Disease-Related Risk Factors for CVC-Related Symptomatic Thrombosis in Surgical ICU Inpatients

To report the rate of symptomatic catheter-related venous thrombosis (CRVT) in surgical intensive care unit patients receiving central venous catheters (CVC) and analyze the disease-related risk factors for symptomatic CRVT in SICU patients. A retrospective analysis was performed on 1643 critically ill patients admitted to the SICU from January 2015 to December 2019. Cases were divided into two groups based on the presence of symptomatic CRVT, and the variables of interest were extracted from the electronic medical record system. Logistic univariate and multivariate regression analyses were used to determine the risk factors of SCRVT. A total of 209 symptomatic CRVT events occurred among 2114 catheters. Multivariate analysis showed that trauma (odds ratio [OR], 2.046; 95% condence interval [CI] [1.325-3.160], P = 0.001), major surgery (OR, 2.457; 95% CI [1.641-3.679], P = 0.000), and heart failure (OR, 2.087; 95% CI [1.401-3.111], P = 0.000) were independent risk factors for symptomatic CRVT in SICU. The AUROC for this model was 0.610 (95% CI [0.569-0.651], P=0.000). The incidence rate was 9.89%. For patients hospitalized in the SICU, especially those admitted with these three conditions, thromboprophylaxis and/or mechanical prophylaxis should be actively provided to reduce the occurrence of symptomatic CRVT.


Introduction
Hospital-acquired venous thromboembolism (VTE) has received increasing attention in medical institutions due to its increased morbidity and mortality among hospitalized patients [1][2][3][4] . A number of studies have identi ed several important risk factors for hospital-acquired thrombus, of which CVC is an important risk factor [5][6][7] . Symptomatic CRVT is a special type of hospital-acquired VTE. Due to the convenience of CVC in intravenous drug injection, renal replacement therapy, monitoring of vital signs and other aspects, the use of catheters in clinical practice is becoming increasingly common, and the occurrence of CRVT events is also increasing 8 .
CVCs were used more frequently in ICU inpatients given their critical illness 3,[9][10][11] . Many studies on CRVT in ICU patients have been reported, and it has been found that venous catheter diameter, number of lumen, intubation site, blood transfusion, parenteral nutrition, sedation and other factors are related to CVC-related thrombosis [12][13][14] . Critical and severe patients are treated in the ICU. To our knowledge, no studies have been conducted on the correlation between CVC-related thrombosis and major diseases in ICU patients. The purpose of this study was to investigate disease-related risk factors for symptomatic CRVT in SICU inpatients.

Patients And Methods
Ethics statement.
This retrospective cohort study was approved by the Medical Ethics Committee of Ganzhou People's Hospital, and the methods were performed in accordance with the approved guidelines.
Major surgery referred to the operation performed under general anesthesia. Major surgery referred to the operation performed under general anesthesia, the operation time was more than 2 hours, patients' breathing, circulation and other organ function instability might occur and the patients need life support treatment after the operation.
CVC insertion: According to the therapeutic needs, intravenous catheterization was performed by quali ed doctors under ultrasound guidance or nonultrasound guidance. The insertion site was based on the patient's condition and the operating doctor at the time of surgery. The insertion sites included the internal jugular vein, subclavian vein or femoral vein.
Symptomatic CRVT: Symptomatic CRVT referred to thrombosis at the site of CVC insertion into the deep vein. This condition results in symptoms, such as redness, swelling and pain in the local or the area of venous re ux. The administering physician decide whether to perform an ultrasound examination to determine the presence of a catheter-related thrombosis.
Venous duplex ultrasonography (VDU): All VDUs were performed by certi ed ultrasonography technologists and interpreted by an attending radiologist. The thrombus was described as complete thrombus, mural thrombus, and no thrombus according to the relationship between thrombus volume and vascular lumen. Data analysis.
The cases were divided into two groups based on the presence of symptomatic CRVT. The continuous data of the two groups are described by means ± standard deviations (SDs) and compared using t tests for 2 independent samples. Nonparametric data are expressed as median (interquartile range) and compared using the Mann-Whitney test. The categorical data were presented as percentages and compared with the χ2 test or Fisher exact test. Kaplan-Meier curves were applied to analyze the cumulative incidence of symptomatic CRVT. Univariate and multivariate logistic regression analyses were used for disease risk factor analysis. Variables with a two-tailed P< 0.1 on univariate analysis were included in a multivariate regression model to identify independent predictors of symptomatic CRVT. ORs and 95% CIs are reported. Area under the receiver operator curve (AUROC) is used to assess predictive value of the model. All tests were two-sided with a signi cance level of 0.05 and were performed using SPSS software (ver. 24.0; IBM Corp., Armonk, NY, USA).

