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The Burden of Cognitive Dysfunction in COVID-19

The FLARE Four

  • Delirium, coma and long-term cognitive dysfunction are distressingly common in critical illness and can be understood as part of a common syndrome—acute brain dysfunction
  • Acute brain dysfunction is a concern in COVID-19 because the circumstances of the pandemic (staffing shortages, heavy sedation, lack of family interaction) led to difficulty in implementing many practices known to reduce acute brain dysfunction
  • As a result, delirium incidence in critical COVID-19 has been reported to be high compared to pre-pandemic levels. This may be expected to lead to an increased number of patients suffering post-intensive care syndrome after their ICU discharge
  • Evidence-based interventions developed prior to the COVID-19 pandemic, such as the ABCDEF bundle, should be implemented to the greatest extent possible in order to decrease the incidence of acute brain dysfunction in COVID-19

Many people are asking…what is the burden of cognitive dysfunction in COVID-19?


Acute brain dysfunction manifesting as delirium and coma is a highly prevalent form of organ dysfunction in critically ill patients, particularly those receiving mechanical ventilation. Among critically ill patients, it is associated with increased morbidity and long-term sequelae comprising physical, cognitive and emotional symptoms, referred to as post-intensive care syndrome (PICS). PICS significantly impacts the quality of life for both survivors and their family members for years following hospital discharge. Years of research targeting delirium prevention and treatment have included both pharmacologic intervention and non-pharmacologic strategies. To date, the most successful strategies for decreasing the prevalence of intensive care unit (ICU) delirium include targeting light sedation, reducing benzodiazepine exposure and mobilizing patients. The challenges presented by the COVID-19 pandemic, however, have strained clinicians and hospital systems, frequently resulting in a deviation from these best practices. (Challenges with sedation practice in COVID-19 were reviewed in FLARE on May 2, 2020.) Consequently, critically ill COVID-19 patients have shown a profound burden of acute brain dysfunction. Given the burden of acute brain dysfunction and the additional burden posed by isolation common among COVID-19 survivors, these patients are at an exaggerated risk for the long-term development of PICS-related cognitive dysfunction or acquired dementia.

This FLARE is written by Christina Boncyk, MD; Matthew F. Mart, MD; Brenda T Pun, DNP, RN; Rafael Badenes, MD, PhD; Pratik P. Pandharipande, MD, MSCI; E. Wesley Ely, MD, MPH, of Vanderbilt University Medical Center.

What Do We Know About Delirium in the ICU?

There are several known risk factors for delirium that include age, impaired baseline cognitive function, severity of illness, mechanical ventilation, medication administration (particularly benzodiazepines and increased sedation) and sepsis, among others. Due to the numerous physiologic and pharmacologic derangements associated with critical illness, delirium is common in the ICU with older studies describing a prevalence of over 80% in mechanically ventilated patients. Even though delirium is extremely prevalent, up to 3 out of 4 cases will be undetected if not systematically assessed using validated delirium-monitoring instruments because of the hypoactive motoric predominance of symptoms at the bedside. Early identification of delirium serves as an alert to team members to consider contributing factors and alter patient care to mitigate the duration of delirium. This is important as increased duration of delirium is associated with worse patient outcomes, specifically mortality and cognitive impairment among survivors. We now know that the use of multimodal and interprofessional management approaches that require care team buy-in and coordination have dramatically lowered the prevalence and duration of delirium.

Proven Strategies to Reduce the Burden of Brain Dysfunction in the ICU

Within the ICU, the ABCDEF (A2F) bundle has been the most widely adopted and studied strategy to reduce the burden of brain dysfunction. Implementation has been shown to improve patient outcomes, specifically decreasing delirium duration, when implemented across hospitals and care settings. The tenets of the A2F bundle are drawn from over 30 original investigations and are designed to optimize patient safety. They include:

  • Assessing and treating pain
  • Both awakening and breathing trials
  • Choice of appropriate sedation
  • Delirium monitoring and management
  • Early mobility and exercise
  • Family engagement and empowerment

The A2F bundle is supported by the Society of Critical Care Medicine as a pillar of the ICU Liberation Initiative and has been shown to be an independent predictor of reductions in delirium, coma, and duration of mechanical ventilation and ICU stay in a dose-dependent manner (i.e., higher compliance yields incrementally better results) across multiple settings (Figure 1).

Figure 1

The association between proportional performance of the ABCDEF bundle and delirium and coma (Pun et al, Crit Care Med, 2019).

Figure 2

The association between percent performance of the ABCDEF bundle and ICU discharge, hospital discharge, and death (Pun et al, Crit Care Med, 2019).

While each component has been shown to be effective individually, the impact of the A2F bundle is strongest when it is performed together, as each component influences the strength of all others (Figure 2). As stated by others, the whole is greater than the sum of the parts. For example, daily awakening trials and spontaneous breathing trials are both independently shown to decrease time to extubation and improve patient outcomes; however, they are most effective when paired and performed together—activities that require coordination and planning between physicians, nurses and respiratory therapists.

