Next Article in Journal
Patient Perspectives After Trapeziectomy Versus Carpometacarpal Prosthesis: A Qualitative Thematic Analysis of Ten Bilateral Cases
Previous Article in Journal
Robotic Pancreaticoduodenectomy: Current Evidence and Future Perspectives
Previous Article in Special Issue
Role of Extracellular Vesicles as Mediators of Cell Communication and Novel Biomarkers in Sepsis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 14
Issue 23
10.3390/jcm14238374
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

From Resuscitation to Rehabilitation: The Post-Intensive Care Syndrome Continuum in Sepsis Care

by
Matthew Sherman
1,*,
Perry Lim
2,
Tariq Cheema
3,
Briana DiSilvio
3 and
Perry Tiberio
3
1
Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA 15212, USA
2
Drexel University College of Medicine, Philadelphia, PA 19104, USA
3
Division of Pulmonary and Critical Care, Allegheny Health Network, Pittsburgh, PA 15212, USA
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(23), 8374; https://doi.org/10.3390/jcm14238374
Submission received: 30 August 2025 / Revised: 2 November 2025 / Accepted: 20 November 2025 / Published: 26 November 2025
(This article belongs to the Special Issue New Diagnostic and Therapeutic Trends in Sepsis and Septic Shock)
Browse Figures
Versions Notes

Abstract

Sepsis and septic shock affect nearly 49 million people worldwide each year. Although advances in early recognition and evidence-based management have improved survival, many patients experience long-term cognitive, physical, and psychological impairments collectively known as post-intensive care syndrome (PICS). These sequelae often extend to families and caregivers (PICS-F), resulting in lasting declines in quality of life. Recovery from sepsis represents a continuum that begins during intensive care and extends into survivorship. Decisions regarding analgesia, sedation, delirium prevention, mobilization, and family engagement shape this recovery trajectory. The ABCDEF bundle provides an evidence-based framework to mitigate these long-term effects through structured approaches to pain control, paired awakening and breathing trials, targeted sedation, early mobility, and family involvement. This narrative review synthesizes current evidence on PICS in sepsis and septic shock and examines how implementation of the ABCDEF bundle across the continuum of care can reduce the incidence and severity of post-ICU impairments. Reframing sepsis survivorship as an ongoing process rather than an endpoint underscores the need for critical care practices that promote not only survival but also restoration of function, cognition, and quality of life.

1. Introduction

Sepsis, a condition characterized by a profound and dysregulated systemic response to infection, affects nearly 40% of patients admitted to intensive care units (ICU) [1,2,3]. Advances in early recognition and evidence-based management have led to substantial reductions in mortality over the past two decades [1,4,5,6,7]. Yet, as survival has improved, the focus of critical care has expanded beyond acute resuscitation to encompass the long-term sequelae of critical illness. Many sepsis survivors experience new or worsening cognitive, physical, and psychological impairments—collectively termed post-intensive care syndrome (PICS)—that persist long after hospital discharge [8,9,10].
Recovery from sepsis thus represents a continuum that begins during ICU care and extends into survivorship. Within this continuum, the ABCDEF (A2F) bundle—which integrates pain and sedation management, spontaneous awakening and breathing trials, delirium monitoring, early mobility, and family engagement—provides a structured framework to improve both short- and long-term outcomes. In this review, we discuss current evidence on PICS among patients with sepsis and septic shock, emphasizing how implementation of the ABCDEF bundle across the continuum of care may mitigate long-term cognitive, physical, and psychological impairments and promote meaningful recovery after sepsis.

2. Methods

A targeted narrative review using PubMed and the Cochrane Library from January 2000 to August 2025 was performed. Search terms included ‘sepsis’, ‘septic shock’, ‘post-intensive care syndrome’ and were combined with ‘cognitive’, ‘cognitive dysfunction’, ‘physical’, ‘physical dysfunction’, ‘mental health’, ‘mental disorder’, ‘anxiety’, ‘depression’, ‘post-traumatic stress disorder’, and ‘psychological’. Consensus meetings and statements and large cohort studies were prioritized. Landmark studies and significant topic-specific contributions preceding 2000 were retained as foundational background.

2.1. The Recovery Trajectory: From Resuscitation to Rehabilitation

Sepsis and septic shock affect nearly 49 million people annually with mortality ranging from 15 to 50% [11,12,13,14,15,16]. Continued efforts to improve outcomes have led to several updates to the Surviving Sepsis Campaign, most recently published in 2021 [17]. These guidelines emphasize key interventions such as appropriate volume resuscitation, early antibiotic administration, vasoactive therapy with advanced hemodynamic monitoring, and early ICU admission [17]. While these strategies have contributed to reduced mortality, patients with these syndromes continue to experience prolonged ICU stays and complex treatment regimens [2]. As advances in sepsis management have reduced mortality, there has been increased recognition of the complicated recovery experience of these patients.
Recovery from sepsis begins at the moment of resuscitation (Figure 1). Early resuscitation quality remains a critical determinant of outcomes. Delays in antibiotic initiation have consistently demonstrated stepwise increases in mortality, with each hour of delay after hypotension associated with a significant rise in mortality [18,19]. Similarly, excessive fluid resuscitation has been linked to higher rates of pulmonary edema, acute kidney injury, and prolonged mechanical ventilation, particularly in patients with cardiac or renal dysfunction [20,21,22]. Conversely, adherence to early, balanced resuscitation principles—timely antibiotics, cautious volume expansion, and hemodynamic-guided vasopressor use—has been associated with shorter ICU stays, improved organ recovery, and decreased long-term cognitive and physical impairment [17]. Each decision—from antibiotic timing and volume resuscitation to sedative choice and depth of sedation—has lasting effects on patients’ long-term recovery trajectories. Recognizing this as a longitudinal process—one in which early ICU decisions influence outcomes in the form of post-intensive care syndrome—helps reframe sepsis management as a continuum from survival to recovery.

2.2. Post-Intensive Care Syndrome (PICS)

Defined in 2010 by the Society of Critical Care Medicine, post-intensive care syndrome (PICS) encompasses new or worsening impairments in physical, cognitive, or mental health that arise following survival of a critical illness [8]. The overall prevalence of PICS in survivors of septic shock is high, and the reported prevalence depends on the study population and timing of assessment. A recent meta-analysis including more than 10,000 ICU survivors reported a PICS prevalence of 54–62% up to two years after hospital discharge [9]. In patients with septic shock, a 2025 multicenter study demonstrated that 85% met criteria for PICS at discharge, with 45% continuing to experience symptoms at one year [10]. The following sections summarize current evidence on PICS as it relates to sepsis and septic shock, focusing on prevalence, risk factors (Figure 2), underlying mechanisms, clinical manifestations, and long-term outcomes.

2.3. PICS-Cognitive Dysfunction

Sepsis and septic shock syndromes are characterized by profound neuroinflammatory responses that disrupt blood–brain barrier integrity, impair cerebral perfusion, and alter neurotransmission. These mechanisms contribute to the development of delirium and subsequent cognitive dysfunction, key components of PICS [10]. Delirium occurs in up to 70% of septic ICU patients, and retrospective studies report significant cognitive impairment in nearly 30% of survivors one year after critical illness [10,23,24]. Risk factors include older age, pre-existing neurocognitive disorders such as Alzheimer’s dementia, and prolonged exposure to sedatives, analgesics, or mechanical ventilation. The presence and duration of ICU delirium constitute the strongest predictors of long-term cognitive dysfunction [23,25]. These impairments can persist for several years, with one study showing cognitive impairment among survivors of severe sepsis for up to 8 years after acute illness [26].

2.4. PICS-Physical Impairment

Sepsis and septic shock trigger a cascade of systemic and cellular responses that contribute to profound skeletal muscle injury and physical impairment. Pro-inflammatory cytokines, microvascular dysfunction, mitochondrial injury, and catabolic hormone signaling lead to critical illness myopathy and polyneuropathy, the primary mechanisms underlying post-ICU weakness [27,28,29]. Among survivors of septic shock, physical dysfunction is reported in approximately 25–65% at one year [9,10,30]. Clinical manifestations include generalized and respiratory muscle weakness, impaired mobility, difficulty regaining muscle mass, incontinence, sexual dysfunction, fatigue, dysphagia, and sleep disturbances [31,32]. Major risk factors include older age, pre-existing frailty, multisystem organ failure, prolonged immobilization, extended duration of mechanical ventilation, hyperglycemia, corticosteroid exposure, and use of neuromuscular blockade [27,33]. Physical impairment, which has been shown to persistent in up to 90% of survivors at 3 years often coexists with psychological disorders, compounding recovery challenges [34].

