Pharmacotherapy Review 2021: Post-Intensive Care Syndrome

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Pharmacotherapy Review 2021: Post-Intensive Care Syndrome

INTRODUCTION

Each year, more than 5 million Americans are admitted to intensive care units (ICUs).2-4 Approximately 4 million patients survive these ICU admissions; however, many enter a cycle of recurrent illness and re-hospitalization, and few reach a full recovery. In recent years, the mortality rate for ICU admissions has decreased steadily, leading to an increasing number of ICU survivors.5

Patient Case: AB is a 78-year-old male nursing home resident with a past medical history of type 2 diabetes, asthma, hypertension, depression, and mild dementia. His nurse reported progressive shortness of breath over the past few days and called emergency medical services when she realized his oxygen saturation was 68%. On arrival to the emergency department, he was emergently intubated for acute respiratory failure and transferred to the intensive care unit. Subsequent chest radiography showed severe bilateral pneumonia.

DEFINING POST-INTENSIVE CARE SYNDROME

Post-intensive care syndrome (PICS) was defined in 2012 at a Society of Critical Care Medicine (SCCM) conference focused on improving long-term outcomes after critical illness. PICS was defined as “new or worsening problems in physical, cognitive, or mental health status arising after a critical illness and persisting beyond acute care hospitalization.”3 The term was designed to be applied to either an ICU survivor (PICS) or to a family member (PICS-F). The stakeholders’ conference further designed a conceptual framework for both PICS and PICS-F that addresses the mental health concerns, cognitive impairment, and physical impairment that can be observed following an ICU admission (Table 1).

Table 1. Conceptual Framework of Post-Intensive Care Unit Syndrome3
Person Affected Domains Potential Long-Term Consequences
Patient Cognitive Impairment Executive function, memory, attention
Mental Health Anxiety, acute stress reaction, depression, post-traumatic stress disorder/post-traumatic stress symptoms
Physical Impairment Pulmonary, neuromuscular
Family Mental Health Anxiety, acute stress reaction, depression, post-traumatic stress disorder/post-traumatic stress symptoms, complicated grief

Cognitive Impairment After Critical Illness

The Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors6 study (BRAIN-ICU) was a multicenter, prospective, cohort study that enrolled 821 medical ICU patients with respiratory failure or shock.6 The study measured global cognition and executive function 3 and 12 months after ICU discharge with the goal of estimating the prevalence of long-term cognitive impairment after an ICU stay and determining the association between ICU delirium and post-ICU cognitive deficits. Cognitive impairment was identified in more than 50% of patients; little improvement occurred between 3 and 12 months, and little difference was found between younger and older patients.

At 12 months, 34% of patients had cognitive impairment consistent with that observed after a moderate traumatic brain injury, and 20% had impairment equivalent to Alzheimer’s disease. Additionally, longer duration of ICU delirium was independently associated with global cognition scores at 12 months. The cognitive domains of executive functioning, memory, and attention were especially affected, leading to problems with planning, problem-solving, behavioral control, depression, and anxiety. As demonstrated by the BRAIN-ICU study, cognitive impairment following an ICU stay can be substantial and long-lasting.5

Mental Health After Critical Illness

ICU survivors face significant mental health concerns that persist well beyond the acute hospitalization (Table 2).

In a study of 180 survivors of medical, surgical, and trauma ICU admissions, 50% experienced posttraumatic stress symptoms (PTSS), 33% had clinical anxiety, and 27% had depression 1 year after ICU discharge.7 Furthermore, the rates of diagnosis of each of these conditions were not statistically different between time points of 4–6 weeks, 3 months, and 12 months post-ICU stay, which suggests that mental health concerns presenting soon after an ICU stay do not improve over at least the first post-ICU year. Factual recall of the ICU admission and memory of pain were independent predictors of posttraumatic stress symptoms, whereas patients with a higher educational level and optimism as a personality trait were less likely to experience posttraumatic stress symptoms.

A similar incidence of depression (33%) was present in the BRAIN-ICU cohort at 12 months.8 This rate was considerably higher in patients with a pre-ICU history of depression (43%) and remained high in those without a reported history (29%). Mental health diagnoses are common after an ICU admission and may negatively affect quality of life.

