Pro-Con Debate: Should Critically Ill Patients Undergo Procedures at Bedside or in the Operating Room?

Nonoperating room anesthesia (NORA) is a fast-growing field in anesthesiology, wherein anesthesia care is provided for surgical procedures performed outside the main operating room (OR) pavilion. Advances in medical science and technology have led to an increasing number of procedures being moved out of the operating room to procedural suites. One such NORA location is the intensive care unit (ICU), where a growing number of urgent and emergent procedures are being performed on medically unstable patients. ICU-NORA allows medical care to be provided to patients who are too sick to tolerate transport between the ICU and the OR. However, offering the same, high-quality, and safe care in this setting may be challenging. It requires special planning and a thorough consideration of the presence of life-threatening comorbidities and location-specific and ergonomic barriers. In this Pro-Con commentary article, we discuss these special considerations and argue in favor of and against routinely performing procedures at the bedside in the ICU versus in the OR.

Long-term clinical outcomes in critically ill patients with sepsis and pre-existing low muscle mass: a retrospective cohort study.

PURPOSE: Critically ill patients with sepsis account for significant disease morbidity and healthcare costs. Low muscle mass has been proposed as an independent risk factor for poor short-term outcomes, although its effect on long-term outcomes remains unclear. METHODS: Retrospective cohort analysis of patients treated at a quaternary care medical center over 6 years (09/2014 - 12/2020). Critically ill patients meeting Sepsis-3 criteria were included, with low muscle mass defined by [Formula: see text] 5th percentile skeletal muscle index, measured at the L3 lumbar level (L3SMI) on Computed-Tomography (CT) scan ([Formula: see text] 41.6 cm2/m2 for males and [Formula: see text] 32.0 cm2/m2 for females). L3SMI was calculated by normalizing the CT-measured skeletal muscle area to the square of the patient's height (in meters). Measurements were taken from abdominal/pelvic CT scan obtained within 7 days of sepsis onset. The prevalence of low muscle mass and its association with clinical outcomes, including in-hospital and one-year mortality, and post-hospitalization discharge disposition in survivors, was analyzed. Unfavorable post-hospitalization disposition was defined as discharge to a location other than the patient's home. RESULTS: Low muscle mass was present in 34 (23%) of 150 patients, with mean skeletal muscle indices of 28.0 ± 2.9 cm2/m2 and 36.8 ± 3.3 cm2/m2 in females and males, respectively. While low muscle mass was not a significant risk factor for in-hospital mortality (hazard ratio 1.33; 95% CI 0.64 - 2.76; p = 0.437), it significantly increased one-year mortality after adjusting for age and illness severity using Cox multivariate regression (hazard ratio 1.9; 95% CI 1.1 - 3.2; p = 0.014). Unfavorable post-hospitalization discharge disposition was not associated with low muscle mass, after adjusting for age and illness severity in a single, multivariate model. CONCLUSION: Low muscle mass independently predicts one-year mortality but is not associated with in-hospital mortality or unfavorable hospital discharge disposition in critically ill patients with sepsis.

Comparing Long-Term Prognosis in Chronic Critically Ill Patients: A Case Series Study of Medical versus Surgical Sepsis.

Background and Objectives: Chronic critical illness (CCI) is a syndrome characterized by persistent organ dysfunction that requires critical care therapy for ≥14 days. Sepsis and respiratory failure constitute the two primary causes of CCI. A better understanding of this patient population and their clinical course may help to risk-stratify them early during hospitalization. Our objective was to identify whether the source of sepsis (medical versus surgical) affected clinical trajectory and prognosis in patients developing CCI. Materials and Methods: We describe a cohort of patients having acute respiratory failure and sepsis and requiring critical care therapy in the medical (MICU) or surgical (SICU) critical care units for ≥14 days. Given the relative infrequency of CCI, we use a case series design to examine mortality, functional status, and place of residence (home versus non-home) at one year following their index hospitalization. Results: In medical patients developing CCI (n = 31), the severity of initial organ dysfunction, by SOFA score, was significantly associated with the development of CCI (p = 0.002). Surgical patients with CCI (n = 7) experienced significantly more ventilator-free days within the first 30 days following sepsis onset (p = 0.004), as well as less organ dysfunction at day 14 post-sepsis (p < 0.0001). However, one-year mortality, one-year functional status, and residency at home were not statistically different between cohorts. Moreover, 57% of surgical patients and 26% of medical patients who developed CCI were living at home for one year following their index hospitalization (p = 0.11). Conclusions: While surgical patients who develop sepsis-related CCI experience more favorable 30-day outcomes as compared with medical patients, long-term outcomes do not differ significantly between groups. This suggests that reversing established organ dysfunction and functional disability, regardless of etiology, is more challenging compared to preventing these complications at an earlier stage.