2.5. PICS-Psychological Disorders

The activation of inflammatory and neuroendocrine pathways in sepsis and critical illness disrupt the hypothalamic–pituitary–adrenal axis, alter neurotransmitter balance, and dysregulate sleep–wake and stress responses [35,36]. These pathophysiologic processes may predispose survivors to a range of psychological sequelae, including depression, anxiety, and post-traumatic stress disorder (PTSD) [37]. The reported prevalence of psychological disorders following sepsis varies widely but remains consistently high across studies. Anxiety affects approximately 32–46%, depression 29–40%, and PTSD 12–44% of survivors within the first year after ICU discharge [10,38,39,40,41]. A German cohort study found that 54.8% of sepsis survivors were diagnosed with a mental health impairment (MHI) within the first year [42]. Compounding this burden is an increased risk of self-injurious behavior (aHR 1.15) and suicidality (aHR 1.22) following ICU admission [43]. Risk factors for the psychological components of PICS include younger age, pre-existing mental health conditions, sleep disturbances during hospitalization, and respiratory failure requiring mechanical ventilation [44,45]. These disorders can persist for months to years after discharge, in one study PTSD affected up to 25% of ICU survivors for as long as 8 years after discharge, leading to reduced quality of life, impaired social reintegration, and increased caregiver strain [26].

2.6. PICS-Family and Financial Impact

Often considered the fourth PICS domain, PICS-Family (PICS-F) refers to the adverse psychological, physical, and social effects experienced by family members or caregivers following a loved one’s critical illness [8,46,47]. These effects are driven by sustained stress, sleep disruption, anticipatory grief, and moral distress related to surrogate decision-making and prolonged uncertainty [46]. Common manifestations include fatigue, cognitive slowing, and poor sleep quality [48,49]. The predominant psychological sequelae mirror those seen in patients with PICS—anxiety, depression, and PTSD—affecting up to 70% of family members [48,50]. Risk is highest for spouses, those experiencing poor communication with ICU staff, those with a prior history of mental illness, and when the patient experiences severe illness or death [26]. The burden can persist for years, especially when patients survive with disability or die during their ICU stay [26].
In addition to physical and psychological effects, socioeconomic challenges—described as the “fifth domain”, PICS-Financial—further compound family burden. Up to one-third of caregivers report loss of household income [51], and those experiencing anxiety or depression demonstrate reduced work productivity and increased absenteeism [52].
Having outlined the manifestations of post-intensive-care-syndrome, the following section focuses on preventive strategies implemented during the acute and recovery phases of sepsis that shape this trajectory of recovery.

2.7. Intervention and Prevention Using the A2F Bundle

A 2013 collaborative meeting produced updated ICU Pain, Agitation, and Delirium (ICU-PAD) guidelines and ultimately laid the foundation for the subsequent development of the ABCDEF bundle in 2018 [53,54]. The ABCDEF bundle (Figure 3) provides an evidence-based guide that offers clinicians and institutions opportunities to optimize ICU patient recovery and outcomes [53]. A recent 2024 multicenter, prospective cohort study found that implementation and adherence of the ABCDEF bundle in mechanically ventilated adult ICU patients led to reduced ICU length of stay, days of mechanical ventilation, and percentage of patients requiring more than 7 days in the ICU. These outcomes all represent targetable risk factors associated with PICS [55]. The following section highlights each component of the ABCDEF bundle and its application in the critically ill, septic shock population (Table 1).

2.7.1. Assess, Prevent, and Treat Pain

Pain is a prevalent and clinically significant symptom that is often underreported or underassessed in ICU settings, particularly among sedated or mechanically ventilated patients [56]. It arises from multiple sources, including invasive catheters, underlying illness or surgery, and immobility. In communicative patients, the 1–10 numerical rating scale (NRS) is recommended for pain assessment, whereas the Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT) are preferred for non-communicative patients [54,57]. The 2013 ICU-PAD guidelines advise analgesic medication for uncontrolled pain (defined as NRS > 4, BPS > 5, or CPOT > 3) and prior to procedures [53,54,57]. Whenever feasible, non-opioid medications and non-pharmacologic strategies—such as repositioning, heat or cold application, relaxation techniques, guided mindfulness—should be employed, though opioids remain first-line for non-neuropathic pain [58].
In sepsis and septic shock, systemic inflammation and altered cytokine signaling can alter nociceptive processing and patient’s pain thresholds. Poorly controlled pain during critical illness is linked to physiologic stress response, delayed recovery, and long-term mental health consequences [59]. A 2024 meta-analysis evaluating pain and delirium in older hospitalized adults demonstrated delirium to be twice as likely to occur with pain at rest and three times more likely with severe pain [60]. Inadequately treated pain also contributes to anxiety, depression, poor sleep, and demoralization, and both patients and families identify uncontrolled pain to be some of the most distressing aspects of ICU care [61]. Therefore, pain in patients with sepsis and septic shock should be systematically assessed and promptly treated to minimize complications and promote recovery.

2.7.2. Both Spontaneous Awakening Trials (SAT) and Spontaneous Breathing Trials (SBT)

Mechanical ventilation is required in substantial proportion of patients with sepsis and septic shock, with rates ranging from 13 to 40%, with rates higher in patients with higher severity of illness [62,63]. These patients often receive continuous sedation to facilitate comfort and ventilator synchrony, which can inadvertently contribute to prolonged ventilation and delayed recovery.
Spontaneous awakening trials (SAT) involve the temporary cessation of all sedatives and analgesics to allow increased patient arousal while monitoring for evidence of uncontrolled, acute pain. Deep sedation in the first 48 h of ICU admission is associated with prolonged mechanical ventilation times, increased need for tracheostomy, and increased hospital and long-term death [64,65,66]. Conversely, SATs are associated with a 2-day reduction in days of mechanical ventilation and a 3.5-day reduction in ICU length of stay [67].
Spontaneous breathing trials (SBT) represent the reduction in ventilator support to assess patients’ ability to breathe spontaneously. SBTs are frequently implemented in ventilator weaning protocols and reduce the duration of mechanical ventilation [68,69]. When paired together, SAT and SBT improve patient outcomes. A multicenter, randomized controlled study demonstrated a 3.1-day reduction in mechanical ventilation and 3.8-day shorter ICU stay among patients receiving paired SAT and SBT compared to SBT alone [70].
Although data specific to patients with sepsis and septic shock are limited, early coordination of SAT and SBT in this population should be prioritized once hemodynamic stability is achieved. Implementing these protocols can shorten duration of ventilation, decreased ICU length of stay, and potentially mitigate the long-term sequelae of PICS.

2.7.3. Choice of Analgesia and Sedation

Psychoactive medications are frequently required in the ICU, yet excessive sedation remains a major barrier to extubation and an independent risk factor for delirium. Reliable assessment tools are essential to target light sedation, balancing comfort with alertness. The Richmond-Agitation Sedation Scale (RASS), a 10-level numerical scale, has demonstrated high interrater reliability across many ICU settings. In a retrospective study of patients with sepsis, lower RASS scores—reflecting deeper sedation—were independently associated with worse prognosis and highly mortality [71]. The Riker Sedation-Agitation Scale serves as another validated alternative [72]. Sedation depth should be individualized, with frequent reassessment to maintain ligh sedation targets (RASS 0 to −1) whenever clinically feasible.
Once appropriate monitoring is in place, the next priority is selecting sedative and analgesic agents that minimize adverse cognitive outcomes. Commonly used medications include propofol, dexmedetomidine, midazolam, lorazepam, fentanyl, hydromorphone, morphine, and ketamine [73]. In septic patients, early studies comparing dexmedetomidine with benzodiazepine-based sedation demonstrated significantly lower rates of delirium and coma, with favorable trends toward shorter ventilation duration and improved 28-day survival [74]. These findings reinforced the association between benzodiazepine exposure and increased risk of delirium [75,76]. More recently, a study comparing dexmedetomidine and propofol reported similar outcomes in delirium, ventilator-free days, mortality, and long-term cognitive impairment [77].
For patients with sepsis and septic shock requiring mechanical ventilation, sedation should be carefully titrated to the lightest effective level. Preference for non-benzodiazepine agents—such as propofol or dexmedetomidine—offers the potential to reduce delirium incidence, shorten ventilation duration, and improve long-term cognitive impairment associated with PICS.

