Initial fractal exponent of heart rate variability is associated with success of early resuscitation in patients with severe sepsis or septic shock: a prospective cohort study.
ABSTRACT: Heart rate variability (HRV) reflects autonomic nervous system tone as well as the overall health of the baroreflex system. We hypothesized that loss of complexity in HRV upon intensive care unit (ICU) admission would be associated with unsuccessful early resuscitation of sepsis.We prospectively enrolled patients admitted to ICUs with severe sepsis or septic shock from 2009 to 2011. We studied 30 minutes of electrocardiogram, sampled at 500 Hz, at ICU admission and calculated heart rate complexity via detrended fluctuation analysis. Primary outcome was vasopressor independence at 24 hours after ICU admission. Secondary outcome was 28-day mortality.We studied 48 patients, of whom 60% were vasopressor independent at 24 hours. Five (10%) died within 28 days. The ratio of fractal alpha parameters was associated with both vasopressor independence and 28-day mortality (P = .04) after controlling for mean heart rate. In the optimal model, Sequential Organ Failure Assessment score and the long-term fractal ? parameter were associated with vasopressor independence.Loss of complexity in HRV is associated with worse outcome early in severe sepsis and septic shock. Further work should evaluate whether complexity of HRV could guide treatment in sepsis.
Project description:BACKGROUND:Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. METHODS:AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. RESULTS:Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ? 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). CONCLUSIONS:AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.
Project description:Background:Community-acquired pneumonia (CAP) is a leading cause of sepsis and common presentation to emergency department (ED) with a high mortality rate. The prognostic prediction value of sequential organ failure assessment (SOFA) and quick SOFA (qSOFA) scores in CAP in ED has not been validated in detail. The aim of this research is to investigate the prognostic prediction value of SOFA, qSOFA, and admission lactate compared with that of other commonly used severity scores (CURB65, CRB65, and PSI) in septic patients with CAP in ED. Methods:Adult septic patients with CAP admitted between Jan. 2017 and Jan. 2019 with increased admission SOFA???2 from baseline were enrolled. The primary outcome was 28-day mortality. The secondary outcome included intensive care unit (ICU) admission, mechanical ventilation, and vasopressor use. Prognostic prediction performance of the parameters above was compared using receiver operating characteristic (ROC) curves. Kaplan-Meier survival curves were compared using optimal cutoff values of qSOFA and admission lactate. Results:Among the 336 enrolled septic patients with CAP, 89 patients died and 247 patients survived after 28-day follow-up. The CURB65, CRB65, PSI, SOFA, qSOFA, and admission lactate levels were statistically significantly higher in the death group (P < 0.001). qSOFA and SOFA were superior and the combination of qSOFA?+?lactate and SOFA?+?lactate outperformed other combinations of severity score and admission lactate in predicting both primary and secondary outcomes. Patients with admission qSOFA?<?2 or lactate???2?mmol/L showed significantly prolonged survival than those patients with qSOFA???2 or lactate?>?2?mmol/L (log-rank ? 2?=?59.825, P < 0.001). The prognostic prediction performance of the combination of qSOFA and admission lactate was comparable to the full version of SOFA (AUROC 0.833 vs. 0.795, Z?=?1.378, P=0.168 in predicting 28-day mortality; AUROC 0.868 vs. 0.895, Z?=?1.022, P=0.307 in predicting ICU admission; AUROC 0.868 vs. 0.845, Z?=?0.921, P=0.357 in predicting mechanical ventilation; AUROC 0.875 vs. 0.821, Z?=?2.12, P=0.034 in predicting vasopressor use). Conclusion:qSOFA and SOFA were superior to CURB65, CRB65, and PSI in predicting 28-day mortality, ICU admission, mechanical ventilation, and vasopressor use for septic patients with CAP in ED. Admission qSOFA with lactate is a convenient and useful predictor. Admission qSOFA???2 or lactate?>?2?mmol/L would be very helpful in discriminating high-risk patients with a higher mortality rate.
Project description:BACKGROUND:Sepsis is a serious syndrome that is caused by an unbalanced host inflammatory response to an infection. The cytokine network plays a pivotal role in the orchestration of inflammatory response during sepsis. IL-26 is an emerging proinflammatory member of the IL-10 cytokine family with multifaceted actions in inflammatory disorders. However, its role in the pathogenesis of sepsis remains unknown. METHODS:Serum IL-26 level was measured and analyzed in 52 septic patients sampled on the day of intensive care unit (ICU) admission, 18 non-septic ICU patient controls, and 30 healthy volunteers. In addition, the effects of recombinant human IL-26 on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis were determined. RESULTS:On the day of ICU admission, the patients with sepsis showed a significant increase in serum IL-26 levels compared with ICU patient controls and healthy volunteers, and the serum IL-26 levels were related to the severity of sepsis. Nonsurvivors of septic patients displayed significantly higher serum IL-26 levels compared with survivors. A high serum IL-26 level on ICU admission was associated with 28-day mortality, and IL-26 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, administration of recombinant human IL-26 increased lethality in CLP-induced polymicrobial sepsis. Despite a lower bacterial load, septic mice treated with recombinant IL-26 had higher concentrations of IL-1?, IL-4, IL-6, IL-10, IL-17A, TNF-?, CXCL1, and CCL2 in peritoneal lavage fluid and blood and demonstrated more severe multiple organ injury (including lung, liver and kidney) as indicated by clinical chemistry and histopathology. Furthermore, septic mice treated with recombinant human IL-26 showed an increased neutrophil recruitment to the peritoneal cavity. CONCLUSIONS:Septic patients had elevated serum IL-26 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-26 in increasing lethality despite promoting antibacterial host responses.
