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Modalities of fluid management in patients sustaining the acute respiratory distress syndrome (ARDS) are challenging and controversial. Optimal fluid management should provide adequate oxygen delivery to the body, while avoiding inadvertent increase in lung edema which further impairs gas exchange. In ARDS patients, positive fluid balance has been associated with prolonged mechanical ventilation, longer ICU and hospital stay, and higher mortality. Accordingly, a restrictive strategy has been compared to a more liberal approach in randomized controlled trials conducted in various clinical settings. Restrictive strategies included fluid restriction guided by the monitoring of extravascular lung water, pulmonary capillary wedge or central venous pressure, and furosemide targeted to diuresis and/or albumin replacement in hypoproteinemic patients. Overall, restrictive strategies improved oxygenation significantly and reduced duration of mechanical ventilation, but had no significant effect on mortality. Fluid management may require different approaches depending on the time course of ARDS (i.e., early vs. late period). The effects of fluid strategy management according to ARDS phenotypes remain to be evaluated. Since ARDS is frequently associated with sepsis-induced acute circulatory failure, the prediction of fluid responsiveness is crucial in these patients to avoid hemodynamically inefficient-hence respiratory detrimental-fluid administration. Specific hemodynamic indices of fluid responsiveness or mini-fluid challenges should be preferably used. Since the positive airway pressure contributes to positive fluid balance in ventilated ARDS patients, it should be kept as low as possible. As soon as the hemodynamic status is stabilized, correction of cumulated fluid retention may rely on diuretics administration or renal replacement therapy.

Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. NCT02960854.

Objective To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. Design A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations. Methods Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. Results The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction? Conclusions While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock. Electronic supplementary material The online version of this article (10.1007/s00134-018-5175-z) contains supplementary material, which is available to authorized users.

Sepsis is among the most common conditions encountered in critical care, with extraordinarily high prevalence in many developed countries.1,2 Septic shock is widely considered the leading cause of death in many western ICU’s, contributing significantly more in healthcare utilization due to the higher complexity of illness and intensity of life-saving interventions. Severe sepsis and septic shock are more consistent in incidence, at least in developed countries,3 but it is less well understood how much variation there is in sepsis between developed and developing countries.4 Infection prevalence varies tremendously between hospitals and countries, and directly influences the risk of patient mortality.5 The prevalence of infection and sepsis in critically ill patients is among the highest in Brazil,6,7 where variations in critical care beds, healthcare delivery programs and constraints on healthcare resources are common, comparable at least to the ones found within Europe.8 Fortunately for patients, although constituting a tremendous challenge for healthcare services worldwide, this increase in prevalence has been accompanied by a decrease in mortality since the late 1970’s or early 1980’s. This change, that has be well documented in the USA2 and Europe9, but as well in other good epidemiological studies aggregating clinical trials demonstrating a reduction in case-fatality rate. Is this a global and universal phenomenon? Has this turning point in mortality been attained in countries with fewer resources and/or with more heterogeneous health care systems such as Brazil?8 Can we explain it by looking at the countries with greater variability? Our greater understanding of sepsis epidemiology and pathophysiology led to the Barcelona Declaration in 2002 and to the launch of the Surviving Sepsis Campaign (SSC), for which the foundation of implementation rests on delivering optimal care using a “bundle” approach, first proposed by the Institute for Healthcare Improvement (IHI).10 The bundled approach to sepsis care has been shown to be effective in many settings, with more consistent and timely application of evidence-based care, reductions in practice variability, and improvements in both institutional and patient-centered outcomes.11,12,13 However, these findings are almost exclusively reported from the developed world,11,14 and given the human and material resources needed for effective sepsis bundles, we must wonder if sepsis bundles are appropriate, feasible and cost-effective, especially in the developing world?15 In this issue of Intensive Care Medicine, Noritomi and colleagues16 undertook to establish the feasibility, efficacy and cost of implementing a comprehensive sepsis bundle in Brazil. In collaboration with the Latin American Sepsis Institute, they implemented a multifaceted sepsis quality improvement program over 21 months in 10 vertically integrated managed care non-teaching hospitals in Sao Paulo, representing 1,650 hospital beds and 191 ICU beds. The program intended to extend the classical recommendations of the SSC by including more extensive educational, screening and treatment components, particularly by ensuring that all aspects of the program were continuously monitored and improved. During the program period, they identified 2120 patients with severe sepsis and septic shock and increased the compliance with the entire sepsis bundle by 4-fold (from 13% to 62%). These changes resulted in a patients being identified progressively earlier and at a lower illness severity, and were associated with a decrease in hospital mortality, a decrease in hospital costs and an increase in health-related quality of life. Can we explain these very important findings with what we understand today? Possibly, yes. First, the authors went beyond the classical SSC 2008 approach and implemented revised bundles that were accompanied by more emphasis on continuous support of education and process improvement. While this was a similar approach to that by by Ferrer in Cataluna in 2008, it was more effective in changing behavior and care processes, and resulted in even more impactful results.11 Second, the notion that sepsis is a time-dependent disease was strongly stressed in this Brazilian study. At least based upon the regression analyses, we can also explain a significant portion of the results through early administration of antibiotics, and to a lesser degree by earlier and more aggressive fluid challenge in hypotensive patients. Perhaps most importantly, this project was successful because of the planning and societal support necessary for success in a large-scale quality improvement program. We should always remember the data from the SOAP study in 20021 and from the EPIC II study in 20085 in which the prevalence of sepsis in an ICU was strongly correlated to all-cause mortality in that ICU, suggesting that greater attention to this group of patients will produce a broader effect for all critically ill patients admitted to that ICU. Overall, we must congratulate the authors for four important reasons: They proved behind any doubt that it is possible to conduct very high quality research in a country with limited resources and very heterogeneous patients and healthcare systems.8 Second, they demonstrated that a dedicated quality improvement program will improve sepsis outcomes despite differences in organisms, different typologies of patients and different health care systems.5 Third, they impressively demonstrated that SSC 2008 (and we hope SSC 2012) can be improved and effectively incorporated into an inclusive package of education, awareness and clinical support. Fourth, the current results suggest that countries like Brazil are closing the gap to more developed countries at a greater pace than expected by passage of time alone. With these results, the challenge is now set for more countries to prove that we can do the same or better. And to determine and demonstrate what aspects of the SSC guidelines and sepsis bundles are most effective and necessary in each healthcare setting, in order to customize care delivery on both a regional or institutional basis and on an individual patient basis. Obviously, many questions remain. Is Brazil representative of the rapidly evolving “BRIC” countries, or is Brazil a unique phenomenon among them? Are developing countries more similar to western nations than we realize, perhaps only being time-shifted backwards? Do the results translate to countries with even more difficulties than Brazil, including the most severely under-developed countries, even if the bundles and the associated measures must be changed? These questions are only a few that prove why we must continue learning from international collaborations, as much improvement yet lies ahead.