|Year : 2023 | Volume
| Issue : 1 | Page : 36-40
Clinical presentations and prognosis of delirium in patients with coronavirus disease 2019: A prospective cohort analysis
Riddhi Jamubhai Bhagora M.B.B.S , Pradhyuman Chaudhary M.D , Dharshni Ramar M.B.B.S , Prakash Mehta
Department of Psychiatry, GMERS Medical College, Sola Civil Hospital, Ahmedabad, Gujarat, India
|Date of Submission||22-Dec-2022|
|Date of Decision||24-Jan-2023|
|Date of Acceptance||26-Jan-2023|
|Date of Web Publication||28-Mar-2023|
Sola, Ahmedabad - 308 060, Gujarat
Source of Support: None, Conflict of Interest: None
Background: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has emerged as one of the biggest health threats of our generation. Since its outbreak, COVID-19 has been showing many typical and some atypical manifestations. One of the common complications in COVID-19 is delirium. Delirium should be detected at the earliest to reduce mortality in COVID-19. Methods: We prospectively studied hospitalized adult (age ≥ 18 years) patients with confirmed COVID-19 from May 1 to May 31, 2021, at GMERS Medical College and Civil Hospital, Sola, Ahmedabad, India. We included all patients suffering from COVID-19 and diagnosed with delirium in the study. Delirium was assessed using the Confusion Assessment Method and Richmond Agitation Sedation Scale. Follow-up was done for delirium patients on days 0, 5, 10, and 30. Results: We included 1,233 patients in the analysis. The incidence of delirium was found 2.43% in which 63.3% were hypoactive delirium while 36.7% were hypoactive delirium presentation. The mean age ± standard deviation of delirium patients was 68.33 ± 14.67 years (range = 46-92) years, and 20 (66.7%) were male and 10 (33.3%) were female. The result of the study also showed statistical significance between deaths in patients of confirmed cases of COVID-19 with delirium (93.33%) than patients of confirmed cases of COVID-19 without delirium (12.38%, p < 0.001). Conclusion: The presence of delirium was associated with increased risk of mortality in hospitalized adults with COVID-19.
Keywords: Confusion Assessment Method score, mortality, Richmond Agitation Sedation Scale, systemic diseases
|How to cite this article:|
Bhagora RJ, Chaudhary P, Ramar D, Mehta P. Clinical presentations and prognosis of delirium in patients with coronavirus disease 2019: A prospective cohort analysis. Taiwan J Psychiatry 2023;37:36-40
|How to cite this URL:|
Bhagora RJ, Chaudhary P, Ramar D, Mehta P. Clinical presentations and prognosis of delirium in patients with coronavirus disease 2019: A prospective cohort analysis. Taiwan J Psychiatry [serial online] 2023 [cited 2023 May 28];37:36-40. Available from: http://www.e-tjp.org/text.asp?2023/37/1/36/372641
| Introduction|| |
There were unidentified cases of viral pneumonia first reported in Wuhan, Hubei Province, China, in December 2019 . The disease is characterized by severe acute respiratory syndrome and has gradually spread around the world, known as coronavirus disease 2019 (COVID-19) by the World Health Organization .
Delirium is an acute decline in both the level of consciousness and cognitive function. The presentation of delirium often involves perceptual disturbances, abnormal psychomotor activity, and sleep cycle impairment. It has an acute onset and fluctuates throughout the day and improves quickly upon recognition and treatment of the cause. It can be caused/precipitated by hypoxemia, infection, electrolyte imbalance, alcohol withdrawal, systemic inflammation, or metabolic imbalance. All of the causative factors can lead to organ dysfunction ,,.
The viral infection initiates an inflammatory response in the central nervous system (CNS). Neutrophils and monocytes infiltrate the CNS within hours of becoming infected. This neutrophil disrupts the permeability of the blood–brain barrier. Activated macrophages and microglia play a critical rôle in the destruction of myelin, which leads to memory failure and short- and long-term cognitive dysfunction ,,. A large amount of myelin damaged as a result of neuroinflammation is potentially immunogenic and reactivate macrophages, triggering a vicious cycle supporting additional inflammation. This process may contribute to an increased incidence of neuropsychological abnormalities in patients with severe infection and septicemia. This is thought an important reason for poor neurological outcome and the development of delirium . Further studies are required to confirm this hypothesis.