2.7.4. Delirium: Assess, Prevent, and Manage

Delirium is a major concern in the ICU and is a strong predictor of prolonged cognitive dysfunction following critical illness. It occurs in approximately 50–75% of mechanically ventilated patients [58] and ranges from 24 to 76% in patients with sepsis and septic shock in the ICU [78,79]. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) remains the most widely validated tool for identifying delirium and is based on four core features: acute change in mental status, inattention, altered level of consciousness, and disorganized thinking. A positive CAM-ICU requires both acute altered mentation and inattention with either altered level of consciousness or disorganized thinking and has a 95.9% specificity for delirium. When combined with the RASS, the CAM-ICU may be used to identify subtypes of delirium [80,81,82]. Hyperactive delirium (CAM-ICU positive, RASS ≥ 1) is characterized by agitation, restlessness and emotional lability [80], whereas hypoactive delirium (CAM-ICU positive, RASS ≤ 0) presents as withdrawal and decreased arousal. The latter is more common in the critically ill and was accounted for 89% of delirious patients in the 2018 MIND-USA trial [70,82]; though less frequent, hyperactive delirium, is associated with a more favorable prognosis [80].
Prevention of delirium in septic patients requires both optimal sepsis resuscitation and mitigation of delirium-provoking factors such as uncontrolled pain, oversedation, and sleep disruption [10,25,83]. Effective management emphasizes proactive prevention through light sedation, avoidance of anticholinergic and deliriogenic medications, promotion of normal sleep–wake cycles, and early mobilization. While antipsychotics have historically been used for treatment, evidence does not support routine pharmacologic therapy. The MIND-USA study found no difference in delirium duration between haloperidol, ziprasidone, and placebo [84], and the AID-ICU trial similarly demonstrated no improvement in mortality, delirium duration, or days alive and out of the hospital with haloperidol use [85]. Quetiapine has shown modest benefit in hyperactive delirium, with reduced delirium severity, shorter ICU stays, and improved sleep quality compared to haloperidol, thought without a demonstrated survival benefit [86]. Beyond its sedative role, dexmedetomidine has also shown potential therapeutic benefit in the management of established ICU delirium, shortening delirium duration and increasing ventilator-free days compared to haloperidol or placebo, albeit at the cost of increased rates of bradycardia [87].
Therefore, in patients with sepsis and septic shock, daily delirium screening with validated tools such as the CAM-ICU, combined with proactive prevention—including light sedation, sleep preservation, and early mobilization—should be standard practice to reduce delirium-related morbidity and long-term cognitive impairment.

2.7.5. Early Mobility and Exercise

Early critical care practices traditionally emphasized deep sedation and immobilization [69]. Over time, mounting evidence has shown that prolonged immobility contributes to loss of lean muscle mass, longer hospitalizations, and persistent functional decline that can last up to five years after discharge [88,89,90]. The inflammatory and catabolic state of sepsis and septic shock further accelerates muscle breakdown, amplifying the risk of ICU-acquired weakness and subsequent physical impairment [29].
Understandably, clinicians may hesitate to pursue early physical therapy and ambulation in patients receiving invasive therapies such as mechanical ventilation, continuous renal replacement therapy, and extracorporeal oxygenation. However, evidence supports the feasibility of collaborative mobilization efforts in these complex patients [91,92]. Early initiation of physical rehabilitation—particularly within the first three days of ICU admission—was associated with improved survival, shorter duration of delirium, and greater likelihood of regaining functional independence at discharge [93,94]. In sepsis-specific cohorts, early mobilization (within 3 days) significantly reduced ICU-acquired weakness at hospital discharge [95]
Despite these proven benefits, establishing a sustainable ICU rehabilitation program remains challenging, requiring engaged multidisciplinary champions, adequate staffing, and institutional support [96]. Nevertheless, integrating early mobility into sepsis care provides a critical opportunity to mitigate ICU-acquired weakness, preserve cognition, and reduce the physical sequelae of post-intensive-care syndrome. Accordingly, in patients with sepsis and septic shock, early and progressive mobilization should be prioritized to improve functional outcomes and reduce long-term disability.

2.7.6. Family Engagement and Empowerment

In patients with sepsis and septic shock, the acute and unpredictable course of illness places tremendous emotional and decisional strain on families, making structured engagement a vital component of comprehensive care. The impact of critical illness can be as profound for families as for patients themselves. ICU-related factors to PICS-F include poor communication, limited visiting hours, and lack of participation in decision-making [97,98]. A 2018 trial demonstrated that a multicomponent family support intervention—including prescheduled nurse-meetings—improved communication, enhanced understanding of the patient’s condition, and reduced ICU length of stay [99,100]. Similarly, ICU diaries have been shown to help families process the patient’s trajectory, foster emotional recovery, and improve post-discharge adjustment [101].
Ineffective or unclear communication, particularly around prognosis and treatment decisions, is strongly associated with higher family anxiety and depression [102,103]. In contrast, proactive engagement fosters shared understanding, supports value-concordant care, and mitigates caregiver distress. The 2024 Society of Critical Care Medicine (SCCM) Family Guidelines recommend including families on daily rounds and liberalizing visitation policies to enhance involvement and transparency [104].
In summary, family engagement and empowerment should be integral to sepsis and septic shock management. Actively involving families in communication, decision-making, and care planning supports emotional recovery and aligns with evidence linking comprehensive ABCDEF bundle use to improved short- and long-term outcomes [105].

2.8. Rehabilitation and Future Directions

Post-Intensive Care Syndrome Recovery Clinics (PICS-RC), first established in 2012, were modeled after the post-critical care clinics pioneered in the United Kingdom [106,107]. These multidisciplinary programs typically integrate physicians, nurses, pharmacists, behavioral health specialists, and physical or occupational therapists to address the complex constellation of cognitive, physical, and psychological impairments affecting ICU survivors and their families [107].
Recognizing the high prevalence and multidimensional burden of PICS, the Society of Critical Care Medicine (SCCM) recommends that patients at elevated risk be screened for post-ICU impairments within 2–4 weeks after discharge and, when feasible, be referred for follow-up in a PICS-RC clinic within 6–12 weeks [108,109]. The 2021 Surviving Sepsis Guidelines further support this approach, advocating that all survivors of sepsis and septic shock undergo comprehensive evaluation of physical, cognitive, and psychological domains following hospitalization [17].
During PICS-RC visits, standardized assessments such as the Montreal Cognitive Assessment (MOCA), Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale-Revised (IES-R), and a 6 min walk test are commonly employed to quantify deficits and guide individualized rehabilitation plans [108,109]. Early identification of impairment allows for timely interventions, potentially reducing long-term disability and caregiver burden.
Evidence supporting PICS-RC remains mixed. A randomized pilot study of an ICU recovery program suggested a longer time to hospital readmission compared to usual care, thought it was underpowered for clinical endpoints [110]. A larger pragmatic RCT using a coordinator-led mobile, nurse-led recovery program in survivors of respiratory failure did not show significant improvement in 12-month outcomes, including QOL and mortality [111]. Observational cohorts consistently report high rates of detecting cognitive, psychological, and functional impairments with frequent modifications to treatment plans at follow-up, thus supporting the role of clinics in coordinating rehabilitation [112]. While PICS-RCs are feasible and can improve processes of care, the quality of evidence for improvement in mortality, readmissions, or health-related QOL remains low due to heterogeneity in study methods and small study sizes—underscoring the need for larger, multicenter trials.
Ongoing research dedicated to PICS will be critical to improving outcomes for patients with sepsis and septic shock. Leveraging large-scale electronic health record data through networks such as the Critical and Acute Illness Recovery Organization (CAIRO) may enable development of predictive models to identify sepsis survivors most vulnerable to PICS—facilitating early intervention, personalized post-ICU care pathways, and more efficient resource allocation. In parallel, optimizing analgesic and sedative strategies remains central to preventing delirium—a key mediator of long-term cognitive dysfunction. Emerging data suggest that dexmedetomidine, increasingly utilized in septic shock, may confer benefits beyond sedation, including reduced vasopressor requirements and potential survival advantages [113,114]. Clarifying its mechanistic effects on catecholamine responsiveness, neuroinflammation, and brain recovery represents an essential next step in understanding how early ICU management influences long-term survivorship outcomes.
Looking ahead, research should prioritize not only the pathophysiologic mechanisms of PICS but also implementation strategies to enhance adherence to the ABCDEF bundle and strengthen post-ICU follow-up care. Large-scale multicenter initiatives, such as SCCM’s ICU Liberation Collaborative, demonstrate that sustained compliance requires institutional investment, workflow integration, and multidisciplinary engagement. Moreover, health systems research is needed to examine how disparities in socioeconomic status, health literacy, and access to rehabilitation influence PICS outcomes. Incorporating telehealth-based follow-up and digital monitoring tools into PICS recovery models may extend the reach of care to underserved populations.