Project description:Critical care needs have been rising in recent decades as populations age and comorbidities increase. Sepsis-related admissions to critical care contribute up to 50% of volume and septic shock carries a 35-54% fatality rate. Improvements in sepsis-related care and mortality would have a significant impact of a resource-intensive area of health care delivery. Unfortunately, research has been hampered by the lack of an animal model that replicates the complex care provided to humans in an intensive care unit (ICU). We developed a protocol to provide full ICU type supportive care to Rhesus macaques. This included mechanical ventilation, continuous sedation, fluid and electrolyte management and vasopressor support in response to Ebolavirus-induced septic shock. The animals accurately recapitulated human responses to a full range of ICU interventions (e.g. fluid resuscitation). This model can overcome current animal model limitations by accurately emulating the complexity of ICU care and thereby provide a platform for testing new interventions in critical care and sepsis without placing patients at risk.
Project description:<h4>Background</h4>The optimal timing of lactate measurement for septic patients in the intensive care unit (ICU) remains controversial, and whether initiating and repeating the lactate measurement earlier could make a difference for septic patients with an elevated lactate level remains unexplored.<h4>Methods</h4>This was a retrospective observational study that included septic patients with an initial lactate level >?2.0?mmol/L after ICU admission, and all data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The main exposure of interest was the early lactate measurement, which was defined as an initial lactate level measurement within 1?h after ICU admission. The primary outcome was 28-day mortality.<h4>Results</h4>A total of 2642 eligible subjects were enrolled, including 738 patients who had initial lactate measurements completed within 1?h (EL group) and 1904 patients who had initial lactate measurements completed more than 1?h after ICU admission (LL group). A significant beneficial effect of early lactate measurement in terms of 28-day mortality was observed: the adjusted odds ratio (OR) was 0.69 (95% CI 0.55-0.87; p?=?0.001), and the mediation effect of the time to initial vasopressor administration was significant (average causal mediation effect (ACME) -?0.018; 95% CI -?0.005 approximately to -?0.036; p?<?0.001). A strong relationship between delayed initial lactate measurement and risk-adjusted 28-day mortality was noted (OR 1.04; 95% CI 1.02-1.05; p?<?0.001). Each hour of delay in remeasuring the lactate level was associated with an increase in 28-day mortality in the EL group (OR 1.09; 95% CI 1.04-1.15; p?<?0.001). Further analysis demonstrated that repeating the measurement 3?h after the initial lactate measurement led to a significant difference.<h4>Conclusions</h4>Early lactate measurement is associated with a lower risk-adjusted 28-day mortality rate in septic patients with lactate levels >?2.0?mmol/L. A shorter time to the initial vasopressor administration may contribute to this relationship. Repeating the lactate measurement within 3?h after the initial measurement is appropriate for patients whose lactate levels were measured within 1?h of admission.
Project description:The lack of a patent source of infection after 24 hours of management of shock considered septic is a common and disturbing scenario. We aimed to determine the prevalence and the causes of shock with no diagnosis 24 hours after its onset, and to compare the outcomes of patients with early-confirmed septic shock to those of others.We conducted a pragmatic, prospective, multicenter observational cohort study in ten intensive care units (ICU) in France. We included all consecutive patients admitted to the ICU with suspected septic shock defined by clinical suspicion of infection leading to antibiotic prescription plus acute circulatory failure requiring vasopressor support.A total of 508 patients were admitted with suspected septic shock. Among them, 374 (74 %) had early-confirmed septic shock, while the 134 others (26 %) had no source of infection identified nor microbiological documentation retrieved 24 hours after shock onset. Among these, 37/134 (28 %) had late-confirmed septic shock diagnosed after 24 hours, 59/134 (44 %) had a condition mimicking septic (septic shock mimicker, mainly related to adverse drug reactions, acute mesenteric ischemia and malignancies) and 38/134 (28 %) had shock of unknown origin by the end of the ICU stay. There were no differences between patients with early-confirmed septic shock and the remainder in ICU mortality and the median duration of ICU stay, of tracheal intubation and of vasopressor support. The multivariable Cox model showed that the risk of day-60 mortality did not differ between patients with or without early-confirmed septic shock. A sensitivity analysis was performed in the subgroup (n?=?369/508) of patients meeting the Sepsis-3 definition criteria and displayed consistent results.One quarter of the patients admitted in the ICU with suspected septic shock had no infection identified 24 hours after its onset and almost half of them were eventually diagnosed with a septic shock mimicker. Outcome did not differ between patients with early-confirmed septic shock and other patients.