In course of COVID-19, chances of delirium are high in hospitalized patients. Factors influencing it are sedatives, neurological conditioning, a secondary effects of other organ faliures and environmental factors which include prolonged mechanical ventilation time, social isolation, emotional stress, sleep cycle impairment. For COVID-19, delirium and coma are serious manifestations of acute cerebral dysfunction, which are linked to poor outcome and mortality in critically ill patients.
Delirium in the context of COVID-19 can be caused by acute respiratory distress (ARD) syndrome, immune overactivation (referred to as cytokine storm), or viral meningoencephalitis. A study was found that 12% of COVID-19 patients presented themselves with delirium and a total of 33% experienced it during their hospital stay . Bacterial, viral, and aseptic meningoencephalitides were discovered in delirium . Cytokines (interleukin [IL]-6, IL-2, tumor necrosis factor, and vascular endothelial growth factor) were discovered to be elevated in delirium . Due to varied etiologies other than COVID-19, ARD itself has a higher incidence of delirium . Thus, three major known complications of COVID-19 infection have a well-known association with delirium and mortality. Delirium is associated with both poor short-term outcomes, which include institutionalization, increased length of hospital stays, increased number of complications, and mortality, and adverse long-term psychiatric sequelae such as depression, post-traumatic stress disorder, sleep disturbances, cognitive impairment, and not attaining premorbid functions ,. In the present study, we intended to find out the clinical parameter of delirium in COVID-19 patients and the outcome of patients with delirium.
| Methods|| |
The prospective cohort study was conducted at GMERS Medical College and Civil Hospital, Sola, Ahmedabad, Gujarat, India. From May 1, 2020, to May 30, 2020, all consecutive patients admitted to the intensive care units (ICUs) and wards of a COVID-19-designated hospital with a positive result by severe acute respiratory syndrome coronavirus 2 nasopharyngeal swab polymerase chain reaction test were included in the record data. Patients under the age of 18 years and those unwilling to give consent were excluded from the study.
The Institutional Ethics Committee for Human Research-PG Research at GMERS Medical College and Civil Hospital, Sola, Ahmedabad, Gujarat, India, approved the study protocol (protocol number = GMERSMCS/IEC/20/2021 and date of approval = June 26, 2021) with the need of obtaining the signed informed consents from the study patients. Then, we assessed the information of the sociodemographic characteristics of the patients, their clinical parameters at admission, the status of their comorbidity, and the severity of their disease at admission. A subsample of a cohort of patients diagnosed having delirium by a consultant psychiatrist was taken for a further prospective study. During the study, 1,233 patients were admitted for management of COVID-19 infection, of these 53 patients were referred and 30 patients were diagnosed with delirium by a consultant psychiatrist and 23 patients were diagnosed with depression, anxiety, and other psychiatry diseases. We also gathered data on assisted oxygenation, laboratory variables, and mortality on days 0, 5, 10, and 30.
Confusion Assessment Method
Confusion Assessment Method score is a valid and commonly used score for quickly recognizing delirium within 3–5 min .
Richmond Agitation Sedation Scale
After the patient being assessed for delirium, the motoric subtype of delirium is classified using the Richmond Agitation Sedation Scale (RASS). The RASS is a standard sedation scale, which has a range of − 5 to + 4. A patient with a RASS of 0 is calm and alert, whereas RASS + 1 to + 4 indicates hyperactive delirium and RASS − 1 to − 5 indicates hypoactive delirium. Scores were assigned based on observing and responding to auditory and physical stimulation .
We used the Chi-square test to compare categorical variables and Student's t-test (normal distribution) or Wilcoxon's rank sum test (nonnormal distribution) to compare numerical variables. We used logistic regression models to explore the association between the overall occurrence of delirium and inhospital death, admission to intensive care, and ventilator use. We used logistic regressions as our primary multivariable analyzing method because we could not determine precise dates of delirium onset using our current design.
