By Kathryn Radigan, MD, MSc

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Post-intensive care syndrome (PICS) is defined as a new or worsening impairment in physical, cognitive, or mental health status that arises after critical illness and persists beyond acute care hospitalization.1 More recently, the United States has reported more than 30 million COVID-19 cases and more than a half a million deaths.2 In the setting of a pandemic in which the numbers of critically ill have skyrocketed and the severity of illness is overwhelming, the care of persistent symptoms after critical illness is predicted to be our next public health crisis. Prolonged symptoms that develop during or after COVID-19 that persist for more than 12 weeks and are not explained by an alternative diagnosis are referred to collectively as “post-COVID-19” in this article. As intensive care unit (ICU) providers, we must learn how to prevent, treat, and intervene on the psychiatric, cognitive, and physical sequelae of critical illness in a setting burdened with more challenges than ever before.

Epidemiology

It is estimated that up to 80% of patients with acute respiratory failure in need of mechanical ventilation will develop PICS.1 Although many post-COVID-19 symptoms overlap with PICS, it is not clear whether the symptoms described after COVID-19, or “post-COVID-19,” will be the same as PICS, and even patients with mild COVID-19 illness, including outpatients, can have prolonged symptoms and disabilities. Persistent physical symptoms post-COVID-19 illness can include fatigue, weakness, dyspnea, chest pain, and cough. Similar to PICS, psychological sequelae may include post-traumatic stress disorder (PTSD), anxiety, and depression, while cognitive sequelae may include poor memory, inability to concentrate, imbalance, and “brain fog.”

For patients who are hospitalized with moderate to severe COVID-19, only 13% were symptom-free at 60 days following onset of illness.3 In patients who were discharged from the hospital with acute COVID-19, 87.4% reported persistence of at least one symptom, particularly fatigue and dyspnea. Interestingly, only 5% of these patients were intubated, and 15% received noninvasive mechanical ventilation.3 In one study, investigators assessed COVID-19 patients four to eight weeks after discharge and found that 72% of patients reported new illness-related fatigue, 65.6% experienced breathlessness, 46.9% had psychological distress including PTSD, and 68.8% had a drop in EQ-5D, a quality of life score based on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. These numbers were unexpectedly high considering that only one of the patients had been on mechanical ventilation.4 In another study where one-third of the patients were mechanically ventilated, interviews were conducted at least one month (average 72 days) after their critical illness; almost all patients experienced asthenia and dyspnea, and 40% experienced from acute stress disorder.5

Risk Factors

Risk factors for PICS include mechanical ventilation, acute respiratory distress syndrome (ARDS), delirium, sepsis, corticosteroids, sedation, hyperglycemia, immobility, hypoxia, and previous history of neuromuscular disorders, psychiatric illness, or dementia.1 Additional psychiatric risk factors include traumatic or delusional memories in the ICU, female gender, physical restraints, younger age, pre-ICU psychiatric symptoms, less education, and personality type. Unfortunately, COVID-19 has been regarded as the best recipe to worsen PICS.6 Although many of the risk factors are similar to PICS, patients with COVID-19 infection typically undergo prolonged mechanical ventilation and have extended ICU lengths of stay. Patients also are at risk for specific complications, including shoulder subluxation and brachial plexus injuries that may occur with proning, diaphragmatic dysfunction, laryngeal injury, dysphagia, and dysphonia, which may add to the burden of physical sequelae after critical illness.6

Approximately one-third of acute respiratory failure or shock survivors experience cognitive impairment, with neuropsychological test scores consistent with moderate traumatic brain injury.7 COVID-19 has been described as a “delirium factory,” and periods of prolonged delirium may lead to worse cognitive outcomes.8 COVID-19 patients are at accelerated risk for delirium due to direct central nervous system (CNS) invasion, induction of CNS inflammatory mediators, secondary effects related to other organ system failure, sedation, prolonged mechanical ventilation time, immobilization, and other needed but unfortunate environmental factors, including social isolation and quarantine without family. A lack of family visitation, rehabilitation, spiritual care, and limited contact with ICU clinicians and nurses likely leads to further reduction in cognitive stimulation, reorientation, and reassurance.6

One-quarter to one-third of ICU survivors also experience anxiety, depression, and/or PTSD that persists for up to five years.9 COVID-19 survivors have a high prevalence of emergent psychiatric sequelae, including a higher than average incidence of PTSD, major depression, anxiety, obsessive-compulsive symptomatology, and insomnia.10 This is worsened by reduced access to family, pleasurable activities, and rehabilitation in the setting of COVID-19.6

Prevention and Treatment in the ICU and During Follow-Up

To minimize the risk of developing PICS, clinicians should execute evidence-based management of ARDS and the ABCDEF bundle.8 Likewise, we also should adopt similar strategies to prevent “post-COVID-19” while considering the added challenges and adaptations necessary during a pandemic.

