The Standardized Prophylaxis and Risk Factors for Venous Thromboembolism in Patients of Respiratory Intensive Care Unit: A Retrospective Observational Study

Abstract

Background

Critically ill patients in intensive care unit (ICU) are at high risk of venous thromboembolism (VTE). The standardized prophylaxis of VTE in these patients and the appropriate prevention protocols are not very clear.

Method

We enrolled 426 patients admitted to respiratory intensive care unit (RICU), all of them underwent Padua risk scoring and patients at high risk of VTE also underwent bleeding risk scoring. We compared the VTE prevention methods that followed the guidelines between two different bleeding risk groups and the VTE incidence of these two groups. We also analyzed the risk factors for VTE in RICU patients.

Results

In patients admitted to RICU, the rate of overall VTE prophylaxis was 71.3% (295/414), but the rate of standardized prophylaxis of VTE was only 32.6% (135/414). The standardized prophylaxis rate of VTE in high-risk bleeding patients was 40.3%, much higher than the 22.2% in low-risk bleeding patients (P < 0.001). There was also a significant difference in the incidence of VTE between the two groups (26.9%vs3.4%, P < 0.001). 70 (16.9%) patients in RICU developed VTE, the multivariable logistic regression analysis showed that immobilization time, pulmonary encephalopathy, oral or inject corticosteroids, trauma or surgery within 3 months were independent risk factors of VTE in patients admitted to RICU, while pharmacological prophylaxis was a protective factor for VTE. The receiver operating characteristic (ROC) curve showed that the above composite indicators had a higher predictive value for RICU patients with VTE, with a ROC area under the curve (AUC) of 0.925 (95%CI 0.894–0.956, P < 0.001).

Conclusion

Although the overall prophylaxis rate of VTE in patients admitted to RICU was high, the rate of standardized prevention was not ideal. Pharmacological prophylaxis may play an important role in preventing VTE in RICU patients and fruther studies are needed to explore the optimal thromboprophylaxis protocol for critically ill patients.

Keywords

anticoagulants deep venous thrombosis pulmonary embolism thrombosis prophylaxis venous thromboembolism

Introduction

Venous thromboembolism (VTE), which consists of pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT), is a serious complication in chronic disease patients and often results in significant mortality or long-term disability. In Intensive Care Unit (ICU), because of immobilization, critical illness, multiple comorbidities and other risk factors, the patients have much higher risk of VTE than ordinary ward inpatients.^1,2 VTE in critically ill patients is a key problem of continuous concern for clinical doctors worldwide, as it's difficult to balance the clinical consequences of thrombosis with the bleeding complications caused by anticoagulation.³ But as a preventable complication, timely risk assessment and correct prophylaxis can effectively reduce the incidence of VTE in critically ill patients.⁴

According to present guidelines, patients admitted to the ICU should undergo VTE risk assessment and bleeding risk assessment.⁵ For critically ill patients at high risk of VTE who are also at high risk of bleeding, graduated compression stockings (GCS) or intermittent pneumatic compression (IPC) are recommended to be used for mechanical thromboprophylaxis; for those with low risk of bleeding, low molecular-weight heparin (LMWH) is the choice for pharmacologic thromboprophylaxis.⁵ However, due to concerns among physicians about bleeding complications and other reasons, VTE prophylaxis practice in ICUs may be limited. A study from Spain found that approximately 41% of critically ill patients received inappropriate prophylaxis and 19% which did not receive any prophylaxis.⁶ In China, research has shown that even though the VTE prophylaxis rate for critically ill patients can reach 90%,^7,8 the incidence of VTE still remained at 14.3%.⁷ But the above results are limited to Beijing and Zhejiang province, the rate of VTE prophylaxis varies in clinical practice, further research is needed on the prophylaxis and occurrence of VTE in critically ill patients in other regions of China.

Moreover, the recent studies on the risk factors for VTE in critically ill patients mostly focus on comprehensive ICUs or neurocritical care patients,^8–10 most of these patients are admitted due to major surgeries or trauma, resulting in a significantly high risk of VTE. However, there is a relative lack of research on critically ill patients in internal medicine who have not experienced trauma or undergone surgical procedures. Hence, the respiratory intensive care unit (RICU) as a large group should not be ignored, and tracheotomy, mechanical ventilation, acute respiratory distress syndrome (ARDS) and other respiratory specific diseases can significantly affect the occurrence of VTE.¹¹ So far, there is no single study exists which explores the risk factors of VTE in RICU patients.

