Recovery after critical illness: putting the puzzle together—a consensus of 29
Azoulay et al. Critical Care
Recovery after critical illness: putting the puzzle together-a consensus of 29
Medical Intensive Care Unit 0
Hôpital Saint-Louis 0
ECSTRA team 0
0 and clinical epidemiology, UMR 1153 (Center of Epidemiology and Biostatistics Sorbonne Paris Cité, CRESS), INSERM, Paris Diderot Sorbonne University , Paris , France
In this review, we seek to highlight how critical illness and critical care affect longer-term outcomes, to underline the contribution of ICU delirium to cognitive dysfunction several months after ICU discharge, to give new insights into ICU acquired weakness, to emphasize the importance of value-based healthcare, and to delineate the elements of family-centered care. This consensus of 29 also provides a perspective and a research agenda about post-ICU recovery.
Mechanical ventilation; Sedation; Delirium; Weakness; Intensive care; Muscular disorder; Cognitive dysfunction; Depression; Traumatic stress
Over the past 25 years there has been a burgeoning
critical care literature addressing the issue of longer-term
outcomes, including survival, quality of life, morbidity,
functional status, joblessness, and costs of care for ICU
]. Attention has also focused on
ICUacquired weakness as a generalized neuromuscular
disorder that may dominate the longer-term trajectory,
increase ventilatory dependence, and impede survival
and ability to return to baseline functional status [
These observations have prompted studies of mobilization
at an early stage of critical illness and post-critical illness
rehabilitation. The international critical care community
has become increasingly aware that bed rest and
immobilization in patients with sepsis or respiratory or
multiple organ failure and post-ICU inflammatory states
are associated with skeletal muscle wasting and increased
weakness and impaired longer-term physical and
neurocognitive function. In this review, we seek to highlight
how critical illness and critical care (for example, sedation
practices) affect longer-term outcomes, to underline the
contribution of ICU delirium to cognitive dysfunction
several months after ICU discharge, to give new insights
into ICU acquired weakness, to emphasize the importance
of value-based healthcare, and to delineate the elements
of family-centered care. Longer-term outcomes are
analyzed as the result of both the acute illness (pneumonia,
trauma, stroke, anoxic brain injury, myocardial infarction,
spinal cord injury, burn, etc.) and the critical care
experience and related burden. It is likely that most of the
deleterious effects of critical care also apply to acute care,
with regard to both the prevalence and the mechanisms
that lead to weakness, delirium, cognitive impairment,
worsening of chronic organ dysfunction, or any other
significant sequels. The severity of acute illness determines
the degree of impairment (with age and length of ICU
stay) and the chronic disease status determines the
trajectory of recovery.
There is no doubt that critical illness causally affects
longterm outcomes. However, additional research is warranted
to account for existing gaps and limitations in the
literature. For example, age, frailty, and comorbidities are risk
factors for critical illness but also modulate its
longerterm impact. By collecting data on longer-term morbidity
without being aware of pre-existing comorbidities, studies
often provide a biased picture of ICU survivors. Validation
of proxy reports may be important to understand pre-ICU
status, such as the physical aspect of frailty, cognitive and
mental health, as well as psychological and social status,
and identify adequate targets for improvement [
Premorbid physical, cognitive, and mental health status must
be considered for patients and caregivers. Studies report
that, regardless of age, appreciable numbers of survivors
of critical illness have acute severe cognitive deficits
(affecting memory, attention, processing speed, and
executive function) that improve only slightly after several
]. However, severe cognitive defects may affect
primarily the sickest critically ill patients.
ICU delirium and cognitive dysfunction
Guidelines for the management of pain, agitation, and
delirium have highlighted the need to recognize
delirium, an acute disorder that may be present in up to 80%
of mechanically ventilated patients. Delirium and its
duration are associated with neurocognitive dysfunction and
may be associated with mortality over the first year after
critical illness [
]. However, in observational studies
delirium has been identified by clinicians in one-third of
cases at best [
]. The ABCDEF bundle (assess, prevent,
and manage pain, perform both SAT and SBT with
safety screens and failure criteria, adequate choice of
analgesia and sedation, delirium assessment and
management, early mobility and exercise, and family
engagement and empowerment) recognizes the
interconnectedness of cognitive, physical, and psychosocial
issues and is attracting attention to help address these
issues around recognition [
]. Data from a
multihospital quality improvement initiative in California
incorporating >6000 patients demonstrated a dose
response for compliance such that for every 10% increase
in compliance with the ABCDEFs, there was an
independent increase in both survival and reduction in
delirium/coma days even after adjusting for age, acute
severity of illness, and being on or off mechanical
Post-ICU psychological morbidity persists over time.