Table 2. Incidence of Mental Health Diagnoses in ICU Survivors7-9
Diagnosis Incidence 3 Months Post-ICU Incidence 12 Months Post-ICU
Depression 37% 27%–33%
History of depression 52% 43%
No history of depression 30% 29%
Post-traumatic stress disorder 7% 7%
Post-traumatic stress symptoms 23% 22-50%
Anxiety 23%–48%

Physical Impairment After Critical Illness

Physical impairment after critical illness may consist of ICU-acquired weakness and/or pulmonary dysfunction. ICU-acquired weakness occurs as a result of axonal neuropathy, primary myopathy, or both, and affects 25%–80% of ICU survivors based on the duration of mechanical ventilation.10 ICU-acquired weakness may persist for years after ICU discharge. Risk factors include higher severity of illness, sepsis, multiple organ failure, prolonged immobilization, hyperglycemia, older age, corticosteroids, and neuromuscular blocking agents.10

Impaired pulmonary function occurs as a result of muscle wasting, weakness, and immobility. Herridge et al. studied long-term pulmonary function in 105 survivors of acute respiratory distress syndrome (ARDS).11 The 6-minute walk test is an assessment of heart and lung function during which the distance walked at patients’ normal pace for 6 minutes is measured.12 It was used in this study to assess functional status and to give an indication of pulmonary function. Three months after ICU discharge, the average 6-minute walk test was 49% of the predicted distance.11 This improved to only 76% of the predicted value at 5 years, suggesting persistence of the impact of an ICU stay on pulmonary function. Similarly, 48% of patients were able to return to work 1 year after ICU discharge, and 77% returned to work 5 years later.

Activities of daily living (ADLs) include tasks such as feeding, ambulating, transferring, toileting, dressing, and bathing, while instrumental activities of daily living (IADLs) consist of using the telephone, shopping, preparing food, housekeeping, doing laundry, using transportation, and handling medications and finances.13 Nearly one-third of ICU survivors have at least partial disability in ADLs at 12 months, and about one-quarter of survivors have at least partial disability in IADLs.8

The combination of physical impairment related to ICU-acquired weakness and pulmonary dysfunction contributes to the inability to perform ADLs and IADLs and a decrease in quality of life.

PREVALENCE OF POST-INTENSIVE CARE SYNDROME

When the 3 domains of cognitive, psychological, and physical impairment are considered together, PICS has been reported to have a prevalence of 64% at 3 months and 56% at 12 months after an ICU stay.14 Given the more than 4 million ICU survivors in the United States annually, upwards of 2.5 million Americans will be directly affected by PICS each year. However, this condition is often unrecognized. Both critical care and primary care providers must be aware of PICS and its different manifestations so that interventions can be taken to prevent, recognize, and treat the syndrome.

Significant risk factors for PICS have been identified. These include older age, female gender, previous mental health problems, disease severity, negative ICU experience, and delirium.15 To prevent PICS, modifiable risk factors — such as delirium and the patient’s ICU experience — should be areas of focus for the multidisciplinary team.

Between 10% and 75% of family members of ICU survivors experience clinical anxiety associated with critical care of loved ones, and 8% to 42% of family members experience PTSS.9 One-third of family members required medications for anxiety and/or depression. Additionally, family members may experience exacerbations of their own chronic health conditions and suffer further stress from financial insecurity resulting from hospital stay costs. This complicated grief and ensuing depression, anxiety, and PTSS may persist for years, and family dynamics may never return to their baseline state.

IMPACT OF DELIRIUM ON PICS

Delirium is defined in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders as “a disturbance of consciousness and cognition that develops over a short period of time (hours to days) and fluctuates over time.”16,17 ICU delirium is characterized by an acute onset of cerebral dysfunction along with 3 characteristics: (1) a change or fluctuation in baseline mental status, (2) inattention, and (3) altered level of consciousness and/or disorganized thinking.18 ICU delirium may present with hyperactive, hypoactive, or mixed features. Hyperactive delirium may be characterized by agitation, restlessness, and emotional lability, making it easy to recognize.

