Delirium Incidence, Duration and Severity in Critically Ill Patients with COVID-19

Background Delirium incidence, duration and severity in patients admitted to the intensive care unit (ICU) due to COVID-19 is not known. Methods We conducted an observational study at two large urban academic Level 1 trauma centers. Consecutive patients admitted to the ICU with a positive SARS-CoV-2 nasopharyngeal swab polymerase chain reaction test from March 1st, 2020 to April 27, 2020 were included. Individuals younger than 18 years of age, without any documented delirium assessments (CAM-ICU), or without a discharge disposition were excluded. The primary outcomes were delirium rates and delirium duration and the secondary outcome was delirium severity. Outcomes were assessed for up to the first 14 days of ICU stay. Results Of 243 consecutive patients with confirmed COVID-19 admitted to the ICU, 144 met eligibility criteria and were included in the analysis. Delirium occurred in 73.6% (106/144) and delirium or coma occurred in 76.4% (110/144). Sixty-three percent of patients were positive for delirium on the first CAM-ICU assessment. The median duration of delirium and coma was 7 days (IQR: 3-10), and the median delirium duration was 5 days (IQR: 2-7). The median CAM-ICU-7 score was 6 (IQR: 4-7) representing severe delirium. Mechanical ventilation was associated with greater odds of developing delirium (OR: 42.1, 95%CI: 13.0-137.1). Mortality was 26.4% in patients with delirium compared to 15.8% in patients without delirium. Conclusions 73.6% of patients admitted to the ICU with COVID-19 experience delirium that persists for approximately 1 week. Invasive mechanical ventilation is significantly associated with odds of delirium. Clinical attention to prevent and manage delirium and reduce delirium duration and severity is urgently needed for patients with COVID-19.


Introduction
The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) novel coronavirus (COVID-19) has emerged as a global pandemic and is associated with rapid spread, severe respiratory failure and significant morbidity and mortality. 1,2 As clinical experience with COVID-19 grows, neurologic manifestations of the disease are receiving increased attention. A recently published small case series from France reported delirium occurred in 26/40 (65%) of patients admitted to the intensive care unit with COVID-19. 3 However, the duration and severity of delirium in critically ill COVID-19 patients have not been well described.
Delirium is a serious neurologic syndrome independently associated with longer duration of mechanical ventilation, prolonged ICU and hospital stays, increased mortality, and institutionalization after discharge. [4][5][6][7][8] Increasing levels of delirium severity and duration amplify these outcomes, and are independently associated with worsening cognitive and functional outcomes post discharge. [9][10][11][12] Prior to COVID-19, the prevalence of delirium in mechanically ventilated patients has been decreasing from a historically high rate of 80% to a range of 16.5-33%. [13][14][15][16][17][18][19] In the setting of the current global health crisis, hospital resources have been stretched to their limits to meet the needs of a large number of critically ill patients. The unintended impact of limited resources on clinical practice has raised concerns that current ICU delirium rates have returned to the historically high levels. [20][21][22] As of May 23, 2020, there are 1.64 million confirmed COVID-19 cases in the US and approximately 12% of COVID-19 patients required intensive care unit (ICU) level care. 1, 2,23 In this context, delirium is likely to pose a longterm public health challenge if rates in the United States are as high as recently reported in France.
Therefore, we conducted this study at two large academic health systems in urban Midwest to measure incidence of delirium, delirium duration and delirium severity, and investigate risk factors associated with delirium in critically ill patients admitted with COVID-19.

Methods
The observational study was conducted at two large, urban, academic, Level  admitted after April 27, 2020, patients with no delirium assessments recorded in the electronic medical record for the duration of the follow up period, and those still admitted to the ICU or hospital at the end of the study period. We excluded patients remaining admitted to the ICU or hospital to accurately identify delirium duration and to prevent confounding of downstream effects of delirium on mortality and length of stay. Clinical outcomes were followed up until April 29, 2020 (date inclusive) or until the patient transferred out of the ICU.

Exposures and Outcomes
The main exposure variables were patients' demographics, comorbidities, laboratory results and severity of illness at admission. The primary outcomes were rate of delirium and delirium/coma duration during the first 14 days of admission to the ICU. Delirium/coma duration was defined by the number of days the patient was alive and had documented delirium or coma, representing duration of abnormal cognitive status. Patients who were discharged from the intensive care unit prior to 14 days did not have subsequent delirium or coma assessments performed outside the ICU. Coma was assessed using the Richmond Agitation Sedation Scale . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 1, 2020. . https://doi.org/10.1101/2020.05.31.20118679 doi: medRxiv preprint (RASS) and delirium was identified through the Confusion Assessment Method for the ICU (CAM-ICU). Coma was defined as a RASS score of -4 or -5, making patients ineligible for a CAM-ICU screening, while patients with a RASS score of -3 or greater were eligible for a CAM- Hyperactive delirium was defined as a RASS score of +1 to +4 at the time of positive CAM-ICU, and hypoactive delirium was defined as a RASS score -3 to 0 with a positive CAM-ICU score.
The secondary outcome of delirium severity was assessed using the Confusion Assessment Method for the Intensive Care Unit-7 (CAM-ICU-7) which requires all components of the CAM-ICU to be assessed for each patient rather than a dichotomous CAM-ICU positive or negative result. The CAM-ICU-7 was implemented into the electronic medical record at Eskenazi Health in 2017, and is assessed twice daily in the subset of patients receiving care at this hospital site.

