A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial☆

In this editorial [1], the sentence: Certainly under physiological conditions, it would seem that cortisol facilitates beta-receptor binding of catecholamines to vascular smooth muscle, allowing noradrenaline to exert its vasopressor effect. should have read: Certainly under physiological conditions, it would seem that cortisol facilitates adrenoceptor binding of catecholamines to vascular smooth muscle, allowing noradrenaline to exert its vasopressor effect. The authors apologise for this error.

Severe Sepsis and Septic Shock: Should Blood Be Transfused To Raise Mixed Venous Oxygen Saturation?

PurposeThe objective of this study was to develop a new nomogram that can predict 28-day mortality in severe sepsis and/or septic shock patients using a combination of several biomarkers that are inexpensive and readily available in most emergency departments, with and without scoring systems.Materials and MethodsWe enrolled 561 patients who were admitted to an emergency department (ED) and received early goal-directed therapy for severe sepsis or septic shock. We collected demographic data, initial vital signs, and laboratory data sampled at the time of ED admission. Patients were randomly assigned to a training set or validation set. For the training set, we generated models using independent variables associated with 28-day mortality by multivariate analysis, and developed a new nomogram for the prediction of 28-day mortality. Thereafter, the diagnostic accuracy of the nomogram was tested using the validation set.ResultsThe prediction model that included albumin, base excess, and respiratory rate demonstrated the largest area under the receiver operating characteristic curve (AUC) value of 0.8173 [95% confidence interval (CI), 0.7605–0.8741]. The logistic analysis revealed that a conventional scoring system was not associated with 28-day mortality. In the validation set, the discrimination of a newly developed nomogram was also good, with an AUC value of 0.7537 (95% CI, 0.6563–0.8512).ConclusionOur new nomogram is valuable in predicting the 28-day mortality of patients with severe sepsis and/or septic shock in the emergency department. Moreover, our readily available nomogram is superior to conventional scoring systems in predicting mortality.

Point: Adherence to Early Goal-Directed Therapy: Does It Really Matter? Yes. After a Decade, the Scientific Proof Speaks for Itself

Guidelines recommend corticosteroids and vasopressin to treat septic shock as per specifi c indications [1]. However, the results from trials evaluating both drugs confl ict. For corticosteroids, the 2002 Annane and colleagues study showed a survival benefi t for hydrocortisone/fl udro cortisone treatment in patients with an inappropriate cortisol response to a high-dose adrenocorticotropic hormone (ACTH) test [2], while the Corticosteroid Th erapy of Septic Shock (CORTICUS) trial found no diff erence in survival by patients’ response to ACTH [3]. Th e Vasopressin and Septic Shock Trial (VASST) demon strated a survival benefi t in less severe septic shock, but guidelines espouse use ‘in patients refractory to other vasopressors’ [1,4]. Clinical variability, leading to over treatment, may have negative eff ects on survival. To evaluate the impact of these evi dence limitations, we surveyed physicians in the Critical Illness Outcomes Study (CIOS). We developed a 15-item, self-administered survey to charac terize physician practice patterns for use of corticosteroids and vasopressin in septic shock. Th e survey, conducted anonymously and with implied consent, was distributed to 92 members of the CIOS listserv. Recipients were encouraged to solicit survey completion by their colleagues. CIOS is a multicenter study among 68 ICUs designed to determine whether ICU-based organi zational and structural factors are associated with patientrelated outcomes. Th e survey fulfi lled Stanford Institutional Review Board exemption guidelines. To address when clinicians would use corticosteroids, we asked partici pants to rate their agreement (fi ve-point Likert scale) for the following situations: blood pressure poorly responsive to fl uid resuscitation and vasopressor therapy; an inappropriate response to ACTH testing [2]; and a history of treatment with corticosteroids within the prior 6 months. Likert responses were evalu ated by Pearson

In Sepsis, a Report of No Difference May Make a Lot of Difference

Clinical Effectiveness and Early Goal-Directed Therapy for Severe Sepsis and Septic Shock

Prognostic value of extravascular lung water and its potential role in guiding fluid therapy in septic shock after initial resuscitation

