Development Of Chronic Critical Illness Research Articles

TRANSCRIPTOMIC DIFFERENCES IN PERIPHERAL MONOCYTE POPULATIONS IN SEPTIC PATIENTS BASED ON OUTCOME.

Postsepsis early mortality is being replaced by survivors who experience either a rapid recovery and favorable hospital discharge or the development of chronic critical illness with suboptimal outcomes. The underlying immunological response that determines these clinical trajectories remains poorly defined at the transcriptomic level. As classical and nonclassical monocytes are key leukocytes in both the innate and adaptive immune systems, we sought to delineate the transcriptomic response of these cell types. Using single-cell RNA sequencing and pathway analyses, we identified gene expression patterns between these two groups that are consistent with differences in TNF-α production based on clinical outcome. This may provide therapeutic targets for those at risk for chronic critical illness in order to improve their phenotype/endotype, morbidity, and long-term mortality.

The effect of glucose variability on the development of chronic critical illness and mortality in critically-ill COVID-19 patients

The effect of glucose variability on the development of chronic critical illness and mortality in critically-ill COVID-19 patients

Does glycemic variability affect development of chronic critical illness and mortality in the intensive care unit?

Does glycemic variability affect development of chronic critical illness and mortality in the intensive care unit?

Defining critical illness using immunological endotypes in patients with and without sepsis: a cohort study

BackgroundSepsis is a heterogenous syndrome with limited therapeutic options. Identifying immunological endotypes through gene expression patterns in septic patients may lead to targeted interventions. We investigated whether patients admitted to a surgical intensive care unit (ICU) with sepsis and with high risk of mortality express similar endotypes to non-septic, but still critically ill patients using two multiplex transcriptomic metrics obtained both on admission to a surgical ICU and at set intervals.MethodsWe analyzed transcriptomic data from 522 patients in two single-site, prospective, observational cohorts admitted to surgical ICUs over a 5-year period ending in July 2020. Using an FDA-cleared analytical platform (nCounter FLEX®, NanoString, Inc.), we assessed a previously validated 29-messenger RNA transcriptomic classifier for likelihood of 30-day mortality (IMX-SEV-3) and a 33-messenger RNA transcriptomic endotype classifier. Clinical outcomes included all-cause mortality, development of chronic critical illness, and secondary infections. Univariate and multivariate analyses were performed to assess for true effect and confounding.ResultsSepsis was associated with a significantly higher predicted and actual hospital mortality. At enrollment, the predominant endotype for both septic and non-septic patients was adaptive, though with significantly different distributions. Inflammopathic and coagulopathic septic patients, as well as inflammopathic non-septic patients, showed significantly higher frequencies of secondary infections compared to those with adaptive endotypes (p < 0.01). Endotypes changed during ICU hospitalization in 57.5% of patients. Patients who remained adaptive had overall better prognosis, while those who remained inflammopathic or coagulopathic had worse overall outcomes. For severity metrics, patients admitted with sepsis and a high predicted likelihood of mortality showed an inflammopathic (49.6%) endotype and had higher rates of cumulative adverse outcomes (67.4%). Patients at low mortality risk, whether septic or non-septic, almost uniformly presented with an adaptive endotype (100% and 93.4%, respectively).ConclusionCritically ill surgical patients express different and evolving immunological endotypes depending upon both their sepsis status and severity of their clinical course. Future studies will elucidate whether endotyping critically ill, septic patients can identify individuals for targeted therapeutic interventions to improve patient management and outcomes.

A Transcriptomic Severity Metric That Predicts Clinical Outcomes in Critically Ill Surgical Sepsis Patients.

