The main result of our study is that severe COVID-19 patients admitted in the ICU showed altered microcirculatory status in the peripheral muscle, and the degree of such alterations correlated with the severity of the respiratory disease. To our knowledge, this is the first study evaluating the peripheral microcirculation in critically ill COVID-19 patients at the bedside using non-invasive NIRS.
Our findings reinforce the idea of a systemic microvascular involvement in severe COVID-19 patients, and further supports the association between the degree of endothelial dysfunction (ED), expressed as poor microvascular reactivity, and the severity of the disease, including the respiratory involvement . There is growing evidence supporting the role of ED in the time course of severe COVID-19. Several mechanisms have been proposed to contribute to ED, including direct endothelial cell damage produced by the virus, down-regulation of the angiotensin-converting enzyme 2 (ACE2) receptors, the inflammatory response of the host, or even as a results of tissue hypoxia in the setting of severe hypoxemia, among others [17,18,19,20,21,22,23]. Some authors suggest that COVID-19 might be considered an endothelial disease [8, 19, 20], and those patients with more severe forms, probably due to individual predisposition, will develop not only respiratory disease, but also systemic disease, with generalized ED, coagulopathy, disseminated intravascular coagulation (DIC), and multi-organ failure [22, 23]. Our study does not provide insights in the mechanisms of ED, but confirms that microvascular reactivity, as a surrogate of endothelial function, can be properly evaluated and monitored in severe COVID-19 patients by means of non-invasive near-infrared spectroscopy technologies. Of note, the technology does not allow for the evaluation of other aspects of the endothelium that might be altered in COVID-19, such as the barrier function or the control of the coagulation.
ED also plays a key role in ARDS induced by other causes, such as sepsis or other respiratory viral infections. In fact, microvascular reactivity alterations, evaluated by means of NIRS, have been associated with poor prognosis in a mixed population of ARDS patients , and in a small series of patients with acute lung injury due to influenza AH1N1 . Such observations, and ours, would be complementary, pointing towards the value of evaluating microvascular reactivity by means of NIRS technologies, independently of the underlying disease that led to endothelial damage. Accordingly, microvascular reactivity evaluation, as a reflection of endothelial function, might be a useful tool for prognostic purposes in several critical conditions. Whether microvascular reactivity is associated with poor prognosis, in terms of mortality, in COVID-19 patients is currently being investigated in a large multicenter trial (NCT04689477; Hemocovid19-project.org). This study is an interim report from the larger trial. Since ED is an old companion of several critical conditions, the larger trial will also address the issue of whether there are differences in the degree of alterations in microvascular reactivity in COVID and non-COVID populations, and its impact on outcomes. Clearly, our findings on microvascular reactivity alterations are not expected to be limited to COVID-19 patients, nor useful as a specific diagnostic tool for detecting COVID-19, but only as a quantification of the involvement of the systemic endothelium in the process of the disease. Furthermore, the value of microvascular reactivity alterations in heterogeneous populations may notably differ from our findings.
To date, large series of COVID-19 patients have demonstrated that some comorbidities such as hypertension, diabetes, cardiovascular diseases, and obesity are associated with higher risk of developing severe disease [26,27,28]. Such observations have been linked to increased ACE2 expression in those conditions, and therefore an increased vulnerability of the endothelial cells to the action of the virus. Although our sample size might be limited, our regression analysis points towards the importance of endothelial function evaluation, independent of any underlying comorbidities.
In addition to compromised microvascular reactivity, we also observed significant impairments in local tissue metabolic rate, as reflected by impaired DeO2 values in COVID-19 patients, as compared to healthy volunteers. Such alterations, also observed in other conditions such as sepsis [10,11,12], reflect the inability of the explored area to properly use the oxygen available, and might be caused by microvascular thrombosis, tissue edema, and/or mitochondrial dysfunction. We cannot distinguish the underlying mechanism, but note that it does occur, and that it reveals microvascular disease.