Patient baseline characteristics.
From January 2015 to December 2019, a total of 4904 patients were admitted to the SICU, including 249 patients <18 years old, 1989 patients whose length of stay in the ICU <3 days, 245 patients who had given up treatment, 13 patients with CVC complicated thrombosis before admission to the ICU, 765 patients without CVC, and 1643 patients with CVC. The rate of catheter use was 68.2% (1643/2408). Among them, 1,187 patients had one catheter, 380 patients had two catheters, 76 patients had three or more catheters. The total number of CVC was 2196. In total, 82 catheters with an intubation duration of <3 days were excluded from the study. Thus, 2114 catheters were included in the analysis, and each catheter was analyzed as a case ( Figure 1). Symptomatic CRVT occurred in 209 CVCs of the patients. The incidence of CRVT was 9.89%, and approximately 75% of thrombotic events occurred within 17 days of catheter placement ( Figure 2). The 2114 patients were divided into two groups according to whether symptomatic CRVT occurred. We found signi cant differences in age (P = 0.000), BMI (P = 0.000), APACHE II score (P = 0.001), length of ICU stay (P = 0.000), endotracheal intubation time (P = 0.000), CVC indwelling time (P = 0.000), anticoagulation therapy (P = 0.034), and anticoagulant contraindications (P = 0.005) between the two groups. Patient clinical characteristics are presented in Table 1.