Clinically deployable methods for the rapid and accurate prediction of sepsis severity that could elicit a meaningful change in clinical practice are currently lacking. We evaluated a whole-blood, multiplex host-messenger RNA expression metric, Inflammatix-Severity-2, for identifying septic, hospitalized patients' likelihood of 30-day mortality, development of chronic critical illness, discharge disposition, and/or secondary infections. Retrospective, validation cohort analysis. Single, academic health center ICU. Three hundred thirty-five critically ill adult surgical patients with sepsis. None. Whole blood was collected in PAXgene Blood RNA collection tubes at 24 hours after sepsis diagnosis and analyzed using a custom 29-messenger RNA classifier (Inflammatix-Severity-2) in a Clinical Laboratory Improvement Amendments certified diagnostic laboratory using the NanoString FLEX platform. Among patients meeting Sepsis-3 criteria, the Inflammatix-Severity-2 severity score was significantly better (p < 0.05) at predicting secondary infections (area under the receiver operating curve 0.71) and adverse clinical outcomes (area under the receiver operating curve 0.75) than C-reactive protein, absolute lymphocyte counts, total WBC count, age, and Charlson comorbidity index (and better, albeit nonsignificantly, than interleukin-6 and Acute Physiology and Chronic Health Evaluation II). Using multivariate logistic regression analysis, only combining the Charlson comorbidity index (area under the receiver operating curve 0.80) or Acute Physiology and Chronic Health Evaluation II (area under the receiver operating curve 0.81) with Inflammatix-Severity-2 significantly improved prediction of adverse clinical outcomes, and combining with the Charlson comorbidity index for predicting 30-day mortality (area under the receiver operating curve 0.79). The Inflammatix-Severity-2 severity score was superior at predicting secondary infections and overall adverse clinical outcomes compared with other common metrics. Combining a rapidly measured transcriptomic metric with clinical or physiologic indices offers the potential to optimize risk-based resource utilization and patient management adjustments that may improve outcomes in surgical sepsis. Hospitalized patients who are septic and present with an elevated IMX-SEV2 severity score and preexisting comorbidities may be ideal candidates for clinical interventions aimed at reducing the risk of secondary infections and adverse clinical outcomes.

The impact of sarcopenia and acute muscle mass loss on long-term outcomes in critically ill patients with intra-abdominal sepsis.

BackgroundSarcopenia is a known risk factor for poor outcomes across many chronic diseases. The impact on outcomes of both pre‐existing sarcopenia and acute muscle wasting (AMW) in acute critical illness caused by sepsis remain unclear.MethodsWe conducted a prospective longitudinal cohort study of critically ill patients with intra‐abdominal sepsis utilizing abdominal computed tomography at sepsis onset to determine baseline skeletal muscle index (SMI). Biomarkers of inflammation and catabolism were measured through 28 days while hospitalized. We performed follow‐up evaluations of strength and physical function at 3, 6, and 12 months, with interval CT analyses at 3 and 12 months to evaluate changes in muscle mass. Measured clinical outcomes included development of chronic critical illness (≥14 days in intensive care with persistent organ dysfunction), long‐term functional status, and 1 year mortality.ResultsAmong 47 sepsis patients enrolled (mean age 53 ± 14 years), half (n = 23; 49%) were sarcopenic at baseline. Overall, sepsis patients exhibited acute and persistent muscle wasting with an average 8% decrease in SMI from baseline at 3 months (P = 0.0008). Sarcopenic (SAR) and non‐sarcopenic (NSAR) groups were similar in regards to age and comorbidity burden. SAR patients had greater acute physiologic derangement (APACHE II, 18 vs. 12.5), higher incidence of multiple organ failure (57% vs. 17%), longer hospital (21 vs. 12 days) and intensive care unit length of stays (13 vs. 4 days), and higher inpatient mortality (17% vs. 0%; all P < 0.05). Pre‐existing SAR was a strong independent predictor of early death or developing chronic critical illness (odds ratio 11.87, 95% confidence interval CI 1.88–74.9; P = 0.009, area under the curve 0.880) and was associated with significantly higher risk of 1‐year mortality (34.9% vs. 4.2%, p = 0.007). Lower baseline SMI was also predictive of poor functional status at 12 months (OR 0.89, 95% confidence interval 0.80–0.99; p = 0.039, area under the curve 0.867). Additionally, SAR patients had AMW with persistent muscle mass loss at 3 months that was associated with decreased health‐related quality of life and SF‐36 physical function domains (P < 0.05). Persistent AMW at 3 months was not predictive of mortality or poor functional status, with return to near‐baseline muscle mass among sepsis survivors by 6 months.ConclusionsCritically ill patients have an acute and persistent loss of muscle mass after intra‐abdominal sepsis, which is associated with decreased health‐related quality of life and physical function at 3 months. However, pre‐existing sarcopenia, rather than persistent acute muscle mass loss at 3 months after sepsis, is independently associated with poor long‐term functional status and increased 1 year mortality.

