Cohort profile of BIGPROMISE: a perioperative biobank of a high-risk surgical population.

PURPOSE: Postoperative complications increase mortality, disability and costs. Advanced understanding of the risk factors for postoperative complications is needed to improve surgical outcomes. This paper discusses the rationale and profile of the BIGPROMISE (biomarkers to guide perioperative management and improve outcome in high-risk surgery) cohort, that aims to investigate risk factors, pathophysiology and outcomes related to postoperative complications. PARTICIPANTS: Adult patients undergoing major surgery in two tertiary teaching hospitals. Clinical data and blood samples are collected before surgery, at the end of surgery and on the first, second and third postoperative day. At each time point a panel of cardiovascular, inflammatory, renal, haematological and metabolic biomarkers is assessed. Aliquots of plasma, serum and whole blood of each time point are frozen and stored. Data on severe complications are prospectively collected during 30 days after surgery. Functional status is assessed before surgery and after 120 days using the WHO Disability Assessment Schedule (WHODAS) 2.0. Mortality is followed up until 2 years after surgery. FINDINGS TO DATE: The first patient was enrolled on 8 October 2021. Currently (1 January 2024) 3086 patients were screened for eligibility, of whom 1750 (57%) provided informed consent for study participation. Median age was 66 years (60; 73), 28% were female, and 68% of all patients were American Society of Anaesthesiologists (ASA) physical status class 3. Most common types of major surgery were cardiac (49%) and gastro-intestinal procedures (26%). The overall incidence of 30-day severe postoperative complications was 16%. FUTURE PLANS: By the end of the recruitment phase, expected in 2026, approximately 3000 patients with major surgery will have been enrolled. This cohort allows us to investigate the role of pathophysiological perioperative processes in the cause of postoperative complications, and to discover and develop new biomarkers to improve risk stratification for adverse postoperative outcomes. TRIAL REGISTRATION NUMBER: NCT05199025.

Monocyte state 1 (MS1) cells in critically ill patients with sepsis or non-infectious conditions: association with disease course and host response.

BACKGROUND: Sepsis is a life-threatening condition arising from an aberrant host response to infection. Recent single-cell RNA sequencing investigations identified an immature bone-marrow-derived CD14+ monocyte phenotype with immune suppressive properties termed "monocyte state 1" (MS1) in patients with sepsis. Our objective was to determine the association of MS1 cell profiles with disease presentation, outcomes, and host response characteristics. METHODS: We used the transcriptome deconvolution method (CIBERSORTx) to estimate the percentage of MS1 cells from blood RNA profiles of patients with sepsis admitted to the intensive care unit (ICU). We compared these profiles to ICU patients without infection and to healthy controls. Host response dysregulation was further studied by gene co-expression network and gene set enrichment analyses of blood leukocytes, and measurement of 15 plasma biomarkers indicative of pathways implicated in sepsis pathogenesis. RESULTS: Sepsis patients (n = 332) were divided into three equally-sized groups based on their MS1 cell levels (low, intermediate, and high). MS1 groups did not differ in demographics or comorbidities. The intermediate and high MS1 groups presented with higher disease severity and more often had shock. MS1 cell abundance did not differ between survivors and non-survivors, or between patients who did or did not acquire a secondary infection. Higher MS1 cell percentages were associated with downregulation of lymphocyte-related and interferon response genes in blood leukocytes, with concurrent upregulation of inflammatory response pathways, including tumor necrosis factor signaling via nuclear factor-κB. Previously described sepsis host response transcriptomic subtypes showed different MS1 cell abundances, and MS1 cell percentages positively correlated with the "quantitative sepsis response signature" and "molecular degree of perturbation" scores. Plasma biomarker levels, indicative of inflammation, endothelial cell activation, and coagulation activation, were largely similar between MS1 groups. In ICU patients without infection (n = 215), MS1 cell percentages and their relation with disease severity, shock, and host response dysregulation were highly similar to those in sepsis patients. CONCLUSIONS: High MS1 cell percentages are associated with increased disease severity and shock in critically ill patients with sepsis or a non-infectious condition. High MS1 cell abundance likely indicates broad immune dysregulation, entailing not only immunosuppression but also anomalies reflecting exaggerated inflammatory responses.

The association between preoperative multidisciplinary team care and patient outcome in frail patients undergoing cardiac surgery.

