Continuing Education Activity

As intensive care unit (ICU) mortality rates have fallen in recent decades, there is increasing recognition that ICU survivors often face debilitating physical, cognitive, and mental health impairments that persist for months to years following critical illness recovery. This phenomenon, referred to as Post-Intensive Care Syndrome (PICS), may be mitigated by the adoption of certain clinical practices during hospitalization while treatment often requires continued outpatient management. Even being a witness to the stress and trauma of the ICU experience can have long-lasting impacts on family members, manifesting as adverse mental health outcomes referred to as PICS-family (PICS-f). This activity describes the etiology, diagnosis, prevention, and management of PICS and PICS-f and highlights the role of the multidisciplinary team in treating patients with these conditions.

Objectives:

• Describe the etiology and risk factors of PICS and PICS-family (PICS-f).
• Explain the evaluation and diagnosis of patients experiencing impairments of PICS and PICS-f.
• Summarize the ICU practices that may prevent the development of PICS and PICS-f.
• Review the prognosis and potential long-lasting complications of PICS and PICS-f.

Introduction

While the short-term outcomes of ICU patients have dramatically improved over the last half-century, it is increasingly recognized that many ICU survivors experience declines in physical and cognitive functioning that persist well beyond their acute hospitalization. Psychiatric sequelae, including anxiety, depression, and post-traumatic stress disorder (PTSD) are also prevalent among both ICU survivors and their family members. Attendees of a 2010 meeting of the Society of Critical Care Medicine coined the term Post Intensive Care Syndrome (PICS) to describe new and persistent declines in physical, cognitive, and mental health functioning that follow an ICU stay and for which other causes, such as traumatic brain injury (TBI) or cerebrovascular accident (CVA), have been excluded. The term PICS-F is applied to the close family members of ICU patients who experience subsequent adverse mental health outcomes, the most common of which are sleep deprivation, anxiety, depression, and complicated grief.[1]

In the last few decades, there has been a rise in the rate of pediatric ICU (PICU) utilization. In contrast, the mortality in this population has steadily fallen, resulting in a growing number of pediatric ICU survivors at risk for the impairments of PICS. The impacts of impairments following an ICU stay in pediatric patients deserve special attention as these occur within the already dynamic state of childhood development. Additionally, because even healthy children are inherently dependent upon the support of their parents and other caregivers, a child’s recovery from a PICU stay inevitably impacts the entire family unit. Re-integration into school and other peer groups is a particular challenge for pediatric ICU survivors, while their siblings also face extraordinary social and emotional stressors. At a time that would otherwise represent peak economic productivity, parents of critically ill children often must cut back on work hours or withdraw from employment completely, resulting in financial consequences that persist long after the illness. For this reason, the PICS-pediatric (PICS-p) framework includes the fourth domain of social health applicable to all family members of the PICU patient.[2]

Etiology

Much of the prolonged physical impairments of Post Intensive Care Syndrome (PICS) arise from ICU-acquired muscle weakness (ICUAW), defined as a diffuse symmetrical decrease in skeletal muscle strength for which other causes have been excluded. The clinical manifestations of ICUAW may include difficulty in ventilator weaning, impairments in speaking or swallowing, and generalized weakness of the limbs. ICUAW is further subdivided into muscle deconditioning, critical illness polyneuropathy (CIP), and critical illness myopathy (CIM), the latter two of which may coexist as critical illness neuromyopathy (CINM).[3]

Mechanical ventilation results in rapid wasting of the respiratory musculature due to automatic unloading, with diaphragmatic thinning evident on CT scan in as little as two days.[4] Tolerance of tracheal intubation and mechanical ventilation is usually only possible with the administration of opiates and sedatives, which further exacerbate disuse mediated atrophy by dampening the neural activation of the respiratory musculature.[3] Additionally, if neuromuscular blockers must be used to facilitate patient-ventilator synchrony, as in severe acute respiratory distress syndrome (ARDS), weakness resulting directly from these agents may be present for up to a week after their cessation and mimics the myopathy observed after spinal or other denervation injuries.[5] Similar to the unloading of the respiratory musculature by mechanical ventilation, prolonged bed rest, and other forms of immobilization also rapidly weaken the limb and trunk muscles of ICU patients.