Therefore, our study aimed to investigate the standardized prophylaxis of VTE in RICU patients as well as to explore the risk factors for VTE in these patients.

Patients and Methods

Patients

This is a retrospective observational study. Patients admitted to the RICU of The First Affiliated Hospital of Chongqing Medical University, China, between January first, 2021 and December 31st, 2023, were enrolled in this study. All patients ≥18 years admitted to RICU were included in this study. The exclusion criteria were: (1) length of stay in RICU <72 h; (2) pregnant patients; (3) patients diagnosed with VTE when admitted in RICU; (4) patients with incomplete data. This study was in accordance with principles of the 1964 Declaration of Helsinki and its amendments. The study was approved by the institutional review board of the hospital.

VTE Risk Assessment and Bleeding Risk Assessment

All critically ill patients admitted to RICU underwent VTE risk assessment. Because patients admitted to RCIU were due to internal medical conditions rather than surgical procedures, the assessment scales used in this study was the Padua Score,¹² which included eleven indicators as followed: (1) active cancer-3 points; (2) previous VTE-3 points; (3) reduced mobility at least 3 days-3 points; (4) already known thrombophilic condition-3 points; (5) recent(≤1 month) trauma and/or surgery-2 points; (6) elderly age ≥ 70 years-1 point; (7) heart and/or respiratory failure-1point; (8) acute myocardial infarction or ischemic stroke-1 point; (9) acute infection and/or rheumatologic disorder-1 point; (10) obesity(BMI ≥ 30)-1 point; (11) undertaking hormone therapy-1 point, the score of ≥4 indicated high risk of VTE, while a score of <4 indicated low risk.

For RICU patients at high risk of VTE, a bleeding risk assessment should be conducted. The evaluation tool was IMPROVE bleeding risk score,¹³ which included thirteen indicators: (1) moderate renal failure, GFR30–59 ml/min/m²–1 point; (2) male-1 point; (3) age between 40–84 years old-1.5 points; (4) malignant tumor-2 points; (5) rheumatic diseases-2 points; (6) central venous catheterization-2 points; (7) ICU hospitalization-2.5 points; (8) severe renal failure, GFR < 30 ml/min/m²–2.5 points; (9) liver failure(INR > 1.5)-2.5 points; (10) age ≥ 85 years old-3.5 points; (11) platelet count < 50 × 10⁹/L-4 points; (12) bleeding occurred within 3 months prior to admission-4 points; (13) active gastroduodenal ulcer-4.5 points, those who scored ≥ 7 were defined as a high risk of bleeding, while a score of <7 indicated low risk of bleeding.

Standard Prophylaxis of VTE in RICU Patients

According to the guidelines from American College of Chest Physicians (ACCP), patients with high risk of VTE who admitted to ICU should undergo the bleeding risk assessment. For patients with active hemorrhage or high risk of hemorrhage, physical prophylaxis should be performed, such as intermittent pneumatic compression (IPC) or graduated compression stockings (GCS); while those with low risk of bleeding should receive medication prophylaxis or a combination of physical and medication prophylaxis, and the low-molecular-weight heparin (LMWH) was the preferred drug.⁵ Patients who followed above prophylaxis protocol were defined as standardized prophylaxis, otherwise they were defined as non-standardized prophylaxis.

Data Collection

Baseline characteristics of the patients including age, sex, APACHE II score, smoking history, medical history, comorbidities, treatment methods and medication, the first laboratory tests conducted after admission. In addition, our study also collected respiratory specific comorbidities to investigate their impact on VTE.