One year after ICU discharge, up to one-third of patients
have symptoms of depression [
], but pre-illness
psychiatric history can be found in only 11–38% of patients
]. The link between pre-illness and post-ICU
psychiatric disorders is not yet completely understood.
Physical weakness, the ability to exercise and return to
work, is severely impaired in more than half of ARDS
]. Polyneuropathy, myopathy, and disuse
atrophy can be detected early using clinical testing and
electrophysiology, develop in approximately 25% of
patients requiring prolonged mechanical ventilation, and
are associated with increased mortality . Respiratory
muscle weakness, and more particularly diaphragmatic
dysfunction, has been reported in about half of patients
at the time of ICU admission and are associated with
increased mortality [
diaphragmatic dysfunction occurs in half the patients after
prolonged controlled mechanical ventilation or ventilation
with high-level support, but can also be caused by sepsis
alone (without prolonged mechanical ventilation) [
]. Diaphragmatic weakness follows muscle fiber
injury, atrophy, and remodeling and is associated with
asynchrony, weaning failure, prolonged ventilation,
and ICU and hospital readmission [
may not be documented at clinical examination a
long time after ICU discharge; however, all patients
report varying levels of perceived weakness that
prevents them from performing vigorous exercise [
Studies have assessed benefits from interventions to
avoid immobilization, bed rest, and muscle atrophy.
Trials have evaluated early mobilization and
rehabilitation, neuromuscular electrical stimulation (NMES), cycle
ergometry, and functional electrical stimulation assisted
cycling. In an early trial by Morris et al. [
therapy translated into reduced time to first getting out
of bed and shorter ICU and hospital length of stay. The
intervention was also associated with lower 1-year
mortality or readmission. In a seminal trial performed at
three ICUs, early physical and occupational therapy
resulted in a shorter duration of mechanical ventilation
and delirium and increased proportions of patients
returning to pre-ICU functional status or returning
]. However, more recent studies have reported
a lack of clinical benefits from exercise rehabilitation or
intensive physical therapy [
]. One randomized trial
of 240 patients discharged from ICU found that
hospital-based rehabilitation, including increased
physical and nutritional therapy plus information provision,
did not improve physical recovery or quality of life, but
improved patient satisfaction with many aspects of
]. However, early application of standardized
mobilization has been recently reported to be effective
in improving patients’ functional mobility at hospital
discharge in surgical ICU patients [
The role of nutritional support in reducing
ICUacquired weakness remains unclear. One RCT indicated
an increased weakness and delayed recovery with early
parenteral nutrition [
]. Further work is needed to
investigate the role of high- compared to low-dose protein
combined with active and passive mobilization during
the acute phase and post-acute phase of critical illness in
]. Evidence is needed to reconcile the lack of
clinical benefit from nutritional interventions and the
high probability that increasing substrate (protein) may
actually enhance muscle proteolysis [
Role of sedation
A major challenge in assessing shorter- and longer-term
physical and psychological morbidity in ICU survivors is
the use of early and prolonged sedation. Sedation has an
effect on time to weaning, clinician’s ability to
implement early mobilization, cognitive dysfunction,
healthrelated quality of life (HRQOL), and mortality [
the SLEAP trial, lack of recall of ICU events was
reported by 26% of patients at day 28 [
delusional memories that have been associated with altered
HRQOL and post-traumatic stress symptoms were
reported in 70% at day 28. In this study, lack of recall of
ICU events was independently associated with the use of
midazolam and fentanyl, but delusional memories were
not. Other studies reported variable results. Treggiari
and colleagues conducted a randomized trial indicating
that light, compared with deep sedation, reduced ICU
length of stay and duration of ventilation without
negatively affecting subsequent patient mental health or
patient safety [
]. More studies are needed to improve
our knowledge of the merits and potential harms from
Specific attention to the diagnosis, prevention, treatment,
and control of pain is a major component of high-quality
care, as pain increases physiologic stress response,
negatively affects HRQOL, and can become chronic.
