Etiology of Myocardial Injury in Critically Ill Patients with Sepsis: A Cohort Study.

Rationale: Myocardial injury occurs frequently during sepsis and is independently associated with mortality. However, its etiology remains largely unknown. Objectives: To assess the relative contributions of hyperinflammation, activated coagulation, and endothelial dysfunction to myocardial injury in critically ill patients with sepsis. Methods: We included consecutive patients with sepsis presenting to two tertiary intensive care units in the Netherlands between 2011 and 2013. High-sensitivity cardiac troponin I as well as a wide range of plasma biomarkers related to inflammation, coagulation, and endothelial function were measured. Structural equation modeling was used to construct latent variables representing each of these pathophysiological constructs and to subsequently study their associations with troponin elevation while adjusting for confounders. Results: We analyzed 908 (88%) of 1,037 eligible patients, 553 (61%) of whom had raised high-sensitivity cardiac troponin I levels upon intensive care unit admission. The latent variables included interleukin (IL)-6, IL-8, and IL-1ß for inflammation; platelet count, prothrombin time, and protein C for coagulation; and soluble E-selectin, intercellular adhesion molecule-1, and angiopoietin-2 for endothelial function. After adjustment for age and cardiovascular comorbidities, structural equation modeling analysis showed that activated coagulation was independently associated with elevated troponin during sepsis (standardized regression coefficient, 0.551; 95% confidence interval [CI], 0.257-0.845; P < 0.001) whereas hyperinflammation and endothelial dysfunction were not (standardized regression coefficient, -0.161; 95% CI, -0.418 to 0.096 and -0.054; 95% CI, -0.168 to 0.060, respectively). Conclusions: Our findings suggest that myocardial injury during sepsis is mediated by systemic activation of coagulation rather than by circulating inflammatory mediators or activation of the endothelium. These findings may guide evaluation of strategies to protect the myocardium during sepsis. Clinical trial registered with clinicaltrials.gov (NCT01905033).

Robustness of sepsis-3 criteria in critically ill patients.

BACKGROUND: Early recognition of sepsis is challenging, and diagnostic criteria have changed repeatedly. We assessed the robustness of sepsis-3 criteria in intensive care unit (ICU) patients. METHODS: We studied the apparent incidence and associated mortality of sepsis-3 among patients who were prospectively enrolled in the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) cohort in the Netherlands, and explored the effects of minor variations in the precise definition and timing of diagnostic criteria for organ failure. RESULTS: Among 1081 patients with suspected infection upon ICU admission, 648 (60%) were considered to have sepsis according to prospective adjudication in the MARS study, whereas 976 (90%) met sepsis-3 criteria, yielding only 64% agreement at the individual patient level. Among 501 subjects developing ICU-acquired infection, these rates were 270 (54%) and 260 (52%), respectively (yielding 58% agreement). Hospital mortality was 234 (36%) vs 277 (28%) for those meeting MARS-sepsis or sepsis-3 criteria upon presentation (p < 0.001), and 121 (45%) vs 103 (40%) for those having sepsis onset in the ICU (p < 0.001). Minor variations in timing and interpretation of organ failure criteria had a considerable effect on the apparent prevalence of sepsis-3, which ranged from 68 to 96% among those with infection at admission, and from 22 to 99% among ICU-acquired cases. CONCLUSION: The sepsis-3 definition lacks robustness as well as discriminatory ability, since nearly all patients presenting to ICU with suspected infection fulfill its criteria. These should therefore be specified in greater detail, and applied more consistently, during future sepsis studies. TRIAL REGISTRATION: The MARS study is registered at ClinicalTrials.gov (identifier NCT01905033).

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).

Validation of a Novel Molecular Host Response Assay to Diagnose Infection in Hospitalized Patients Admitted to the ICU With Acute Respiratory Failure.