3. Conclusions

Advances in early recognition and aggressive resuscitation have markedly improved survival among patients with sepsis and septic shock. Yet this success has introduced a new imperative: addressing the growing burden of post-treatment complications. As the prevalence and impact of post-intensive care syndrome (PICS) become increasingly recognized, the focus of critical care must extend beyond immediate survival toward optimizing recovery and long-term function.
Framing sepsis survivorship as a continuum—from acute resuscitation through long-term rehabilitation—underscores that the quality of recovery is determined by decisions made early in critical illness. The ABCDEF bundle provides a practical framework to bridge this continuum, reducing the incidence and severity of PICS while promoting meaningful recovery.
Ultimately, sepsis and septic shock should be viewed not only as acute medical emergencies but as sentinel events for enduring physical, cognitive, and psychological sequelae. By integrating early rehabilitation, structured follow-up through PICS recovery clinics, and ongoing support for patients and families, critical care professionals can redefine success in sepsis—not merely by survival, but by restoration of function and life participation.

Author Contributions

M.S. served as the primary author of this manuscript with editorial support provided by P.L., P.T., B.D. and T.C. Diagrams and figures were developed by M.S., P.T. and P.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

An international review board statement and informed consent were not obtained given the narrative review nature of this manuscript.

Data Availability Statement

All data can be found through literature search utilizing the methods detailed in the methods section of this manuscript. There are no potential conflicts of interest to disclose.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.-D.; Coopersmith, C.M.; et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315, 801–810. [Google Scholar] [CrossRef]
  2. Sakr, Y.; Jaschinski, U.; Wittebole, X.; Szakmany, T.; Lipman, J.; Ñamendys-Silva, S.A.; Hernandez, G.; Leone, M.; Bauer, M.; Vincent, J.L. Sepsis in Intensive Care Unit Patients: Worldwide Data from the Intensive Care over Nations Audit. Open Forum Infect. Dis. 2018, 5, 313. [Google Scholar] [CrossRef] [PubMed]
  3. Vincent, J.L.; Sakr, Y.; Sprung, C.L.; Ranieri, V.M.; Reinhart, K.; Gerlach, H.; Moreno, R.; Carlet, J.; Le Gall, J.R.; Payen, D.; et al. Sepsis in European intensive care units: Results of the SOAP study. Crit. Care Med. 2006, 34, 344–353. [Google Scholar] [CrossRef] [PubMed]
  4. Kaukonen, K.M.; Bailey, M.; Suzuki, S.; Pilcher, D.; Bellomo, R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 2014, 311, 1308–1316. [Google Scholar] [CrossRef] [PubMed]
  5. Afshar, M.; Arain, E.; Ye, C.; Emily, G.; Xie, M.; Lee, J.; Churpek, M.M.; Durazo-Arvizu, R.; Markossian, T.; Joyce, C. Patient Outcomes and Cost-Effectiveness of a Sepsis Care Quality Improvement Program in a Health System. Crit. Care Med. 2019, 47, 1371–1379. [Google Scholar] [CrossRef]
  6. Bone, R.C.; Balk, R.A.; Cerra, F.B.; Dellinger, R.P.; Fein, A.M.; Knaus, W.A.; Schein, R.M.; Sibbald, W.J. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992, 101, 1644–1655. [Google Scholar] [CrossRef]
  7. Levy, M.M.; Fink, M.P.; Marshall, J.C.; Abraham, E.; Angus, D.; Cook, D.; Cohen, J.; Opal, S.M.; Vincent, J.L.; Ramsay, G.; et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003, 29, 530–538. [Google Scholar] [CrossRef]
  8. Needham, D.M.; Davidson, J.; Cohen, H.; Hopkins, R.O.; Weinert, C.; Wunsch, H.; Zawistowski, C.; Bemis-Dougherty, A.; Berney, S.C.; Bienvenu, O.J.; et al. Improving long-term outcomes after discharge from intensive care unit: Report from a stakeholders’ conference. Crit. Care Med. 2012, 40, 502–509. [Google Scholar] [CrossRef]
  9. Ayenew, T.; Gete, M.; Gedfew, M.; Getie, A.; Afenigus, A.D.; Edmealem, A.; Amha, H.; Alem, G.; Tiruneh, B.G.; Messelu, M.A.; et al. Prevalence of Post-intensive care syndrome among intensive care unit-survivors and its association with intensive care unit length of stay: Systematic review and meta-analysis. PLoS ONE 2025, 20, e0323311. [Google Scholar] [CrossRef]
  10. Liu, K.; Watanabe, S.; Nakamura, K.; Nakano, H.; Motoki, M.; Kamijo, H.; Ayaka, M.; Ishii, K.; Morita, Y.; Hongo, T.; et al. One-year outcomes in sepsis: A prospective multicenter cohort study in Japan. J. Intensive Care 2025, 13, 23. [Google Scholar] [CrossRef]
  11. Rudd, K.E.; Johnson, S.C.; Kristina, E.; Shackelford, K.A.; Tsoi, D.; Kievlan, D.R.; Colombara, D.V.; Ikuta, K.S.; Kissoon, N.; Finfer, S.; et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study. Lancet 2020, 395, 200–211. [Google Scholar] [CrossRef]
  12. La Via, L.; Sangiorgio, G.; Stefani, S.; Marino, A.; Nunnari, G.; Cocuzza, S.; La Mantia, I.; Cacopardo, B.; Stracquadanio, S.; Spampinato, S.; et al. The Global Burden of Sepsis and Septic Shock. Epidemiologia 2024, 5, 456–478. [Google Scholar] [CrossRef]
  13. Liu, V.; Escobar, G.J.; Greene, J.D.; Soule, J.; Whippy, A.; Angus, D.C.; Iwashyna, T.J. Hospital Deaths in Patients with Sepsis From 2 Independent Cohorts. JAMA 2014, 312, 90–92. [Google Scholar] [CrossRef] [PubMed]
  14. Shankar-Hari, M.; Harrison, D.A.; Rowan, K.M. Differences in Impact of Definitional Elements on Mortality Precludes International Comparisons of Sepsis Epidemiology—A Cohort Study Illustrating the Need for Standardized Reporting. Crit. Care Med. 2016, 44, 2223–2230. [Google Scholar] [CrossRef] [PubMed]
  15. Machado, F.R.; Cavalcanti, A.B.; Bozza, F.A.; Ferreira, E.M.; Carrara, F.S.A.; Sousa, J.L.; Caixeta, N.; Salomao, R.; Angus, D.C.; Azevedo, L.C.P.; et al. The epidemiology of sepsis in Brazilian intensive care units (the Sepsis PREvalence Assessment Database, SPREAD): An observational study. Lancet Infect. Dis. 2017, 17, 1180–1189. [Google Scholar] [CrossRef] [PubMed]
  16. Divatia, J.V.; Amin, P.R.; Ramakrishnan, N.; Kapadia, F.N.; Todi, S.; Sahu, S.; Govil, D.; Chawla, R.; Kulkarni, A.P.; Samavedam, S.; et al. Intensive Care in India: The Indian Intensive Care Case Mix and Practice Patterns Study. Indian J. Crit. Care Med. 2016, 20, 216–225. [Google Scholar] [CrossRef]
  17. Evans, L.; Rhodes, A.; Alhazzani, W.; Antonelli, M.; Coopersmith, C.M.; French, C.; Machado, F.R.; Mcintyre, L.; Ostermann, M.; Prescott, H.C.; et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021, 47, 1181–1247. [Google Scholar] [CrossRef]
  18. Kumar, A.; Roberts, D.; Wood, K.E.; Light, B.; Parrillo, J.E.; Sharma, S.; Suppes, R.; Feinstein, D.; Zanotti, S.; Taiberg, L.; et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 2006, 34, 1589–1596. [Google Scholar] [CrossRef]
  19. Andersson, M.; Östholm-Balkhed, Å.; Fredrikson, M.; Holmbom, M.; Hällgren, A.; Berg, S.; Hanberger, H. Delay of appropriate antibiotic treatment is associated with high mortality in patients with community-onset sepsis in a Swedish setting. Eur. J. Clin. Microbiol. Infect. Dis. 2019, 38, 1223–1234. [Google Scholar] [CrossRef]