The ABCDEF bundle includes the following strategies:

A: Assessment and treatment of pain;

B: Both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs);

C: Choice of sedation;

D: Delirium monitoring and management;

E: Early ambulation in the ICU;

F: Family engagement and empowerment.

The struggle to apply the ABCDEF bundle amid the pandemic is substantial. One study that investigated the implementation of the bundle among ICU patients with COVID-19 reported that only 45% of patients received regular pain assessment, 28% had both SATs and SBTs, 52% received regular sedation assessment, 35% received regular delirium assessment, and 47% experienced early mobility and exercise.11 It is worth noting that implementation rates of the assessment of pain and delirium were higher in ICUs with specific protocols.

While in the ICU and preparing to transition out of the ICU, it is important to use optimal handoff communication to the next team and educate the patient and/or family. The ABCDEF bundle highlights the importance of patient-centered care, which emphasizes specific patient preferences, needs, and values to ensure that these guide clinical decisions.18 This is especially important during the COVID-19 pandemic, but it takes additional creativity and efforts from the care provider.

Assessment and Treatment of Pain. Pain assessment may be compromised because patients are more commonly deeply sedated because of the need for neuromuscular blocking agents (NMBA) and/or the nurse is not in the room as frequently.12 To address these concerns, many institutions have adopted the critical-care pain observation tool (CPOT) or the Behavioral Pain Score (BPS).8 These pain assessment tools may be completed from a distance in response to changes in facial expressions, body movements, and/or ventilator compliance. It also is important to note that patients may be experiencing painful neuropathies caused by viral invasion of peripheral nerves or by prolonged immobility and may respond better to pregabalin or gabapentin.13 Clinicians also must monitor for opioid tachyphylaxis, a rapid tolerance that may develop after opioid exposure, which can occur as soon as two days after the initiation of opioid infusion.

Both SATs and SBTs. SATs and SBTs with daily sedative interruption and ventilator liberation practices must continue on a daily basis if at all possible.8 These will not be possible during paralysis or in proned patients, but patients should be assessed regularly for the ability to stop paralysis and proning. In the PROSEVA study, proning was stopped for continued improvement in oxygenation (PaO2:FiO2 ≥ 150 mmHg, FiO2 ≤ 0.6, positive end-expiratory pressure [PEEP] ≤ 10 cm H2O) maintained for at least four hours after the end of the last prone session.14

Choice of Sedation. Sedation goals, measured by the Richmond Agitation-Sedation Scale or the Sedation Assessment Score, must be set daily, and not all patients require deep sedation.8 Use of agents that do not suppress the respiratory drive, such as antipsychotics or alpha-2 agonists, may be helpful in assisting in the discontinuation of potent sedatives. The addition of longer-acting opioids and sedatives also may reduce the risk of withdrawal reactions. Generally, clinicians must not forget to optimize ventilator settings before increasing or initiating opioids, sedation, or NMBA.

In COVID-19 patients who require substantial sedation, placement of the intravenous infusion pumps in the hallway has become routine to reduce the amount of contact a caregiver may need with a COVID-19-infected patient. Longer lengths of extension tubing may require the administration of greater priming amounts when new opioid, sedative, or NMBA infusion bags are hung.12 This may result in higher cumulative doses of sedatives administered.

Delirium. Delirium risk factors are much higher in our COVID-19 patients as a result of isolation from family and the clinical team.15 It is also thought to be worse because of the clotting issues associated with COVID-19, hypoxia, immobilization, excessive sedation, and even the virus itself.16 To prevent delirium, the Confusion Assessment Method for the ICU (CAM-ICU) or other delirium assessment scores must be used as a standard.12 Remembering the acronym, Dr. DRE, also is helpful.8 Dr. stands for disease remediation and optimization of the treatment of COVID-19 itself. Other improvements may be made through drug removal (DR), SATs and SBTs, and optimization of the environment (E) by promoting mobilization and sleep, structure of day and night cycles, use of home hearing aids and glasses, noise reduction, maintenance of a bowel regimen, virtual or in-person family visitation, and even opening the blinds. Venous and arterial lines, catheters, and physical restraints should be minimized if possible. In cases of new delirium, it is important to evaluate for acute sepsis, neurologic injury, or the need for electrolyte/fluid replacement.12 A reduction or discontinuation of benzodiazepines and/or corticosteroids may be needed; ketamine or dexmedetomidine may be considered as replacements in some cases.

