In this single center prospective study, we observed that brain hemodynamics were impaired in a large proportion of critically ill COVID-19 patients on mechanical ventilation. In particular, early assessment of these patients showed higher intracranial pressure and lower brain compliance among those who were still on ventilation or who had died within the first 7 days since study admission. Moreover, a score composed on different parameters related to brain perfusion and compliance could identify such patients with a high accuracy. Nevertheless, these alterations were not associated with ICU mortality.
Currently, there are no data on alterations in intracranial hemodynamics and/or compliance in COVID-19 patients, although several studies have shown an increased occurrence of cerebrovascular events in low-risk patients, being associated with coagulation disorders and the formation of clots in the large intracranial vessels or into the brain microvasculature.32 Nervous system invasion mechanism has been described as direct viral penetration of nerve endings and traveling within the axons or by the systemic circulation, via the infected endothelial cells of brain vessels or epithelial cells in the choroid plexus or the disruption of the blood-brain barrier; also, neuroinflammation, which is triggered by systemic inflammatory response and organ damage, can contribute to brain dysfunction through activation of microglial cells.33 The clinical consequences of this phenomena are consistent with cerebrovascular events, brain swelling, seizures and encephalopathy, which could be further enhanced by the use of specific therapies, such as mechanical ventilation, sedatives or extra-corporeal membrane oxygenation (ECMO).34
The role of TCD-derived parameters (mCBFV, PI, eICP and eCPP) on the assessment of cerebral hemodynamics in critically ill patients without a primary brain injury is well established, with relevant data on the role of altered autoregulation in the pathogenesis of septic encephalopathy35 or of reduced mCBFV in association with severe post-anoxic brain damage,36 although the association with long-term neurological outcome needs to be further evaluated. In hospitalized COVID-19 patients, higher mCBV and lower vasoreactivity were observed than matched healthy volunteers37. Also, in a small recent study using cerebral ultrasound, eICP was higher and diastolic CBFV lower in COVID-19 patients developing neurological complications when compared to others38. The authors added also the estimation of ICP using the optic nerve sheath diameter measure (ONSD) measurement with cerebral ultrasound, which was not available in our study. Moreover, mortality was higher in our study than this report (60% vs.33%), and differences in patients’ selection and management as well as a different study endpoint precluded any additional comparison. Moreover, there is lack of studies dealing with this B4C device in critically ill patients; although this new technique provides an unique assessment of cerebral compliance, which would be complementary to TCD-derived variables, more prospective data are needed to validate this non-invasive and relatively low-cost technique as a reliable bedside neuromonitoring in critically ill patients.
We did not specifically evaluate which factors could influence alterations in brain hemodynamics or compliance. Changes in PaCO2, mean arterial pressure, pH, sodium or temperature could also lead to altered brain hemodynamics.39–41 Because of the relatively small sample size and different patterns of TCD and P2/P1 alterations, we could not assess the association of systemic abnormalities with some specific patterns, such as low mCBFV, high eICP or P2/P1. However, as all these variables are complementary and evaluate different aspect of brain hemodynamics, we could obtain a composite derived score with a high predictive accuracy for early UO. Further studies would be required to confirm the validity of such score and its association with clinically relevant neurologic symptoms or syndromes (i.e. encephalopathy, delirium, ischemic events) or its correlation with other neuromonitoring tools, such as brain oximetry or electroencephalography.
This study has several limitations to acknowledge. First, our findings showed association and not causality between UO and alterations in cerebral hemodynamics. Routine daily assessment of these variables as of potential therapies to restore “normal” brain hemodynamics will be in this setting. Second, the correlation between the B4C system and other surrogate of brain compliance, such as invasive ICP monitoring, is not validated yet. The thresholds applied in our study were however extrapolated from the previous knowledge on ICC and ICP research. As this system acquires intracranial information through an extracranial technique, precaution is needed. Third, we could not perform neurological imaging during the study period, which is a hindrance to elucidate the etiology of the alterations in intracranial pressure pulse waveform in COVID-19, whether as primary CNS injury or secondary to respiratory or other systemic complications. Forth, availability of operators to assess brain hemodynamics restricted study exclusively for severe COVID-19 admitted to the ICU. Finally, we used a composite endpoint of early systemic dysfunction, which is not specific for brain damage; long-term neurological assessment should be evaluated in future studies in association with early disturbances of brain perfusion and compliance.