OBJECTIVES: Discrimination between infectious and noninfectious causes of acute respiratory failure is difficult in patients admitted to the ICU after a period of hospitalization. Using a novel biomarker test (SeptiCyte LAB), we aimed to distinguish between infection and inflammation in this population. DESIGN: Nested cohort study. SETTING: Two tertiary mixed ICUs in the Netherlands. PATIENTS: Hospitalized patients with acute respiratory failure requiring mechanical ventilation upon ICU admission from 2011 to 2013. Patients having an established infection diagnosis or an evidently noninfectious reason for intubation were excluded. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Blood samples were collected upon ICU admission. Test results were categorized into four probability bands (higher bands indicating higher infection probability) and compared with the infection plausibility as rated by post hoc assessment using strict definitions. Of 467 included patients, 373 (80%) were treated for a suspected infection at admission. Infection plausibility was classified as ruled out, undetermined, or confirmed in 135 (29%), 135 (29%), and 197 (42%) patients, respectively. Test results correlated with infection plausibility (Spearman's rho 0.332; p < 0.001). After exclusion of undetermined cases, positive predictive values were 29%, 54%, and 76% for probability bands 2, 3, and 4, respectively, whereas the negative predictive value for band 1 was 76%. Diagnostic discrimination of SeptiCyte LAB and C-reactive protein was similar (p = 0.919). CONCLUSIONS: Among hospitalized patients admitted to the ICU with clinical uncertainty regarding the etiology of acute respiratory failure, the diagnostic value of SeptiCyte LAB was limited.

Myocardial Injury in Patients With Sepsis and Its Association With Long-Term Outcome.

BACKGROUND: Sepsis is frequently complicated by the release of cardiac troponin, but the clinical significance of this myocardial injury remains unclear. We studied the associations between troponin release during sepsis and 1-year outcomes. METHODS AND RESULTS: We enrolled consecutive patients with sepsis in 2 Dutch intensive care units between 2011 and 2013. Subjects with a clinically apparent cause of troponin release were excluded. High-sensitivity cardiac troponin I (hs-cTnI) concentration in plasma was measured daily during the first 4 intensive care unit days, and multivariable Cox regression analysis was used to model its association with 1-year mortality while adjusting for confounding. In addition, we studied cardiovascular morbidity occurring during the first year after hospital discharge. Among 1258 patients presenting with sepsis, 1124 (89%) were eligible for study inclusion. Hs-cTnI concentrations were elevated in 673 (60%) subjects on day 1, and 755 (67%) ever had elevated levels in the first 4 days. Cox regression analysis revealed that high hs-cTnI concentrations were associated with increased death rates during the first 14 days (adjusted hazard ratio, 1.72; 95% confidence interval, 1.14-2.59 and hazard ratio, 1.70; 95% confidence interval, 1.10-2.62 for hs-cTnI concentrations of 100-500 and >500 ng/L, respectively) but not thereafter. Furthermore, elevated hs-cTnI levels were associated with the development of cardiovascular disease among 200 hospital survivors who were analyzed for this end point (adjusted subdistribution hazard ratio, 1.25; 95% confidence interval, 1.04-1.50). CONCLUSIONS: Myocardial injury occurs in the majority of patients with sepsis and is independently associated with early-but not late-mortality, as well as postdischarge cardiovascular morbidity.

Associations Between Enteral Colonization With Gram-Negative Bacteria and Intensive Care Unit-Acquired Infections and Colonization of the Respiratory Tract.