Early Ambulation in the ICU. In deeply sedated patients, range-of-motion exercises at least daily may be helpful even if physical therapy is not available.12 It is crucial to consult physical therapy and occupational therapy as soon as possible.17

Family Presence, Engagement, and Empowerment. It is important to orient and update both patients and family regularly through phone conversations and video conferences if visitation is not allowed. Use technology devices, headphones, and telemedicine tools when needed for assistance.8 If at all possible, make visual and vocal contact with the family, caregivers, and/or friends a daily requirement, even if lack of time and heavy workload are factors.

Diagnostic Approach in Follow-Up Clinics

Post-COVID clinics are beginning to serve the needs of patients experiencing post-COVID-19 effects. These clinics typically see patients within one week and definitely no later than two to three weeks after discharge through a telemedicine visit. The timing of the visit is important since it has been found that COVID-19 rates of readmission or death were higher than for pneumonia or heart failure during the first 10 days after discharge following COVID-19 hospitalization.19 Clinicians providing care in the hospital and in post-COVID-19 clinics ought to objectively review dyspnea and fatigue as well as cognitive, psychiatric, and physical complaints. Cognitive complaints often include difficulties in accomplishing executive tasks, attention, concentration, memory, mental processing speed, and executive function. Psychiatric complaints can vary substantially and include anxiety, depression, PTSD, and insomnia. Physical complaints include weakness that ranges from generalized poor mobility with multiple falls to paresis. The identification of each component should start as an inpatient, followed by an outpatient evaluation and elucidation of specific findings for each domain, corroborated by examination and confirmatory testing when necessary. If the patient has persistent, concerning respiratory symptoms during the initial visit, the clinician can consider further work-up with high-resolution computed tomography (CT), pulmonary function, echocardiogram, and/or six-minute walk tests.20 After the initial visit, most clinics will see patients with regular follow-up as indicated by symptom burden and clinical improvement.

Some of these patients also may be seen in pulmonary follow-up clinics where standardized screening measures to complement symptom-directed clinical assessment still is recommended but a multidisciplinary team is not readily available. For cognitive evaluation, the Montreal Cognitive Assessment is recommended.21 Patients with moderate-severe cognitive impairment (score < 18) should be referred for neuropsychological and speech-language pathology evaluation and management. Depression, anxiety, and PTSD are common. To evaluate these objectively, the Hospital Anxiety and Depression Scale (HADS) and the Impact of Event Scale, respectively, are recommended.22 A review of activities of daily living (ADLs) and a six-minute walk test may be helpful to evaluate functional impairment.23 Weakness may be further evaluated through a formal assessment by a medical professional (e.g., physical therapy, occupational therapy) trained in the diagnosis of ICU-acquired weakness. Electromyography and nerve conduction studies can confirm neuromuscular weakness relating to critical illness myopathy (CIM) or critical illness polyneuropathy (CIP). In general, there should be an extremely low threshold to consult and involve a multidisciplinary team, including neurologists, neuropsychologists, psychiatrists, physical therapy, occupational therapy, and speech therapy.

Prognosis

Improvement in PICS is seen over months to years.1 Polyneuropathy may recover more slowly than myopathy and may extend beyond five years. There often is improvement in some activities of daily living within months, but gaining full independence with certain activities can take more than a year if not longer, especially with six-minute walk distance. Depression may improve over the first year of recovery, but PTSD and anxiety often persist beyond the first year. The cognitive decline that often is appreciated may improve over the first year, but residual deficits often persist beyond six years. Patients with PICS have an increased risk of mortality in the subsequent years after hospital discharge, up to 73% in patients who require prolonged mechanical ventilation.24

Summary

Given the number of critically ill patients during the COVID-19 pandemic, the number of patients diagnosed with post-COVID-19 also has grown significantly. Critical care physicians have the opportunity to optimize long-term function and quality of life for COVID-19 survivors. It is paramount to prevent, recognize, and treat post-COVID-19 symptoms with the ABCDEF Bundle. Furthermore, taking the initiative to develop a post-ICU clinic designed specifically with the COVID-19 survivor in mind and adapting it with available resources may be the next best step in fostering recovery following critical illness for this population. 

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