The metabolic response to stress in critical illness: updated review on the pathophysiological mechanisms, consequences, and therapeutic implications

Survivors of critical illness face a variety of challenges during convalescence. One such challenge is termed the post-intensive care syndrome (PICS). PICS is defined by disordered cognition, persistent weakness, distorted psychosocial functioning, and may also impact family members (PICS-F). Current efforts to reduce the incidence of PICS include bundled approaches to care that appear to reduce ventilator and ICU length of stay, delirium, and coma while enhancing survival. These interventions are supported by an ICU diary, and engaging family members in rounds, shared decision-making, and supportive care. Management approaches after discharge include structured physical rehabilitation, post-ICU clinics, and peer support groups. An important and vulnerable subset of PICS patients demonstrates chronic critical illness. This subgroup is defined by a more than 14-day ICU stay accompanied by persistent inflammation, infection, and catabolism as well as organ failure. The elderly with malnutrition may be a unique set of patients with chronic critical illness. Survivors of chronic critical illness are likely overrepresented in the PICS population and represent an ideal target group for intervention. New and persistent comorbidity, increased financial expenditure, and decreased independence may all reinforce the key elements of PICS. This constellation of findings further degrades outcomes in a group whose triumph in a high-intensity care center may not match their trajectory upon repatriation home after surviving critical illness as an inpatient. Routine screening for PICS may enhance outcomes by directing patients—and their family members—into focused care paths.

COVID-19 recovery: potential treatments for post-intensive care syndrome

Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery

Chronic resuscitation patients who have survived the acute phase of a disease represent a fast-growing cohort of patients requiring specialized medical assistant in intensive care and resuscitation units (ICRU) for several months or years. The term "chronic critical illness" (CCI) was proposed for such patients in the mid-80s of the last century. Patients with CCI make up from 5 to 20% of ICRU. Over time, they develop homeostasis disorders resulting in multiple organ failure and death. Mortality in CCI exceeds that of the majority of malignant neoplasms and functional dependence remains in most of survivors. In the present review, the attempt is made to show the main links of CCI pathogenesis which, if acted upon, can prevent unfavorable outcome. The publications describing epidemiology of CCI, its outcomes, and clinical phenotype have been analyzed. Several researchers consider CCI as a result of persistent inflammation, immunosuppression, and catabolism syndrome. Some works show the importance of nutrition for ICRU patients. The role of gastrointestinal tract in CCI formation has been noted. The effect of intensive therapy on microbiota of the ICRU patients has been demonstrated. Microbiome disturbances in dysbiosis and sepsis have been considered, as well as the effect of intestinal microbiome on the distant organs. Post-intensive care syndrome is a significant constituent of CCI. The main sequelae of the syndrome, as well as the general questions of its prevention and treatment, have been denoted.

Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is known as a prolonged immunodeficiency that occurs after severe infection. Few studies have demonstrated a direct relationship between PIICS and physical dysfunction in post-intensive care syndrome (PICS). We herein investigated how each component of PICS was affected by the diagnosis of PIICS during hospitalization and examined the relationship between PIICS and PICS using PICS assessments performed at the Hitachi General Hospital PICS Clinic. The 273 patients who visited the PICS clinic at one month after discharge from the ICU at Hitachi General Hospital were included in the study. We used the diagnostic criteria for PIICS described in previous studies. At least two of the following blood test values on day 14 of hospitalization had to be met for a diagnosis of PIICS: C-reactive protein (CRP) > 2.0 mg/dL, albumin (Alb) < 3.0 g/dL, and lymphocytes (Lym) < 800/μL. Blood test values closest to day 14 out of 11-17 days of hospitalization were used. The primary outcome was a Barthel Index (BI) < 90, while secondary outcomes were the results of various PICS assessments, including mental and cognitive impairments, performed at the PICS clinic. We supplemented missing data with multiple imputations by chained equations. We performed a nominal logistic regression analysis with age, sex, BMI, SOFA, and the presence of PIICS as variables for BI < 90. Forty-three out of two hundred seventy-three PICS outpatients met the diagnostic criteria for PIICS during hospitalization. In comparisons with non-PIICS patients, significantly higher severity scores for APACHE II and SOFA and a longer hospital stay were observed in PIICS patients, suggesting a higher clinical severity. The primary outcome, BI, was lower in the PIICS group (97.5 (58.5, 100) vs. 100 (95, 100), p = 0.008), as were the secondary outcomes (FSS-ICU: 35 (31, 35) vs. 35 (35, 35), MRC score: 55 (50.25, 58) vs. 58 (53, 60), grip strength: 16.45 (9.2, 25.47) vs. 20.4 (15.3, 27.7)). No significant differences were noted in mental or cognitive function assessments, such as HADS, IES-R, and SMQ. A multivariable analysis supplemented with missing data revealed that PIICS (odds ratio: 1.23 (1.08-1.40 p = 0.001) and age (odds ratio: 1.007 (1.004-1.01), p < 0.001) correlated with BI < 90, independent of clinical severity such as sequential organ failure assessment (SOFA). Similar results were obtained in the sensitivity analysis excluding missing data. The present study revealed a strong relationship between PIICS and post-discharge PICS physical dysfunction in patients requiring intensive care.