In a prospective cohort study of 614 medical ICU patients, hyperactive delirium was the least prevalent phenotype, affecting only 1.6% of patients with delirium.19 Hypoactive delirium was much more common, affecting 43.5% of patients with ICU delirium. It is characterized by decreased responsiveness, withdrawal, and apathy. These patients are typically calm and may be withdrawn, leading to under-diagnosis. Mixed delirium was the most common phenotype, affecting 54.1% of patients with ICU delirium. Patients with mixed delirium fluctuate between hypoactive and hyperactive states.

ICU delirium can be detected and quantified using 2 scoring systems: the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). Both the CAM-ICU and ICDSC are validated tools for use in the ICU setting and can reliably detect the presence of delirium even when assessed by nonpsychiatric ICU professionals and in patients who are intubated. Since hypoactive delirium is common, delirium may not always be apparent in the absence of validated tools for its assessment. Therefore, use of these tools is paramount to recognizing delirium in ICU patients.16,205,19

Delirium occurs in up to 80% of mechanically ventilated patients and is credited for the physical, cognitive, and mental health impairment associated with PICS.21 In a prospective cohort study of 224 mechanically ventilated patients, ICU delirium was associated with increased 6-month mortality (15% vs. 34%, hazard ratio [HR] = 3.2 [95% CI 1.4–7.7]), doubling of hospital length of stay (11 vs. 21 days, HR = 2.0 [95% CI 1.4–3.0]), increased duration of mechanical ventilation, increased health care costs, and the development of long-term cognitive impairment.22

Several strategies have been described for preventing ICU delirium. Pharmacologic prophylaxis against delirium using antipsychotic agents has been studied but not proven beneficial.23 The REDUCE trial randomized nearly 1,800 ICU patients considered to be at risk for delirium to receive prophylactic haloperidol or placebo 3 times daily.23,24 There was no difference in the incidence of delirium, the duration of delirium- and coma-free days, or any other clinical outcomes evaluated. Nonpharmacologic interventions have been better validated for their utility in decreasing the incidence of ICU delirium. These nonpharmacologic interventions include repeated orientation, provision of cognitively stimulating activities, normalization of the sleep/wake cycle, early mobilization, timely removal of catheters and physical restraints, provision of hearing aids and eyeglasses, minimization of unnecessary stimulation (especially at night), and clustering of patient care activities.

Patient Case: After 4 days in the ICU, AB remains mechanically ventilated and has developed severe acute respiratory distress syndrome, for which he has been pharmacologically paralyzed. Several of his home medications have been resumed. His current medication profile includes propofol, fentanyl, cisatracurium, and regular insulin continuous infusions; scheduled ceftriaxone, azithromycin, subcutaneous heparin, famotidine, albuterol/ipratropium, methylprednisolone, atorvastatin, donepezil; and as-needed oxycodone, diphenhydramine, haloperidol, ondansetron, acetaminophen, and cyclobenzaprine. He has a urinary catheter, a central intravenous line, 2 peripheral intravenous lines, and an arterial line for continuous blood pressure monitoring. He also has sequential compression devices on his bilateral lower extremities and is in 2-point restraints due to intermittent agitation. He is receiving blood glucose checks every hour for titrating his regular insulin infusion and is receiving scheduled medications at 6 time points throughout the day. What interventions could be made during AB’s acute hospitalization to decrease the risk of PICS?

STRATEGIES TO DECREASE PICS IN PATIENTS AND FAMILIES

A number of strategies have been proposed to reduce the incidence of PICS in both patients and their families.

Medication Management in the ICU

A primary mode of preventing PICS from developing is minimizing PICS risk factors while the patient is still in the ICU. The ICU Liberation Bundle (formerly referred to as the ABCDEF Bundle) is implemented in the ICU setting to reduce delirium, improve pain management, and reduce the long-term consequences of PICS (Table 3).25 In an evaluation comparing delirium in an ICU before and after implementing the ICU Liberation Bundle, bundle implementation was associated with a decreased risk of developing delirium, decreased time in delirium, fewer days on a mechanical ventilator, and a greater chance of achieving early mobilization.26

Table 3. ICU Liberation (ABCDEF) Bundle25
Component Description
A Assess, prevent, and manage pain
B Both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs)
C Choice of analgesia and sedation
D Delirium: assess, prevent, and manage
E Early mobility and exercise
F Family engagement and empowerment

During the acute ICU stay, great care should be taken to evaluate each medication on a patient’s profile for its deliriogenic potential. Numerous medications associated with ICU delirium are commonly recognized (such as benzodiazepines, anticholinergics, and corticosteroids), while others are less widely known (such as cefepime, theophylline, and diuretics) (Table 4).

