Diagnosing invasive pulmonary aspergillosis in ICU patients: putting the puzzle together Purpose of review The approach to diagnose invasive pulmonary aspergillosis in the absence of lung biopsy in ICU patients is reviewed. This approach should be based on four pillars: mycology, medical imaging, underlying conditions, and acute disease expression. Recent findings Diagnosing invasive pulmonary aspergillosis in the absence of histopathologic evidence is a matter of probability weighting. Initiating antifungal therapy in an early phase and with a lower likelihood of disease might outweigh further diagnostic workout with further delay in appropriate treatment. However, in ICU patients, a preemptive antifungal strategy has not been established yet. Summary For mycology, a positive galactomannan test on serum or broncho-alveolar lavage fluid is highly indicative of invasive pulmonary aspergillosis. The meaning of positive culture results, lateral-flow device test, or PCR-assay is ambiguous. A negative galactomannan or PCR test has high negative predictive value. Clinical features suggestive for invasive fungal disease on CT-scan are highly indicative but rare in ventilated patients. An immunocompromised status indicates high-risk. chronic obstructive pulmonary disease, hepatic cirrhosis, and AIDS indicate moderate risk. Invasive pulmonary aspergillosis in the absence of underlying conditions is rare. Acute diseases frequently associated with invasive pulmonary aspergillosis include sepsis and/or respiratory insufficiency because of influenza, acute respiratory distress syndrome, or pneumonia. Correspondence to Stijn Blot, Department of Internal Medicine & Pediatrics, Ghent University, Campus UZ Gent, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Tel: +3292326216; e-mail: stijn.blot@UGent.be Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Historic review of long-term outcomes research Purpose of review This review summarizes the results from long-term intensive care outcome research over the past 50 years. Key findings from early studies are reflected in citations of contemporary research. Recent findings The postintensive care syndrome (PICS) is a multifaceted entity of residual disability and complications burdening survivors of critical illness. Some interventions applied early in the history of outcomes research have now been confirmed as effective in counteracting specific PICS components. Summary Interest in patient-centred outcomes has been present since the beginning of modern intensive care. Findings from early long-term studies remain valid even in the face of contemporary large registries that facilitate follow-up of larger cohorts. A further understanding of the mechanisms leading to experienced physical and psychological impairment of PICS will be essential to the design of future intervention trials. Correspondence to Christian Rylander, MD, Associate Professor, Medical Director, Intensive Care Unit, 96/CIVA, Department of Anaesthesia and Intensive Care, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden. Tel: +46 31 342 83 32; e-mail: christian.rylander@vgregion.se Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Deadoption of low-value practices in the ICU Purpose of review Change of practice in the ICU, particularly the discontinuation of approaches, which are no longer felt to be beneficial, can be challenging. This review will examine this issue and outline current thinking regarding how to best approach it. Recent findings Practices in medicine that do not provide patients benefit and possibly cause harm exist throughout medicine and are called low-value practices. Some low-value practices have successfully been removed from the ICU whereas others remain. The process of removing these practices from established care is often called deadoption. Low-value practices that are simply ineffective but produce comparatively less harm or cost, may represent a significant challenge to deadoption. Additionally, although no single intervention has been identified as the preferred method of deadoption of a low-value practice, we advocate for a multimodal approach. Summary Deadoption in the intensive care unit of practices that either cause harm or are significantly costly relative to their benefit remains an elusive goal. Attempts at deadoption should target local ICU circumstances, while still encompassing the spectrum of care outside the ICU, engage nursing more fully, promote the use of local champions, especially peers, and recognize the requirement to seek sustainability. Correspondence to Robert C. Hyzy, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, 3916 Taubman Center, Ann Arbor, MI 48109, USA. E-mail: rhyzy@umich.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Challenges in conducting long-term outcomes studies in critical care Purpose of review Evaluating longer term mortality, morbidity, and quality of life in survivors of critical illness is a research priority. This review details the challenges of long-term follow-up studies of critically ill patients and highlights recently proposed methodological solutions. Recent findings Barriers to long-term follow-up studies of critical care survivors include high rates of study attrition because of death or loss to follow-up, data missingness from experienced morbidity, and lack of standardized outcome as well as reporting of key covariates. A number of recent methods have been proposed to reduce study patients attrition, including minimum data set selection and visits to transitional care or home settings, yet these have significant downsides as well. Conducting long-term follow-up even in the absence of such models carries a high expense, as personnel are very costly, and patients/families require reimbursement for their time and inconvenience. Summary There is a reason why many research groups do not conduct long-term outcomes in critical care: it is very difficult. Challenges of long-term follow-up require careful consideration by study investigators to ensure our collective success in data integration and a better understanding of underlying mechanisms of mortality and morbidity seen in critical care survivorship. Correspondence to M. Elizabeth Wilcox, MD, MPH, Division of Respirology, Department of Medicine, Toronto Western Hospital, McLaughlin Wing 2–411M, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8. E-mail: elizabeth.wilcox@mail.utoronto.ca Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