Project description:<h4>Background</h4>Soluble CD40 ligand (sCD40L) exhibits proinflammatory and procoagulant effects. Recent data indicated that sCD40L plays a significant role in septic patients. The aim of the present study was to determine sCD40L changes in surgical patients without sepsis (SWS) and surgical sepsis patients (SS) during the first 3 days after intensive care unit (ICU) admission and to observe the association between sCD40L and mortality.<h4>Methods</h4>Time changes in sCD40L levels were assessed for 3?days after ICU admission in 49 patients with SS and compared with those in 19 SWS patients. Serum sCD40L concentration was detected by ELISA. Survival at 28?days served as the endpoint.<h4>Results</h4>SS had significantly higher sCD40L levels than SWS and control patients. We observed an association between sCD40L levels ?1028.75?pg/mL at day 2 and 28-day mortality (odds ratio?=?7.888; 95% confidence interval?=?1.758 to 35.395; P?=?0.007). We could not discover any significant differences in sex, presence of septic shock, site of infection, length of stay in the ICU, PaO<sub>2</sub>/FiO<sub>2</sub> ratio, incidence of AKI, ARDS, or type of surgery between nonsurvivors and survivors.<h4>Conclusions</h4>Septic patients show persistently higher circulating sCD40L levels in the first 3 days after ICU admission, and serum sCD40L levels are associated with the mortality of patients with sepsis. Thus, serum sCD40L may be used as a reliable biomarker and therapeutic target in sepsis.
Project description:Septic shock is the most severe complication of sepsis, associated with high mortality. The patient’s response to supportive therapy is very heterogeneous and the underlying mechanisms are still elusive. In order to identify which are the actors (genes and pathways) that play a role in establishing the response, we investigate the whole blood transcriptome in septic shock patients with positive and negative responses to early supportive hemodynamic therapy, assessed by changes in SOFA scores within the first 48 hours from ICU admission. We pinpointed genes and pathways that are differently modulated and enriched respectively within 48hrs between responders and non-responders. Overall design: We analyzed 31 patients (17 Responders and 14 Not Responders to early therapy). For each patient, 2 samples were collected. In particular the first sample (T1) collected within 16 hours from ICU admission whereas the second (T2) collected within 48 hours from ICU admission. Experimental groups (Responders and Not Responders) are defined accordingly with SOFA scores improvements within 48 hours.
Project description:Introduction:Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)-a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay-for kidney events in sepsis and septic shock. Methods:The Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality. Results:Median age was 66 years (interquartile range 55-75), and 28-day mortality was 22% (95% confidence interval [CI] 19%-25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median = 65 [IQR = 45-106] vs. 179 [114-242]; 53 [39-70] vs. 133 [79-196] pmol/l; and 70 [47-121] vs. 174 [93-242] pmol/l, all P < 0.0001), also after adjustment for confounding factors (adjusted odds ratio = 3.3 [95% CI = 1.8-6.0], 3.9 [95% CI = 2.1-7.2], and 3.4 [95% CI = 1.9-6.2], all P < 0.0001). Penkid increase preceded elevation of serum creatinine with WRF and was low in renal recovery. Conclusion:Admission penkid concentration was associated with MAKEs, AKI, and WRF in a timely manner in septic patients.
Project description:<h4>Background</h4>Mottling score, a tissue perfusion parameter, is correlated with outcome in septic shock patients. However, its predictive value on mortality according to prognostic covariates such as vasopressor dose and other tissue perfusion parameters remains unknown.<h4>Methods</h4>Mottling score and tissue perfusion parameters were recorded at ICU admission (H0), H-6, H 12, and H-24 and used to assess the predictive value of mottling score on 14-day mortality in a development cohort. Results were then validated in an independent cohort of septic shock patients in Brazil.<h4>Results</h4>Overall, 259 patients with sepsis or septic shock were included, 14-day mortality was 37%. Factors associated with death were mottling score (OR 2.26 [95% CI, 1.72-2.97]), arterial lactate level (OR 1.29 [1.11-1.5]), and urine output <?0.5?ml/Kg/h (OR 3.03 [1.37-6.69]). The C statistic for the model was 0.90 in the development cohort and 0.76 in the validation cohort. The predictive value of mottling score was not affected by vasopressor doses (p for interaction?=?0.33): OR for mottling score ranged from 2.34 [1.10-3.15] in patients without vasopressor to 3.84 [1.98-7.43] in patients infused with high doses of vasopressor (>?0.8??g/kg/min). There was no difference in the effect of mottling score on mortality according to mean arterial pressure, heart rate, cardiac index, and urine output, but we found a significant interaction between arterial lactate level and mottling score (p?=?0.04). The predictive value of the mottling score remains significant when using the recent SEPSIS-3 definition of septic shock. Finally, a decrease of mottling score during resuscitation was significantly associated with better outcome after adjustment on SOFA score (p?=?0.001).<h4>Conclusions</h4>Our results support the high prognostic value of mottling score for 14-day mortality in septic patients, whatever vasopressor dosage and other perfusion parameters. Mottling score variations during resuscitation are also predictive of mortality.