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Sepsis causes significant morbidity and mortality worldwide. Resuscitation is a cornerstone of management. This review covers five areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about the harms of fluid, practice is evolving toward smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60–65 mm Hg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, although it is not universally accepted. Similarly, although guidelines suggest the use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving toward fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation. [ABSTRACT FROM AUTHOR]

Rationale: The effects of balanced crystalloid versus saline on clinical outcomes for ICU patients may be modified by the type of fluid that patients received for initial resuscitation and by the type of admission. Objectives: To assess whether the results of a randomized controlled trial could be affected by fluid use before enrollment and admission type. Methods: Secondary post hoc analysis of the BaSICS (Balanced Solution in Intensive Care Study) trial, which compared a balanced solution (Plasma-Lyte 148) with 0.9% saline in the ICU. Patients were categorized according to fluid use in the 24 hours before enrollment in four groups (balanced solutions only, 0.9% saline only, a mix of both, and no fluid before enrollment) and according to admission type (planned, unplanned with sepsis, and unplanned without sepsis). The association between 90-day mortality and the randomization group was assessed using a hierarchical logistic Bayesian model. Measurements and Main Results: A total of 10,520 patients were included. There was a low probability that the balanced solution was associated with improved 90-day mortality in the whole trial population (odds ratio [OR], 0.95; 89% credible interval [CrI], 0.66-10.51; probability of benefit, 0.58); however, probability of benefit was high for patients who received only balanced solutions before enrollment (regardless of admission type, OR, 0.78; 89% CrI, 0.56-1.03; probability of benefit, 0.92), mostly because of a benefit in unplanned admissions due to sepsis (OR, 0.70; 89% CrI, 0.50-0.97; probability of benefit, 0.96) and planned admissions (OR, 0.79; 89% CrI, 0.65-0.97; probability of benefit, 0.97). Conclusions: There is a high probability that balanced solution use in the ICU reduces 90-day mortality in patients who exclusively received balanced fluids before trial enrollment. Clinical trial registered with www.clinicaltrials.gov (NCT02875873). [ABSTRACT FROM AUTHOR]

Background: Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure. Methods: This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. Results: The following six priority recommendations were developed by the working group: 1) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; 2) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; 3) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; 4) further development of the tools necessary for the real-time application of precision medicine approaches; 5) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and 6) the securement and maintenance of adequate and sustainable funding for precision medicine efforts. Conclusions: Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS. [ABSTRACT FROM AUTHOR]

Most randomized trials are designed and analyzed using frequentist statistical approaches such as null hypothesis testing and P values. Conceptually, P values are cumbersome to understand, as they provide evidence of data incompatibility with a null hypothesis (e.g., no clinical benefit) and not direct evidence of the alternative hypothesis (e.g., clinical benefit). This counterintuitive framework may contribute to the misinterpretation that the absence of evidence is equal to evidence of absence and may cause the discounting of potentially informative data. Bayesian methods provide an alternative, probabilistic interpretation of data. The reanalysis of completed trials using Bayesian methods is becoming increasingly common, particularly for trials with effect estimates that appear clinically significant despite P values above the traditional threshold of 0.05. Statistical inference using Bayesian methods produces a distribution of effect sizes that would be compatible with observed trial data, interpreted in the context of prior assumptions about an intervention (called "priors"). These priors are chosen by investigators to reflect existing beliefs and past empirical evidence regarding the effect of an intervention. By calculating the likelihood of clinical benefit, a Bayesian reanalysis can augment the interpretation of a trial. However, if priors are not defined a priori, there is a legitimate concern that priors could be constructed in a manner that produces biased results. Therefore, some standardization of priors for Bayesian reanalysis of clinical trials may be desirable for the critical care community. In this Critical Care Perspective, we discuss both frequentist and Bayesian approaches to clinical trial analysis, introduce a framework that researchers can use to select priors for a Bayesian reanalysis, and demonstrate how to apply our proposal by conducting a novel Bayesian trial reanalysis. [ABSTRACT FROM AUTHOR]

The article presents the discussion on feasibility trials being underappreciated being an essential part of building a solid evidence-based practice. Topics include prostacyclin attenuating endotheliopathy mainly through local prostacyclin and platelet adhesion inhibition; and reporting the treatment effect in survivors leading to an overcounting of mortality across most of the endpoints.