Acute Brain Dysfunction in COVID-19 Patients

Delirium on presentation or, more generally, "abnormal neurologic examinations" at admission have been described in patients with COVID-19. To investigate the prevalence of delirium within this population, Pun and colleagues performed a large multinational, cohort investigation of over 2,000 critically ill COVID-19 patients. Delirium and coma were measured prospectively using validated instruments to describe the overwhelming burden of acute brain dysfunction within this population. While a recently completed multicenter study that adhered to A2F bundle guidelines reported a delirium prevalence of less than 50% (marking an example of the scope of delirium reduction seen in recent years), Pun and colleagues found a resurgence of delirium—up to 80% of critically ill COVID-19 patients developed delirium and coma. Over the 21-day study period, the median number of days alive and without coma and delirium was only 5 [0-14]. Additionally, A2F bundle components were incorporated into practice in only about 25% of eligible days. Benzodiazepine usage was associated with a higher risk of brain dysfunction while family visitation was associated with decreased risk of delirium. These results are concerning, but echo reports of COVID-19 patient care deviating away from multicomponent care bundles and receiving higher doses of sedative and analgesics than patients without COVID-19.

Challenges to Diagnosis and Management of Acute Brain Dysfunction in COVID-19

The COVID-19 pandemic has strained health care providers across hospital systems and intensive care units. As the number of patients has grown exponentially, so have the number of COVID-19-related ICU admissions. Management of these admissions has necessitated rapid adaptation of care teams to expand critical care coverage outside of usual ICU locations and utilization of health care personnel not otherwise caring for the critically ill. Previously avoided sedatives (e.g., benzodiazepines) are frequently used due to concerns about medication shortages and the perceived need for deep sedation. Additionally, infection control concerns frequently result in limited interaction with health care providers and limited or complete visitation restrictions for family members. As a result, delirium prevention bundles previously implemented as standard of care are frequently sidelined. While these surge and workflow adaptations have been successful in helping to accommodate and provide care to the increasing number of patients, they directly or indirectly may be contributing to acute brain dysfunction among COVID-19 patients. Thoughtful and deliberate strategies to navigate limited personnel, medications or equipment may help to improve bundle compliance and patient care delivery.

ABCDEF Care Bundle and COVID-19 Specific Challenges to Implementation


A: Assess, prevent & manage pain

Bundle Intervention: Assess pain with CPOT or BPS scales, NRS if patient able to self-report; use of regional analgesia and non-opioid adjuncts; analgesia-based sedation techniques with fentanyl

COVID-19-Specific Barriers to Implementation: Isolation policies limiting pain assessments; medication shortages

COVID-19 Specific Barrier Guidance: Covid-19 Sedation Summary Guideline

B: Both SAT & SBT

Bundle Intervention: Daily linked SAT and SBT; interprofessional team coordination of care

COVID-19-Specific Barriers to Implementation: Provider reluctance; staffing shortages; inability to implement coordination at large scale

COVID-19 Specific Barrier Guidance:

C: Choice of sedation

Bundle Intervention: Targeted light sedation when able; avoidance of benzodiazepines; dexmedetomidine if at high risk for delirium or weaning mechanical ventilation

COVID-19-Specific Barriers to Implementation: Ventilator dyssynchrony; medication shortages

COVID-19 Specific Barrier Guidance: 

D: Delirium monitoring & management

Bundle Intervention: Routine assessments with CAM-ICU, CAM-ICU-7, or ICDSC; non-pharmacologic interventions including sleep hygiene

COVID-19-Specific Barriers to Implementation: Isolation policies limiting pain assessments; staffing shortage

COVID-19 Specific Barrier Guidance: Understanding and Addressing the Long-term Outcomes of COVID-19 ICU Survivors

E: Early mobility & exercise

Bundle Intervention: Physical and occupational therapy assessment; coordinate activity with SAT or periods of no sedation; passive range of motion

COVID-19-Specific Barriers to Implementation: Isolation policies limiting staff and family engagement; provider reluctance; staffing shortages

COVID-19 Specific Barrier Guidance: Creative Approaches for Early Mobility in Patients 

F: Family engagement & empowerment

Bundle Intervention: Unit orientation; education; emotional and verbal support; empowerment; participation in multidisciplinary rounds

COVID-19-Specific Barriers to Implementation: Isolation policies limiting visitation; family reluctance or fear; illness in family members

COVID-19 Specific Barrier Guidance:

Familial Engagement: A Particular Challenge

A powerful component uniquely affected by this infectious disease pandemic has been family engagement and empowerment. Lack of family support (even via virtual aids) is associated with an increased burden of acute brain dysfunction. Delirium and associated isolation, even after recovery of acute illness, contribute to patient loneliness, stress, anxiety, depression and post-traumatic stress syndromes—especially in patients with baseline cognitive impairment and dementia. COVID-19 patients have also described significant depressive symptoms on self-reported scales, although the true prevalence is limited without formal clinical diagnostic assessments.