Discussion
The study con rmed that the incidence of symptomatic CRVT among SICU inpatients was 9.89% and revealed that the independent risk factors of symptomatic CRVT included trauma, major surgery, and heart failure based on the SICU primary disease risk model (AUROC = 0.610).
Given the high risk of developing venous thromboembolism, hospital-acquired VTE is extremely high in ICU patients, but its incidence has been reported differently by various medical institutions. One study analyzed SICU patients with duplex sonography performed during CVC placement or within 7 days after CVC removal and found that fty-nine CRVTs were diagnosed in 28% of patients 15 . Gibson, C. D. et al.
retrospectively analyzed the occurrence of vein thrombosis among hospitalized patients in the medical ICU, and selected patients with suspected limb thrombosis for ultrasound examination. The incidence of thrombosis was 16%, and the catheter usage rate of patients with thrombosis was 55.26%. However, the incidence of symptomatic CRVT was not further analyzed 16 . Chen, Y. et al. studied symptomatic thrombosis associated with peripherally inserted CVC in cancer patients and found that the incidence of symptomatic CRVT was 6.7% 17 . The incidence of symptomatic CRVT in our study was 9.89%. The difference may be related to the study population and statistical methods.
The traumatically injured are at an especially high risk for VTE [18][19][20][21] . In the absence of pharmacologic prophylaxis, those with severe injuries have a risk of VTE that surpasses 50% 22 . Immediately after the injury, the delicate homeostasis balance of coagulation in the system is disturbed by the reduction of functional protein C, the reduction of antithrombin and the cessation of acute brinolysis, leading to the state of hypercoagulability [23][24][25] . The combination of endothelial and tissue injury, vascular stasis and hypercoagulability 26 represents a high risk factor for early VTE in this population, especially in patients with severe multiple trauma 27 27 . Most of the wounds in the population in our study involved multiple injuries, including major compound injuries of head, neck, chest and/or abdomen. The incidence of symptomatic CRVT was 16.1%, which did not seem high. However, the VTE here did not include thrombosis unrelated to CVC.
Given that major surgery may result in unstable respiratory, circulatory and other organ functions, patients need to be admitted to SICU for life support after surgery. The major operations of the center mainly include abdominal surgery, cardiac surgery, open brain surgery and multiple injury repair surgery.
These types of operations are characterized by long operation time, a large amount of blood loss, need for blood transfusion, and the need to be performed under general anesthesia, and all of these parameters contribute to the risk of venous thrombosis formation 29,30 . At present, clinical researchers in different surgical specialties, including general surgery 31 , orthopedics 32 , thoracic surgery 33 , urology 34 , tumor surgery 35 and neurosurgery 36 , found that the incidence of VTE after major surgery is relatively high, ranging from 3.6% 31 to 21.3% 36 . They believe that major surgery is a risk factor for VTE and that active prevention is needed 8 . The current study population included 255 patients admitted to the SICU due to major surgery, among which 41 patients (13.9%) had SCRVT. Major surgery was an independent risk factor for symptomatic CRVT in this group.
Heart failure accounts for a high proportion of SICU inpatients, and symptomatic CRVT was noted in 16.2% (47/290) in patients admitted to ICU due to heart failure in this study. Basnet, S. et al. found that the incidence of heart failure associated with VTE increased yearly by analyzing inpatient with heart failure from 2000 to 2013 37 . Wilson, T. J. et al. analyzed the risk factors for thrombosis associated with peripherally inserted CVC in inpatients and found that heart failure (OR, 2.62; 95% CI, 1.01-6.83) was associated with the occurrence of a CRVT 38 . Heart failure is characterized by a prothrombotic state, which not only increases the risk for cardioembolic events and ischemic stroke 39 but also increases the risk for deep venous thrombosis (DVT) and pulmonary embolism (PE), which together constitute VTE 40 .
In a study of 13,728 subjects, Fanola, C. L. et al. reported that over a 22-year period, heart failure occurred in 2,696 (20%) patients, and 729 VTE events were identi ed. Heart failure was associated with an increased long-term risk of VTE (OR 4.39, 95% CI [2.58-3.80]) that was independent of multiple risk factors for venous thromboembolism 41 .
This study also noted that a long duration of CVC intubation 42 and long endotracheal intubation 16,18 could increase symptomatic CRVT occurrence in SICU patients. In this study population, anticoagulation therapy was insu cient due to anticoagulation contraindication, and the comparison of anticoagulation therapy between the two groups was statistically signi cant (P = 0.005), which may also increase the occurrence of symptomatic CRVT. Therefore, especially after major surgery 8 or trauma 26 , patients should undergo active measures to prevent thrombosis, and anticoagulation drugs should be given if there is no anticoagulation contraindication. Otherwise, mechanical prophylaxis to prevent thrombus should be performed. In addition, this study also suggested that age, BMI, APACHE II score, length of ICU stay and other factors were signi cantly different in the comparison between the two groups, which was basically consistent with the results of previous studies 12,16,17,43 .
Our study has several limitations. First, it involved a single center and a relatively small number of patients. Second, this was a retrospective study performed using electronic medical records, and the study population was quite heterogeneous, which possibly introduced the potential for information bias. In addition, only symptomatic CRVT was analyzed in this study. Nonsymptomatic CRVT was not included in the analysis, which potentially resulted in the incidence of CRVT being greatly underestimated. Therefore, a multicenter, prospective randomized controlled study is necessary to further evaluate the risk factors associated with CRVT in patients in the SICU catheter-related thrombi disease.

Conclusions
The incidence of symptomatic CRVT in the SICU population was 9.89%. Trauma, major surgery and heart failure are independent disease risk factors for symptomatic CRVT. For patients hospitalized in the SICU, especially those admitted with these three conditions, thromboprophylaxis and/or mechanical prophylaxis should be actively provided to reduce the occurrence of symptomatic CRVT.

Declarations
Author Contributions Y.F.L. conceptualized and designed the study. Y.F.L., Y.LZ. and Z.M.K. performed and supervised data collection. X.C.L., Y.LZ. contributed in data analysis. X.C.L. and G.F.Z. prepared the rst draft of the paper. X.C.L., Y.L.Z. and Z.M.K. contributed equally to this article and share co-rst authorship. All the authors contributed in revision of the manuscript. All the authors have read and approved the nal manuscript.
Competing Interests: The author(s) declare no competing interests.     The AUROC for the predictive model