Some medications, such as opioids, are associated with decreased incidence of delirium when used effectively to treat pain, but are associated with increased rates of delirium in other settings where they are perhaps overused.27,28 Similarly, both hyperglycemia and hypoglycemia are associated with cognitive dysfunction in critically ill patients; thus, careful monitoring and management of blood glucose is important to prevent dysglycemias, subsequent delirium, and long-term cognitive impairment.29

In addition to medications with deliriogenic potential, medications that cause muscle weakness are frequently used in the ICU setting, and these can contribute to ICU-acquired weakness and long-term physical impairments following an ICU stay. Medications affecting both delirium and muscle weakness should be reviewed daily, and their use should be minimized. While these medications are at times necessary for optimizing patient care and outcomes (e.g., hydrocortisone to treat relative adrenal insufficiency in septic shock), they can be avoided in other scenarios. For example, a home medication of oxybutynin for overactive bladder can contribute to delirium and should not be continued in a patient admitted to the ICU with a Foley catheter in place.

Table 4. Medications Associated With Delirium and Neuromuscular Weakness in the ICU
Delirium Muscle Weakness
Corticosteroids Neuromuscular blocking agents
Digoxin Corticosteroids
Narcotics Aminoglycosides
Lithium Clindamycin
Beta-blockers
Non-steroidal anti-inflammatory drugs
Dopamine agonists
Antihistamines (both histamine-1 and -2 antagonists)
Antispasmodics
Anticholinergics
Tricyclic antidepressants
Paroxetine
Disopyramide
Diuretics
Skeletal muscle relaxants
Theophylline
Fluoroquinolones
Cefepime
Benzodiazepines
Inhaled anesthetics
Ketamine

Medication profiles of patients in ICUs should be reviewed in detail on a daily basis to ensure that each medication remains necessary, is free from adverse effects or interactions, and that the dose, route, and frequency of administration are appropriate. Transitions of care are another important opportunity to review and optimize a patient’s medication profile. The risk of adverse drug events increases during each transition of care (e.g., from the ICU to an inpatient bed, or from an inpatient bed to home), and this risk is increased by cognitive impairment and polypharmacy (more than 5 medications per day), both of which are common in critically ill patients. Importantly, two-thirds of medications deemed to be inappropriate at the time of hospital discharge were started in the ICU setting.30,31

Furthermore, the number of medications prescribed in the hospital setting is an independent risk factor for delirium. All of these aspects highlight the importance of careful medication management and the need for deprescribing to minimize the risk of delirium, adverse drug events, and PICS.

Deprescribing is defined as the “process of tapering or discontinuing medications to minimize polypharmacy and improve patients’ outcomes.”31 This process is outlined in Table 5. The sixth step, which is specific to the ICU setting, is determining whether the medication has a current indication. This is an important step, as medications that were needed prior to admission may still be appropriate upon discharge home but may not have a role in the acute care setting (e.g., cetirizine for seasonal allergies).

Table 5. Process of Deprescribing in the ICU Setting31
Step Action
1 Determine that each medication has an indication
2 Consider the overall potential harm of the medications in determining how many agents should be discontinued
3 Assess each individual drug to determine whether it should be discontinued
4 Prioritize the order of medications to be discontinued
5 Initiate and monitor a drug discontinuation plan
6 Determine if medication has a current indication

Another medication-oriented strategy that has been proposed for reducing the risk of ICU delirium is deemed “Stop, THINK, Medicate.”31 The first step, “Stop”, involves stopping or decreasing the doses of deliriogenic medications, particularly sedatives. THINK provides an acronym for considerations to make prior to initiating pharmacologic treatment for delirium (Table 6). Finally, “Medicate” suggests the use of second-generation (atypical) antipsychotics or dexmedetomidine to manage delirium (particularly hyperactive delirium) only after deliriogenic medications have been minimized and other contributing factors have been considered.