Outcomes

The primary outcome of this study was newly developed VTE events during the RICU stay, including DVT and PTE. DVT was diagnosed by color doppler venous ultrasonography of the extremities, while computed tomography pulmonary angiography (CTPA) was used for PTE diagnosis. The secondary outcomes were bleeding events. The bleeding events included major bleeding, clinically relevant non-major bleeding and minor bleeding. The major bleeding events were defined as a decrease in hemoglobin levels of ≥ 20 g/L, bleeding after transfusion of more than 2 units of red blood cell therapy, retroperitoneal bleeding, intracranial bleeding, hemorrhagic shock, and fatal bleeding. Clinically relevant non-major bleeding was defined as bleeding that requires medical intervention by professional medical personnel, results in hospitalization or elevation of treatment level, or requires face-to-face evaluation. Minor bleeding was defined as a bleeding event that does not require any medical attention and does not meet the criteria for major bleeding or clinically relevant non severe bleeding.¹⁴

Statistical Analysis

Using frequency (percentage) to describe Categorical variables and the Chi-square test and Fisher's exact test were used to test the differences between groups. Continuous variables were summarized using the median and interquartile range (IQR) due to their non-normal distribution. Group differences were assessed using the Mann–Whitney U test or the Kruskal–Wallis H test. Univariate and multivariate logistics regression analyses were conducted to explore the risk factors of VTE events in RICU. Variables with a significance level of P < 0.05 were incorporated into the multivariate analysis. Logistic regression was utilized for the multivariate analysis, with a P-value of less than 0.05 denoting statistical significance. Receiver operating characteristic curve (ROC) curves were applied to analysis the predictors of VTE in RICU patients. All analyses were performed using IBM SPSS 27.0.

Results

Characteristics of the Patients

Figure 1 shows the study flowchart. From January first, 2021 to December 31st, 2023, a total of 847 patients aged ≥ 18 years were admitted to the RICU of The First Affiliated Hospital of Chongqing Medical University, 2 of them were pregnant patients, 225 cases were diagnosed with DVT or PE when admitted to RICU, 177 patients stayed in RICU for less than 72 h and 17 patients had incomplete clinical data. Finally, 426 patients were included in this study. The Padua risk score was performed on 426 patients, of which 12 patients were at low risk of VTE, and another 414 cases were at high risk of VTE. Among the 12 low-risk patients, 2 underwent physical prophylaxis and there was no occurrence of VTE and bleeding events. Bleeding risk assessment was conducted on 414 high-risk VTE patients, of whom 176 had low risk of bleeding and 238 had high risk of bleeding.

Figure 1.

Flow chart of the study populations. Abbreviations: RICU, respiratory intensive care unit; LOS, length of hospital stay; VTE, venous thromboembolism.

Standard Prophylaxis of VTE in RICU Patients and Outcomes

Among 414 patients at high risk of VTE, the total rate of VTE prophylaxis was 71.3%(295/414), and the rate of standardized prophylaxis of VTE was 32.6% (135/414). In the high risk of bleeding group, 40.3% (96/238) of patients had received standardized prophylaxis, which was significantly higher than the 22.2% (39/176) in the low risk of bleeding group (P < 0.001) (Table 1). However, the incidence of VTE in the high risk of bleeding group was also significantly higher than that in the low risk of bleeding group (26.9%vs3.4%, P < 0.001). The incidence of major bleeding, clinically relevant non-major bleeding and minor bleeding also showed statistical differences between the two groups (16.0%vs4.0%, P < 0.001; 7.1%vs1.1%, P = 0.004;14.7%vs2.3%, P < 0.001) (Table 1).

Table 1.

Comparison of Standardized Prophylaxis and Outcomes Between Two Different Bleeding Risk Groups.

	High Risk of Bleeding(n = 238)	Low Risk of Bleeding(n = 176)	P value
standardized prophylaxis, n (%)	96 (40.3)	39 (22.2)	<0.001
VTE occurrence, n (%)	64 (26.9)	6 (3.4)	<0.001
Major bleeding, n (%)	38 (16.0)	7 (4.0)	<0.001
Clinically relevant non-major bleeding, n (%)	17 (7.1)	2 (1.1)	0.004
Minor bleeding, n (%)	35 (14.7)	4 (2.3)	<0.001
Padua score (IQR)	6（5,8）	6（5,6）	<0.001

Abbreviations: VTE, venous thromboembolism; IQR, interquartile range.