OBJECTIVE: To evaluate the influence of preoperative multidisciplinary team (MDT) care on perioperative management and outcomes of frail patients undergoing cardiac surgery. BACKGROUND: Frail patients are at increased risk for complications and poor functional outcome after cardiac surgery. In these patients, preoperative MDT care may improve outcomes. METHODS: Between 2018 and 2021, 1168 patients aged 70 years or older were scheduled for cardiac surgery, of whom 98 (8.4%) frail patients were referred for MDT care. The MDT discussed surgical risk, prehabilitation, and alternative treatment. Outcomes of MDT patients were compared with 183 frail patients (non-MDT group) from a historical study cohort (2015-2017). Inverse probability of treatment weighting was used to minimize bias from nonrandom allocation of MDT versus non-MDT care. Outcomes were severe postoperative complications, total days in hospital after 120 days, disability, and health-related quality of life after 120 days. RESULTS: This study included 281 patients (98 MDT and 183 non-MDT patients). Of the MDT patients, 67 (68%) had open surgery, 21 (21%) underwent minimally invasive procedures, and 10 (10%) received conservative treatment. In the non-MDT group, all patients had open surgery. Fourteen (14%) MDT patients experienced a severe complication versus 42 (23%) non-MDT patients (adjusted relative risk, 0.76; 95% CI, 0.51-0.99). Adjusted total days in hospital after 120 days was 8 days (interquartile range, 3-12 days) versus 11 days (interquartile range, 7-16 days) for MDT and non-MDT patients, respectively (P = .01). There was no difference in disability or health-related quality of life. CONCLUSIONS: Preoperative MDT care for frail patients undergoing cardiac surgery is associated with alterations in surgical management and with a lower risk for severe complications.

Cohort profile of PLUTO: a perioperative biobank focusing on prediction and early diagnosis of postoperative complications.

PURPOSE: Although elective surgery is generally safe, some procedures remain associated with an increased risk of complications. Improved preoperative risk stratification and earlier recognition of these complications may ameliorate postoperative recovery and improve long-term outcomes. The perioperative longitudinal study of complications and long-term outcomes (PLUTO) cohort aims to establish a comprehensive biorepository that will facilitate research in this field. In this profile paper, we will discuss its design rationale and opportunities for future studies. PARTICIPANTS: Patients undergoing elective intermediate to high-risk non-cardiac surgery are eligible for enrolment. For the first seven postoperative days, participants are subjected to daily bedside visits by dedicated observers, who adjudicate clinical events and perform non-invasive physiological measurements (including handheld spirometry and single-channel electroencephalography). Blood samples and microbiome specimens are collected at preselected time points. Primary study outcomes are the postoperative occurrence of nosocomial infections, major adverse cardiac events, pulmonary complications, acute kidney injury and delirium/acute encephalopathy. Secondary outcomes include mortality and quality of life, as well as the long-term occurrence of psychopathology, cognitive dysfunction and chronic pain. FINDINGS TO DATE: Enrolment of the first participant occurred early 2020. During the inception phase of the project (first 2 years), 431 patients were eligible of whom 297 patients consented to participate (69%). Observed event rate was 42% overall, with the most frequent complication being infection. FUTURE PLANS: The main purpose of the PLUTO biorepository is to provide a framework for research in the field of perioperative medicine and anaesthesiology, by storing high-quality clinical data and biomaterials for future studies. In addition, PLUTO aims to establish a logistical platform for conducting embedded clinical trials. TRIAL REGISTRATION NUMBER: NCT05331118.

Advanced glycation end products for preoperative frailty screening in older cardiac surgery patients.