How should we treat acinetobacter pneumonia? Purpose of review To describe recent data about Acinetobacter baumannii pneumonia epidemiology and the therapeutic options including adjunctive nebulized therapy. Recent findings A. baumannii is a major cause of nosocomial pneumonia in certain geographic areas affecting mainly debilitated patients, with prolonged hospitalization and broad-spectrum antimicrobials. Inappropriate empirical treatment has clearly been associated with increased mortality in A. baumannii pneumonia. Carbapenems may not be considered the treatment of choice in areas with high rates of carbapenem-resistant A. baumannii. Nowadays, polymyxins are the antimicrobials with the greatest level of in-vitro activity. Colistin is the antimicrobial most widely used although polymyxin B is associated with less renal toxicity. It is clear that lung concentrations of polymyxins are suboptimal in a substantial proportion of patients. This issue has justified the use of combination therapy or adjunctive nebulized antibiotics. Current evidence does not allow us to recommend combination therapy for A. baumannii pneumonia. Regarding nebulized antibiotics, it seems reasonable to use in patients who are nonresponsive to systemic antibiotics or A. baumannii isolates with colistin minimum inhibitory concentrations close to the susceptibility breakpoints. Cefiderocol, a novel cephalosporin active against A. baumannii, may represent an attractive therapeutic option if ongoing clinical trials confirm preliminary results. Summary The optimal treatment for multidrug-resistant A. baumannii pneumonia has not been established. New therapeutic options are urgently needed. Well designed, randomized controlled trials must been conducted to comprehensively evaluate the effectiveness and safety of nebulized antibiotics for the treatment of A. baumannii pneumonia. Correspondence to José Garnacho-Montero, Unidad Clínica de Cuidados Intensivos, Hospital Universitario Virgen Macarena, Sevilla, Spain. Tel: +34 677594510; e-mail: jgarnachom@gmail.com Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Intravenous immunoglobulin for adjunctive treatment of severe infections in ICUs Purpose of review This review focuses on the emerging literature regarding the use of intravenous immunoglobulins (IVIg) in critically ill patients with severe infections. The aim is to provide an accessible summary of the most recent evidence of IVIg use in sepsis and septic shock and to help clinicians to understand why there is still equipoise regarding the potential benefit of this adjunctive therapy in this setting. Recent findings Observational studies with propensity score matching analyses and investigating the effect of IVIg in severe infections including necrotizing soft tissue infection have been recently published. These studies suffer important flaws precluding robust conclusion to be drawn. Some recent randomized controlled trials raised interesting findings supportive of personalized medicine but are likely to be underpowered or confounded. Summary Insufficient evidence is available to support IVIg use in sepsis and septic shock, apart from the specific case of streptococcal toxic shock syndrome. Current literature suggests that IVIg efficacy in sepsis or septic shock could depend on the IVIg preparation (IgM-enriched or minimal IgM), time of administration (<24 h), dose, and the inflammatory/immunomodulation profile of the patients. Investigator-initiated research, incorporating these parameters, is warranted to determine whether IVIg benefits critically ill patients with severe infection. Correspondence to Cécile Aubron, MD, Ph.D., Centre Hospitalier Régional et Universitaire de Brest, site La Cavale Blanche, Bvd Tanguy Prigent, 29609 Brest Cedex, France. Tel.: +61 2 98 34 71 81;. fax: +61 2 98 34 79 65; e-mail: cecile.aubron@chu-brest.fr,cecile.aubron@monash.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Defining standard of practice: pros and cons of the usual care arm Purpose of review The aim if this review is to describe the use of usual care arms in randomized trials. Recent findings Randomization of patients to an experimental or a control arm remains paramount for the estimation of average causal effects. Selection of the control arm is as important as the definition of the intervention, and it might include a placebo control, specific standards of care, protocolized usual care, or unrestricted clinical practice. Usual care control arms may enhance generalizability, clinician acceptability of the protocol, patient recruitment, and ensure community equipoise, while at the same time introducing significant variability in the care delivered in the control group. This effect may reduce the difference in treatments delivered between the two groups and lead to a negative result or the requirement for a larger sample size. Moreover, usual care control groups can be subject to changes in clinician behavior induced by the trial itself, or by secular trends in time. Summary Usual care control arms may enhance generalizability while introducing significant limitations. Potential solutions include the use of pretrial surveys to evaluate the extent to which a protocolized control arm reflects the current standard of care and the implementation of adaptive trials. Correspondence to Neill K.J. Adhikari, MDCM M.Sc., Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room D108, Toronto, ON, Canada