The detailed analysis of thrombosis prophylaxis protocol revealed that the proportion of patients in the high-risk bleeding group who did not receive any form of thrombosis prophylaxis was 32.8%, which was significantly higher than that in the low-risk bleeding group (23.3%) (P = 0.035) (Table 2). In the high risk of bleeding group, 40.3% of patients had only received physical prophylaxis, while the proportion in the low-risk bleeding group was 54.5%, and there was a statistical difference between the two groups (P = 0.004) (Table 2). Among the patients at high risk of bleeding, 12.2% had only received pharmacological prophylaxis, 14.7% had received a combination of physical and pharmacological prophylaxis, while the proportion in low risk of bleeding group were 6.8% and 15.3% respectively (Table 2).

Table 2.

Comparison of Specific Methods for Thrombosis Prophylaxis Between Two Different Bleeding Risk Groups.

	High Risk of Bleeding(n = 238)	Low Risk of Bleeding(n = 176)	P value
Physical prophylaxis, n (%)	96（40.3）	96（54.5）	0.004
Pharmacological prophylaxis, n (%)	29（12.2）	12（6.8）	0.071
Physical combined pharmacological prophylaxis, n (%)	35（14.7）	27（15.3）	0.858
Without thrombosis prophylaxis, n (%)	78（32.8）	41（23.3）	0.035

The Characteristics of Venous Thromboembolism in RICU Patients

Among 414 patients at high risk of VTE,70 (16.9%) developed VTE during hospitalization. The median time from admission to VTE occurrence was 9 (6.5, 11.0) days. Among the 70 patients,1 case was simply pulmonary embolism (medium-low risk), 1 patient had DVT combined with pulmonary embolism (medium-low risk), and the remaining 68 patients simply developed DVT. Among the patients who developed DVT, 48 patients (68.6%) developed calf intermuscular vein thrombosis, 9 patients (12.9%) developed fibular vein and popliteal vein thrombosis, and 12 patients (17.1%) had calf intermuscular vein thrombosis combined with fibular or popliteal vein thrombosis.

Univariable and Multivariable Analysis of the Risk Factors of VTE in RICU Patients

The univariable analysis results of general conditions, laboratory tests, comorbidities, respiratory related diseases, medication and treatments of patients in VTE group and non-VTE group are shown in Table 3, 4 and 5. The results showed that there were no significant differences between the two groups in gender, smoking history, leukocyte, platelet, COPD, non-invasive mechanical ventilation, mechanical prophylaxis of VTE, etc (P＞0.05). Compared with the non-VTE group, there were significant differences in immobilization time, MODS, sepsis, ARDS, prothrombin activity, deep vein catheterization, albumin infusion, etc (P < 0.001).

Table 3.

Comparison of Basic Conditions and Comorbidities Between VTE Group and non-VTE Group.

	VTE (n = 70)	Non-VTE (n = 344)	P Value
Age (years, IQR)	75（65,81）	69（59,77）	0.009
Male, n (%)	53（75.7）	260（75.6）	0.981
Smoking history, n (%)	40（57.1）	181（52.6）	0.489
APACHE II(IQR)	22（17,27）	13（9,16）	<0.001
Immobilization time (days, IQR)	18（11,24）	7（5,10）	<0.001
Trauma or surgery within 3 months, n (%)	29（41.4）	30（8.7）	<0.001
Comorbidity, n (%)
Diabetes	23（32.9）	87（25.3）	0.191
Hypertension	33（47.1）	155（45.1）	0.749
Coronary heart disease	18（25.7）	57（16.6）	0.07
Heart failure	25（35.7）	87（25.3）	0.074
Atrial fibrillation	7（10.0）	24（7.0）	0.381
Malignant tumor	23（32.9）	75（21.8）	0.047
Rheumatic disease	5（7.1）	15（4.4）	0.355
Cerebrovascular disease	10（14.3）	38（11.0）	0.44
MODS	33（47.1）	8（2.3）	<0.001
Sepsis	47（67.1）	28（8.1）	<0.001
Respiratory disease, n (%)
COPD	30（42.9）	172（50.0）	0.276
Pulmonary tuberculosis	5（7.1）	24（7.0）	>0.999
Asthma	1（1.4）	16（4.7）	0.327
Pulmonary hypertension	8（11.4）	44（12.8）	0.754
Cor pulmonale	11（15.7）	76（22.1）	0.232
ILD	14（20.0）	57（16.6）	0.488
Bronchiectasia	10（14.3）	54（15.7）	0.766
ARDS	19（27.1）	10（2.9）	<0.001
Pneumothorax	3（4.3）	13（3.8）	0.741
Pulmonary encephalopathy	15（21.4）	8（2.3）	<0.001

Abbreviations: VTE, venous thromboembolism; MODS, multiple organ dysfunction; ILD, interstitial lung disease; ARDS, acute respiratory distress syndrome.