The post-intensive care syndrome (PICS) refers to the long-term physical, psychological and cognitive impairments experienced by intensive care unit (ICU) survivors, while PICS-Family (PICS-F) affects their family members. Despite preventive strategies during the ICU stay, PICS remains a significant concern impacting survivors' quality of life, increasing the healthcare costs, and complicating recovery. Prehabilitation offers a promising approach to mitigating PICS and PICS-F, especially when the ICU stay can be anticipated, such as in the case of major surgery. Recent literature indicates that prehabilitation - interventions designed to enhance patients' functional capacity before critical illness - may mitigate the risk and severity of PICS. Studies have demonstrated that prehabilitation programs can improve muscle strength, reduce anxiety levels and enhance overall quality of life in ICU survivors. Family prehabilitation (prehabilitation-F) is also introduced as a potential intervention to help families to cope with the stress of critical illness. This article aims to explore the role of multimodal prehabilitation and post-ICU follow-up in preventing and managing PICS and PICS-F, focusing on improving patient outcomes, supporting families and optimising healthcare resources. Combining prehabilitation with post-ICU follow-up in peri-critical care clinics could streamline resources and improve outcomes, creating a holistic care pathway. These clinics, focused on both pre-ICU and post-ICU care, would thus address PICS from multiple angles. However, the heterogeneity of patient populations and prehabilitation protocols present challenges in standardising the interventions. Further research is necessary to establish optimal prehabilitation strategies tailored to individual patient needs and to demonstrate their utility in terms of patient outcome.

With the implementation of new intensive care unit (ICU) therapies in the 1970s, multiple organ failure (MOF) emerged as a fulminant inflammatory phenotype leading to early ICU death. Over the ensuing decades, with fundamental advances in care, this syndrome has evolved into a lingering phenotype of chronic critical illness (CCI) leading to indolent late post-hospital discharge death. In 2012, the University of Florida (UF) Sepsis Critical Illness Research Center (SCIRC) coined the term Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) to provide a mechanistic framework to study CCI in surgical patients. This was followed by a decade of research into PICS-CCI in surgical ICU patients in order to define the epidemiology, dysregulated immunity, and long-term outcomes after sepsis. Other focused studies were performed in trauma ICU patients and emergency department sepsis patients. Early deaths were surprisingly low (4%); 63% experienced rapid recovery. Unfortunately, 33% progressed to CCI, of which 79% had a poor post-discharge disposition and 41% were dead within one year. These patients had biomarker evidence of PICS, and these biomarkers enhanced clinical prediction models for dismal one-year outcomes. Emergency myelopoiesis appears to play a central role in the observed persistent immune dysregulation that characterizes PICS-CCI. Older patients were especially vulnerable. Disturbingly, over half of the older CCI patients were dead within one year and older CCI survivors remained severely disabled. Although CCI is less frequent (20%) after major trauma, PICS appears to be a valid concept. This review will specifically detail the epidemiology of CCI, PICS biomarkers, effect of site of infection, acute kidney injury, effect on older patients, dysfunctional high-density lipoproteins, sarcopenia/cachexia, emergency myelopoiesis, dysregulated erythropoiesis, and potential therapeutic interventions.