Development of chronic pain is associated with a number of
patient-related psychological factors and predisposing
factors (older age, female gender). In addition, chronic pain
depends on initial pain management and is more common
when pain lasts for a long time or is of high intensity or
]. The current US opioid crisis,
however, serves as a reminder of the potential for development
of opioid use disorder in the context of prolonged,
prescribed analgesia. The concept of eCASH (early Comfort
using Analgesia, minimal Sedatives and maximal Humane
care) was recently developed  wherein analgesia is
considered first, and sedation kept minimal, unless
absolutely necessary. Better humanity of care with improved
communication may minimize the need for sedation.
Attention to pain control and opioid-sparing behaviors may
have the potential to decrease in ICU-acquired weakness
and delirium, but also to mitigate the opioid crisis and its
serious moral, social, and cultural impact.
Other long-term effects
In the frailest patients (such as those suffering acute
exacerbations of COPD, heart failure, and cirrhosis),
critical care illness could be a precipitating event for the
late life spiral. Persistent multisystem organ dysfunction,
persistent immune dysregulation, atrial fibrillation,
stroke, residual end-organ damage, chronic kidney
failure, exacerbation of pre-existing chronic disease, and
microbiome alterations may all contribute to the increased
morbidity and mortality of ICU survivors [
instance, persistent elevation of IL-6 and IL-10 at ICU
discharge is associated with cause-specific mortality,
chiefly from cardiovascular disease (accelerated atheroma)
and cancer [
], with persistent inflammation associated
with muscle weakness [
]. Along the same lines, the
prevalence of endocrinopathy is high after critical care
illness, with potentially long-lasting (if not indefinite)
alteration of cortisol, anterior pituitary hormones, or
target organ hormones [
Critical illness triggers existential questions and invokes
matters of spirituality—a core dimension of health
according to the World Health Organization
clinicians are increasingly aware of the way in which
psychological, social, cultural, spiritual, behavioral, and
economic factors influence how illness affects our lives—a
concept satirically labeled “personomics” [
incorporation of personomics and patient-centered care in
educational curricula and at the bedside during direct
patient care is beginning to be accorded increasing
importance. Many nurses, doctors, spiritual care clinicians, and
other professionals are aware of the value of
presencing—being physically and emotionally available to patients and
families, treating them with dignity, and helping to them
address the powerlessness and the learned helplessness
they often experience. Compassion has emerged among
the most important attributes for critical care clinicians
]. Acts of compassion are crucial for those likely to live
as well as for the dying. Person-centered healthcare from
the perspective of the critically ill means understanding
“what matters most” to individuals not only while they are
critically ill but also afterwards, including the relative
importance of living independently, having a social role,
being cognitively intact, being pain-free, and/or resuming
the ability to work.
Family outcomes are also of paramount importance [
Increasing attention is being given to improving
clinicians’ skills with regard to eliciting and exchanging
information, non-verbal communication, conflict prevention
and resolution, end-of-life care, and grief counseling.
Unfortunately, to date, the results of interventions to
improve family outcomes have been mixed.