Table 4.

Comparison of Laboratory Examination Between VTE Group and non-VTE Group.

	VTE (n = 70)	Non-VTE (n = 344)	P Value
Leukocyte (×10⁹/L) (IQR)	9.71（6.80,13.59）	9.11（6.93,12.15）	0.183
Neutrophil(×10⁹/L) (IQR)	8.66（5.63,11.87）	7.37（5.35,10.16）	0.042
Erythrocyte(×10⁹/L) (±SD)	3.65 ± 0.85	4.18 ± 0.98	<0.001
Hemoglobin (g/L) (±SD)	101 ± 26	122 ± 28	<0.001
Platelet (×10⁹/L) (IQR)	182（132,255）	202（150,270）	0.114
Urea	9.9（6.3,14.6）	6.9（5.0,9.2）	<0.001
Creatinine	78（60,114）	66（52,84）	0.004
Uric acid (μmol/L) (IQR)	260（166,375）	297（213,376）	0.168
Albumin(g/L) (IQR)	27（25,31）	31（28,36）	<0.001
Total bilirubin (μmol/L) (IQR)	11.2（7.5,15.7）	10.5（7.4,15.6）	0.773
Direct bilirubin (μmol/L) (IQR)	4.6（2.4,8.7）	3.6（1.8，5.6）	0.014
ALT (U/L) (IQR)	30（21,51）	25（18,42）	0.038
AST (U/L) (IQR)	40（27,71）	30（22,41）	<0.001
LDH(U/L) (IQR)	344（213,622）	253（189,434）	0.013
D-Dimer(mg/L) (IQR)	3.99（1.95,8.25）	1.10（0.51,2.11）	<0.001
INR(IQR)	1.07（1.00,1.18）	1.06（0.98,1.15）	0.127
PTA (%) (IQR)	78.2（66.4,93.4）	88.2（75.0,102.8）	<0.001
APTT(s)(IQR)	29.1（26.1,33.1）	28.4（26.1,31.4）	0.207
Fbg (g/L)	4.26（2.68,6.37）	4.16（2.98,5.80）	0.788

Abbreviations: VTE, venous thromboembolism; ALT, alanine aminotransferase; AST, aspartate transaminase; LDH, lactate dehydrogenase; INR, international standardized ratio; PTA, prothrombin activity; APTT, activated partial thromboplastin time; Fbg, fibrinogen; IQR, interquartile range; SD, standard deviation.

Table 5.

Comparison of Medication and Treatments Methods Between VTE Group and non-VTE Group.

	VTE (n = 70)	Non-VTE (n = 344)	P Value
Diuretic, n (%)	57（81.4）	89（25.9）	<0.001
Radiotherapy, chemotherapy, or targeted therapy, n (%)	11（15.7）	28（8.1）	0.048
Lipid-lowering drugs, n (%)	12（17.1）	43（12.5）	0.297
Antiplatelet drugs, n (%)	4（5.7）	31（9.3）	0.338
Vasoactive drugs, n (%)	45（64.3）	33（9.6）	<0.001
β₂-adrenoceptor agonist, n (%)	33（47.1）	146（42.4）	0.469
Anticholinergic drugs, n (%)	34（48.6）	170（49.4）	0.897
Theophylline drugs, n (%)	29（41.4）	151（43.9）	0.704
Oral or inject corticosteroids, n (%)	27（38.6）	56（16.3）	<0.001
Analgesic, sedative drugs, n (%)	51（72.9）	50（14.5）	<0.001
CRRT, n (%)	10（14.3）	5（1.5）	<0.001
Non-invasive mechanical ventilation, n (%)	55（78.6）	282（82.0）	0.504
Tracheotomy, n (%)	12（17.1）	8（2.3）	<0.001
Tracheal intubation, n (%)	44（62.9）	31（9.3）	<0.001
Respiratory stimulants, n (%)	4（5.7）	6（1.7）	0.07
Deep vein catheterization, n (%)	58（82.9）	46（13.4）	<0.001
Blood component transfusion, n (%)	27（38.6）	25（7.3）	<0.001
Thrombosis prophylaxis, n (%)
Mechanical prophylaxis alone	26（37.1）	166（48.3）	0.089
Pharmacological prophylaxis alone	2（2.9）	39（11.3）	0.03
Pharmacological combined mechanical prophylaxis	6（8.6）	56（16.3）	0.099
Pharmacological prophylaxis and pharmacological mechanical combinated prophylaxis	8（11.4）	95（27.6）	0.004