BACKGROUND: Advanced glycation end products (AGEs) are potential biomarkers of biological age. Skin Auto Fluorescence (SAF) can assess AGEs non-invasively. We evaluated the association of SAF levels with frailty and its predictive ability for adverse outcomes in older cardiac surgery patients. METHODS: This was a retrospective analysis of prospectively acquired data from a two-center observational cohort study. We measured SAF level in cardiac surgery patients aged ≥70. Primary outcome was preoperative frailty. A comprehensive frailty assessment was performed before surgery based on 11 individual tests assessing the physical, mental, and social domain. Frailty was defined as at least 1 positive test in each domain. Secondary outcome measures were severe postoperative complications and a composite endpoint of 1-year disability (defined by WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) questionnaire) or mortality. RESULTS: Among 555 enrolled patients, 122 (22%) were frail. SAF level was most strongly associated with dependent living status (aRR 2.45 (95% CI 1.28-4.66)) and impaired cognition (aRR 1.61 (95% CI 1.10-2.34)). A decision algorithm to identify frail patients including SAF level, sex, prescription drugs, preoperative hemoglobin, and EuroSCORE II resulted in a C-statistic of 0.72 (95% CI 0.67-0.77). SAF level was also associated with disability or death after 1 year (aRR 1.38 (95% CI 1.06-1.80)). The aRR for severe complications was 1.28 (95% CI 0.87-1.88). CONCLUSIONS: Higher SAF level is associated with frailty in older cardiac surgery patients, as well as an increased risk of death or disability. This biomarker could potentially optimize preoperative risk stratification for cardiac surgery.

Comparative clinical manifestations and immune effects of cytomegalovirus infections following distinct types of immunosuppression.

BACKGROUND: Cytomegalovirus (CMV) infection is a well-recognised complication of solid organ and hematopoietic cell transplantation. However, CMV infection also occurs in patients with human immunodeficiency virus infection, previously immunocompetent intensive care unit patients, and individuals on immunosuppressive medications for various underlying diseases. OBJECTIVES: This review describes the comparative effects of CMV infection in distinct types of acquired immunosuppression. SOURCES: Selected peer-reviewed publications on CMV infections published until December 2021. CONTENT: CMV infection affects various organ systems through direct cytolytic mechanisms but may also exert indirect effects by promoting pro-inflammatory and immunosuppressive responses. This has been well studied in transplant recipients, for whom antiviral prophylaxis and pre-emptive therapy have now become standard practice. These strategies not only prevent direct CMV disease manifestations but also mitigate various immunopathological processes to reduce graft-vs.-host disease, graft rejection, and the occurrence of secondary bacterial and fungal infections. The efficacy of neither prophylactic nor pre-emptive treatment of CMV infection has been demonstrated for patients with critical illness- or medication-induced immunosuppression. Many observational studies have shown an independent association between CMV reactivation and a prolonged duration of mechanical ventilation or increased mortality in the intensive care unit. Furthermore, data suggest that CMV reactivation may increase pulmonary inflammation and prolong the duration of mechanical ventilation. IMPLICATIONS: A large number of observational and experimental studies suggest attributable morbidity and mortality related to CMV infection, not only in transplant recipients and patients with human immunodeficiency virus infection but also in patients with critically illness- or medication-induced immunosuppression. Adequately powered randomised controlled trials investigating the efficacy of prophylaxis or pre-emptive treatment of CMV infection in these patients are lacking, with a notable exception for transplant recipients.

Delirium and long-term psychopathology following surgery in older adults.

OBJECTIVE: To describe the risk of postoperative delirium and long-term psychopathology (depression, anxiety or post-traumatic stress syndrome (PTSS)) in older adults. METHODS: 255 elderly patients (≥ 65 years) undergoing major surgery (planned surgical time > 60 min) in a tertiary hospital were compared to 76 non-surgical controls from general practice. Patients were assessed twice daily for postoperative delirium using the Confusion Assessment Method (CAM(-ICU)), nursing delirium screening scale (NuDESC) and validated chart review. Before surgery and 3 and 12 months thereafter, the participants filled in the Hospital Anxiety and Depression Scale (HADS), the Geriatric Depression Scale (GDS-15) and the Post-Traumatic Stress Syndrome-14-Questions Inventory (PTSS-14). Non-surgical controls filled in the same questionnaires with similar follow-up. RESULTS: Patients were more often male, had higher American Society of Anesthesiologists scores and more often had a spouse compared to controls (p < 0.005). Forty-three patients (18%) developed postoperative delirium, who were significantly older, had higher ASA scores and lower estimated IQ scores compared to the patients who did not develop delirium (p < 0.05). There were no differences in psychopathology at baseline and 3-month follow-up between patients and controls. At 12-months, surgical patients less frequently scored positive for depression (7% versus 16%) and anxiety (2% versus 10%) compared to nonsurgical controls (p < 0.05). We did not observe differences in occurrence of psychopathology between patients who had and had not developed postoperative delirium. CONCLUSION: Our results suggest that the older surgical population, with or without postoperative delirium, does not appear to be at greater risk of developing psychopathology. WHY DOES THIS PAPER MATTER?: The older surgical population does not appear to be at greater risk of developing psychopathology, neither seems this risk influenced by the occurrence of postoperative delirium.