Data Collection
Research assistants familiar with electronic medical systems at the hospitals (Cerner PowerChart, Epic Health Systems) abstracted study data from the medical record, including CAM-ICU assessments performed by clinical nurses, and results were entered directly into an electronic REDCap database. Data obtained from the medical record included patient demographics (age, gender, self-reported race), insurance status, comorbidities, vital signs, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 1, 2020. Health Evaluation Score (APACHE-II) was calculated using laboratory values, vital signs, and neurologic assessments from first 24 hours of ICU admission.

Statistical Analysis
Demographic and clinical characteristics were compared between patients who had delirium positive and those without delirium using two-sample t-tests (normal data) and Wilcoxon Rank Sum tests (skewed data) for continuous outcomes or Fisher's Exact test for categorical variables. Summary statistics including median and inter-quartile range (IQR) were provided for patients with delirium. Logistic regression was used including demographic or clinical characteristics that were significantly different between patients with delirium and those without delirium as independent variables to identify factors associated with delirium.

Results
Two-hundred forty-three consecutive patients with COVID-19 were admitted from March 1, 2020 to April 27, 2020 to the ICUs at two hospital systems. We excluded 99 patients; 21 did not have any delirium assessments, and 78 remained admitted at the end of the follow up period (see Supplementary Figure 1). In total, 144 patients comprised the study cohort.
Demographics and clinical characteristics for the cohort are presented in Table 1. The mean . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Delirium and Coma in Critically Ill Patients with COVID-19
Delirium occurred in 73.6% (106/144) of patients in the study, whereas delirium or coma occurred in 76.4% (110/144). Forty-four percent of patients experienced coma. Of patients with delirium, 63.2% were positive on the first CAM-ICU assessment, and 36.8% developed delirium on a subsequent CAM-ICU screening. As shown in Table 1

Delirium Duration, Subtypes of Delirium and Delirium Severity
The median duration of delirium and coma was 7 days (IQR: 3-10) (see Table 2), and median delirium duration was 5 days (IQR: 2-7). Patients had a median RASS of -2 (IQR: -3,0) at the time of ICU admission indicating light sedation. Figure 1 shows the daily rates of patient's delirium, coma or delirium/coma-free status for up to 14 days of ICU admission. In our study . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 1, 2020. . https://doi.org/10.1101/2020.05.31.20118679 doi: medRxiv preprint cohort, hypoactive delirium occurred in 86.8% of patients on the first CAM-ICU assessment, and the median duration of hypoactive delirium was 4 days (IQR: 2-4). Details of the subtypes of delirium are shown in Table 2 and Figure 2. In the subset of patients with delirium severity assessments (n=73), the median CAM-ICU-7 score was 6 (IQR: 4-7) representing severe delirium.