In a single-center, before–after study design, a day-3
family conference reduced the number of days without
consensus between ICU clinicians and family members
and decreased ICU length of stay [
]. A multicenter,
randomized trial indicated that a proactive communication
strategy that includes end-of-life family conferences and a
bereavement leaflet significantly reduces, in family
members, symptoms of anxiety, depression, and post-traumatic
stress 3 months after a patient’s death [
]. Participation of
a nurse or social worker trained for 2 days to facilitate
communication within the ICU team and address
communication needs and conflicts has been associated with reduced
symptoms of depression at 6 months, as well as reducing
ICU length of stay and costs [
]. However, a multi-faceted,
nurse-focused, interprofessional quality improvement
intervention on end-of-life care proved ineffective in one of the
largest and most generalizable studies to date [
In a multicenter randomized clinical trial among patients
receiving 7 days of mechanical ventilation, one or two
structured family meetings led by palliative care specialists
(without formal palliative care consultation) demonstrated
no benefits, and possibly greater post-traumatic stress
symptoms in the intervention group [
]. Another trial
investigated the effects of an eight-session, simulation-based
communication skills intervention for internal medicine
and nurse practitioner trainees on patient- and
familyreported outcomes. The intervention was associated with
no change in the quality of communication, but
significantly increased patient depression scores [
increased rates of post-traumatic stress and depression
symptoms were found in bereaved relatives randomized to
receive a condolence letter [
]. These studies highlight
the need to better identify those family members in need
of intra and post-ICU interventions, to identify measures
of caregiver outcomes that are responsive to intervention,
and to continue to evaluate both short- and long-term
outcomes of our interventions before including them in the
standard of care. Finally, an extended family visitation
policy in the ICU can be associated with reduced occurrence
of delirium and shorter length of delirium/coma and ICU
For the immediate future, the research agenda is rich and
challenging. Ample data on the long-term (years) adverse
effects of relatively short periods (weeks) of critical illness
are available. Additional trials based on the insights gained
should be conducted and could be designed with
reasonable equipoise. Studies to date suggest that early
interventions may be beneficial, and later interventions less so.
Yet, we also need to better understand whether there is a
vulnerable period during which damage could result from
an intervention being “too early”. Common definitions
need to be better developed to create a shared glossary of
terms related to ICU recovery.
Collaboration is essential between scientists and
clinicians define the cerebral and neuromuscular complications
of critical illness in terms of the pathophysiologic and
pathobiological mechanisms. Further studies focused on
early physical therapy are needed to determine the most
appropriate target population who are most likely to
benefit with attention paid to the specific comorbidities or
diagnoses to facilitate risk stratification and to promote
response to treatment. Residual axonal loss should be
evaluated in patients with critical illness polyneuropathy and
persistent physical impairment and fatigue. Altered muscle
regeneration should be examined in patients with critical
illness myopathy and persistent physical impairment and
fatigue. These collaborative efforts may lead to promising
novel treatments such as mesenchymal cell therapy [
Perhaps most importantly, effective interventions must
be developed, tested, and implemented, at various levels,
to improve patients’ and caregivers’ abilities to cope with
critical illness and its sequelae (prevent tissue
impairment, rehabilitate activity limitations, compensate
limitations, or adapt with reduction in quality of life). Some
evidence exists that rehabilitation should start early
during critical illness, but modalities of rehabilitation
remain to be tested and clarified. Although additional
studies are needed to reconcile uncertainties about early
physical and occupational therapy, addressing the
detrimental effects of immobilization and sedation is urgent
as they are already known to impair physical and
cognitive status. Whether weaning strategies should be
tailored based on respiratory muscle monitoring prior to
extubation requires further evaluation. More research is
needed to further document the (non)recovery of the
neuro-endocrine alterations that occur during critical
illness and on how these correlate with/affect the legacy
of an ICU stay.
Future perspectives and research agenda
In the near future, we are committed to sharing practical
strategies to increase the rigor, efficiency, and impact of
individual observational studies and randomized trials.