Background: Enteral and respiratory tract colonization with gram-negative bacteria may lead to subsequent infections in critically ill patients. We aimed to clarify the interdependence between gut and respiratory tract colonization and their associations with intensive care unit (ICU)-acquired infections in patients receiving selective digestive tract decontamination (SDD). Methods: Colonization status of the rectum and respiratory tract was determined using twice-weekly microbiological surveillance in mechanically ventilated subjects receiving SDD between May 2011 and June 2015 in a tertiary medical-surgical ICU in the Netherlands. Acquisition of infections was monitored daily by dedicated observers. Marginal structural models were used to determine the associations between gram-negative rectal colonization and respiratory tract colonization, ICU-acquired gram-negative infection, and ICU-acquired gram-negative bacteremia. Results: Among 2066 ICU admissions, 1157 (56.0%) ever had documented gram-negative carriage in the rectum during ICU stay. Cumulative incidences of ICU-acquired gram-negative infection and bacteremia were 6.0% (n = 124) and 2.1% (n = 44), respectively. Rectal colonization was an independent risk factor for both respiratory tract colonization (cause-specific hazard ratio [CSHR], 2.93 [95% confidence interval {CI}, 2.02-4.23]) and new gram-negative infection in the ICU (CSHR, 3.04 [95% CI, 1.99-4.65]). Both rectal and respiratory tract colonization were associated with bacteremia (CSHR, 7.37 [95% CI, 3.25-16.68] and 2.56 [95% CI, 1.09-6.03], respectively). Similar associations were observed when Enterobacteriaceae and glucose nonfermenting gram-negative bacteria were analyzed separately. Conclusions: Gram-negative rectal colonization tends to be stronger associated with subsequent ICU-acquired gram-negative infections than gram-negative respiratory tract colonization. Gram-negative rectal colonization seems hardly associated with subsequent ICU-acquired gram-negative respiratory tract colonization.

An Unbalanced Inflammatory Cytokine Response Is Not Associated With Mortality Following Sepsis: A Prospective Cohort Study.

OBJECTIVE: The prevailing theory of host response during sepsis states that an excessive production of pro-inflammatory mediators causes early deaths, whereas a predominantly anti-inflammatory response may lead to immunosuppression, secondary infection, and late deaths. We assessed inflammatory (im)balance by measuring pro-inflammatory interleukin-6 and anti-inflammatory interleukin-10 during three distinct time periods after sepsis, and assessed its association with mortality. DESIGN: Prospective observational cohort. SETTING: Two tertiary mixed ICUs in The Netherlands. PATIENTS: Consecutive patients presenting with severe sepsis or septic shock from 2011 to 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We repeatedly measured plasma interleukin-6 and interleukin-10 concentrations using cytometric bead array. Poisson regression was used to analyze the relation between inflammatory markers measured on 1) ICU admission and day 4 mortality, 2) day 4 and day 28 mortality, and 3) ICU discharge and 1-year mortality. Secondary outcome was development of ICU-acquired infections. Among 708 patients, 86 (12%) died within 4 days, 140 (20%) died between days 4 and 28, and an additional 155 (22%) died before 1 year. Interleukin-6 and interleukin-10 levels were both independently associated with mortality, but the balance of this response as modelled by an interleukin-6 and interleukin-10 interaction term was not (relative risk, 0.99; 95% CI, 0.95-1.04 on admission; relative risk, 1.02; 95% CI, 0.98-1.06 on day 4; and relative risk, 1.12; 95% CI, 0.98-1.29 at ICU discharge). However, inflammatory imbalance on day 4 was associated with development of ICU-acquired infections (subdistribution hazard ratio, 0.87; 95% CI, 0.77-0.98). CONCLUSIONS: Although both interleukin-6 and interleukin-10 productions are associated with death, the balance of these inflammatory mediators does not seem to impact either early, intermediate, or late mortality in patients presenting to the ICU with sepsis.

Short-Course Adjunctive Gentamicin as Empirical Therapy in Patients With Severe Sepsis and Septic Shock: A Prospective Observational Cohort Study.