Owing to the development of intensive care units, many patients survive their initial insults but progress to chronic critical illness (CCI). Patients with CCI are characterized by prolonged hospitalization, poor outcomes, and significant long-term mortality. Some of these patients get into a state of persistent low-grade inflammation, suppressed immunity, and ongoing catabolism, which was defined as persistent inflammation, immunosuppression, and catabolism syndrome (PICS) in 2012. Over the past few years, some progress has been made in the treatment of PICS. However, most of the existing studies are about the role of persistent inflammation and suppressed immunity in PICS. As one of the hallmarks of PICS, hypercatabolism has received little research attention. In this review, we explore the potential pathophysiological changes and molecular mechanisms of hypercatabolism and its role in PICS. In addition, we summarize current therapies for improving the hypercatabolic status and recommendations for patients with PICS.

INTRODUCTION: Currently, there is an increase in the number of patients who are classified as chronically critically ill patients. OBJECTIVE: The review is aimed at studying the indicators of the immune status of chronically critically ill patients. MATERIALS AND METHODS: PubMed and Google Scholar were used to identify relevant articles. The following 3 searches were performed: “chronically critically ill patients AND immune”, “chronic critical illness AND immune”, “persistent inflammation, immunosuppression, and catabolism syndrome AND immune”. The literature review was limited from 2012 to August 2022. The inclusion criteria were as follows: (1) patients with chronic critical illness (CCI) or persistent inflammation, immunosuppression and catabolism syndrome (PICS); (2) comparison groups are at least one of the specified — patients undergoing rapid recovery, healthy volunteers; (3) parameters of the immune status, inflammation and catabolism are the study endpoints; (4) original articles. To assess the validity of the results, a risk of bias assessment was performed for each study included in the analysis. The risk of bias in non-randomised studies of exposures (ROBINS-E) tool was used. The Delphi method was executed in two rounds by three researchers to assess bias. RESULTS: Chronically critically ill patients with the immunosuppressive status have reduced levels of HLA-DR and ALC and elevated sPD-L1 and IL-10 levels. The results of the studies were rated at ‘high’ and ‘moderate’ risk of reporting bias. Their findings should be considered as low-quality results. CONCLUSIONS: Chronic critical illness is a poorly understood condition that periodically occurs in patients in the ICU. The immune status of chronically critically ill patients is a debatable issue, as the current data are insufficient to draw a definitive conclusion. Based on the systematic review, further prospective trials are required to study the immune status of chronically critically ill patients.

Lipids have been utilized historically as a calorie dense means to ensure delivery of essential fatty acids (FA). Since the development of mixed lipid emulsion and investigation of immunomodulatory formulas, there has been an awakening that not all lipids are created equal. This narrative review focuses on contemporary evidence in the utilization of lipids (namely omega 3 fatty acids) in both acute and chronic critical illness. Though randomized control trials and meta-analyses provide little guidance regarding clinical practice for patients suffering from chronic critical illness, available literature suggests the potential to use lipid formulas to decrease the inflammatory cycle that drives catabolism. Additionally, this review will address the expanding evidence that specialized pro-resolving mediators (SPMs) may be the future of immunomodulating inflammation in acute and chronic critical illness and the persistent inflammation, immunosuppression, and catabolic syndrome (PICS). Although societal guidelines, expert consensus, and literature support the use of omega 3 fatty acids in the acute critically ill population, more research is needed regarding omega 3 fatty acids for chronic critical illness and PICS.

Clinical and technological advances promoting early hemorrhage control and physiologic resuscitation as well as early diagnosis and optimal treatment of sepsis have significantly decreased in-hospital mortality for many critically ill patient populations. However, a substantial proportion of severe trauma and sepsis survivors will develop protracted organ dysfunction termed chronic critical illness (CCI), defined as ≥14 days requiring intensive care unit (ICU) resources with ongoing organ dysfunction. A subset of CCI patients will develop the persistent inflammation, immunosuppression, and catabolism syndrome (PICS), and these individuals are predisposed to a poor quality of life and indolent death. We propose that CCI and PICS after trauma or sepsis are the result of an inappropriate bone marrow response characterized by the generation of dysfunctional myeloid populations at the expense of lympho- and erythropoiesis. This review describes similarities among CCI/PICS phenotypes in sepsis, cancer, and aging and reviews the role of aberrant myelopoiesis in the pathophysiology of CCI and PICS. In addition, we characterize pathogen recognition, the interface between innate and adaptive immune systems, and therapeutic approaches including immune modulators, gut microbiota support, and nutritional and exercise therapy. Finally, we discuss the future of diagnostic and prognostic approaches guided by machine and deep-learning models trained and validated on big data to identify patients for whom these approaches will yield the greatest benefits. A deeper understanding of the pathophysiology of CCI and PICS and continued investigation into novel therapies harbor the potential to improve the current dismal long-term outcomes for critically ill post-injury and post-infection patients.