Fundamental researches have shown that soluble CD73 (sCD73) can inhibit inflammatory response and limit excessive tissue damage caused by continuous immune cell activation. A Finnish prospective, observational study of acute kidney injury (FINNAKI) showed no association between sCD73 and 90-day mortality in sepsis patients. Clinical data of this study was used for secondary analysis to explore whether the relationship between sCD73 and 90-day mortality was consistent in septic shock and non-septic shock patients. The FINNAKI study was a prospective, observational cohort study conducted in 17 intensive care units (ICUs) in Finland from September 1st, 2011 to February 1st, 2012. Sepsis/septic shock was defined according to Sepsis-1 definition. Demographic characteristics, treatment, comorbidities and 90-day mortality of the patients were analyzed. To evaluate the difference (interaction test) between the relationship of sCD73 and 90-day mortality in septic shock and non-septic shock patients, likelihood ratio test was used to integrate the product term (sCD73×septic shock or non-septic shock) into multivariable Logistic regression. Sensitivity analysis was performed with the definition of Sepsis-3. The interaction between sCD73 and 90-day mortality in patients with septic shock and non-septic shock were verified by generalized additive model (GAM). A total of 588 patients with severe sepsis/septic shock were enrolled. 164 patients died in 90 days, and the 90-day mortality was 27.89%. Based on the Sepsis-1 definition, there were 159 non-septic shock patients and 429 septic shock patients. Compared with the non-septic shock patients, lactate (Lac) level, sequential organ failure assessment (SOFA) score, fluid balance on the first day, and ratio of mechanical ventilation, 12-hour acute kidney injury (AKI), renal replacement therapy (RRT), and postoperative ICU transition in the septic shock patients were significantly increased and the proportion of emergency admission to ICU was significantly decreased. Based on the Sepsis-3 definition, there were 383 non-septic shock patients and 205 septic shock patients; the results of clinical data analysis between the two groups were similar to those based on Sepsis-1. Based on Sepsis-1, there was no significant difference in 90-day mortality between non-septic shock and septic shock patients [23.90% (38/159) vs. 29.37% (126/429), P > 0.05]. However, based on Sepsis-3, the 90-day mortality of patients with septic shock was significantly higher than that of patients with non-septic shock [37.56% (77/205) vs. 22.72% (87/383), P < 0.01]. Multivariate Logistic regression analysis and interaction test showed that after adjusting all confounding factors (except the number of complications) in non-sepsis shock and sepsis shock patients, sCD73 and 90-day mortality were significantly different in both Sepsis-1 and Sepsis-3. The P values for interaction tests were 0.046 and 0.027, respectively. In patients with non-septic shock, sCD73 tended to be positively associated with 90-day mortality [Sepsis-1: odds ratio (OR) = 1.46, 95% confidence interval (95%CI) was 0.99-2.13, P = 0.053; Sepsis-3: OR = 1.34, 95%CI was 1.02-1.74, P = 0.034]. In septic shock patients, sCD73 tended to be negatively associated with 90-day mortality (Sepsis-1: OR = 0.91, 95%CI was 0.69-1.20, P = 0.494; Sepsis-3: OR = 0.80, 95%CI was 0.55-1.17, P = 0.249). The results of GAM model validation were consistent with the results of Logistic regression equation cross validation. The relationship between sCD73 and 90-day mortality is significantly different from patients with non-sepsis shock and sepsis shock. In patients with non-sepsis shock, sCD73 is trend to positively associated with 90-day mortality, and there is a negative trend between sCD73 and 90-day mortality in patients with septic shock.

To evaluate the association between concomitant arginine-vasopressin (AVP)/hydrocortisone therapy and mortality in severe septic shock patients. This retrospective study included severe septic shock patients treated with supplementary AVP. To test the association between concomitant AVP/hydrocortisone use and mortality, a multivariate regression and Cox model (adjusted for admission year, initial AVP dosage and the Sepsis-related Organ Failure Assessment score before AVP) as well as a propensity score-based analysis were used. In both models, intensive care unit (ICU) and 28-day mortality served as outcome variables. One hundred fifty-nine patients were included. Hydrocortisone was administered to 76 (47.8%) at a median daily dosage of 300 (200-300) mg. In the multivariate logistic regression model, concomitant use of AVP and hydrocortisone was associated with a trend towards lower ICU (OR, 0.51; CI 95%, 0.24-1.08; p = 0.08) and 28-day (HR, 0.69; CI 95%, 0.43-1.08; p = 0.11) mortality. The probability of survival at day 28, as predicted by the regression model, was significantly higher in patients treated with concomitant AVP and hydrocortisone compared to those receiving AVP without hydrocortisone (p = 0.001). In a propensity score-based analysis, ICU (45 vs. 65%; OR, 0.69; CI 95% 0.38-1.26; p = 0.23) and 28-day mortality (35.5 vs. 55%; OR, 0.59; CI 95%, 0.27-1.29; p = 0.18) was not different between patients treated with (n = 40) or without concomitant hydrocortisone (n = 40). Concomitant AVP and hydrocortisone therapy may be associated with a survival benefit in septic shock. An adequately powered, randomised controlled trial appears warranted to confirm these preliminary, hypothesis-generating results.