  20. Messmer, A.S.; Zingg, C.; Müller, M.; Gerber, J.L.; Schefold, J.C.; Pfortmueller, C.A. Fluid Overload and Mortality in Adult Critical Care Patients—A Systematic Review and Meta-Analysis of Observational Studies. Crit. Care Med. 2020, 48, 1862–1870. [Google Scholar] [CrossRef]
  21. Schrier, R.W. Fluid administration in critically ill patients with acute kidney injury. Clin. J. Am. Soc. Nephrol. 2010, 5, 733–739. [Google Scholar] [CrossRef] [PubMed]
  22. Zampieri, F.G.; Bagshaw, S.M.; Semler, M.W. Fluid Therapy for Critically Ill Adults with Sepsis: A Review. JAMA 2023, 329, 1967–1980. [Google Scholar] [CrossRef] [PubMed]
  23. Ehlenbach, W.J.; Hough, C.L.; Crane, P.K.; Haneuse, S.J.P.A.; Carson, S.S.; Curtis, J.R.; Larson, E.B. Association Between Acute Care and Critical Illness Hospitalization and Cognitive Function in Older Adults. JAMA 2010, 303, 763–770. [Google Scholar] [CrossRef] [PubMed]
  24. Jesus Pereira, I.; Santos, M.; Sganzerla, D.; Robinson, C.C.; Souza, D.d.; Kochhann, R.; Falavigna, M.; Azevedo, L.; Bozza, F.; Sharshar, T.; et al. Long term cognitive dysfunction among critical care survivors: Associated factors and quality of life—A multicenter cohort study. Ann. Intensive Care 2024, 14, 116. [Google Scholar] [CrossRef]
  25. Tasker, R.C.; Menon, D.K. Critical Care and the Brain. JAMA 2016, 315, 749–750. [Google Scholar] [CrossRef]
  26. Herridge, M.S.; Azoulay, É. Outcomes after Critical Illness. N. Engl. J. Med. 2023, 388, 913–924. [Google Scholar] [CrossRef]
  27. Kress, J.P.; Hall, J.B. ICU-Acquired Weakness and Recovery from Critical Illness. N. Engl. J. Med. 2014, 370, 1626–1635. [Google Scholar] [CrossRef]
  28. Rocheteau, P.; Chatre, L.; Briand, D.; Mebarki, M.; Jouvion, G.; Bardon, J.; Crochemore, C.; Serrani, P.; Lecci, P.P.; Latil, M.; et al. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat. Commun. 2015, 6, 10145. [Google Scholar] [CrossRef]
  29. Callahan, L.A.; Supinski, G.S. Sepsis-induced myopathy. Crit. Care Med. 2009, 37 (Suppl. S10), S354–S367. [Google Scholar] [CrossRef]
  30. Beumeler, L.F.E.; van Wieren, A.; Buter, H.; van Zutphen, T.; Bruins, N.A.; de Jager, C.M.; Koopmans, M.; Navis, G.J.; Boerma, E.C. Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: A retrospective single-centre study. PLoS ONE 2020, 15, e0243981. [Google Scholar] [CrossRef]
  31. Gupta, L.; Subair, M.N.; Munjal, J.; Singh, B.; Bansal, V.; Gupta, V.; Jain, R. Beyond survival: Understanding post-intensive care syndrome. Acute Crit. Care 2024, 39, 226–233. [Google Scholar] [CrossRef]
  32. Altman, M.T.; Knauert, M.P.; Pisani, M.A. Sleep Disturbance After hospitalization and critical illness: A systematic review. Ann. Am. Thorac. Soc. 2017, 14, 1457–1468. [Google Scholar] [CrossRef]
  33. De Jonghe, B.; Lacherade, J.C.; Sharshar, T.; Outin, H. Intensive care unit-acquired weakness: Risk factors and prevention. Crit. Care Med. 2009, 37 (Suppl. S10), S309–S315. [Google Scholar] [CrossRef] [PubMed]
  34. Fleischmann-Struzek, C.; Born, S.; Kesselmeier, M.; Ely, E.W.; Töpfer, K.; Romeike, H.; Bauer, M.; Bercker, S.; Bodechtel, U.; Fiedler, S.; et al. Functional dependence following intensive care unit-treated sepsis: Three-year follow-up results from the prospective Mid-German Sepsis Cohort (MSC). Lancet Reg. Health Eur. 2024, 46, 101066. [Google Scholar] [CrossRef] [PubMed]
  35. Da Costa, L.H.A.; Santos-Junior, N.N.; Catalão, C.H.R.; Rocha, M.J.A. Microglial Activation Modulates Neuroendocrine Secretion During Experimental Sepsis. Mol. Neurobiol. 2021, 58, 2133–2144. [Google Scholar] [CrossRef] [PubMed]
  36. Kanczkowski, W.; Sue, M.; Zacharowski, K.; Reincke, M.; Bornstein, S.R. The role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis. Mol. Cell. Endocrinol. 2015, 408, 241–248. [Google Scholar] [CrossRef]
  37. Van den Berghe, G.; Téblick, A.; Langouche, L.; Gunst, J. The hypothalamus-pituitary-adrenal axis in sepsis- and hyperinflammation-induced critical illness: Gaps in current knowledge and future translational research directions. EBioMedicine 2022, 84, 104284. [Google Scholar] [CrossRef]
  38. Prescott, H.C.; Angus, D.C. Enhancing Recovery from Sepsis: A Review. JAMA 2018, 319, 62–75. [Google Scholar] [CrossRef]
  39. Schwitzer, E.; Jensen, K.S.; Brinkman, L.; DeFrancia, L.; VanVleet, J.; Baqi, E.; Aysola, R.; Qadir, N. Survival ≠ Recovery. A Narrative Review of Post-Intensive Care Syndrome. CHEST Crit. Care 2023, 1, 100003. [Google Scholar] [CrossRef]
  40. Hatch, R.; Young, D.; Barber, V.; Griffiths, J.; Harrison, D.A.; Watkinson, P. Anxiety, depression, and post-traumatic stress disorder after critical illness: A UK-wide prospective cohort study. Crit. Care 2018, 22, 310. [Google Scholar] [CrossRef]
  41. Mikkelsen, M.E.; Christie, J.D.; Lanken, P.N.; Biester, R.C.; Thompson, B.T.; Bellamy, S.L.; Localio, A.R.; Demissie, E.; Hopkins, R.O.; Angus, D.C.; et al. The adult respiratory distress syndrome cognitive outcomes study: Long-term neuropsychological function in survivors of acute lung injury. Am. J. Respir. Crit. Care Med. 2012, 185, 1307–1315. [Google Scholar] [CrossRef] [PubMed]
  42. Sell, S.; Fleischmann-Struzek, C.; Spoden, M.; Rosendahl, J. Mental health in the first year after ICU-treated sepsis: Analysis of administrative diagnoses in German health claims data. Gen. Hosp. Psychiatry 2025, 93, 109–115. [Google Scholar] [CrossRef] [PubMed]
  43. Fernando, S.M.; Qureshi, D.; Sood, M.M.; Pugliese, M.; Talarico, R.; Myran, D.T.; Herridge, M.S.; Needham, D.M.; Rochwerg, B.; Cook, D.J.; et al. Suicide and self-harm in adult survivors of critical illness: Population-based cohort study. BMJ 2021, 373, n973. [Google Scholar] [CrossRef] [PubMed]
  44. Hopkins, R.O.; Key, C.W.; Suchyta, M.R.; Weaver, L.K.; Orme, J.F., Jr. Risk factors for depression and anxiety in survivors of acute respiratory distress syndrome. Gen. Hosp. Psychiatry 2010, 32, 147–155. [Google Scholar] [CrossRef]
  45. Al-Abri, M.A. Sleep deprivation and depression: A bi-directional association. Sultan Qaboos Univ. Med. J. 2015, 15, e4–e6. [Google Scholar] [CrossRef]
  46. Davidson, J.E.; Jones, C.; Bienvenu, O.J. Family response to critical illness: Postintensive care syndrome-family. Crit. Care Med. 2012, 40, 618–624. [Google Scholar] [CrossRef]
  47. Petrinec, A.B.; Martin, B.R. Post-intensive care syndrome symptoms and health related quality of life in family decision makers of critically ill patients. Palliat. Support. Care 2018, 16, 719–724. [Google Scholar] [CrossRef]
  48. Choi, J.; Tate, J.A.; Donahoe, M.P.; Ren, D.; Hoffman, L.A.; Chasens, E.R. Sleep in family caregivers of ICU survivors for two months post-ICU discharge. Intensive Crit. Care Nurs. 2016, 37, 11–18. [Google Scholar] [CrossRef]
  49. Shirasaki, K.; Hifumi, T.; Isokawa, S.; Hashiuchi, S.; Tanaka, S.; Yanagisawa, Y.; Takahashi, O.; Otani, N. Postintensive Care Syndrome-Family Assoiiated with COVID-19 Infection. Crit. Care Explor. 2022, 4, e0725. [Google Scholar]