Emergency use of sugammadex after failure of standard reversal drugs and postoperative pulmonary complications: A retrospective cohort study.

Background and Aims: The use of sugammadex instead of neostigmine for the reversal of neuromuscular blockade may decrease postoperative pulmonary complications. It is unclear if this finding is applicable to situations where sugammadex is administered after the administration of neostigmine. The objective of this study was to compare the incidence of a composite outcome measure of major postoperative pulmonary complications in patients who received sugammadex as a rescue agent after neostigmine versus those who received sugammadex alone for reversal of neuromuscular blockade. Material and Methods: This retrospective cohort study analyzed the medical records of adult patients who underwent elective inpatient noncardiac surgery under general anesthesia and received sugammadex for reversal of neuromuscular blockade, at a tertiary care academic hospital between August 2016 and November 2018. Results: A total of 1,672 patients were included, of whom 1,452 underwent reversal with sugammadex alone and 220 received sugammadex following reversal with neostigmine/glycopyrrolate. The composite primary outcome was diagnosed in 60 (3.6%) patients. Comparing these two groups, and after adjusting for confounding factors, patients who received sugammadex after reversal with neostigmine had more postoperative pulmonary complications than those reversed with sugammadex alone (6.8% vs. 3.1%, odds ratio, 2.29; 95% confidence interval [CI], 1.25 to 4.18; P = 0.006). Conclusion: The use of sugammadex following reversal with neostigmine was associated with a higher incidence of postoperative pulmonary complications as compared to the use of sugammadex alone. The implications of using sugammadex after the failure of standard reversal drugs should be investigated in prospective studies.

Renohepatic crosstalk: a review of the effects of acute kidney injury on the liver.

Several theories regarding acute kidney injury (AKI)-related mortality have been entertained, although mounting evidence supports the paradigm that impaired kidney function directly and adversely affects the function of several remote organs. The kidneys and liver are fundamental to human metabolism and detoxification, and it is therefore hardly surprising that critical illness complicated by hepatorenal dysfunction portends a poor prognosis. Several diseases can simultaneously impact the proper functioning of the liver and kidneys, although this review will address the impact of AKI on liver function. While evidence for this relationship in humans remains sparse, we present supportive studies and then discuss the most likely mechanisms by which AKI can cause liver dysfunction. These include 'traditional' complications of AKI (uremia, volume overload and acute metabolic acidosis, among others) as well as systemic inflammation, hepatic leukocyte infiltration, cytokine-mediated liver injury and hepatic oxidative stress. We conclude by addressing the therapeutic implications of these findings to clinical medicine.

Failure to Rescue After Severe Acute Kidney Injury in Patients Undergoing Non-Cardiac Surgery.