Predictors for extubation failure in COVID-19 patients using a machine learning approach.

INTRODUCTION: Determining the optimal timing for extubation can be challenging in the intensive care. In this study, we aim to identify predictors for extubation failure in critically ill patients with COVID-19. METHODS: We used highly granular data from 3464 adult critically ill COVID patients in the multicenter Dutch Data Warehouse, including demographics, clinical observations, medications, fluid balance, laboratory values, vital signs, and data from life support devices. All intubated patients with at least one extubation attempt were eligible for analysis. Transferred patients, patients admitted for less than 24 h, and patients still admitted at the time of data extraction were excluded. Potential predictors were selected by a team of intensive care physicians. The primary and secondary outcomes were extubation without reintubation or death within the next 7 days and within 48 h, respectively. We trained and validated multiple machine learning algorithms using fivefold nested cross-validation. Predictor importance was estimated using Shapley additive explanations, while cutoff values for the relative probability of failed extubation were estimated through partial dependence plots. RESULTS: A total of 883 patients were included in the model derivation. The reintubation rate was 13.4% within 48 h and 18.9% at day 7, with a mortality rate of 0.6% and 1.0% respectively. The grandient-boost model performed best (area under the curve of 0.70) and was used to calculate predictor importance. Ventilatory characteristics and settings were the most important predictors. More specifically, a controlled mode duration longer than 4 days, a last fraction of inspired oxygen higher than 35%, a mean tidal volume per kg ideal body weight above 8 ml/kg in the day before extubation, and a shorter duration in assisted mode (< 2 days) compared to their median values. Additionally, a higher C-reactive protein and leukocyte count, a lower thrombocyte count, a lower Glasgow coma scale and a lower body mass index compared to their medians were associated with extubation failure. CONCLUSION: The most important predictors for extubation failure in critically ill COVID-19 patients include ventilatory settings, inflammatory parameters, neurological status, and body mass index. These predictors should therefore be routinely captured in electronic health records.

Human plasma IgG1 repertoires are simple, unique, and dynamic.

Although humans can produce billions of IgG1 variants through recombination and hypermutation, the diversity of IgG1 clones circulating in human blood plasma has largely eluded direct characterization. Here, we combined several mass-spectrometry-based approaches to reveal that the circulating IgG1 repertoire in human plasma is dominated by a limited number of clones in healthy donors and septic patients. We observe that each individual donor exhibits a unique serological IgG1 repertoire, which remains stable over time but can adapt rapidly to changes in physiology. We introduce an integrative protein- and peptide-centric approach to obtain and validate a full sequence of an individual plasma IgG1 clone de novo. This IgG1 clone emerged at the onset of a septic episode and exhibited a high mutation rate (13%) compared with the closest matching germline DNA sequence, highlighting the importance of de novo sequencing at the protein level. A record of this paper's transparent peer review process is included in the supplemental information.

Association between delay in intensive care unit admission and the host response in patients with community-acquired pneumonia.

BACKGROUND: A delay in admission to the intensive care unit (ICU) of patients with community-acquired pneumonia (CAP) has been associated with an increased mortality. Decisions regarding interventions and eligibility for immune modulatory therapy are often made at the time of admission to the ICU. The primary aim of this study was to compare the host immune response measured upon ICU admission in CAP patients admitted immediately from the emergency department (direct ICU admission) with those who were transferred within 72 h after admission to the general ward (delayed ICU admission). METHODS: Sixteen host response biomarkers providing insight in pathophysiological mechanisms implicated in sepsis and blood leukocyte transcriptomes were analysed in patients with CAP upon ICU admission in two tertiary hospitals in the Netherlands. RESULTS: Of 530 ICU admissions with CAP, 387 (73.0%) were directly admitted and 143 (27.0%) had a delayed admission. Patients with a delayed ICU admission were more often immunocompromised (35.0 versus 21.2%, P = .002) and had more malignancies (23.1 versus 13.4%, P = .011). Shock was more present in patients who were admitted to the ICU directly (46.6 versus 33.6%, P = .010). Delayed ICU admission was not associated with an increased hospital mortality risk (hazard ratio 1.25, 95% CI 0.89-1.78, P = .20). The plasma levels of biomarkers (n = 297) reflecting systemic inflammation, endothelial cell activation and coagulation activation were largely similar between groups, with exception of C-reactive protein, soluble intercellular adhesion molecule-1 and angiopoietin-1, which were more aberrant in delayed admissions compared to direct ICU admissions. Blood leukocyte transcriptomes (n = 132) of patients with a delayed ICU admission showed blunted innate and adaptive immune response signalling when compared with direct ICU admissions, as well as decreased gene expression associated with tissue repair and extracellular matrix remodelling pathways. CONCLUSIONS: Blood leukocytes of CAP patients with delayed ICU admission show evidence of a more immune suppressive phenotype upon ICU admission when compared with blood leukocytes from patients directly transferred to the ICU. TRIAL REGISTRATION: Molecular Diagnosis and Risk Stratification of Sepsis (MARS) project, ClinicalTrials.gov identifier NCT01905033.