In addition to skeletal muscle atrophy from disuse, inflammatory mediators, electrolyte imbalances, endocrine dysfunction, and poor nutritional status also frequently contribute to the myopathy of ICUAW by impairing protein synthesis and promoting proteolysis.[3] Vitamin D deficiency, which is quite common in the general population and exacerbated by sunlight deprivation in hospitalized patients, is also probably an underappreciated and reversible contributor to skeletal muscle weakness in the ICU setting, particularly among those with darker skin tones.[6] Many of these factors, as well as microvascular ischemia, also likely underlie the neuropathic components of ICUAW.[7] The cognitive impairment of PICS may manifest as deficits in memory, processing speed, or attention that persist up to years following ICU discharge.[8] Risk factors for these deficits in ICU survivors include prolonged or frequent periods of hyper- or hypoglycemia and pre-existing cognitive deficits.[7] A large study from 1999 of ARDS patients also found that more extended and more profound periods of hypoxia during the ICU period correlated with an increased risk for cognitive deficits one year later.[9] There is also a secure link between ICU delirium and the subsequent cognitive deficits of PICS. The 2013 BRAIN ICU study of over 800 ICU patients revealed that a longer duration of delirium, but interestingly not a coma, increased the risk of cognitive impairment one year post-discharge.[10]

PICS also includes impairments in mental health function, including depression, anxiety, and post-traumatic stress disorder (PTSD). These psychiatric sequelae are perhaps not surprising, given that the experience of being an ICU patient is often isolating, frightening, and dehumanizing. Repetitive exposure to physical pain and discomfort is also frequent, as is a general feeling of disorientation and confusion that arises from prolonged sedation or delirium. Risk factors for the development of mental health problems following an ICU stay include a personal history of psychiatric illness, female gender, and younger age. Exposure to sedative agents during the ICU stay, and limited recall of the ICU experience also increases the risk of subsequent mental health impairments. At the same time, the emergence of intrusive traumatic memories and nightmares during hospitalization may herald problems that persist post-discharge.[11] There is also evidence to suggest that hypoglycemia and hypoxia not only increase the risk of cognitive dysfunction in ICU survivors but may contribute to depressive symptoms as well.[12][13]

The experience of being a family member of an ICU patient is increasingly recognized as a significant psychological stressor that can trigger subsequent mental health problems, referred to as PICS-f.  Risk factors for family members to develop PICS-f include female gender, younger age, lower educational level, and previous history of mental health disorders. Spouses of ICU patients are particularly at risk as are the unmarried parents of critically ill children. However, overall the family members of pediatric ICU patients compared to adults are less likely to develop the syndrome.[14] There is conflicting evidence regarding whether family involvement in medical decision-making is protective or predictive of subsequent PICS-f, and cultural factors may explain differences across studies. For example, a French study found that being a decision-maker and particularly having to be involved in end-of-life decisions increased the risk of PICS-f.[15] Conversely, a US study identified that family members who adopted a passive role in decision-making were actually at increased risk for adverse mental health sequelae.[16] These seemingly contradictory findings may be explained by differences between the two countries regarding the acceptability and pervasiveness of shared medical decision-making. While shared decision-making is the norm in the US, the practice is not as well established in France, and family members may be more likely to find involvement in making decisions for a critically ill loved one to be psychologically burdensome or even traumatic.[14]