Table 6. THINK Acronym Used in the “Stop, THINK, Medicate” Strategy for Reducing ICU Delirium31
Condition Explanation/Example
Toxic situations Congestive heart failure, shock, dehydration, acute kidney/liver injury
Hypoxemia Partial pressure of oxygen in arterial blood < 80%
Infection/Immobilization Sepsis, nosocomial infection
Nonpharmacologic interventions Hearing aids, eyeglasses, reorientation, sleep protocols, music therapy, noise control, mobilization
K (hypokalemia/hyperkalemia) Or other electrolyte abnormalities

Early Mobility Programs

Early mobility is an important component of the ICU Liberation Bundle. It has been associated with positive outcomes when implemented in the ICU setting. These programs have been associated with decreased hospital length of stay, incidence of delirium, hospital readmission, and mortality. Additionally, patients have greater muscle strength, an increased ability to ambulate and perform self-care, and an increased rate of return to independent functioning at the time of hospital discharge when they receive early mobility in the ICU setting.32

Early mobility can take different forms depending on the patient’s level of sedation. For comatose patients (–4 or –5 on the Richmond Agitation–Sedation Scale [RASS]), early mobility may be as simple as passive range of motion exercises, such as forearm pronation, elbow flexion/extension, internal/external hip rotation, hip abduction/adduction, and foot dorsiflexion/plantar flexion.33 For a patient who is moderately to lightly sedated (RASS –3 or –2), early mobility may consist of both passive range of motion exercises and moving from a lying to sitting position. For patients who are alert and not agitated (RASS –1, 0, or +1), early mobility can progress from active range of motion exercises to sitting, standing, walking, and training in ADLs.

Even for a patient who is intubated and mechanically ventilated, standing and walking exercises are possible, but do require multiple personnel to ensure patient safety while managing the endotracheal tube, ventilator, intravenous lines, urinary catheters, and other devices.33 Lack of personnel is often a barrier to effectively implementing early mobilization in the ICU. When the availability of trained physical therapists is limited, their reach can be expanded by training the bedside nurse and family members to assist with passive range of motion and some other exercises.

ICU Diaries

Because of the altered level of consciousness that many patients experience while in the ICU, amnesia is a common and distressing complaint often associated with the mental health aspect of PICS. ICU diaries provide patients and their families with a factual account of their admission to aid in filling memory gaps and fostering psychological recovery. These have traditionally been kept by nursing staff and are updated daily for the duration of the ICU admission. Entries may include information about the patient’s condition, procedures and treatments, names of visitors, significant happenings in the unit, or even current events in the news.

Studies have validated the use of ICU diaries, citing decreased rates of posttraumatic stress disorder, anxiety, and postdischarge depression.34 In facilities where staffing limitations prevent nurses from keeping an ICU diary, loved ones may be encouraged to keep their own diary to share with the patient. 

Healing Environments of Care

Maintaining an environment conducive to healing is important, especially in the ICU. Nonpharmacological interventions aimed at decreasing anxiety and delirium are often overlooked but can be the most helpful. Patients should be frequently oriented to time, place, and situation, allowing them to better understand and participate in their own care. The room should be a comfortable temperature and excess noise should be avoided. Interventions should be taken to help patients maintain a normal sleep/wake cycle, and overnight labs and vital checks should be avoided if possible. Furthermore, staff should determine whether patients require sensory aids such as eyeglasses or hearing aids at baseline, and these should be obtained from family when possible.

Functional Reconciliation Checklist

A functional reconciliation checklist — which starts with an assessment of preadmission physical, cognitive, and mental status — is used to track progress during and post-ICU admission. While in the ICU, these checklists are a great way to facilitate communication between therapists who work with the patient (e.g., physical, speech, occupational) and the medical team. After discharge, the checklists can be used by outpatient providers to monitor for continued improvement and coordinate additional therapy if needed.