An interesting finding of our study was that no differences in microcirculatory involvement were detected when comparing patients receiving invasive MV and those receiving non-invasive respiratory support. Such findings may be surprising, since patients receiving MV were likely more severe. In this study, we do have detected an association between the degree of ARDS severity according to the degree of hypoxemia, but we have not explored the association with other respiratory parameters, such as respiratory mechanics. The decision to intubate a patient was not protocolized/standardized in our study, and the attending physicians in each participating center made independent clinical decisions. Therefore, a certain degree of variability in the management of hypoxemia among centers is expected. The approach to managing hypoxemia in COVID-19 patients is a complex debate. Some authors propose a less invasive approach, since many patients exhibit what has been named "happy" or "silent hypoxemia" [29,30,31]. The decision to intubate COVID-19 patients based only on a certain degree of hypoxemia has been questioned, but the truth is that it is still a current practice in the clinical scenario, and even in many randomized controlled trials. For instance, in a recent multicenter trial analyzing the use of awake prone positioning, mortality did not differ between patients treated with high-flow nasal cannula and patients that required mechanical ventilation , highlighting the issue that the use of mechanical ventilation might not be only associated with the severity of the illness, but also to different practices among clinicians when facing the management of hypoxemia in COVID-19 patients. On that behalf, we hope our larger trial will provide more relevant information on this subject.
Furthermore, the lack of differences in microvascular reactivity between invasive and non-invasive MV are important in order to rule out the effect of drugs, such as sedative agents or norepinephrine, as the only explanation to peripheral microcirculatory alterations in ARDS patients. Sedation (deep sedation) might appear as one of the causes of altered microcirculation in COVID, but we already observed equivalent alterations in awake patients receiving HFNC or Venturi mask, without apparent cardiovascular problems. To date, microcirculatory impairment has been extensively associated with hemodynamic alterations, such as in septic shock [8,9,10]. Of note, none of the studied patients showed increased plasma lactate levels, and only twelve patients were receiving vasopressors for maintaining adequate blood pressure values.
The primary limitation of this study is the restriction of enrollment to patients with severe forms of COVID-19, and therefore our results might not be valid for mild or moderate forms of the disease, i.e., not requiring intensive care support. In fact, in those patients with less severe presentations of COVID-19, systemic involvement might be limited, and endothelial dysfunction is lower , and thus, peripheral microvascular reactivity might appear within normal ranges. Moreover, no measurements prior to IRCU/ICU admission were available, and thus, whether ED precedes respiratory deterioration cannot be deduced. On that point, a small study showed that elevated angiopoietin-2 levels, as a marker of endothelial activation, measured early in the emergency department, were associated with the need for ICU admission . Additional studies should explore the value of early microvascular reactivity evaluation in order to detect those patients with mild forms of the disease who might further deteriorate.
Secondly, arterial blood gas analysis was only computed in MV patients, and the utilization of SpO2/FiO2 may have some limitations, namely peripheral disturbances, and its lack of sensitivity to take into account the presence of hyperoxemia. However, since many patients included in the trial were receiving non-invasive therapies, and did not have an arterial line, SpO2/FiO2 was taken as a surrogate of PaO2/FiO2 in order to reflect respiratory involvement. Although a linear correlation between such parameter and NIRS-derived variables might be affected by the exposed limitations, SpO2/FiO2 has been previously validated for classifying the severity of ARDS . In addition, in those patients where PaO2 was also obtained, the correlation between PaO2/FiO2 and SpO2/FiO2 was strong (r = 0.9). The lack of peripheral disturbances observed in our population (no relevant cardiovascular issues in our sample) might also account for the strong relationship between these two parameters, but that might not be the case for other clinical scenarios, such as critical conditions with severe hemodynamic impairment.
In our study, most patients were already receiving treatments with potential effects on the microcirculation, such as heparin or corticosteroids. Regrettably, our design does not allow for evaluating the impact of such therapies on the microcirculation.
Finally, this preliminary data was not powered for mortality assessment, but rather to detect microcirculatory alterations in COVID-19 patients, compared to healthy volunteers. The observed association with SF ratio points towards a potential prognostic value when referred to mortality [34, 35]. On that behalf, a larger trial is being conducted in order to test the association between impaired microvascular reactivity and mortality in COVID-19 patients admitted to the IRCU/ICU.