Epidemiology

As the global population ages and ICU survival rates increase, more and more people are at risk for Post Intensive Care Syndrome (PICS), Post Intensive Care Syndrome for family members (PICS-f), and Post Intensive Care Syndrome- pediatrics (PICS-p).[17] Reported rates of these syndromes vary considerably in the scientific literature due to differences in the study population, periods of follow-up, and methods of assessing impairment; however, there is consensus that PICS, PICS-f, and PICS-p are typical and observed across cultures. Physical impairment is present in 25-80% of adult ICU survivors. It is even more prevalent among survivors of sepsis[18], possibly due to the involvement of inflammatory cytokines in the pathogenesis of ICUAW.[19] Cognitive dysfunction occurs in up to 80% of adult ICU survivors, and while this generally improves over time, these changes may persist for years, particularly following recovery from ARDS or sepsis. Rates of Post Traumatic Stress Disorder (PTSD) have been reported in up to 50% of adult ICU survivors, and this particular malady also tends to persist for years following hospital discharge.[18]

A recent study by Marra and colleagues of 406 adult ICU patients from five US medical centers evaluated the co-occurrence of PICS impairments 3- and 12- months post-discharge. These investigators found 64% and 56% of survivors had one or more PICS impairments after 3 and 12 months, respectively. The co-occurrence of impairments across two or more domains was also found to be shared with cognitive and psychological problems being the most persistent over time. Additionally, increased education level and lower frailty scores were positively correlated with being PICS free at both points of follow-up.[20] The BRAIN-ICU longitudinal cohort study of critical care survivors in the Nashville, TN area found a 29% prevalence of depression at 12 months post-discharge, but a relatively low rate of PTSD at 7%. In this population, over a quarter still required aid in the necessary activities of daily living (ADL) in one year.[21] Up to 75% of family members of ICU patients develop symptoms consistent with PICS-f, with approximately a third requiring psychiatric medication for management.[18] The most common mental health problem in family members is anxiety, with depression and PTSD being somewhat less frequent.[14] Importantly, PICS-f may exacerbate the existing physical health problems in family members as well as contribute to financial and substance abuse issues.[18]

Because the PICS-p framework was only recently distinguished from the adult literature, the prevalence of impairment in pediatric ICU survivors not well defined. However, a recent high-quality scoping review of the subject revealed functional impairment rates of up to 36% at discharge, 26% at six months, and 19% at two years among pediatric ICU survivors. These authors noted that assessing functional impairment in the pediatric population is particularly challenging as the measurement tools used must be appropriate for both age and developmental trajectory.[22] In advanced countries, PICU mortality rates have fallen from approximately 5% to 2.5% since the year 2000.[22][23] Because pediatric ICU patients are more likely to survive than their adult counterparts, recognizing the scope of persistent morbidity in this population is of particular need for further study.

Pathophysiology

Distinct pathophysiologic mechanisms are accounting for the three domains of impairment included in Post Intensive Care Syndrome (PICS): physical, cognitive, and mental-health related. Prolonged immobilization and inflammatory cytokines activate the ubiquitin-proteasome system, autophagy-lysosome system, and other intracellular pathways within the skeletal muscle to cause increased levels of proteolysis and catabolism, manifesting clinically as the sarcopenia and myopathy characteristic of ICUAW.[24][19]

When ICUAW involves neuropathy, this is thought to arise from microvascular ischemia, which impairs neuronal mitochondrial function and causes demyelination.[25] The pathophysiologic mechanisms underlying the cognitive impairments of PICS are less well understood, but microglial activation, oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways have all be implicated.[8] Neuroinflammation also probably plays a role as higher levels of IL-6 and IL-10 have been associated with decreased cognitive performance up to 4 years post-ICU discharge.[26]

History and Physical

Providers eliciting a history from a patient who has recovered from a critical illness should focus their questions on the physical, cognitive, and mental health impairments included in Post Intensive Care Syndrome (PICS). Supplementary information from caregivers and family can also help in assessing the patient’s level of functioning, particularly in the presence of ongoing cognitive deficits. Some researchers have proposed performing a “functional reconciliation,” inspired by the ubiquitous “medication reconciliation,” to compare the patient’s current functionality to that before the ICU stay. This “functional reconciliation” should include assessment of ADLs, exercise tolerance, mood, and indicators of cognitive function, including the return to work or the ability to manage one’s affairs.[27]