INTRODUCTION: Many deaths after surgery can be attributed to "failure to rescue," which may be a better surgical quality indicator than the occurrence of a postoperative complication. Acute kidney injury (AKI) is one such postoperative complication associated with high mortality. The purpose of this study is to identify perioperative risk factors associated with failure to rescue among patients who develop postoperative AKI. METHODS: We identified adult patients who underwent non-cardiac surgery between 2012 and 2018 and experienced postoperative severe AKI (an increase in blood creatinine concentration of >2 mg/dL above baseline or requiring hemodialysis) from the American College of Surgeons National Surgical Quality Improvement Program database. Multivariable logistic regression was used to identify risk factors for failure to rescue among patients who developed severe AKI. RESULTS: Among 5,765,904 patients who met inclusion criteria, 26,705 (0.46%) patients developed postoperative severe AKI, of which 6834 (25.6%) experienced failure to rescue. Risk factors with the strongest association (adjusted odds ratio >1.5) with failure to rescue in patients with AKI included advanced age, higher American Society of Anesthesiologists class, presence of preoperative ascites, disseminated cancer, septic shock, and blood transfusion within 72 h of surgery start time. CONCLUSIONS: About one-fourth of patients who develop severe AKI after non-cardiac surgery die within 30 d of surgery. Both patient- and surgery-related risk factors are associated with this failure to rescue. Further studies are needed to identify early and effective interventions in high-risk patients who develop postoperative severe AKI to prevent the antecedent mortality.

Prerenal acute kidney injury-still a relevant term in modern clinical practice?

The traditional taxonomy of acute kidney injury (AKI) has remained pervasive in clinical nephrology. While the terms 'prerenal', 'intrarenal' and 'postrenal' highlight the diverse pathophysiology underlying AKI, they also imply discrete disease pathways and de-emphasize the nature of AKI as an evolving clinical syndrome with multiple, often simultaneous and overlapping, causes. In a similar vein, prerenal AKI comprises a diverse spectrum of kidney disorders, albeit one that is often managed by using a standardized clinical algorithm. We contend that the term 'prerenal' is too vague to adequately convey our current understanding of hypoperfusion-related AKI and that it should thus be avoided in the clinical setting. Practice patterns among nephrologists indicate that AKI-related terminology plays a significant role in the approaches that clinicians take to patients that have this complex disease. Thus, it appears that precise terminology does impact the treatment that patients receive. We will outline differences in the diagnosis and management of clinical conditions lying on the so-called prerenal disease spectrum to advocate caution when administering intravenous fluids to these clinically decompensated patients. An understanding of the underlying pathophysiology may, thus, avert clinical missteps such as fluid and vasopressor mismanagement in tenuous or critically ill patients.

Post-operative intensive care unit admission after elective non-cardiac surgery: A single-center analysis of the NSQIP database.

BACKGROUND: Admission to the intensive care unit (ICU) after surgery can be associated with significant morbidity and mortality. This observational cohort study aims to identify perioperative factors associated with post-operative ICU admission in patients undergoing elective non-cardiac surgery. METHODS: Data from the ACS NSQIP® database at a tertiary care academic medical center were analyzed from January 2011 to September 2016. Univariable and multivariable logistic regression of patient and surgery-specific characteristics was performed to assess association with post-operative ICU admission. The Current Procedural Terminology (CPT) and International Classification of Diseases (ICD-9) billing codes, as well as associated outcomes, were reviewed. RESULTS: Of 5254 database patient records, 1150 met our inclusion criteria. Elevated body mass index (BMI), longer procedure duration and a diagnosis of disseminated cancer were associated with post-operative ICU admission. Prostatectomy and morbid obesity were the most common CPT and ICD-9 codes identified. Patients who were admitted to the ICU after surgery had a longer hospital length of stay (LOS), had a higher frequency of readmission, re-operation, and in-hospital mortality. CONCLUSION: Admission to the ICU after elective non-cardiac surgery is common. Our analysis of the ACS NSQIP® database identified elevated BMI, longer duration of surgery and disseminated cancer as predictors of post-operative ICU admissions in patients undergoing elective non-cardiac surgery.

CHA2DS2-VASc Score and In-Hospital Mortality in Critically Ill Patients With New-Onset Atrial Fibrillation.