  50. Pochard, F.; Azoulay, E.; Chevret, S.; Lemaire, F.; Hubert, P.; Canoui, P.; Grassin, M.; Zittoun, R.; le Gall, J.R.; Dhainaut, J.F.; et al. Symptoms of anxiety and depression in family members of intensive care unit patients: Ethical hypothesis regarding decision making capacity. Crit. Care Med. 2001, 29, 1893–1897. [Google Scholar] [CrossRef]
  51. Griffiths, J.; Hatch, R.A.; Bishop, J.; Morgan, K.; Jenkinson, C.; Cuthbertson, B.H.; Brett, S.J. An exploration of social and economic outcome and asscoiated health-related quality of life after critical illness in general intensive care unit survivors: A 12-month follow-up study. Crit. Care 2013, 17, R100. [Google Scholar] [CrossRef]
  52. De Oliveria, C.; Saka, M.; Bone, L.; Jacobs, R. The Role of Mental Health on Workplace Productivity: A critical review of the literature. Appl. Health Econ. Health Policy 2023, 21, 167–193. [Google Scholar] [CrossRef]
  53. Marra, A.; Ely, E.W.; Pandharipande, P.P.; Patel, M.B. The ABCDEF Bundle in Critical Care. Crit. Care Clin. 2017, 33, 225–243. [Google Scholar] [CrossRef]
  54. Barr, J.; Fraser, G.L.; Puntillo, K.; Ely, E.W.; Gélinas, C.; Dasta, J.F.; Davidson, J.E.; Devlin, J.W.; Kress, J.P.; Joffe, A.M.; et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit. Care Med. 2013, 41, 263–306. [Google Scholar] [CrossRef]
  55. Barr, J.; Downs, B.; Ferrell, K.; Talebian, M.; Robinson, S.; Kolodisner, L.; Kendall, H.; Holdych, J. Improving Outcomes in Mechanically Ventilated Adult ICU Patients Following Implementation of the ICU Liberation (ABCDEF) Bundle Across a Large Healthcare System. Crit. Care Explor. 2024, 6, e1001. [Google Scholar] [CrossRef] [PubMed]
  56. Payen, J.F.; Chanques, G.; Mantz, J.; Hercule, C.; Auriant, I.; Leguillou, J.L.; Binhas, M.; Genty, C.; Rolland, C.; Bosson, J.L. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: A prospective multicenter patient-based study. Anesthesiology 2007, 106, 687–695. [Google Scholar] [CrossRef] [PubMed]
  57. Puntillo, K.A.; Max, A.; Timsit, J.F.; Vignoud, L.; Chanques, G.; Robleda, G.; Roche-Campo, F.; Mancebo, J.; Divatia, J.V.; Soares, M.; et al. Determinants of procedural pain intensity in the intensive care unit. The Europain® study. Am. J. Respir. Crit. Care Med. 2014, 189, 39–47. [Google Scholar] [CrossRef]
  58. Erstad, B.L.; Puntillo, K.; Gilbert, H.C.; Grap, M.J.; Li, D.; Medina, J.; Mularski, R.A.; Pasero, C.; Varkey, B.; Sessler, C.N. Pain management principles in the critically ill. Chest. 2009, 135, 1075–1086. [Google Scholar] [CrossRef]
  59. Martyn, J.A.J.; Mao, J.; Bittner, E.A. Opioid Tolerance in Critical Illness. N. Engl. J. Med. 2019, 380, 365–378. [Google Scholar] [CrossRef]
  60. White, N.; Bazo-Alvarez, J.C.; Koopmans, M.; West, E.; Sampson, E.L. Understanding the association between pain and delirium in older hospital inpatients: Systematic review and meta-analysis. Age Ageing 2024, 53, afae073. [Google Scholar] [CrossRef]
  61. Baumbach, P.; Götz, T.; Günther, A.; Weiss, T.; Meissner, W. Prevalence and Characteristics of Chronic Intensive Care–Related Pain: The Role of Severe Sepsis and Septic Shock. Crit. Care Med. 2016, 44, 1129–1137. [Google Scholar] [CrossRef] [PubMed]
  62. Freundlich, R.E.; Li, G.; Leis, A.; Engoren, M. Factors Associated with Initiation of Mechanical Ventilation in Patients With Sepsis: Retrospective Observational Study. Am. J. Crit. Care 2023, 32, 358–367. [Google Scholar] [CrossRef] [PubMed]
  63. Kim, G.; Oh, D.K.; Lee, S.Y.; Park, M.H.; Lim, C.M.; Korean Sepsis Alliance (KSA) Investigators. Impact of the timing of invasive mechanical ventilation in patients with sepsis: A multicenter cohort study. Crit. Care 2024, 28, 297. [Google Scholar] [CrossRef] [PubMed]
  64. Shehabi, Y.; Bellomo, R.; Reade, M.C.; Bailey, M.; Bass, F.; Howe, B.; McArthur, C.; Seppelt, I.M.; Webb, S.; Weisbrodt, L.; et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am. J. Respir. Crit. Care Med. 2012, 186, 724–731. [Google Scholar] [CrossRef]
  65. Tanaka, L.M.; Azevedo, L.C.; Park, M.; Schettino, G.; Nassar, A.P.; Réa-Neto, A.; Tannous, L.; Souza-Dantas, V.C.; Torelly, A.; Lisboa, T.; et al. Early sedation and clinical outcomes of mechanically ventilated patients: A prospective multicenter cohort study. Crit. Care 2014, 18, R156. [Google Scholar] [CrossRef]
  66. Balzer, F.; Weiss, B.; Kumpf, O.; Treskatsch, S.; Spies, C.; Wernecke, K.D.; Krannich, A.; Kastrup, M. Early deep sedation is associated with decreased in-hospital and two-year follow-up survival. Crit. Care 2015, 19, 197. [Google Scholar] [CrossRef]
  67. Kress, J.P.; Pohlman, A.S.; O’Connor, M.F.; Hall, J.B. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N. Engl. J. Med. 2000, 342, 1471–1477. [Google Scholar] [CrossRef]
  68. Pandharipande, P.; Banerjee, A.; McGrane, S.; Ely, E.W. Liberation and animation for ventilated ICU patients: The ABCDE bundle for the back-end of critical care. Crit. Care 2010, 14, 157. [Google Scholar] [CrossRef]
  69. Ely, E.W.; Baker, A.M.; Dunagan, D.P.; Burke, H.L.; Smith, A.C.; Kelly, P.T.; Johnson, M.M.; Browder, R.W.; Bowton, D.L.; Haponik, E.F. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N. Engl. J. Med. 1996, 335, 1864–1869. [Google Scholar] [CrossRef]
  70. Girard, T.D.; Kress, J.P.; Fuchs, B.D.; Thomason, J.W.; Schweickert, W.D.; Pun, B.T.; Taichman, D.B.; Dunn, J.G.; Pohlman, A.S.; Kinniry, P.A.; et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): A randomised controlled trial. Lancet 2008, 371, 126–134. [Google Scholar] [CrossRef]
  71. Wei, W.; Fang, D.; Hu, X.; Zhou, Y.; Fu, J.; Wu, G. The impact of sedation and analgesia scores on prognosis in critically ill sepsis patients with sepsis-associated encephalopathy: A retrospective analysis. Front. Neurol. 2025, 16, 1622964. [Google Scholar] [CrossRef] [PubMed]
  72. Ely, E.W.; Truman, B.; Shintani, A.; Thomason, J.W.; Wheeler, A.P.; Gordon, S.; Francis, J.; Speroff, T.; Gautam, S.; Margolin, R.; et al. Monitoring sedation status over time in ICU patients: Reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA 2003, 289, 2983–2991. [Google Scholar] [CrossRef] [PubMed]
  73. Devlin, J.W.; Skrobik, Y.; Gélinas, C.; Needham, D.M.; Slooter, A.J.C.; Pandharipande, P.P.; Watson, P.L.; Weinhouse, G.L.; Nunnally, M.E.; Rochwerg, B.; et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit. Care Med. 2018, 46, e825–e873. [Google Scholar] [CrossRef] [PubMed]
  74. Pandharipande, P.P.; Pun, B.T.; Herr, D.L.; Maze, M.; Girard, T.D.; Miller, R.R.; Shintani, A.K.; Thompson, J.L.; Jackson, J.C.; Deppen, S.A.; et al. Effect of Sedation with Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients: The MENDS Randomized Controlled Trial. JAMA 2007, 298, 2644–2653. [Google Scholar] [CrossRef]
  75. Pandharipande, P.; Shintani, A.; Peterson, J.; Pun, B.T.; Wilkinson, G.R.; Dittus, R.S.; Bernard, G.R.; Ely, E.W. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006, 104, 21–26. [Google Scholar] [CrossRef]