Abbreviations: VTE, venous thromboembolism; CRRT, continuous renal replacement therapy.

Multivariate logistic regression analysis was performed on variables with P < 0.05 (Table 6), and the results showed that immobilization time (OR 1.106,95%CI [1.024–1.195], P = 0.010), pulmonary encephalopathy (OR 25.277,95%CI [3.196–199.909], P = 0.002), oral or inject corticosteroids (OR 3.705,95%CI [1.019–13.462], P = 0.047), trauma or surgery within 3 months (OR 9.250,95%CI [2.519–33.970], P < 0.001) were independent risk factors of VTE in patients admitted to RICU (Table 6); while pharmacological prophylaxis of thrombosis was a protective factor for VTE in patients admitted to RICU (OR 0.014,95%CI 0.001–0.325, P = 0.008).

Table 6.

Multivariate Logistic Regression Analysis of Risk Factors of VTE.

Variables	OR (95% CI)	P value
immobilization time	1.106 (1.024–1.195)	0.010
pulmonary encephalopathy	25.277 (3.196–199.909)	0.002
oral or inject corticosteroids	3.705 (1.019–13.462)	0.047
trauma or surgery within 3 months	9.250 (2.519–33.970)	<0.001

Abbreviations: VTE, venous thromboembolism; CI, confidence interval; OR, odds ratio.

Receiver operating characteristic curve (ROC) analysis was conducted to evaluate the predictive capability of the composite indicators for VTE in patients admitted to the RICU. Taking whether the patient had VTE as the status variable and immobilization time + pulmonary encephalopathy + oral or inject corticosteroids + trauma or surgery within 3 months + pharmacological prophylaxis as test variables of the composite indicator, the analysis of the ROC curve indicated that the area under the curve (AUC) for composite indicators in predicting VTE was 0.925. (95%CI 0.894–0.956, P < 0.001) (Figure 2).

Figure 2.

Discriminatory accuracy for predicting RICU patients with VTE by receiver operator characteristics (ROC) analysis calculating area under the curve (AUC).

Discussion

This is the first study to investigate the standardized prophylaxis of venous thromboembolism in critically ill patients. In our study, although 71.3% of the patients admitted to RICU had received the prevention of venous thromboembolism, the rate of standardized prophylaxis was only 32.6% and approximately 16.9% of the patients had VTE events, which indicated that the thromboprophylaxis protocol of critically ill patients needs to be improved. Compared to previous studies focused on comprehensive ICUs or neurocritical care patients, our study analyzed the impact of respiratory diseases on VTE occurrence. Pulmonary encephalopathy significantly affected the occurrence of VTE, in addition, long term immobilization, oral or inject corticosteroids and trauma or surgery within 3 months were also the independent risk factors of VTE in RICU patients, while pharmacological prophylaxis of thrombosis was a protective factor.

The prevention protocol of venous thromboembolism in critically ill patients has long been controversial. Existing guidelines suggest that all patients admitted to ICU should receive appropriate thromboprophylaxis based on bleeding risk classification in spite of the relatively low grade of evidence.^5,15,16 Previous studies have found that with the increasing awareness of prevention among the medical staff, the thrombosis prophylaxis rate of critically ill patients could be increased to 70%-90%,^7,8,17 but the incidence of VTE still fluctuated between 10%-31%,^17,18 indicating that a considerable number of patients admitted to ICU have inappropriate thromboprophylaxis and the physicians’ neglect of the standardized thromboprophylaxis in critically ill patients.