OBJECTIVE: To examine the role of the CHA2DS2-VASc (Congestive heart failure; Hypertension; Age ≥75 years [doubled]; Diabetes; previous Stroke, transient ischemic attack, or thromboembolism [doubled]; Vascular disease; Age 65-75 years; and Sex category) score as a prognostic marker of in-hospital mortality in critically ill patients who develop new-onset atrial fibrillation (NOAF). DESIGN: Retrospective analyses. SETTING: A single-center study in a tertiary care academic medical center. PARTICIPANTS: The study comprised all adult patients with NOAF admitted to noncardiac intensive care units (ICUs) at a tertiary care academic institution between January 2009 and March 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors retrospectively reviewed electronic medical records of all adult patients admitted to noncardiac ICUs at a tertiary care academic institution between January 2009 and March 2016. Patients with NOAF were identified and their CHA2DS2-VASc score was calculated. The authors evaluated the association of CHA2DS2-VASc score and its individual components with in-hospital mortality in these patients. A total of 640 (1.7% [38,708 patients]; 95% CI 1.5%-1.8%) patients developed NOAF during the study period. The in-hospital mortality rate in patients included in the analysis was 14.3%. There was no association between in-hospital mortality and CHA2DS2VASc score. However, the likelihood of in-hospital death was 1.56  times greater for patients having atrial fibrillation and concomitant vascular disease (95% CI 1.003-2.429; p = 0.049). CONCLUSIONS: New-onset atrial fibrillation is common in critically ill patients and is associated with high in-hospital mortality. The authors found that the CHA2DS2-VASc score itself is not a reliable prognostic marker of in-hospital mortality in these patients. However, the presence of vascular disease in patients with NOAF may increase the mortality associated with this disease.

Anesthetic Management of Elderly Patients With Down Syndrome: A Case Report.

In 1930, the life expectancy of patients with Down syndrome was about 10 years; today, their life expectancy is more than 60 years. With aging, there is an increased need for anesthesia and surgery. There is, however, no published information regarding the anesthetic management of older adults with Down syndrome. In this report, we described the anesthetic management of a 50-year-old woman with Down syndrome undergoing major cervical spine surgery. Components of the anesthetic that we thought would be difficult such as intravenous line placement and endotracheal intubation were accomplished without difficulty. Despite our best efforts, our patient nevertheless experienced both emergence delirium and postoperative vomiting. We advocate that physicians, advanced practice providers, and registered nurses be aware of the unique perianesthesia needs of older patients with Down syndrome.

Stroke prophylaxis in critically-ill patients with new-onset atrial fibrillation.

Despite a high incidence of new onset atrial fibrillation (NOAF) in critically ill patients and its association with short and long-term incidence of stroke, there is limited data assessing anticoagulation on hospital discharge in these patients. We retrospectively reviewed electronic medical records of all adult patients admitted to non-cardiac ICUs at our institution between January 2009 and March 2016. Patients with NOAF were identified and CHA2DS2-VASc score of ICU survivors was calculated. Prescription of oral anticoagulant therapy on hospital discharge was analyzed. A total of 640 (1.7% [38,708 patients]; 95% CI 1.5%, 1.8%) patients developed NOAF during the study period. CHA2DS2-VASc score was calculated for 615 patients, of which 82.2% had a CHA2DS2-VASc score ≥ 2. Of the 428 eligible patients, only 96 patients (22.4%) were discharged on oral anticoagulant therapy. Patients with a history of congestive heart failure (33.7% vs. 19.7%) and stroke/TIA or other thromboembolic disease (35.9% vs. 18.0%) were more likely to be discharged on an oral anticoagulant. Patients with a higher score were also more likely to be discharged on an oral anticoagulant (OR 1.27; 95% CI 1.10, 1.47). NOAF is common in critically ill patients admitted to non-cardiac ICUs and a significant proportion of these patients have a CHA2DS2-VASc score ≥ 2. However, only a minority of them are discharged on an oral anticoagulant. There is a need to identify ways to improve implementation of effective stroke prophylaxis in these patients.

The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice.

The serotonin syndrome is a medication-induced condition resulting from serotonergic hyperactivity, usually involving antidepressant medications. As the number of patients experiencing medically-treated major depressive disorder increases, so does the population at risk for experiencing serotonin syndrome. Excessive synaptic stimulation of 5-HT2A receptors results in autonomic and neuromuscular aberrations with potentially life-threatening consequences. In this review, we will outline the molecular basis of the disease and describe how pharmacologic agents that are in common clinical use can interfere with normal serotonergic pathways to result in a potentially fatal outcome. Given that serotonin syndrome can imitate other clinical conditions, an understanding of the molecular context of this condition is essential for its detection and in order to prevent rapid clinical deterioration.