  76. Seymour, C.W.; Pandharipande, P.P.; Koestner, T.; Hudson, L.D.; Thompson, J.L.; Shintani, A.K.; Ely, E.W.; Girard, T.D. Diurnal sedative changes during intensive care: Impact on liberation from mechanical ventilation and delirium. Crit. Care Med. 2012, 40, 2788–2796. [Google Scholar] [CrossRef]
  77. Hughes, C.G.; Mailloux, P.T.; Devlin, J.W. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N. Engl. J. Med. 2021, 384, 1424–1436. [Google Scholar] [CrossRef]
  78. Li, X.; Tang, Y.; Bai, Z.; Liang, X.; Huang, X.; Chen, J.; Cheng, H.; Lyu, J.; Wang, Y. Assessing the Risk of Delirium and Death in Sepsis Using the Braden Score: A Retrospective Study. J. Clin. Nurs. 2025, 34, 2779–2790. [Google Scholar] [CrossRef]
  79. Schramm, P.; Klein, K.U.; Falkenberg, L.; Berres, M.; Closhen, D.; Werhahn, K.J.; David, M.; Werner, C.; Engelhard, K. Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium. Crit. Care 2012, 16, R181. [Google Scholar] [CrossRef]
  80. Gusmao-Flores, D.; Salluh, J.I.; Chalhub, R.A.; Quarantini, L.C. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC) for the diagnosis of delirium: A systematic review and meta-analysis of clinical studies. Crit. Care 2012, 16, R115. [Google Scholar] [CrossRef]
  81. Pun, B.T.; Ely, E.W. The importance of diagnosing and managing ICU delirium. Chest 2007, 132, 624–636. [Google Scholar] [CrossRef] [PubMed]
  82. Marcantonio, E.R.; Goldman, L.; Mangione, C.M.; Ludwig, L.E.; Muraca, B.; Haslauer, C.M.; Donaldson, M.C.; Whittemore, A.D.; Sugarbaker, D.J.; Poss, R.; et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994, 271, 134–139. [Google Scholar] [CrossRef] [PubMed]
  83. Pandharipande, T.D.; Girard, J.C.; Jackson, A.; Morandi, A.; Thompson, J.L.; Pun, B.T.; Brummel, N.E.; Hughes, C.G.; Vasilevskis, E.E.; Shintani, A.K.; et al. Long-Term Cognitive Impairment after Critical Illness. N. Engl. J. Med. 2013, 369, 1306–1316. [Google Scholar] [CrossRef] [PubMed]
  84. Girard, T.D.; Exline, M.C.; Carson, S.S. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N. Engl. J. Med. 2018, 379, 2506–2516. [Google Scholar] [CrossRef]
  85. Andersen-Ranberg, N.C.; Poulsen, L.M.; Perner, A.; Hästbacka, J.; Morgan, M.; Citerio, G.; Collet, M.O.; Weber, S.O.; Andreasen, A.S.; Bestle, M.; et al. Haloperidol vs. placebo for the treatment of delirium in ICU patients: A pre-planned, secondary Bayesian analysis of the AID-ICU trial. Intensive Care Med. 2023, 49, 411–420. [Google Scholar] [CrossRef]
  86. Zakhary, T.; Ahmed, I.; Luttfi, I.; Montasser, M. Quetiapine Versus Haloperidol in the Management of Hyperactive Delirium: Randomized Controlled Trial. Neurocrit. Care 2024, 41, 550–557. [Google Scholar] [CrossRef]
  87. Reade, M.C.; Eastwood, G.M.; Bellomo, R.; Bailey, M.; Bersten, A.; Cheung, B.; Davies, A.; Delaney, A.; Ghosh, A.; van Haren, F.; et al. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients with Agitated Delirium: A Randomized Clinical Trial. JAMA 2016, 315, 1460–1468. [Google Scholar] [CrossRef]
  88. Herridge, M.S.; Cheung, A.M.; Tansey, C.M.; Matte-Martyn, A.; Diaz-Granados, N.; Al-Saidi, F.; Cooper, A.B.; Guest, C.B.; Mazer, C.D.; Mehta, S.; et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N. Engl. J. Med. 2003, 348, 683–693. [Google Scholar] [CrossRef]
  89. Herridge, M.S.; Tansey, C.M.; Matte, A.; Tomlinson, G.; Diaz-Granados, N.; Cooper, A.; Guest, C.B.; Mazer, C.D.; Mehta, S.; Stewart, T.E.; et al. Functional disability 5 years after acute respiratory distress syndrome. N. Engl. J. Med. 2011, 364, 1293–1304. [Google Scholar] [CrossRef]
  90. Sacanella, E.; Perez-Castejon, J.M.; Nicolas, J.M.; Masanés, F.; Navarro, M.; Castro, P.; López-Soto, A. Functional status and quality of life 12 months after discharge from a medical ICU in healthy elderly patients: A prospective observational study. Crit. Care 2011, 15, R105. [Google Scholar] [CrossRef]
  91. Dammeyer, J.; Dickinson, S.; Packard, D.; Baldwin, N.; Ricklemann, C. Building a protocol to guide mobility in the ICU. Crit. Care Nurs. Q. 2013, 36, 37–49. [Google Scholar] [CrossRef]
  92. Freeman, R.; Maley, K. Mobilization of intensive care cardiac surgery patients on mechanical circulatory support. Crit. Care Nurs. Q. 2013, 36, 73–88. [Google Scholar] [CrossRef] [PubMed]
  93. Schweickert, W.D.; Pohlman, M.C.; Pohlman, A.S.; Nigos, C.; Pawlik, A.J.; Esbrook, C.L.; Spears, L.; Miller, M.; Franczyk, M.; Deprizio, D.; et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial. Lancet 2009, 373, 1874–1882. [Google Scholar] [CrossRef] [PubMed]
  94. Moss, M.; Nordon-Craft, A.; Malone, D.; Van Pelt, D.; Frankel, S.K.; Warner, M.L.; Kriekels, W.; McNulty, M.; Fairclough, D.L.; Schenkman, M. A Randomized Trial of an Intensive Physical Therapy Program for Acute Respiratory Failure Patients. Am. J. Respir. Crit. Care Med. 2015, 193, 1101–1110. [Google Scholar] [CrossRef] [PubMed]
  95. Sakai, Y.; Taniuchi, K.; Karasawa, T.; Matsui, K.; Matsumoto, T.; Ikegami, S.; Imamura, H.; Horiuchi, H. The Impact of Early Mobilization on the Incidence of Intensive Care Unit-Acquired Weakness in Patients with Sepsis in the Critical Care-The Shinshu Multicenter Prospective Cohort Study (EROSCCS Study). J. Clin. Med. 2025, 14, 5904. [Google Scholar] [CrossRef]
  96. Eakin, M.N.; Ugbah, L.; Arnautovic, T.; Parker, A.M.; Needham, D.M. Implementing and sustaining an early rehabilitation program in a medical intensive care unit: A qualitative analysis. J. Crit. Care 2015, 30, 698–704. [Google Scholar] [CrossRef]
  97. Naef, R.; Von Felten, S.; Ernst, J. Factors influencing post-ICU psychological distress in family members of critically ill patients: A linear mixed-effects model. Biopsychosoc. Med. 2021, 15, 4. [Google Scholar] [CrossRef]
  98. Ito, Y.; Tsubaki, M.; Kobayashi, M.; Yagome, S.; Sakaguchi, Y. Effect size estimates of risk factors for post-intensive care syndrome-family: A systematic review and meta-analysis. Heart Lung 2023, 59, 1–7. [Google Scholar] [CrossRef]
  99. White, D.B.; Angus, D.C.; Sields, A.M.; Buddadhumaruk, P.; Pidro, C.; Paner, C.; Chaitin, E.; Chang, C.H.; Pike, F.; Weissfeld, L.; et al. A Randomized Trial of a Family-Support Intervention in Intensive Crae Units. N. Engl. J. Med. 2018, 378, 2365–2375. [Google Scholar] [CrossRef]
  100. Cameron, M.A.; Schleien, C.L.; Morris, M.C. Parental presence on pediatric intensive care unit rounds. J. Pediatr. 2009, 155, 522–528. [Google Scholar] [CrossRef]
  101. Mickelson, R.S.; Piras, S.E.; Brown, L.; Carlile, C.; Drumright, K.S.; Boehm, L. The use and usefulness of ICU diaries to support family members of critically ill patients. J. Crit. Care 2021, 61, 168–176. [Google Scholar] [CrossRef]
  102. Anderson, W.G.; Arnold, R.M.; Angus, D.; Bryce, C.L. Passive decision making preference is associated with anxiety and depression in relatives of patients in the intensive care unit. Crit. Care 2009, 24, 249–254. [Google Scholar] [CrossRef]
  103. Krishnamoorthy, D.; Snthilkumar, V.R.; Ramakrishan, N.; Ramakrishnan, N.; Vignesh, C. Decision making preferences and levels of anxiety and depression in family members admitted to the ICU. Indian J. Crit. Care Med. 2025, 29, 155–163. [Google Scholar] [PubMed]