Sirtuin 2 expression levels may predict the progression of sepsis survivors to chronic critical illness.

BackgroundSirtuin 2 (SIRT2) is a conserved deacetylase that participates in the regulation of inflammation in sepsis. In this observational prospective study, we investigated the predictive value of the SIRT2 expression level in the development of chronic critical illness (CCI) in patients with sepsis.MethodsA total of 128 critically ill patients with sepsis or septic shock were enrolled and assigned to the CCI group, rapid recovery (RAP) group, or early death group according to their clinical trajectories. Patients’ demographic and clinical information, as well as laboratory data, including C-reactive protein (CRP) level and total lymphocyte counts, were collected. Blood samples were obtained at admission and on days 1, 4, 7, 10, 14, and 21 (days 14 and 21 for the CCI group only). Peripheral blood mononuclear cells were isolated, and SIRT2 expression was measured by real-time polymerase chain reaction. Serum levels of interleukin (IL)-6 and IL-10 were measured by enzyme-linked immunosorbent assay.ResultsOur cohort included 37 CCI and 82 RAP patients, and 9 early death patients, who died within 14 days of intensive care unit (ICU) admission. Compared with the RAP group, CCI patients showed elevated CRP and IL-6 levels throughout the observation period, reflecting a sustained inflammatory response. However, decreases in total lymphocyte count and IL-10 expression in these patients were indicative of immunosuppression. SIRT2 mRNA level was lower in CCI and RAP patients compared with healthy controls at the initial stage of hospitalization, but increased starting on day 4 and continued to increase for the duration of hospitalization. By day 10, SIRT2 expression had almost returned to normal in RAP patients; however, in CCI patients, it continued to increase until the end of the observation period. A receiver-operating characteristic curve analysis showed that the expression level of SIRT2 at 10 days predicts the occurrence of CCI (P<0.05).ConclusionsSIRT2 expression may be a useful marker for identifying sepsis survivors who are at risk of progressing to CCI.

Persistently increased cell-free DNA concentrations only modestly contribute to outcome and host response in sepsis survivors with chronic critical illness

BackgroundAlthough early survival from sepsis has improved with timely resuscitation and source control, survivors frequently experience persistent inflammation and develop chronic critical illness. We examined whether increased copy number of endogenous alarmins, mitochondrial DNA, and nuclear DNA are associated with the early “genomic storm” in blood leukocytes and the development of chronic critical illness in hospitalized patients with surgical sepsis. MethodsA prospective, observational, cohort study of critically ill septic patients was performed at a United States tertiary health care center. Blood samples were obtained at multiple time points after the onset of sepsis. Droplet Digital polymerase chain reaction (Bio-Rad Laboratories, Hercules, CA) was performed to quantify RHO (nuclear DNA) and MT-CO2 (mitochondrial DNA) copies in plasma. Leukocyte transcriptomic expression of 63 genes was also measured in whole blood. ResultsWe enrolled 112 patients with surgical sepsis. Two experienced early death, 69 recovered rapidly, and 41 developed chronic critical illness. Both mitochondrial DNA and nuclear DNA copy number were increased in all sepsis survivors, but early nuclear DNA, and not mitochondrial DNA, copy number was further increased in patients who developed chronic critical illness. Cell-free DNA copy number was associated with in-hospital but not long-term (180-day and 365-day) mortality and were only weakly correlated with leukocyte transcriptomics. ConclusionIncreased cell-free DNA copy number persists in survivors of sepsis but is not strongly associated with leukocyte transcriptomics. Nuclear DNA but not mitochondrial DNA copy number is associated with adverse, short-term, clinical trajectories and outcomes.

Prevalence and development of chronic critical illness in acute patients admitted to a respiratory intensive care setting