A review of the role of immune cells in acute kidney injury.

Acute kidney injury (AKI) is a systemic disease occurring commonly in patients who are critically ill. Etiologies of AKI can be septic or aseptic (nephrotoxic, or ischemia-reperfusion injury). Recent evidence reveals that innate and adaptive immune responses are involved in mediating damage to renal tubular cells and in recovery from AKI. Dendritic cells, monocytes/macrophages, neutrophils, T lymphocytes, and B lymphocytes all contribute to kidney injury. Conversely, M2 macrophages and regulatory T cells are essential in suppressing inflammation, tissue remodeling and repair following kidney injury. AKI itself confers an increased risk for developing infection owing to increased production and decreased clearance of cytokines, in addition to dysfunction of immune cells themselves. Neutrophils are the predominant cell type rendered dysfunctional by AKI. In this review, we describe the bi-directional interplay between the immune system and AKI and summarize recent developments in this field of research.

Kidney Injury and Electrolyte Abnormalities in Liver Failure.

The liver and kidney are key organs of metabolic homeostasis in the body and display complex interactions. Liver diseases often have direct and immediate effects on renal physiology and function. Conversely, acute kidney injury (AKI) is a common problem in patients with both acute and chronic liver diseases. AKI in patients with acute liver failure is usually multifactorial and involves insults similar to those seen in the general AKI population. Liver cirrhosis affects and is directly affected by aberrations in systemic and renal hemodynamics, inflammatory response, renal handling of sodium and free water excretion, and additional nonvasomotor mechanisms. Subsequent problems, for example, worsening ascites, hyponatremia, and AKI, often complicate management of patients with chronic progressive liver disease and add to their morbidity and mortality. Thus, AKI must be carefully defined and diagnosed in patients with liver disease. The kidney also plays a pivotal role in balancing acid-base disturbances resulting from advanced liver disease, making AKI in the setting of end-stage liver disease very difficult to manage clinically. While renal dysfunction in these patients often resolves following orthotopic liver transplant, dialysis may be required as a bridge to transplantation to mitigate the metabolic disarray found in these critically ill patients.

Clinical Utility of Extracorporeal Cytokine Hemoadsorption Therapy: A Literature Review.

Cytokines play a critical role in coordinating and amplifying a host immune response to infection. The normal pattern of localized and systemic release of proinflammatory and anti-inflammatory cytokines varies on the basis of the disease process. A dysregulated cytokine response can lead to a hyper-inflammatory condition called a cytokine storm. This is believed to contribute to the pathophysiology of sepsis and septic shock, a condition carrying high morbidity and mortality in critically ill patients. Extracorporeal cytokine hemoadsorption is an emerging technology utilized in the treatment of dysregulated inflammatory states such as sepsis, although there is a paucity of clinical evidence supporting its outcomes benefits. We assess the peer-reviewed literature relating to cytokine hemoadsorption in the context of sepsis and suggest areas of future research incorporating this novel technology.

Association between Initial Fluid Choice and Subsequent In-hospital Mortality during the Resuscitation of Adults with Septic Shock.