Discussion
In this observational study of COVID-19 patients admitted to the ICU at 2 large hospitals, 74% of patients experienced delirium, delirium occurred early in the ICU course (within the first two days), and the abnormal cognitive states of delirium or coma persisted for median length of one week. In addition, patients with COVID-19 experienced severe delirium, and invasive mechanical ventilation was associated with a marked increase in odds of delirium. While mortality rates did not statistically differ by delirium status likely due to the small sample size of patients without delirium, we found mortality to be 10% higher in patients with delirium. To the best of our knowledge, our study is the first to describe delirium rates, duration and severity in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 1, 2020. . critically ill patients with COVID-19 using standardized delirium assessment tools. Due to the increased risk of mortality and morbidity following delirium, including the development of longterm cognitive impairment and post intensive care syndrome, this study has important implications for clinical practice, the recovery of patients with COVID-19 admitted to intensive care, public health decision making, and even future research priorities. 26,27 Our study findings represent a significant departure from recently reported trends in rates of ICU delirium, including rates of mechanical ventilation (36%), delirium (22.7%), and coma (24.0%) at our own center during the influenza pandemic occurring in 2009-2010 (see Supplementary Table 2). Reductions in the prevalence of ICU delirium from a historical high of 80% to rates of 16.5-33% have been reported over the past two years. 13 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
While effective pharmacological therapies for treatment of COVID-19 as well as delirium are not yet available, our study sheds light on an alarming burden of delirium and coma in patients admitted to the ICU and the need for continued efforts on delirium prevention. Following and implementing evidence-based ICU practices (such as the ABCDEF bundle) to minimize delirium occurrence and severity under the pandemic conditions will likely remain an ongoing challenge. 30 The continued use of screening tools for delirium and delirium severity can also provide bedside clinicians with dynamic assessments to measure the impact of interventions in real-time. 9,12 As resources shrink in the face of the pandemic and the health care response disrupts, it is imperative to continue to follow and implement time-tested evidence-based practices. Finally, delirium in critically ill patients has been associated with long-term cognitive decline. 10,36 If other studies confirm higher rates of delirium in COVID-19 ICU patients, longitudinal follow-up will be crucial to understand the full impact of COVID-19 and understand the pathophysiology of COVID-19 related delirium.
Our study does have important limitations. This analysis is limited by its reliance on data from the medical record including clinician-administered delirium assessments. The limitation of clinician-administered delirium assessments has been minimized by the rigorous implementation and continued education on the CAM-ICU and CAM-ICU-7 at the participating institutions. Our analysis also does not include medication exposure data, adherence to the ABCDEF bundle at the patient level, education levels, baseline functional status, or baseline cognitive function and therefore we are unable to fully explain the rates of delirium seen in our study. Our analysis is also limited to delirium and coma assessments performed in the first fourteen days of ICU stay, and therefore we are unable to describe the trajectory of delirium and coma for the duration of the hospitalization in this report. Strengths of the study include incorporation of delirium severity data, a racially and socioeconomically diverse cohort of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 1, 2020. . https://doi.org/10.1101/2020.05.31.20118679 doi: medRxiv preprint patients and protocolized delirium assessments conducted by bedside clinicians at two high volume and high acuity centers.

Conclusion
We found that in contrast to recent rates of delirium in ICU patients, 74% of patients with COVID-19 develop delirium which persists for approximately 1 week, and occurs at high severity. Invasive mechanical ventilation is significantly associated with delirium development.
Given these findings, continued attention to prevent and manage delirium is critical.
. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 1, 2020. .

Delirium Severity, median (IQR)
CAM-ICU-7 score 6 (4-7) Delirium was defined as a positive CAM-ICU assessment in the patient medical record for up to 14 days during their ICU COVID-19 stay. Coma was defined by Richmond Agitation Sedation Score of -4 or -5. Duration of delirium was defined as number of days patient was CAM-ICU positive on either morning or afternoon assessment for up to 14 days while admitted to the ICU. Duration of coma was defined as number of days patient had coma by RASS score on either morning or afternoon assessment for up to 14 days of ICU stay. Hypoactive delirium was defined by (RASS) of -1 to -3 with positive CAM-ICU, Hyperactive delirium was defined by a RASS score of +1 to +3 with positive CAM-ICU. Delirium severity was measured using the CAM-ICU-7 in 73 patients (0-7, 0-2: no delirium; 3-5: mild to moderate delirium; 6-7: severe delirium).
Abbreviations: CAM-ICU and CAM-ICU-7=Confusion Assessment Method-Intensive Care Unit, ICU=Intensive Care Unit, IQR=Interquartile Range, RASS= Richmond Agitation and Sedation Scale . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 1, 2020. .  Table 3 describes the clinical outcomes in COVID-19 patients admitted to the ICU. The overall cohort is described then divided by delirium status (positive CAM-ICU). Univariate testing was completed to investigate statistical significance.
Abbreviations: ICU=Intensive Care Unit, IQR=Interquartile Range, LOS=Length of Stay . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 1, 2020. . Daily percentages do not equal 100% due to incomplete assessments, death, or discharge from intensive care unit. Delirium was defined as a positive CAM-ICU assessment on either morning or afternoon assessment. Coma was defined by Richmond Agitation Sedation Score of -4 or -5. Without delirium or coma was defined by RASS greater than -4 and a negative CAM-ICU on either morning or afternoon assessment. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 1, 2020. .

Figure 2. Subtypes of Delirium in Critically Ill Patients with COVID-19 Who Developed Delirium (n=106)
CAM-ICU and RASS assessments were performed up to twice daily while patient was admitted to the intensive care unit. Hypoactive delirium was defined by Richmond Agitation Sedation Scale (RASS) of -1 to -3 with positive CAM-ICU, Hyperactive delirium was defined by a RASS score of +1 to +3 with positive CAM-ICU. Mixed delirium: patients with both hyperactive and hypoactive delirium assessment on a given ICU day. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 1, 2020. .