IntroductionChronic Critical Illness (chronic CI) is a condition associated to patients surviving an episode of acute respiratory failure (ARF). The prevalence and the factors associated with the development of chronic CI in the population admitted to a Respiratory Intensive Care Unit (RICU) have not yet been clarified. MethodsAn observational prospective cohort study was undertaken at the RICU of the University Hospital of Modena (Italy). Patients mechanically ventilated with ARF in RICU were enrolled. Demographics, severity scores (APACHEII, SOFA, SAPSII), and clinical condition (septic shock, pneumonia, ARDS) were recorded on admission. Respiratory mechanics and inflammatory-metabolic blood parameters were measured both on admission and over the first week of stay. All variables were tested as predictors of chronic CI through univariate and multivariate analysis. ResultsChronic CI occurred in 33 out of 100 patients observed. Higher APACHEII, the presence of septic shock, diaphragmatic dysfunction (DD) at sonography, multidrug-resistant (MDR) bacterial infection, the occurrence of a second infection during stay, and a C-reactive protein (CRP) serum level inceasing 7 days over admission were associated with chronic CI. Septic shock was the strongest predictor of chronic CI (AUC = 0.92 p < 0.0001). ConclusionsChronic CI is frequent in patients admitted to RICU and mechanically ventilated due to ARF. Infection-related factors seem to play a major role as predictors of this syndrome.

Persistently Elevated Glucagon-Like Peptide-1 Levels among Critically Ill Surgical Patients after Sepsis and Development of Chronic Critical Illness and Dismal Long-Term Outcomes

Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin secretion, cellular glucose uptake, and has immune-regulatory functions. Glucagon-like peptide-1 is markedly altered after trauma and sepsis, but the implications remain unclear. We performed an analysis of a prospective, longitudinal cohort study of critically ill surgical patients with sepsis. Patient characteristics and clinical data were collected, as well as peripheral blood sampling for biomarker analysis, out to 28 days after sepsis onset. We prospectively adjudicated sepsis diagnosis, severity, clinical outcomes, and 6-month follow-up. The cohort included 157 septic surgical patients with significant physiologic derangement (Maximum Sequential Organ Failure Assessment [SOFA] score 8, interquartile range [IQR] 4 to 11), a high rate of multiple organ failure (50.3%), and septic shock (24.2%). Despite high disease severity, both early death (<14 days; n= 4, 2.9%) and overall inpatient mortality were low (n= 12, 7.6%). However, post-discharge 6-month mortality was nearly 3-fold higher (19.7%). Both GLP-1 and interleukin [IL]-6 levels were significantly elevated for 21 days (p ≤ 0.01) in patients who developed chronic critical illness (CCI) compared with patients with a rapid recovery. Elevated GLP-1 at 24 hours was a significant independent predictor for the development of CCI after controlling for IL-6 and glucose levels (p= 0.027), and at day 14 for death or severe functional disability at 6 months (WHO/Zubrod score 4-5, p= 0.014). Elevated GLP-1 within 24 hours of sepsis is a predictor of early death or persistent organ dysfunction. Among early survivors, persistently elevated GLP-1 levels at day 14 are strongly predictive of death or severe functional disability at 6 months. Persistently elevated GLP-1 levels may be a marker of a nonresolving catabolic state that is associated with muscle wasting and dismal outcomes after sepsis and chronic critical illness.

The Development of Chronic Critical Illness Determines Physical Function, Quality of Life, and Long-Term Survival Among Early Survivors of Sepsis in Surgical ICUs.

This study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness. Single-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes. Two surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center. Adult critically ill patients that survived 14 days or longer after sepsis onset. None. Baseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures. Surgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after sepsis.

Self-reported fatigue following intensive care of chronically critically ill patients: a prospective cohort study

BackgroundProtracted treatment on intensive care unit (ICU) sets the patients at increased risk for the development of chronic critical illness (CCI). Muscular and cardio-respiratory deconditioning are common long-term sequelae, going along with a state of chronic fatigue. At present, findings regarding the frequency, long-term course, and associated factors of self-reported fatigue following ICU treatment of CCI patients are lacking.MethodsCCI patients with the diagnosis of critical illness polyneuropathy/myopathy (CIP/CIM) were assessed at three time points. Four weeks following the discharge from ICU at acute care hospital (t1), eligibility for study participation was asserted. Self-reported fatigue was measured using the Multidimensional Fatigue Inventory (MFI-20) via telephone contact at 3 (t2, n = 113) and 6 months (t3, n = 91) following discharge from ICU at acute care hospital.ResultsAt both 3 and 6 months, nearly every second CCI patient showed clinically relevant fatigue symptoms (t2/t3: n = 53/n = 51, point prevalence rates: 46.9%/45.1%). While total fatigue scores remained stable in the whole sample, female patients showed a decrease from 3 to 6 months. The presence of a coronary heart disease, the perceived fear of dying at acute care ICU, a diagnosis of major depression, and the perceived social support were confirmed as significant correlates of fatigue at 3 months. At 6 months, male gender, the number of medical comorbidities, a diagnosis of major depression, and a prior history of anxiety disorder could be identified. A negative impact of fatigue on the perceived health-related quality of life could be ascertained.ConclusionsNearly every second CCI patient showed fatigue symptoms up to 6 months post-ICU. Patients at risk should be informed about fatigue, and appropriate treatment options should be offered to them.Trial registrationThe present study was registered retrospectively at the German Clinical Trials Register (date of registration: 13th of December 2011; registration number: DRKS00003386). Date of enrolment of the first participant to the present trial: 09th of November 2011.

