This study measured the incidence of delirium in hospitalized COVID-19 patients and explored associated risk factors. A considerable frequency of delirium (17.42%) was encountered and a significant association with patient severity, diabetes mellitus and -most notably- the need of mechanical ventilation was found. Mechanical ventilation appears to be the single most important precipitating factor for delirium development.
Previous studies that have measured delirium in COVID-19 have reported higher frequencies, mainly due to difference in patient selection (12, 24) since they included only ICU patients. Severity of COVID-19, evidenced by higher NEWS2 score and the need of ICU hospitalization, is associated to higher incidence of delirium, as reported before (24). In our patients, delirium was associated with older age, as described in previous studies in critically-ill patients, either with COVID-19 (25) or in other settings (26, 27).
Comorbidities have been reported as risk factor for delirium on previous COVID-19 series (27, 28) and in general ICU population (29, 30). In our cohort diabetes mellitus type 2 was the comorbidity with the strongest association to delirium. Other comorbidities such as obesity and arterial hypertension appeared to be associated to delirium in bivariate analysis but the trend was not maintained in multivariate analysis. Obesity, although slightly more frequent among delirium patients, was not associated to delirium either. Parkinson’s disease was present in only two patients; both of them developed delirium during hospitalization. Other authors have reported delirium in patients with dementia (27, 28), in smokers (15) or in patients with a higher number of comorbidities (31). In our cohort only seven patients had a baseline cognitive deficit. Although most of them had severe disease, this condition was not associated with delirium.
Functional status before admission was poor in delirium patients, indicating a diminished physiological reserve to face the disease and the hospitalization. This decreased autonomy could be the result of a decreased cognitive status or a compromised physical capacity, both of which have been associated to delirium (25). Comorbidities and frailty are associated to the decrease in functional status, and they have recently been found to be associated with a higher incidence of delirium among elderly people suffering of COVID − 19 (25). We cannot be sure about the causes of decreased mRs in our series upon discharge and its association with delirium. Our delirium patients were older and had a higher incidence of arterial hypertension and diabetes mellitus type II, which are presumably associated with frailty and a decreased functionality (32, 33).
The association of neurological symptoms at admission and delirium has not been widely explored, Ticinesi reports an association of neuropsychiatric entities (dementia and epilepsy) with subsequent delirium (28). By contrast, we found a negative association between the presence of any neurologic symptom and the occurrence of delirium. This was particularly notable with headache at admission, which was more frequent in patients who did not develop delirium; and happened to a lesser extent with anosmia/hyposmia and dysgeusia, which were all less frequent among patients who developed delirium although no significant association was found on multivariate analysis. Interestingly, Amanat et al., in a series of 873 patients, found a high incidence of neurological manifestations both early and late in the course of disease; they report a negative association between headaches and severity of COVID-19 (34) in consonance with our finding.
Muscle weakness, by contrast, was strongly associated with a higher incidence of delirium. To our knowledge, this is the first report of such association. We speculate that muscle weakness is a sign of skeletal muscle impairment; This damage is shared by the respiratory muscles and ultimately leads to respiratory failure, later associated with need of mechanical ventilation, which, besides involving the use of opioids and hypnotics, increases the time and extent of physical dependence, routine disruption, and social isolation; all factors that increase the risk of delirium (35).
Delirium is thus more frequent among patients admitted to ICU that tend to accumulate most of the factors associated with this condition: most had mechanical ventilation and sedation for several days, and some developed shock or required tracheostomy. Mechanical ventilation as a marker of disease severity (hypoxia, inflammation, and organ failure) and a therapeutic maneuver linked to sedation, is accompanied by the greater disruption of social links, autonomy and circadian rhythm, all factors associated with delirium (35). In our series, mechanical ventilation was always accompanied by sedation based on a protocol of hypnosis with midazolam and analgesia with fentanyl, making it difficult to identify which one of these two drugs has a stronger association with delirium. The effects of these drugs are to be considered as part of the association between mechanical ventilation and delirium.
Our previous evaluation of delirium among ICU patients found a higher prevalence of delirium (29.7%) in a general population of critically ill patients with a variety of medical and surgical conditions that required ICU admission (36). That assessment included patients with a lesser severity of respiratory failure and, perhaps, a minor inflammatory status, but the sedation used was deeper and longer than it is currently in use. Furthermore, our cohort of COVID-19 patients, also considered patients from the general ward and we used one test (CAM-ICU) applied by trained physicians to patients, when the medical staff suspected delirium. The incidence of delirium when considering only the sub-group with ICU admission was 24.9%; consistent with previously reported frequencies of delirium in ICU patients either during or before the COVID-19 pandemic (28, 36). We may have missed cases of delirium since patients underwent only one delirium assessment as part of the study and the diagnosis could be missed, although it is unlikely given that patients underwent daily routine assessments by study staff in ICU and general ward.
The severity of the SARS-CoV-2 infection has been linked to a significant inflammatory state, in the same way we found that higher serum levels of inflammatory markers such as lactic dehydrogenase, C-reactive protein, neutrophil/lymphocyte index and D dimer were associated to the development of delirium (Table 2). Other authors have linked the pathogenesis of delirium to the inflammatory state both in COVID-19 (13) and other forms of ICU admission (37).
D dimer is associated with intravascular coagulation and venous thromboembolism in COVID-19 (38) and other clinical situations (39) and it is considered a marker of disease severity (40). Our findings open the way to further study the roll of micro-thrombosis in the pathogenesis of delirium, as proposed by MacLullich (37). On the other hand, it has been proposed that inflammatory mediators promote the activation of endothelial cells of the brain vasculature; consequently, they secrete soluble prostaglandins into the brain parenchyma leading to brain disfunction activation of neural center by afferences of vagus nerve (37). Our data suggest that the presence of inflammatory mediators participates in the genesis of cognitive dysfunction in COVID − 19 patients.
Functionality of patients at discharge (mRS) was affected by delirium reflecting either the higher severity of disease or the impact of delirium in cognition and functionality after acute illness. As a consequence, less patients in the delirium group could be discharged home, and had to go to other hospices or rehabilitation units. This relationship has been already reported in COVID-19 patients (41) and has been previously recognized in other settings (35). The relationship between delirium and mortality could not be explored in this study since most deaths occurred in mechanically ventilated patients for whom delirium assessment would have occurred after extubation. Therefore, estimation of the association between death and delirium would be biased towards survival among delirium patients.
Our study has multiple strengths which comprise the inclusion of consecutive patients, high quality of the recorded data and the application of a standardized delirium assessment performed by trained physicians that employed the CAM-ICU criteria for diagnosis. It is to be noted that the study site was not overwhelmed by the influx of COVID-19 patients, and did not suffer from shortages of medications or protective equipment during the study period; an aspect to be considered for generalization of our results to other scenarios during this pandemic.