Putative antiviral effects of propofol in COVID-19.

Editor—Propofol, a short-acting i.v. anaesthetic drug, is commonly used as a first-line agent to sedate intubated coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS) in the ICU. The COVID-19 global pandemic has led to a shortage of propofol in many countries. Recently, it has been highlighted that patients receiving propofol sedation are at a risk of exacerbated infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that subsequently affects the severity of COVID-19. Studies in vitro have indicated that propofol treatment can upregulate angiotensin-converting enzyme 2 (ACE2) expression, an essential receptor involved in the internalisation of SARS-CoV-2. , The suggestion that propofol contributes to the aggravation of the condition of intubated patients with COVID-19 by promoting SARS-CoV-2 cell entry has led to the use of alternative sedative drugs.

This hypothesis has led to increasing uncertainty and concern surrounding the use of propofol in patients with COVID-19; however, it remains unclear whether there is a direct association between drugs that increase ACE2 expression and the risk posed to patients with COVID-19. Fang and colleagues analysed data from three clinical studies on COVID-19 during the early outbreak in Wuhan, China, and extrapolated that the severity of COVID-19 might increase in patients with diabetes and hypertension taking ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which cause a significant increase in ACE2 expression, as observed in animal studies. However, a recent clinical study has shown that the use of ACEIs and ARBs was not closely associated with the diagnosis and severity of COVID-19 amongst patients with hypertension. Although daily intake of ACEIs and ARBs significantly increases ACE2 mRNA expression and activity in rats, this effect might not exist in humans. Evidence to support this came from a study investigating the expression and subcellular localisation of ACE2 in the upper and lower respiratory tracts of human donor tissues. That study provides strong evidence that the use of ACEIs and ARBs does not increase susceptibility to SARS-CoV-2 infection by enhancing ACE2 expression in either the initial or early essential cellular site of viral entry during respiratory transmission.

In fact, propofol, via enhanced ACE2 expression, might have favourable effects on the vascular endothelium in patients with COVID-19. Propofol protects endothelial cells of human pulmonary artery by increasing transcription of ACE2 via a phosphatidylinositol 3-kinase-dependent mechanism, and its activity in cell membranes. Propofol can also inhibit vascular endothelial cell apoptosis by activating the ACE2/angiotensin-(1–7)/Mas signalling pathway and increasing nitric oxide levels, the endothelium-derived relaxing factor, by upregulating the expression and phosphorylation of endothelial nitric oxide synthase. Elevated ACE2 expression increases anti-inflammatory effects that suppress the systemic inflammatory cascade induced by SARS-CoV-2. The multiple actions of propofol, including significant anti-inflammatory, anti-thrombotic, and fewer immunosuppressive effects, may facilitate recovery from lung injury in COVID-19.

Propofol might also act as an antiviral agent in infected cells. It could inhibit SARS-CoV-2 entry and transmission by increasing the apparent size and number of lipid rafts and by dissociating cholesterol-sensitive proteins from monosialotetrahexosylganglioside-1 (GM-1) lipid rafts in vitro. Propofol might have an antiviral effect by inhibiting the sigma-1 receptor, , a potential antiviral target against COVID-19. Based on these properties, we summarise the potential mechanisms by which propofol might be advantageous in patients with COVID-19 (Fig. 1 ). Although physiological models of SARS-CoV-2 infection present a theoretical risk of propofol, these findings cannot be extrapolated to a clinical setting, where propofol exacerbates COVID-19. As the benefits outweigh the risks, we conclude that propofol should not be avoided because of concerns regarding ACE2 and diagnosis or aggravation of COVID-19.

Fig 1

Putative mechanisms of the protective effects mediated by propofol in patients with COVID-19. Propofol may exert direct antiviral effects by disturbing GM1 lipid rafts and inhibiting sigma-1 receptors, and by indirect effects, including anti-inflammation, anti-thrombosis, and reduced immunosuppression. Additionally, elevated ACE2 expression induced by propofol treatment may protect pulmonary artery endothelial cells, inhibit apoptosis in vascular endothelial cells, and suppress SARS-CoV-2-induced systemic inflammatory cascade. ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; eNOS, endothelial nitric oxide synthase; GM-1, monosialotetrahexosylganglioside-1; iDC, immature Dendritic Cell; IL-1β, interleukin-1β; IL-6, interleukin-6; NO, nitric oxide; NTG, nitroglycerine; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TNF-α, tumour necrosis factor-α.

However, prolonged sedation with propofol infusions for intubated and mechanically ventilated patients with COVID-19 and ARDS may have adverse side-effects, such as propofol infusion syndrome, neuroleptic malignant syndrome, and critical illness myopathy. Therefore, prolonged propofol infusions might not be the ideal choice for patients with COVID-19 in the ICU. Other sedatives, including midazolam and dexmedetomidine, provide suitable alternatives to propofol in such patients.

Declarations of interest

The authors declare that they have no conflicts of interest.

Funding

(ZR2020QH291 and ZR2020MH126); (2019GSF108228); Qingdao Key Health Discipline Development Fund (2019); Qingdao Outstanding Health Professional Development Fund (2019).