BACKGROUND: Currently, guidelines recommend initial resuscitation with intravenous (IV) crystalloids during severe sepsis/septic shock. Albumin is suggested as an alternative. However, fluid mixtures are often used in practice, and it is unclear whether the specific mixture of IV fluids used impacts outcomes. The objective of this study is to test the hypothesis that the specific mixture of IV fluids used during initial resuscitation, in severe sepsis, is associated with important in-hospital outcomes. METHODS: Retrospective cohort study includes patients with severe sepsis who were resuscitated with at least 2 l of crystalloids and vasopressors by hospital day 2, patients who had not undergone any major surgical procedures, and patients who had a hospital length of stay (LOS) of at least 2 days. Inverse probability weighting, propensity score matching, and hierarchical regression methods were used for risk adjustment. Patients were grouped into four exposure categories: recipients of isotonic saline alone ("Sal" exclusively), saline in combination with balanced crystalloids ("Sal + Bal"), saline in combination with colloids ("Sal + Col"), or saline in combination with balanced crystalloids and colloids ("Sal + Bal + Col"). In-hospital mortality was the primary outcome, and hospital LOS and costs per day (among survivors) were secondary outcomes. RESULTS: In risk-adjusted Inverse Probability Weighting analyses including 60,734 adults admitted to 360 intensive care units across the United States between January 2006 and December 2010, in-hospital mortality was intermediate in the Sal group (20.2%), lower in the Sal + Bal group (17.7%, P < 0.001), higher in the Sal + Col group (24.2%, P < 0.001), and similar in the Sal + Bal + Col group (19.2%, P = 0.401). In pairwise propensity score-matched comparisons, the administration of balanced crystalloids by hospital day 2 was consistently associated with lower mortality, whether colloids were used (relative risk, 0.84; 95% CI, 0.76 to 0.92) or not (relative risk, 0.79; 95% CI, 0.70 to 0.89). The association between colloid use and in-hospital mortality was inconsistent, and survival was not uniformly affected, whereas LOS and costs per day were uniformly increased. Results were robust in sensitivity analyses. CONCLUSIONS: During the initial resuscitation of adults with severe sepsis/septic shock, the types of IV fluids used may impact in-hospital mortality. When compared with the administration of isotonic saline exclusively during resuscitation, the coadministration of balanced crystalloids is associated with lower in-hospital mortality and no difference in LOS or costs per day. When colloids are coadministered, LOS and costs per day are increased without improved survival. A large randomized controlled trial evaluating crystalloid choice is warranted. Meanwhile, the use of balanced crystalloids seems reasonable. (Anesthesiology 2015; 123:1385-93).

Time-Dependent Variation in Immunoparalysis Biomarkers Among Patients with Sepsis and Critical Illness.

Immunoparalysis is a significant concern in patients with sepsis and critical illness, potentially leading to increased risk of secondary infections. This study aimed to perform a longitudinal assessment of immune function over the initial two weeks following the onset of sepsis and critical illness. We compared ex vivo stimulated cytokine release to traditional markers of immunoparalysis, including monocyte Human Leukocyte Antigen (mHLA)-DR expression and absolute lymphocyte count (ALC). A total of 64 critically ill patients were recruited in a tertiary care academic medical setting, including 31 septic and 33 non-septic patients. Results showed that while mHLA-DR expression significantly increased over time, this was primarily driven by the non-septic subset of critically ill patients. ALC recovery was more prominent in septic patients. Ex vivo stimulation revealed significant increases in TNF and IL-6 production over time in septic patients. However, IFNγ production varied with the stimulant used and did not show significant recovery when normalized to cell count. No significant correlation was found between mHLA-DR expression and other immunoparalysis biomarkers. These findings suggest the need for more nuanced immune monitoring approaches beyond the traditional 'sepsis' versus 'non-sepsis' classifications in critically ill patients. It also provided further evidence of a potential window for targeted immunotherapeutic interventions in the first week of critical illness.

Enhancing Sepsis prognosis: Integrating social determinants and demographic variables into a comprehensive model for critically ill patients.

BACKGROUND: The Sequential Organ Failure Assessment (SOFA) score monitors organ failure and defines sepsis but may not fully capture factors influencing sepsis mortality. Socioeconomic and demographic impacts on sepsis outcomes have been highlighted recently. OBJECTIVE: To evaluate the prognostic value of SOFA scores against demographic and social health determinants for predicting sepsis mortality in critically ill patients, and to assess if a combined model increases predictive accuracy. METHODS: The study utilized retrospective data from the MIMIC-IV database and prospective external validation from the Penn State Health cohort. A Random Forest model incorporating SOFA scores, demographic/social data, and the Charlson Comorbidity Index was trained and validated. FINDINGS: In the MIMIC-IV dataset of 32,970 sepsis patients, 6,824 (20.7%) died within 30 days. A model including demographic, socioeconomic, and comorbidity data with SOFA scores improved predictive accuracy beyond SOFA scores alone. Day 2 SOFA, age, weight, and comorbidities were significant predictors. External validation showed consistent performance, highlighting the importance of delta SOFA between days 1 and 3. CONCLUSION: Adding patient-specific demographic and socioeconomic information to clinical metrics significantly improves sepsis mortality prediction. This suggests a more comprehensive, multidimensional prognostic approach is needed for accurate sepsis outcome predictions.