Family-Centered Care Programs

The impact that critical illness can have on a patient’s family members, including development of PICS-F, cannot be understated. Family-centered care programs are specifically designed to provide support in a way that is respectful and responsive to each individual’s needs and values.35 These programs are considered essential to high-quality ICU care and may include visitation policies that allow for frequent family presence, scheduled family meetings with the medical team, and consults to additional support services such as care coordinators, chaplains, or palliative care.

Understandable Communication

Transparent communication is imperative in developing trust and rapport with a patient’s family. It is important to assess family members’ medical literacy and to tailor conversations accordingly. Routine family conferences using the VALUE mnemonic (Table 7) ensure consistent communication and understanding between the family and the medical team.36

Table 7. VALUE Mnemonic for Clinician–Family Communication36
Component Description
V Value family statements
A Acknowledge emotions
L Listen
U Understand the patient as a person
E Elicit questions

Shared Decision-making

In recent decades, health care has moved away from strictly physician-led decision-making to a model that incorporates all members of the medical team, including the patient. During times of critical illness, a patient’s family often finds themselves tasked with making surrogate decisions for their loved one. This can be difficult to navigate as family members must balance patient values and advanced directives along with their own desires. As an ICU clinician, it is important to be transparent about the patient’s condition and prognosis while supporting the family in the treatment that they choose or choose not to pursue. Consulting patient advocates, chaplains, and palliative care services in these situations can be useful in providing additional support for the family.

Family Presence and Participation

Family presence during an ICU admission may decrease the odds of developing both PICS and PICS-F. Family members frequently can help reorient the patient and may provide a sense of normalcy during a time that can be distressing and confusing. For the family, being physically present can be helpful in processing their loved one’s critical illness. For example, some facilities allow for family members to be present during resuscitation efforts if they choose. Although it may be distressing for some, others believe that it provides closure, especially if the resuscitation is not successful. If this practice is used, it is important to provide support (such as a social worker) to the family during this time.

Family Training and Expectations

After an ICU admission, members of the patient’s family may be facing the new reality of providing care. Involving family in patient care activities during the ICU admission can help to improve confidence in their caregiving skills and give family members a greater sense of inclusion in their loved one’s recovery. Family education programs have been associated with reduced generalized and posttraumatic stress, depression, and anxiety.

Postdischarge Follow-up Programs

Unfortunately, the health care needs of a critically ill patient do not end at discharge. Postdischarge follow-up programs have been used for more than 20 years in European and Scandinavian countries and seem to be gaining traction in the United States. These programs are designed to address the diverse needs of patients after an ICU discharge, including assessing and treating any persistent physical, cognitive, and mental problems.

Most programs employ a variety of clinicians (such as prescribers specialized in critical care, palliative care, primary care, and rehabilitation; dietitians, social workers or case managers, critical care nurses, physical/occupation/speech therapists, neuropsychologists, and clinical pharmacists) who work as an interdisciplinary team to meet the specific needs of post-ICU patients.37 Pharmacists are most often involved in medication reconciliation and optimization, as transitions of care are notoriously high risk for medication mistakes. Although these programs have been anecdotally beneficial, it is unknown which subgroup of patients would benefit most or what would be the ideal interval for follow-up.

Although the field is expanding, most post-ICU patients in the United States do not currently have access to a follow-up program. For this reason, primary care has been referred to as the unrecognized member of the intensive care team.38 As patients transition back into outpatient care, general practitioners will be expected to manage their medical conditions; however, most have not been trained on how to identify or treat the lasting cognitive and mental effects that their patients may experience after a critical illness. ICU practitioners can address this possible gap in care by proactively educating patients and their families about PICS risk factors, making appropriate referrals prior to discharge (e.g., physical or occupational therapy, psychiatry, etc.), and providing resources on how to seek help after discharge if necessary.

CONCLUSION

PICS has a significant impact on patients and families, affecting nearly two-thirds of patients admitted to the ICU and negatively affecting cognition, mental health, and physical abilities. Risk factors for PICS should be considered and minimized while the patient is in the ICU and after discharge. Clinician awareness can be helpful in preventing and managing PICS symptoms both during the acute illness and after discharge. Ultimately, transparency between the medical team and patients and their families is an important key in improving communication and preventing PICS.

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