Prone Position and the Risk of Venous Thrombosis in COVID-19 Patients with Respiratory Failure

Several lines of evidence attest that ventilation in prone position may significantly improve lung function in critically ill patients with acute respiratory distress syndrome (ARDS) due to the more uniform distribution of tidal volume and improved recruitment, which contribute to ameliorate the ventilation–perfusion ratio.[1] Nevertheless, the overall clinical benefit of long periods of pronation over the supine position during mechanical ventilation remains controversial, even in patients with coronavirus disease 2019 (COVID-19)-related ARDS.[1] A recent meta-analysis of seven retrospective cohort studies including 5216 COVID-19 patients concluded that intensive care unit (ICU) mortality was higher in the prone position, while no significant differences were found in terms of cumulative or hospital mortality, length of stay in the ICU, and duration of mechanical ventilation between prone and supine positions.[2] In addition, there is evidence that the prone position may have several adverse side effects, some of which are clearly acknowledged (e.g., pressure ulcers, nerve injury, bleeding, displacement of medical devices, etc.),[3] while others are often overlooked. The risk of developing venous thromboembolism (VTE) in prone patients who are already at increased risk of thrombosis due to COVID-19 is one such underestimated complication.

Using a simple search in PubMed and Scopus with the keywords “prone” and “COVID-19” and “pulmonary embolism” or “deep vein thrombosis” or “venous thromboembolism” with no language or time restrictions, we identified 58 studies, 4 of which (all cross-sectional, case reports were excluded) described the occurrence of VTE episodes in patients with COVID-19 requiring oxygen support due to respiratory impairment and/or failure ([Table 1]).

Table 1 Summary of articles reporting the occurrence of venous thromboembolism in coronavirus disease 2019 patients needing oxygen support due to respiratory impairment and/or failure

Authors	Study design	Population	VTE (prone vs. supine)
Soumagne et al 2020[4]	Cross-sectional	44 COVID-19 patients mechanically ventilated in the ICU	The number of prone positions per patient and the cumulative number of days spent in prone position were significantly higher in patients with acute PE than in those without.
Gebhard et al 2021[5]	Cross-sectional	21 COVID-19 patients mechanically ventilated in the ICU	Prone position time was longer in patients diagnosed with DVT compared with those who were not.
Massart et al 2023[6]	Cross-sectional	153 COVID-19 patients mechanically ventilated and treated with ECMO	Rate of PE 2-fold higher in patients maintained in prone position
Bargoud et al 2023[7]	Cross-sectional	184 COVID-19 patients with nonmechanical oxygen supply	Rate of PE 3-fold higher in patients maintained in prone position

Abbreviations: COVID-19, coronavirus diseases 2019; DVT, deep vein thrombosis; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; PE, pulmonary embolism; VTE, venous thromboembolism.

In the first study, Soumagne et al[4] studied 44 COVID-19 patients who developed ARDS and had to be admitted to the ICU with mechanical ventilation (mean age: 64 ± 12 years; 82% men). Seventeen (38.6%) of these patients developed acute pulmonary embolism (PE), whereas 27 did not. The number of prone positions per patient (5.3 ± 2.4 vs. 3.2 ± 2.3; p = 0.04) and the cumulative number of days spent in the prone position (7.5 ± 2.7 vs. 4.8 ± 3.1; p = 0.03) was significantly higher in patients with acute PE than in those without. In another study published by Gebhard et al,[5] the authors screened for deep vein thrombosis (DVT) 21 COVID-19 patients (median age, 64 years, interquartile range [IQR], 58–68 years; 76 men) who developed ARDS and required intensive management. After 7 days in the ICU, the prone position time was found to be longer in patients who were diagnosed with DVT (n = 11; median prone positioning time, 71 hours; IQR: 19–104 hours) compared with those who were not (n = 10; median prone positioning time, 28 hours; IQR: 0–73 hours; p = 0.01).

Massart et al studied 517 patients (mean age: 55 years: IQR: 47–61 years; 78% men) with COVID-19-related ARDS,[6] who needed veno-venous extracorporeal membrane oxygenation (ECMO), either maintained in prone or supine position during mechanical ventilation and ECMO. In a subgroup analysis of matched cohorts (153 pairs of patients in prone or supine positioning), the rate of DVT was similar between groups (9.2% prone vs. 10.5% supine position; p = 0.848), whereas that of PE was almost double (but without achieving clinical significance, probably because of the relatively low number of thrombotic episodes) in patients in prone position compared with those supine (10.5% prone vs. 5.2% supine position; p = 0.137; odds ratio: 2.1; 95% confidence interval [CI]: 0.9–5.1). Bargoud et al studied a cohort of 184 COVID-19 patients (mean age: 64 ± 17 years; 51% men),[7] equally divided to stay in prone or supine position during noninvasive oxygen supplementation. The rate of PE was 3-fold higher (3.3 vs. 1.1%; odds ratio: 3.1; 95% CI: 0.3–30.0; p = 0.31; statistical significance not achieved probably due to the low number of thrombotic episodes) in patients maintained in prone position. One remaining study published by Musso et al,[8] was excluded from our analysis since no episodes of either lower limb DVT or PE occurred in 243 patients (81 maintained in prone position) with moderate-to-severe hypoxemic COVID-19-related respiratory failure treated with noninvasive ventilation. However, nine episodes of upper limb venous thrombosis were diagnosed, 5% in patients in prone position versus 3% in controls (odds ratio: 1.6; 95% CI: 0.4–6.1).

It is also noteworthy that another recent study conducted on 340 patients subjected to degenerative cervical spine surgery[9] evidenced that prone positioning was an independent predictor of DVT along with advanced age, presence of varicose veins, and bleeding loss. A reliable pathogenetic mechanism was also proposed by these authors, encompassing iliac cushions that may compress iliac veins and thereby reduce venous flow within these vessels, thus promoting venous stasis and increasing the risk of DVT and, consequently, of PE.

Despite the small sample size of these studies and the lack of randomized clinical trials specifically addressing the risk of developing VTE in the prone versus supine position during mechanical ventilation, these preliminary results suggest that prone positioning may contribute to increase an already elevated risk of developing venous thrombosis in COVID-19 patients with respiratory failure, likely due to position-related reduction in venous blood flow, up to stasis.[10] Although regional perfusion remains relatively unchanged in patients with non-COVID ARDS placed in the prone position, the combination of gravity and impaired perfusion due to the increased burden of vascular occlusion (caused by in situ pulmonary thrombosis) may ultimately compromise regional lung perfusion in ARDS of COVID-19 patients ([Fig. 1]). Therefore, as lung injury advances, the benefit of maintaining a prone positioning to improve gas exchange diminishes, with patients instead placed at increased risk of thrombosis.[11] Therefore, specific thrombosis prophylaxis protocols should be defined for COVID-19 patients with ARDS who are placed in the prone position for a prolonged period of time, especially those requiring mechanical ventilation or ECMO. Moreover, due to such increased risk of developing venous thrombosis, it may be advisable to refrain from maintaining prone positioning in the so-called “nonresponders” (i.e., in those with ARDS but without significant respiratory improvement after pronation) immediately after the initial pronation sessions.[12]

Fig. 1 Relationship between gas exchange and acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) patients placed in prone position. In typical ARDS, the lung tissue is mostly occupied by exudate (blue) and can be still recovered with forced oxygenation. In COVID-19 ARDS, large portions of tissue are occupied by thrombosis (red) and cannot be recovered.

Publikationsverlauf

Artikel online veröffentlicht:
11. Mai 2024

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