BACKGROUND.: Metaanalyses failed to demonstrate clinical benefits of beta lactam plus aminoglycoside combination therapy compared to beta lactam monotherapy in patients with sepsis. However, few data exist on the effects of short-course adjunctive aminoglycoside therapy in sepsis patients with organ failure or shock. METHODS.: We prospectively enrolled consecutive patients with severe sepsis or septic shock in 2 intensive care units in the Netherlands from 2011 to 2015. Local antibiotic protocols recommended empirical gentamicin add-on therapy in only 1 of the units. We used logistic regression analyses to determine the association between gentamicin use and the number of days alive and free of renal failure, shock, and death, all on day 14. RESULTS.: Of 648 patients enrolled, 245 received gentamicin (222 of 309 [72%] in hospital A and 23 of 339 [7%] in hospital B) for a median duration of 2 days (interquartile range, 1-3). The adjusted odds ratios associated with gentamicin use were 1.39 (95% confidence interval [CI], 1.00-1.94) for renal failure, 1.34 (95% CI, 0.96-1.86) for shock duration, and 1.41 (95% CI, 0.94-2.12) for day-14 mortality. Based on in vitro susceptibilities, inappropriate (initial) gram-negative coverage was given in 9 of 245 (4%) and 18 of 403 (4%) patients treated and not treated with gentamicin, respectively (P = .62). CONCLUSIONS.: Short-course empirical gentamicin use in patients with sepsis was associated with an increased incidence of renal failure but not with faster reversal of shock or improved survival in a setting with low prevalence of antimicrobial resistance.

Epidemiology of Multiple Herpes Viremia in Previously Immunocompetent Patients With Septic Shock.

Background: Systemic reactivations of herpesviruses may occur in intensive care unit (ICU) patients, even in those without prior immune deficiency. However, the clinical relevance of these events is uncertain. Methods: In this study we selected patients admitted with septic shock and treated for more than 4 days from a prospectively enrolled cohort of consecutive adults in the mixed ICUs of 2 tertiary care hospitals in the Netherlands. We excluded patients who had received antiviral treatment in the week before ICU admission and those with known immunodeficiency. We studied viremia episodes with cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), and varicella zoster virus (VZV) by weekly polymerase chain reaction in plasma. Results: Among 329 patients, we observed 399 viremia episodes in 223 (68%) patients. Viremia with CMV, EBV, HHV-6, HSV-1, HSV-2, and VZV was detected in 60 (18%), 157 (48%), 80 (24%), 87 (26%), 13 (4%), and 2 (0.6%) patients, respectively; 112 (34%) patients had multiple concurrent viremia events. Crude mortality in the ICU was 36% in this latter group compared to 19% in remaining patients (P < .01). After adjustment for potential confounders, time-dependent bias, and competing risks, only concurrent CMV and EBV reactivations remained independently associated with increased mortality (adjusted subdistribution hazard ratio, 3.17; 95% confidence interval, 1.41-7.13). Conclusions: Herpesvirus reactivations were documented in 68% of septic shock patients without prior immunodeficiency and frequently occurred simultaneously. Concurrent reactivations could be independently associated with mortality. Clinical Trials Registration: NCT01905033.

The Host Response in Patients with Sepsis Developing Intensive Care Unit-acquired Secondary Infections.

RATIONALE: Sepsis can be complicated by secondary infections. We explored the possibility that patients with sepsis developing a secondary infection while in the intensive care unit (ICU) display sustained inflammatory, vascular, and procoagulant responses. OBJECTIVES: To compare systemic proinflammatory host responses in patients with sepsis who acquire a new infection with those who do not. METHODS: Consecutive patients with sepsis with a length of ICU stay greater than 48 hours were prospectively analyzed for the development of ICU-acquired infections. Twenty host response biomarkers reflective of key pathways implicated in sepsis pathogenesis were measured during the first 4 days after ICU admission and at the day of an ICU-acquired infection or noninfectious complication. MEASUREMENTS AND MAIN RESULTS: Of 1,237 admissions for sepsis (1,089 patients), 178 (14.4%) admissions were complicated by ICU-acquired infections (at Day 10 [6-13], median with interquartile range). Patients who developed a secondary infection showed higher disease severity scores and higher mortality up to 1 year than those who did not. Analyses of biomarkers in patients who later went on to develop secondary infections revealed a more dysregulated host response during the first 4 days after admission, as reflected by enhanced inflammation, stronger endothelial cell activation, a more disturbed vascular integrity, and evidence for enhanced coagulation activation. Host response reactions were similar at the time of ICU-acquired infectious or noninfectious complications. CONCLUSIONS: Patients with sepsis who developed an ICU-acquired infection showed a more dysregulated proinflammatory and vascular host response during the first 4 days of ICU admission than those who did not develop a secondary infection.