M4N 3M5. Tel.: +1 416 480 4522;. e-mail: neill.adhikari@utoronto.ca Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Population enrichment for critical care trials: phenotypes and differential outcomes Purpose of review Sepsis and acute respiratory distress syndrome (ARDS) are two heterogenous acute illnesses where numerous RCTs have indeterminate results. We present a narrative review on the recent developments in enriching patient populations for future sepsis and ARDS trials. Recent findings Many researchers are actively pursuing enrichment strategies to reduce heterogeneity to increase the sensitivity of future trials. Enrichment refers to the use of measurable patient characteristics, known before randomisation, to refine trial populations. Biomarkers could increase the diagnostic certainty of sepsis, whereas chest radiology training to enhance reliability of interpretation and stabilisation period of mechanical ventilation have been considered to increase the diagnostic certainty of ARDS. Clinical and biomarker data analyses identifies four to six sepsis clinical phenotypes and two ARDS clinical phenotypes. Similarly, leukocyte gene expression data identifies two to four sepsis molecular phenotypes. Use of a test-dose identifies ARDS subpopulations who are likely to benefit from higher PEEP. Early-phase trials report how a biomarker that is altered by the intervention, such as lymphocyte count for recombinant interleukin-7 therapy and higher check point inhibitor expression for anti-check point treatments in sepsis, could identify a higher treatment effect population for future trials. Summary Enrichment reduces heterogeneity and will enhance the sensitivity of future trials. However, enrichment, even when it identifies more homogenous populations, may not be efficient to deploy in trials or clinical practice. Correspondence to Dr Manu Shankar-Hari, MSc PhD FRCA FFICM, Critical care Offices, Guy's and St Thomas’ NHS Foundation Trust London SE17EH, UK. E-mail: manu.shankar-hari@kcl.ac.uk, Twitter handle: @msh_manu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Severe influenza: overview in critically ill patients Purpose of review Overview of influenza infection, focusing on outcome and complications in critically ill patients. We also discuss relevant elements in immunopathogenesis and their role as predictors of severity. Recent findings Pandemic influenza A (H1N1) virus circulates seasonally and remains the predominant subtype among intensive care patients. Mortality in acute respiratory failure (ARF) is around 20%, independent of influenza subtypes. During severe infection, the imbalance between pro-inflammatory and anti-inflammatory molecules, such as Th1 and Th17 cytokines, is associated with complicated infections and mortality. Primary viral pneumonia presents in more than 70% of ICU influenza patients and more than 50% develop acute respiratory distress syndrome. Bacterial secondary infection occurs in 20% of severe cases and Streptococcus pneumoniae and Staphylococcus aureus remain the prevalent pathogens. Myocarditis and late-onset cardiovascular complications are associated with mortality. Antiviral therapy within 48 h after onset, avoidance of corticosteroids and rescue therapies for ARF or myocarditis, such as extracorporeal membrane oxygenation, improve survival. Summary The present review summarizes current knowledge on pathogenesis and clinical manifestations of severe influenza. Immunological dysfunction during viral infection correlates with severity and mortality among ICU patients. A theranostics strategy should be implemented to improve outcomes. Correspondence to Pedro Palma, Serviço de Doenças Infecciosas, Centro Hospitalar Universitário de São João, Alameda do Professor Hernâni Monteiro, 4200-319 Porto, Portugal. Tel: +351 225 512 100; fax: +351 225 512 329; e-mail: pedropalmamartins@gmail.com;pedro.martins@hsjoao.min-saude.pt Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

In the pursuit of partnership: patient and family engagement in critical care medicine Purpose of review Patient and family partnership in critical care medicine research and clinical care is essential to achieve patient and family-centered care. Although there is an increasing interest in patient and family engagement, research is lacking to direct clinicians and researchers on how to provide opportunities for meaningful engagement. We review the recent literature and provide examples from our own experiences to guide all parties in this important and emerging area. Recent findings Though the literature is relatively nascent, studies suggest that there is a desire to engage patients and families in critical care medicine research and clinical care, however, uncertainty exists on how to achieve this goal. Engagement exists on a spectrum from presence to shared decision-making and direct contributions to care; most engagement in critical care medicine involves participation in research and presence at the bedside. Expectation management is essential for meaningful engagement and true partnership. Challenges to patient and family engagement exist, including determining appropriate compensation, aligning engagement with needs and skills, and recruitment, training and retention. These challenges can be mitigated with thoughtful planning and management. Summary Patient and family engagement in critical care medicine is an emerging field that requires further study to support definitive conclusions. Until then, it is important to match interested patients and family members with appropriate opportunities and provide training and support to ensure meaningful engagement. Correspondence to Kirsten M. Fiest, Department of Critical Care Medicine, Alberta Health Services and University of Calgary, Ground Floor, McCaig Tower, 3134 Hospital Drive NW, Calgary, AB, Canada T2N 4Z6. Tel: +1 4039440732; e-mail: kmfiest@ucalgary.ca Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.