Plasma Ferritin as Marker of Macrophage Activation-Like Syndrome in Critically Ill Patients With Community-Acquired Pneumonia.

OBJECTIVES: Plasma ferritin levels above 4,420 ng/mL have been proposed as a diagnostic marker for macrophage activation-like syndrome in sepsis and used for selection of sepsis patients for anti-inflammatory therapy. We here sought to determine the frequency, presentation, outcome, and host response aberrations of macrophage activation-like syndrome, as defined by admission ferritin levels above 4,420 ng/mL, in critically ill patients with community-acquired pneumonia. DESIGN: A prospective observational cohort study. SETTING: ICUs in two tertiary hospitals in the Netherlands. PATIENTS: One hundred fifty-three patients admitted with community-acquired pneumonia. MEASUREMENTS AND MAIN RESULTS: Patients were stratified in community-acquired pneumonia-macrophage activation-like syndrome (n = 15; 9.8%) and community-acquired pneumonia-control groups (n = 138; 90.2%) based on an admission plasma ferritin level above or below 4,420 ng/mL, respectively. Community-acquired pneumonia-macrophage activation-like syndrome patients presented with a higher disease severity and had a higher ICU mortality (46.7% vs 12.3% in community-acquired pneumonia-controls; p = 0.002). Twenty-three plasma biomarkers indicative of dysregulation of key host response pathways implicated in sepsis pathogenesis (systemic inflammation, cytokine responses, endothelial cell activation, and barrier function, coagulation activation) were more disturbed in community-acquired pneumonia-macrophage activation-like syndrome patients. Hematologic malignancies were overrepresented in community-acquired pneumonia-macrophage activation-like syndrome patients (33.3% vs 5.1% in community-acquired pneumonia-controls; p = 0.001). In a subgroup analysis excluding patients with hematologic malignancies (n = 141), differences in mortality were not present anymore, but the exaggerated host response abnormalities in community-acquired pneumonia-macrophage activation-like syndrome patients remained. CONCLUSIONS: Macrophage activation-like syndrome in critically ill patients with community-acquired pneumonia occurs more often in patients with hematologic malignancies and is associated with deregulation of multiple host response pathways.

Elevated trefoil factor 3 plasma levels in critically ill patients with abdominal sepsis or non-infectious abdominal illness.

Trefoil factor 3 (TFF3) is a small peptide secreted mainly by goblet cells in the gut, where it plays a key role in gastrointestinal defence and repair. Plasma TFF3 has been reported as a biomarker of intestinal injury and as such it has been evaluated as a marker of disease activity in colitis. Impaired gut barrier function has been postulated as the "motor" of critical illness. We here sought to determine the temporal dynamics of plasma TFF3 in adult patients admitted to intensive care unit with abdominal sepsis or after major abdominal surgery for a non-infectious condition (post-op GI patients). TFF3 was measured in plasma obtained from 143 patients with abdominal sepsis and 98 post-op GI patients on admission to the intensive care (day 0) and at days 2 and 4 thereafter. Abdominal sepsis patients showed sustained elevated plasma TFF3 levels from day 0 to 4 relative to healthy control values, while in post-op GI patients admission TFF3 levels were not increased, only rising at day 2 and 4. In both patient groups, the presence of shock was associated with higher TFF3 levels. Moreover, patients with 3 or more organs failing had higher plasma TFF3 concentrations. While plasma TFF3 was higher in sepsis patients who did not survive until day 30, TFF3 levels were not independently associated with 30-day mortality in a Cox regression analysis. These results could support the theory that intestinal injury contributes to the pathogenesis of critical illness. Future studies are needed to elucidate whether the proposed gut dysfunction precedes or supersedes organ dysfunction in time.