Prior Use of Calcium Channel Blockers Is Associated With Decreased Mortality in Critically Ill Patients With Sepsis: A Prospective Observational Study.

OBJECTIVES: Experimental studies suggest that calcium channel blockers can improve sepsis outcome. The aim of this study was to determine the association between prior use of calcium channel blockers and the outcome of patients admitted to the ICU with sepsis. DESIGN: A prospective observational study. SETTING: The ICUs of two tertiary care hospitals in the Netherlands. PATIENTS: In total, 1,060 consecutive patients admitted with sepsis were analyzed, 18.6% of whom used calcium channel blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Considering large baseline differences between calcium channel blocker users and nonusers, a propensity score matched cohort was constructed to account for differential likelihoods of receiving calcium channel blockers. Fifteen plasma biomarkers providing insight in key host responses implicated in sepsis pathogenesis were measured during the first 4 days after admission. Severity of illness over the first 24 hours, sites of infection and causative pathogens were similar in both groups. Prior use of calcium channel blockers was associated with improved 30-day survival in the propensity-matched cohort (20.2% vs 32.9% in non-calcium channel blockers users; p = 0.009) and in multivariate analysis (odds ratio, 0.48; 95% CI, 0.31-0.74; p = 0.0007). Prior calcium channel blocker use was not associated with changes in the plasma levels of host biomarkers indicative of activation of the cytokine network, the vascular endothelium and the coagulation system, with the exception of antithrombin levels, which were less decreased in calcium channel blocker users. CONCLUSIONS: Prior calcium channel blocker use is associated with reduced mortality in patients following ICU admission with sepsis.

White blood cell count and new-onset atrial fibrillation after cardiac surgery.

BACKGROUND: Postoperative new-onset atrial fibrillation (PNAF) is the most common complication following cardiac surgery. The inflammatory response, as a potential underlying mechanism, has been extensively studied. In small studies, the white blood cell count (WBC) has been shown to be the only consistent inflammatory marker associated with PNAF. This study aimed to determine the association between perioperative WBC response and PNAF in a larger study cohort. METHODS: Patients ≥18years, undergoing elective cardiac surgery with a preoperative sinus rhythm were included. WBC was routinely measured preoperatively, and daily during the first four postoperative days. Main outcomes were the difference between peak postoperative WBC and neutrophil/lymphocyte ratio (N/L ratio) and preoperative WBC and N/L ratio (ΔWBC and ΔN/L ratio respectively). Development of PNAF was evaluated in all patients with continuous 12-lead ECG monitoring. RESULTS: 657 patients were included and 277 (42%) developed PNAF. Univariable analyses showed a statistically significant relationship between ΔWBC (P=0.030) and ΔN/L ratio (P=0.002), and PNAF. In multivariable analysis no significant relationship was found between ΔWBC (OR: 1.14 per 1×109/L increase; 95% CI: 0.65-2.03; P=0.645), ΔN/L ratio (OR: 1.65 per 1×109/L increase; 95% CI: 0.94-2.90; P=0.089), and PNAF. Increasing age (OR: 1.08 per year; 95% CI: 1.01-1.16; P=0.022) and (additional) valve surgery (versus CABG) (OR: 4.96; 95% CI: 2.07-6.91; P≤0.001) were associated with PNAF. CONCLUSIONS: The perioperative WBC response and its components were not associated with the development of PNAF.

Incidence, Predictors, and Outcomes of New-Onset Atrial Fibrillation in Critically Ill Patients with Sepsis. A Cohort Study.

