinated the study. Kun Wang wrote the paper, performed the statistical analysis and interpreted the data. Zhihua Li, Deguang Kong, Wenbo Zhou and Shenghua Cao recruited subjects and collected the data. Qiuxia Cui and Yu Liu contacted participants, took responsibility for the follow-up and collected the data. Conflicts of interest
to the endothelium and phlebitis caused by needle and drug stimulation; third, voluntary immobilization of patients due to the needle and prolonged retention of the needle; finally, predisposition of MayThurner syndrome patients to thrombosis [16–18]. In many developing countries like China, nurses in the surgical department have to manage several patients per working day and some may have little time to place the intraoperative venous indwelling needle. The great saphenous vein is an easier and more common venipuncture site because it is thicker in diameter and shallower in position. In our study, the great saphenous vein was chosen as the insertion site in 99.3% of the patients. The left lower limb was more likely to be punctured than the right lower limb (64.6% versus 34.8%), which was a compelling finding but ignored by most nurses. In order to leave wider space to the surgeons, patients were always placed in the reverseTrendelenburg position on the operating table during thyroid operation. In this position, the upper limbs of patients were immobilized close to walls of the chest and wrapped in the operating sheet. Under the circumstances, the upper limb IVA was not accepted by anesthetists who needed to inject muscle relaxant or other drugs during the operation. After being transferred to the operating room, patients' right lower limbs were often blocked by the operating board of the scrub nurse, which made it difficult to be punctured, and intravenous injection by the anesthetist would also become uncomfortable if the needle indwelled in the right lower limb. Therefore, the nurse first considered the left lower limb as the insertion side. Only when the left lower limb was inappropriate would the right lower limb or upper limbs be considered. However, the left lower limb was not an appropriate insertion site in our study. This is a significant finding for clinical practice and requires further studies. The rate of VTE was found to be low in our study, although no patients received pharmacologic or mechanical prophylaxis. As reported by other studies [19], the incidence of VTE increased as the number of risk factors increased; the rate increased to 0.38% in patients with one risk factor and 2.07% in patients with two risk factors. The VTE rate was higher in patients underwent total thyroidectomy (0.54%) than other patients, but no significance was found. Considering the complications, we believed that the routine use of pharmacologic prophylaxis was not mandatory in patients who had undergone thyroid surgery and the use of anticoagulation therapy should be determined based on the patients' risk factors. This study has some potential limitations: the patients were not screened for VTE routinely so that asymptomatic DVTs were missed; the overall incidence of VTE after thyroid surgery was so low that we only encountered 18cases of DVTs. In conclusion, even without prophylaxis, the incidence of VTE after thyroid surgery is quite low in Chinese patients. The left lower limb was not an appropriate insertion site for the IVA. Routine use of pharmacologic prophylaxis was not mandatory. For patients with several risk factors, thromboprophylaxis should be administered based on a comprehensive evaluation of patient characteristics.
None. Funding No external funding. References [1] M.K. Gould, D.A. Garcia, S.M. Wren, et al., Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (2012) e227S–e277S. [2] K.T. Horlander, D.M. Mannino, K.V. Leeper, Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data, Arch. Intern. Med. 163 (2003) 1711–1717. [3] S.C. Tso, V. Wong, V. Chan, et al., Deep vein thrombosis and changes in coagulation and fibrinolysis after gynaecological operations in Chinese: the effect of oral contraceptives and malignant disease, Br. J. Haematol. 46 (1980) 603–612. [4] M. Hirose, K. Inada, Postoperative deep vein thrombosis–early diagnosis and prophylaxis, Jpn. Circ. J. 48 (1984) 111–117. [5] C.H. Lee, L.J. Lin, C.L. Cheng, et al., Incidence and cumulative recurrence rates of venous thromboembolism in the Taiwanese population, J. Thromb. Haemost. 8 (2010) 1515–1523. [6] H.Y. Yhim, M.J. Jang, S.M. Bang, et al., Incidence of venous thromboembolism following major surgery in Korea: from the Health Insurance Review and Assessment Service database, J. Thromb. Haemost. 12 (2014) 1035–1043. [7] S. Goodacre, In the clinic. Deep venous thrombosis, Ann. Intern. Med. 149 (2008) (Itc3-1). [8] M. Roy, V. Rajamanickam, H. Chen, et al., Is DVT prophylaxis necessary for thyroidectomy and parathyroidectomy? Surgery 148 (2010) 1163–1168 (discussion 8-9). [9] A. Sezer, N. Tuncbilek, S. Gultiken, et al., The risk of venous thromboembolism with thyroid surgery, Endocrinologist 20 (2010) 236–239. [10] C.E. Reinke, R.A. Hadler, G.C. Karakousis, et al., Does the presence of thyroid cancer increase the risk of venous thromboembolism in patients undergoing thyroidectomy? Surgery 150 (2011) 1275–1285. [11] L. Parkin, S. Sweetland, A. Balkwill, et al., Body mass index, surgery, and risk of venous thromboembolism in middle-aged women: a cohort study, Circulation 125 (2012) 1897–1904. [12] M. Herskovitz, E. Kouperberg, M.M. Krausz, et al., Young patient with acute ischemic stroke due to papillary carcinoma of the thyroid, J. Clin. Neurosci. 19 (2012) 1593–1594. [13] D.J. Tiede, A. Tefferi, R. Kochhar, et al., Paraneoplastic cholestasis and hypercoagulability associated with medullary thyroid carcinoma. Resolution with tumor debulking, Cancer 73 (1994) 702–705. [14] E. Raveh, M. Cohen, T. Shpitzer, et al., Carcinoma of the thyroid: a cause of hypercoagulability? Ear Nose Throat J. 74 (1995) 110–112. [15] G. Lal, T.V. Brennan, J. Hambleton, et al., Coagulopathy, marantic endocarditis, and cerebrovascular accidents as paraneoplastic features in medullary thyroid cancer– case report and review of the literature, Thyroid 13 (2003) 601–605. [16] R. May, J. Thurner, The cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins, Angiology 8 (1957) 419–427. [17] K.D. Zander, B. Staat, H. Galan, May-Thurner syndrome resulting in acute iliofemoral deep vein thrombosis in the postpartum period, Obstet. Gynecol. 111 (2008) 565–569. [18] A. Narayan, J. Eng, L. Carmi, et al., Iliac vein compression as risk factor for left- versus right-sided deep venous thrombosis: case-control study, Radiology 265 (2012) 949–957. [19] M. Sakon, Y. Maehara, H. Yoshikawa, et al., Incidence of venous thromboembolism following major abdominal surgery: a multi-center, prospective epidemiological study in Japan, J. Thromb. Haemost. 4 (2006) 581–586.