Potential of Parameters of Iron Metabolism for the Diagnosis of Anemia of Inflammation in the Critically Ill.

BACKGROUND: Anemia of inflammation (AI) is the most common cause of anemia in the critically ill, but its diagnosis is a challenge. New therapies specific to AI are in development, and they require accurate detection of AI. This study explores the potential of parameters of iron metabolism for the diagnosis of AI during an ICU stay. METHODS: In a nested case-control study, 30 patients developing AI were matched to 60 controls. The iron parameters were determined in plasma samples during an ICU stay. Receiver operating characteristic curves were used to determine the iron parameter threshold with the highest sensitivity and specificity to predict AI. Likelihood ratios as well as positive and negative predictive values were calculated as well. RESULTS: The sensitivity of iron parameters for diagnosing AI ranges between 62 and 76%, and the specificity between 57 and 72%. Iron and transferrin show the greatest area under the curve. Iron shows the highest sensitivity, and transferrin and transferrin saturation display the highest specificity. Hepcidin and ferritin show the lowest specificity. At an actual anemia prevalence of 53%, the diagnostic accuracy of iron, transferrin, and transferrin saturation was fair, with a positive predictive value between 71 and 73%. Combining iron, transferrin, transferrin saturation, hepcidin, and/or ferritin levels did not increase the accuracy of the AI diagnosis. CONCLUSIONS: In this explorative study on the use of different parameters of iron metabolism for diagnosing AI during an ICU stay, low levels of commonly measured markers such as plasma iron, transferrin, and transferrin saturation have the highest sensitivity and specificity and outperform ferritin and hepcidin.

Tenascin C Plasma Levels in Critically Ill Patients with or Without Sepsis: A Multicenter Observational Study.

Tenascin C (TNC) is an extracellular matrix protein able to modulate the immune response. Knowledge regarding its role during sepsis and general critical illness is still limited. We here assessed the temporal dynamics of plasma TNC during sepsis and nonseptic critical illness, its capacity to predict patient outcome, and its specificity toward infection. TNC plasma concentrations were measured in 895 consecutive sepsis patients on ICU admission, day 2 and 4 thereafter, and, in a subset, before ICU discharge. To assess TNC diagnostic value, we compared patients with abdominal sepsis (N = 143) to noninfectious abdominal surgery controls (N = 98), and patients with severe community-acquired pneumonia (CAP, N = 227) to patients whose CAP diagnosis was retrospectively refuted (no-CAP controls, N = 70). Plasma TNC levels were persistently elevated in sepsis patients compared with healthy volunteers throughout the ICU stay. TNC levels varied by the site of infection and increased with the number of organs failing. Association of TNC levels with 30-day mortality could be wholly attributed to differences in disease severity. Noninfectious ICU patients also showed elevated TNC levels, albeit with different temporal dynamics. Although admission TNC was higher in CAP than in no-CAP patients, it performed poorly in distinguishing the 2 groups.TNC plasma levels are persistently elevated during sepsis and nonseptic critical illness. In sepsis patients, they are reflective of disease severity more than independent predictors of mortality. Despite higher levels in patients with infection compared with noninfectious controls, TNC does not perform sufficiently to be used as a standalone biomarker discriminating sepsis from noninfectious critical illness.

A pilot study of a novel molecular host response assay to diagnose infection in patients after high-risk gastro-intestinal surgery.