RATIONALE: Patients admitted to intensive care units with sepsis are prone to developing cardiac dysrhythmias, most commonly atrial fibrillation. OBJECTIVES: To determine the incidence, risk factors, and outcomes of atrial fibrillation in a cohort of critically ill patients with sepsis. METHODS: We assessed the association between atrial fibrillation and mortality using time-dependent competing risks survival analysis. Subsequently, for development of a risk score estimating the probability of a first occurrence of atrial fibrillation within the following 24 hours, we performed logistic regression analysis. MEASUREMENTS AND MAIN RESULTS: Among 1,782 patients with sepsis admitted to two tertiary intensive care units in the Netherlands between January 2011 and June 2013, a total of 1,087 episodes of atrial fibrillation occurred in 418 (23%) individuals. The cumulative risk of new-onset atrial fibrillation was 10% (95% confidence interval [CI], 8-12), 22% (95% CI, 18-25), and 40% (95% CI, 36-44) in patients with sepsis, severe sepsis, and septic shock, respectively. New-onset atrial fibrillation was associated with a longer stay (hazard ratio [HR], 0.55; 95% CI, 0.48-0.64), an increased death rate (HR, 1.52; 95% CI, 1.16-2.00), and an overall increased mortality risk (subdistribution HR, 2.10; 95% CI, 1.61-2.73) when considering discharge as a competing event. A simple risk score for daily prediction of atrial fibrillation occurrence yielded good discrimination (C statistic, 0.81; 95% CI, 0.79-0.84) and calibration (chi-square, 9.38; P = 0.31), with similar performance in an independent validation cohort (C statistic, 0.80; 95% CI, 0.76-0.85). CONCLUSIONS: Atrial fibrillation is a common complication of sepsis and independently associated with excess mortality. A simple risk score may identify patients at high risk of this complication. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).

The predictive value of early acute kidney injury for long-term survival and quality of life of critically ill patients.

BACKGROUND: Prognostic factors for the combination of long-term survival and health-related quality of life (HRQoL) after intensive care unit (ICU) stay have not yet been studied. Our aim was to assess whether early acute kidney injury (eAKI), AKI occurring on the first day of ICU admission, is an independent predictor of this combined one-year outcome. METHODS: We included all patients admitted to the mixed ICU of the University Medical Centre Utrecht between July 2009 and April 2013, excluding patients with chronic dialysis, cardiac surgery, and length of stay shorter than 24 hours. eAKI was defined using the risk, injury, failure, loss, end-stage renal failure (RIFLE) classification, using a newly developed algorithm to classify AKI based on routinely collected patient data. In one-year survivors, HRQoL was measured using the EuroQoL 5D-3L™ (EQ-5D) questionnaire. The primary outcome measure was "poor outcome", defined as an EQ-5D index score <0.4 or death after one year follow up. A multivariable Poisson regression model was performed to adjust for age, comorbidities, admission type and severity of disease factors. RESULTS: We enrolled 2,420 patients, of whom 871 (36.0 %) died within one year. An additional 286 of 1549 one-year survivors (11.8 %) experienced low HRQoL. The respective incidence of the RIFLE classes, risk, injury and failure, were 456 (18.8 %), 253 (10.5 %) and 123 (5.1 %). After adjustment for other covariates, the RIFLE classes, injury and failure, were independently associated with poor outcome (adjusted relative risk 1.14, 95 % CI 1.01, 1.29; p = 0.03, and 1.25, 95 % CI 1.01, 1.55; p = 0.04), when compared to no eAKI patients . The constituents of this composite outcome were also analysed separately. In a Cox regression model the RIFLE classes, injury and failure, were significantly associated with mortality (adjusted hazard ratio 1.35, 95 % CI 1.11, 1.65; p <0.01, and 1.78, 95 % CI 1.38, 2.30; p <0.01). In one-year survivors specifically, none of the RIFLE classes were significantly associated with low HRQoL. CONCLUSIONS: ICU patients with moderate or severe AKI during the first 24 hours have a higher probability of mortality or low HRQoL (combined poor outcome), one year after ICU admission. Together with other available early prognostic factors, information on early acute kidney injury could improve informed decision-making on the continuation or withdrawal of treatment in ICU patients.