To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis. Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear. PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions. CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0-3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88). Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology.

Sepsis-induced multiple-organ failure (MOF) has plagued surgical intensive care units (ICUs) for decades. Early nutrition (principally enteral) improves hospital outcomes of high-risk ICU patients. The purpose of this study is to document how the growing epidemic of chronic critical illness (CCI) patients responds to adequate evidence-based ICU nutrition. This retrospective post hoc subgroup analysis of an ongoing sepsis database identified 56 CCI patients who received early, adequate nutrition per an established surgical ICU protocol compared with 112 matched rapid-recovery (RAP) patients. The matched CCI and RAP groups had similar baseline characteristics. Serial biomarkers showed that CCI patients remained persistently inflamed with ongoing stress metabolism and that despite receiving evidence-based protocol nutrition, they had persistent catabolism and immunosuppression with more secondary infections. More CCI patients were discharged to poor nonhome destinations (ie, skilled nursing facilities, long-term acute care, hospice) (81% vs 29%, P < 0.05). At 12-month follow-up, CCI patients had worse functional status by Zubrod score (3.17 vs 1.62, P < 0.001) and Short Physical Battery Testing (4.78 vs 8.59, P < 0.02), worse health-related quality of life by EQ-5D-3L descriptive measures (9.07 vs 7.45, P < 0.003), and lower survival (67% vs 92%, P < 0.05). Despite early, adequate, evidence-based ICU nutrition, septic surgical ICU patients who develop CCI exhibit persistent inflammation, immunosuppression, and catabolism with unacceptable long-term morbidity and mortality. Although current evidence-based ICU nutrition may improve short-term ICU outcomes, novel adjuncts are needed to improve long-term outcomes for CCI patients.

Critical illness, an extreme form of severe physical stress, is characterized by important endocrine and metabolic changes. The development of critical care medicine has made possible survival from conditions that were previously rapidly fatel, and as a result many patients now enter a prolonged phase of chronic or persistent critical illness. Acute endocrine adaptations are directed towards providing energy and substrates for the vital fight or flight response in the context of exogenous substrate deprivation. Distinct endocrine and metabolic alterations characterize the chronic phase of critical illness, which seems to no longer be solely beneficial and may hamper recovery and rehabilitation. Onset of the stressful event causes an acute activation of pulsatile hormonal release from the anterior pituitary, followed by suppression in the chronic phase of illness, ultimately resolving to normality if recovery occurs.

Dysregulated host immune responses to infection often occur, leading to sepsis, multiple organ failure, and death. Some patients rapidly recover from sepsis, but many develop chronic critical illness (CCI), a debilitating condition that impacts functional outcomes and long-term survival. The “Persistent Inflammation, Immunosuppression, and Catabolism Syndrome” (PICS) has been postulated as the underlying pathophysiology of CCI. We propose that PICS is initiated by an early genomic and cytokine storm in response to microbial invasion during the early phase of sepsis. However, once source control, antimicrobial coverage, and supportive therapies have been initiated, we propose that the persistent inflammation in patients developing CCI is a result of ongoing endogenous alarmin release from damaged organs and loss of muscle mass. This ongoing alarmin and danger-associated molecular pattern signaling causes chronic inflammation and a shift in bone marrow stem cell production toward myeloid cells, contributing to chronic anemia and lymphopenia. We propose that therapeutic interventions must target the chronic organ injury and lean tissue wasting that contribute to the release of endogenous alarmins and the expansion and deposition of myeloid progenitors that are responsible for the propagation and persistence of CCI.