PURPOSE: SeptiCyte LAB measures the expression of four host-response RNAs in peripheral blood to distinguish sepsis from sterile inflammation. This study evaluates whether sequential monitoring of this assay has diagnostic utility in patients after esophageal surgery. MATERIALS AND METHODS: Patients who developed a complication within 30 days following esophageal surgery and a random sample of 100 patients having an uncomplicated course. SeptiCyte LAB scores (ranging 0-10 reflecting increasing likelihood of infection) were compared to post-hoc physician adjudication of infection likelihood. RESULTS: Among 370 esophagectomy patients, 120 (32%) subjects developed a complication requiring ICU (re)admission, 63 (53%) of whom could be analyzed. Immediate postoperative SeptiCyte LAB scores were highly variable, yet similar for patients having a complicated and uncomplicated postoperative course (median score of 2.4 (IQR 1.6-3.3) versus 2.2 (IQR 1.3-3), respectively). In a direct comparison of patients developing a confirmed infectious (n = 34) and non-infectious complication (n = 12), addition of SeptiCyte LAB to CRP improved diagnostic discrimination of infectious complications (AUC 0.88 (95%CI 0.77-0.99)) compared to CRP alone (AUC 0.76 (95%CI 0.61-0.91); p = .04). CONCLUSIONS: Sequential measurement of SeptiCyte LAB may have diagnostic value in the monitoring of surgical patients at high risk of postoperative infection, but its clinical performance in this setting needs to be validated.

Epidemiology and outcomes of source control procedures in critically ill patients with intra-abdominal infection.

PURPOSE: To describe the characteristics and procedural outcomes of source control interventions among Intensive Care Unit (ICU) patients with severe intra-abdominal-infection (IAI). MATERIAL AND METHODS: We identified consecutive patients with suspected IAI in whom a source control intervention had been performed in two tertiary ICUs in the Netherlands, and performed retrospective in-depth case reviews to evaluate procedure type, diagnostic yield, and adequacy of source control after 14 days. RESULTS: A total of 785 procedures were observed among 353 patients, with initial interventions involving 266 (75%) surgical versus 87 (25%) percutaneous approaches. Surgical index procedures typically involved IAI of (presumed) gastrointestinal origin (72%), whereas percutaneous index procedures were mostly performed for infections of the biliary tract/pancreas (50%) or peritoneal cavity (33%). Overall, 178 (50%) patients required multiple interventions (median 3 (IQR 2-4)). In a subgroup of 236 patients having their first procedure upon ICU admission, effective source control was ultimately achieved for 159 (67%) subjects. Persistence of organ failure was associated with inadequacy of source control at day 14, whereas trends in inflammatory markers were non-predictive. CONCLUSIONS: Approximately half of ICU patients with IAI require more than one intervention, yet successful source control is eventually achieved in a majority of cases.

Myocardial Injury in Critically Ill Patients with Community-acquired Pneumonia. A Cohort Study.

Rationale: Myocardial injury, as reflected by elevated cardiac troponin levels in plasma, is common in patients with community-acquired pneumonia (CAP), but its temporal dynamics and etiology remain unknown. Objectives: Our aim was to determine the incidence of troponin release in patients with CAP and identify risk factors that may point to underlying etiologic mechanisms. Methods: We included consecutive patients admitted with severe CAP to two intensive care units in the Netherlands between 2011 and 2015. High-sensitivity cardiac troponin I was measured daily during the first week. We used multivariable linear regression to identify variables associated with troponin release on admission, and we used mixed-effects regression to model the daily rise and fall of troponin levels over time. Results: Of 200 eligible patients, 179 were included, yielding 792 observation days. A total of 152 (85%) patients developed raised troponin levels greater than 26 ng/L. Baseline factors independently associated with troponin release included coronary artery disease (176% increase; 95% confidence interval [CI], 11-589), smoking (248% increase; 95% CI, 33-809), and higher Acute Physiology and Chronic Health Evaluation IV score (2% increase; 95% CI, 0.8-3.3), whereas Staphylococcus aureus as a causative pathogen was protective (70% reduction; 95% CI, 18-89). Time-dependent risk factors independently associated with daily increase in troponin concentrations included reduced platelet count (2.3% increase; 95% CI, 0.6-4), tachycardia (1.5% increase; 95% CI, 0.1-2.9), hypotension (6.2% increase; 95% CI, 2.1-10.6), dobutamine use (44% increase; 95% CI, 12-85), prothrombin time (8.2% increase; 95% CI, 0.2-16.9), white cell count (1.7% increase; 95% CI, 0-3.5), and fever (22.7% increase; 95% CI, 0.1-49.6). Conclusions: Cardiac injury develops in a majority of patients with severe CAP. Myocardial oxygen supply-demand mismatch and activated inflammation/coagulation are associated with this injury. Clinical trial registered with www.clinicaltrials.gov (NCT01905033).

Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study.

BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis. METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models. RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus -15% when compared with CMVs+ and +37% versus +4% when compared with CMVs-) and decreased IL-1RA (-41% versus 0% and -49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA. CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.