In this study, the overall standardized prophylaxis rate of VTE in RICU patients was only 32.6%, and the rate in high-risk bleeding group (40.3%) was much higher than that in low-risk bleeding group (22.2%), one of the reasons was that patients in the high-risk bleeding group have a more severe comprehensive condition, which led to a greater attention and standardization of thrombosis prevention by medical staff for this group of patients. In addition, under the standardized prophylaxis protocol and consideration of hemorrhage events, the physical prevention of patients in high-risk bleeding group had better compliance than the medication prophylaxis or a combination of physical and medication prophylaxis required by low-risk bleeding patients in clinical practice. However, the incidence of VTE in patients with high bleeding risk was still higher than that in patients with low bleeding risk, this may due to the higher proportion of comorbidities such as sepsis and MODS, as well as a higher risk of VTE under Padua score in high bleeding risk group. More importantly, the proportion of patients in this group who did not receive any form of thromboprophylaxis was significantly higher than that in low bleeding risk group, also resulting in the difference of VTE incidence between the two groups.

A meta-analysis of randomized controlled trials found that medication prophylaxis primarily with LMWH could reduce the incidence of VTE in critically ill patients, while the efficacy and safety of combination pharmacologic therapy and mechanical compressive devices was unclear.⁴ Some previous studies have found no difference between the administration of chemical VTE prophylaxis alone compared to the combined VTE prophylaxis strategy.^19,20 The efficacy of physical prevention of thrombosis in critically ill patients is still uncertain and existing research focus more on evidence of IPC.^21,22 In the present study, the use of IPC alone was the major thromboprophylaxis pattern for patients admitted to RICU no matter which bleeding risk group it was and fewer patients had received medication prophylaxis or combined prevention strategy, which may lead to the relatively high incidence rate of VTE events. This initiate the consideration that whether physical thromboprophylaxis alone can only generate placebo effect for critically ill patients and the comparison of the effectiveness of physical thromboprophylaxis and other prevention protocols in critically ill patients at high risk of bleeding may be an important research topic in the future.

Due to their comorbidities and the use of multiple medications and interventions, part of critically ill patients were inevitably prone to hemorrhage,²³ the risk of bleeding and thrombosis should be individualized balanced when select the type of thromboprophylaxis. In this study, there was no statistically significant difference in the medication prophylaxis or combination prevention rates between the two different bleeding risk groups, which indicated insufficient emphasis by medical staff on the standardized prevention of VTE in patients with low bleeding risk, and the relatively aggressive drug prevention in the high-risk bleeding group might further lead to the occurrence of bleeding events in these patients.

At present, there is no specific VTE risk assessment tool for critically ill patients, so it's important to recognize the risk factors for VTE in patients admitted to ICU. Viarasilpa T et al had developed the "ICU-VTE score” with high predictive accuracy (C-statistic 0.87, 95%CI [0.85–0.88]), which included six indicators as followed: central venous catheterization, immobilization greater than or equal to 4 days, prior history of venous thromboembolism, mechanical ventilation, lowest hemoglobin during hospitalization greater than or equal to 9 g/dL and platelet count at admission greater than 250,000/μL.²⁴ Nevertheless, the use of drugs such as vasopressors had not been included in the analysis of risk factors this score.²⁴ This study had thoroughly included the comorbidities and treatment medication of RICU patients as far as possible to explore the potential factors for VTE occurrence.