We are also committed to ensuring that key training and
relevant practical experiences for junior investigators,
clinical researchers, and scientists from diverse
disciplines are encouraged to help build more and better
multicenter and multinational collaboration. In future
studies, proper use of statistical methods will be required
(i.e., informative censoring, the competing risk and
time-dependent nature of covariates, such as the
occurrence of infection or delirium). Moreover, publicly
disclosing adjustment models with the coefficients and the
variables used will help reconcile apparent paradoxes in
the literature. Lastly, access to data from large
prospective studies for secondary analysis, single patient
metaanalysis, etc. may also provide additional evidence to
guide practices at the bedside. Long-term chronic pain,
addiction, and dependencies need to be studied in ICU
survivors using valid tools that help us understand
predictors of ICU-related opioid dependency, and the
complex relationship between post-ICU chronic pain
and opioid use and dependency. Moreover, multimodal
analgesic interventions to avoid ICU opioid dependency
and empirically validated psycho-social protocols to
address opioid use disorders are much needed. Also,
because delirium has a longer-term impact on mortality
and cognitive function, and because drug therapy alone
will likely be insufficient to prevent or treat it fully,
priority should be given to testing on a large scale the
clinical impact of the ABCDEF bundle and the ICU
Liberation Initiative, as well as how the overall
management of the human body affects that of the brain [
Systematic post-ICU follow-up may assist patients and
family caregivers with their perspective of recovery. They
need to know what to expect, so as to understand the path
to recovery, to acknowledge uncertainties, and to be
equipped to adjust to the later sequelae. More research is
needed to help determine what interventions can usefully
be implemented in ICU follow-up clinics and the
appropriate physical intervention programs. Furthermore,
patients’ and family members’ experiences should be used to
guide effective interventions to provide the best comfort
and holistic care, to better address the needs of patients
and their families, and improve our ability to alleviate the
post-ICU burden for surviving patients and their loves
ones, as well as the grief symptoms of bereaved family
members. Finally, elements of palliative care need to be
integrated early into the care of the sickest critically ill
patients, whatever the goals of care, with the sole aim of
improving the ICU experience for those who are dying
and for those who will face the challenging period of
postICU recovery. ICU clinicians should be trained in
structured communication approaches, multidisciplinary
interventions to increase the emphasis on patient values for
supporting preference-sensitive decisions in the face of
uncertainty, delivery of support aids such as printed
materials and diaries, and dignity-conserving care.
ARDS: Acute respiratory distress syndrome; ICU: Intensive care unit
Availability of data and materials
EA, JLV, and MH designed the review framework and coordinated and
drafted the manuscript. DCA, YMA, LB, SJB, GC, DJC, JRC, CCDS, EWE, JH, SH,
NH, ROH, TJI, SJ, NL, SM, DMN, JN, KP, MQ, KR, GR, GVDB, JVDH, and HW
drafted parts of the manuscript and revised/edited the manuscript.
All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1Medical Intensive Care Unit, Hôpital Saint-Louis, ECSTRA team, Biostatistics
and clinical epidemiology, UMR 1153 (Center of Epidemiology and
Biostatistics Sorbonne Paris Cité, CRESS), INSERM, Paris Diderot Sorbonne
University, Paris, France. 2Erasme Hospital, Université libre de Bruxelles,
Brussels, Belgium. 3The University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA. 4King Abdullah International Medical Research Center,
King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
5St. Michael’s Hospital, Toronto, ON, Canada. 6Department of Surgery and
Cancer Imperial College, London, UK. 7Università Milano Bicocca, Milano, Italy.
8McMaster University Medical Center, Hamilton, ON, Canada. 9Cambia
Palliative Care Center of Excellence, Seattle, WA, USA. 10Toronto General
Research Institute, University of Toronto, Toronto, ON, Canada. 11Vanderbilt
University School of Medicine, and TN Valley Veteran’s Affairs Geriatric
Research Education Clinical Center (GRECC), Nashville, TN, USA. 12The
University of Chicago, Chicago, IL, USA. 13Perelman School of Medicine,
Philadelphia, PA, USA. 14St Thomas Hospital, London, UK. 15Intermountain
Medical Center, Murray, UT, USA. 16Psychology Department and
Neuroscience Center, Brigham Young University, Provo, UT, USA. 17University
of Michigan Health System, and Ann Arbor Veterans Affairs Healthcare
System, Ann Arbor, MI, USA. 18Saint-Eloi Hospital, Montpellier, France.
19University of Brescia at Spedali Civili, Brescia, Italy. 20Mount Sinai Hospital,
Toronto, ON, Canada. 21Johns Hopkins University School of Medicine,
Baltimore, MD, USA. 22Memorial Sloan Kettering Cancer Center, and Weill
Cornell Medical College New York, New York, NY, USA. 23University of
California, San Francisco, CA, USA. 24University Hospital Göttingen, Göttingen,
Germany. 25Intensive Care National Audit & Research Centre, London, UK.
26Sunnybrook Health Sciences Centre, Toronto, ON, Canada. 27University
Hospital Leuven, Leuven, Belgium. 28Radboud University Nijmegen Medical
Centre, Nijmegen, Netherlands. 29Toronto General Research Institute,
University of Toronto, UHN - University Health Network, Toronto, ON,
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