A full physical exam, including assessment of vital signs, should also be performed when assessing a patient after recovery from critical illness as the medical condition may remain tenuous. The patient’s overall appearance may give clues to their functional and health status. For example, bitemporal wasting may indicate sarcopenia, while poor hygiene may suggest limited independence in ADLs. The assessment would not be complete until an evaluation of the patient’s affect and body language that may indicate underlying mental health problems. Specific attention should be paid to the neurologic exam to evaluate for signs of myopathy and or neuropathy given the prevalence of ICUAW. A limited cognitive assessment, such as the Mini-Mental Status Exam, should also be performed and, if indicative of deficits, should be followed up by more comprehensive neurocognitive testing.

Evaluation

Identifying symptoms consistent with a diagnosis of Post Intensive Care Syndrome (PICS) can be challenging as there is limited continuity of care between the ICU, rehabilitation or nursing facilities, and home care.[1] While specific post-ICU clinics are relatively common in the UK’s National Healthcare System, this is not the case in the US, where PICS is usually best evaluated in the primary care setting.[28] For this reason, it is imperative that primary care providers and others who see former ICU patients in the outpatient setting be aware of the hallmarks of PICS.

Vanderbilt University established a post-ICU clinic, termed the ICU Recovery Center, in 2012 to identify and treat PICS. While this model may not be feasible in all centers, certain aspects of it may be replicable in typical primary care or post-operative settings. The first visit typically takes place two weeks post-hospital discharge. It includes spirometry and a six-minute walk test to evaluate for physical impairment, screening for mental health problems, and a brief cognitive assessment, such as the Montreal Cognitive Assessment or Mini-Mental Status exam. In this visit, a review of the patient’s ICU course such that the patient’s recollection of events can be reconciled with an actual timeline of events. The developers of Vanderbilt’s ICU Recovery Center acknowledge several factors that limit the Center’s effectiveness, including losses to follow-up and appointment no-shows.[29]

Several groups have developed questionnaires to aid in the detection of PICS in the outpatient setting.[30][31] An advantage of these screening questionnaires is that they can be administered remotely as transportation to outpatient clinics is often a problem for recovering ICU patients. Some authors have also reported success in utilizing telemedicine to evaluate patients for symptoms of PICS remotely.[32] Other aspects of evaluation require inpatient visits, for example, electromyography and nerve conduction studies can help to distinguish myopathy and neuropathy from generalized weakness, as the PT/OT approaches to address these conditions are different.[3]

Treatment / Management

Unfortunately, the efficacy of post-ICU clinics and other services to address the Post Intensive Care Syndrome (PICS) once it has occurred is modest at best.  For example, a recent Cochrane Review of studies investigating the impact of ICU follow-up services found limited effectiveness in terms of improving health-related quality of life (HRQoL).[33] Therefore, the best treatment for the PICS syndrome is preventative measures that are initiated immediately in the ICU setting. The ABCDEF bundle of care is an evidence-based approach to preventing PICS and is being incorporated into the ICU care at over 70 major hospitals throughout the US as part of the ICU Liberation Collaboration:[34]

• A- Assessment, management, and prevention of pain
• B- Both spontaneous breathing trials and spontaneous awakening trials
• C- Choice of sedation and analgesia (maintain a relatively light level of sedation and avoid benzodiazepines)
• D- Delirium assessment, prevention, and management
• E- Early mobility and exercise
• F- Family engagement and empowerment

Collectively, these measures address the physical impairments of PICS by preventing immobility and prolonged mechanical ventilation, the cognitive impairments by minimizing the exposure to sedatives and preventing delirium, and the mental health impairments by promoting patient-centered care. One well-studied method to address the mental health aspects of PICS and PICS-f is the use of ICU diaries, written chronological accounts of the ICU stay, often with accompanying pictures, that are shared with survivors and their family members during and after the ICU stay. Because ICU patients often have limited or distorted memories of their ICU experience due to sedation and delirium, these diaries can be re-orienting and serve as an enduring reminder of the patient’s medical progress. A meta-analysis found that the use of ICU diaries was associated with a decreased incidence of depression and anxiety in ICU survivors, while HRQoL scores also improved. ICU diaries also reduced the risk of PTSD in family members, but the evidence supporting this conclusion was not as robust.[35]