Combining pulmonary encephalopathy might increase the risk of VTE, because its pathogeny—severe hypoxemia, can lead to hypercoagulability through multiple mechanisms.²⁵ Some studies have found that hypoxemia increases the hematocrit, which in turn changes blood rheology and viscosity²⁶; hypoxemia can also affect the liver and alter the synthesis of anticoagulant factors²⁵; elevated levels of hypoxia-inducible factor-1 (HIF-1) and the transcription factor nuclear factor kappa B (NF-kB) are also influenced by hypoxemia, resulting in the upregulation of procoagulant factors, including tissue factor (TF) and factor VIII.^25,27,28 Modification of pulmonary encephalopathy or hypoxemia may improve the patient's hypercoagulable state. Patients with pulmonary encephalopathy may experience prolonged immobilization due to neurological and psychiatric symptoms, as well as the use of sedatives. Long term immobilization can lead to blood stasis, followed by local cellular hypoxia and activation of endothelial cells, which is the beginning of the thrombotic process.²⁹ Recent trauma or surgery is another important risk factor of VTE, as the stringent state can lead to hypercoagulability through oxidative stress, systemic inflammatory response, long-term bed rest and surrounding tissue edema, promoting the formation of thrombus.^29,30 Previous studies have found the association between corticosteroids and pulmonary embolism increased with the dose of corticosteroids, thus establishing a solid dose–response relationship.^31,32 As a commonly used medication for respiratory diseases and patients in RICU, corticosteroids can promote hypercoagulability by increasing various coagulation factors and fibrinogen, thereby increasing the risk of VTE.^33,34

In this study, pharmacological prophylaxis was found to be a protective factor against VTE in patients admitted to RICU, this was corresponded to previous findings.^4,7 As mentioned earlier, research have found that compared to combination prophylaxis, pharmacological prophylaxis has a similar risk of VTE and less bleeding events,^4,19 so we can reasonably speculate that the combination prophylaxis may not be the main prevention protocol for VTE in critically ill patients and pharmacological prophylaxis may play a more important role in these patients. But the optimal plan, dosage, and duration for preventing thrombosis in critically ill patients require prospective studies to explore and individualized evaluation based on patients.

There were some limitations in this study. Firstly, this was a single-center, retrospective study, which was prone to confounding factors. Secondly, during the hospitalization at RICU, the risk of VTE and bleeding in patients might vary depending on their condition, and the corresponding thromboprophylaxis methods should also have been changed accordingly, so it had been difficult to accurately group patients, which might affect the validity of the results. We tried to reduce these interferences by grouping the patients based on their longest duration of bleeding risk before end-points events. Thirdly, although obesity is a recognized risk factor for VTE, the majority of RICU patients in our study were critically ill and transferred to the ward on a flat bed, resulting in missing data on height and weight. Fourthly, COVID-19 has been confirmed as a risk factor for VTE by many studies, and most patients may use glucocorticoids, which further increases the risk of VTE. However, considering that the relevant data cannot be fully obtained and was not included in this study, this is also worth noting in future research. Lastly, this study only included the clinical data of patients during their hospitalization and did not follow-up the patients after discharge, which might omit the occurrence of VTE in patients 90-days after discharge (defined as in-hospital VTE events).

Conclusion

In summary, the medical staff in RICU have a strong awareness of thromboprophylaxis, and the overall prophylaxis rate in patients was relatively high. However, the rate of standardized prophylaxis was not ideal, which was less than 50%, especially for patients with low-risk bleeding. Further research is needed to focus on the optimal prophylaxis protocol of venous thromboembolism in critically ill patients, particularly in patients at high risk of bleeding. Meanwhile, actively remedying hypoxemia and pulmonary encephalopathy, and early rehabilitation exercise of the lower limbs have a positive effect on preventing the occurrence of VTE. Additional studies are necessary to explore the risk factors and risk assessment models for VTE in critically ill patients.

Footnotes

ORCID iD

Bin-Yan Fu

Ethical Considerations

Ethical approval to report this case series was obtained from the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University(K2023-500), which waived the requirement for informed consent given the study's retrospective observational nature.

Author Contributions/CRediT

Bin-Yan Fu: Data curation; Investigation; Writing—original draft. Sheng-Xin Fan: Data curation; Investigation; Writing—original draft. Jia-Zhou Liu: Data curation; Investigation; Methodology. Yu-Liang Liu: Data curation; Investigation; Methodology. XiaoHui Wang: Supervision; Validation; Writing—review & editing. Hong Chen: Supervision; Validation; Writing—review & editing.

Funding

This study was funded by (1) National Key R&D Program of China (2023YFC2507203); (2) Health Appropriate Technology Promotion Program of Chongqing (2017jstg31, 2018jstg012, 2019jstg023, 2022jstg005); (3) Famous Teacher Program (Medical Field) of Chongqing Municipal Health Commission (CQYC20220203178).

Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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