LABORATORIO DE URGENCIAS

Outcomes After Critical Illness

.

                                                Margaret S. Herridge, M.D., M.P.H.and Élie Azoulay, M.D., Ph.D.

 
                                                                           N Engl J Med 2023; 388:913-924

The specialty of critical care has achieved important advances in survival for many patients with the most complex disorders. Along with these advances, however, there has been an increasing awareness of the complicated and persistent morbidity that follows critical illness. Episodes of critical illness result in multidimensional acquired or exacerbated conditions that may persist for years after the critical illness and may not be wholly reversible. Health inequities may worsen these outcomes.
The coronavirus disease 2019 (Covid-19) pandemic, which has resulted in the largest cohort of critical illness survivors and families in history, heightened awareness of the ubiquity of multidimensional disability after critical illness. A continuum of care for patients and families after critical illness, extending from the intensive care unit (ICU) to community or primary care, must become the standard of care and be developed concurrently with a prioritization of basic science inquiry to elucidate the multiple mechanisms of morbidity. Transparent and public reporting of long-term ICU outcomes is fundamental for obtaining informed consent to initiate and continue ICU treatment, aligning care with patient and family values, and ensuring accountability for the high human and financial costs of these outcomes.

 Patient Outcomes after Critical Illness

The description of the acute respiratory distress syndrome (ARDS) in 1967 initiated a cascade of studies that evolved from reports on short-term mortality and pulmonary outcomes to the current literature on multidimensional ICU outcomes.
In early case series evaluating outcomes in ARDS survivors, mild restrictive or obstructive deficits were reported on pulmonary-function testing, with a reduction in diffusion capacity,² but subsequent studies did not directly implicate pulmonary function in observed decrements in health-related quality of life.^3-5 In 1998, Schelling et al. highlighted the prevalence of post-traumatic stress disorder (PTSD) after ARDS, associated with traumatic ICU memories.⁷ The following year, Hopkins and colleagues reported neurocognitive and psychological dysfunction, including persistent cognitive dysfunction in 30% of ARDS survivors at 1 year and impaired memory, attention, or concentration or decreased mental processing speed in 80%.⁶
In 2003, the Toronto ARDS Outcomes Program extended this emerging description of the post-ARDS syndrome to include multidimensional disorders and long-term functional disability associated with persistent muscle wasting and weakness, in the context of normal–to–near-normal pulmonary function. A decrease in the distance walked in 6 minutes was linked to impaired health-related quality of life and increased health care use at 1, 2, and 5 years of follow-up after ICU discharge.^8-10 As with earlier observations from De Jonghe and colleagues on paresis in a general ICU population,¹¹ decreased post-ICU walking distance in 6 minutes was associated with female sex, a high burden of comorbidity, and exposure to systemic glucocorticoids. Similar outcomes and determinants of the 6-minute walking distance were validated by the Johns Hopkins Improving Care of Acute Lung Injury Patients (ICAP) group¹² and by the multicenter ARDSNet Long-Term Outcomes Study (ALTOS).¹³ Pfoh and colleagues also observed durable physical impairment in ARDS survivors up to 5 years after ICU discharge and a continued functional decline over that period in a substantial proportion of patients.¹⁴ Similar observations were reported by Cuthbertson et al. in a 5-year follow-up in a general ICU population¹⁵ and by Lone et al. in a Scottish population-based study.¹⁶

ICU-acquired weakness is prevalent among ICU survivors¹⁷ and encompasses a critical illness myopathy (myosin-depletion myopathy), polyneuropathy (axonopathy), or a combination of these disorders. Modifiable risk factors (immobility, hyperglycemia, and treatment with glucocorticoids and neuromuscular blockers) and nonmodifiable risk factors (multiple organ dysfunction, severe illness, and prolonged duration of illness or ICU stay) have been well described previously. ICU-acquired weakness accounts for an increased number of days of mechanical ventilation, a prolonged ICU stay, a complex transition to post-ICU care, an increased number of emergency department visits or hospital and ICU readmissions, and increased long-term disposition and health care costs. This condition may be permanent.