Rationale: A recent randomized controlled trial showed that a peripheral perfusion-guided resuscitation strategy was associated with lower mortality and less organ dysfunction when compared with lactate-guided resuscitation strategy in patients with septic shock, but the difference in the primary outcome, 28-day mortality, did not reach the proposed statistical significancethreshold(P=0.06). We tested different analytic methods to aid in the interpretation of these results. Objectives: To reassess the results of the ANDROMEDA-SHOCK trial using both Bayesian and frequentist frameworks. Methods: All patients recruited in ANDROMEDA-SHOCK were included. Both a post hoc Bayesian analysis and a mixed logistic regression analysis were performed. The Bayesian analysis included four different priors (optimistic, neutral, null, and pessimistic) for mortality endpoints. The probability of having a Sequential Organ Failure Assessment in the lowest quartile at 72 hours was assessed using Bayesian networks. Measurements and Main Results: In the Bayesian analysis, the posterior probability that a peripheral perfusion-targeted resuscitation strategy is superior to lactate-targeted resuscitation at 28 days was above 90% for all priors; the probability ofbenefit at 90 days was above 90% for all but the pessimistic prior. Using an optimistic prior, posterior median odds ratios were 0.61 (95% credible interval, 0.41-0.90) and 0.68 (95% credible interval, 0.47-1.01) for 28-day and 90-day mortality, respectively. The comparable frequentist odds ratios for 28-day and 90-day mortality were0.61(95%confidenceinterval[CI],0.38-0.92)and0.70(95%CI, 0.45-1.08), respectively. The odds that that patients in the peripheral perfusion-targeted resuscitation arm had Sequential Organ Failure Assessmentscoresinthelowerquartileat72hourswas1.55(95%CI, 1.02-2.37). Conclusions: Peripheral perfusion-targeted resuscitation may result in lower mortality and faster resolution of organ dysfunction when compared with a lactate-targeted resuscitation strategy. [ABSTRACT FROM AUTHOR]

Rationale: A recent randomized controlled trial showed that a peripheral perfusion-guided resuscitation strategy was associated with lower mortality and less organ dysfunction when compared with lactate-guided resuscitation strategy in patients with septic shock, but the difference in the primary outcome, 28-day mortality, did not reach the proposed statistical significance threshold (P = 0.06). We tested different analytic methods to aid in the interpretation of these results.Objectives: To reassess the results of the ANDROMEDA-SHOCK trial using both Bayesian and frequentist frameworks.Methods: All patients recruited in ANDROMEDA-SHOCK were included. Both a post hoc Bayesian analysis and a mixed logistic regression analysis were performed. The Bayesian analysis included four different priors (optimistic, neutral, null, and pessimistic) for mortality endpoints. The probability of having a Sequential Organ Failure Assessment in the lowest quartile at 72 hours was assessed using Bayesian networks.Measurements and Main Results: In the Bayesian analysis, the posterior probability that a peripheral perfusion-targeted resuscitation strategy is superior to lactate-targeted resuscitation at 28 days was above 90% for all priors; the probability of benefit at 90 days was above 90% for all but the pessimistic prior. Using an optimistic prior, posterior median odds ratios were 0.61 (95% credible interval, 0.41-0.90) and 0.68 (95% credible interval, 0.47-1.01) for 28-day and 90-day mortality, respectively. The comparable frequentist odds ratios for 28-day and 90-day mortality were 0.61 (95% confidence interval [CI], 0.38-0.92) and 0.70 (95% CI, 0.45-1.08), respectively. The odds that that patients in the peripheral perfusion-targeted resuscitation arm had Sequential Organ Failure Assessment scores in the lower quartile at 72 hours was 1.55 (95% CI, 1.02-2.37).Conclusions: Peripheral perfusion-targeted resuscitation may result in lower mortality and faster resolution of organ dysfunction when compared with a lactate-targeted resuscitation strategy. [ABSTRACT FROM AUTHOR]