Quality communication between the ICU team and family members is also thought to decrease the risk of PICS-f. This can be achieved by regularly scheduled family conferences, strategies of empathic listening, avoidance of medical jargon, and the involvement of social workers, psychotherapists, and clergy members.[18] A recent study also found decreased rates of PTSD in family members who participated in a novel approach that included direct participation in bedside care rituals for the ICU patient.[36]

Differential Diagnosis

Post Intensive Care Syndrome (PICS) is a complex disease process that overlaps with many other disorders.

• The physical impairments of PICS should be differentiated from other causes of weakness or neurological deficit, including stroke or disorders of the spine.
• Electrolyte, endocrine, or nutritional deficiencies giving rise to these symptoms should also be ruled out and addressed.
• While cognitive decline resulting from PICS should be differentiated from other causes of dementia, there may be overlap between the two, particularly in elderly populations. While the course of different forms of dementia, such as Alzheimer is typically progressive, cognitive impairments arising as part of PICS tend to be more stable over time. Additionally, memory deficits are usually less pronounced in PICS than in other dementia syndromes, while attention and processing speed are more significantly impacted.
• Severe depression, which may be a component of PICS, can also masquerade as cognitive decline with pronounced deficits in attention and concentration. It is essential to distinguish between the two as the former is amenable to antidepressants and psychotherapy while the latter is not.
• The mental health manifestations of PICS-f are similarly complex and may exist within the context of other life-long psychiatric diagnoses. Providers treating these patients should also entertain the possibility of organic sources of these problems and not merely ascribe them entirely to the experience of having had a loved one in intensive care.

Prognosis

The long-term prognosis of Post Intensive Care Syndrome (PICS) is highly variable. It depends mainly on the severity of critical illness, degree of impairment at hospital discharge, and preexisting functionality. The physical impairments of PICS are more amenable to improvement, particularly with the use of PT/OT, while the cognitive and mental health problems may be more persistent. The study by Marra et al. of 406 US ICU survivors found that while the rate of physical impairment improved from 23% to 17% between 3- and 12-months post-discharge, improvements in the cognitive or mental health domains were more modest with roughly a third of patients experiencing deficits at both time points.[20]

Cognitive deficits have been reported in 25% of ARDS survivors six years post-discharge, with similarly high rates of persistent cognitive impairment observed in the sepsis population as well.[18] While cognitive deficits following ICU recovery may be similar in magnitude to those noted in other forms of dementia such as Alzheimer disease, the course of ICU acquired cognitive deficits is usually not progress and sometimes may even improve over time.[8]

Although the literature regarding the prognosis of PICS-p is sparse, it appears that the rate and persistence of deficits in pediatric ICU survivors are similar to those in the adult population.[37] While PICS-f is quite common in the close family members of ICU patients, the mental health impacts usually lessen naturally with time, and improvements can be further augmented with psychotherapy and sometimes medication.[14]

Complications

The long-term socioeconomic impacts of Post Intensive Care Syndrome (PICS) and PICS-f are substantial with patients and their family members often unable to return to full employment. A study of ICU survivors in the UK found that at one year post-discharge, 22% still required aid with daily care ant that usually this was accomplished by unpaid family members. Subsequently, 28% of those in the study reported a negative impact on family income as a result of the ICU stay and recovery.[38] A similar survey conducted in the United States found a decrease in employment affecting 50% of ICU survivors, with half of those being newly unemployed.[39] Family members experiencing mental health problems associated with PICS-f not only face declines in outside employment but may also lack the resiliency to be active caregivers for their relatives who often require assistance long after the ICU discharge.[40]