Dear Editor, We thank Dr. Salvadori and his colleagues for their interest in our work [1] and the constructive comments. In view of the evolving controversy regarding the effects of hydrocortisone therapy in sepsis during the study period (January to December 2009), the use of hydrocortisone was strictly reserved for patients with septic shock requiring escalating norepinephrine doses. This explains why only one patient suffering from septic shock received hydrocortisone (continuous infusion of 200 mg/day) at study enrollment. Unfortunately, this precludes evaluation of the influence of hydrocortisone on the binary occurrence of adverse cardiac events in our study population. At the occurrence of an adverse cardiac event, 15 of 21 septic shock patients (71.4 %) received a continuous hydrocortisone infusion at a median (interquartile range, IQR) daily dose of 192 (192–288) mg. The absolute number of adverse cardiac events did not differ between septic shock patients with or without hydrocortisone therapy [4 (2.5–6) versus 3 (2–7)] in both an unadjusted (p = 0.64) and adjusted (p = 0.12) model (model adjustment for Simplified Acute Physiology Score II, need for renal replacement therapy, presence of chronic liver diseases). Interestingly, however, patients on hydrocortisone developed adverse cardiac events at higher median vasopressor load [0.48 (0.36–0.54) lg/kg/min] than patients who did not receive hydrocortisone [0.18 (0.06–0.43) lg/kg/min] in both an unadjusted (p = 0.005) and adjusted model (p = 0.006). The type of adverse cardiac event had no influence on this association (p = 0.17 and p = 0.13, respectively). Carrying the hypothesis of Salvadori and colleagues on a potentially protective effect of hydrocortisone on the occurrence of adverse cardiac events during catecholamine vasopressor therapy further, one may speculate that hydrocortisone raised the individual threshold at which catecholamine vasopressors may induce adverse cardiac events in our study patients with septic shock. Taking the post hoc character of this analysis and the low number of septic shock patients developing adverse cardiac events (n = 21) into consideration, these data must be regarded as purely hypothesis-generating. Further studies are, therefore, needed to evaluate the influence of a hydrocortisone therapy on the occurrence of adverse (cardiac) events during catecholamine vasopressor therapy in septic shock.

Determining the endpoint of resuscitation in septic shock is essential to enhance effectiveness, prevent over-resuscitation, and improve outcomes. We designed this study to investigate whether sublingual microcirculation monitoring can serve as an effective marker for assessing the efficacy of resuscitation therapy in septic shock. A total of 72 septic shock patients were included in our final analysis, excluding those with heart function impairments, including sepsis-induced cardiomyopathy. Sublingual microcirculation parameters were measured at two time points: prior to resuscitation and 6 hours post-resuscitation. Additionally, the values of macrocirculatory parameters, blood gas analysis variables, and organ prognosis indicators were collected at multiple time points before and after resuscitation. Spearman correlation analysis was performed to assess the correlations among these variables. Furthermore, the ROC curve analysis method was employed to evaluate the predictive performance of sublingual microcirculation parameters and other relevant factors for patient prognosis. Finally we determined the optimal threshold of PPV6h by anchoring it to three key aspects: tissue oxygenation (Lac24h), organ dysfunction progression (△APACHE II3d and △SOFA3d), and long-term outcomes (Adverse Prognosis and 28-day mortality). Sublingual microcirculation variables post-resuscitation showed no significant correlation with conventional circulation variables. PPV6h had the highest predictive efficacy for 28-day prognosis, better than PcvO26h, the best predictor among conventional variables. The optimal PPV6h threshold (68.6%) was determined using three key criteria mentioned above. Patients meeting this threshold after resuscitation showed improved microcirculation (lower lactate levels and faster clearance), reduced organ dysfunction (lower APACHE II and SOFA scores, less need for CRRT), and better long-term outcomes (fewer vasoactive drugs, 28-day lower mortality). Our study highlights the potential utility of sublingual microcirculation as an adjunctive tool for reflecting the effectiveness of resuscitation therapy and proposes that the PPV6h > 68.6% may serve as a target for early goal-directed therapy in future studies.

Use of Albumin as a Resuscitative Fluid in the Intensive Care Unit.

Levosimendan And Septic Cardiomyopathy: A Key That May Have Found Its Lock?

BackgroundSepsis, including severe sepsis and septic shock, is a major cause of morbidity and mortality. Albumin and C-reactive protein (CRP) are considered as good diagnostic markers for sepsis. Thus, initial CRP and albumin levels were combined to ascertain their value as an independent predictor of 180-day mortality in patients with severe sepsis and septic shock.Materials and MethodsWe conducted a retrospective cohort study involving 670 patients (>18 years old) who were admitted to the emergency department and who had received a standardized resuscitation algorithm (early goal-directed therapy) for severe sepsis and septic shock, from November 2007 to February 2013, at a tertiary hospital in Seoul, Korea. The outcome measured was 180-day all-cause mortality. A multivariate Cox proportional hazard model was used to identify the independent risk factors for mortality. A receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive accuracy of the CRP/albumin ratio at admission.ResultsThe 180-day mortality was 28.35% (190/670). Based on the multivariate Cox proportional hazard analysis, age, the CRP/albumin ratio at admission (adjusted HR 1.06, 95% CI 1.03–1.10, p<0.001), lactate level at admission (adjusted HR 1.10, 95% CI 1.05–1.14, p<0.001), and the Sequential Organ Failure Assessment (SOFA) score at admission (adjusted HR 1.12, 95% CI 1.07–1.18, p<0.001) were independent predictors of 180-day mortality. The area under the curve of CRP alone and the CRP/albumin ratio at admission for 180-day mortality were 0.5620 (P<0.001) and 0.6211 (P<0.001), respectively.ConclusionThe CRP/albumin ratio was an independent predictor of mortality in patients with severe sepsis or septic shock.