Chronic Critical Illness and Persistent Inflammation: What can we Learn from the Elderly, Injured, Septic, and Malnourished?

Patients in the intensive care unit (ICU) who develop chronic critical illness significantly stress the clinical capacity and financial resources of healthcare systems. Although vast improvements have been made in critical care management, outcomes for this ICU subset remain poor. A hallmark for patients who progress to chronic critical illness is the development of persistent inflammation and immunosuppression. The risk factors associated with the development of chronic critical illness include increased age, medical comorbidities, severe injury, septic shock, and malnutrition. Interestingly, each of these clinical states bears strikingly similar immune defects, often resulting in the activation of a persistent inflammatory state. Strategies aimed at the prevention or early recognition of this state of immune compromise may help improve outcomes for these individuals and minimize the number who progress to chronic critical illness. This review explores the current knowledge regarding the immune defects associated with the development of persistent inflammation, the ways in which it can manifest clinically, attempted therapeutic interventions to date, and future insights into improving outcomes for this patient population.

Strategies to prevent sepsis-induced intensive care unit–acquired weakness: are there any options? Commentary on “Comparison of melatonin and oxytocin in the prevention of critical illness polyneuropathy in rats with surgically induced sepsis”

* Corresponding author. Department of Surg Suite 2M, New York, NY 10003. Tel.: þ1 212 E-mail address: mleitman725@me.com (I 0022-4804/$ e see front matter a 2013 Elsev http://dx.doi.org/10.1016/j.jss.2012.12.019 Intensive care unit-acquired weakness (ICUAW) is one of the leading causes of morbidity in critically ill patients and a significant risk factor for the development of chronic critical illness. In 2008, 727,000 patients were hospitalized for sepsis, with mortality rate of 17% at an estimated cost of $14.6 billion [1]. The risk of critical illness neuromuscular abnormalities in

Critical Illness Neuromyopathy and the Role of Physical Therapy and Rehabilitation in Critically Ill Patients

Neuromuscular complications of critical illness are common, and can be severe and persistent, with substantial impairment in physical function and long-term quality of life. While the etiology of ICU-acquired weakness (ICUAW) is multifactorial, both direct (ie, critical illness neuromyopathy) and indirect (ie, immobility/disuse atrophy) complications of critical illness contribute to it. ICUAW is often difficult to diagnose clinically during the acute phase of critical illness, due to the frequent use of deep sedation, encephalopathy, and delirium, which impair physical examination for patient strength. Despite its limitations, physical examination is the starting point for identification of ICUAW in the cooperative patient. Given the relative cost, invasiveness, and need for expertise, electrophysiological testing and/or muscle biopsy may be reserved for weak patients with slower than expected improvement on serial clinical examination. Currently there are limited interventions to prevent or treat ICUAW, with tight glycemic control having the greatest supporting evidence. There is a paucity of clinical trials evaluating the specific role of early rehabilitation in the chronic critically ill. However, a number of studies support the benefit of intensive rehabilitation in patients receiving chronic mechanical ventilation. Furthermore, emerging data demonstrate the safety, feasibility, and potential benefit of early mobility in critically ill patients, with the need for multicenter randomized trials to evaluate potential short- and long-term benefits of early mobility, including the potential to prevent the need for prolonged mechanical ventilation and/or the development of chronic critical illness, and other novel treatments on patients' muscle strength, physical function, quality of life, and resource utilization. Finally, the barriers, feasibility, and efficacy of early mobility in both medical and other ICUs (eg, surgical, neurological, pediatric), as well as in the chronic critically ill, have not been formally evaluated and require exploration in future clinical trials.