The lingering effects of PICS are particularly disruptive to the cognitive, social, and emotional development of pediatric ICU survivors, while their families are also profoundly impacted. Not only are there economic consequences as parents must cut back on work hours to care for their ailing child, but parents also have insufficient time and emotional reserve to attend to other siblings in the household fully. It is for this reason that the fourth domain of social health has been incorporated into the PICS-p framework.[2]

Deterrence and Patient Education

Implementation of the ABCDEF bundle of care within the ICU setting can mitigate the development of Post Intensive Care Syndrome (PICS). Improved patient handoffs that focus on functionality, in addition to the traditional organ systems-based approach can also likely enhance the continuity of care that ICU patients receive during the remainder of their hospital stay and recovery period. Identification of persistent deficits as a result of PICS is often made in the outpatient setting, so primary care providers must be aware of this syndrome so that patients can be appropriately referred for follow-up services.  Debriefing patients and family members at the time of ICU or hospital discharge is also essential as most members of the lay public are unaware of the signs of PICS.[1] Given the high incidence of mental health sequelae in ICU survivors and their family members, routine referral to low-cost, accessible psychotherapy service is not unwarranted.

Pearls and Other Issues

The novel coronavirus that emerged in Wuhan, China, in December 2019 and subsequently spread worldwide as a pandemic has uniquely challenged healthcare systems globally. Epicenters of the COVID-19 pandemic, including Wuhan, northern Italy, and the New York City area, have already seen their ICU resources stretched to the near breaking point. While only a few of those infected will require ICU care, due to near-universal susceptibility, this total number of COVID-19 patients who will need such resources before a vaccine or definitive therapy are developed vastly.  It can be predicted that COVID-19 ICU patients will be particularly susceptible to the impairments of Post Intensive Care Syndrome (PICS). Adherence to the ABCDEF bundle of care is challenging, if not impossible when ICUs become overwhelmed. Further, COVID-19 ICU patients have unusually high incidences of delirium due to the presence of encephalopathy, sepsis, and the need for prolonged mechanical intubation inherent to the disease.[41] While the long-term consequences of COVID-19 remain unknown, the demand for rehabilitation services for these patients is likely to be high.[42]

To minimize the transmissibility of the novel coronavirus in hospital systems, many institutions have employed extremely restrictive patient visitation policies such that most COVID-19 patients spend the majority of their hospitalization in near-complete isolation. While these measures are understandable and necessary, the mental health consequences for both patients and their families are likely to be substantial. Primary care providers and others working in the outpatient setting should be prepared to screen COVID-19 ICU survivors and their family members for the mental health impairments of PICS, including PTSD. Hospital systems should develop plans to minimize the isolation of COVID-19 infection through the use of telemedicine mental health services and technologies to facilitate virtual visitation with family and friends.

Enhancing Healthcare Team Outcomes

Successfully implementing the ABCDEF bundle of care to prevent the development of Post Intensive Care Syndrome (PICS) necessitates a multidisciplinary approach. Practical assessment and management of pain may incorporate pain management teams. The use of regional or neuraxial anesthesia for the management of acute pain can spare the sedating effects of opiates. Implementation of spontaneous breathing trials and spontaneous awakening trials requires the participation of both respiratory therapists for execution and nurses for monitoring.

Similarly, minimizing excess sedation requires buy-in from nursing teams and may benefit from the involvement of hospital pharmacists in the appropriate selection of agents. Practical delirium assessment and management involves the entire team and may incorporate design considerations, such as the presence of windows in patient rooms to allow for natural lighting. Early mobility and exercise of ICU patients are essential. Still, very taxing on nursing staff, and institutions must be prepared to support nursing teams with other staff members who can facilitate early mobilization while minimizing fall risk. Successfully engaging family members requires frequent structured communication from ICU physicians and the use of translation services when necessary. Patient advocates, clergy members, and other hospital representatives from outside the ICU can also aid in maintaining clear communication with family members.