ICU outcomes data highlight myriad coexisting conditions including frailty; oral and dental complications; swallowing difficulties; taste changes; vision or hearing loss; a new need for renal replacement therapy; procedure-related trauma (incontinence, rectal or urethral trauma, vocal cord dysfunction, or tracheal stenosis); entrapment neuropathies; endocrinopathies; heterotopic ossification; frozen joints and contractures; rotator cuff injuries from a prolonged prone position; cosmetic concerns related to alopecia, nail changes, scarring, and disfigurement from tracheostomy, placement of arterial or central lines, or extracorporeal membrane oxygenation (ECMO) sites; and complicated pressure injuries. Traumatic memories, unremitting stress from the ICU experience, and ICU-acquired disability may have a profound effect on caregivers and other family members, including children, and may represent an antecedent for intergenerational trauma.¹⁸

Frailty is defined by diminished strength and endurance and reduced physiological functioning, which increase the risks of dependency and death. When frailty occurs or worsens after ICU admission, it is associated with increased in-hospital and long-term mortality, increased functional dependency, a reduced health-related quality of life, a lower likelihood of a return to community-based living, and a greater likelihood of hospital readmission.

The Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study¹⁹ has shown that 1-year cognitive outcomes among ICU survivors are independent of age, similar in severity to mild Alzheimer’s-type dementia or moderate traumatic brain injury, and related to cortical loss, white-matter injury, or both during critical illness. The duration of ICU delirium is the most potent risk factor for 1-year global cognitive dysfunction and impaired executive function. Additional risk factors include hypoxemia, blood glucose dysregulation, conservative fluid management, no statin exposure during critical illness, sepsis-induced encephalopathy, immobility, deep coma, sleep disruption, and separation from family.

Mood disorders, which are persistent and prevalent among ICU survivors, include PTSD (in 25% of survivors up to 8 years), depressive symptoms and anxiety symptoms (in 17 to 43% and 23 to 48%, respectively, at 1 year), suicidality, and substance misuse. These disorders may be related to injury of the limbic system during critical illness. Risk factors for mood disorders include previous psychiatric illness, prolonged mechanical ventilation, prolonged ICU stay, episodes of hypoglycemia, and prolonged exposure to sedative and narcotic agents.²⁰

Pressure injuries are also common. The recent Decubitus in Intensive Care Units study showed a point prevalence of pressure injuries that was close to 30%.²¹ The severity of pressure injuries is associated with mortality in a dose-dependent relationship, and risk factors include older age, diabetes mellitus, cardiovascular disease, vasopressor use, a prolonged prone position, prolonged mechanical ventilation, use of ECMO, and a prolonged ICU stay.

Observations of long-term multisystem disorders after critical illness are robust and reported across diverse patient populations and international studies. Dissemination of this knowledge has been limited, however, even within the specialty of critical care.²² There is a need to move beyond illness defined by disposition, toward a continuum of patient and family care encompassing both pre- and post-ICU periods. In addition, priority should be given to educational engagement with critical care colleagues, ICU stakeholders, interprofessional team members, trainees, and primary care physicians about changing patient and family needs before, during, and after ICU care. Critical illness is only one phase of an illness and is defined not solely by the need for ventilatory or hemodynamic support but also by how preexisting health status interacts with severe illness, the effects of exposure to technological supports, and ICU-related iatrogenesis.

Risk and Trajectories of Post-ICU Disability

Age is a fundamental marker of senescence with loss of organ reserve and is a central determinant of survival and disability after critical illness.²³ When increasing age is combined with the need for mechanical ventilation, the rates of patient illness and death rise substantially.²⁴ In a U.S. cohort of ICU patients over the age of 60 years, 45% of the patients died within the first year after critical illness, and depression and disability in activities of daily living were associated with decrements in health-related quality of life among the patients who survived.²⁵

With increasing age and severity of illness, health status before the development of critical illness becomes a fundamental determinant of the post-ICU outcome. Social isolation, frailty, cognitive impairment, and impaired functioning before ICU admission are also associated with an increase in the risk of disability after discharge in older patients.^26,27 Frailty and an age of 80 years or older have central prognostic importance with respect to the risk of death in the ICU and at 30 days after discharge.²⁸

ICU patients may be risk-stratified on the basis of the degree of weakness that develops in the ICU. ICU-acquired weakness is associated with a lower likelihood of weaning from mechanical ventilation, increased health care costs, and 1-year mortality. Severe and persistent weakness at ICU discharge further increases 1-year mortality.²⁹