Statistical analysis was carried out using the International Business Machine Statistical Package for the Social Science version 20 for Windows (IBM SPSS, Inc., Armonk, New York, USA). The differences between the groups were considered significant if p-values were small than 0.05.
| Results|| |
During the study, 30 (2.49%) of the 1,233 patients developed delirium. Of 30 patients, 20 of these patients were in COVID-19 wards, while 10 patients were on intensive critical care. The mean age of the patients was 68.33 ± 14.67 (range = 46-92) years. Males (n = 20, 66.7%) were diagnosed twice than females (n = 10, 33.3%). Furthermore, 11 (36.66%) patients were < 65 years old, and 19 (63.33%) patients were more than 65 years.
[Table 1] compares the main characteristics and comorbidities of individuals who had delirium and those who did not. We identified symptoms affecting three different systems: respiratory (breathlessness and chest pain), musculoskeletal (weakness and headache), and gastrointestinal (diarrhea and anorexia). These systems were found to be significantly associated with development of delirium (p < 0.001 for all those symptoms). The three major comorbidities that were found to be important risk factors for the development of delirium were hypertension (46.67%, p < 0.001), diabetes (30%, p < 0.01), and thyroid disease (13.3%, p < 0.01). Delirium was not significantly associated with ischemic heart disease or CV stroke. While 16.66% of patients were reported to have no major comorbidity. The mortality rate was 28 (93.33%) in 30 patients suffering from delirium and 121 (12.38%) in 1203 patients not suffering from delirium.
|Table 1: Determinants of delirium in hospitalized coronavirus disease 2019 patients (n = 1,233)|
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[Table 2] shows the assisted oxygenation and laboratory parameters for patients with delirium. Throughout their admission, all patients required oxygen support. A sum of 56.66% of patients needed a nonrebreather mask, 16.66% invasive ventilation, 16.66% bilevel positive airway pressure, and 10% an oxygen mask. The laboratory results showed that 76.6% of the patients had an electrolyte imbalance. Totally, 40% of patients had hyponatremia while 30% of them had hypernatremia. Patients with delirium were followed up on days 0, 5, 10, and 30. Totally, 28 patients of delirium died before the first follow-up on day 5. Hyperactive delirium accounted for 19 (63.3%) patients and hypoactive delirium accounted for the rest of 11 (36.7%) patients.
|Table 2: Assisted oxygenation, laboratory parameters, and mortality in patients with delirium (n = 30)|
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A stepwise logistic regression model with forward selection, accounting for age, gender, status at admission, and medical comorbidity showing differences at admission between patients with or without delirium, showed that the development of delirium during hospital stay was positively associated with O2 status (O2 +ve/−ve) at admission and medical comorbidity [Table 3].
|Table 3: Results of a multinomial logistic regression model with forward selection, testing the anamnestic and clinical factors at hospital admission independently associated with the development of delirium in a group of 1,233 patients with suspect coronavirus disease 2019 pneumonia|
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| Discussion|| |
In this study, we did 53 psychiatric evaluations in 1233 patients hospitalized with COVID-19 infection. Out of these, 30 patients (2.49%) were diagnosed with delirium while 23 patients were diagnosed with neurotic disorder (other mental disorders). As shown in [Table 1], we found that most of the affected patients were above 65 years of age. The mean age ± standard deviation of patients with delirium in our study was 68.33 ± 14.67 years [Table 1]. This finding is higher than that reported during a non-COVID-19 epidemic in an intensive care patient study . Helms et al. found that in COVID-19 patients with delirium that the mean age is 62 years , a figure close to our study [Table 1]. In addition, we also found that 66.67% of our cohort was male. This figure is similar to what was found in the study done by Helms et al., reporting that men are more affected than women . This may be because smoking is associated with higher expression of ACE2 receptors . In this study [Table 1], a high prevalence of delirium was found in men and among the elderly, as well as among patients who were hospitalized for COVID-19. This prevalence is consistent with what is known about the risk of developing delirium in these groups of people ,,,.
