This study shows that elevated ONSD/ED is common in severe Covid-19 cases and is associated with significantly longer ICU-LOS in these patients. The association between ONSD/ED and ICU-LOS was not explained by background factors such as age, gender, or comorbidities, nor by the timing of ONSD measurement during ICU stay. It was also unrelated to ventilator modes or settings, cumulative prone positioning time, and degree of hemodynamic, respiratory, or renal impairment at the time of ONSD/ED measurement.
Our findings closely match those of the only previous study evaluating PCI non-invasively in patients with severe Covid-19 using ONSD ultrasound. In this study, ONSD was measured in 49 patients and 10 of them (18.9%) were estimated to have an elevated ICP. These patients had significantly longer ICU-LOS than patients with estimated normal ICP (45 days versus 36 days) but showed no significant difference in ICU or hospital mortality.6. We analyzed longer-term outcomes by comparing 90-day mortality between groups. Another difference between this study and ours is that we corrected ONSD for ED.
High ICP is not the only possible explanation for a high ONSD. Optic neuritis also causes increased ONSD and has been reported in Covid-199.16. This is, however, a rare complication of Covid-19 and so we believe it is unlikely to cause the 20% occurrence of elevated ONSD that we see in this study. Prone positioning is a common treatment strategy in severe cases of Covid-19. Prone position often results in facial edema and in some cases elevated intraocular pressure17. It is unclear whether repeated prone positioning and accumulated prone positioning time affect ONSD. Prone positioning is performed daily in many patients with severe Covid-19 in our intensive care facility and tends to increase with increasing disease severity. If accumulated supine positioning time affects ONSD, it would confound our results. However, we detected no significant difference in accumulated prone positioning time between patients with normal and high ONSD/ED. Accumulated prone positioning time therefore cannot explain the association between ICU-LOS and ONSD/ED in our data.
ONSD has a well-established association with ICP9.10 and was not related to the background factors or any of the potential confounders that were measured in our cohort. We therefore believe that the most likely interpretation of our results is that elevated PCI may be common and associated with adverse outcomes in Covid-19. There are several possible explanations for why an elevated ICP would occur in severe Covid-19. Elevated ventilator pressures and right ventricular failure are common in respiratory failure in general and in severe cases of Covid-19 in particular18,19,20,21. Both affect central venous pressure and therefore ICP22,23,24. Hypothetically, there could be a cumulative effect where sustained high ventilator pressures and sustained right ventricular failure over time cause and exacerbate cerebral edema. High ventilator pressures are likely associated with longer ICU-LOS due to lung injury and are therefore a potential confounder in our study. There were, however, no significant differences in ventilation patterns or ventilation pressures between patients with normal and high ONSD/ED at the time of ONSD/ED measurement in our data. Hypercapnia can also cause elevated ICP25. This is a common phenomenon in the advanced, severe stage of Covid-1920 and is often allowed in respiratory failure to facilitate protective ventilation of the lungs19. Again, no significant differences in pCO2 between patients with normal and high ONSD/ED were found in our data. We do not believe that ventilator pressures or hypercapnia are determinants of the association between ONSD/ED and ICU-LOS. Systemic inflammation and neuroinflammation are other possible mechanisms for cerebral edema and thus elevated ICP, alongside hypoxic injury caused by hypoxemia, vascular complications, and thromboembolic events. All of these can occur in severe cases of Covid-191,2,3 and are plausible explanations for our findings.
The suggestion that elevated ICP may be common in severe cases of Covid-19 and is associated with adverse outcomes is clinically important. Firstly because it brings a new perspective on the permissive hypercapnia strategy mentioned above. Hypercapnia does not appear to be the determining factor in our results and pCO2 levels were moderate overall in our cohort. Higher pCO2 levels will however further elevate ICP in patients with ICP instability25. Second, a practice has emerged, based on the experiences of several intensive care units, of sometimes positioning severe Covid-19 cases flat or even in the Trendelenburg position as a lifesaving maneuver. This is due to the paradoxical improvement in lung compliance sometimes observed in severe cases of Covid-19 at these positions, a phenomenon that has recently been reviewed.26. These positions along with permissive hypercapnia will inevitably increase ICP25.27. No patient was in the Trendelenburg position when the ONSD/ED was measured. If elevated PCI is a contributing factor to outcomes in severe Covid-19, this should be considered when discussing these mentioned treatment strategies. Similarly, treatment strategies regarding blood pressure targets, serum osmolality, and dialysis doses in patients with acute renal failure may need to be revised if elevated ICP is truly a factor in severe Covid-19. . Additionally, the ability to predict ICU-LOS based on ONSD/ED may be clinically relevant. A reliable tool for predicting ICU-LOS duration can inform decisions such as timing of tracheostomy and patient transfer. The ICU-LOS forecast could provide valuable information for management decisions regarding resource allocation.
There are limitations to this study, the most obvious being the small sample size. There may be a difference in 90-day mortality and associations between ICU-LOS and other parameters that this study could not detect. There were no statistically significant differences in comorbidities between the groups, but our small sample size may be insufficient to detect potentially true differences. Also, the small sample size can make the results sensitive to outliers. Importantly, however, our results were robust throughout the sensitivity analyses, as previously described. The convenience sampling strategy that was necessary to perform this study during an ongoing pandemic made it vulnerable to selection bias. Furthermore, this strategy led to the estimation of ICP at different time points during the patients’ ICU stay. This could have affected the results if the ONSD had changed during the course of the illness. But since the day of the ONSD/ED measurement was not correlated with ONSD/ED, we don’t think it interferes with the results. Outcome measures pose another set of limitations in this study. ICU-LOS is likely to be confounded by ICU mortality, but our results were robust throughout the sensitivity analysis to the exclusion of ICU mortality cases. Neither ICU-LOS nor survival provide information on long-term quality of life or neurological function. This may be one of the biggest limitations of this study. Finally, it should be emphasized that ONSD ultrasound does not give precise ICP values. This is an ICP substitute and false positives are to be expected. Additionally, there is no consensus regarding the ONSD/ED threshold for identifying elevated PCI. Our threshold at 0.295mm is based on unpublished data currently under peer review.
Since ONSD/ED showed no association with the baseline factors or any of the potential confounders we measured, we still believe that an elevated ICP is the most likely explanation for the ONSD/ED high in this cohort.