Rehabilitation and Recovery in Patients and Families after One Week of Mechanical Ventilation (RECOVER), a multicenter Canadian cohort study, showed that functional status 7 days after ICU discharge (assessed with the Functional Independence Measure) determined disability outcome trajectories based on age and the length of the ICU stay in a diverse sample of medical and surgical patients, transplant recipients, and patients undergoing ECMO who were mechanically ventilated for 2 or more weeks.³⁰ Trajectories were independent of the diagnosis on ICU admission, but determined discharge disposition, status with respect to hospital or ICU readmission, use of health care services, and survival status at 1 year of follow-up. Among patients who were older than 66 years of age and spent 2 or more weeks in the ICU, mortality was 40% at 1 year, and the survivors incurred substantial multidimensional disability. Each additional decade of age and each additional week spent in the ICU beyond 2 weeks were independently associated with increased multidimensional disability and mortality at 1 year after ICU discharge. French investigators also reported a longer ICU stay as an important independent risk factor for death within 1 year after discharge, in addition to older age, coexisting conditions, need for red-cell transfusion, and deranged clinical physiology factors at the time of ICU discharge.³¹ Elevated biomarkers of cardiac and vascular failure accounted for an increase in the risk of death by a factor of almost 3.
These data on the robust clinical risk factors for poor outcomes after discharge from the ICU, as well as the outcome trajectories for high-risk patients, provide a rationale for trials of limited treatment in the ICU and weekly discussion of the goals of care with patients and family caregivers after an ICU stay of 2 weeks or more.
The discussions should candidly frame outcome expectations, including increased risks of disability and death, as part of the process of obtaining informed consent to ongoing ICU treatment and in an effort to mitigate suffering on the part of patients and family members. The high risks of increased disability and death with a protracted ICU stay should negate any practice of committing critically ill patients to indefinite trials of mechanical ventilation or ECMO support.

Post-ICU Syndromes

There are several overlapping constructs for the post-ICU condition, which highlight anticipated disorders resulting from severe lung injury, sepsis, and prolonged mechanical ventilation. The emerging post-Covid critical illness outcomes literature reflects these multidimensional sequelae to 1 year of follow-up.⁴⁷ In 2010, after reports on the outcomes of ARDS, Iwashyna et al. reported important decrements in cognition and function among survivors of severe sepsis, which persisted through 8 years of follow-up.⁴⁸ The post-sepsis syndrome has been widely reported, with documentation of the spectrum of sepsis-related, long-term disorders, as well as possible mitigation strategies.^49-51

In 1985, Girard and Raffin introduced the concept of chronic critical illness to highlight patients who received prolonged mechanical ventilation.⁵² In 2010, Nelson et al. documented the role of prolonged mechanical ventilation (for 1 to 3 weeks) in the syndrome of chronic critical illness and extended the definition of the syndrome to include ICU-acquired weakness, brain dysfunction, endocrinopathy, malnutrition, recurrent infections, pressure injuries, and symptom-related distress.⁵³ Mortality in this diverse patient group was reported as 48 to 68%. Hough et al. reported that patient age, platelet count, requirement for vasopressors, dialysis, and nontrauma admission determined 1-year mortality in survivors of 2 weeks of mechanical ventilation.⁵⁴ Unroe and colleagues detailed 1-year outcomes after 3 weeks of mechanical ventilation, reporting that only 9% of patients have a good outcome with functional independence, and 65% have a poor outcome (complete functional dependency or death), with byzantine post-ICU care transitions.⁵⁵ Only 20% of patients surviving chronic critical illness will return home, and the majority will be discharged to skilled nursing facilities with incurred costs in the billions.⁵⁶ In 2012, Needham et al.⁵⁷ and Davidson et al.⁵⁸ introduced the post–intensive care syndrome and the counterpart of that syndrome in family members, respectively, as additional constructs to elevate public awareness of the post-ICU condition and to group common features of post-ICU disorders, including physical and cognitive disabilities and mood disorders, in both patients and their families. The extended post–intensive care syndrome has recently been added to further expand the broad spectrum of disorders that develops after critical illness.⁵⁹ The persistent syndrome of inflammation, immunosuppression, and catabolism has also been hypothesized to promote poor recovery and rehabilitation and extends beyond multiple organ dysfunction in patients with chronic critical illness.⁶⁰