Predicting Organ Dysfunction in Septic and Critically Ill Patients: A Prospective Cohort Study Using Rapid Ex Vivo Immune Profiling.

OBJECTIVES: While cytokine response patterns are pivotal in mediating immune responses, they are also often dysregulated in sepsis and critical illness. We hypothesized that these immunological deficits, quantifiable through ex vivo whole blood stimulation assays, may be indicative of subsequent organ dysfunction. DESIGN: In a prospective observational study, adult septic patients and critically ill but nonseptic controls were identified within 48 hours of critical illness onset. Using a rapid, ex vivo assay based on responses to lipopolysaccharide (LPS), anti-CD3/anti-CD28 antibodies, and phorbol 12-myristate 13-acetate with ionomycin, cytokine responses to immune stimulants were quantified. The primary outcome was the relationship between early cytokine production and subsequent organ dysfunction, as measured by the Sequential Organ Failure Assessment score on day 3 of illness (SOFAd3). SETTING: Patients were recruited in an academic medical center and data processing and analysis were done in an academic laboratory setting. PATIENTS: Ninety-six adult septic and critically ill nonseptic patients were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Elevated levels of tumor necrosis factor and interleukin-6 post-endotoxin challenge were inversely correlated with SOFAd3. Interferon-gamma production per lymphocyte was inversely related to organ dysfunction at day 3 and differed between septic and nonseptic patients. Clustering analysis revealed two distinct immune phenotypes, represented by differential responses to 18 hours of LPS stimulation and 4 hours of anti-CD3/anti-CD28 stimulation. CONCLUSIONS: Our rapid immune profiling technique offers a promising tool for early prediction and management of organ dysfunction in critically ill patients. This information could be pivotal for early intervention and for preventing irreversible organ damage during the acute phase of critical illness.

Macrophage-derived human resistin promotes perivascular adipose tissue dysfunction in experimental inflammatory arthritis.

Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA). Resistin is an adipokine that induces adipose tissue inflammation and activation of monocytes/macrophages via adenylate cyclase-associated protein-1 (CAP1). Resistin levels are increased in RA and might cause perivascular adipose tissue (PVAT) dysfunction, leading to vascular damage and CVD. This study aimed to investigate the role of resistin in promoting PVAT dysfunction by increasing local macrophage and inflammatory cytokines content in antigen-induced arthritis (AIA). Resistin pharmacological effects were assessed by using C57Bl/6J wild-type (WT) mice, humanized resistin mice expressing human resistin in monocytes-macrophages (hRTN+/-/-), and resistin knockout mice (RTN-/-) with AIA and respective controls. We investigated AIA disease activity and functional, cellular, and molecular parameters of the PVAT. Resistin did not contribute to AIA disease activity and its concentrations were augmented in the PVAT and plasma of WT AIA and hRTN+/-/- AIA animals. In vitro exposure of murine arteries to resistin impaired vascular function by decreasing the anti-contractile effect of PVAT. WT AIA mice and hRTN+/-/- AIA mice exhibited PVAT dysfunction and knockdown of resistin prevented it. Macrophage-derived cytokines, markers of types 1 and 2 macrophages, and CAP1 expression were increased in the PVAT of resistin humanized mice with AIA, but not in knockout mice for resistin. This study reveals that macrophage-derived resistin promotes PVAT inflammation and dysfunction regardless of AIA disease activity. Resistin might represent a translational target to reduce RA-driven vascular dysfunction and CVD.