Handling Time-dependent Variables: Antibiotics and Antibiotic Resistance.

Elucidating quantitative associations between antibiotic exposure and antibiotic resistance development is important. In the absence of randomized trials, observational studies are the next best alternative to derive such estimates. Yet, as antibiotics are prescribed for varying time periods, antibiotics constitute time-dependent exposures. Cox regression models are suited for determining such associations. After explaining the concepts of hazard, hazard ratio, and proportional hazards, the effects of treating antibiotic exposure as fixed or time-dependent variables are illustrated and discussed. Wider acceptance of these techniques will improve quantification of the effects of antibiotics on antibiotic resistance development and provide better evidence for guideline recommendations.

Chronic antiplatelet therapy is not associated with alterations in the presentation, outcome, or host response biomarkers during sepsis: a propensity-matched analysis.

PURPOSE: Sepsis is a major health burden worldwide. Preclinical investigations in animals and retrospective studies in patients have suggested that inhibition of platelets may improve the outcome of sepsis. In this study we investigated whether chronic antiplatelet therapy impacts on the presentation and outcome of sepsis, and the host response. METHODS: We performed a prospective observational study in 972 patients admitted with sepsis to the mixed intensive care units (ICUs) of two hospitals in the Netherlands between January 2011 and July 2013. Of them, 267 patients (27.5%) were on antiplatelet therapy (95.9% acetylsalicylic acid) before admission. To account for differential likelihoods of receiving antiplatelet therapy, a propensity score was constructed, including variables associated with use of antiplatelet therapy. Cox proportional hazards regression was used to estimate the association of antiplatelet therapy with mortality. RESULTS: Antiplatelet therapy was not associated with sepsis severity at presentation, the primary source of infection, causative pathogens, the development of organ failure or shock during ICU stay, or mortality up to 90 days after admission, in either unmatched or propensity-matched analyses. Antiplatelet therapy did not modify the values of 19 biomarkers providing insight into hallmark host responses to sepsis, including activation of the coagulation system, the vascular endothelium, the cytokine network, and renal function, during the first 4 days after ICU admission. CONCLUSIONS: Pre-existing antiplatelet therapy is not associated with alterations in the presentation or outcome of sepsis, or the host response.

Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome.

PURPOSE: Cytomegalovirus (CMV) reactivation occurs frequently in patients with the acute respiratory distress syndrome (ARDS) and has been associated with increased mortality. However, it remains unknown whether this association represents an independent risk for poor outcome. We aimed to estimate the attributable effect of CMV reactivation on mortality in immunocompetent ARDS patients. METHODS: We prospectively studied immunocompetent ARDS patients who tested seropositive for CMV and remained mechanically ventilated beyond day 4 in two tertiary intensive care units in the Netherlands from 2011 to 2013. CMV loads were determined in plasma weekly. Competing risks Cox regression was used with CMV reactivation status as a time-dependent exposure variable. Subsequently, in sensitivity analyses we adjusted for the evolution of disease severity until onset of reactivation using marginal structural modeling. RESULTS: Of 399 ARDS patients, 271 (68%) were CMV seropositive and reactivation occurred in 74 (27%) of them. After adjustment for confounding and competing risks, CMV reactivation was associated with overall increased ICU mortality (adjusted subdistribution hazard ratio (SHR) 2.74, 95% CI 1.51-4.97), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (HR) 1.58, 95% CI 0.86-2.90) and a reduced successful weaning rate (indirect effect; cause specific HR 0.83, 95% CI 0.58-1.18). These associations remained in sensitivity analyses. The population-attributable fraction of ICU mortality was 23% (95% CI 6-41) by day 30 (risk difference 4.4, 95% CI 1.1-7.9). CONCLUSION: CMV reactivation is independently associated with increased case fatality in immunocompetent ARDS patients who are CMV seropositive.