The continuum of critical illness lends itself to the complementary construct of a continuum of tailored care, nutrition, follow-up, and rehabilitation
Patients come to the ICU with variations in health status, baseline nutrition status, and organ resilience. Optimal outcomes require tailored multimodal management at each transition in care.
There is an expansive literature on interventions before, during, and after an episode of critical illness that is beyond the scope of this review. A succinct overview of evidence-based ICU practice for optimal outcomes has been effectively articulated in the ABCDEF bundle: assess, prevent, and manage pain; both spontaneous awakening trials and spontaneous breathing trials; choice of analgesia and sedation; delirium: assess, prevent, and manage; early mobility and exercise; and family engagement and empowerment.⁶¹ The suspension of these practices during the Covid-19 pandemic exacerbated many of the disorders described above, underscoring the fundamental importance of such practices with respect to outcomes.
Policies of isolation have altered the processes of ICU care for which family centeredness is paramount, deeply affecting patients, caregivers, children, and health care providers.

Post-ICU Follow-up and Rehabilitation

The first reports of post-ICU follow-up originated from groups in the United Kingdom, and the early work was led by Jones, Skirrow, and Griffiths.⁶² To date, there is contradictory literature on the efficacy of ICU-based follow-up and rehabilitation programs.^63-65 
Patient heterogeneity and differences in pre-ICU health profiles and post-ICU recovery trajectories pose a major challenge to the development and testing of these programs. Results may have more to do with the study sample and the patients’ baseline health and nutrition⁶⁶ status before their critical illness than to the nature of the follow-up and rehabilitation interventions. Important guidelines have been established for follow-up and rehabilitation after discharge from the ICU, but the evidence base for guiding practice in this area is still sparse.⁶⁷ Limitations include the timing and choice of multidimensional core outcomes and the duration of follow-up after an intervention, as well as the absence of robust knowledge of the mechanistic determinants of multisystem organ injury and repair and how they interact with tailored nutrition management and the timing and intensity of exercise and mental health programs.

In 2009, Schweickert and colleagues evaluated a combined intervention of daily interruption of sedation with exercise and mobilization within 72 hours after the initiation of mechanical ventilation in patients with baseline functional independence.⁶⁴ As compared with usual care, this intervention was associated with improved functional independence at hospital discharge, suggesting the potential for resilience in patients who were functionally independent before they became critically ill. The improved function resulting from early goal-directed mobilization in a surgical ICU population⁶⁵ may further reinforce the important effect of premorbid status on the effectiveness of rehabilitation. The positive effect of a post-ICU 6-week self-care and rehabilitation manual⁶² underscores the overarching principle of tailored care and nutrition⁶⁸ after critical illness, and the effect of a diary intervention on PTSD highlights the ability to target and mitigate mood disorders. Interdisciplinary and interprofessional programs for post-ICU follow-up and rehabilitation, ranging from nurse-led clinic follow-up to exercise programs to programmatic approaches to nutrition and rehabilitation, have achieved modest improvements in functioning or quality of life, but some have noted improved patient-reported satisfaction.^15,30,69-71 
Historical models of such approaches can be found in the literature on cardiac and pulmonary rehabilitation.^72,73 

Conclusions and Recommendations

The field of critical care has made enormous gains in its mission to save lives.
Critical illness, however, changes a life trajectory and is often a traumatic experience for the entire family. The next challenge for critical care is to look beyond the ICU, hospital discharge, and survival at 30 and 90 days and to embrace the construct of ICU care as part of a continuum of care, with the goal of optimizing care transitions and long-term multidimensional functioning for surviving patients and their families.
The literature on long-term ICU outcomes is robust across a broad spectrum of patient and caregiver groups, yet long-term outcomes are not a prominent part of the ICU lexicon.
Our patients and their families need this to change. 
The international burden of post-Covid critical care illness makes this an urgent public health priority. The ICU community can — and should — make mitigation of suffering and a sense of futility in the ICU and of disability after discharge our next priorities. Stepping away from our historical compartmentalization of critical illness and establishing a longer, 1-year time horizon as the practice standard for assessing the myriad consequences of ICU care provide an opportunity for education, advocacy, continuity of care, and accountability for critically ill patients, their caregivers, their children, and our health care system.

NOTE: Portions of the indicated publication are presented. The full text, bibliography, tables and charts must be consulted in the original journal.