In our study, hyperactive delirium was the most common presentation among patients. Khan et al. found that the high rates of hypoactive delirium have been found in their study. This finding may be associated with oxygen desaturated, electrolytes imbalance and infection. When oxygen levels in the brain are low, neurotransmitters, such as glutamate and dopamine, are released in high amounts. This might explain why people with delirium tend to be hyperactive and have trouble sleeping. In addition, low oxygen levels can lead to reduced synthesis and release of acetylcholine, which can also cause delirium ,,.
Our study [Table 1] showed that hypertension (p < 0.001), diabetes (p < 0.01), and thyroid disease (p < 0.01) were significantly more risk factors for the development of delirium. A study conducted in China found that chronic obstructive pulmonary disease, diabetes, hypertension, and malignancy were risk factors of developing the composite endpoint . D'Adamo et al. found that in older adults, a viral infection such as COVID-19, fever, and hypoxemia may trigger delirium . We found that systemic symptoms affecting the respiratory symptom such as breathless (p < 0.001), musculoskeletal symptom such as weakness (p < 0.001), and gastrointestinal system such as diarrhea (p < 0.001) were significantly more associated with delirium development [Table 1]. The study was found that a majority of the patients required oxygen supplementation, with some requiring oxygen at a high flow due to severe desaturation. Recent research suggests that cerebral desaturation may be a trigger for delirium, and that the need for oxygen supplementation may be related to delirium. This could explain why in some people delirium develops more quickly and they require more intensive care than patients of nondelirium ,,,.
Our study findings showed a low incidence and significantly more mortality in delirium (p < 0.001) in the cohort [Table 1]. In contrast, previous studies found incidence rates between 10% and 20% ,,. In contrast to our study, a previous study done in a French ICU at the Strasbourg University Hospital found that 84.3% (118 out of 140) of patients developed delirium with severe disturbances of awareness, attention, and cognition . Another study by Prajapati et al., in 2021, from Ahmedabad city found a high prevalence of delirium in COVID-19 patients, about 10% (30 out of 300) .
A meta-analysis by Shao et al. , Pranata et al. , and Hariyanto et al.  showed that delirium is associated with 2- to 3-fold higher overall mortality in patients of delirium than patients of nondelirium, wherein our study [Table 1] showed significantly higher mortality rates in patients of delirium (p < 0.001). Increasing evidence supports a higher incidence of delirium and other neuropsychiatric manifestations with COVID-19, with 22%–33% incidence a finding has been previously reported in hospitalized patients ,. A meta-analysis of 44 studies by Salluh et al., in 2015, showed that delirium is associated with poorer outcomes . Delirium is one of the common presenting symptoms of COVID-19 and should be added to the list of signs to watch for in older patients with COVID-19 ,,. It may be due to multiple factors involved in COVID-19 such as cytokine storm, late detection of delirium, and higher prevalence of comorbidities in these population. Several shortcomings may explain this finding, such as high hospitalization rate during the COVID-19 pandemic, delayed recognition of early signs of delirium, late referral due to any other medical condition, and referral done only after observing significant behavioral disturbances.
The readers are warned not to overinterpret the study results because this study has two major limitations:
- This study is a single-center study. All patients were recruited from GMERS Medical College and Civil Hospital, Sola, Ahmedabad, India. The generalization of the study results to the whole India is doubtful due to the representation of small group of patients.
- Some demographic data were missing at the time of assessment, for example, education and occupation of the patients (since caregivers were not allowed in COVID-19 ward).
In spite of limitations, this study represents one of the reports of delirium epidemiology and clinical correlates in a large group of patients hospitalized with COVID-19, confirming that delirium is one of the complications of the severe forms of this novel disease.
The results of this study showed that patients with COVID-19 and delirium had worse outcomes, and that delirium was an important clinical marker for identifying patients who were at high risk for negative outcomes, such as death. Early detection, robust management, and prevention are necessary to reduce mortality and morbidity due to delirium in patients with COVID-19.
| Financial Support and Sponsorship|| |
The authors deny any financial support in doing this study.
| Conflicts of Interest|| |
The authors declare no conflicts of interest in writing this report.
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[Table 1], [Table 2], [Table 3]