  104. Davidson, J.E.; Aslakson, R.A.; Long, A.C.; Puntillo, K.A.; Kross, E.K.; Hart, J.; Cox, C.E.; Wunsch, H.; Wickline, M.A.; Nunnally, M.E.; et al. Guidelines for Family-Centered Care in the Neonatal, Pediatric, and Adult ICU. Crit. Care Med. 2017, 45, 103–128. [Google Scholar] [CrossRef] [PubMed]
  105. Pun, B.T.; Balas, M.C.; Barnes-Daly, M.A.; Thompson, J.L.; Aldrich, J.M.; Barr, J.; Byrum, D.; Carson, S.S.; Devlin, J.W.; Engel, H.J.; et al. Caring for Critically Ill Patients with the ABCDEF Bundle: Results of the ICU Liberation Collaborative in Over 15,000 Adults. Crit. Care Med. 2019, 47, 3–14. [Google Scholar] [CrossRef] [PubMed]
  106. Waldmann, C.S. Intensive after care after intensive care. Curr. Anaesth. Crit. Care 1998, 9, 134–139. [Google Scholar] [CrossRef]
  107. Sevin, C.M.; Bloom, S.L.; Jackson, J.C.; Wang, L.; Ely, E.W.; Stollings, J.L. Comprehensive care of ICU survivors: Development and implementation of an ICU recovery center. J. Crit. Care 2018, 46, 141–148. [Google Scholar] [CrossRef]
  108. Nakanishi, N.; Liu, K.; Hatakeyama, J.; Kawauchi, A.; Yoshida, M.; Sumita, H.; Miyamoto, K.; Nakamura, K. Post-intensive care syndrome follow-up system after hospital discharge: A narrative review. J. Intensive Care 2024, 12, 2. [Google Scholar] [CrossRef]
  109. Mikkelsen, M.E.; Still, M.; Anderson, B.J.; Bienvenu, O.J.; Brodsky, M.B.; Brummel, N.; Butcher, B.; Clay, A.S.; Felt, H.; Ferrante, L.E.; et al. Society of Critical Care Medicine’s International Consensus Conference on Prediction and Identification of Long-Term Impairments After Critical Illness. Crit. Care Med. 2020, 48, 1670–1679. [Google Scholar] [CrossRef]
  110. Bloom, S.L.; Stollings, J.L.; Kirkpatrick, O.; Wang, L.; Byrne, D.W.; Sevin, C.M.; Semler, M.W. Randomized Clinical Trial of an ICU Recovery Pilot Program for Survivors of Critical Illness. Crit. Care Med. 2019, 47, 1337–1345. [Google Scholar] [CrossRef]
  111. Khan, B.A.; Perkins, A.J.; Khan, S.H.; Unverzagt, F.W.; Lasiter, S.; Gao, S.; Wang, S.; Zarzaur, B.L.; Rahman, O.; Eltarras, A.; et al. Mobile Critical Care Recovery Program for Survivors of Acute Respiratory Failure: A Randomized Clinical Trial. JAMA Netw. Open 2024, 7, e2353158. [Google Scholar] [CrossRef]
  112. Mayer, K.P.; Boustany, H.; Cassity, E.P.; Soper, M.K.; Kalema, A.G.; Kolpek, J.H.; Montgomery-Yates, A.A. ICU Recovery Clinic Attendance, Attrition, and Patient Outcomes: The Impact of Severity of Illness, Gender, and Rurality. Crit. Care Explor. 2020, 2, e0206. [Google Scholar] [CrossRef]
  113. Ezz Al-Regal, A.R.; Ramzy, E.A.; Atia, A.A.A.; Emara, M.M. Dexmedetomidine for Reducing Mortality in Patients with Septic Shock: A Randomized Controlled Trial (DecatSepsis). Chest 2024, 166, 1394–1405. [Google Scholar] [CrossRef]
  114. Cioccari, L.; Luethi, N.; Bailey, M.; Shehabi, Y.; Howe, B.; Messmer, A.S.; Proimos, H.K.; Peck, L.; Young, H.; Eastwood, G.M.; et al. The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: A subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial. Crit. Care 2020, 24, 441. [Google Scholar] [CrossRef]
Jcm 14 08374 g001
Figure 1. Proposed Continuum from Resuscitation.
Figure 1. Proposed Continuum from Resuscitation.
Jcm 14 08374 g001
Jcm 14 08374 g002
Figure 2. Risk Factors for the Development of PICS in Patients with Sepsis and Septic Shock.
Figure 2. Risk Factors for the Development of PICS in Patients with Sepsis and Septic Shock.
Jcm 14 08374 g002
Jcm 14 08374 g003
Figure 3. A-F ICU Liberation Bundle for Reduction in Post-Intensive Care Syndrome Morbidity.
Figure 3. A-F ICU Liberation Bundle for Reduction in Post-Intensive Care Syndrome Morbidity.
Jcm 14 08374 g003
Table 1. ABCDEF Bundle Assessment Tools, Interventions, and Benefits.
Table 1. ABCDEF Bundle Assessment Tools, Interventions, and Benefits.
Assess, Prevent, and Treat PainBoth SAT and SBTChoice of Analgesia and Sedation Delirium: Assess, Prevent, and ManageEarly Mobility and ExerciseFamily Engagement and Empowerment
Assessment ToolsNumerical Rating Scale (NRS); Behavioral Pain Scale (BPS); Critical-Care Pain Observation Tool (CPOT)SAT and SBT Screening ProtocolsRichmond Agitation–Sedation Scale (RASS); Riker Sedation–Agitation ScaleConfusion Assessment Method for the ICU (CAM-ICU); Intensive Care Delirium Screening Checklist (ICDSC)Physical/occupational therapy screening tools; functional strength scalesFamily satisfaction/engagement surveys; documentation of participation in rounds
InterventionRoutine pain assessment; pre-procedure analgesia; multimodal analgesia favoring non-opioid and non-pharmacologic adjunctsPaired SAT and SBTLight sedation targeting RASS 0 to –1; preference for non-benzodiazepine agents (propofol, dexmedetomidine)Daily screening; minimize benzodiazepines; maintain sleep–wake cycles; early mobilityProgressive mobility within 72 h of stability; multidisciplinary rehab teamStructured family meetings, ICU diaries, open visitation, inclusion on rounds
Short term BenefitsReduced agitation, stress response, and physiologic instabilityShorter ventilation duration and ICU stay; decreased deliriumLess delirium, shorter ventilation and ICU stayReduced delirium duration, fewer days of comaReduced delirium, shorter ventilation and LOSImproved communication, shorter LOS, lower family anxiety/depression
Long term BenefitsLower risk of anxiety, depression, and chronic pain syndromesLower mortality, improved functional recovery, reduced PICS riskImproved cognition and reduced long-term neurocognitive impairmentImproved cognitive outcomes, reduced long-term neuropsychiatric morbidityImproved functional independence and quality of life; reduced PICS-related weaknessReduced PICS-F burden, enhanced caregiver recovery, better long-term adherence to care goals
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Sherman, M.; Lim, P.; Cheema, T.; DiSilvio, B.; Tiberio, P. From Resuscitation to Rehabilitation: The Post-Intensive Care Syndrome Continuum in Sepsis Care. J. Clin. Med. 2025, 14, 8374. https://doi.org/10.3390/jcm14238374

AMA Style

Sherman M, Lim P, Cheema T, DiSilvio B, Tiberio P. From Resuscitation to Rehabilitation: The Post-Intensive Care Syndrome Continuum in Sepsis Care. Journal of Clinical Medicine. 2025; 14(23):8374. https://doi.org/10.3390/jcm14238374

Chicago/Turabian Style

Sherman, Matthew, Perry Lim, Tariq Cheema, Briana DiSilvio, and Perry Tiberio. 2025. "From Resuscitation to Rehabilitation: The Post-Intensive Care Syndrome Continuum in Sepsis Care" Journal of Clinical Medicine 14, no. 23: 8374. https://doi.org/10.3390/jcm14238374

APA Style

Sherman, M., Lim, P., Cheema, T., DiSilvio, B., & Tiberio, P. (2025). From Resuscitation to Rehabilitation: The Post-Intensive Care Syndrome Continuum in Sepsis Care. Journal of Clinical Medicine, 14(23), 8374. https://doi.org/10.3390/jcm14238374

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Article metric data becomes available approximately 24 hours after publication online.
Back to TopTop