Implications of Brain Dysfunction on Survivorship and COVID-Long Haul Syndrome

Survivors of critical illness suffer from cognitive, functional and neuropsychological impairments for months to years following hospital discharge (Figure 3). This constellation of symptoms that encompass PICS frequently prevents survivors from returning to their pre-illness quality of life, independence and work. Early reports in patients surviving COVID-19 have described similar persistent symptoms affecting a multitude of organ systems, termed post-acute COVID-19, long COVID or COVID-19 long haul syndrome. Given the increasing number of critical illness survivors as a result of the COVID-19 pandemic, there is potential for creating an epidemic of patients with PICS.

Figure 3

The co-occurrence of PICS symptoms at 3 and 12 months (Marra A, et al. Crit Care Med, 2018).

Figure 4

Heath status data from patients across the spectrum of mild to critical COVID-19 disease (van den Borst, et al., Clin Infect Dis, 2020).

Delirium is one of the strongest predictors of cognitive impairment among survivors and the high rates of brain dysfunction seen in COVID-19 patients put these patients at increased risk. Similar to the high proportion of cognitive impairment identified in previous studies of PICS in ICU survivors, early data has suggested COVID-19 survivors diagnosed with delirium demonstrate lower cognitive scores on the Telephone Interview for Cognitive Status (TICS) assessments at 4-weeks following hospital discharge. van den Borst and colleagues studied COVID-19 survivors at three months following hospital discharge and found over a third of these patients reported physical and/or cognitive difficulties, specifically in the domains of physical functioning, fatigue and quality of life—similar to results found in other ICU survivors with PICS. Notably, however, they did not find illness severity (mild, moderate or severe symptoms) to be associated with physical or cognitive status at three months (Figure 4), meaning that the incidence of these deficits was similar in mildly ill patients as in severity ill.

These findings are similar to those shown within a recent study of 238 COVID-19 survivors in Northern Italy. Patients were studied at 4-months following hospital discharge and demonstrated a significant burden of physical functional impairment (53.8%) and post-traumatic stress symptoms (17.2%). While data was collected retrospectively without the inclusion of delirium or coma diagnoses, ICU admission was not found to be independently associated with physical functional impairment, and mode of oxygen delivery (i.e., nasal cannula, mechanical ventilation) was not independently associated with post-traumatic stress symptoms. Together these studies draw into question how, or if, the severity of illness is associated with PICS symptoms within this population, but suggest a larger at-risk population. The burden of PICS symptoms among survivors and the scale of those affected is a unique challenge presented by this pandemic.

Impact on Patient Recovery

It is difficult to draw further conclusions surrounding the long-term implications of acute brain dysfunction on survivorship following COVID-19 infection as this disease has only been recognized for a little over a year. While faced with these limitations, however, there are important insights we can gain from prior coronavirus pandemic studies as well the breadth of existing literature investigating its impact on survivorship following other forms of acute respiratory distress syndrome (ARDS). ARDS is defined by a profound inflammatory response in the lung parenchyma; however, there is substantial systemic inflammation that can promote cognitive decline and neurodegenerative disease. COVID-19 infection results in an increase in these same inflammatory mediators and studies in older adults have demonstrated evidence of cognitive impairment and motor deficits following discharge. In the setting of ARDS, this is also shown to be associated with long-term cognitive impairments in up to 78% of patients at one year following hospital discharge and in about half of patients at two years.

Studies on the SARS-CoV-1 epidemic in 2003 that infected 8,000 people and killed 900 people worldwide have also focused on long-term follow-up. These studies at 1-, 2-, and up 15-year follow-up intervals have revealed a decrease in health-related quality of life metrics in survivors compared to their age-matched controls. Survivors also reported high levels of psychological distress (59%) and psychiatric disorders that persisted up to 30-months of follow-up (33%). These patients, not unlike many current COVID-19 survivors, face additional stressors related to their illness including loss of income, fear, death of friends and/or relatives, isolation and social stigma. Many of these psychological symptoms, similar to diagnosing acute brain dysfunction, can go undetected and untreated if not routinely assessed by health care providers.


Acute brain dysfunction is highly prevalent in COVID-19 patients. Focusing on light sedation strategies, avoidance of benzodiazepines, daily spontaneous awakening and breathing trials, family engagement, and delirium monitoring and management are key to limiting the impact of delirium and coma on long-term outcomes after COVID-19 critical illness. The impact of acute brain dysfunction on PICS symptoms and patient recovery likely qualitatively mirrors that of other ICU survivors, however, the quantity of this population is dramatically increased and may pose significant public health challenges in the future. Focusing on current best-practice techniques including multicomponent care bundles should be adhered to as much as possible to help mitigate these risks.


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